基于氯霉胺骨架的氨肽酶N抑制剂的设计、合成及其活性研究
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摘要
研究背景：氨肽酶N(APN/CD13; EC 3.4.11.2),是一类锌离子依赖性金属蛋白酶,其广泛存在于人的多种组织中,在不同细胞(上皮细胞、内皮细胞、成纤维细胞和白细胞等)表面均有表达。相比于正常细胞,该酶在肿瘤细胞表面高水平表达,其在恶性肿瘤生长、侵袭、转移以及新血管的形成过程中扮演重要角色,成为研究抗癌药物的一个重要靶点。
目前,已有报道的天然抑制剂如：Bestatin, Probestatin, Amastatin, Curcumin等在预防和治疗肿瘤方面取得一定的积极效果。Bestatin作为第一个上市的APN抑制剂,临床上已经用于治疗急性成年人非淋巴性白血病。另外,人们还合成了许多小分子APN抑制剂,如α-氨基磷酸类抑制剂,β-氨基硫醇类抑制剂,以及本课题组报道的环酰亚胺类抑制剂,L-赖氨酸衍生物抑制剂等。
本研究以APN为靶点,设计合成了一系列小分子类肽化合物,并对其进行初步的生物活性筛选,以期发现具有良好APN抑制活性的抗癌先导化合物。
研究方法：在本实验室前期研究工作中发现的活性先导物1,2-二氨基-3-苯丙烷结构基础上,结合文献调研,解析APN的三维晶体结构及其与抑制剂的作用模式和特点,选择了与该活性结构相类似的氯霉胺为基本骨架,并在此基础上选择能与酶活性中心的疏水性口袋相互作用的不同侧链与之拼合进行衍生化。结构修饰主要考虑以下三个因素：1)引入不同体积和长度的疏水侧链,考察立体效应对酶的作用。2)侧链中选择不同的吸电子基和斥电子基,考察不同电性效应对酶的作用。3)侧链中选择可能与酶相互作用的氢键基团,以增强化合物与酶的亲和力。本研究综合利用计算机辅助药物设计软件的优势,对设计的化合物与酶进行柔性对接打分,选择分值较高的化合物进行化学合成。同时,对其分子量、脂水分配系数、氢键受体和氢键供体数进行了预测,采用Lipinski规则进一步筛选,最终设计了三个系列115个全新结构的目标化合物。目标化合物的合成以氯霉胺为起始原料,采用了氨基保护,选择性氧化,溴代,叠氮化,还原,缩合等多个反应步骤完成,采用红外光谱、核磁共振氢谱、电喷雾质谱、X-ray单晶衍射等方法确证其化学结构。
生物活性研究选用体外抑酶(APN, MMP-2)活性试验、肿瘤细胞(HL-60,ES-2,K549等)生长抑制试验和小鼠体内抗肿瘤转移试验对目标化合物进行了初步活性评价,从中筛选出具有较好活性的氯霉胺类APN抑制剂作为抗癌先导化合物。
研究结果：本研究最终合成了115个目标化合物,其中大部分化合物产率较高,纯度良好,所有化合物进行了化学结构确证。经文献检索,所合成的目标化合物为新型结构,未见相关报道。
本研究合成的78个A系列目标化合物中,大部分化合物对APN具有抑制活性,其中化合物9e(9e'),9m(9m'),9r(9r')和9s(9s’)活性较好。B系列化合物相比于A系列化合物,整体上活性有明显提高。其中,化合物12w,12x和12y的IC5035μM以下,接近于阳性对照药Bestatin的APN抑制活性。然而,B系列化合物同样也显示出较强的MMP-2抑制活性。在C系列中,化合物16k,161与阳性对照药Bestatin的活性相当,且对MMP-2的抑制活性较低,显示了良好的抑酶选择性。
本研究在对上述目标化合物进行抑酶活性试验的基础上,利用计算机软件进行了初步定量构效关系研究。采用比较分子力场分析方法(CoMFA)建立了具有较高的交叉验证系数q2和一定预测能力的定量构效关系(QSAR)模型。通过对CoMFA模型立体场等势线图和静电场等势线图的分析,提出了化合物下一轮结构优化的方案,为氯霉胺类APN抑制剂的进一步研究奠定了基础。
体外细胞抑瘤实验结果表明,多数化合物对高表达APN的肿瘤细胞显示出良好的抑制效果。其中,化合物161、12w表现出与阳性对照药相当的肿瘤细胞抑制活性。
体内小鼠抗肿瘤转移试验结果证明,化合物12w和161均有一定的抑制荷肝癌H22小鼠肿瘤细胞转移的作用。其中,化合物12w的抑制率为48.51%,小于阳性对照药Bestatin(抑制率为58.04%),161的抑制率达到了56.49%,接近阳性对照药Bestatin。
研究结论：本研究基于APN的晶体结构及抑制剂与酶的作用模式,借助计算机软件进行合理药物设计并合成的氯霉胺类化合物具有较好的APN抑制活性。所设计的合成路线科学合理,起始原料经济易得。通过初步的活性测试发现了具有进一步研究价值的活性化合物。其中,化合物12w,161可以作为抗癌先导化合物用于下一轮的结构优化。同时,基于化合物结构和活性数据建立了有一定预测能力的定量构效关系模型,为今后新型APN抑制剂的研究奠定了基础。
Objective:Aminopeptidase N (APN/CD13; EC 3.4.11.2), a zinc-dependent membrane metalloproteinase, is present in a wide variety of human tissues and the surface of cell types (endothelial, epithelial, fibroblast, leukocyte). Compared with normal cells, APN is over-expressed on the surface of some tumor cells. It is demonstrated that this enzyme plays a crucial role in the process of tumor growth, invasion, metastasis and promoting the angiogenesis. Therefore, APN is considered as an important target in anti-cancer drug discovery and development.
So far, many natural inhibitors such as Bestatin, Phebestin, Probestatin, Amastatin, Curcumin have been reported and proved to be clinically efficacious for the treatment of tumor. Bestatin, the first marketed drug as natural aminopeptidase N inhibitor in Japan in 1987, now is clinically used to prolong the survival of patients with acute adult nonlymphcytic leukemia. In recent years, numerous synthetic APN inhibitors(APNI) have been reported, such asα-aminophosphonates APNI, a-aminoboronic acid APNI,β-thiols APNI,2,6-piperidinedione-N-acetamide derivatives APNI, L-lysine derivatives APNI, AHPA (β-Amino-α-Hydroxyl-phenylbutanoic acid) derivatives APNI and so on.
In this study, we designe and synthesize a series of small molecule peptido-mimetics based on the APN as target. Their preliminary biological activity screening are subsequently conducted in order to find out effective APN inhibitors as anti-cancer lead compounds.
Methods:According to the binding characteristics learned from the three dimensional crystal structure of APN and the mode of action of APN-inhibitor complex reported in literatures, we choose the chloramphenicol amine as the novel scaffold based on the active structure of 3-phenylpropane-1,2-diamine scaffold which was previous reported by our group. To improve the interaction with the hydrophobic pockets in the active site of APN, several fragments were introduced to the scaffold. This scaffold is optimized with following chemical modification:i) The different space volume and length of side chains were chosen to investigate the interaction of stereoscopic effect with APN. ii) Various electron-attracting groups and electron-pushing groups were introduced so as to investigate the interaction of electric effect with APN. iii) The groups which can form hydrogen bond with the enzyme were taken to enhance affinity. All the target compounds were rationally designed by CADD, FlexX docking and virtual screening. Meantime, the properties of all these compounds like molecular weight, lipid-water partition, the number of hydrogen bond receptor and hydrogen bond donor were predicted and screened by Lipinski rules before synthesis.115 novel target compounds were designed and synthesized by using chloramphenicol amine as starting material, through amino protection, selective oxidation, bromination, azide, reduction, condensation and other reaction steps. The structure were confirmed by IR,1H NMR, ESI-MS, X-ray crystal diffraction methods.
In addition, enzyme assay (APN, MMP-2), cancer cell (HL-60, ES-2, K562, A549, H7402,2PLC) proliferation assay and the mice experiment in vivo were processed in this research.
Results:In this study 115 target compounds were synthesized and most of the compounds were obtained in high yield and good purity. All of the compounds were novel without any relevant reports in literature.
In series A, the preliminary activity evaluation against APN showed that some compounds possessed moderate inhibitory activities. Among 78 target compounds, 9e(9e'),9m(9m'),9r(9r') and 9s(9s') were the most potential. Compared with series A,25 compounds in series B exhibited better inhibitory activities. The IC50 of compounds 12w,12x and 12y were below 35μM, which were close to that of the positive control Bestatin. However, the high inhibition of MMP-2 was also observed. In series C, compound 161 was found to be the most active. The inhibitory activity was similar to that of Bestatin. Generally speaking, compounds in series C showed low activities towards MMP-2. It is worth mentioning that compounds 16k and 161 not only had a high inhibition against APN, but also represented low inhibition towards MMP-2, which suggested that both the compound have good selectivity against enzymes.
The structure activity relationship (SAR) was summarized based on the test results of the target compounds with the scaffold chloramphenicol amine in the previous enzyme assay. Comparative Molecular Field Analysis (CoFAR) was utilized to establish the QASR model of target compounds, which showed good cross-validated coefficient q2 and predictive potency. According to the the steric contour map and the electrostatic contour map of the CoMFA model, a program on the further structural optimization was proposed.
The test results of growth inhibition against six tumor cells in vitro indicated that most potent APN inhibitors displayed good inhibitory effect against the growth of these tumor cells. Compound 161 exhibited very similar potency against the proliferation of tumor cells compared with that of Bestatin. Compound 12w showed better inhibitory effect towards all the tumor cells than Bestatin.
In vivo experiments, compound 12w and 161 showed high potency against tumor cell H22 metastasis with the inhibition rates 48.51% and 58.04% respectively in mice. While the inhibition rate for the positive control Bestatin was 56.49%.
Conclusions:In conclusion, based on CADD and the virtual screening with APN as target chloramphenicol amine derivatives were designed and synthesized as APN inhibitors. We reported a convenient and economical method of the synthesis of APN inhibitors. Preliminary activity assays showed that most compounds displayed good APN inhibitory effects. Some compound such as 12w,161 showed better activities than the positive control Bestatin and could be used as lead compounds in the future. We also established a QASR model of target compounds, which is beneficial for the design of novel APN inhibitor in the further study.
目前,已有报道的天然抑制剂如：Bestatin, Probestatin, Amastatin, Curcumin等在预防和治疗肿瘤方面取得一定的积极效果。Bestatin作为第一个上市的APN抑制剂,临床上已经用于治疗急性成年人非淋巴性白血病。另外,人们还合成了许多小分子APN抑制剂,如α-氨基磷酸类抑制剂,β-氨基硫醇类抑制剂,以及本课题组报道的环酰亚胺类抑制剂,L-赖氨酸衍生物抑制剂等。
本研究以APN为靶点,设计合成了一系列小分子类肽化合物,并对其进行初步的生物活性筛选,以期发现具有良好APN抑制活性的抗癌先导化合物。
研究方法：在本实验室前期研究工作中发现的活性先导物1,2-二氨基-3-苯丙烷结构基础上,结合文献调研,解析APN的三维晶体结构及其与抑制剂的作用模式和特点,选择了与该活性结构相类似的氯霉胺为基本骨架,并在此基础上选择能与酶活性中心的疏水性口袋相互作用的不同侧链与之拼合进行衍生化。结构修饰主要考虑以下三个因素：1)引入不同体积和长度的疏水侧链,考察立体效应对酶的作用。2)侧链中选择不同的吸电子基和斥电子基,考察不同电性效应对酶的作用。3)侧链中选择可能与酶相互作用的氢键基团,以增强化合物与酶的亲和力。本研究综合利用计算机辅助药物设计软件的优势,对设计的化合物与酶进行柔性对接打分,选择分值较高的化合物进行化学合成。同时,对其分子量、脂水分配系数、氢键受体和氢键供体数进行了预测,采用Lipinski规则进一步筛选,最终设计了三个系列115个全新结构的目标化合物。目标化合物的合成以氯霉胺为起始原料,采用了氨基保护,选择性氧化,溴代,叠氮化,还原,缩合等多个反应步骤完成,采用红外光谱、核磁共振氢谱、电喷雾质谱、X-ray单晶衍射等方法确证其化学结构。
生物活性研究选用体外抑酶(APN, MMP-2)活性试验、肿瘤细胞(HL-60,ES-2,K549等)生长抑制试验和小鼠体内抗肿瘤转移试验对目标化合物进行了初步活性评价,从中筛选出具有较好活性的氯霉胺类APN抑制剂作为抗癌先导化合物。
研究结果：本研究最终合成了115个目标化合物,其中大部分化合物产率较高,纯度良好,所有化合物进行了化学结构确证。经文献检索,所合成的目标化合物为新型结构,未见相关报道。
本研究合成的78个A系列目标化合物中,大部分化合物对APN具有抑制活性,其中化合物9e(9e'),9m(9m'),9r(9r')和9s(9s’)活性较好。B系列化合物相比于A系列化合物,整体上活性有明显提高。其中,化合物12w,12x和12y的IC5035μM以下,接近于阳性对照药Bestatin的APN抑制活性。然而,B系列化合物同样也显示出较强的MMP-2抑制活性。在C系列中,化合物16k,161与阳性对照药Bestatin的活性相当,且对MMP-2的抑制活性较低,显示了良好的抑酶选择性。
本研究在对上述目标化合物进行抑酶活性试验的基础上,利用计算机软件进行了初步定量构效关系研究。采用比较分子力场分析方法(CoMFA)建立了具有较高的交叉验证系数q2和一定预测能力的定量构效关系(QSAR)模型。通过对CoMFA模型立体场等势线图和静电场等势线图的分析,提出了化合物下一轮结构优化的方案,为氯霉胺类APN抑制剂的进一步研究奠定了基础。
体外细胞抑瘤实验结果表明,多数化合物对高表达APN的肿瘤细胞显示出良好的抑制效果。其中,化合物161、12w表现出与阳性对照药相当的肿瘤细胞抑制活性。
体内小鼠抗肿瘤转移试验结果证明,化合物12w和161均有一定的抑制荷肝癌H22小鼠肿瘤细胞转移的作用。其中,化合物12w的抑制率为48.51%,小于阳性对照药Bestatin(抑制率为58.04%),161的抑制率达到了56.49%,接近阳性对照药Bestatin。
研究结论：本研究基于APN的晶体结构及抑制剂与酶的作用模式,借助计算机软件进行合理药物设计并合成的氯霉胺类化合物具有较好的APN抑制活性。所设计的合成路线科学合理,起始原料经济易得。通过初步的活性测试发现了具有进一步研究价值的活性化合物。其中,化合物12w,161可以作为抗癌先导化合物用于下一轮的结构优化。同时,基于化合物结构和活性数据建立了有一定预测能力的定量构效关系模型,为今后新型APN抑制剂的研究奠定了基础。
Objective:Aminopeptidase N (APN/CD13; EC 3.4.11.2), a zinc-dependent membrane metalloproteinase, is present in a wide variety of human tissues and the surface of cell types (endothelial, epithelial, fibroblast, leukocyte). Compared with normal cells, APN is over-expressed on the surface of some tumor cells. It is demonstrated that this enzyme plays a crucial role in the process of tumor growth, invasion, metastasis and promoting the angiogenesis. Therefore, APN is considered as an important target in anti-cancer drug discovery and development.
So far, many natural inhibitors such as Bestatin, Phebestin, Probestatin, Amastatin, Curcumin have been reported and proved to be clinically efficacious for the treatment of tumor. Bestatin, the first marketed drug as natural aminopeptidase N inhibitor in Japan in 1987, now is clinically used to prolong the survival of patients with acute adult nonlymphcytic leukemia. In recent years, numerous synthetic APN inhibitors(APNI) have been reported, such asα-aminophosphonates APNI, a-aminoboronic acid APNI,β-thiols APNI,2,6-piperidinedione-N-acetamide derivatives APNI, L-lysine derivatives APNI, AHPA (β-Amino-α-Hydroxyl-phenylbutanoic acid) derivatives APNI and so on.
In this study, we designe and synthesize a series of small molecule peptido-mimetics based on the APN as target. Their preliminary biological activity screening are subsequently conducted in order to find out effective APN inhibitors as anti-cancer lead compounds.
Methods:According to the binding characteristics learned from the three dimensional crystal structure of APN and the mode of action of APN-inhibitor complex reported in literatures, we choose the chloramphenicol amine as the novel scaffold based on the active structure of 3-phenylpropane-1,2-diamine scaffold which was previous reported by our group. To improve the interaction with the hydrophobic pockets in the active site of APN, several fragments were introduced to the scaffold. This scaffold is optimized with following chemical modification:i) The different space volume and length of side chains were chosen to investigate the interaction of stereoscopic effect with APN. ii) Various electron-attracting groups and electron-pushing groups were introduced so as to investigate the interaction of electric effect with APN. iii) The groups which can form hydrogen bond with the enzyme were taken to enhance affinity. All the target compounds were rationally designed by CADD, FlexX docking and virtual screening. Meantime, the properties of all these compounds like molecular weight, lipid-water partition, the number of hydrogen bond receptor and hydrogen bond donor were predicted and screened by Lipinski rules before synthesis.115 novel target compounds were designed and synthesized by using chloramphenicol amine as starting material, through amino protection, selective oxidation, bromination, azide, reduction, condensation and other reaction steps. The structure were confirmed by IR,1H NMR, ESI-MS, X-ray crystal diffraction methods.
In addition, enzyme assay (APN, MMP-2), cancer cell (HL-60, ES-2, K562, A549, H7402,2PLC) proliferation assay and the mice experiment in vivo were processed in this research.
Results:In this study 115 target compounds were synthesized and most of the compounds were obtained in high yield and good purity. All of the compounds were novel without any relevant reports in literature.
In series A, the preliminary activity evaluation against APN showed that some compounds possessed moderate inhibitory activities. Among 78 target compounds, 9e(9e'),9m(9m'),9r(9r') and 9s(9s') were the most potential. Compared with series A,25 compounds in series B exhibited better inhibitory activities. The IC50 of compounds 12w,12x and 12y were below 35μM, which were close to that of the positive control Bestatin. However, the high inhibition of MMP-2 was also observed. In series C, compound 161 was found to be the most active. The inhibitory activity was similar to that of Bestatin. Generally speaking, compounds in series C showed low activities towards MMP-2. It is worth mentioning that compounds 16k and 161 not only had a high inhibition against APN, but also represented low inhibition towards MMP-2, which suggested that both the compound have good selectivity against enzymes.
The structure activity relationship (SAR) was summarized based on the test results of the target compounds with the scaffold chloramphenicol amine in the previous enzyme assay. Comparative Molecular Field Analysis (CoFAR) was utilized to establish the QASR model of target compounds, which showed good cross-validated coefficient q2 and predictive potency. According to the the steric contour map and the electrostatic contour map of the CoMFA model, a program on the further structural optimization was proposed.
The test results of growth inhibition against six tumor cells in vitro indicated that most potent APN inhibitors displayed good inhibitory effect against the growth of these tumor cells. Compound 161 exhibited very similar potency against the proliferation of tumor cells compared with that of Bestatin. Compound 12w showed better inhibitory effect towards all the tumor cells than Bestatin.
In vivo experiments, compound 12w and 161 showed high potency against tumor cell H22 metastasis with the inhibition rates 48.51% and 58.04% respectively in mice. While the inhibition rate for the positive control Bestatin was 56.49%.
Conclusions:In conclusion, based on CADD and the virtual screening with APN as target chloramphenicol amine derivatives were designed and synthesized as APN inhibitors. We reported a convenient and economical method of the synthesis of APN inhibitors. Preliminary activity assays showed that most compounds displayed good APN inhibitory effects. Some compound such as 12w,161 showed better activities than the positive control Bestatin and could be used as lead compounds in the future. We also established a QASR model of target compounds, which is beneficial for the design of novel APN inhibitor in the further study.
引文
[]]. Eaton, L. World cancer rates set to doubie by 2020[J]. British Med. J.,2003,326,728.
[2]. Jeffery, C.J. Moonlighting proteins:old proteins learning new tricks[J]. Trends Genet 2003,19, 415-417.
[3]. Antczak, C; De, M.I.; Bauvois, B. Ectopeptidases in pathophysiology[J]. Bioessays 2001, 23(3):251-260.
[4]. Jung, K.; Pergande, M.; Wischke, U.W. Characterization of particulate and soluble variants of the brush-border enzymes alanine aminopeptidase, alkaline phosphatase and a-glutamyltransferase in human urine[J]. Biomed Biochim Acta 1984, 43(12):1357-1364.
[5]. Favaloro, E.J.; Browning, T.; Facey, D. CD13 (GP150; aminopeptidase N):predominant functional activity in blood is localized to plasma and is not cell-surface associated[J]. Exp Hematol,1993,27(13):1695-1701.
[6]. Kawai, M.; Otake, Y.; Hara, Y. High-molecular-mass isoform of aminopeptidase N/CD13 in serum from cholestatic patients[J]. Clinica Chimica Acta,2003,330(1-2):141-149.
[7]. Van Hensbergen, Y.; Broxterman, H.J.; Hanemaaijer, R.; Jorna, A.S.; Van Lent, N.A.; Verheul, H.M.; Pinedo, H.M.; Hoekman, K. Soluble aminopeptidase N/CD13 in malignant and nonmalignant effusions and intratumoral fluid[J]. Clin Cancer Res,2002,8(12):3747-3754.
[8]. Curnis, F.; Arrigoni, G.; Sacchi, A.; Fischetti, L.; Arap, W.; Pasqualini, R.; Corti, A. Differential binding of drugs containing the NGR motif to CD 13 isoforms in tumor vessels, epithelia, and myeloid cells[J]. Cancer Res,2002,62(3):867-874.
[9]. Hooper, N.M. Families of zinc metalloproteases[J]. FEBS Lett,1994,354(1):1-6.
[10]. Pfleiderer, G.; Celliers, P.G. Isolation of an aminopeptidase from kidney particles[J]. Biochem. Z.1963,339,186-189.
[11]. Bauvois, B.; Dauzonne, D. Aminopeptidase-N/CD13 (EC 3.4.11.2) inhibitors:chemistry, biological evaluations, and therapeutic prospects[J]. Med. Res. Rev,2006,26(1):88-130.
[12]. Riemann, D.; Kehlen, A.; Langner, J. CD13-not just a marker in leukemia typing[J]. Immunology Today,1999,20(2):83-88.
[13]. Razak, K.; Newland, A.C. The significance of aminopeptidases and haematopoietic cell differentiation[J]. Blood Rev,1992,6(4):243-250.
[14]. Firla, B.; Arndt, M; Frank, K.; Thiel, U.; Ansorge, S.; Tager, M.; Lendeckel, U. Extracellular cysteines define ectopeptidase (APN, CD13) expression and function[J]. Free Radical Biologyand Medicine,2002,32(7):584-595.
[15]. Vlahovic, P.; Stefanovic, V. Kidney ectopeptidases. Structure, functions and clinical significance[J]. Pathol Biol (Paris),1998,46(10):779-786.
[16]. Kotlo, K.; Shukla, S.; Tawar, U.; Skidgel, R.A.; Danziger, R.S. Aminopeptidase N reduces basolateral Na+-K+-ATPase in proximal tubule cells[J]. Am J Physiol Renal Physiol.,2007, 293(4):F1047-1053.
[17]. Noble, F.; Banisadr, G.:Jardinaud, F.; Popovici, T.; Lai-Kuen, R.; Chen, H.; Bischoff, L. Parsadaniantz, S.M.; Fournie-Zaluski, M.C.; Roques, B.P. First discrete autoradiographic distribution of aminopeptidase N in various structures of rat brain and spinal cord using the selective iodinated inhibitor [1251]RB 129[J]. Neuroscience,2001,105(2):479-488.
[18]. Waksman, G.; Bouboutou, R.; Devin, J.; Bourgoin, S.; Cesselin, F.; Hamon, M.; Fournie-Zaluski, M.-C.; Roques, B.P. In vitro and in vivo effects of kelatorphan on enkephalin metabolism in rodent brain[J]. European Journal of Pharmacology,1985,117(2): 233-243.
[19]. Montiel, J.L.; Cornille, F.; Roques, B.P.; Noble, F. Nociceptin/orphanin FQ metabolism:role of aminopeptidase and endopeptidase 24.15[J]. JNeurochem,1997,68(1):354-361.
[20]. Lerche, C; Vogel, L.K.; Shapiro, L.H.; Noren, O.; Sjostrom, H. Human aminopeptidase N is encoded by 20 exons[J]. Mamm Genome,1996,7(9):712-713.
[21]. Watt, V.M.; Willard, H.F. The human aminopeptidase N gene:isolation, chromosome localization, and DNA polymorphism analysis[J]. Hum Genet,1990,85(6):651-654.
[22]. Thompson, J.D.; Gibson, T.J.; Plewniak, F. The ClustalX windows interface:flexible strategies for multiple sequence alignment aided by quality analysis tools[J]. Nucleic Acids Res.,1997,24,4876-4882.
[23]. Rost, N.D.; Barrett, A.J. MEROPS:the peptidase database[J]. Nucl. Acida Res.2000, 28(1):323-325.
[24]. Sjostrom, H.; Noren, O.; Olsen, J. Structure and function of aminopeptidase N[J]. Adv Exp Med Biol 2000,47725-34.
[25]. Luciani, N.; Marie-Claire, C; Ruffet, E.; Beaumont, A.; Roques, B.P.; Fournie-Zaluski, M.-C. Characterization of Glu350 as a critical residue involved in the N-terminal amine binding site of aminopeptidase N (EC 3.4.11.2):Insights into Its Mechanism of Action[J]. Biochemistry,1998,37(2):686-692.
[26]. Grembecka, J.; Mucha, A.; Cierpicki, T; Kafarski, P. The most potent organophosphorus inhibitors of leucine aminopeptidase. structure-based design, chemistry, and activity[J]. Journal of Medicinal Chemistry,2003,46(13):2641-2655.
[27]. Onohara, Y.; Nakajima, Y.; Ito, K.; Xu, Y; Nakashima, K.; Ito, T; Yoshimoto, T. Crystallization and preliminary X-ray characterization of aminopeptidase N from Escherichia coli[J]. Acta Crystallogr Sect F Struct Biol Cryst Commun,2006,62(Pt 7): 699-701.
[28]. Ito, K.; Nakajima, Y; Onohara, Y; Takeo, M.; Nakashima, K.; Matsubara, F.; Ito, T.; Yoshimoto, T. Crystal structure of aminopeptidase N (proteobacteria alanyl aminopeptidase) from Escherichia coli and conformational change of methionine 260 involved in substrate recognition[J]. J Biol Chem,2006,281(44):33664-33676.
[29]. Addlagatta, A.; Gay, L.; Matthews, B.W. Structure of aminopeptidase N from Escherichia coli suggests a compartmentalized, gated active site[J]. Proc Natl Acad Sci U S A,2006, 103(36):13339-13344.
[30]. Nocek, B.; Mulligan, R.; Bargassa, M.; Collart, F.; Joachimiak, A. Crystal structure of aminopeptidase N from human pathogen Neisseria meningitidis[J]. Proteins:Structure, Function, and Bioinformatics,2007,70(1):273-279.
[31]. Rudberg, P.C.; Tholander, F.; Thunnissen, M.; Haeggstrom, J.Z. Leukotriene A(4) hydrolase/aminopeptidase-Glutamate 271 is a catalytic residue with specific roles in two distinct enzyme mechanisms[J]. Journal of Biological Chemistry,2002,277(2):1398-1404.
[32]. Jiang, W.; Bond, J.S. Families of metalloendopeptidases and their relationships[J]. FEBS Lett.,1992,572(2):100-114.
[33]. Hangauer, D.G.; Monzingo, A.F.; Matthews, B.W. An interactive computer graphics study of thermolysin-catalyzed peptide cleavage and inhibition by N-carboxymethyl dipeptides[J]. Biochemistry,1984,25(24):5730-5741.
[34]. Holmes, M.A.; Matthews, B.W. Binding of hydroxamic acid inhibitors to crystalline thermolysin suggests a pentacoordinate zinc intermediate in catalysis[J]. Biochemistry,1981, 20(24):6912-6920.
[35]. Mina-Osorio, P. The moonlighting enzyme CD13:old and new functions to target[J]. Trends in Molecular Medicine 2008,14,(8) 361-371.
[36]. Tomita, M.; Obara, H.; Takesue, Y.; Tamura, H.; Miyajima, S.; Taguchi, R.; Ikezawa, H. Purification of glycosylphosphatidylinositol-anchoring aminopeptidase N from the plasma membrane of larval midgut epithelial cells of the silkworm, Bombyx mori[J]. Int. J. Biochem.,1994,26(8):977-986.
[37]. Zini, S.; Fournie-Zaluski, M.C.; Chauvel, E.; Roques, B.P.; Corvol, P.; Llorens-Cortes, C. Identification of metabolic pathways of brain angiotensin Ⅱ and Ⅲ using specific aminopeptidase inhibitors:predominant role of angiotensin Ⅲ in the control of vasopressin release[J]. Proc Natl Acad Sci U S A,1996,93(21):11968-11973.
[38]. Lendeckel, U.; Arndt, M; Frank, K.; Wex, T.; Ansorge, S. Role of alanyl aminopeptidase in growth and function of human T cells (review) [J]. Int J Mol Med,1999,4(1):17-27.
[39]. Giros, B.; Gros, C.; Solhonne, B.; Schwartz, J.C. Characterization of aminopeptidases responsible for inactivating endogenous (Met5) enkephalin in brain slices using peptidase inhibitors and anti-aminopeptidase M antibodies[J]. Mol Pharmacol,1986,29(3):281-287.
[40]. Furuhashi, M.; Mizutani, S.; Kurauchi, O.; Kasugai, M.; Narita, O.; Tomoda, Y. In vitro degradation of opioid peptides by human placental aminopeptidase M[J]. Exp Clin Endocrinol,1988,92(2):235-237.
[41]. Miller, B.C.; Thiele, D.L.; Hersh, L.B.; Cottam, G..L. Methionine enkephalin is hydrolyzed by aminopeptidase N on CD4+ and CD8+ spleen T cells[J]. Archives of Biochemistry and Biophysics,1994,311(1):174-179.
[42]. Lendeckel, U.; Kahne, T.; Riemann, D.; Neubert, K.; Arndt, M.; Reinhold, D. Review:the role of membrane peptidases in immune functions[J]. Adv Exp Med Biol,2000,477,1-24.
[43]. Ahmad, S.; Wang, L.; Ward, P.E. Dipeptidyl(amino)peptidase IV and aminopeptidase M metabolize circulating substance P in vivo[J]. J Pharmacol Exp Ther,1992,260(3): 1257-1261.
[44]. Kanayama, N.; Kajiwara, Y.; Goto, J.; Maradny, E.; Maehara, K.; Andou, K.; Terao, T. Inactivation of interleukin-8 by aminopeptidase N (CD13) [J]. JLeukoc Biol,1995,57(1): 129-134.
[45]. Liotta, L.A.; Steeg, P.S. Cancer metastasis and angiogenesis:an imbalance of positive and negative regulation[J]. Cell,1991,64(2):327-336.
[46]. Menrad, A.; Speicher, D.; Wacker, J.; Herlyn, M. Biochemical and functional characterization of aminopeptidase N expressed by human melanoma cells[J]. Cancer Res, 1993,55(6):1450-1455.
[47]. Fujii, H.; Nakajima, M.; Saiki, I.; Yoneda, J.; Azuma, I.; Tsuruo, T. Human melanoma invasion and metastasis enhancement by high expression of aminopeptidase N/CD13[J]. Clin Exp Metastasis,1995,13(5):337-344.
[48]. Kitamura, Y; Watanabe, M; Komatsubara, S.; Sakata, Y. Urinary excretion of glycine prolile dipeptidile aminopeptidase,N-acetyl-β-D-glucosaminidase, alanine aminopeptidase and low molecular protein in patients with renal cell carcinoma[J]. Hinyokika Kiyo,1990, 36(5):535-539.
[49]. Ikeda, N.; Nakajima, Y.; Tokuhara, T.; Hattori, N.; Sho, M.; Kanehiro, H.; Miyake, M. Clinical significance of aminopeptidase N/CD 13 expression in human pancreatic carcinoma[J]. Clin Cancer Res,2003,9(4):1503-1508.
[50]. Hashida, H.; Takabayashi, A.; Kanai, M.; Adachi, M.; Kondo, K.; Kohno, N.; Yamaoka, Y.; Miyake, M. Aminopeptidase N is involved in cell motility and angiogenesis:Its clinical significance in human colon cancer[J]. Gastroenterology,2002,122(2):376-386.
[51]. Ishii, K.; Usui, S.; Sugimura, Y.; Yamamoto, H.; Yoshikawa, K.; Hirano, K. Inhibition of aminopeptidase N (APN) and urokinase-type plasminogen activator (uPA) by zinc suppresses the invasion activity in human urological cancer cells[J]. Biol Pharm Bull,2001, 24(3):226-230.
[52]. Carl-McGrath, S.; Lendeckel, U.; Ebert, M.; Wolter, A.B.; Roessner, A.; Rocken, C. The ectopeptidases CD 10, CD 13, CD26, and CD 143 are upregulated in gastric cancer[J]. Int J Oncol,2004,25(5):1223-1232.
[53]. Kehlen, A.; Lendeckel, U.; Dralle, H.; Langner, J.; Hoang-Vu, C. Biological significance of aminopeptidase N/CD13 in thyroid carcinomas[J]. Cancer Res,2003,63(23):8500-8506.
[54]. Riemann, D.; Gohring, B.; Langner, J. Expression of aminopeptidase N/CD13 in tumour-infiltrating lymphocytes from human renal cell carcinoma[J]. Immunology Letters, 1994,42(1-2):19-23.
[55]. Balog, T.; Marotti, T.; Sverko, V.; Marotti, M.; Krolo, I.; Rocic, B.; Karapanda, N. Enkephalin degradating enzymes in pheochromocytoma patients[J]. Oncol Rep,2003,10(1): 253-258.
[56]. Mitsui, T.; Nomura, S.; Itakura, A. Role of aminopeptidases in the blood pressure regulation[J]. Biol. Pharm. Bull,2004,27(6):768-771.
[57]. Dixon, J.; Kaklamanis, L.; Turley, H.; Hickson, I.D.; Leek, R.D.; Harris, A.L.; Gatter, K.C. Expression of aminopeptidase-N (CD 13) in normal tissues and malignant neoplasms of epithelial and lymphoid origin[J]. J Clin Pathol,1994,47(1):43-47.
[58]. Sato, Y. Role of aminopeptidase in angiogenesis[J]. Biol Pharm Bull,2004,27(6):772-776.
[59]. Ishii, K.; Usui, S.; Sugimura, Y; Yoshida, S.; Hioki, T.; Tatematsu, M; Yamamoto, H.; Hirano, K. Aminopeptidase N regulated by zinc in human prostate participates in tumor cell invasion[J]. International Journal of Cancer,2001,92(1):49-54.
[60]. Kido, A.; Krueger, S.; Haeckel, C; Roessner, A. Inhibitory effect of antisense aminopeptidase N (APN/CD13) cDNA transfection on the invasive potential of osteosarcoma cells[J]. Clin Exp Metastasis,2003,20(7):585-592.
[61]. Saiki,I.; Yoneda, J.; Azuma, I.; Fujii, H.; Abe, F.; Nakajima, M.; Tsuruo, T. Role of aminopeptidase N(CD13) in tumor-cell invasion and extracellular matrix degradation[J]. International Journal of Cancer,1993,54(1):137-143.
[62]. Hanahan, D.; Folkman, J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis[J]. Cell,1996,86(3):353-364.
[63]. Bhagwat, S.V.; Petrovic, N.; Okamoto, Y; Shapiro, L.H. The angiogenic regulator CD13/APN is a transcriptional target of Ras signaling pathways in endothelial morphogenesis[J]. Blood,2003,101(5):1818-1826.
[64]. Zetter, B.R. Angiogenesis and tumor metastasis[J]. Annu. Rev. Med,1998,49,407-424.
[65]. Bussolino, F.; Mantovani, A.; Persico, G. Molecular mechanisms of blood vessel formation[J]. Trends Biochem. Sci.,1997,22(7):251-256.
[66]. Santos, A.N.; Langner, J.; Herrmann, M.; Riemann, D. Aminopeptidase N/CD13 is directly linked to signal transduction pathways in monocytes[J]. Cellular Immunology,2000,201(1): 22-32.
[67]. Lohn, M.; Mueller, C.; Langner, J. Cell cycle retardation in monocytoid cells induced by aminopeptidase N (CD13)[J]. Leuk Lymphoma,2002,43(2):407-413.
[68]. Ansorge, S.; Schon, E.; Kunz, D. Membrane-bound peptidases of lymphocytes:functional implications[J]. Biomed Biochim Acta,1991,50(4-6):799-807.
[69]. Mishima, Y.; Matsumoto-Mishima, Y.; Terui, Y.; Katsuyama, M.; Yamada, M.; Mori, M.; Ishizaka, Y.; Ikeda, K.; Watanabe, J.; Mizunuma, N.; Hayasawa, H.; Hatake, K. Leukemic cell-surface CD13/aminopeptidase N and resistance to apoptosis mediated by endothelial cells[J]. J Natl Cancer Inst,2002,94(13):1020-1028.
[70].林茂芳；何静松；蔡真等.氨肽酶抑制剂Bestatin通过激活半胱天冬酶-3诱导HL-60细胞凋亡[J].中华血液学志2001,22(7)：348-350.
[71]. Pulido-Cejudo, G; Conway, B.; Proulx, P. Bestatin-mediated inhibition of leucine aminopeptidase may hinder HIV infection[J]. Antiviral Res.,1997,36(3):167-177.
[72]. Schiffmann, E.; Corcoran, B.A.; Wahl, S. N-formylmethionyl peptides as chemoattractants for leukocytes[J]. Proceedings of the National Academy of Sciences of the United States of America,1975,72(3):1059-1062.
[73]. Mechtersheimer, G.; Moller, P. Expression of aminopeptidase N (CD13) in mesenchymal tumors[J]. Am JPathol,1990,137(5):1215-1222.
[74]. Look, A.T.; Ashmun, R.A.; Shapiro, L.H.; Peiper, S.C. Human myeloid plasma membrane glycoprotein CD13 (gp150) is identical to aminopeptidase N[J]. J Clin Invest,1989,83(4): 1299-1307.
[75]. Li, B.X.; Ge, J.W.; Li, Y.J. Porcine aminopeptidase N is a functional receptor for the PEDV coronavirus[J]. Virology,2007,365(1):166-172.
[76]. Soderberg, C; Giugni, T.D.; Zaia, J.A.; Larsson, S.; Wahlberg, J.M.; Moller, E. CD13 (human aminopeptidase N) mediates human cytomegalovirus infection[J]. J Virol,1993, 67(11):6576-6585.
[77]. Marotti, T.; Balog, T.; Munic, V.; Sobocanec, S.; Abramic, M. The link between met-enkephalin-induced down-regulation of APN activity and the release of superoxide anion[J]. Neuropeptides,2000,34(2):121-128.
[78]. Noble, F.; Smadja, C.; Valverde, O.; Maldonado, R.; Coric, P.; Turcaud, S.; Fournie-Zaluski, M.-C; Roques, B.P. Pain-suppressive effects on various nociceptive stimuli (thermal, chemical, electrical and inflammatory) of the first orally active enkephalin-metabolizing enzyme inhibitor RB 120[J]. Pain,1997,73(3):383-391.
[79]. Gros, C.; Giros, B.; Schwartz, J.C. Identification of aminopeptidase M as an enkephalin-inactivating enzyme in rat cerebral membranes. Biochemistry,1985,24(9): 2179-2185.
[80]. Hattori, A. Processing of antigenic peptides by aminopeptidases[J]. Biol. Pharm. Bull.,2004, 27(6):777-780.
[81]. Bedir, A.; Ozener, I.C.; Emerk, K. Urinary leucine aminopeptidase is a more sensitive indicator of early renal damage in non-insulin-dependent diabetics than microalbuminuria[J]. Nephron,1996,74(1):110-113.
[82]. Shimizu, T.; Tani, K.; Hase, K.; Ogawa, H.; Huang, L.; Shinomiya, F.; Sone, S. CD13/aminopeptidase N-induced lymphocyte involvement in inflamed joints of patients with rheumatoid arthritis[J]. Arthritis & Rheumatism,2002,46(9):2330-2338.
[83]. Sloane, P.D.; Zimmerman, S.; Suchindran, C. The public health impact of Alzheimer's disease,2000-2050:potential implication of treatment advances[J]. Annu. Rev. Public Health.,2002,23:(213-231).
[84]. Xu, Y.; Wellner, D.; Scheinberg, D.A. Substance P and bradykinin are natural inhibitors of CD13/Aminopeptidase N[J]. Biochemical and Biophysical Research Communications,1995, 208(2):664-674.
[85]. Curnis, F.; Sacchi, A.; Borgna, L.; Magni, F.; Gasparri, A.; Corti, A. Enhancement of tumor necrosis factor alpha antitumor immunotherapeutic properties by targeted delivery to aminopeptidase N (CD13)[J]. Nat Biotechnol,2000,18(11):1185-1190.
[86]. Ichinose, Y.; Genka, K.; Koike, T. Randomized double-blind placebo-controlled trial of Bestatin in patients with resected stage I squamous-cell lung carcinoma[J]. J. Natl. Cancer Inst.,2003,95(8):605-610.
[87]. Curnis, F.; Gasparri, A.; Sacchi, A.; Cattaneo, A.; Magni, F.; Corti, A. Targeted delivery of IFN-γ to tumor vessels uncouples antitumor from counterregulatory mechanisms[J]. Cancer Res,2005,65(7):2906-2913.
[88]. Lendeckel, U.; Kahne, T.; Riemann, D.; Neubert, K.; Arndt, M.; Reinhold, D. The role of membrane peptidases in immune functions[J]. Adv Exp Med Biol,2000,477,1-24.
[89]. Sedo, A.; Vlasicova, K.; Bartak, P.; Vespalec, R.; Vicar, J.; Simanek, V.; Ulrichova, J. Quaternary benzo[c].phenanthridine alkaloids as inhibitors of aminopeptidase N and dipeptidyl peptidase Ⅳ[J]. Phytother Res,2002,76(1):84-87.
[90]. Umezawa, H.; Aoyagi, T; Suda, H. Bestatin, an inhibitor of aminopeptidase B, produced by actinomycetes[J]. J. Antibiot.,1976,29(1):97-99.
[91]. Ota, K.; Kurita, S. Immunotherapy with bestatin for acute non-Lymphocytic Leukemia(ANLL)in adults[J]. Jpn. J. Cancer Chemother.,1984,11(2):2442-2750.
[92]. Leyhausen, G.; Schuster, D.K.; Vaith, P.; Zahn, R.K.; Umezawa, H.; Falke, D.; Muller, W.E. Identification and properties of the cell membrane bound leucine aminopeptidase interacting with the potential immunostimulant and chemotherapeutic agent bestatin[J]. Biochem Pharmacol,1983,32(6):1051-1057.
[93]. Matsas, R.; Stephenson, S.L.; Hryszko, J.; Kenny, A.J.; Turner, A.J. The metabolism of neuropeptides. Phase separation of synaptic membrane preparations with Triton X-114 reveals the presence of aminopeptidase N[J]. Biochem J.,1985,231(2):445-449.
[94]. Wilkes, S.H.; Prescott, J.M. The slow, tight binding of bestatin and amastatin to aminopeptidases[J]. J Biol Chem,1985,260(24):13154-13162.
[95]. Harbeson, S.L.; Rich, D.H. Inhibition of arginine aminopeptidase by bestatin and arphamenine analogs. Evidence for a new mode of binding to aminopeptidases[J]. Biochemistry,1988,27(19):7301-7310.
[96]. Tieku, S.; Hooper, N.M. Inhibition of aminopeptidases N, A and W. A reevaluation of the actions of bestatin and inhibitors of angiotensin converting enzyme[J]. Biochem. Pharmacol.,1992,44(9):1725-1730.
[97]. Schalk, C; d'Orchymont, H.; Jauch, M. F.; Tarnus, C.3-Amino-2-tetralone derivatives: novel potent and selective inhibitors of aminopeptidase-M (EC 3.4.11.2)[J]. Arch Biochem Biophys,1994,311(1):42-46.
[98]. Tarnus, C; Orchymont, H.3-Amino-2-hydroxy-propionaldehyde and 3-amino-1- hydroxypropan-2-one derivatives:New classes of aminopeptidase inhibitors[J]. Bioorg Med Chem,1996,4(8):1287-1297.
[99]. Lee, J.; Shim, J.S.; Jung, S.A.; Lee, S.T.; Kwon, H.J.N-Hydroxy-2-(naphthalene-2-ylsulfanyl)-acetamide, a novel hydroxamic acid-based inhibitor of aminopeptidase N and its anti-angiogenic activity [J]. Bioorganic & Medicinal Chemistry Letters,2005,15(1): 181-183.
[100].Melzig, M.F.; Bormann, H. Betulinic acid inhibits aminopeptidase Nactivity[J]. Planta Med, 1998,64(7):655-657.
[101].Shim, J.S.; Kim, J.H.; Cho, H.Y.; Yum, Y.N.; Kim, S.H.; Park, H.J.; Shim, B.S.; Choi, S.H.; Kwon, H.J. Irreversible inhibition of CD13/Aminopeptidase N by the antiangiogenic agent curcumin[J]. Chemistry & Biology,2003,10(8):695-704.
[102].Ahmad, S.; Ward, P.E. Role of aminopeptidase activity in the regulation of the pressor activity of circulating angiotensins[J]. J Pharmacol Exp Ther,1990,252(2):643-650.
[103].Kobayashi, S.; Isobe, T.; Ohno, M.A stereocontrolled synthesis of (-)-bestatin from an acyclic allylamine by iodocyclocarbamation[J]. Tetrahedron Lett,1984,25(44):5079-5082.
[104]. Pearson, W.H.; Hines, J.V. Synthesis of β-amino-α-hydroxy acids via aldol condensation of a chiral glycolate enolate. Synthesis of (-)-bestatin[J]. J Org Chem,1989,54(17): 4235-4237.
[105]. Suda, H.; Takita, T.; Aoyagi, T.; Umezawa, H. The chemical synthesis of bestatin[J]. J Antibiot,1976,29(5):600-601.
[106]. Wasserman, H.H.; Xia, M.; Petersen, A.K.; Jorgensen, M.R.; Curtis, E.A. Synthesis of the peptidic α-hydroxy amides phebestin, probestin, and bestatin from a-keto amide precursors[J]. Tetrahedron Lett,1999,40(34):6163-6166.
[107].Bergmeier, S.C.; Stanchina, D.M. Acylnitrene route to vicinal amino alcohols. Application to the synthesis of (-)-bestatin and analogues[J]. Journal of Organic Chemistry,1999,64(8): 2852-2859.
[108].Nemoto, H.; Ma, R.; Suzuki, I.; Shibuya, M. A new one-pot method for the synthesis of α-siloxyamides from aldehydes or ketones and its application to the synthesis of (-)-bestatin[J]. Org Lett,2000,2(26):4245-4247.
[109].Righi, G.; Achille, C.; Pescatore, G.; Bonini, C. New stereoselective synthesis of the peptidic aminopeptidase inhibitors bestatin, phebestin and probestin[J]. Tetrahedron Lett,2003, 44(37):6999-7002.
[110].Wasserman, H.H.; Petersen, A.K.; Xia, M. Application of acyl cyanophosphorane methodology to the synthesis of protease inhibitors:Poststatin, eurystatin, phebestin, probestin, and bestatin[J]. Tetrahedron,2003,59(35):6771-6784.
[111].Lee, J.H.; Lee, B.W.; Jang, K.C.; Jeong, I.Y.; Yang, M.S.; Lee, S.G.; Park, K.H. Chirospecific synthesis of the(2S,3R)-and(2S,3S)-3-amino-2-hydroxy-4-phenylbutanoic acids from sugar:Application to (-)-bestatin[J]. Synthesis,2003,6(6):829-836.
[112].Nishizawa, R.; Saino, T.; Takita, T; Suda, H.; Aoyagi, T; Umezawa, H. Synthesis and structure-activity relations of bestatin analogs, inhibitors of aminopeptidase B[J]. Journal of Medicinal Chemistry,1977,20(4):510-515.
[113].Saino, T.; Seya, K.; Nishizawa, R.; Takita, T.; Aoyagi, T.; Umezawa, H. Synthesis of p-hydroxyubenimex[J]. J Antibiot,1987,40(8):1165-1169.
[114]. Ocain, T.D.; Rich, D.H. Synthesis of sulfur-containing analogues of bestatin. Inhibition of aminopeptidases by alpha-thiolbestatin analogues[J]. J Med Chem,1988,31(11): 2193-2199.
[115].Gordon, E.M.; Godfrey, J.D.; Delaney, N.G.; Asaad, M.M.; Von, L.D.; Cushman, D.W. Design of novel inhibitors of aminopeptidases[J]. Synthesis of peptide-derived diamino thiols and sulfur replacement analogues of bestatin. J Med Chem,1988,31(11):2199-2211.
[116].Murray, H.; Turner, A.J.; Kenny, A.J. The aminopeptidase activity in the human T-cell lymphoma line (Jurkat) is not at the cell surface and is not aminopeptidase N (CD-13)[J]. Biochem J,1994,298 (Pt 2):353-360.
[117].Aoyagi, T.; Tobe, H.; Kojima, F. Amastatin, an inhibitor of aminopeptidase A, produced by actinomycetes[J]. J. Antibiot.,1978,31(6):636-638.
[118]. Tobe, H.; Morishima, H.; Naganawa, H.; Takita, T.; Aoyagi, T.; Umezawa, H. Structure and chemical synthesis of amastatin[J]. Agric Biol Chem,1979,43(3):591-596.
[119].Rich, D.H.; Moon, B.J.; Boparai, A.S. Synthesis of (2S,3R)-3-amino-2-hydroxy-5-methylhexanoic acid derivatives. Application to the synthesis of amastatin, an inhibitor of aminopeptidase[J]. J Org Chem,1980,45(12):2288-2290.
[120].Tobe, H.; Morishima, H.; Aoyagi, T.; Umezawa, H.; Ishiki, K.; Nakamura, K.; Yoshioka, T.; Shimauchi, Y.; Inui, T. Synthesis and structure-activity relationships of amastatin analogues, inhibitors of aminopeptidase A[J]. Agric Biol Chem,1982,46(7):1865-1872.
[121].Repic, L. B.; Kidric, J.; Kralj, B. Lapstatin, a new aminopeptidase inhibitor produced by Streptomyces rimosus, inhibits autogenous aminopeptidases[J]. Arch. Microbiol,1999, 171(6):397-404.
[122].Aoyagi, T.; Yoshida, S.; Nakamura, Y; Shigihara, Y; Hamada, M.; Takeuchi, T. Probestin, a new inhibitor of aminopeptidase M, produced by Streptomyces azureus MH663-2F6. I. Taxonomy, production, isolation, physico-chemical properties and biological activities[J]. J Antibiot (Tokyo),1990,43(2):143-148.
[123].Nagai, M.; Kojima, F.; Naganawa, H.; Hamada, M.; Aoyagi, T.; Takeuchi, T. Phebestin, a new inhibitor of aminopeptidase N, produced by Streptomyces sp. MJ716-m3[J]. J Antibiot (Tokyo),1997,50(1):82-84.
[124].Chung, M.C.; Lee, H.J.; Chun, H.K.; Lee, C.H.; Kim, S.I.; Kho, Y.H. Bestatin analogue from Streptomyces neyagawaensis SL-387[J]. Biosci Biotechnol Biochem,1996,60(5): 898-900.
[125].Chung, M.C.; Chun, H.K.; Han, K.H.; Lee, H.J.; Lee, C.H.; Kho, Y.H. MR-387A and B, new aminopeptidase N inhibitors, produced by Streptomyces neyagawaensis SL-387[J]. J Antibiot (Tokyo) 1996,49(1):99-102.
[126].Chung, M.C.; Lee, C.H.; Lee, H.J.; Kho, YH.; Chun, H.K. Biosynthesis of peptide inhibitor MR-387 by Streptomyces neyagawaensis[J]. Biotechnol Lett,1997,19(7):607-610.
[127].Yoshida, S.; Aoyagi, T.; Takeuchi, T. Biosynthetic study of leuhistin, a new inhibitor of aminopeptidase M[J]. J Antibiot (Tokyo),1991,44(6):683-684.
[128].Aoyagi, T.; Yoshida, S.; Matsuda, N.; Ikeda, T.; Hamada, M.; Takeuchi, T. Leuhistin, a new inhibitor of aminopeptidase M, produced by Bacillus laterosporus BMI156-14F1. I. Taxonomy, production, isolation, physico-chemical properties and biological activities[J]. J Antibiot (Tokyo),1991,44(6):573-578.
[129].Yoshida, S.; Naganawa, H.; Aoyagi, T.; Takeuchi, T.; Takeuchi, Y.; Kodama, Y. Leuhistin, a new inhibitor of aminopeptidase M, produced by Bacillus laterosporus BMI156-14F1.11. Structure determination of leuhistin[J]. J Antibiot (Tokyo),1991,44(6):579-581.
[130].Gordon, J.J.; Kelly, B.K.; Miller, GA. Actinonin:An antibiotic substance produced by an actinomycete[J]. Nature,1962,195:701-702.
[131].Egan, M.E.; Pearson, M.; Weiner, S.A. Curcumin, a major constituent of turmeric, corrects cystic fibrosis defects[J]. Science 2004,304(5670):600-602.
[132].Arabshahi, L.; Schmitz, F. J. Brominated tyrosine metabolites from an unidentified sponge[J]. J Org Chem,1987,52(16):3584-3586.
[133].Shim, J.S.; Lee, H.S.; Shin, J.; Kwon, H.J. Psammaplin A, a marine natural product, inhibits aminopeptidase N and suppresses angiogenesis in vitro[J]. Cancer Letters,2004,203(2): 163-169.
[134].Yamamoto, Y.; Li, Y.H.; Ushiyama, I.; Nishimura, A.; Ohkubo, I.; Nishi, K. Puromycin-sensitive alanyl aminopeptidase from human liver cytosol:purification and characterization[J]. Forensic Science International,2000,113(1-3):143-146.
[135].Kakuta, H.; Tanatani, A.; Nagasawa, K.; Hashimoto, Y. Specific nonpeptide inhibitors of puromycin-sensitive aminopeptidase with a 2,4(1 H,3H)-quinazolinedione skeleton[J]. Chem Pharm Bull (Tokyo),2003,57,(11) 1273-1282.
[136].Chen, H.X.; Roques, B.P.; Fournie-Zaluski, M.C. Design of the first highly potent and selective aminopeptidase N (EC 3.4.11.2) inhibitor[J]. Bioorganic & Medicinal Chemistry Letters,1999,9(11):1511-1516.
[137].Chen, H.; Bischoff, L.; Fournie-Zaluski, M.C.; Roques, B.P. Synthesis of 2(S)-benzyl-3-[hydroxy(1prime(R)-aminoethyl)phosphinyl]propanoyl-L-3-iodotyrosine:a radiolabelled inhibitor of aminopeptidase N[J]. Journal of Labelled Compounds and Radiopharmaceuticals,2000,43(2):103-111.
[138].Chen, H.; Noble, F.; Coric, P.; Fournie-Zaluski, M.C.; Roques, B.P. Aminophosphinic inhibitors as transition state analogues of enkephalin-degrading enzymes:a class of central analgesics[J]. Proc Natl Acad Sci USA,1998,95(20):12028-12033.
[139].Grembecka, J.; Mucha, A.; Cierpicki, T.; Kafarski, P. The most potent organophosphorus inhibitors of leucine aminopeptidase. Structure-based design, chemistry, and activity[J]. J Med Chem,2003,46(13):2641-2655.
[140].Georgiadis, D.; Vazeux, G.; Llorens-Cortes, C.; Yiotakis, A.; Dive, V. Potent and selective inhibition of zinc aminopeptidase A (EC 3.4.11.7, APA) by glutamyl aminophosphinic peptides:Importance of glutamylaminophosphinic residue in the P1 position[J]. Biochemistry,2000,39,(15) 1152-1155.
[141].Vassiliou, S.; Xeilari, M.; Yiotakis, A.; Grembecka, J.; Pawelczak, M.; Kafarski, P.; Mucha, A. A synthetic method for diversification of the P1'substituent in phosphinic dipeptides as a tool for exploration of the specificity of the S1'binding pockets of leucine aminopeptidases[J]. Bioorganic & Medicinal Chemistry,2007,15(9):3187-3200.
[142].Grzywa, R.; Oleksyszyn, J. First synthesis of α-aminoalkyl-(N-substituted)thiocarbamoyl-phosphinates:Inhibitors of aminopeptidase N (APN/CD13) with the new zinc-binding group[J]. Bioorganic& Medicinal Chemistry Letters,2008,18(13):3734-3736.
[143].Roques, B.P.; Noble, F. Dual inhibitors of enkephalin-degrading enzymes (neutral endopeptidase 24.11 and aminopeptidase N) as potential new medications in the management of pain and opioid addiction[J]. NIDA Res Monogr,1995,147,104-145.
[144].Penning, T.D.; Askonas, L.J.; Djuric, S.W.; Haak, R.A.; Yu, S.S.; Michener, M.L.; Krivi, G.G.; Pyla, E.Y. Kelatorphan and related analogs:Potent and selective inhibitors of leukotriene A4 hydrolase[J]. Bioorg Med Chem Lett,1995,5(21):2517-2522.
[145].Chen, H.; Noble, F.; Roques, B.P.; Fournie-Zaluski, M.C. Long lasting antinociceptive properties of enkephalin degrading enzyme (NEP and APN) inhibitor prodrugs[J]. J Med Chem,2001,44(21):3523-3530.
[146].Roques, B.P. Insights into peptide and protein function:A convergent approach[J]. J Pept Sci,2001,7(2):63-73.
[147].Flipo, M.; Beghyn, T.; Charton, J.; Leroux, V.A.; Deprez, B.P.; Deprez-Poulain, R.F. A library of novel hydroxamic acids targeting the metallo-protease family:Design, parallel synthesis and screening[J]. Bioorganic & Medicinal Chemistry,2007,15(1):63-76.
[148]. Wang, J.; Xu, W. The preparation of novel L-iso-glutamine derivativesas potential antitumor agents[J]. J. Chem. Res. Synop.,2003,12, (789-791).
[149].Li, Q.; Fang, H.; Xu, W. Novel 3-galloylamido-N'-substituted-2,6-piperidinedione-N-acetamide peptidomimetics as metalloproteinase inhibitors[J]. Bioorg.Med.Chem.Letters, 2007,17(10):2935-2938.
[150].Mou, J.J.; Fang, H.; Jing, F.B.; Wang, Q.; Liu, Y.Z.; Zhu, H.W.; Shang, L.Q.; Wang, X.J.; Xu, W.F. Design, synthesis and primary activity evaluation of L-arginine derivatives as amino-peptidase N/CD13 inhibitors[J]. Bioorg.Med. Chem.,2009,17(13):4666-4673.
[151].Wang, Q.; Chen, M.Y.; Zhu, H.W.; Zhang, J.; Fang, H.; Wang, B.H.; Xu, W.F. Design, synthesis, and QSAR studies of novel lysine derives as amino-peptidase N/CD13 inhibitors[J]. Bioorganic & Medicinal Chemistry,2008,16(10):5473-5481.
[152].Fournie-Zaluski, M.C.; Coric, P.; Turcaud, S.; Bruetschy, L.; Lucas, E.; Noble, F.; Roques, B.P. Potent and systemically active aminopeptidase N inhibitors designed from active-site investigation[J]. Journal of Medicinal Chemistry,1992,35(7):1259-1266.
[153].Gros, C.; Giros, B.; Schwartz, J.C.; Vlaiculescu, A.; Costentin, J.; Lecomte, J.M. Potent inhibition of cerebral aminopeptidases by carbaphethiol, a parenterally active compound[J]. Neuropeptides,1988,12(3):111-118.
[154].Reaux, A.; de Mota, N.; Zini, S.; Cadel, S.; Fournie-Zaluski, M.C.; Roques, B.P.; Corvol, P.; Llorens-Cortes, C.PC 18, a specific aminopeptidase N inhibitor, induces vasopressin release by increasing the half-life of brain angiotensin Ⅲ[J]. Neuroendocrinology,1999,69(5): 370-376.
[155].Chauvel, E.N.; Coric, P.; Llorens-Cortes, C; Wilk, S.; Roques, B.P.; Fournie-Zaluski, M.C. Investigation of the active site of aminopeptidase A using a series of new thiol-containing inhibitors[J]. Journal of Medicinal Chemistry.,1994,37(9):1339-1346.
[156].Chauvel, E.N.; Llorens-Cortes, C; Coric, P.; Wilk, S.; Roques, B.P.; Fournie-Zaluski, M.C. Differential Inhibition of aminopeptidase A and aminopeptidase N by new β-Amino thiols[J]. Journal of Medicinal Chemistry,1994,37(18):2950-2957.
[157].Reaux, A.; Iturrioz, X.; Vazeux, G.; Fournie-Zaluski, M.C.; David, C.; Roques, B.P.; Corvol, P.; Llorens-Cortes, C. Aminopeptidase A, which generates one of the main effector peptides of the brain renin-angiotensin system, angiotensin Ⅲ, has a key role in central control of arterial blood pressure[J]. Biochem Soc Trans,2000,28(4):435-440.
[158].Noble, F.; Soleilhac, J.M.; Soroca-Lucas, E.; Turcaud, S.; Fournie-Zaluski, M.C.; Roques, B.P. Inhibition of the enkephalin-metabolizing enzymes by the first systemically active mixed inhibitor prodrug RB 101 induces potent analgesic responses in mice and rats. Journal of Pharmacology and Experimental Therapeutics,1992,261(1):181-190.
[159].Shenvi, A.B. α-Aminoboronic acid derivatives:Effective inhibitors of aminopeptidases. Biochemistry,1986,25(6):1286-1291.
[160].Andersson, L.; Isley, T.C.; Wolfenden, R. α-Aminoaldehydes:transition state analog inhibitors of leucine aminopeptidase. Biochemistry,1982,21(17):4177-4180.
[161]Jahreis, G.; Fittkau, S.; Aurich, H. α-Aminomethylketones as inhibitors of a membrane-bound alanine aminopeptidase. Biomed Biochim Acta.,1987,46(10):683-686.
[162]. Ocain, T.D.; Rich, D.H. a-Keto amide inhibitors of aminopeptidases. J. Med. Chem.,1992, 35(3):451-456.
[163]. Ma, T.; Xu, W.F.; Wang, J.L.; Yuan, Y.M. Design, synthesis and anti-cancer activity of AHPA derivatives. Chinese J Med Chem,2003,13(2):70-75.
[164].Miyachi, H.; Kato, M.; Kato, F.; Hashimoto, Y. Novel potent nonpeptide aminopeptidase N inhibitors with a cyclic imide skeleton. Journal of Medicinal Chemistry,1998,41(3): 263-265.
[165].Takahashi, H.; Komoda, M.; Kakuta, H.; Hashimoto, Y. Preparation of novel specific aminopeptidase inhibitors with a cyclic imide skeleton. Yakugaku Zasshi,2000,120(10): 909-921.
[166].Shimazawa, R.; Takayama, H.; Kato, F.; Kato, M.; Hashimoto, Y. Nonpeptide small-molecular inhibitors of dipeptidyl peptidase Ⅳ:N-phenylphthalimide analogs. Bioorganic & Medicinal Chemistry Letters,1999,9(4):559-562.
[167].Komoda, M.; Kakuta, H.; Takahashi, H.; Fujimoto, Y.; Kadoya, S.; Kato, F.; Hashimoto, Y. Specific inhibitor of puromycin-sensitive aminopeptidase with a homophthalimide skeleton: Identification of the target molecule and a structure-activity relationship study. Bioorg Med Chem,2001,9(1):121-131.
[168].Lindsay, C.K.; Gomez, D.E.; Thorgeirsson, U.P. Effect of flavone acetic acid on endothelial cell proliferation:evidence for antiangiogenic properties Anticancer Res,1996,16(1): 425-431.
[169].Bibby, M.C.; Double, J.A. Flavone acetic acid from laboratory to clinic and back. AntiCancer Drugs,1993,4(1):3-17.
[170].Parellada, J.; Suarez, G; Guinea, M. Inhibition of zinc metallopeptidases by flavonoids and related phenolic compounds:Structure-activity relationships. J Enzyme Inhib,1998,13(5): 347-359.
[171].Bormann, H.; Melzig, M.F. Inhibition of metallopeptidases by flavonoids and related compounds. Pharmazie,2000,55(2):129-132.
[172].Ehrlich, J.; Bartz, Q.R.; Smith, R.M.; Joslyn, D.A.; Burkholder, P.R. Chloromycetin, a new antibiotic from a soil actinomycete. Science,1947,106,417.
[173].Shin, W.; Pyo, M. The crystal and molecular structure of chloramphenicol base. Bull Kor Chem Soc,1984,5(4):158-162.
[174].Liu, Z.S.; Fang, Z.L. Combination of flow injection with capillary electrophoresis. Part 2. chiral separation of intermediate enantiomers in chloramphenicol synthesis. Anal Chim Acta, 1997,353(2):199-205.
[175].Sachchidananda, B.; Sankar, B.P.; Chandan, M. Inhibition of rat liver mitochondrial monoamine oxidase by chloramphenicol and 2-amino-1-p-nitrophenylpropane-1,3-diol. J Pharm Sci,1978,67(4):480-482.
[176].Shatilo, V.A.; Zaritskii, A.M.; Kudrya, T.N.; Shtepanek, A.S. Effect of 1-(p-nitrophenyl)-2-amino-1,3-propanediol and β-chloroethyl-phosphonic acid derivatives on growth of enterobacteria. Mikrobiologicheskii Zhurnal,1984,46(4):39-42.
[177].Kudrya, T.N.; Karabanov, Y.V.; Shtepanek, A.S. N-dialkyl-substituted derivatives of 1-[(p-nitrophenyl)-2-amino]ethanol and 1,3-propanediols and their physiological activity. Fiziologicheski Aktivnye Veshchestva,1981,13,64-66.
[178].Hazra, B.G; Pore, V.S.; Dey, S.K.; Datta, S.; Darokar, M.P.; Saikia, D.; Khanujab, S.S.; Thakura, A. Bile acid amides derived from chiral amino alcohols:novel antimicrobials and antifungals. Bioorg Med Chem Lett,2004,14(3):773-777.
[179].Kudrya, T.N.; Protopopova, G.V.; Reidalova, L.I.; Lagoshina, N.S.; Telyuk, V.G. Phosphorylated derivatives of 1-(p-nitrophenyl)-2-amino-1,3-propanediol(d,l-threo form)and their physiological activity. Fiziologicheski Aktivnye Veshchestva,1980,12, 22-25.
[180].Drainas, D.; Petros, M.; Coutsogeorgopoulos, C. Aminoacyl analogs of chloramphenicol: examination of the kinetics of inhibition of peptide bond formation. J Med Chem,1993, 36(23):3542-3545.
[181].Johansson, D.; Jessen, C.H.; Pohlsgaard, J.; Jensen, K.B.; Vester, B.; Pedersena, E.B.; Nielsen, P. Design, synthesis and ribosome binding of chloramphenicol nucleotide and intercalator conjugates. Bioorg Med Chem Lett,2005,75(8):2079-2083.
[182].金道忠；朱兴族.神经酰胺代谢及凋亡信号调节.生命科学，2006,18(5)：481-486.
[183].Murakami, T.; Furusawa, K.; Tamai, T.,; Yoshikai, K.; Nishikawa, M. Synthesis and biological properties of novel sphingosine derivatives. Bioorg Med Chem Lett,2005,15(4): 1115-1119.
[184].Selzner, M.; Bielawska, A.; Morse, M.A.; Rudiger, H.A.; Sindram, D.; Hannun, Y.A.; Clavien, P.A. Induction of apoptotic cell death and prevention of tumor growth by ceramide analogues in metastatic human colon cancer. Cancer Res,2001,61(2):1233-1240.
[185].Szulc, Z.M.; Mayroo, N.; Bai, A.P.; Bielawski, J.; Liu, X.; Norris, J.S.; Hannuna, Y.A.; Bielawska, A. Novel analogs of D-e-MAPP and B13. Part 1:Synthesis and evaluation as potential anticancer agents. Bioorg Med Chem,2008,16(2):1015-1031.
[186].Bai, A.; Szulc, Z.M.; Bielawski, J.; Mayroo, N.; Liu, X.; Norris, J.; Hannun, Y.A.; Bielawska, A. Synthesis and bioevaluation of Ш-N-amino analogs of B13. Bioorg Med Chem, 2009,17,1840-1848.
[187].Mincione, F.; Starnotti, M.; Masini, E.; Bacciottini, L.; Scrivanti, C.; Casini, A.; Vullo, D.; Scozzafavad, A.; Supurand, C.T. Carbonic anhydrase inhibitors:Design of thioureido sulfonamides with potent isozyme Ⅱ and Ⅻ inhibitory properties and intraocular pressure lowering activity in a rabbit model of glaucoma. Bioorg Med Chem Lett,2005,15(17): 3821-3827.
[188].Vullo, D.; Steffansen, B.; Brodin, B.; Supuran, C.T.; Scozzafava, A.; Nielsen, C.U. Carbonic anhydrase inhibitors:Transepithelial transport of thioureido sulfonamide inhibitors of the cancer-associated isozyme IX is dependent on efflux transporters. Bioorg Med Chem,2006, 14(7):2418-2427.
[189].Lee, J.; Kwon, M.; Lee, K.H.; Jeong, S.; Hyun, S.; Shin, K.J.; Yu, J. An approach to enhance specificity against RNA targets using heteroconjugates of aminoglycosides and chloramphenicol(or linezolid). J Am Chem Soc,2004,126(7):1956-1957.
[1].陈凯先主编.计算机辅助药物设计：原理、方法及应用,上海科学技术出版社,2000.
[2].徐筱杰主编.计算机辅助药物分子设计,化学工业出版社,2004.
[3].叶德泳主编.计算机辅助药物设计导论,化学工业出版社,2004.
[4].徐文方主编.药物设计学,人民卫生出版社,2007.
[5].徐文方主编.新药设计与开发,科学出版社,2001.
[6]. Veselovsky, A.V.; Ivanov, A.S. Strategy of computer-aided drug design[J]. Curr Drug Targets Infect Disord,2003,5(1):33-40.
[7]. Reddy, C.S.; Vijayasarathy, K.; Srinivas, E. et al. Homology modeling of membrane proteins:a critical assessment[J]. Comput Biol Chem,2006,30(2):120-126.
[8]. DesJarlais, R.L.; Dixon, J.S. A shape-and chemistry-based docking method and its use in the design of HIV-1 protease inhibitors[J]. J. Comput. Aided Mol. Des.,1994,8,231-242.
[9]. Iwata, Y.; Arisawa, M; Hamada, R.; Kita, Y.; Mizutani, M.Y.; Tomioka, N.; Itai, A.; Miyamoto, S. Discovery of novel aldose reductase inhibitors using a protein structure-based approach:3d-database search followed by design and synthesis[J]. J. Med. Chem.2001,44, 1718-1728.
[10]. Enyedy, I.J.; Ling, Y.; Nacro, K.; Tomita, Y; Wu, X.; Cao, Y; Guo, R.; Li, B.; Zhu, X.; Huang, Y; Long, Y. Discovery of small-molecule inhibitors of Bcl-2 through structure-based computer screening[J]. J. Med. Chem.2001,44,4313-4378.
[11]. Cramer, R.D.; Patterson, D.E.; Bunce, I.D. Comparative molecular field analysis (CoMFA).1.Effect of shape on binding of steroids to carrier proteins[J]. J Am Chem Soc,1988,110:5959-5967.
[12]. Klebe, G; Abraham, U.; Mietzner, T. Molecular similarity indices in a comparative analysis (CoMSIA) of drug molecules to correlate and predict their biological activity[J]. J Med Chem,1994,57(24):4130-4146.
[13]. Onohara Y., Nakajima Y, Ito K. et al. Crystallization and preliminary X-ray characterization of aminopeptidase N from Escherichia coli[J]. Acta. Cryst.,2006,62(7):699-701.
[14]. Shang, L.; Fang, H.; Zhu, H.; Wang, X.; Wang, Q.; Mu, J.; Wang, B.; Kishioka, S.; Xu, W. Design, synthesis and SAR studies of tripeptide analogs with the scaffold 3-phenylpropane-1,2-diamine as aminopeptidase N/CD13 inhibitors[J]. Bioorganic & Medicinal Chemistry,2009,17(7):2775-2784.
[15]. Wang, Q.; Chen, M.Y.; Zhu, H.W.; Zhang, J.; Fang, H.; Wang, B.H.; Xu, W.F. Design, synthesis, and QSAR studies of novel lysine derives as amino-peptidase N/CD13 inhibitors[J]. Bioorganic & Medicinal Chemistry,2008,16(10):5473-5481.
[16]. Tarnus, C. Orchymont, H.3-Amino-2-hydroxy-propionaldehyde and 3-amino-1-hydroxypropan-2-one derivatives:New classes of aminopeptidase inhibitors[J]. Bioorg Med Chem 1996,4,(8) 1287-1297.
[17]. Hooper, N.M. Families of zinc metalloproteases[J]. FEBS Lett.,1994,354(1):1-6.
[18]. Addlagatta, A.; Gay, L.; Matthews, B.W. Structural basis for the unusual specificity of Escherichia coli aminopeptidase N[J]. Biochemistry,2008,47(19):5303-5311.
[19]. Yang, K.; Wang, Q.; Su, L.; Fang, H.; Wang, X.; Gong, J.; Wang, B.; Xu, W. Design and synthesis of novel chloramphenicol amine derivatives as potent aminopeptidase N (APN/CD13)inhibitors[J]. Bioorganic & Medicinal Chemistry 2009,17(11):3810-3817.
[20].杨二冰.李正名.药物分子设计中的Lipinski规则[J].化学通报,2006,69(1)：16-19.
[1]. Murakami, T.; Furusawa, K.; Tamai, T.; Yoshikai, K.; Nishikawa, M. Synthesis and biological properties of novel sphingosine derivatives[J]. Bioorg. Med. Chem. Lett.,2005,15, 1115-1119.
[2]. Jiang, Y.; Han, J.; Yu, C.; Vass, O.; Searle, P.; Browne, P.; Knox, R.; Hu, L. Design, synthesis, and biological evaluation of cyclic and acyclic nitrobenzylphosphoramide mustards for E. coli nitroreductase activation[J]. J. Med. Chem.2006,49,4333-4343.
[3]. Chellemi F. Synthesis by conventional methods of human growth hormone peptide fragments[J]. Int J Pept Protein Res,1975,7(2):43-48.
[4]. Ciriminna, R.; Bolm, C.; Fey, T.; Pagliaro, M. Sol-Gel ormosils doped with TEMPO as recyclable catalysts for the selective oxidation of alcohols[J]. Adv. Synth. Catal,2002, 344(2):159-163
[5]. Testa M.L.; Ciriminna, R.; Hajji, C; Garcia, E.Z.; Ciclosi, M.; Arques, J.S.; Pagliaro, M. Oxidation of amino diols mediated by homogeneous and heterogeneous TEMPO[J]. Advanced Synthesis & Catalysis,2004,346(6):655-660.
[6]. Jordis, U.; Sauter, F.; Siddiqi, S.M. Synthesis of (1S,4S)-2-thia-5-azabicyclo[2.2.1]heptane[J]. Indian J Chem Sec B,1989,28(4):294-296.
[7]. Kim, S.; Lee, J.I.; Kim, Y.C. A simple and mild esterification method for carboxylic acids using mixed carboxylic-carbonic anhydrides[J]. JOrg Chem,1985,50(5):560-565.
[8]. Rijkers, T.S.; Adams, H.P.H.M.; Hemker, H.C.; Tesser, G.I. A convenient synthesis of amino acid p-nitroanilides; synthons in the synthesis of protease substrates[J]. Tetrahedron,1995, 57(41):11235-11250.
[9]. Oyamada, H.; Saito, T.; Inaba, S.; Ueki, M. Reinvestigation of the phosphazo method and synthesis of N-(t-butoxycarbonyl)-L-arginine p-nitroanilide and a chromogenic enzyme substrate for the factor Xa[J]. Bull.Chem.Soc.Jpn.1991,64(4):1422-1424.
[10]. Wilhelm, P. α-Amino acid p-nitroanilides. Ger.1967, DE 1243204.
[11]. Spies, J.R. Dimorphism of formyl-d-and l-methionine and the effect of hrdrochloric acid on the rotation of d-and l-methionine[J]. JBiol Chem,1950,182(1):439-442.
[12]. Amblard, M.; Rodriguez, M.; Martinez, J.N-benzhydryl-glycolamide(OBg esters) as carboxyl protecting groups in peptide synthesis[J]. Tetrahedron,1988,44(16):5101-5108.
[13]. Roethle, P.A.; Hernandez, P.T.; Trauner, D. Exploring biosynthetic relationships among furanocembranoids:synthesis of (-)-bipinnatin j, (+)-intricarene, (+)-rubifolide, and (+)-isoepilophodione B[J]. Org. Lett,2006,8(25):5901-5904.
[14]. Magid, R.M.; Fruchey, O.S.; Johnson, W.L.; Allen, T.G.. Hexachloroacetone/triphenyl phosphine:a mild reagent for the regioselective and stereospecific production of allylic chlorides from the alcohols[J]. J. Org. Chem.1979,44(3):359-363.
[15]. Davis, N.J.; Flitscb, S.L. Selective oxidation of monosaccharide derivatives to uranic acids[J]. Tetrahedron,1993,34(1):1181-1184.
[16]. McKillop, A.; Richard, J.K. Taylor, et al. An improved procedure for the preparation of the garner aldehyde and its use for the synthesis of N-proteced 1-Halo-2-(R)-amino-3-butenes[J]. Syntheis,1994,31-33.
[17]. Hirschmann, R.; Strachan, R.G.; Schwam, H. The controlled synthesis of peptides in aqueous medium.3. Use of Leuchs' anhydrides in the synthesis of dipeptides. Mechanism and control of side reactions[J]. J Org Chem,1967,32(11):3415-3425.
[1]. Drag,M; Grembecka, J. α-Aminoalkylphosphonates as a tool in experimental optimisation of P1 side chain shape of potential inhibitors in S1 pocket of leucineand neutral aminopeptidases[J]. Eur. J. Med. Chem.2005,40(8):764-771.
[2].刘冰心.淡水鱼肌肉亮氨酸氨肽酶的分离纯化与性质研究[J].集美大学硕士学位论文，2007.
[3]. Kyrieleis, O.P.; Goettig, P.; Kiefersauer, R.; Huber, R.; Brandstetter, H. Crystal structures of the tricorn interacting factor F3 from thermoplasma acidophilum, a zinc aminopeptidase in three different conformations[J]. Journal of Molecular Biology,2005,349(4):787-800.
[4]. Beti, R.; Cattaneo, A.; Gabriel, J.M.; Ojha, M.A novel N-α-acetyl alanine aminopeptidase from allomyces arbuscula[J]. Biochimie,2002,84(4):309-319.
[5]. Shimizu, T.; Tani, K.; Hase, K.; Ogawa, H.; Huang, L.; Shinomiya, F.; Sone, S. CD13/aminopeptidase N-induced lymphocyte involvement in inflamed joints of patients with rheumatoid arthritis[J]. Arthritis & Rheumatism,2002,46(9):2330-2338.
[6]. Baragi, V.M.; Shaw, B.J.; Renkiewicz, R.R. A versatile assay for gelatinase using succinylated gelatin[J]. Anal. Biochem.2000,286(1):267-273.
[7]. Chappelet-tordo, D.; Lazdunski, C; Murgier, M.; Lazdunski, A. Aminopeptidase N from Escherichia coli.Ionizable active-center groups and substrate specificity [J]. European Journal of Biochemistry,1977,81(2):299-305.
[8]. Flipo, M.; Beghyn, T.; Charton, J.; Leroux, V.A.; Deprez, B.P.; Deprez-Poulain, R.F. A library of novel hydroxamic acids targeting the metallo-protease family:Design, parallel synthesis and screening[J]. Bioorganic & Medicinal Chemistry,2007,15(1):63-76.
[9]. Ito, K.; Nakajima, Y; Onohara, Y; Takeo, M.; Nakashima, K.; Matsubara, F; Ito, T.; Yoshimoto, T. Crystal structure of aminopeptidase N (proteobacteria alanyl aminopeptidase) from Escherichia coli and conformational change of methionine 260 involved in substrate recognition[J]. J Biol Chem,2006,281(44):33664-33676.
[10]. Nagai, M.; Kojima, F; Naganawa, H.; Hamada, M.; Aoyagi, T.; Takeuchi, T. Phebestin, a new inhibitor of aminopeptidase N, produced by Streptomyces sp. MJ716-m3[J]. J Antibiot (Tokyo), 1997,50,(1)82-84.
[11]. Aoyagi, T.; Yoshida, S.; Nakamura, Y; Shigihara, Y; Hamada, M.; Takeuchi, T. Probestin, a new inhibitor of aminopeptidase M, produced by Streptomyces azureus MH663-2F6.I. Taxonomy, production, isolation, physico-chemical properties and biological activities[J]. J Antibiot (Tokyo), 1990,43(2):143-148.
[12].何静松；林茂芳；麦文渊等.乌苯美司对人白血病细胞生长抑制及其机制探讨[J].浙江大学学报(医学版)2002,31(4)：259-264.
[13]. Sehine, K.; Fuji, H.; Abe, F. Induction of apoptosis by Bestatin (ubenimex) in human leukemic cell lines[J]. Leukemia,1999,13(5):729-734.
[14]. Urabe, A. Immunotherapy with bestatin for acute nonlympgocytic leukemia in adults[J]. Ann Hematol,1993,67,63-66.
[15].李海燕；方肇勤；梁尚华.小鼠移植性肝癌(H22)模型的研究及在中医药抗肿瘤中的应用[J].中国中医基础医学杂志，2000,6(1)：27-30.
[1]. FlexXTM is distributed by Tripos Inc.,1699 South Hanley Rd., St. Louis, Missouri, USA (http://www.tripos.com).
[2]. Rarey, M.; Kramer, B.; Lengauer, T.A fast Flexible docking method using an incremental construction algorithm[J]. J. Mol.Biol,1996,261,470-489.
[3]. BiopolymerTM is distributed by Tripos Inc.,1699 South Hanley Rd., St. Louis, Missouri, USA (http://www. tripos. com).
[4]. Kellenberger, E.; Rodrigo, J.; Muller, P. Comparative evaluation of eight docking tools for docking and virtual screening accuracy[J]. Proteins.,2004,57(2):225-242.
[5]. Hooper, N.M. Families of zinc metalloproteases[J]. FEBS Lett,1994,354(1):1-6.
[6]. Ito, K.; Nakajima, Y.; Onohara, Y.; Takeo, M.; Nakashima, K.; Matsubara, F.; Ito, T.; Yoshimoto, T. Crystal structure of aminopeptidase N (proteobacteria alanyl aminopeptidase) from Escherichia coli and conformational change of methionine 260 involved in substrate recognition[J]. J Biol Chem,2006,281(44):33664-33676.
[7]. Berman, H.M.; Westbrook, J.; Feng, Z. et al. The Protein Data Bank[J]. Nucleic Acids Res.,2000, 28(1):235-242.
[8]. Vajragupta, O.; Boonchoong, P.; Wongkrajang, Y. Comparative quantitative structure-activity study of radical scavengers[J]. Bioorg Med Chem,2000,8(11):2617-2628.
[9]. Cramer, R.D.; Patterson, D.E.; Bunce, J.D. Recent advances in comparative molecular field analysis (CoMFA)[J]. Prog Clin Biol Res.,1989,291(1):161-165.
[10]. SYBYL 7.0, Tripos Inc.:1699 South Hanley Rd., St. Louis, Missouri,63144.
[11]. Wang, Q.; Chen, M.Y.; Zhu, H.W.; Zhang, J.; Fang, H.; Wang, B.H.; Xu, W.F. Design, synthesis, and QSAR studies of novel lysine derives as amino-peptidase N/CD13 inhibitors[J]. Bioorganic & Medicinal Chemistry,2008,16(10):5473-5481.
[12]. Zhang, J.; Wang, Q.; Fang, H.; Xu, W. F.; Liu, A.; Du, G. H. Design, synthesis, inhibitory activity and SAR studies of hydrophosbi p-aminosalicylic acid derivatives as neuraminidase inhibitors[J]. Bioorg. Med. Chem.,2008,16(7):3839-3847.
[13]. Yang, K.; Wang, Q.; Su, L.; Fang, H.; Wang, X.; Gong, J.; Wang, B.; Xu, W. Design and synthesis of novel chloramphenicol amine derivatives as potent aminopeptidase N (APN/CD13) inhibitors[J]. Bioorganic & Medicinal Chemistry,2009,17(11):3810-3817.
[2]. Jeffery, C.J. Moonlighting proteins:old proteins learning new tricks[J]. Trends Genet 2003,19, 415-417.
[3]. Antczak, C; De, M.I.; Bauvois, B. Ectopeptidases in pathophysiology[J]. Bioessays 2001, 23(3):251-260.
[4]. Jung, K.; Pergande, M.; Wischke, U.W. Characterization of particulate and soluble variants of the brush-border enzymes alanine aminopeptidase, alkaline phosphatase and a-glutamyltransferase in human urine[J]. Biomed Biochim Acta 1984, 43(12):1357-1364.
[5]. Favaloro, E.J.; Browning, T.; Facey, D. CD13 (GP150; aminopeptidase N):predominant functional activity in blood is localized to plasma and is not cell-surface associated[J]. Exp Hematol,1993,27(13):1695-1701.
[6]. Kawai, M.; Otake, Y.; Hara, Y. High-molecular-mass isoform of aminopeptidase N/CD13 in serum from cholestatic patients[J]. Clinica Chimica Acta,2003,330(1-2):141-149.
[7]. Van Hensbergen, Y.; Broxterman, H.J.; Hanemaaijer, R.; Jorna, A.S.; Van Lent, N.A.; Verheul, H.M.; Pinedo, H.M.; Hoekman, K. Soluble aminopeptidase N/CD13 in malignant and nonmalignant effusions and intratumoral fluid[J]. Clin Cancer Res,2002,8(12):3747-3754.
[8]. Curnis, F.; Arrigoni, G.; Sacchi, A.; Fischetti, L.; Arap, W.; Pasqualini, R.; Corti, A. Differential binding of drugs containing the NGR motif to CD 13 isoforms in tumor vessels, epithelia, and myeloid cells[J]. Cancer Res,2002,62(3):867-874.
[9]. Hooper, N.M. Families of zinc metalloproteases[J]. FEBS Lett,1994,354(1):1-6.
[10]. Pfleiderer, G.; Celliers, P.G. Isolation of an aminopeptidase from kidney particles[J]. Biochem. Z.1963,339,186-189.
[11]. Bauvois, B.; Dauzonne, D. Aminopeptidase-N/CD13 (EC 3.4.11.2) inhibitors:chemistry, biological evaluations, and therapeutic prospects[J]. Med. Res. Rev,2006,26(1):88-130.
[12]. Riemann, D.; Kehlen, A.; Langner, J. CD13-not just a marker in leukemia typing[J]. Immunology Today,1999,20(2):83-88.
[13]. Razak, K.; Newland, A.C. The significance of aminopeptidases and haematopoietic cell differentiation[J]. Blood Rev,1992,6(4):243-250.
[14]. Firla, B.; Arndt, M; Frank, K.; Thiel, U.; Ansorge, S.; Tager, M.; Lendeckel, U. Extracellular cysteines define ectopeptidase (APN, CD13) expression and function[J]. Free Radical Biologyand Medicine,2002,32(7):584-595.
[15]. Vlahovic, P.; Stefanovic, V. Kidney ectopeptidases. Structure, functions and clinical significance[J]. Pathol Biol (Paris),1998,46(10):779-786.
[16]. Kotlo, K.; Shukla, S.; Tawar, U.; Skidgel, R.A.; Danziger, R.S. Aminopeptidase N reduces basolateral Na+-K+-ATPase in proximal tubule cells[J]. Am J Physiol Renal Physiol.,2007, 293(4):F1047-1053.
[17]. Noble, F.; Banisadr, G.:Jardinaud, F.; Popovici, T.; Lai-Kuen, R.; Chen, H.; Bischoff, L. Parsadaniantz, S.M.; Fournie-Zaluski, M.C.; Roques, B.P. First discrete autoradiographic distribution of aminopeptidase N in various structures of rat brain and spinal cord using the selective iodinated inhibitor [1251]RB 129[J]. Neuroscience,2001,105(2):479-488.
[18]. Waksman, G.; Bouboutou, R.; Devin, J.; Bourgoin, S.; Cesselin, F.; Hamon, M.; Fournie-Zaluski, M.-C.; Roques, B.P. In vitro and in vivo effects of kelatorphan on enkephalin metabolism in rodent brain[J]. European Journal of Pharmacology,1985,117(2): 233-243.
[19]. Montiel, J.L.; Cornille, F.; Roques, B.P.; Noble, F. Nociceptin/orphanin FQ metabolism:role of aminopeptidase and endopeptidase 24.15[J]. JNeurochem,1997,68(1):354-361.
[20]. Lerche, C; Vogel, L.K.; Shapiro, L.H.; Noren, O.; Sjostrom, H. Human aminopeptidase N is encoded by 20 exons[J]. Mamm Genome,1996,7(9):712-713.
[21]. Watt, V.M.; Willard, H.F. The human aminopeptidase N gene:isolation, chromosome localization, and DNA polymorphism analysis[J]. Hum Genet,1990,85(6):651-654.
[22]. Thompson, J.D.; Gibson, T.J.; Plewniak, F. The ClustalX windows interface:flexible strategies for multiple sequence alignment aided by quality analysis tools[J]. Nucleic Acids Res.,1997,24,4876-4882.
[23]. Rost, N.D.; Barrett, A.J. MEROPS:the peptidase database[J]. Nucl. Acida Res.2000, 28(1):323-325.
[24]. Sjostrom, H.; Noren, O.; Olsen, J. Structure and function of aminopeptidase N[J]. Adv Exp Med Biol 2000,47725-34.
[25]. Luciani, N.; Marie-Claire, C; Ruffet, E.; Beaumont, A.; Roques, B.P.; Fournie-Zaluski, M.-C. Characterization of Glu350 as a critical residue involved in the N-terminal amine binding site of aminopeptidase N (EC 3.4.11.2):Insights into Its Mechanism of Action[J]. Biochemistry,1998,37(2):686-692.
[26]. Grembecka, J.; Mucha, A.; Cierpicki, T; Kafarski, P. The most potent organophosphorus inhibitors of leucine aminopeptidase. structure-based design, chemistry, and activity[J]. Journal of Medicinal Chemistry,2003,46(13):2641-2655.
[27]. Onohara, Y.; Nakajima, Y.; Ito, K.; Xu, Y; Nakashima, K.; Ito, T; Yoshimoto, T. Crystallization and preliminary X-ray characterization of aminopeptidase N from Escherichia coli[J]. Acta Crystallogr Sect F Struct Biol Cryst Commun,2006,62(Pt 7): 699-701.
[28]. Ito, K.; Nakajima, Y; Onohara, Y; Takeo, M.; Nakashima, K.; Matsubara, F.; Ito, T.; Yoshimoto, T. Crystal structure of aminopeptidase N (proteobacteria alanyl aminopeptidase) from Escherichia coli and conformational change of methionine 260 involved in substrate recognition[J]. J Biol Chem,2006,281(44):33664-33676.
[29]. Addlagatta, A.; Gay, L.; Matthews, B.W. Structure of aminopeptidase N from Escherichia coli suggests a compartmentalized, gated active site[J]. Proc Natl Acad Sci U S A,2006, 103(36):13339-13344.
[30]. Nocek, B.; Mulligan, R.; Bargassa, M.; Collart, F.; Joachimiak, A. Crystal structure of aminopeptidase N from human pathogen Neisseria meningitidis[J]. Proteins:Structure, Function, and Bioinformatics,2007,70(1):273-279.
[31]. Rudberg, P.C.; Tholander, F.; Thunnissen, M.; Haeggstrom, J.Z. Leukotriene A(4) hydrolase/aminopeptidase-Glutamate 271 is a catalytic residue with specific roles in two distinct enzyme mechanisms[J]. Journal of Biological Chemistry,2002,277(2):1398-1404.
[32]. Jiang, W.; Bond, J.S. Families of metalloendopeptidases and their relationships[J]. FEBS Lett.,1992,572(2):100-114.
[33]. Hangauer, D.G.; Monzingo, A.F.; Matthews, B.W. An interactive computer graphics study of thermolysin-catalyzed peptide cleavage and inhibition by N-carboxymethyl dipeptides[J]. Biochemistry,1984,25(24):5730-5741.
[34]. Holmes, M.A.; Matthews, B.W. Binding of hydroxamic acid inhibitors to crystalline thermolysin suggests a pentacoordinate zinc intermediate in catalysis[J]. Biochemistry,1981, 20(24):6912-6920.
[35]. Mina-Osorio, P. The moonlighting enzyme CD13:old and new functions to target[J]. Trends in Molecular Medicine 2008,14,(8) 361-371.
[36]. Tomita, M.; Obara, H.; Takesue, Y.; Tamura, H.; Miyajima, S.; Taguchi, R.; Ikezawa, H. Purification of glycosylphosphatidylinositol-anchoring aminopeptidase N from the plasma membrane of larval midgut epithelial cells of the silkworm, Bombyx mori[J]. Int. J. Biochem.,1994,26(8):977-986.
[37]. Zini, S.; Fournie-Zaluski, M.C.; Chauvel, E.; Roques, B.P.; Corvol, P.; Llorens-Cortes, C. Identification of metabolic pathways of brain angiotensin Ⅱ and Ⅲ using specific aminopeptidase inhibitors:predominant role of angiotensin Ⅲ in the control of vasopressin release[J]. Proc Natl Acad Sci U S A,1996,93(21):11968-11973.
[38]. Lendeckel, U.; Arndt, M; Frank, K.; Wex, T.; Ansorge, S. Role of alanyl aminopeptidase in growth and function of human T cells (review) [J]. Int J Mol Med,1999,4(1):17-27.
[39]. Giros, B.; Gros, C.; Solhonne, B.; Schwartz, J.C. Characterization of aminopeptidases responsible for inactivating endogenous (Met5) enkephalin in brain slices using peptidase inhibitors and anti-aminopeptidase M antibodies[J]. Mol Pharmacol,1986,29(3):281-287.
[40]. Furuhashi, M.; Mizutani, S.; Kurauchi, O.; Kasugai, M.; Narita, O.; Tomoda, Y. In vitro degradation of opioid peptides by human placental aminopeptidase M[J]. Exp Clin Endocrinol,1988,92(2):235-237.
[41]. Miller, B.C.; Thiele, D.L.; Hersh, L.B.; Cottam, G..L. Methionine enkephalin is hydrolyzed by aminopeptidase N on CD4+ and CD8+ spleen T cells[J]. Archives of Biochemistry and Biophysics,1994,311(1):174-179.
[42]. Lendeckel, U.; Kahne, T.; Riemann, D.; Neubert, K.; Arndt, M.; Reinhold, D. Review:the role of membrane peptidases in immune functions[J]. Adv Exp Med Biol,2000,477,1-24.
[43]. Ahmad, S.; Wang, L.; Ward, P.E. Dipeptidyl(amino)peptidase IV and aminopeptidase M metabolize circulating substance P in vivo[J]. J Pharmacol Exp Ther,1992,260(3): 1257-1261.
[44]. Kanayama, N.; Kajiwara, Y.; Goto, J.; Maradny, E.; Maehara, K.; Andou, K.; Terao, T. Inactivation of interleukin-8 by aminopeptidase N (CD13) [J]. JLeukoc Biol,1995,57(1): 129-134.
[45]. Liotta, L.A.; Steeg, P.S. Cancer metastasis and angiogenesis:an imbalance of positive and negative regulation[J]. Cell,1991,64(2):327-336.
[46]. Menrad, A.; Speicher, D.; Wacker, J.; Herlyn, M. Biochemical and functional characterization of aminopeptidase N expressed by human melanoma cells[J]. Cancer Res, 1993,55(6):1450-1455.
[47]. Fujii, H.; Nakajima, M.; Saiki, I.; Yoneda, J.; Azuma, I.; Tsuruo, T. Human melanoma invasion and metastasis enhancement by high expression of aminopeptidase N/CD13[J]. Clin Exp Metastasis,1995,13(5):337-344.
[48]. Kitamura, Y; Watanabe, M; Komatsubara, S.; Sakata, Y. Urinary excretion of glycine prolile dipeptidile aminopeptidase,N-acetyl-β-D-glucosaminidase, alanine aminopeptidase and low molecular protein in patients with renal cell carcinoma[J]. Hinyokika Kiyo,1990, 36(5):535-539.
[49]. Ikeda, N.; Nakajima, Y.; Tokuhara, T.; Hattori, N.; Sho, M.; Kanehiro, H.; Miyake, M. Clinical significance of aminopeptidase N/CD 13 expression in human pancreatic carcinoma[J]. Clin Cancer Res,2003,9(4):1503-1508.
[50]. Hashida, H.; Takabayashi, A.; Kanai, M.; Adachi, M.; Kondo, K.; Kohno, N.; Yamaoka, Y.; Miyake, M. Aminopeptidase N is involved in cell motility and angiogenesis:Its clinical significance in human colon cancer[J]. Gastroenterology,2002,122(2):376-386.
[51]. Ishii, K.; Usui, S.; Sugimura, Y.; Yamamoto, H.; Yoshikawa, K.; Hirano, K. Inhibition of aminopeptidase N (APN) and urokinase-type plasminogen activator (uPA) by zinc suppresses the invasion activity in human urological cancer cells[J]. Biol Pharm Bull,2001, 24(3):226-230.
[52]. Carl-McGrath, S.; Lendeckel, U.; Ebert, M.; Wolter, A.B.; Roessner, A.; Rocken, C. The ectopeptidases CD 10, CD 13, CD26, and CD 143 are upregulated in gastric cancer[J]. Int J Oncol,2004,25(5):1223-1232.
[53]. Kehlen, A.; Lendeckel, U.; Dralle, H.; Langner, J.; Hoang-Vu, C. Biological significance of aminopeptidase N/CD13 in thyroid carcinomas[J]. Cancer Res,2003,63(23):8500-8506.
[54]. Riemann, D.; Gohring, B.; Langner, J. Expression of aminopeptidase N/CD13 in tumour-infiltrating lymphocytes from human renal cell carcinoma[J]. Immunology Letters, 1994,42(1-2):19-23.
[55]. Balog, T.; Marotti, T.; Sverko, V.; Marotti, M.; Krolo, I.; Rocic, B.; Karapanda, N. Enkephalin degradating enzymes in pheochromocytoma patients[J]. Oncol Rep,2003,10(1): 253-258.
[56]. Mitsui, T.; Nomura, S.; Itakura, A. Role of aminopeptidases in the blood pressure regulation[J]. Biol. Pharm. Bull,2004,27(6):768-771.
[57]. Dixon, J.; Kaklamanis, L.; Turley, H.; Hickson, I.D.; Leek, R.D.; Harris, A.L.; Gatter, K.C. Expression of aminopeptidase-N (CD 13) in normal tissues and malignant neoplasms of epithelial and lymphoid origin[J]. J Clin Pathol,1994,47(1):43-47.
[58]. Sato, Y. Role of aminopeptidase in angiogenesis[J]. Biol Pharm Bull,2004,27(6):772-776.
[59]. Ishii, K.; Usui, S.; Sugimura, Y; Yoshida, S.; Hioki, T.; Tatematsu, M; Yamamoto, H.; Hirano, K. Aminopeptidase N regulated by zinc in human prostate participates in tumor cell invasion[J]. International Journal of Cancer,2001,92(1):49-54.
[60]. Kido, A.; Krueger, S.; Haeckel, C; Roessner, A. Inhibitory effect of antisense aminopeptidase N (APN/CD13) cDNA transfection on the invasive potential of osteosarcoma cells[J]. Clin Exp Metastasis,2003,20(7):585-592.
[61]. Saiki,I.; Yoneda, J.; Azuma, I.; Fujii, H.; Abe, F.; Nakajima, M.; Tsuruo, T. Role of aminopeptidase N(CD13) in tumor-cell invasion and extracellular matrix degradation[J]. International Journal of Cancer,1993,54(1):137-143.
[62]. Hanahan, D.; Folkman, J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis[J]. Cell,1996,86(3):353-364.
[63]. Bhagwat, S.V.; Petrovic, N.; Okamoto, Y; Shapiro, L.H. The angiogenic regulator CD13/APN is a transcriptional target of Ras signaling pathways in endothelial morphogenesis[J]. Blood,2003,101(5):1818-1826.
[64]. Zetter, B.R. Angiogenesis and tumor metastasis[J]. Annu. Rev. Med,1998,49,407-424.
[65]. Bussolino, F.; Mantovani, A.; Persico, G. Molecular mechanisms of blood vessel formation[J]. Trends Biochem. Sci.,1997,22(7):251-256.
[66]. Santos, A.N.; Langner, J.; Herrmann, M.; Riemann, D. Aminopeptidase N/CD13 is directly linked to signal transduction pathways in monocytes[J]. Cellular Immunology,2000,201(1): 22-32.
[67]. Lohn, M.; Mueller, C.; Langner, J. Cell cycle retardation in monocytoid cells induced by aminopeptidase N (CD13)[J]. Leuk Lymphoma,2002,43(2):407-413.
[68]. Ansorge, S.; Schon, E.; Kunz, D. Membrane-bound peptidases of lymphocytes:functional implications[J]. Biomed Biochim Acta,1991,50(4-6):799-807.
[69]. Mishima, Y.; Matsumoto-Mishima, Y.; Terui, Y.; Katsuyama, M.; Yamada, M.; Mori, M.; Ishizaka, Y.; Ikeda, K.; Watanabe, J.; Mizunuma, N.; Hayasawa, H.; Hatake, K. Leukemic cell-surface CD13/aminopeptidase N and resistance to apoptosis mediated by endothelial cells[J]. J Natl Cancer Inst,2002,94(13):1020-1028.
[70].林茂芳；何静松；蔡真等.氨肽酶抑制剂Bestatin通过激活半胱天冬酶-3诱导HL-60细胞凋亡[J].中华血液学志2001,22(7)：348-350.
[71]. Pulido-Cejudo, G; Conway, B.; Proulx, P. Bestatin-mediated inhibition of leucine aminopeptidase may hinder HIV infection[J]. Antiviral Res.,1997,36(3):167-177.
[72]. Schiffmann, E.; Corcoran, B.A.; Wahl, S. N-formylmethionyl peptides as chemoattractants for leukocytes[J]. Proceedings of the National Academy of Sciences of the United States of America,1975,72(3):1059-1062.
[73]. Mechtersheimer, G.; Moller, P. Expression of aminopeptidase N (CD13) in mesenchymal tumors[J]. Am JPathol,1990,137(5):1215-1222.
[74]. Look, A.T.; Ashmun, R.A.; Shapiro, L.H.; Peiper, S.C. Human myeloid plasma membrane glycoprotein CD13 (gp150) is identical to aminopeptidase N[J]. J Clin Invest,1989,83(4): 1299-1307.
[75]. Li, B.X.; Ge, J.W.; Li, Y.J. Porcine aminopeptidase N is a functional receptor for the PEDV coronavirus[J]. Virology,2007,365(1):166-172.
[76]. Soderberg, C; Giugni, T.D.; Zaia, J.A.; Larsson, S.; Wahlberg, J.M.; Moller, E. CD13 (human aminopeptidase N) mediates human cytomegalovirus infection[J]. J Virol,1993, 67(11):6576-6585.
[77]. Marotti, T.; Balog, T.; Munic, V.; Sobocanec, S.; Abramic, M. The link between met-enkephalin-induced down-regulation of APN activity and the release of superoxide anion[J]. Neuropeptides,2000,34(2):121-128.
[78]. Noble, F.; Smadja, C.; Valverde, O.; Maldonado, R.; Coric, P.; Turcaud, S.; Fournie-Zaluski, M.-C; Roques, B.P. Pain-suppressive effects on various nociceptive stimuli (thermal, chemical, electrical and inflammatory) of the first orally active enkephalin-metabolizing enzyme inhibitor RB 120[J]. Pain,1997,73(3):383-391.
[79]. Gros, C.; Giros, B.; Schwartz, J.C. Identification of aminopeptidase M as an enkephalin-inactivating enzyme in rat cerebral membranes. Biochemistry,1985,24(9): 2179-2185.
[80]. Hattori, A. Processing of antigenic peptides by aminopeptidases[J]. Biol. Pharm. Bull.,2004, 27(6):777-780.
[81]. Bedir, A.; Ozener, I.C.; Emerk, K. Urinary leucine aminopeptidase is a more sensitive indicator of early renal damage in non-insulin-dependent diabetics than microalbuminuria[J]. Nephron,1996,74(1):110-113.
[82]. Shimizu, T.; Tani, K.; Hase, K.; Ogawa, H.; Huang, L.; Shinomiya, F.; Sone, S. CD13/aminopeptidase N-induced lymphocyte involvement in inflamed joints of patients with rheumatoid arthritis[J]. Arthritis & Rheumatism,2002,46(9):2330-2338.
[83]. Sloane, P.D.; Zimmerman, S.; Suchindran, C. The public health impact of Alzheimer's disease,2000-2050:potential implication of treatment advances[J]. Annu. Rev. Public Health.,2002,23:(213-231).
[84]. Xu, Y.; Wellner, D.; Scheinberg, D.A. Substance P and bradykinin are natural inhibitors of CD13/Aminopeptidase N[J]. Biochemical and Biophysical Research Communications,1995, 208(2):664-674.
[85]. Curnis, F.; Sacchi, A.; Borgna, L.; Magni, F.; Gasparri, A.; Corti, A. Enhancement of tumor necrosis factor alpha antitumor immunotherapeutic properties by targeted delivery to aminopeptidase N (CD13)[J]. Nat Biotechnol,2000,18(11):1185-1190.
[86]. Ichinose, Y.; Genka, K.; Koike, T. Randomized double-blind placebo-controlled trial of Bestatin in patients with resected stage I squamous-cell lung carcinoma[J]. J. Natl. Cancer Inst.,2003,95(8):605-610.
[87]. Curnis, F.; Gasparri, A.; Sacchi, A.; Cattaneo, A.; Magni, F.; Corti, A. Targeted delivery of IFN-γ to tumor vessels uncouples antitumor from counterregulatory mechanisms[J]. Cancer Res,2005,65(7):2906-2913.
[88]. Lendeckel, U.; Kahne, T.; Riemann, D.; Neubert, K.; Arndt, M.; Reinhold, D. The role of membrane peptidases in immune functions[J]. Adv Exp Med Biol,2000,477,1-24.
[89]. Sedo, A.; Vlasicova, K.; Bartak, P.; Vespalec, R.; Vicar, J.; Simanek, V.; Ulrichova, J. Quaternary benzo[c].phenanthridine alkaloids as inhibitors of aminopeptidase N and dipeptidyl peptidase Ⅳ[J]. Phytother Res,2002,76(1):84-87.
[90]. Umezawa, H.; Aoyagi, T; Suda, H. Bestatin, an inhibitor of aminopeptidase B, produced by actinomycetes[J]. J. Antibiot.,1976,29(1):97-99.
[91]. Ota, K.; Kurita, S. Immunotherapy with bestatin for acute non-Lymphocytic Leukemia(ANLL)in adults[J]. Jpn. J. Cancer Chemother.,1984,11(2):2442-2750.
[92]. Leyhausen, G.; Schuster, D.K.; Vaith, P.; Zahn, R.K.; Umezawa, H.; Falke, D.; Muller, W.E. Identification and properties of the cell membrane bound leucine aminopeptidase interacting with the potential immunostimulant and chemotherapeutic agent bestatin[J]. Biochem Pharmacol,1983,32(6):1051-1057.
[93]. Matsas, R.; Stephenson, S.L.; Hryszko, J.; Kenny, A.J.; Turner, A.J. The metabolism of neuropeptides. Phase separation of synaptic membrane preparations with Triton X-114 reveals the presence of aminopeptidase N[J]. Biochem J.,1985,231(2):445-449.
[94]. Wilkes, S.H.; Prescott, J.M. The slow, tight binding of bestatin and amastatin to aminopeptidases[J]. J Biol Chem,1985,260(24):13154-13162.
[95]. Harbeson, S.L.; Rich, D.H. Inhibition of arginine aminopeptidase by bestatin and arphamenine analogs. Evidence for a new mode of binding to aminopeptidases[J]. Biochemistry,1988,27(19):7301-7310.
[96]. Tieku, S.; Hooper, N.M. Inhibition of aminopeptidases N, A and W. A reevaluation of the actions of bestatin and inhibitors of angiotensin converting enzyme[J]. Biochem. Pharmacol.,1992,44(9):1725-1730.
[97]. Schalk, C; d'Orchymont, H.; Jauch, M. F.; Tarnus, C.3-Amino-2-tetralone derivatives: novel potent and selective inhibitors of aminopeptidase-M (EC 3.4.11.2)[J]. Arch Biochem Biophys,1994,311(1):42-46.
[98]. Tarnus, C; Orchymont, H.3-Amino-2-hydroxy-propionaldehyde and 3-amino-1- hydroxypropan-2-one derivatives:New classes of aminopeptidase inhibitors[J]. Bioorg Med Chem,1996,4(8):1287-1297.
[99]. Lee, J.; Shim, J.S.; Jung, S.A.; Lee, S.T.; Kwon, H.J.N-Hydroxy-2-(naphthalene-2-ylsulfanyl)-acetamide, a novel hydroxamic acid-based inhibitor of aminopeptidase N and its anti-angiogenic activity [J]. Bioorganic & Medicinal Chemistry Letters,2005,15(1): 181-183.
[100].Melzig, M.F.; Bormann, H. Betulinic acid inhibits aminopeptidase Nactivity[J]. Planta Med, 1998,64(7):655-657.
[101].Shim, J.S.; Kim, J.H.; Cho, H.Y.; Yum, Y.N.; Kim, S.H.; Park, H.J.; Shim, B.S.; Choi, S.H.; Kwon, H.J. Irreversible inhibition of CD13/Aminopeptidase N by the antiangiogenic agent curcumin[J]. Chemistry & Biology,2003,10(8):695-704.
[102].Ahmad, S.; Ward, P.E. Role of aminopeptidase activity in the regulation of the pressor activity of circulating angiotensins[J]. J Pharmacol Exp Ther,1990,252(2):643-650.
[103].Kobayashi, S.; Isobe, T.; Ohno, M.A stereocontrolled synthesis of (-)-bestatin from an acyclic allylamine by iodocyclocarbamation[J]. Tetrahedron Lett,1984,25(44):5079-5082.
[104]. Pearson, W.H.; Hines, J.V. Synthesis of β-amino-α-hydroxy acids via aldol condensation of a chiral glycolate enolate. Synthesis of (-)-bestatin[J]. J Org Chem,1989,54(17): 4235-4237.
[105]. Suda, H.; Takita, T.; Aoyagi, T.; Umezawa, H. The chemical synthesis of bestatin[J]. J Antibiot,1976,29(5):600-601.
[106]. Wasserman, H.H.; Xia, M.; Petersen, A.K.; Jorgensen, M.R.; Curtis, E.A. Synthesis of the peptidic α-hydroxy amides phebestin, probestin, and bestatin from a-keto amide precursors[J]. Tetrahedron Lett,1999,40(34):6163-6166.
[107].Bergmeier, S.C.; Stanchina, D.M. Acylnitrene route to vicinal amino alcohols. Application to the synthesis of (-)-bestatin and analogues[J]. Journal of Organic Chemistry,1999,64(8): 2852-2859.
[108].Nemoto, H.; Ma, R.; Suzuki, I.; Shibuya, M. A new one-pot method for the synthesis of α-siloxyamides from aldehydes or ketones and its application to the synthesis of (-)-bestatin[J]. Org Lett,2000,2(26):4245-4247.
[109].Righi, G.; Achille, C.; Pescatore, G.; Bonini, C. New stereoselective synthesis of the peptidic aminopeptidase inhibitors bestatin, phebestin and probestin[J]. Tetrahedron Lett,2003, 44(37):6999-7002.
[110].Wasserman, H.H.; Petersen, A.K.; Xia, M. Application of acyl cyanophosphorane methodology to the synthesis of protease inhibitors:Poststatin, eurystatin, phebestin, probestin, and bestatin[J]. Tetrahedron,2003,59(35):6771-6784.
[111].Lee, J.H.; Lee, B.W.; Jang, K.C.; Jeong, I.Y.; Yang, M.S.; Lee, S.G.; Park, K.H. Chirospecific synthesis of the(2S,3R)-and(2S,3S)-3-amino-2-hydroxy-4-phenylbutanoic acids from sugar:Application to (-)-bestatin[J]. Synthesis,2003,6(6):829-836.
[112].Nishizawa, R.; Saino, T.; Takita, T; Suda, H.; Aoyagi, T; Umezawa, H. Synthesis and structure-activity relations of bestatin analogs, inhibitors of aminopeptidase B[J]. Journal of Medicinal Chemistry,1977,20(4):510-515.
[113].Saino, T.; Seya, K.; Nishizawa, R.; Takita, T.; Aoyagi, T.; Umezawa, H. Synthesis of p-hydroxyubenimex[J]. J Antibiot,1987,40(8):1165-1169.
[114]. Ocain, T.D.; Rich, D.H. Synthesis of sulfur-containing analogues of bestatin. Inhibition of aminopeptidases by alpha-thiolbestatin analogues[J]. J Med Chem,1988,31(11): 2193-2199.
[115].Gordon, E.M.; Godfrey, J.D.; Delaney, N.G.; Asaad, M.M.; Von, L.D.; Cushman, D.W. Design of novel inhibitors of aminopeptidases[J]. Synthesis of peptide-derived diamino thiols and sulfur replacement analogues of bestatin. J Med Chem,1988,31(11):2199-2211.
[116].Murray, H.; Turner, A.J.; Kenny, A.J. The aminopeptidase activity in the human T-cell lymphoma line (Jurkat) is not at the cell surface and is not aminopeptidase N (CD-13)[J]. Biochem J,1994,298 (Pt 2):353-360.
[117].Aoyagi, T.; Tobe, H.; Kojima, F. Amastatin, an inhibitor of aminopeptidase A, produced by actinomycetes[J]. J. Antibiot.,1978,31(6):636-638.
[118]. Tobe, H.; Morishima, H.; Naganawa, H.; Takita, T.; Aoyagi, T.; Umezawa, H. Structure and chemical synthesis of amastatin[J]. Agric Biol Chem,1979,43(3):591-596.
[119].Rich, D.H.; Moon, B.J.; Boparai, A.S. Synthesis of (2S,3R)-3-amino-2-hydroxy-5-methylhexanoic acid derivatives. Application to the synthesis of amastatin, an inhibitor of aminopeptidase[J]. J Org Chem,1980,45(12):2288-2290.
[120].Tobe, H.; Morishima, H.; Aoyagi, T.; Umezawa, H.; Ishiki, K.; Nakamura, K.; Yoshioka, T.; Shimauchi, Y.; Inui, T. Synthesis and structure-activity relationships of amastatin analogues, inhibitors of aminopeptidase A[J]. Agric Biol Chem,1982,46(7):1865-1872.
[121].Repic, L. B.; Kidric, J.; Kralj, B. Lapstatin, a new aminopeptidase inhibitor produced by Streptomyces rimosus, inhibits autogenous aminopeptidases[J]. Arch. Microbiol,1999, 171(6):397-404.
[122].Aoyagi, T.; Yoshida, S.; Nakamura, Y; Shigihara, Y; Hamada, M.; Takeuchi, T. Probestin, a new inhibitor of aminopeptidase M, produced by Streptomyces azureus MH663-2F6. I. Taxonomy, production, isolation, physico-chemical properties and biological activities[J]. J Antibiot (Tokyo),1990,43(2):143-148.
[123].Nagai, M.; Kojima, F.; Naganawa, H.; Hamada, M.; Aoyagi, T.; Takeuchi, T. Phebestin, a new inhibitor of aminopeptidase N, produced by Streptomyces sp. MJ716-m3[J]. J Antibiot (Tokyo),1997,50(1):82-84.
[124].Chung, M.C.; Lee, H.J.; Chun, H.K.; Lee, C.H.; Kim, S.I.; Kho, Y.H. Bestatin analogue from Streptomyces neyagawaensis SL-387[J]. Biosci Biotechnol Biochem,1996,60(5): 898-900.
[125].Chung, M.C.; Chun, H.K.; Han, K.H.; Lee, H.J.; Lee, C.H.; Kho, Y.H. MR-387A and B, new aminopeptidase N inhibitors, produced by Streptomyces neyagawaensis SL-387[J]. J Antibiot (Tokyo) 1996,49(1):99-102.
[126].Chung, M.C.; Lee, C.H.; Lee, H.J.; Kho, YH.; Chun, H.K. Biosynthesis of peptide inhibitor MR-387 by Streptomyces neyagawaensis[J]. Biotechnol Lett,1997,19(7):607-610.
[127].Yoshida, S.; Aoyagi, T.; Takeuchi, T. Biosynthetic study of leuhistin, a new inhibitor of aminopeptidase M[J]. J Antibiot (Tokyo),1991,44(6):683-684.
[128].Aoyagi, T.; Yoshida, S.; Matsuda, N.; Ikeda, T.; Hamada, M.; Takeuchi, T. Leuhistin, a new inhibitor of aminopeptidase M, produced by Bacillus laterosporus BMI156-14F1. I. Taxonomy, production, isolation, physico-chemical properties and biological activities[J]. J Antibiot (Tokyo),1991,44(6):573-578.
[129].Yoshida, S.; Naganawa, H.; Aoyagi, T.; Takeuchi, T.; Takeuchi, Y.; Kodama, Y. Leuhistin, a new inhibitor of aminopeptidase M, produced by Bacillus laterosporus BMI156-14F1.11. Structure determination of leuhistin[J]. J Antibiot (Tokyo),1991,44(6):579-581.
[130].Gordon, J.J.; Kelly, B.K.; Miller, GA. Actinonin:An antibiotic substance produced by an actinomycete[J]. Nature,1962,195:701-702.
[131].Egan, M.E.; Pearson, M.; Weiner, S.A. Curcumin, a major constituent of turmeric, corrects cystic fibrosis defects[J]. Science 2004,304(5670):600-602.
[132].Arabshahi, L.; Schmitz, F. J. Brominated tyrosine metabolites from an unidentified sponge[J]. J Org Chem,1987,52(16):3584-3586.
[133].Shim, J.S.; Lee, H.S.; Shin, J.; Kwon, H.J. Psammaplin A, a marine natural product, inhibits aminopeptidase N and suppresses angiogenesis in vitro[J]. Cancer Letters,2004,203(2): 163-169.
[134].Yamamoto, Y.; Li, Y.H.; Ushiyama, I.; Nishimura, A.; Ohkubo, I.; Nishi, K. Puromycin-sensitive alanyl aminopeptidase from human liver cytosol:purification and characterization[J]. Forensic Science International,2000,113(1-3):143-146.
[135].Kakuta, H.; Tanatani, A.; Nagasawa, K.; Hashimoto, Y. Specific nonpeptide inhibitors of puromycin-sensitive aminopeptidase with a 2,4(1 H,3H)-quinazolinedione skeleton[J]. Chem Pharm Bull (Tokyo),2003,57,(11) 1273-1282.
[136].Chen, H.X.; Roques, B.P.; Fournie-Zaluski, M.C. Design of the first highly potent and selective aminopeptidase N (EC 3.4.11.2) inhibitor[J]. Bioorganic & Medicinal Chemistry Letters,1999,9(11):1511-1516.
[137].Chen, H.; Bischoff, L.; Fournie-Zaluski, M.C.; Roques, B.P. Synthesis of 2(S)-benzyl-3-[hydroxy(1prime(R)-aminoethyl)phosphinyl]propanoyl-L-3-iodotyrosine:a radiolabelled inhibitor of aminopeptidase N[J]. Journal of Labelled Compounds and Radiopharmaceuticals,2000,43(2):103-111.
[138].Chen, H.; Noble, F.; Coric, P.; Fournie-Zaluski, M.C.; Roques, B.P. Aminophosphinic inhibitors as transition state analogues of enkephalin-degrading enzymes:a class of central analgesics[J]. Proc Natl Acad Sci USA,1998,95(20):12028-12033.
[139].Grembecka, J.; Mucha, A.; Cierpicki, T.; Kafarski, P. The most potent organophosphorus inhibitors of leucine aminopeptidase. Structure-based design, chemistry, and activity[J]. J Med Chem,2003,46(13):2641-2655.
[140].Georgiadis, D.; Vazeux, G.; Llorens-Cortes, C.; Yiotakis, A.; Dive, V. Potent and selective inhibition of zinc aminopeptidase A (EC 3.4.11.7, APA) by glutamyl aminophosphinic peptides:Importance of glutamylaminophosphinic residue in the P1 position[J]. Biochemistry,2000,39,(15) 1152-1155.
[141].Vassiliou, S.; Xeilari, M.; Yiotakis, A.; Grembecka, J.; Pawelczak, M.; Kafarski, P.; Mucha, A. A synthetic method for diversification of the P1'substituent in phosphinic dipeptides as a tool for exploration of the specificity of the S1'binding pockets of leucine aminopeptidases[J]. Bioorganic & Medicinal Chemistry,2007,15(9):3187-3200.
[142].Grzywa, R.; Oleksyszyn, J. First synthesis of α-aminoalkyl-(N-substituted)thiocarbamoyl-phosphinates:Inhibitors of aminopeptidase N (APN/CD13) with the new zinc-binding group[J]. Bioorganic& Medicinal Chemistry Letters,2008,18(13):3734-3736.
[143].Roques, B.P.; Noble, F. Dual inhibitors of enkephalin-degrading enzymes (neutral endopeptidase 24.11 and aminopeptidase N) as potential new medications in the management of pain and opioid addiction[J]. NIDA Res Monogr,1995,147,104-145.
[144].Penning, T.D.; Askonas, L.J.; Djuric, S.W.; Haak, R.A.; Yu, S.S.; Michener, M.L.; Krivi, G.G.; Pyla, E.Y. Kelatorphan and related analogs:Potent and selective inhibitors of leukotriene A4 hydrolase[J]. Bioorg Med Chem Lett,1995,5(21):2517-2522.
[145].Chen, H.; Noble, F.; Roques, B.P.; Fournie-Zaluski, M.C. Long lasting antinociceptive properties of enkephalin degrading enzyme (NEP and APN) inhibitor prodrugs[J]. J Med Chem,2001,44(21):3523-3530.
[146].Roques, B.P. Insights into peptide and protein function:A convergent approach[J]. J Pept Sci,2001,7(2):63-73.
[147].Flipo, M.; Beghyn, T.; Charton, J.; Leroux, V.A.; Deprez, B.P.; Deprez-Poulain, R.F. A library of novel hydroxamic acids targeting the metallo-protease family:Design, parallel synthesis and screening[J]. Bioorganic & Medicinal Chemistry,2007,15(1):63-76.
[148]. Wang, J.; Xu, W. The preparation of novel L-iso-glutamine derivativesas potential antitumor agents[J]. J. Chem. Res. Synop.,2003,12, (789-791).
[149].Li, Q.; Fang, H.; Xu, W. Novel 3-galloylamido-N'-substituted-2,6-piperidinedione-N-acetamide peptidomimetics as metalloproteinase inhibitors[J]. Bioorg.Med.Chem.Letters, 2007,17(10):2935-2938.
[150].Mou, J.J.; Fang, H.; Jing, F.B.; Wang, Q.; Liu, Y.Z.; Zhu, H.W.; Shang, L.Q.; Wang, X.J.; Xu, W.F. Design, synthesis and primary activity evaluation of L-arginine derivatives as amino-peptidase N/CD13 inhibitors[J]. Bioorg.Med. Chem.,2009,17(13):4666-4673.
[151].Wang, Q.; Chen, M.Y.; Zhu, H.W.; Zhang, J.; Fang, H.; Wang, B.H.; Xu, W.F. Design, synthesis, and QSAR studies of novel lysine derives as amino-peptidase N/CD13 inhibitors[J]. Bioorganic & Medicinal Chemistry,2008,16(10):5473-5481.
[152].Fournie-Zaluski, M.C.; Coric, P.; Turcaud, S.; Bruetschy, L.; Lucas, E.; Noble, F.; Roques, B.P. Potent and systemically active aminopeptidase N inhibitors designed from active-site investigation[J]. Journal of Medicinal Chemistry,1992,35(7):1259-1266.
[153].Gros, C.; Giros, B.; Schwartz, J.C.; Vlaiculescu, A.; Costentin, J.; Lecomte, J.M. Potent inhibition of cerebral aminopeptidases by carbaphethiol, a parenterally active compound[J]. Neuropeptides,1988,12(3):111-118.
[154].Reaux, A.; de Mota, N.; Zini, S.; Cadel, S.; Fournie-Zaluski, M.C.; Roques, B.P.; Corvol, P.; Llorens-Cortes, C.PC 18, a specific aminopeptidase N inhibitor, induces vasopressin release by increasing the half-life of brain angiotensin Ⅲ[J]. Neuroendocrinology,1999,69(5): 370-376.
[155].Chauvel, E.N.; Coric, P.; Llorens-Cortes, C; Wilk, S.; Roques, B.P.; Fournie-Zaluski, M.C. Investigation of the active site of aminopeptidase A using a series of new thiol-containing inhibitors[J]. Journal of Medicinal Chemistry.,1994,37(9):1339-1346.
[156].Chauvel, E.N.; Llorens-Cortes, C; Coric, P.; Wilk, S.; Roques, B.P.; Fournie-Zaluski, M.C. Differential Inhibition of aminopeptidase A and aminopeptidase N by new β-Amino thiols[J]. Journal of Medicinal Chemistry,1994,37(18):2950-2957.
[157].Reaux, A.; Iturrioz, X.; Vazeux, G.; Fournie-Zaluski, M.C.; David, C.; Roques, B.P.; Corvol, P.; Llorens-Cortes, C. Aminopeptidase A, which generates one of the main effector peptides of the brain renin-angiotensin system, angiotensin Ⅲ, has a key role in central control of arterial blood pressure[J]. Biochem Soc Trans,2000,28(4):435-440.
[158].Noble, F.; Soleilhac, J.M.; Soroca-Lucas, E.; Turcaud, S.; Fournie-Zaluski, M.C.; Roques, B.P. Inhibition of the enkephalin-metabolizing enzymes by the first systemically active mixed inhibitor prodrug RB 101 induces potent analgesic responses in mice and rats. Journal of Pharmacology and Experimental Therapeutics,1992,261(1):181-190.
[159].Shenvi, A.B. α-Aminoboronic acid derivatives:Effective inhibitors of aminopeptidases. Biochemistry,1986,25(6):1286-1291.
[160].Andersson, L.; Isley, T.C.; Wolfenden, R. α-Aminoaldehydes:transition state analog inhibitors of leucine aminopeptidase. Biochemistry,1982,21(17):4177-4180.
[161]Jahreis, G.; Fittkau, S.; Aurich, H. α-Aminomethylketones as inhibitors of a membrane-bound alanine aminopeptidase. Biomed Biochim Acta.,1987,46(10):683-686.
[162]. Ocain, T.D.; Rich, D.H. a-Keto amide inhibitors of aminopeptidases. J. Med. Chem.,1992, 35(3):451-456.
[163]. Ma, T.; Xu, W.F.; Wang, J.L.; Yuan, Y.M. Design, synthesis and anti-cancer activity of AHPA derivatives. Chinese J Med Chem,2003,13(2):70-75.
[164].Miyachi, H.; Kato, M.; Kato, F.; Hashimoto, Y. Novel potent nonpeptide aminopeptidase N inhibitors with a cyclic imide skeleton. Journal of Medicinal Chemistry,1998,41(3): 263-265.
[165].Takahashi, H.; Komoda, M.; Kakuta, H.; Hashimoto, Y. Preparation of novel specific aminopeptidase inhibitors with a cyclic imide skeleton. Yakugaku Zasshi,2000,120(10): 909-921.
[166].Shimazawa, R.; Takayama, H.; Kato, F.; Kato, M.; Hashimoto, Y. Nonpeptide small-molecular inhibitors of dipeptidyl peptidase Ⅳ:N-phenylphthalimide analogs. Bioorganic & Medicinal Chemistry Letters,1999,9(4):559-562.
[167].Komoda, M.; Kakuta, H.; Takahashi, H.; Fujimoto, Y.; Kadoya, S.; Kato, F.; Hashimoto, Y. Specific inhibitor of puromycin-sensitive aminopeptidase with a homophthalimide skeleton: Identification of the target molecule and a structure-activity relationship study. Bioorg Med Chem,2001,9(1):121-131.
[168].Lindsay, C.K.; Gomez, D.E.; Thorgeirsson, U.P. Effect of flavone acetic acid on endothelial cell proliferation:evidence for antiangiogenic properties Anticancer Res,1996,16(1): 425-431.
[169].Bibby, M.C.; Double, J.A. Flavone acetic acid from laboratory to clinic and back. AntiCancer Drugs,1993,4(1):3-17.
[170].Parellada, J.; Suarez, G; Guinea, M. Inhibition of zinc metallopeptidases by flavonoids and related phenolic compounds:Structure-activity relationships. J Enzyme Inhib,1998,13(5): 347-359.
[171].Bormann, H.; Melzig, M.F. Inhibition of metallopeptidases by flavonoids and related compounds. Pharmazie,2000,55(2):129-132.
[172].Ehrlich, J.; Bartz, Q.R.; Smith, R.M.; Joslyn, D.A.; Burkholder, P.R. Chloromycetin, a new antibiotic from a soil actinomycete. Science,1947,106,417.
[173].Shin, W.; Pyo, M. The crystal and molecular structure of chloramphenicol base. Bull Kor Chem Soc,1984,5(4):158-162.
[174].Liu, Z.S.; Fang, Z.L. Combination of flow injection with capillary electrophoresis. Part 2. chiral separation of intermediate enantiomers in chloramphenicol synthesis. Anal Chim Acta, 1997,353(2):199-205.
[175].Sachchidananda, B.; Sankar, B.P.; Chandan, M. Inhibition of rat liver mitochondrial monoamine oxidase by chloramphenicol and 2-amino-1-p-nitrophenylpropane-1,3-diol. J Pharm Sci,1978,67(4):480-482.
[176].Shatilo, V.A.; Zaritskii, A.M.; Kudrya, T.N.; Shtepanek, A.S. Effect of 1-(p-nitrophenyl)-2-amino-1,3-propanediol and β-chloroethyl-phosphonic acid derivatives on growth of enterobacteria. Mikrobiologicheskii Zhurnal,1984,46(4):39-42.
[177].Kudrya, T.N.; Karabanov, Y.V.; Shtepanek, A.S. N-dialkyl-substituted derivatives of 1-[(p-nitrophenyl)-2-amino]ethanol and 1,3-propanediols and their physiological activity. Fiziologicheski Aktivnye Veshchestva,1981,13,64-66.
[178].Hazra, B.G; Pore, V.S.; Dey, S.K.; Datta, S.; Darokar, M.P.; Saikia, D.; Khanujab, S.S.; Thakura, A. Bile acid amides derived from chiral amino alcohols:novel antimicrobials and antifungals. Bioorg Med Chem Lett,2004,14(3):773-777.
[179].Kudrya, T.N.; Protopopova, G.V.; Reidalova, L.I.; Lagoshina, N.S.; Telyuk, V.G. Phosphorylated derivatives of 1-(p-nitrophenyl)-2-amino-1,3-propanediol(d,l-threo form)and their physiological activity. Fiziologicheski Aktivnye Veshchestva,1980,12, 22-25.
[180].Drainas, D.; Petros, M.; Coutsogeorgopoulos, C. Aminoacyl analogs of chloramphenicol: examination of the kinetics of inhibition of peptide bond formation. J Med Chem,1993, 36(23):3542-3545.
[181].Johansson, D.; Jessen, C.H.; Pohlsgaard, J.; Jensen, K.B.; Vester, B.; Pedersena, E.B.; Nielsen, P. Design, synthesis and ribosome binding of chloramphenicol nucleotide and intercalator conjugates. Bioorg Med Chem Lett,2005,75(8):2079-2083.
[182].金道忠；朱兴族.神经酰胺代谢及凋亡信号调节.生命科学，2006,18(5)：481-486.
[183].Murakami, T.; Furusawa, K.; Tamai, T.,; Yoshikai, K.; Nishikawa, M. Synthesis and biological properties of novel sphingosine derivatives. Bioorg Med Chem Lett,2005,15(4): 1115-1119.
[184].Selzner, M.; Bielawska, A.; Morse, M.A.; Rudiger, H.A.; Sindram, D.; Hannun, Y.A.; Clavien, P.A. Induction of apoptotic cell death and prevention of tumor growth by ceramide analogues in metastatic human colon cancer. Cancer Res,2001,61(2):1233-1240.
[185].Szulc, Z.M.; Mayroo, N.; Bai, A.P.; Bielawski, J.; Liu, X.; Norris, J.S.; Hannuna, Y.A.; Bielawska, A. Novel analogs of D-e-MAPP and B13. Part 1:Synthesis and evaluation as potential anticancer agents. Bioorg Med Chem,2008,16(2):1015-1031.
[186].Bai, A.; Szulc, Z.M.; Bielawski, J.; Mayroo, N.; Liu, X.; Norris, J.; Hannun, Y.A.; Bielawska, A. Synthesis and bioevaluation of Ш-N-amino analogs of B13. Bioorg Med Chem, 2009,17,1840-1848.
[187].Mincione, F.; Starnotti, M.; Masini, E.; Bacciottini, L.; Scrivanti, C.; Casini, A.; Vullo, D.; Scozzafavad, A.; Supurand, C.T. Carbonic anhydrase inhibitors:Design of thioureido sulfonamides with potent isozyme Ⅱ and Ⅻ inhibitory properties and intraocular pressure lowering activity in a rabbit model of glaucoma. Bioorg Med Chem Lett,2005,15(17): 3821-3827.
[188].Vullo, D.; Steffansen, B.; Brodin, B.; Supuran, C.T.; Scozzafava, A.; Nielsen, C.U. Carbonic anhydrase inhibitors:Transepithelial transport of thioureido sulfonamide inhibitors of the cancer-associated isozyme IX is dependent on efflux transporters. Bioorg Med Chem,2006, 14(7):2418-2427.
[189].Lee, J.; Kwon, M.; Lee, K.H.; Jeong, S.; Hyun, S.; Shin, K.J.; Yu, J. An approach to enhance specificity against RNA targets using heteroconjugates of aminoglycosides and chloramphenicol(or linezolid). J Am Chem Soc,2004,126(7):1956-1957.
[1].陈凯先主编.计算机辅助药物设计：原理、方法及应用,上海科学技术出版社,2000.
[2].徐筱杰主编.计算机辅助药物分子设计,化学工业出版社,2004.
[3].叶德泳主编.计算机辅助药物设计导论,化学工业出版社,2004.
[4].徐文方主编.药物设计学,人民卫生出版社,2007.
[5].徐文方主编.新药设计与开发,科学出版社,2001.
[6]. Veselovsky, A.V.; Ivanov, A.S. Strategy of computer-aided drug design[J]. Curr Drug Targets Infect Disord,2003,5(1):33-40.
[7]. Reddy, C.S.; Vijayasarathy, K.; Srinivas, E. et al. Homology modeling of membrane proteins:a critical assessment[J]. Comput Biol Chem,2006,30(2):120-126.
[8]. DesJarlais, R.L.; Dixon, J.S. A shape-and chemistry-based docking method and its use in the design of HIV-1 protease inhibitors[J]. J. Comput. Aided Mol. Des.,1994,8,231-242.
[9]. Iwata, Y.; Arisawa, M; Hamada, R.; Kita, Y.; Mizutani, M.Y.; Tomioka, N.; Itai, A.; Miyamoto, S. Discovery of novel aldose reductase inhibitors using a protein structure-based approach:3d-database search followed by design and synthesis[J]. J. Med. Chem.2001,44, 1718-1728.
[10]. Enyedy, I.J.; Ling, Y.; Nacro, K.; Tomita, Y; Wu, X.; Cao, Y; Guo, R.; Li, B.; Zhu, X.; Huang, Y; Long, Y. Discovery of small-molecule inhibitors of Bcl-2 through structure-based computer screening[J]. J. Med. Chem.2001,44,4313-4378.
[11]. Cramer, R.D.; Patterson, D.E.; Bunce, I.D. Comparative molecular field analysis (CoMFA).1.Effect of shape on binding of steroids to carrier proteins[J]. J Am Chem Soc,1988,110:5959-5967.
[12]. Klebe, G; Abraham, U.; Mietzner, T. Molecular similarity indices in a comparative analysis (CoMSIA) of drug molecules to correlate and predict their biological activity[J]. J Med Chem,1994,57(24):4130-4146.
[13]. Onohara Y., Nakajima Y, Ito K. et al. Crystallization and preliminary X-ray characterization of aminopeptidase N from Escherichia coli[J]. Acta. Cryst.,2006,62(7):699-701.
[14]. Shang, L.; Fang, H.; Zhu, H.; Wang, X.; Wang, Q.; Mu, J.; Wang, B.; Kishioka, S.; Xu, W. Design, synthesis and SAR studies of tripeptide analogs with the scaffold 3-phenylpropane-1,2-diamine as aminopeptidase N/CD13 inhibitors[J]. Bioorganic & Medicinal Chemistry,2009,17(7):2775-2784.
[15]. Wang, Q.; Chen, M.Y.; Zhu, H.W.; Zhang, J.; Fang, H.; Wang, B.H.; Xu, W.F. Design, synthesis, and QSAR studies of novel lysine derives as amino-peptidase N/CD13 inhibitors[J]. Bioorganic & Medicinal Chemistry,2008,16(10):5473-5481.
[16]. Tarnus, C. Orchymont, H.3-Amino-2-hydroxy-propionaldehyde and 3-amino-1-hydroxypropan-2-one derivatives:New classes of aminopeptidase inhibitors[J]. Bioorg Med Chem 1996,4,(8) 1287-1297.
[17]. Hooper, N.M. Families of zinc metalloproteases[J]. FEBS Lett.,1994,354(1):1-6.
[18]. Addlagatta, A.; Gay, L.; Matthews, B.W. Structural basis for the unusual specificity of Escherichia coli aminopeptidase N[J]. Biochemistry,2008,47(19):5303-5311.
[19]. Yang, K.; Wang, Q.; Su, L.; Fang, H.; Wang, X.; Gong, J.; Wang, B.; Xu, W. Design and synthesis of novel chloramphenicol amine derivatives as potent aminopeptidase N (APN/CD13)inhibitors[J]. Bioorganic & Medicinal Chemistry 2009,17(11):3810-3817.
[20].杨二冰.李正名.药物分子设计中的Lipinski规则[J].化学通报,2006,69(1)：16-19.
[1]. Murakami, T.; Furusawa, K.; Tamai, T.; Yoshikai, K.; Nishikawa, M. Synthesis and biological properties of novel sphingosine derivatives[J]. Bioorg. Med. Chem. Lett.,2005,15, 1115-1119.
[2]. Jiang, Y.; Han, J.; Yu, C.; Vass, O.; Searle, P.; Browne, P.; Knox, R.; Hu, L. Design, synthesis, and biological evaluation of cyclic and acyclic nitrobenzylphosphoramide mustards for E. coli nitroreductase activation[J]. J. Med. Chem.2006,49,4333-4343.
[3]. Chellemi F. Synthesis by conventional methods of human growth hormone peptide fragments[J]. Int J Pept Protein Res,1975,7(2):43-48.
[4]. Ciriminna, R.; Bolm, C.; Fey, T.; Pagliaro, M. Sol-Gel ormosils doped with TEMPO as recyclable catalysts for the selective oxidation of alcohols[J]. Adv. Synth. Catal,2002, 344(2):159-163
[5]. Testa M.L.; Ciriminna, R.; Hajji, C; Garcia, E.Z.; Ciclosi, M.; Arques, J.S.; Pagliaro, M. Oxidation of amino diols mediated by homogeneous and heterogeneous TEMPO[J]. Advanced Synthesis & Catalysis,2004,346(6):655-660.
[6]. Jordis, U.; Sauter, F.; Siddiqi, S.M. Synthesis of (1S,4S)-2-thia-5-azabicyclo[2.2.1]heptane[J]. Indian J Chem Sec B,1989,28(4):294-296.
[7]. Kim, S.; Lee, J.I.; Kim, Y.C. A simple and mild esterification method for carboxylic acids using mixed carboxylic-carbonic anhydrides[J]. JOrg Chem,1985,50(5):560-565.
[8]. Rijkers, T.S.; Adams, H.P.H.M.; Hemker, H.C.; Tesser, G.I. A convenient synthesis of amino acid p-nitroanilides; synthons in the synthesis of protease substrates[J]. Tetrahedron,1995, 57(41):11235-11250.
[9]. Oyamada, H.; Saito, T.; Inaba, S.; Ueki, M. Reinvestigation of the phosphazo method and synthesis of N-(t-butoxycarbonyl)-L-arginine p-nitroanilide and a chromogenic enzyme substrate for the factor Xa[J]. Bull.Chem.Soc.Jpn.1991,64(4):1422-1424.
[10]. Wilhelm, P. α-Amino acid p-nitroanilides. Ger.1967, DE 1243204.
[11]. Spies, J.R. Dimorphism of formyl-d-and l-methionine and the effect of hrdrochloric acid on the rotation of d-and l-methionine[J]. JBiol Chem,1950,182(1):439-442.
[12]. Amblard, M.; Rodriguez, M.; Martinez, J.N-benzhydryl-glycolamide(OBg esters) as carboxyl protecting groups in peptide synthesis[J]. Tetrahedron,1988,44(16):5101-5108.
[13]. Roethle, P.A.; Hernandez, P.T.; Trauner, D. Exploring biosynthetic relationships among furanocembranoids:synthesis of (-)-bipinnatin j, (+)-intricarene, (+)-rubifolide, and (+)-isoepilophodione B[J]. Org. Lett,2006,8(25):5901-5904.
[14]. Magid, R.M.; Fruchey, O.S.; Johnson, W.L.; Allen, T.G.. Hexachloroacetone/triphenyl phosphine:a mild reagent for the regioselective and stereospecific production of allylic chlorides from the alcohols[J]. J. Org. Chem.1979,44(3):359-363.
[15]. Davis, N.J.; Flitscb, S.L. Selective oxidation of monosaccharide derivatives to uranic acids[J]. Tetrahedron,1993,34(1):1181-1184.
[16]. McKillop, A.; Richard, J.K. Taylor, et al. An improved procedure for the preparation of the garner aldehyde and its use for the synthesis of N-proteced 1-Halo-2-(R)-amino-3-butenes[J]. Syntheis,1994,31-33.
[17]. Hirschmann, R.; Strachan, R.G.; Schwam, H. The controlled synthesis of peptides in aqueous medium.3. Use of Leuchs' anhydrides in the synthesis of dipeptides. Mechanism and control of side reactions[J]. J Org Chem,1967,32(11):3415-3425.
[1]. Drag,M; Grembecka, J. α-Aminoalkylphosphonates as a tool in experimental optimisation of P1 side chain shape of potential inhibitors in S1 pocket of leucineand neutral aminopeptidases[J]. Eur. J. Med. Chem.2005,40(8):764-771.
[2].刘冰心.淡水鱼肌肉亮氨酸氨肽酶的分离纯化与性质研究[J].集美大学硕士学位论文，2007.
[3]. Kyrieleis, O.P.; Goettig, P.; Kiefersauer, R.; Huber, R.; Brandstetter, H. Crystal structures of the tricorn interacting factor F3 from thermoplasma acidophilum, a zinc aminopeptidase in three different conformations[J]. Journal of Molecular Biology,2005,349(4):787-800.
[4]. Beti, R.; Cattaneo, A.; Gabriel, J.M.; Ojha, M.A novel N-α-acetyl alanine aminopeptidase from allomyces arbuscula[J]. Biochimie,2002,84(4):309-319.
[5]. Shimizu, T.; Tani, K.; Hase, K.; Ogawa, H.; Huang, L.; Shinomiya, F.; Sone, S. CD13/aminopeptidase N-induced lymphocyte involvement in inflamed joints of patients with rheumatoid arthritis[J]. Arthritis & Rheumatism,2002,46(9):2330-2338.
[6]. Baragi, V.M.; Shaw, B.J.; Renkiewicz, R.R. A versatile assay for gelatinase using succinylated gelatin[J]. Anal. Biochem.2000,286(1):267-273.
[7]. Chappelet-tordo, D.; Lazdunski, C; Murgier, M.; Lazdunski, A. Aminopeptidase N from Escherichia coli.Ionizable active-center groups and substrate specificity [J]. European Journal of Biochemistry,1977,81(2):299-305.
[8]. Flipo, M.; Beghyn, T.; Charton, J.; Leroux, V.A.; Deprez, B.P.; Deprez-Poulain, R.F. A library of novel hydroxamic acids targeting the metallo-protease family:Design, parallel synthesis and screening[J]. Bioorganic & Medicinal Chemistry,2007,15(1):63-76.
[9]. Ito, K.; Nakajima, Y; Onohara, Y; Takeo, M.; Nakashima, K.; Matsubara, F; Ito, T.; Yoshimoto, T. Crystal structure of aminopeptidase N (proteobacteria alanyl aminopeptidase) from Escherichia coli and conformational change of methionine 260 involved in substrate recognition[J]. J Biol Chem,2006,281(44):33664-33676.
[10]. Nagai, M.; Kojima, F; Naganawa, H.; Hamada, M.; Aoyagi, T.; Takeuchi, T. Phebestin, a new inhibitor of aminopeptidase N, produced by Streptomyces sp. MJ716-m3[J]. J Antibiot (Tokyo), 1997,50,(1)82-84.
[11]. Aoyagi, T.; Yoshida, S.; Nakamura, Y; Shigihara, Y; Hamada, M.; Takeuchi, T. Probestin, a new inhibitor of aminopeptidase M, produced by Streptomyces azureus MH663-2F6.I. Taxonomy, production, isolation, physico-chemical properties and biological activities[J]. J Antibiot (Tokyo), 1990,43(2):143-148.
[12].何静松；林茂芳；麦文渊等.乌苯美司对人白血病细胞生长抑制及其机制探讨[J].浙江大学学报(医学版)2002,31(4)：259-264.
[13]. Sehine, K.; Fuji, H.; Abe, F. Induction of apoptosis by Bestatin (ubenimex) in human leukemic cell lines[J]. Leukemia,1999,13(5):729-734.
[14]. Urabe, A. Immunotherapy with bestatin for acute nonlympgocytic leukemia in adults[J]. Ann Hematol,1993,67,63-66.
[15].李海燕；方肇勤；梁尚华.小鼠移植性肝癌(H22)模型的研究及在中医药抗肿瘤中的应用[J].中国中医基础医学杂志，2000,6(1)：27-30.
[1]. FlexXTM is distributed by Tripos Inc.,1699 South Hanley Rd., St. Louis, Missouri, USA (http://www.tripos.com).
[2]. Rarey, M.; Kramer, B.; Lengauer, T.A fast Flexible docking method using an incremental construction algorithm[J]. J. Mol.Biol,1996,261,470-489.
[3]. BiopolymerTM is distributed by Tripos Inc.,1699 South Hanley Rd., St. Louis, Missouri, USA (http://www. tripos. com).
[4]. Kellenberger, E.; Rodrigo, J.; Muller, P. Comparative evaluation of eight docking tools for docking and virtual screening accuracy[J]. Proteins.,2004,57(2):225-242.
[5]. Hooper, N.M. Families of zinc metalloproteases[J]. FEBS Lett,1994,354(1):1-6.
[6]. Ito, K.; Nakajima, Y.; Onohara, Y.; Takeo, M.; Nakashima, K.; Matsubara, F.; Ito, T.; Yoshimoto, T. Crystal structure of aminopeptidase N (proteobacteria alanyl aminopeptidase) from Escherichia coli and conformational change of methionine 260 involved in substrate recognition[J]. J Biol Chem,2006,281(44):33664-33676.
[7]. Berman, H.M.; Westbrook, J.; Feng, Z. et al. The Protein Data Bank[J]. Nucleic Acids Res.,2000, 28(1):235-242.
[8]. Vajragupta, O.; Boonchoong, P.; Wongkrajang, Y. Comparative quantitative structure-activity study of radical scavengers[J]. Bioorg Med Chem,2000,8(11):2617-2628.
[9]. Cramer, R.D.; Patterson, D.E.; Bunce, J.D. Recent advances in comparative molecular field analysis (CoMFA)[J]. Prog Clin Biol Res.,1989,291(1):161-165.
[10]. SYBYL 7.0, Tripos Inc.:1699 South Hanley Rd., St. Louis, Missouri,63144.
[11]. Wang, Q.; Chen, M.Y.; Zhu, H.W.; Zhang, J.; Fang, H.; Wang, B.H.; Xu, W.F. Design, synthesis, and QSAR studies of novel lysine derives as amino-peptidase N/CD13 inhibitors[J]. Bioorganic & Medicinal Chemistry,2008,16(10):5473-5481.
[12]. Zhang, J.; Wang, Q.; Fang, H.; Xu, W. F.; Liu, A.; Du, G. H. Design, synthesis, inhibitory activity and SAR studies of hydrophosbi p-aminosalicylic acid derivatives as neuraminidase inhibitors[J]. Bioorg. Med. Chem.,2008,16(7):3839-3847.
[13]. Yang, K.; Wang, Q.; Su, L.; Fang, H.; Wang, X.; Gong, J.; Wang, B.; Xu, W. Design and synthesis of novel chloramphenicol amine derivatives as potent aminopeptidase N (APN/CD13) inhibitors[J]. Bioorganic & Medicinal Chemistry,2009,17(11):3810-3817.