两类糖苷类化合物和两类杂环化合物的设计、合成及其生物活性研究
|
摘要
当前,为寻找新的活性分子,通常都是采用合成化合物库的方法对一类分子进行生物活性的研究。这样不但可以对分子的各种生物活性进行广泛的研究,更可以依据大量的测试数据确定一定的构效关系,也就为新药物的研究开发奠定了基础。
一、抑制高致病禽流感病毒H5N1进入宿主的皂苷的合成及构效关系研究
皂苷是一类具有多种药效活性的三萜及甾体的糖缀合物,不仅显示了广谱的抗肿瘤作用而且对多种病毒都具有显著的抑制作用。本论文以首次发现的作用于H5N1高致病禽流感病毒的血凝素蛋白的小分子活性抑制剂——chlorogenin 3-O-β-chacotrioside YC-72 and chlorogenin 6-α-O-actyl-3-O-β-chacotrioside GC-29。为研究该系列化合物的构效关系以便于开发活性更高的H5N1小分子活性抑制剂,我们以化合物YC-72为先导化合物设计合成了8个结构类似物来研究其甾体母核和糖链对活性的影响。研究发现马铃薯三糖熊果酸甲酯衍生物5具有同化合物YC-72相似的抗病毒活性。初步构效关系研究表明:苷元的多稠环结构是活性必需的;马铃薯三糖片段在皂苷抗禽流感病毒中扮演着重要角色,简化为二糖后活性消失。
二、抗肿瘤蒽环鼠李糖苷的合成及构效关系研究
大黄素对多种肿瘤细胞株显示了一定的抑制作用,由于其与DNA的结合能力不强造成了其抗肿瘤作用较弱,而天然存在的大黄素β糖苷显示了很强的细胞毒活性。本文设计合成了三个系列的蒽环鼠李糖糖苷化合物包括大黄素鼠李糖糖苷、蒽酮鼠李糖糖苷和杂原子蒽酮鼠李糖糖苷,并进行了相关的生物活性测试,初步阐明了其构效关系。
为有效地降低蒽酮鼠李糖糖苷的心脏毒性,设计合成了系列在其C-10亚甲基引入Ac的衍生物。活性测试表明C-10亚甲基引入Ac不仅可以提高化合物的细胞毒活性而且可以降低其毒性。
此外,本论文应用生物电子等排体原理设计合成了三个不同系列的杂原子蒽酮鼠李糖糖苷化合物,并进行了相关的生物活性测试,初步阐明了其构效关系,发现了一个具有新型的结构骨架的抗肿瘤先导化合物2-[4-O-(2',3'-Di-O-acetyl-α-L-rhamnopyranosyl)-8-methyl-2H-chromeno[4,3,2-c,d]indazol-2-yl]-1-N, N-diethylethanamine (119)。
采用荧光滴定法测试了所合成的蒽环鼠李糖糖苷类似物与CT-DNA的结合能力。实验结果显示所合成的蒽环鼠李糖糖苷化合物与DNA的作用存在插入结合模式,即化合物插入DNA双链中,与碱基结合,从而可能阻止DNA的进一步复制。这为从分子水平上研究治疗癌症等疾病的新型药物提供了一定的实验依据。
三、选择性PDE4抑制剂的设计、合成及构效关系研究
选择性PDE4抑制剂是一类治疗慢性阻塞性肺病(COPD)的有效药物,但用于临床的现有的选择性PDE4抑制剂大都有致呕吐等副作用。本文通过计算机辅助设计了解了PDE4结合腔的特征和活性位点的结合方式,明确了了选择性PDE4抑制剂的药效团特征,建立了PDE4抑制剂的药效团模型。分别设计合成了以四氢异喹啉和氨基苯酞为骨架的两类小分子杂环化合物,并对部分四氢异喹啉衍生物测试了其相关的生物活性,初步确定了其构效关系,发现了两个对PDE4有较好抑制活性的先导化合物(7-cyclopentyloxy)-6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)(4-hydroxy-3-methoxyphenyl)methanone (155)和Methyl 7-(cyclopentyloxy)-6-methoxy-2-(4-methoxy- benzoyl)-1-phenyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (170)。以化合物155和170为先导化合物进行结构修饰,设计合成了其结构类物物,活性测试正在进行当中。
Nowadays, in order to search new active moleculars, the common methods of constructing the compound library have been adopted. Thus, it is not only extensive studies of many kinds of bioactivities, but also even more establishing some structure-activity relationship based on a lot of testing datas, and establishing the basic for Pharmaprojeccts, too.
1. Synthesis and pharmacological evaluation of novel saponin derivatives with antiviral H5N1 activity
Saponins are complex glycosides of steroids and triterpenes, with significant pharmacological activities, not only show wide spectrum of cytotoxicity against various cancer cells, but also exhibit good antiviral activities and pharmacological effects. Our paper described that an HIV-based pseudotyping system was used to screen our semi-synthesized saponin library for the entry inhibitors against high pathogenic H5N1 infection. The first two small molecule inhibitors chlorogenin 3-O-β-chacotrioside YC-72 and chlorogenin 6-α-O-actyl-3-O-β-chacotrioside GC-29, were discovered. In order to develop additional small molecule inhibitors with enhanced activity, compound YC-72 was chosen as the lead compound to design and synthesize a series of analogs 1-7 to explore the preliminary structure-activity relations of such these designed molecules around the aglycone and sugar chain. It was found that ursolate saponin 5 showed the similar inhibitory activity as YC-72. These results suggest that the aglycone with more fused rings is favored for the inhibitory activity and the 3-O-β-chacotriosyl residue plays a very important role in antiviral activity, suggesting that attachment of such t sugar chain to some steroids and triterpenes can contribute to enhance inhibitory activity against H5N1 entry.
2. Synthesis and biological evaluation on antitumor activity of novel anthracene L-rhamnopyranoside derivatives
Emodin with many kinds of pharmacological activities, has low DNA binding affinity, low or insignificant cytotoxicity against various cancer cells though it could induce the apoptosis of certain cancer cells. It is proved that the addition of side chain sugar to emodin is usually effective to gain higher antitumor activities. Our paper reported that three different series of anthracene L-rhamnopyranosides including emodin L-rhamnopyranosides、anthrone L-rhamnopyranosides and xanthrone rhamnopyranosides were designed and synthesized, which were evaluated on their cytotoxicity against various cancer cells for study on the structure-activity relationship.
Anthrone L-rhamnopyranosides were synthesized on the basis of the synthesis of emodin L-rhamnopyranosides. In order to reduce side effects of anthrone L-rhamnopyranosides, the introduction of Ac group into methylene proton at C-10 of anthrone was carried out. It was found the introduction of Ac group into methylene proton at C-10 of anthrone not only was helpful to enhance antitumor activities but also could reduce side effects. In addition, three different series of xanthrone L-rhamnopyranosides were designed and synthesized by taking the place of methylene proton at C-10 with O or S-isosteres of the chromophore. Then this thesis made some research on antitumor activities and came to a rude conclusion. Compound 2-[4-O-(2',3'-Di-O-acetyl-α-L-rhamnopyranosy l)-8-methyl-2H-chromeno[4,3,2-c,d]indazol-2-yl]-1-N,N-diethylethanamine(119)with novel structure, exhibited a broad specturm of antitumor activities.
Our paper described that competitive displacement (C50) fluorometric assays with DNA-bound ethidium can be used21 to determine the DNA binding capacity with anthracene L-rhamnopyranosides synthesized. It was proved that anthracene L-rhamnopyranosides could bind with DNA by insertion model, which insert directly double-stranded and bind with base group of DNA to lead to inability of further replication. These results provided some experimental datas which were helpful to develop some new antitumor drugs from molecure level.
3. Synthesis and Biological Evaluation on Activities of Novel, Potent, and Selective PDE4 Inhibitors
It was reported that selective PDE4 inhibitors could be used to efficiently therapy COPD, but selective PDE4 inhibitors in clinic showed some side effects such as vomiting and so on. This paper reported that the combination of cavity characteristics and active cite combination of PDE4 have been confirmed and pharmacophore features of the selective PDE4 inhibitors has been defined. Tetrahydroisowuinolin derivatives and phthalide derivatives were designed and synthesized on the basis of a PDE4 inhibitor pharmacophore model set up through computer simulation. Some tetrahydroisowuinolin derivatives synthesized were evaluated on their activity against PDE4 for study on the structure-activity relationship. (7-cyclopentyloxy)-6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)(4-hydroxy-3-methoxyphenyl)methanone (155) and Methyl 7-(cyclopentyloxy)-6-methoxy-2-(4-methoxy- benzoyl)-1-phenyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (170) showed good activity against PDE4, which were chosen as the lead compounds to design and synthesize another analogs in order to develop selective PDE4 inhibitors with better activity. The further studies on the SAR are in progress.
一、抑制高致病禽流感病毒H5N1进入宿主的皂苷的合成及构效关系研究
皂苷是一类具有多种药效活性的三萜及甾体的糖缀合物,不仅显示了广谱的抗肿瘤作用而且对多种病毒都具有显著的抑制作用。本论文以首次发现的作用于H5N1高致病禽流感病毒的血凝素蛋白的小分子活性抑制剂——chlorogenin 3-O-β-chacotrioside YC-72 and chlorogenin 6-α-O-actyl-3-O-β-chacotrioside GC-29。为研究该系列化合物的构效关系以便于开发活性更高的H5N1小分子活性抑制剂,我们以化合物YC-72为先导化合物设计合成了8个结构类似物来研究其甾体母核和糖链对活性的影响。研究发现马铃薯三糖熊果酸甲酯衍生物5具有同化合物YC-72相似的抗病毒活性。初步构效关系研究表明:苷元的多稠环结构是活性必需的;马铃薯三糖片段在皂苷抗禽流感病毒中扮演着重要角色,简化为二糖后活性消失。
二、抗肿瘤蒽环鼠李糖苷的合成及构效关系研究
大黄素对多种肿瘤细胞株显示了一定的抑制作用,由于其与DNA的结合能力不强造成了其抗肿瘤作用较弱,而天然存在的大黄素β糖苷显示了很强的细胞毒活性。本文设计合成了三个系列的蒽环鼠李糖糖苷化合物包括大黄素鼠李糖糖苷、蒽酮鼠李糖糖苷和杂原子蒽酮鼠李糖糖苷,并进行了相关的生物活性测试,初步阐明了其构效关系。
为有效地降低蒽酮鼠李糖糖苷的心脏毒性,设计合成了系列在其C-10亚甲基引入Ac的衍生物。活性测试表明C-10亚甲基引入Ac不仅可以提高化合物的细胞毒活性而且可以降低其毒性。
此外,本论文应用生物电子等排体原理设计合成了三个不同系列的杂原子蒽酮鼠李糖糖苷化合物,并进行了相关的生物活性测试,初步阐明了其构效关系,发现了一个具有新型的结构骨架的抗肿瘤先导化合物2-[4-O-(2',3'-Di-O-acetyl-α-L-rhamnopyranosyl)-8-methyl-2H-chromeno[4,3,2-c,d]indazol-2-yl]-1-N, N-diethylethanamine (119)。
采用荧光滴定法测试了所合成的蒽环鼠李糖糖苷类似物与CT-DNA的结合能力。实验结果显示所合成的蒽环鼠李糖糖苷化合物与DNA的作用存在插入结合模式,即化合物插入DNA双链中,与碱基结合,从而可能阻止DNA的进一步复制。这为从分子水平上研究治疗癌症等疾病的新型药物提供了一定的实验依据。
三、选择性PDE4抑制剂的设计、合成及构效关系研究
选择性PDE4抑制剂是一类治疗慢性阻塞性肺病(COPD)的有效药物,但用于临床的现有的选择性PDE4抑制剂大都有致呕吐等副作用。本文通过计算机辅助设计了解了PDE4结合腔的特征和活性位点的结合方式,明确了了选择性PDE4抑制剂的药效团特征,建立了PDE4抑制剂的药效团模型。分别设计合成了以四氢异喹啉和氨基苯酞为骨架的两类小分子杂环化合物,并对部分四氢异喹啉衍生物测试了其相关的生物活性,初步确定了其构效关系,发现了两个对PDE4有较好抑制活性的先导化合物(7-cyclopentyloxy)-6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)(4-hydroxy-3-methoxyphenyl)methanone (155)和Methyl 7-(cyclopentyloxy)-6-methoxy-2-(4-methoxy- benzoyl)-1-phenyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (170)。以化合物155和170为先导化合物进行结构修饰,设计合成了其结构类物物,活性测试正在进行当中。
Nowadays, in order to search new active moleculars, the common methods of constructing the compound library have been adopted. Thus, it is not only extensive studies of many kinds of bioactivities, but also even more establishing some structure-activity relationship based on a lot of testing datas, and establishing the basic for Pharmaprojeccts, too.
1. Synthesis and pharmacological evaluation of novel saponin derivatives with antiviral H5N1 activity
Saponins are complex glycosides of steroids and triterpenes, with significant pharmacological activities, not only show wide spectrum of cytotoxicity against various cancer cells, but also exhibit good antiviral activities and pharmacological effects. Our paper described that an HIV-based pseudotyping system was used to screen our semi-synthesized saponin library for the entry inhibitors against high pathogenic H5N1 infection. The first two small molecule inhibitors chlorogenin 3-O-β-chacotrioside YC-72 and chlorogenin 6-α-O-actyl-3-O-β-chacotrioside GC-29, were discovered. In order to develop additional small molecule inhibitors with enhanced activity, compound YC-72 was chosen as the lead compound to design and synthesize a series of analogs 1-7 to explore the preliminary structure-activity relations of such these designed molecules around the aglycone and sugar chain. It was found that ursolate saponin 5 showed the similar inhibitory activity as YC-72. These results suggest that the aglycone with more fused rings is favored for the inhibitory activity and the 3-O-β-chacotriosyl residue plays a very important role in antiviral activity, suggesting that attachment of such t sugar chain to some steroids and triterpenes can contribute to enhance inhibitory activity against H5N1 entry.
2. Synthesis and biological evaluation on antitumor activity of novel anthracene L-rhamnopyranoside derivatives
Emodin with many kinds of pharmacological activities, has low DNA binding affinity, low or insignificant cytotoxicity against various cancer cells though it could induce the apoptosis of certain cancer cells. It is proved that the addition of side chain sugar to emodin is usually effective to gain higher antitumor activities. Our paper reported that three different series of anthracene L-rhamnopyranosides including emodin L-rhamnopyranosides、anthrone L-rhamnopyranosides and xanthrone rhamnopyranosides were designed and synthesized, which were evaluated on their cytotoxicity against various cancer cells for study on the structure-activity relationship.
Anthrone L-rhamnopyranosides were synthesized on the basis of the synthesis of emodin L-rhamnopyranosides. In order to reduce side effects of anthrone L-rhamnopyranosides, the introduction of Ac group into methylene proton at C-10 of anthrone was carried out. It was found the introduction of Ac group into methylene proton at C-10 of anthrone not only was helpful to enhance antitumor activities but also could reduce side effects. In addition, three different series of xanthrone L-rhamnopyranosides were designed and synthesized by taking the place of methylene proton at C-10 with O or S-isosteres of the chromophore. Then this thesis made some research on antitumor activities and came to a rude conclusion. Compound 2-[4-O-(2',3'-Di-O-acetyl-α-L-rhamnopyranosy l)-8-methyl-2H-chromeno[4,3,2-c,d]indazol-2-yl]-1-N,N-diethylethanamine(119)with novel structure, exhibited a broad specturm of antitumor activities.
Our paper described that competitive displacement (C50) fluorometric assays with DNA-bound ethidium can be used21 to determine the DNA binding capacity with anthracene L-rhamnopyranosides synthesized. It was proved that anthracene L-rhamnopyranosides could bind with DNA by insertion model, which insert directly double-stranded and bind with base group of DNA to lead to inability of further replication. These results provided some experimental datas which were helpful to develop some new antitumor drugs from molecure level.
3. Synthesis and Biological Evaluation on Activities of Novel, Potent, and Selective PDE4 Inhibitors
It was reported that selective PDE4 inhibitors could be used to efficiently therapy COPD, but selective PDE4 inhibitors in clinic showed some side effects such as vomiting and so on. This paper reported that the combination of cavity characteristics and active cite combination of PDE4 have been confirmed and pharmacophore features of the selective PDE4 inhibitors has been defined. Tetrahydroisowuinolin derivatives and phthalide derivatives were designed and synthesized on the basis of a PDE4 inhibitor pharmacophore model set up through computer simulation. Some tetrahydroisowuinolin derivatives synthesized were evaluated on their activity against PDE4 for study on the structure-activity relationship. (7-cyclopentyloxy)-6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)(4-hydroxy-3-methoxyphenyl)methanone (155) and Methyl 7-(cyclopentyloxy)-6-methoxy-2-(4-methoxy- benzoyl)-1-phenyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (170) showed good activity against PDE4, which were chosen as the lead compounds to design and synthesize another analogs in order to develop selective PDE4 inhibitors with better activity. The further studies on the SAR are in progress.
引文
[1]. Koeller, K. M.; Wong, C. H. Chem. Rev. 2000, 100 (12), 4465-4493;
[2].中国海洋大学2005级张一纯博士论文
[3]. Kaplan, J.; Korty B. D.; Axelsen, P. H.; Loll, P. J. J. Med. Chem. 2001, 44 (11), 1837-1840;
[4]. Mimaki, Y.; Kameyama, A.; Kuroda, M.; Sashida, Y.; Hirano, T.; Oka, K.; Koike, K; Nikaido, T. Phytochemistry 1997, 44, 305;
[5]. Nakamura, T.; Komori, C.; Lee, Y. Y., Hashimoto, F.; Yahara, S.; Nohara, T.; Ejima, A. Biol. Pharm. Bull 1996, 19 (4), 564; [6. Sun, I. C.; Wang, H. K.; Kashiwada, Y.; Shen, J. K.; Cosentino, L. M.; Chen, C. H.; Yang, L. M.; Lee, K. H. J. Med. Chem. 1998, 41, 4648;
[7]. Soler, F.; Poujade, C.; Evers, M.; Carry, J. C.; Henin, Y.; Bousseau, A.; Huet, T.; Pauwels, R.; De Clercq, E.; Mayaux, J. F.; Le Pecq, J. B.; Dereu, N. J. Med. Chem, 1996, 39, 1069;
[8]. Evers, M.; Poujade, C.; Soler, F.; Ribeill, Y.; James, C.; Lelievre, Y.; Gueguen, J-C.; Reisdorf, D.; Morize, I.; Pauwels, R.; De Clercq, E.; Henin, Y.; Bousseau, A.; Mayaux, J. F.; Le Pecq, J. B.; Dereu, N. J. Med. Chem. 1996, 39, 1056;
[9]. Hashimoto, F.; Kashiwada, Y.; Cosentino, L. M.; Chen, C. H.; Garrett, P. E.; Lee, K. H. Bioorg. Med. Chem. 1997, 5, 2133;
[10]. Huang, L.; Xiong, Y.; Aiken, C.; Chen, C. H. Antimicrob. Agents Chemother. 2004, 48, 663.
[11]. Huang, L.; Ho, P.; Lee, K. H.; Chen, C. H.; Bioorg. Med. Chem. 2006, 14, 2279;
[12]. Konoshima, T.; Yaduda, I.; Kashiwada, Y.; Cosentino, L. M.; Lee, K. H. J. Nat. Prod. 1995, 58, 1372;
[13] Nakamura, O.; Mimaki, Y.; Sashida, Y.; Nikaido, T.; Ohmoto, T. Chem. Pharm. Bull. 1993, 41, 1784;
[14] Parkin, D. M.; Bray, F.; Ferlay, J. Int J. Cancer. 2001, 94, 153-156.
[15]中国海洋大学2007级赵育博士论文
[16] Lown J. W. ; Morgan A. R. ; Yen S. F. ; et al. Biochemistry, 1985, 24, 4028.
[17] Krishnamoorthy C. R. , Yen S. F. , Smith J. C. , et al. Biochemistry, 1986, 25, 5933.
[18] Tanious F. A. , Jekins T. C. , Neidle S. , et al. Biochemistry, 1992, 31, 11632
[19] Fisher G. R.; Patterson L. H. J. Pharm. Pharmacol. , 1991, 43, 65.
[20] Fisher G. R. , Gutierrez P. L. , Oldcorne M. A. , et al. Biochem. Pharmacol. , 1992, 43, 575.
[21] Armitage B. , Yu C. , Devadoss C. , et al. J. Am. Chem. Soc, 1994, 116, 9847.
[22] Kapuscinski J. , Darzynkiewicz Z. Proc. Natl. Acad. Sci. U. S. A. , 1986, 83, 6302.
[23] Fox. M. E. , Smith. P. J. Cancer. Res. 1990, 50, 5813.
[24] Carpranico G. , de Isabella P. , Tinellis S. , et al. Biochemistry. 1994, 32, 3038.
[25] Huang HC. , Lee C R. Chao P D. , et al. Eur . J. Pharmacol. 1991, 25 (3), 289.
[26] Kuo YC, Meng HC, Tsai WJ. J. Inflamm Res. 2001, 50(2), 73.
[27] Lic CC. Chang CH. Yang JJ. et al. J. Ethnopharmacol. 1996, 52(2), 107.
[28] Lee HZ. Br. J. Pharmacol. 2001, 134, 11.
[29] Tan, J.H.; Zhang, Q.-X.; Huang, Z.S.; Chen Y.; Wang, X.D.; Gu, L.Q.; Wu, J.Y.; Eur. J. Med. Chem. 2006, 41, 1041.
[30] Teich L, Daub KS, Kaugel. V, et al. Bioorg. Med. Chem. 2004, 12 (22), 5961.
[31] Lars Teich, Katja Scarlett Daub, Vera Kru¨gel, Ludwig Nissler, Rolf Gebhardtb and Kurt Eger. Bioorg. Med. Chem. 2004, 12, 5961.
[32]陆豫,黄志纾,谭嘉恒,丁岩,卜宪章,安林坤,马林,符立梧,古练权. Chinese Journa1 of Organic Chemistry. 2005, 25, 8944.
[33] Chun, N. L; J. Nat. Prod. 1992, 55, 967.
[34] Le Phuong Mai; Francüoise Gue′ritte; Vincent Dumontet; Mai Van Tri; Bridget Hill; Odile Thoison; Daniel Gue′nard; Thierry Se′venet. J. Nat. Prod. 2001, 64, 1162-1168.
[35] Hsu-Shan Huang. United States Patent Application Publication. Pub. No. Us:2003/0135060.
[36] Hsu-Shan Huang. United States Patent Application Publication. Pub. No: US, 6372785B1.
[37] J. William Lown; Sham M. Sondhi;Sukhendu B;Mandal; John Murphy. J. Org. Chem, 1982, 47, 4304.
[38] J. William Lown; Sham M. Sondhi. J. Org. Chem, 1989, 49, 2844.
[39] Arcamone, F. "Topics in Antibiotic Chemistry"; Sammes, P. G., Ed.; Wiley: New York, 1978, 102.
[40] Neidle, S. "Topics in Antibiotic Chemistry"; Sammes, P. G., Ed.; Wiley: New York, 1978, 242.
[41] Liou, S.-S.; Shieh, W.-L.; Cheng, T.-H.; Won, S.-J.; Lin, C.-N. J. Pharm. Pharmacol, 1993, 45, 791
[42] Cassady, J.M. J. Nat. Prod , 1990, 53, 23.
[43] Vasiliki, G; Ioannis K., K; Nicole P; Panagiotis M; Olga Ch. K; George N. T; Nikos K., K; J. Med. Chem, 2007, 50, 1716.
[44] Kostakis, I. K.; Ghirtis, K.; Pouli, N.; Marakos, P.; Skaltsounis, A. L.; Leonce, S.; Gaignard, D. H.; Atassi, G. Farmaco, 2000, 55, 455.
[45] Kostakis, I. K.; Magiatis, P.; Pouli, N.; Marakos, P.; Skaltsounis, A.L.; Pratsinis, H.; Leonce, S.; Pierre, A. J. Med. Chem, 2002, 45, 2599.
[46]Capps, D. B.; Dunbar, J.; Kesten, S. R.; Shillis, J.; Werbel, L. M.; Plowman, J.; Ward, D. L. J. Med. Chem, 1992, 35, 4770.
[47] Hyzy, M.; Bozko, P.; Konopa, J.; Skladanowski, A. Biochem. Pharmacol, 2005, 69, 801
[48] Madalena, P; Fátima, C; Maria Emília, Sousa; Maria S?o José, N; Madalena, P. Bioorg. Med. Chem, 2002, 10, 3725.
[49] Ying-Shu, Zou; Ai-Jun, Hou; Guo-Fu, Zhu; Yan-Feng, Chen; Han-Dong, Sun; Qin-Shi, Zhao. Bioorg. Med. Chem, 2004, 12, 1947.
[50] Lin, C.-N.; Liou, S.-S.; Lee, T.-H.; Chuang, Y.-C.; Won, S.-J. J. Pharm. Pharmacol, 1996, 48, 539.
[51] Kupchan, S. M.; Streelman, D. R.; Sneden, A. T. J. Nat.Prod, 1980, 43, 296.
[52] Sangwook Woo; Ji Jung; Chongsoon Lee; Youngjoo Kwon; Younghwa Na. Bioorg. Med. Chem. Lett, 2007, 17, 1163..
[53] Roslyn E. W; Frederick E. D; R. V. Citarella. J. Med. Chem, 1979, 22, 9.
[54] Teich L, Daub KS, Kaugel. V, et al. Bioorg. Med. Chem, 2004, 12, 5961.
[55]古练权,陆豫,符立梧,邓焯安,黄志纾,马林,徐忠宪,陈新滋,中国发明专利,公开号CN 1546451A
[56] Zee-Cheng, R. K.-Y.; Cheng, C. C. J. Med. Chem, 1978, 21, 291.
[57] Palumbo, M.; Antonello, C.; Viano, I.; Santiano, M.; Gia, O.;Gastaldi, S.; Marciani Magno, S. Chem.Biol. Interact, 1983, 44, 207.
[58] Denny, W. A.; Atwell, G. J.; Baguley, B. C.; Wakelin, L. P. G. J. Med. Chem, 1985, 28, 1568.
[59] Ippolito Antonini; Paolo Polucci; Amelia Magnano; Sante Martelli. J. Med. Chem, 2001, 44, 3329.
[60] Antonini, I.; Polucci, P.; Jenkins, T. C.; Kelland, L. R.; Menta, E.; Pescalli, N.; Stefanska, B.; Mazerski, J.; Martelli, S. J. Med. Chem, 1997, 40, 3749.
[61] Kostakis, I. K.; Ghirtis, K.; Pouli, N.; Marakos, P.; Skaltsounis, A. L.; Leonce, S.; Gaignard, D. H.; Atassi, G. Farmaco, 2000, 55, 455.
[62] Antonini, I.; Cola, D.; Polucci, P.; Bontemps-Gracz, M.; Borowski, E.; Martelli, S. J. Med. Chem, 1995, 38, 3282.
[63] Antonini, I.; Cola, D.; Martelli, S.; Cholody, W. M.; Konopa, J. Farmaco, 1992, 47, 1035.
[64] Sydney Archer; Kenneth J. Miller; Rabindra Rej; Cecily Periana; Lloyd Fricker. J. Med. Chem, 1982, 25, 220.
[65] Sydney, Archer; Abdel-Hadi Zayed; Rabindra Rej; Thomas A. Rugino. J. Med. Chem, 1983, 26, 1240.
[66] D. Rosi, G. Perruzzotti, E. W. Dennis, D. A. Berberian, H.Freele, and S. Archer. J. Med. Chem, 1967, 10, 867.
[67] J.-H. Tan ; Q.-X. Zhang ; Z.-S. Huang ; Y. Chen ; X.-D. Wang ; L.-Q. Gu ; J.Y. Wu. Eur. J. Med. Chem, 2006, 41, 1041.
[68] Cho?ody, W. M.; Martelli, S.; Konopa, J. J. Med. Chem, 1992, 35, 378.
[69] Scarffe, J. H.; Beaumont, A. R.; Crowther, D. Scarffe, J. H.; Beaumont, A. R.; Crowther, D. Cancer Treat. Rep. 1983, 67, 93.
[70] Costes, N.; Le Deit, H.; Michel, S.; Tillequin, F.; Koch, M.; Pfeiffer, B.; Renard, P.; Leonce, S.; Guilbaud, N.; Kraus-Berthier, L.; Pierre, A.; Atassi, G. J. Med. Chem. 2000, 43, 2395-2402.
[71] Ioannis K. Kostakis; Prokopios Magiatis; Nicole Pouli; Panagiotis Marakos; Alexios-Leandros Skaltsounis; Harris Pratsinis; Stephane Léonce; Alain Pierré. J. Med. Chem, 2002, 45, 2599.
[72] Barnes PG, Belvisi MG, Mak CW. Life Sci, 1993, 52, 521-526.
[73] Peter JB. Thorax, 1998, 53, 137-147.
[74] Rennard SI, Serby CW, Ghafouri M. Chest, 1996, 110, 62-70.
[75] Cazzola M, Donner CF. Drugs, 2000, 60, 307-320.
[76] Cazzola M, Donner CF. Thorax, 1999, 54, 730-736.
[77] Mcevoy CE, Niewoehner DE. Chest, 1997, 111, 732-743.
[78] Vittorio DP, Maria PG. Eur J Med Chem, 2000, 35, 463-480.
[79] Crocker CI, Townley RG. Drugs Today, 1999, 35, 519-535.
[80] Teixxeira MM, Gristwood RW. Trends Pharmacol Sci, 1997, 18, 164-171.
[81] Sofia M, Mormile M, Faraone S. Respiration, 1994, 61, 263-268.
[82] Graul AI. Drugs Future, 2002, 27, 1181-1194.
[83] Hislop AA , Mak JC , Reader JA Eur J Pharmacol, 1998, 359, 211-221.
[84] Trifilieff A, Wyss D,Walker C. The Journal of Pharmacology and Experimental Thera peutics, 2002, 301, 241-248
[85] Thompson WJ. Pharmac Ther, 1991, 51, 13-23.
[86] Eckly AE, Lugnier C. J Pharmacol, 1994; 113, 445-450.
[87] Conti M, Jin SL. Res Mol Biol, 1999, 63, 1-38.
[88] Landells LJ, Szilagy CM, Jones NA. J Pharmacol, 2001, 133, 722-729.
[89] Wang P, Wu P, Ohlet h KM. Mol Pharmacol, 1999, 56, 170-174.
[90] Conti M, jin SLC, Monaco L. Endocrine Rev, 1991, 12, 218-314.
[91] Teixeira M M, Gristwood R W. Trends Pharmacol Sci, 1997, 18, 164-171.
[92] Vittiorio D P, M aria P G. Eur J Med Chem , 2000, 35, 463-480.
[93] Sturton Graham, Fitzgerald Mary. Chest, 2002, 121, 192-196.
[94] Martoin C, Goggel R, Vergelli C Naunyn-Schmiedeberg’s Archives of Pharmacology, 2002, 365, 284-289
[95] Banette M S, Ch ristensen S B. Harmacol Exp Ther, 1998, 284, 420-426.
[96] Malcolm N P. Drugs Fut, 1995, 20, 793-804.
[97] Vittiorio D P, Maria P G. Eur. J. Med. Chem, 2000, 35, 463-480.
[98] Sorbera L A, Leeson P A, Castaner J. Roflumilast; Drugs Fut, 2000, 25, 1261-1264.
[99] Elisabeth B, John LW, Noella G.; J Pharm acol Exp Ther, 2000, 292, 647-653.
[100] Catherine B, Eric A, N adine A.; J Med Chem, 2000, 43, 4850-4867.
[101]. Koehn, F. E.; Gunasekera, M.; Cross, S. S. J. Org. Chem. 1991,56, 1322;
[102]. Jordan, K.Z; J. Nat. Prod. 2004, 67, 330;
[103]. Wang, X., Jia,W., Zhao, A.,Wang, X., Phytother. Res, 2006, 20, 335;
[104]. Mothana, R. A. A.; Awadh Ali, N. A.; Jansen, R.; Wegner, U.; Mentel, R.; Lindequist, U. Fitoterapia, 2003, 74, 177;
[105]. Niedermeyer, Timo H. J; Lindequist, U; Mentel, R; G?rdes, D; Schmidt, E; Thurow, K; Lalk,M; J. Nat. Prod, 2005, 68, 1728;
[106]. Nguyen, D. C.; Uyeki, T. M.; Jadhao, S. J.; Maunes, T.; Shaw, M.; Matsuoka, Y.; Smith, C.; Rowe, T.; Lu, X.; Hall, H.; Xu, X.; Balish, A.; Klimov, A.; Tumpey, T. M.; Swayn, D. E.; Huynh, L. P. T.; Nghiem, H. K.; Nguyen, H. H. T.; Hoang, L. T.; Cox, N. J.; Kata, J. M.; J. Virol, 2005, 79, 4201.
[107]. Liu, H.; Xiao, H.; Lei, F.; Zhu, Q.; Qin, K.; Zhang, X. W.; Zhang, X. L.; Zhao, D.; Wang, G.; Feng, Y.; Ma, J.; Liu, W.; Wang, J.; Gao, G. F.; Science, 2005, 309, 1206.
[108]. Sakurai, N.; Wu, J. H.; Sashida, Y.; Mimaki, Y.; Nikaido, T.; Koike, K.; Itokawa, H.; Lee, K. H.; Bioorg. Med. Chem. Lett, 2004, 14, 1329;
[109]. Sparg, S.G.; Light, M.E.; van Staden, J.; J. Ethnopharmacol, 2004, 94, 219;
[110]. Liu, M. J.; Wang, Z.; Ju, Y.; Zhou, J. B.; Wang, Y.; Wong, R.. N. S.; Biol. Pharm. Bull, 2004, 27, 1059.
[111]. Li, C. -H.; Guo, T. -T.; Wang, P.; Guan, H. -S.; Li, Y. -X. Chin. J. Chem, 2006, 24, 917;
[112]. Danishefsky, S.J.; Allen, J.R.; Angew. Chem. Int. Ed. 2000, 39, 864;
[113] Dark, J.; Iwasawa, N.; Danishefsky, S.J.; Crothers, D.M.; Proc. Natl. Acad. Sci. USA. 1991, 88, 7464;
[114]. Austein, B.M.; Westwood, O.M.R. Protein Targeting and Seceretion Oxford, IRL Press, 1991, 85;
[115]. Coukell A. J.; Faulds D.; Drugs. 1997, 53, 453-462
[116]. Pratesi G.; Decesare M.; Caserini C.; Perego P.; Dal B. L.; Polizzi D.; Clin. Cancer Res. 1998, 4, 2833-2839
[117]. Takahashi T.; Tsukamoto H.; Yamada H.; Bioorg. Med. Chem. Lett. 1998, 8, 113-116
[118]. Tan, J. H.; Zhang, Q. X.; Huang, Z. S.; Chen, Y.; Wang, X. D.; Gu, X. Q.; Wu, J. Y.; Eur. J. Med. Chem. 2006, 41, 1041;
[119]. Solis, P. N; Ravelo, A. G; Gonzalez, A. G.; Gupta, M. P; Phillipson, J. D. Phytochemistry, 1995, 38(2), 477.
[120]. Subash C; Verma; Narendra P. Singh; Arun K. Sinha. J. Chrom A, 2005, 1097, 59.
[121]. Krenn, L.; Presser, A.; Pradhan, R.; Bahr, B.; Paper, D. H.; Mayer, K. K.; Kopp, B. J. Nat. Prod. 2003, 66, 1107.
[122]. Hasan, A; Ahmed, I; Jay, M; Voirin, B. Phytochemistry, 1995, 39, 1211.
[123]. Abegaz, B.M.; Peter, M.; Phytochemistry, 1995, 39, 1411.
[124]. Farid J. Muhtadi; Melville J. R. Moss. Tetrahedron Lett. 1969, 10, 3751.
[125]. Asit K; Chakraborti; Mrinal K; Nayak; Lalima, S. J. Org. Chem. 1999, 64, 8027.
[126]. Kiyomiya K, Matsuo S, Kurebe M. Cancer Chemother Pharmacol, 2001, 47, 51.
[127].卢圣栋.基因工程寻求新途径.科学(上海), 1993, 45, 22.
[128]. Conklin KA. Cancer Ther, 2005,4,110.
[129]. Richardson DR. Pemson LXu X. Mol PharmacoL. 2005, 9, 466.
[130]. Prinz, H; Burgemeister, T; Wiegrebe, W; Müller, K. J. Org. Chem. 1996, 61, 2857
[131]. Scarffe, J. H.; Beaumont, A. R.; Crowther, D. Phase I-II evaluation of acronycine in patiens with multiple myeloma. Cancer Treat. Rep. 1983, 67, 93-94.
[2].中国海洋大学2005级张一纯博士论文
[3]. Kaplan, J.; Korty B. D.; Axelsen, P. H.; Loll, P. J. J. Med. Chem. 2001, 44 (11), 1837-1840;
[4]. Mimaki, Y.; Kameyama, A.; Kuroda, M.; Sashida, Y.; Hirano, T.; Oka, K.; Koike, K; Nikaido, T. Phytochemistry 1997, 44, 305;
[5]. Nakamura, T.; Komori, C.; Lee, Y. Y., Hashimoto, F.; Yahara, S.; Nohara, T.; Ejima, A. Biol. Pharm. Bull 1996, 19 (4), 564; [6. Sun, I. C.; Wang, H. K.; Kashiwada, Y.; Shen, J. K.; Cosentino, L. M.; Chen, C. H.; Yang, L. M.; Lee, K. H. J. Med. Chem. 1998, 41, 4648;
[7]. Soler, F.; Poujade, C.; Evers, M.; Carry, J. C.; Henin, Y.; Bousseau, A.; Huet, T.; Pauwels, R.; De Clercq, E.; Mayaux, J. F.; Le Pecq, J. B.; Dereu, N. J. Med. Chem, 1996, 39, 1069;
[8]. Evers, M.; Poujade, C.; Soler, F.; Ribeill, Y.; James, C.; Lelievre, Y.; Gueguen, J-C.; Reisdorf, D.; Morize, I.; Pauwels, R.; De Clercq, E.; Henin, Y.; Bousseau, A.; Mayaux, J. F.; Le Pecq, J. B.; Dereu, N. J. Med. Chem. 1996, 39, 1056;
[9]. Hashimoto, F.; Kashiwada, Y.; Cosentino, L. M.; Chen, C. H.; Garrett, P. E.; Lee, K. H. Bioorg. Med. Chem. 1997, 5, 2133;
[10]. Huang, L.; Xiong, Y.; Aiken, C.; Chen, C. H. Antimicrob. Agents Chemother. 2004, 48, 663.
[11]. Huang, L.; Ho, P.; Lee, K. H.; Chen, C. H.; Bioorg. Med. Chem. 2006, 14, 2279;
[12]. Konoshima, T.; Yaduda, I.; Kashiwada, Y.; Cosentino, L. M.; Lee, K. H. J. Nat. Prod. 1995, 58, 1372;
[13] Nakamura, O.; Mimaki, Y.; Sashida, Y.; Nikaido, T.; Ohmoto, T. Chem. Pharm. Bull. 1993, 41, 1784;
[14] Parkin, D. M.; Bray, F.; Ferlay, J. Int J. Cancer. 2001, 94, 153-156.
[15]中国海洋大学2007级赵育博士论文
[16] Lown J. W. ; Morgan A. R. ; Yen S. F. ; et al. Biochemistry, 1985, 24, 4028.
[17] Krishnamoorthy C. R. , Yen S. F. , Smith J. C. , et al. Biochemistry, 1986, 25, 5933.
[18] Tanious F. A. , Jekins T. C. , Neidle S. , et al. Biochemistry, 1992, 31, 11632
[19] Fisher G. R.; Patterson L. H. J. Pharm. Pharmacol. , 1991, 43, 65.
[20] Fisher G. R. , Gutierrez P. L. , Oldcorne M. A. , et al. Biochem. Pharmacol. , 1992, 43, 575.
[21] Armitage B. , Yu C. , Devadoss C. , et al. J. Am. Chem. Soc, 1994, 116, 9847.
[22] Kapuscinski J. , Darzynkiewicz Z. Proc. Natl. Acad. Sci. U. S. A. , 1986, 83, 6302.
[23] Fox. M. E. , Smith. P. J. Cancer. Res. 1990, 50, 5813.
[24] Carpranico G. , de Isabella P. , Tinellis S. , et al. Biochemistry. 1994, 32, 3038.
[25] Huang HC. , Lee C R. Chao P D. , et al. Eur . J. Pharmacol. 1991, 25 (3), 289.
[26] Kuo YC, Meng HC, Tsai WJ. J. Inflamm Res. 2001, 50(2), 73.
[27] Lic CC. Chang CH. Yang JJ. et al. J. Ethnopharmacol. 1996, 52(2), 107.
[28] Lee HZ. Br. J. Pharmacol. 2001, 134, 11.
[29] Tan, J.H.; Zhang, Q.-X.; Huang, Z.S.; Chen Y.; Wang, X.D.; Gu, L.Q.; Wu, J.Y.; Eur. J. Med. Chem. 2006, 41, 1041.
[30] Teich L, Daub KS, Kaugel. V, et al. Bioorg. Med. Chem. 2004, 12 (22), 5961.
[31] Lars Teich, Katja Scarlett Daub, Vera Kru¨gel, Ludwig Nissler, Rolf Gebhardtb and Kurt Eger. Bioorg. Med. Chem. 2004, 12, 5961.
[32]陆豫,黄志纾,谭嘉恒,丁岩,卜宪章,安林坤,马林,符立梧,古练权. Chinese Journa1 of Organic Chemistry. 2005, 25, 8944.
[33] Chun, N. L; J. Nat. Prod. 1992, 55, 967.
[34] Le Phuong Mai; Francüoise Gue′ritte; Vincent Dumontet; Mai Van Tri; Bridget Hill; Odile Thoison; Daniel Gue′nard; Thierry Se′venet. J. Nat. Prod. 2001, 64, 1162-1168.
[35] Hsu-Shan Huang. United States Patent Application Publication. Pub. No. Us:2003/0135060.
[36] Hsu-Shan Huang. United States Patent Application Publication. Pub. No: US, 6372785B1.
[37] J. William Lown; Sham M. Sondhi;Sukhendu B;Mandal; John Murphy. J. Org. Chem, 1982, 47, 4304.
[38] J. William Lown; Sham M. Sondhi. J. Org. Chem, 1989, 49, 2844.
[39] Arcamone, F. "Topics in Antibiotic Chemistry"; Sammes, P. G., Ed.; Wiley: New York, 1978, 102.
[40] Neidle, S. "Topics in Antibiotic Chemistry"; Sammes, P. G., Ed.; Wiley: New York, 1978, 242.
[41] Liou, S.-S.; Shieh, W.-L.; Cheng, T.-H.; Won, S.-J.; Lin, C.-N. J. Pharm. Pharmacol, 1993, 45, 791
[42] Cassady, J.M. J. Nat. Prod , 1990, 53, 23.
[43] Vasiliki, G; Ioannis K., K; Nicole P; Panagiotis M; Olga Ch. K; George N. T; Nikos K., K; J. Med. Chem, 2007, 50, 1716.
[44] Kostakis, I. K.; Ghirtis, K.; Pouli, N.; Marakos, P.; Skaltsounis, A. L.; Leonce, S.; Gaignard, D. H.; Atassi, G. Farmaco, 2000, 55, 455.
[45] Kostakis, I. K.; Magiatis, P.; Pouli, N.; Marakos, P.; Skaltsounis, A.L.; Pratsinis, H.; Leonce, S.; Pierre, A. J. Med. Chem, 2002, 45, 2599.
[46]Capps, D. B.; Dunbar, J.; Kesten, S. R.; Shillis, J.; Werbel, L. M.; Plowman, J.; Ward, D. L. J. Med. Chem, 1992, 35, 4770.
[47] Hyzy, M.; Bozko, P.; Konopa, J.; Skladanowski, A. Biochem. Pharmacol, 2005, 69, 801
[48] Madalena, P; Fátima, C; Maria Emília, Sousa; Maria S?o José, N; Madalena, P. Bioorg. Med. Chem, 2002, 10, 3725.
[49] Ying-Shu, Zou; Ai-Jun, Hou; Guo-Fu, Zhu; Yan-Feng, Chen; Han-Dong, Sun; Qin-Shi, Zhao. Bioorg. Med. Chem, 2004, 12, 1947.
[50] Lin, C.-N.; Liou, S.-S.; Lee, T.-H.; Chuang, Y.-C.; Won, S.-J. J. Pharm. Pharmacol, 1996, 48, 539.
[51] Kupchan, S. M.; Streelman, D. R.; Sneden, A. T. J. Nat.Prod, 1980, 43, 296.
[52] Sangwook Woo; Ji Jung; Chongsoon Lee; Youngjoo Kwon; Younghwa Na. Bioorg. Med. Chem. Lett, 2007, 17, 1163..
[53] Roslyn E. W; Frederick E. D; R. V. Citarella. J. Med. Chem, 1979, 22, 9.
[54] Teich L, Daub KS, Kaugel. V, et al. Bioorg. Med. Chem, 2004, 12, 5961.
[55]古练权,陆豫,符立梧,邓焯安,黄志纾,马林,徐忠宪,陈新滋,中国发明专利,公开号CN 1546451A
[56] Zee-Cheng, R. K.-Y.; Cheng, C. C. J. Med. Chem, 1978, 21, 291.
[57] Palumbo, M.; Antonello, C.; Viano, I.; Santiano, M.; Gia, O.;Gastaldi, S.; Marciani Magno, S. Chem.Biol. Interact, 1983, 44, 207.
[58] Denny, W. A.; Atwell, G. J.; Baguley, B. C.; Wakelin, L. P. G. J. Med. Chem, 1985, 28, 1568.
[59] Ippolito Antonini; Paolo Polucci; Amelia Magnano; Sante Martelli. J. Med. Chem, 2001, 44, 3329.
[60] Antonini, I.; Polucci, P.; Jenkins, T. C.; Kelland, L. R.; Menta, E.; Pescalli, N.; Stefanska, B.; Mazerski, J.; Martelli, S. J. Med. Chem, 1997, 40, 3749.
[61] Kostakis, I. K.; Ghirtis, K.; Pouli, N.; Marakos, P.; Skaltsounis, A. L.; Leonce, S.; Gaignard, D. H.; Atassi, G. Farmaco, 2000, 55, 455.
[62] Antonini, I.; Cola, D.; Polucci, P.; Bontemps-Gracz, M.; Borowski, E.; Martelli, S. J. Med. Chem, 1995, 38, 3282.
[63] Antonini, I.; Cola, D.; Martelli, S.; Cholody, W. M.; Konopa, J. Farmaco, 1992, 47, 1035.
[64] Sydney Archer; Kenneth J. Miller; Rabindra Rej; Cecily Periana; Lloyd Fricker. J. Med. Chem, 1982, 25, 220.
[65] Sydney, Archer; Abdel-Hadi Zayed; Rabindra Rej; Thomas A. Rugino. J. Med. Chem, 1983, 26, 1240.
[66] D. Rosi, G. Perruzzotti, E. W. Dennis, D. A. Berberian, H.Freele, and S. Archer. J. Med. Chem, 1967, 10, 867.
[67] J.-H. Tan ; Q.-X. Zhang ; Z.-S. Huang ; Y. Chen ; X.-D. Wang ; L.-Q. Gu ; J.Y. Wu. Eur. J. Med. Chem, 2006, 41, 1041.
[68] Cho?ody, W. M.; Martelli, S.; Konopa, J. J. Med. Chem, 1992, 35, 378.
[69] Scarffe, J. H.; Beaumont, A. R.; Crowther, D. Scarffe, J. H.; Beaumont, A. R.; Crowther, D. Cancer Treat. Rep. 1983, 67, 93.
[70] Costes, N.; Le Deit, H.; Michel, S.; Tillequin, F.; Koch, M.; Pfeiffer, B.; Renard, P.; Leonce, S.; Guilbaud, N.; Kraus-Berthier, L.; Pierre, A.; Atassi, G. J. Med. Chem. 2000, 43, 2395-2402.
[71] Ioannis K. Kostakis; Prokopios Magiatis; Nicole Pouli; Panagiotis Marakos; Alexios-Leandros Skaltsounis; Harris Pratsinis; Stephane Léonce; Alain Pierré. J. Med. Chem, 2002, 45, 2599.
[72] Barnes PG, Belvisi MG, Mak CW. Life Sci, 1993, 52, 521-526.
[73] Peter JB. Thorax, 1998, 53, 137-147.
[74] Rennard SI, Serby CW, Ghafouri M. Chest, 1996, 110, 62-70.
[75] Cazzola M, Donner CF. Drugs, 2000, 60, 307-320.
[76] Cazzola M, Donner CF. Thorax, 1999, 54, 730-736.
[77] Mcevoy CE, Niewoehner DE. Chest, 1997, 111, 732-743.
[78] Vittorio DP, Maria PG. Eur J Med Chem, 2000, 35, 463-480.
[79] Crocker CI, Townley RG. Drugs Today, 1999, 35, 519-535.
[80] Teixxeira MM, Gristwood RW. Trends Pharmacol Sci, 1997, 18, 164-171.
[81] Sofia M, Mormile M, Faraone S. Respiration, 1994, 61, 263-268.
[82] Graul AI. Drugs Future, 2002, 27, 1181-1194.
[83] Hislop AA , Mak JC , Reader JA Eur J Pharmacol, 1998, 359, 211-221.
[84] Trifilieff A, Wyss D,Walker C. The Journal of Pharmacology and Experimental Thera peutics, 2002, 301, 241-248
[85] Thompson WJ. Pharmac Ther, 1991, 51, 13-23.
[86] Eckly AE, Lugnier C. J Pharmacol, 1994; 113, 445-450.
[87] Conti M, Jin SL. Res Mol Biol, 1999, 63, 1-38.
[88] Landells LJ, Szilagy CM, Jones NA. J Pharmacol, 2001, 133, 722-729.
[89] Wang P, Wu P, Ohlet h KM. Mol Pharmacol, 1999, 56, 170-174.
[90] Conti M, jin SLC, Monaco L. Endocrine Rev, 1991, 12, 218-314.
[91] Teixeira M M, Gristwood R W. Trends Pharmacol Sci, 1997, 18, 164-171.
[92] Vittiorio D P, M aria P G. Eur J Med Chem , 2000, 35, 463-480.
[93] Sturton Graham, Fitzgerald Mary. Chest, 2002, 121, 192-196.
[94] Martoin C, Goggel R, Vergelli C Naunyn-Schmiedeberg’s Archives of Pharmacology, 2002, 365, 284-289
[95] Banette M S, Ch ristensen S B. Harmacol Exp Ther, 1998, 284, 420-426.
[96] Malcolm N P. Drugs Fut, 1995, 20, 793-804.
[97] Vittiorio D P, Maria P G. Eur. J. Med. Chem, 2000, 35, 463-480.
[98] Sorbera L A, Leeson P A, Castaner J. Roflumilast; Drugs Fut, 2000, 25, 1261-1264.
[99] Elisabeth B, John LW, Noella G.; J Pharm acol Exp Ther, 2000, 292, 647-653.
[100] Catherine B, Eric A, N adine A.; J Med Chem, 2000, 43, 4850-4867.
[101]. Koehn, F. E.; Gunasekera, M.; Cross, S. S. J. Org. Chem. 1991,56, 1322;
[102]. Jordan, K.Z; J. Nat. Prod. 2004, 67, 330;
[103]. Wang, X., Jia,W., Zhao, A.,Wang, X., Phytother. Res, 2006, 20, 335;
[104]. Mothana, R. A. A.; Awadh Ali, N. A.; Jansen, R.; Wegner, U.; Mentel, R.; Lindequist, U. Fitoterapia, 2003, 74, 177;
[105]. Niedermeyer, Timo H. J; Lindequist, U; Mentel, R; G?rdes, D; Schmidt, E; Thurow, K; Lalk,M; J. Nat. Prod, 2005, 68, 1728;
[106]. Nguyen, D. C.; Uyeki, T. M.; Jadhao, S. J.; Maunes, T.; Shaw, M.; Matsuoka, Y.; Smith, C.; Rowe, T.; Lu, X.; Hall, H.; Xu, X.; Balish, A.; Klimov, A.; Tumpey, T. M.; Swayn, D. E.; Huynh, L. P. T.; Nghiem, H. K.; Nguyen, H. H. T.; Hoang, L. T.; Cox, N. J.; Kata, J. M.; J. Virol, 2005, 79, 4201.
[107]. Liu, H.; Xiao, H.; Lei, F.; Zhu, Q.; Qin, K.; Zhang, X. W.; Zhang, X. L.; Zhao, D.; Wang, G.; Feng, Y.; Ma, J.; Liu, W.; Wang, J.; Gao, G. F.; Science, 2005, 309, 1206.
[108]. Sakurai, N.; Wu, J. H.; Sashida, Y.; Mimaki, Y.; Nikaido, T.; Koike, K.; Itokawa, H.; Lee, K. H.; Bioorg. Med. Chem. Lett, 2004, 14, 1329;
[109]. Sparg, S.G.; Light, M.E.; van Staden, J.; J. Ethnopharmacol, 2004, 94, 219;
[110]. Liu, M. J.; Wang, Z.; Ju, Y.; Zhou, J. B.; Wang, Y.; Wong, R.. N. S.; Biol. Pharm. Bull, 2004, 27, 1059.
[111]. Li, C. -H.; Guo, T. -T.; Wang, P.; Guan, H. -S.; Li, Y. -X. Chin. J. Chem, 2006, 24, 917;
[112]. Danishefsky, S.J.; Allen, J.R.; Angew. Chem. Int. Ed. 2000, 39, 864;
[113] Dark, J.; Iwasawa, N.; Danishefsky, S.J.; Crothers, D.M.; Proc. Natl. Acad. Sci. USA. 1991, 88, 7464;
[114]. Austein, B.M.; Westwood, O.M.R. Protein Targeting and Seceretion Oxford, IRL Press, 1991, 85;
[115]. Coukell A. J.; Faulds D.; Drugs. 1997, 53, 453-462
[116]. Pratesi G.; Decesare M.; Caserini C.; Perego P.; Dal B. L.; Polizzi D.; Clin. Cancer Res. 1998, 4, 2833-2839
[117]. Takahashi T.; Tsukamoto H.; Yamada H.; Bioorg. Med. Chem. Lett. 1998, 8, 113-116
[118]. Tan, J. H.; Zhang, Q. X.; Huang, Z. S.; Chen, Y.; Wang, X. D.; Gu, X. Q.; Wu, J. Y.; Eur. J. Med. Chem. 2006, 41, 1041;
[119]. Solis, P. N; Ravelo, A. G; Gonzalez, A. G.; Gupta, M. P; Phillipson, J. D. Phytochemistry, 1995, 38(2), 477.
[120]. Subash C; Verma; Narendra P. Singh; Arun K. Sinha. J. Chrom A, 2005, 1097, 59.
[121]. Krenn, L.; Presser, A.; Pradhan, R.; Bahr, B.; Paper, D. H.; Mayer, K. K.; Kopp, B. J. Nat. Prod. 2003, 66, 1107.
[122]. Hasan, A; Ahmed, I; Jay, M; Voirin, B. Phytochemistry, 1995, 39, 1211.
[123]. Abegaz, B.M.; Peter, M.; Phytochemistry, 1995, 39, 1411.
[124]. Farid J. Muhtadi; Melville J. R. Moss. Tetrahedron Lett. 1969, 10, 3751.
[125]. Asit K; Chakraborti; Mrinal K; Nayak; Lalima, S. J. Org. Chem. 1999, 64, 8027.
[126]. Kiyomiya K, Matsuo S, Kurebe M. Cancer Chemother Pharmacol, 2001, 47, 51.
[127].卢圣栋.基因工程寻求新途径.科学(上海), 1993, 45, 22.
[128]. Conklin KA. Cancer Ther, 2005,4,110.
[129]. Richardson DR. Pemson LXu X. Mol PharmacoL. 2005, 9, 466.
[130]. Prinz, H; Burgemeister, T; Wiegrebe, W; Müller, K. J. Org. Chem. 1996, 61, 2857
[131]. Scarffe, J. H.; Beaumont, A. R.; Crowther, D. Phase I-II evaluation of acronycine in patiens with multiple myeloma. Cancer Treat. Rep. 1983, 67, 93-94.