新型Pin1小分子抑制剂的设计、合成和构效关系研究
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摘要
Pin1(Protein interaction with NIMA1)是一种新的肽脯氨酰异构酶(PPIases),通过特异性地催化pSer-Pro(p=phosphorous,磷酸化)或pThr-Pro酰胺键的顺反异构化作用,调控许多种细胞周期蛋白的构象,从而调控细胞的分裂与增殖。Pin1在人类多种肿瘤细胞中过表达,包括最常见的宫颈癌、前列腺癌、脑瘤、肺癌、乳腺癌、肝癌和黑素瘤等。研究表明:抑制pin1的表达和功能,可以有效地抑制肿瘤细胞的恶性增殖和侵袭。因此,Pin1抑制剂有望成为具有新作用机制的抗癌药物。
为了寻找特异高活性的Pin1小分子抑制剂,本论文进行了以下几方面的工作:
1、综述了已知的Pin1拟肽类和小分子抑制剂,结合Pin1复合物的晶体结构,总结出Pin1抑制剂的药效团特征,包括三部分:两个疏水性中心和一个氢键或静电作用的基团。
2、本论文共设计合成了三种不同结构类型的目标化合物:1,4-二酮哌嗪类、哒嗪酮类和喹唑啉类。合成新结构类型的目标化合物70个,均经~1H-NMR鉴定,部分化合物经HRMS、~(13)C-NMR和NOE鉴定。
3、在本论文中,利用微波技术固相合成了cis-和trans-3-(3,4-二羟基苄基)-六氢吡咯并[1,2-α]哌嗪-1,4-二酮,缩短了反应时间,提高了反应收率。
4、本论文利用一锅法合成了6-硝基-2,4-二氯喹唑啉。与文献方法比较,简化了操作,减少了尿素的用量,缩短了反应时间,提高了反应收率。
5、采用MTT法,评价了70个目标化合物对不同肿瘤细胞的抑制活性,并进行了构效关系分析。发现5个化合物对不同的肿瘤细胞株的抑制作用在微摩尔水平,其中化合物ZCJ-1036和ZCJ-1111对胃癌细胞(BGC803)、乳腺癌细胞(MCF-7)、肝癌细胞(Bel-7402和HepG2)均有较好的抑制活性。因此,可以化合物ZCJ-1036和ZCJ-1111作为苗头化合物,经过结构改造,期望获得高效低毒、具有新的作用机制的抗癌药物。
Pinl is a phosphorylation-dependent peptidyl-prolyl cis/trans isomerase,which specifically catalyzes the amide bond isomerization of phosphoserine-proline or phosphothreonine-proline in mitotic phosphoproteins.Pin1 induces the conformational changes to control the function of phosphoproteins.Pin1 is significantly overexpressed in many different human cancer cells such as prostate,cervical,lung,hepatic,brain tumors and melanoma etc.Depletion of Pin1 on various human cancer cell lines cause mitotic arrest and apoptosis.Pin1 is an attracting therapeutic target for anticancer and its inhibitors might be potential anticancer drug.
In this thesis,the following work had been carried out in order to develop novel small molecule inhibitors of Pin1.
1.Upon reviewing the known Pinl inhibitors and the crystal structure of Pin1 complex with D-PEPTIDE,the pharmacophore model of Pin1 inhibitors was established.In this model,two hydrophobic groups and a hydrogen bond acceptor were hypothesized.
2.The two key intermediates cis-and trans-3-(3,4-dihydroxybenzyl)-hexahydroprrolo-[1,2-a]pyrazine-1,4-dione were efficiently prepared in solid phase under microwave irradiation.
3.The key intermediate 2,4-dichloro-6-nitroquinazoline was obtained in one-pot reaction. In comparison with literature work,this protocol leads to operational simplicity,small amount of urea and improved yields.
4.Three series of target molecules,including piperizine 1,4-diones,pyridazinones and quinazolines,were designed and synthesized.Total seventy novel target compounds were obtained.All the target molecules were identified by ~1HNMR,and some of them were further confirmed by HRMS,~(13)CNMR and NOE experiment.
5.The anticancer activities of the synthesized target compounds were evaluated on the various tumor cell lines with MTT assay.Five compounds effectively inhibited the growth of tumor cells with IC_(50) values of micromolar level.The structure-activity relationships of synthesized compounds provide some insight for design of new compounds with improved activities.
为了寻找特异高活性的Pin1小分子抑制剂,本论文进行了以下几方面的工作:
1、综述了已知的Pin1拟肽类和小分子抑制剂,结合Pin1复合物的晶体结构,总结出Pin1抑制剂的药效团特征,包括三部分:两个疏水性中心和一个氢键或静电作用的基团。
2、本论文共设计合成了三种不同结构类型的目标化合物:1,4-二酮哌嗪类、哒嗪酮类和喹唑啉类。合成新结构类型的目标化合物70个,均经~1H-NMR鉴定,部分化合物经HRMS、~(13)C-NMR和NOE鉴定。
3、在本论文中,利用微波技术固相合成了cis-和trans-3-(3,4-二羟基苄基)-六氢吡咯并[1,2-α]哌嗪-1,4-二酮,缩短了反应时间,提高了反应收率。
4、本论文利用一锅法合成了6-硝基-2,4-二氯喹唑啉。与文献方法比较,简化了操作,减少了尿素的用量,缩短了反应时间,提高了反应收率。
5、采用MTT法,评价了70个目标化合物对不同肿瘤细胞的抑制活性,并进行了构效关系分析。发现5个化合物对不同的肿瘤细胞株的抑制作用在微摩尔水平,其中化合物ZCJ-1036和ZCJ-1111对胃癌细胞(BGC803)、乳腺癌细胞(MCF-7)、肝癌细胞(Bel-7402和HepG2)均有较好的抑制活性。因此,可以化合物ZCJ-1036和ZCJ-1111作为苗头化合物,经过结构改造,期望获得高效低毒、具有新的作用机制的抗癌药物。
Pinl is a phosphorylation-dependent peptidyl-prolyl cis/trans isomerase,which specifically catalyzes the amide bond isomerization of phosphoserine-proline or phosphothreonine-proline in mitotic phosphoproteins.Pin1 induces the conformational changes to control the function of phosphoproteins.Pin1 is significantly overexpressed in many different human cancer cells such as prostate,cervical,lung,hepatic,brain tumors and melanoma etc.Depletion of Pin1 on various human cancer cell lines cause mitotic arrest and apoptosis.Pin1 is an attracting therapeutic target for anticancer and its inhibitors might be potential anticancer drug.
In this thesis,the following work had been carried out in order to develop novel small molecule inhibitors of Pin1.
1.Upon reviewing the known Pinl inhibitors and the crystal structure of Pin1 complex with D-PEPTIDE,the pharmacophore model of Pin1 inhibitors was established.In this model,two hydrophobic groups and a hydrogen bond acceptor were hypothesized.
2.The two key intermediates cis-and trans-3-(3,4-dihydroxybenzyl)-hexahydroprrolo-[1,2-a]pyrazine-1,4-dione were efficiently prepared in solid phase under microwave irradiation.
3.The key intermediate 2,4-dichloro-6-nitroquinazoline was obtained in one-pot reaction. In comparison with literature work,this protocol leads to operational simplicity,small amount of urea and improved yields.
4.Three series of target molecules,including piperizine 1,4-diones,pyridazinones and quinazolines,were designed and synthesized.Total seventy novel target compounds were obtained.All the target molecules were identified by ~1HNMR,and some of them were further confirmed by HRMS,~(13)CNMR and NOE experiment.
5.The anticancer activities of the synthesized target compounds were evaluated on the various tumor cell lines with MTT assay.Five compounds effectively inhibited the growth of tumor cells with IC_(50) values of micromolar level.The structure-activity relationships of synthesized compounds provide some insight for design of new compounds with improved activities.
引文
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[2]惠起源,魏晓萍.新世纪癌症控制策略与防治目标[J].延安大学学报(医学科学版),2004,2(3),1-2.
[3]Blume-Jensen P,Hunter T.Oncogenic kinase signalling[J].Nature,2001,411:355-365.
[4]Lu KP,Liou YC,Zhou XZ.Pinning down the prolinedirected phosphorylation signaling[J].Trends Cell Biol,2002,12:164-172.
[5]Lu KP,Hanes SD,Hunter T.A human peptidyl-prolyl isomerase essential for regulation of mitosis[J].Nature,1996,380:544-547.
[6]Zhou XZ,Kops O,Werner A,et al.Pin-dependent prolyl isomerization regulates dephosphorylation of cdc25c and tau proteins[J].Mol Cell,2000,6:873-883.
[7]Shen M,Stukenberg PT,Kirschner MW,et al.The essential mitotic peptidyloprolyl isomerase pin binds and regulates mitosis-specific phosphoproteins[J].Genes Dev,1998,12:706-720.
[8]Wulf G,Ryo A,Liou YC,et al.The prolyl isomerase Pin1 in breast development and cancer[J].Breast Cancer Research,2003,5:76-82.
[9]Wulf GM,Ryo A,Wulf GG,et al.Pinl is overexpressed in breast cancer and potentiates the transcriptional activity of phosphorylated c-Jun towards the cyclin D1gene[J].EMBO J,2001,20,3459-3472.
[10]Bao L,Kimzey A,Sauter G,et al.Prevalent overexpression of prolyl isomerase pin1in human cancers[J].American Journal of Pathology,2004,164:1727-1737.
[11]Ryo A,Liou YC,Wulf G,et al.Pin1 is an E2F target gene essential for the Neu/Ras-induced transformation of mammary epithelial cells[J].Mol Cell Biol,2002,22:5281-5295.
[12]Pang RW,Lee TK,Man K,et al.Pin1 expression contributes to hepatic carcinogenesis[J].Journal of Pathology,2006,210:19-25.
[13]Ryo A,Uemura H,Ishiguro H,et al.Stable suppression of tumorigenicity by Pinl-targeted RNA interference in prostate cancer[J].Clin Cancer Res,2005,11:7523-7531.
[14]Lu KP.Prolyl isomerase Pin1 as a molecular target for cancer diagnostics and therapeutics[J].Cancer Cell,2003,4:175-180.
[15]Kuramochi J,Arai T,Ikeda S,et al.High Pin1 expression is associated with tumor progression in colorectal cancer[J].Journal of Surgical Oncology,2006,94:155-160.
[16]Rippmann JF,Hobbie S,Daiber C,et al.Phosphorylation-dependent proline isomerization catalyzed by Pin1 is essential for tumor cell survival and entry into mitosis[J].Cell Growth & Differentiation,2000,11:409-416.
[17]Liou YC,Ryo R,Huang HK,et al.Loss of Pin1 function in the mouse resembles the cyclin D1-null phenotypes[J].Proc Natl Acad Sci USA,2002,99:1335-1340.
[18]Fujimori F,Takahashi K,Uchida C,et al.Mice lacking Pin1 develop normally,but are defective in entering cell cecle from G(0) arrest[J].Biochem Biophys Res Commun,1999,265:658-663.
[19]Zhang YX,F(u丨¨)ssel S,Reimer U,et al.Substrate-based design of reversible Pin1inhibitors[J].Biochemistry,2002,41:11868-11877.
[20]Bayer E,Thutewohl M,Christner C.Identification of hPin1 inhibitors that induce apoptosis in a mammalian Ras transformed cell line[J].Chem.Commun,2005,4:516-518.
[21]Wildemann D,Erdmann F,Alvarez BH,et al.Nanomolar inhibitors of the peptidyl prolyl cis/trans isomerase Pin1 from combinatorial peptide libraries[J].J.Med.Chem,2006,49:2147-2150.
[22]Wang XJ,Xu BL,Mullins AB,et al.Conformationally locked isostere of phosphoser-cis-pro inhibits Pin1 23-fold better than phosphoser-trans-pro isostere[J].J.Am.Chem.Soc,2004,126:15533-15542.
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