6-取代芳基-2-甲氧基喹啉类拓扑异构酶Ⅱα抑制剂的合成及抗肿瘤活性研究
|
摘要
人DNA拓扑异构酶Ⅱα(topoisomerase Ⅱα, Topo Ⅱα)是重要的抗肿瘤药物研究靶标之一.前期研究发现对联三苯类化合物对TopoⅡα有抑制作用,并且抑制人乳腺导管癌细胞增殖.本研究通过对联三苯类化合物的骨架跃迁,设计合成了19个6-取代芳基-2-甲氧基喹啉类衍生物3a～3s,包括取代苯基、氮硫杂环和萘环等.体外人三阴乳腺癌MDA-MB-231细胞株生长抑制实验和Topo Ⅱα抑制实验结果表明, 6-(4-羟甲基苯基)-2-甲氧基喹啉(3b)有明显细胞毒性和Topo Ⅱα抑制活性(IC_(50)=9.9μmol·L~(-1)).研究结果为研发新型Topo Ⅱα抑制剂提供了新方向,对肿瘤的预防和治疗具有重要意义.
Human DNA Topoisomerase Ⅱα(Topo Ⅱα) is one of the important therapeutic targets for the treatment of cancers.Our previous study showed that p-terphenyls have inhibitory effects on Topo Ⅱα and inhibit the proliferation of human breast ductal carcinoma cells. In this study, nineteen 6-substituted aryl-2-methoxyquinolines(3a～3s) were designed, synthesized and evaluated for their cytotoxicity against the growth of human triple negative breast cancer MDA-MB-231 cell line and inhibitory activity against Topo Ⅱα. Among these compounds, 6-(4-(hydroxymethyl)phenyl)-2-methoxyquinoline(3b) showed the most potent activity(IC_(50)=9.9 μmol·L~(-1)). These results have important significance for the further study of aryl quinoline TopoⅡα inhibitors.
Human DNA Topoisomerase Ⅱα(Topo Ⅱα) is one of the important therapeutic targets for the treatment of cancers.Our previous study showed that p-terphenyls have inhibitory effects on Topo Ⅱα and inhibit the proliferation of human breast ductal carcinoma cells. In this study, nineteen 6-substituted aryl-2-methoxyquinolines(3a～3s) were designed, synthesized and evaluated for their cytotoxicity against the growth of human triple negative breast cancer MDA-MB-231 cell line and inhibitory activity against Topo Ⅱα. Among these compounds, 6-(4-(hydroxymethyl)phenyl)-2-methoxyquinoline(3b) showed the most potent activity(IC_(50)=9.9 μmol·L~(-1)). These results have important significance for the further study of aryl quinoline TopoⅡα inhibitors.
引文
[1]Wang, J. C. Annu. Rev. Biochem. 1996, 65, 635.
[2]Azarova, A. M.; Lyu, Y. L.; Lin, C. P.; Tsai, Y. C.; Lau, J. Y.; Wang,J. C.; Liu, L. F. Proc. Natl. Acad. Sci. U. S. A. 2007, 104, 11014.
[3]Deweese, J. E.; Osheroff, N. Nucleic Acids Res. 2009, 37, 738.
[4]Haffner, M. C.; Aryee, M. J.; Toubaji, A.; Esopi, D. M.; Albadine,R.; Gurel, B.; Isaacs, W. B.; Bova, G. S.; Liu, W.; Xu, J.; Meeker, A.K.; Netto, G.; De Marzo, A. M.; Nelson, W. G.; Yegnasubramanian,S. Nat. Genetics 2010, 42, 668.
[5]Liu,S.S.;Zhao,B.B.;Lu,C.H.;Huang,J.J.;Shen,Y.M.Nat.Prod. Commun. 2012, 7, 1057.
[6]Qiu, J.; Zhao, B.; Shen, Y.; Chen, W.; Ma, Y.; Shen, Y. Eur. J. Med.Chem. 2013, 68, 192.
[7]Ibrahim,M.K.;Taghour,M.S.;Metwaly,A.M.;Belal,A.;Mehany,A. B. M.;Elhendawy,M. A.;Yassin, M. M.; Yassin, A.M.;El-Deeb,N.M.;Hafez,E.E.;Elsohly,M.A.;Eissa,I.H.Eur.J.Med. Chem. 2018, 115, 117.
[8]Kaur, G.; Cholia, R. P.; Joshi, G.; Amrutkar, S. M.; Kalra, S.; Mantha, A. K.; Banerjee, U. C.; Kumar, R.. Pham. Chem. Life Sci. 2018,351, e1800023.
[9]Ruchelman, A. L.; Singh, S. K.; Wu, X.; Ray, A.; Yang, J. M.; Li, T.K.; Liu, A.; Liu, L. F.; LaVoie, E. J. Bioorg. Med. Chem. Lett. 2002,12, 3333.
[10]Lu, C. M.; Chen, Y. L.; Chen, H. L; Chen, C. A.; Lu, P. J.; Yang, C.N.; Tzeng, C. C. Bioorg. Med. Chem. 2010, 18, 1948.
[11]Carmichael, J.; DeGraff, W. G.; Gazdar, A. F.; Minna, J. D.; Mitchell, J. B. Cancer Res 1987, 47, 936.
[12]Huang,Y.;Wang,J.;Li,G.;Zheng,Z.;Su,W.FEMSImmunol.Med. Microbiol. 2001, 31, 163.
[13]Chen, W.; Shen, Y.; Li, Z.; Zhang, M.; Lu, C.; Shen, Y. Eur. J. Med.Chem. 2014, 86, 782.
[14]Shen, Y.; Chen, W.; Zhao, B.; Hao, H.; Li, Z.; Lu, C.; Shen, Y. Biochem. Biophys. Res. Commun. 2014, 453, 302.
[15]Shen, Y.; Chen, W.; Li, Z.; Shen, Y. Med. Chem. 2014, 10, 533.
[16]Barrett,J.;Sutcliffe,J.;Gootz,T.Antimicrob.AgentsChemother.1990, 34, 1.
[17]Marini, J. C.; Levene, S. D.; Crothers, D. M.; Englund, P. T. Proc.Natl. Acad. Sci. 1982, 79, 7664.
[18]Xiao, X.; Cushman, M. J. Am. Chem. Soc. 2005, 127, 9960.
[19]Trott, O.; Olson, A. J. J. Comput. Chem. 2010, 31, 455.
[20]Sanner, M. F. J. Mol.-Graphies Modell. 1999, 17, 57.
[21]Morris,G.M.;Huey,R.;Lindstrom,W.;Sanner,M.F.;Belew,R.K.; Goodsell, D. S.; Olson, A. J. J. Comput. Chem. 2009, 30, 2785.
[2]Azarova, A. M.; Lyu, Y. L.; Lin, C. P.; Tsai, Y. C.; Lau, J. Y.; Wang,J. C.; Liu, L. F. Proc. Natl. Acad. Sci. U. S. A. 2007, 104, 11014.
[3]Deweese, J. E.; Osheroff, N. Nucleic Acids Res. 2009, 37, 738.
[4]Haffner, M. C.; Aryee, M. J.; Toubaji, A.; Esopi, D. M.; Albadine,R.; Gurel, B.; Isaacs, W. B.; Bova, G. S.; Liu, W.; Xu, J.; Meeker, A.K.; Netto, G.; De Marzo, A. M.; Nelson, W. G.; Yegnasubramanian,S. Nat. Genetics 2010, 42, 668.
[5]Liu,S.S.;Zhao,B.B.;Lu,C.H.;Huang,J.J.;Shen,Y.M.Nat.Prod. Commun. 2012, 7, 1057.
[6]Qiu, J.; Zhao, B.; Shen, Y.; Chen, W.; Ma, Y.; Shen, Y. Eur. J. Med.Chem. 2013, 68, 192.
[7]Ibrahim,M.K.;Taghour,M.S.;Metwaly,A.M.;Belal,A.;Mehany,A. B. M.;Elhendawy,M. A.;Yassin, M. M.; Yassin, A.M.;El-Deeb,N.M.;Hafez,E.E.;Elsohly,M.A.;Eissa,I.H.Eur.J.Med. Chem. 2018, 115, 117.
[8]Kaur, G.; Cholia, R. P.; Joshi, G.; Amrutkar, S. M.; Kalra, S.; Mantha, A. K.; Banerjee, U. C.; Kumar, R.. Pham. Chem. Life Sci. 2018,351, e1800023.
[9]Ruchelman, A. L.; Singh, S. K.; Wu, X.; Ray, A.; Yang, J. M.; Li, T.K.; Liu, A.; Liu, L. F.; LaVoie, E. J. Bioorg. Med. Chem. Lett. 2002,12, 3333.
[10]Lu, C. M.; Chen, Y. L.; Chen, H. L; Chen, C. A.; Lu, P. J.; Yang, C.N.; Tzeng, C. C. Bioorg. Med. Chem. 2010, 18, 1948.
[11]Carmichael, J.; DeGraff, W. G.; Gazdar, A. F.; Minna, J. D.; Mitchell, J. B. Cancer Res 1987, 47, 936.
[12]Huang,Y.;Wang,J.;Li,G.;Zheng,Z.;Su,W.FEMSImmunol.Med. Microbiol. 2001, 31, 163.
[13]Chen, W.; Shen, Y.; Li, Z.; Zhang, M.; Lu, C.; Shen, Y. Eur. J. Med.Chem. 2014, 86, 782.
[14]Shen, Y.; Chen, W.; Zhao, B.; Hao, H.; Li, Z.; Lu, C.; Shen, Y. Biochem. Biophys. Res. Commun. 2014, 453, 302.
[15]Shen, Y.; Chen, W.; Li, Z.; Shen, Y. Med. Chem. 2014, 10, 533.
[16]Barrett,J.;Sutcliffe,J.;Gootz,T.Antimicrob.AgentsChemother.1990, 34, 1.
[17]Marini, J. C.; Levene, S. D.; Crothers, D. M.; Englund, P. T. Proc.Natl. Acad. Sci. 1982, 79, 7664.
[18]Xiao, X.; Cushman, M. J. Am. Chem. Soc. 2005, 127, 9960.
[19]Trott, O.; Olson, A. J. J. Comput. Chem. 2010, 31, 455.
[20]Sanner, M. F. J. Mol.-Graphies Modell. 1999, 17, 57.
[21]Morris,G.M.;Huey,R.;Lindstrom,W.;Sanner,M.F.;Belew,R.K.; Goodsell, D. S.; Olson, A. J. J. Comput. Chem. 2009, 30, 2785.