2-甲硫基-4-芳胺喹唑啉衍生物的合成及抗肿瘤活性评价
|
摘要
为了寻求高效的新型抗肿瘤药物,设计并合成了一系列新型2-甲硫基-4-苯胺喹唑啉衍生物,对这些化合物在人类四种癌细胞MGC-803(人胃癌细胞)、PC-3(人前列腺癌细胞)、HGC-27(人胃癌细胞)和A549(人非小细胞肺癌细胞)进行抗肿瘤活性评价.结果显示部分化合物具有较好的抗肿瘤活性,其中N-(4-氟苯基)-2-(甲硫基)喹唑啉-4-胺(9c)和N-(4-甲基苯基)-2-(甲硫基)喹唑啉-4-胺(9m)显示出较高的抗肿瘤活性, IC_(50)值分别为0.18和0.68μmol·L~(-1).
In order to find the efficient and novel antitumor drugs,a series of 2-methylthio-4-arylamine quinazoline derivatives were designed and synthesized.The target compounds were evaluated for antitumor activity in vitro on four human cancer cell lines initially including MGC-803,PC-3,HGC-27 and A549.The results showed that some compounds had good antitumor activities,especially N-(4-fluorophenyl)-2-(methylthio)quinazolin-4-amine(9c) and 2-(methylthio)-N-(p-tolyl)-quina-zolin-4-amine(9 m),with IC_(50) values of 0.18 and 0.68 μmol·L~(-1),respectively.
In order to find the efficient and novel antitumor drugs,a series of 2-methylthio-4-arylamine quinazoline derivatives were designed and synthesized.The target compounds were evaluated for antitumor activity in vitro on four human cancer cell lines initially including MGC-803,PC-3,HGC-27 and A549.The results showed that some compounds had good antitumor activities,especially N-(4-fluorophenyl)-2-(methylthio)quinazolin-4-amine(9c) and 2-(methylthio)-N-(p-tolyl)-quina-zolin-4-amine(9 m),with IC_(50) values of 0.18 and 0.68 μmol·L~(-1),respectively.
引文
[1]Sangthong,S.;Krusong,K.;Ngamrojanavanich,N.;Vilaivan,T.;Puthong,S.;Chandchawan,S.;Muangsin,N. Bioorg.Med.Chem.Lett. 2011, 21, 4813.
[2]Cao,R.H.;Fan,W.X.;Guo,L.;Ma,Q.;Zhang,G.X.;Li,J.R.;Chen, X. M.; Ren, Z. H.; Qiu, L. Q. Eur. J. Med. Chem. 2013, 60,135.
[3]VanHorn,K.S.;Burda,W.N.;Fleeman,R.;Shaw,L.N.;Manetsch, R. J. Med. Chem. 2014, 57, 3075.
[4]Liu, F.; Huang, Y. J. Pestic. Biochem. Phys. 2011, 101, 248.
[5]Alafeefy,A.M.;Kadi,A.A.;Al-Deeb,O.A.;El-Tahir,K.E.H.;Al-Jaber, N. A. Eur. J. Med. Chem. 2010, 45, 4947.
[6]Wu, J. W.; Chen, W. T.; Xia, G. X.; Zhang, J.; Shao, J. A.; Tan, B.Q.; Zhang, Z. Z.; Yu, W. W.; Weng, Q. J.; Liu, H. Y.; Hu, M.; Deng,H. L.; Hao, Y.; Shen, J. K.; Yu, Y. P. ACS Med. Chem. Lett. 2013, 4,974.
[7]Zhang, Y. L.; Chen, L.; Xu, H. J.; Li, X. B.; Zhao, L. J.; Wang, W.;Li, B. L.; Zhang, X. Q. Eur. J. Med. Chem. 2018, 147, 77.
[8]Siegel, R.; Naishadham, D.; Jemal, A. CA Cancer J. Clin. 2013, 67,11.
[9]Cui,G.;Cui,M.;Li,Y.;Liang,Y.;Li,W.;Guo,H.;Zha,S.Med.Oncol. 2015, 32, 570.
[10]Mathew,M.P.;Tan,E.;Saeui,C.T.;Bovonratwet,P.;Liu,L.;Bhattacharya, R.; Yarema, K. J. Bioorg. Med. Chem. Lett. 2015, 25,1223.
[11]Smaill,J.B.;Showalter,H.D.H.;Zhou,H.;Bridges,A.J.;Mc Namara, D. J.; Fry, D. W.; Nelson, J. M.; Sherwood, V.; Vincent,P.W.;Roberts,B.J.;Elliott,W.L.;Denny,W.A.J.Med.Chem.2001, 44, 429.
[12]Engelman, J. A.; Zejnullahu, F.; Gale, C.-M.; Lifshits, E.; Gonzales,A.J.;Shimamura,T.;Zhao,F.;Vincent,P.W.;Naumov,G.N.;Bradner, J. E.; Althaus, I. W.; Gandhi, L.; Shapiro, G. I.; Nelson, J.M.; Heymach, J. V.; Meyerson, M.; Wong, K. K.; Janne, P. A. Cancer Res. 2007, 67, 11924.
[13]Li,D.;Ambrogio,L.;Shimamura,T.;Kubo,S.;Takahashi,M.;Chirieac,L. R.; Padera, R. F.; Shapiro, G. I.; Baum, A.; Himmelsbach,F.;Rettig,W.J.;Meyerson,M.;Solca,F.;Greulich,H.;Wong, K. K. Oncogene 2008, 27, 4702.
[14]Al-Rashood, S. T.; Aboldahab, I. A.; Nagi, M. N.; Abouzeid, L. A.;Abdel-Aziz,A.A.M.;Abdel-Hamide,S.G.;Youssef,K.M.;Al-Obaid, A. M.; El-Subbagh, H. I. Bioorg. Med. Chem. 2006, 14,8608.
[15]Shao, K. P.; Zhang, X. Y.; Chen, P. J.; Xue, D. Q.; He, P.; Ma, L. Y.;Zheng,J.X.;Zhang,Q.R.;Liu,H.M.Bioorg.Med.Chem.Lett.2014, 24, 3877.
[16]Wang,C.;Cao,Q.;Yang,H.;Song,P.;Xue,D.;Cui,F.;Gu,Y.;Zhang, X.; Tian, Y.; Zhang, Q.; Liu, H. Chin. J. Org. Chem. 2016,36, 1626(in Chinese).(王超杰,曹钦坡,杨慧,宋攀攀,薛登启,崔飞,顾一飞,张孝松,田亚楠,张秋荣,刘宏民,有机化学, 2016, 36, 1626.)
[17]Li,N.;Xin,J.C.;Ma,Q.S.;Li,E.D.;Meng,Y.Q.;Bao,C.N.;Yang,P.;Song,P.P.;Cui,F.;Cheng,P.J.;Gu,Y.F.;Zhao,P.R.;Ke, Y.; Liu, H. M.; Zhang, Q. R. Chin. J. Org. Chem. 2018, 38, 665(in Chinese).(栗娜,辛景超,马启胜,李二冬,孟娅琪,包崇男,杨鹏,宋攀攀,崔飞,陈鹏举,顾一飞,赵培荣,可钰,刘宏民,张秋荣,有机化学, 2018, 38, 665.)
[18]Xin, J. C.; Li, N.; Ma, Q. S.; Li, E. D.; Meng, X. C.; Ke, Y.; Liu, H.M.; Zhang, Q. R. Chin. J. Org. Chem. 2018, 32, 451(in Chinese).(辛景超,栗娜,马启胜,李二冬,孟祥川,可钰,刘宏民,张秋荣,有机化学, 2018, 32, 451.)
[19]Abdullaev, N. P.;Kayumov,K.; Shakhidoyatov, K. M. Uzb. Khim.Zh. 1997, 2, 29.
[20]Kikelj, D. In Science of Synthesis, Product Class 13:Quinazolines,Vol. 16, Eds.:Yamamoto, Y.; Bellus, D.; Jacobsen, E. N.; Ley, S. V.;Noyori,R.;Regitz,M.;Reider,P.J.;Schaumann,E.;Shinkai,I.;Thimas, E. J.; Trost, B. M., Thieme, Stuttgart, 2004, p. 573.
[21]Song,P.P.;Cui,F.;Li,N.;Xin,J.C.;Ma,Q.S.;Meng,X.C.;Wang, C. J.; Cao, Q. P.; Gu, Y. F.; Ke, Y.; Zhang, Q. R.; Liu, H. M.Chin. J. Chem. 2017, 35, 1633(in Chinese).(宋攀攀,崔飞,栗娜,辛景超,马启胜,孟祥川,王超杰,曹钦坡,顾一飞,可钰,刘宏民,张秋荣,有机化学, 2017, 35, 1633.)
[22]Shao, K. P.; Zhang, X. Yao.; Chen, P. J.; Xue, D. Q.; He, P.; Ma, L.Y.; Zheng, J. X.; Zhang, Q. R.; Liu, H. M. Bioorg. Med. Chem. Lett.2014, 24, 3877.
[23]Chen, P. J.; Yang, A.; Gu, Y. F.; Zhang, X. S.; Shao, K. P.; Xue, D.Q.;He,P.;Jiang,T.F.;Zhang,Q.R.;Liu,H.M.Bioorg.Med.Chem. Lett. 2014, 24, 2741.
[2]Cao,R.H.;Fan,W.X.;Guo,L.;Ma,Q.;Zhang,G.X.;Li,J.R.;Chen, X. M.; Ren, Z. H.; Qiu, L. Q. Eur. J. Med. Chem. 2013, 60,135.
[3]VanHorn,K.S.;Burda,W.N.;Fleeman,R.;Shaw,L.N.;Manetsch, R. J. Med. Chem. 2014, 57, 3075.
[4]Liu, F.; Huang, Y. J. Pestic. Biochem. Phys. 2011, 101, 248.
[5]Alafeefy,A.M.;Kadi,A.A.;Al-Deeb,O.A.;El-Tahir,K.E.H.;Al-Jaber, N. A. Eur. J. Med. Chem. 2010, 45, 4947.
[6]Wu, J. W.; Chen, W. T.; Xia, G. X.; Zhang, J.; Shao, J. A.; Tan, B.Q.; Zhang, Z. Z.; Yu, W. W.; Weng, Q. J.; Liu, H. Y.; Hu, M.; Deng,H. L.; Hao, Y.; Shen, J. K.; Yu, Y. P. ACS Med. Chem. Lett. 2013, 4,974.
[7]Zhang, Y. L.; Chen, L.; Xu, H. J.; Li, X. B.; Zhao, L. J.; Wang, W.;Li, B. L.; Zhang, X. Q. Eur. J. Med. Chem. 2018, 147, 77.
[8]Siegel, R.; Naishadham, D.; Jemal, A. CA Cancer J. Clin. 2013, 67,11.
[9]Cui,G.;Cui,M.;Li,Y.;Liang,Y.;Li,W.;Guo,H.;Zha,S.Med.Oncol. 2015, 32, 570.
[10]Mathew,M.P.;Tan,E.;Saeui,C.T.;Bovonratwet,P.;Liu,L.;Bhattacharya, R.; Yarema, K. J. Bioorg. Med. Chem. Lett. 2015, 25,1223.
[11]Smaill,J.B.;Showalter,H.D.H.;Zhou,H.;Bridges,A.J.;Mc Namara, D. J.; Fry, D. W.; Nelson, J. M.; Sherwood, V.; Vincent,P.W.;Roberts,B.J.;Elliott,W.L.;Denny,W.A.J.Med.Chem.2001, 44, 429.
[12]Engelman, J. A.; Zejnullahu, F.; Gale, C.-M.; Lifshits, E.; Gonzales,A.J.;Shimamura,T.;Zhao,F.;Vincent,P.W.;Naumov,G.N.;Bradner, J. E.; Althaus, I. W.; Gandhi, L.; Shapiro, G. I.; Nelson, J.M.; Heymach, J. V.; Meyerson, M.; Wong, K. K.; Janne, P. A. Cancer Res. 2007, 67, 11924.
[13]Li,D.;Ambrogio,L.;Shimamura,T.;Kubo,S.;Takahashi,M.;Chirieac,L. R.; Padera, R. F.; Shapiro, G. I.; Baum, A.; Himmelsbach,F.;Rettig,W.J.;Meyerson,M.;Solca,F.;Greulich,H.;Wong, K. K. Oncogene 2008, 27, 4702.
[14]Al-Rashood, S. T.; Aboldahab, I. A.; Nagi, M. N.; Abouzeid, L. A.;Abdel-Aziz,A.A.M.;Abdel-Hamide,S.G.;Youssef,K.M.;Al-Obaid, A. M.; El-Subbagh, H. I. Bioorg. Med. Chem. 2006, 14,8608.
[15]Shao, K. P.; Zhang, X. Y.; Chen, P. J.; Xue, D. Q.; He, P.; Ma, L. Y.;Zheng,J.X.;Zhang,Q.R.;Liu,H.M.Bioorg.Med.Chem.Lett.2014, 24, 3877.
[16]Wang,C.;Cao,Q.;Yang,H.;Song,P.;Xue,D.;Cui,F.;Gu,Y.;Zhang, X.; Tian, Y.; Zhang, Q.; Liu, H. Chin. J. Org. Chem. 2016,36, 1626(in Chinese).(王超杰,曹钦坡,杨慧,宋攀攀,薛登启,崔飞,顾一飞,张孝松,田亚楠,张秋荣,刘宏民,有机化学, 2016, 36, 1626.)
[17]Li,N.;Xin,J.C.;Ma,Q.S.;Li,E.D.;Meng,Y.Q.;Bao,C.N.;Yang,P.;Song,P.P.;Cui,F.;Cheng,P.J.;Gu,Y.F.;Zhao,P.R.;Ke, Y.; Liu, H. M.; Zhang, Q. R. Chin. J. Org. Chem. 2018, 38, 665(in Chinese).(栗娜,辛景超,马启胜,李二冬,孟娅琪,包崇男,杨鹏,宋攀攀,崔飞,陈鹏举,顾一飞,赵培荣,可钰,刘宏民,张秋荣,有机化学, 2018, 38, 665.)
[18]Xin, J. C.; Li, N.; Ma, Q. S.; Li, E. D.; Meng, X. C.; Ke, Y.; Liu, H.M.; Zhang, Q. R. Chin. J. Org. Chem. 2018, 32, 451(in Chinese).(辛景超,栗娜,马启胜,李二冬,孟祥川,可钰,刘宏民,张秋荣,有机化学, 2018, 32, 451.)
[19]Abdullaev, N. P.;Kayumov,K.; Shakhidoyatov, K. M. Uzb. Khim.Zh. 1997, 2, 29.
[20]Kikelj, D. In Science of Synthesis, Product Class 13:Quinazolines,Vol. 16, Eds.:Yamamoto, Y.; Bellus, D.; Jacobsen, E. N.; Ley, S. V.;Noyori,R.;Regitz,M.;Reider,P.J.;Schaumann,E.;Shinkai,I.;Thimas, E. J.; Trost, B. M., Thieme, Stuttgart, 2004, p. 573.
[21]Song,P.P.;Cui,F.;Li,N.;Xin,J.C.;Ma,Q.S.;Meng,X.C.;Wang, C. J.; Cao, Q. P.; Gu, Y. F.; Ke, Y.; Zhang, Q. R.; Liu, H. M.Chin. J. Chem. 2017, 35, 1633(in Chinese).(宋攀攀,崔飞,栗娜,辛景超,马启胜,孟祥川,王超杰,曹钦坡,顾一飞,可钰,刘宏民,张秋荣,有机化学, 2017, 35, 1633.)
[22]Shao, K. P.; Zhang, X. Yao.; Chen, P. J.; Xue, D. Q.; He, P.; Ma, L.Y.; Zheng, J. X.; Zhang, Q. R.; Liu, H. M. Bioorg. Med. Chem. Lett.2014, 24, 3877.
[23]Chen, P. J.; Yang, A.; Gu, Y. F.; Zhang, X. S.; Shao, K. P.; Xue, D.Q.;He,P.;Jiang,T.F.;Zhang,Q.R.;Liu,H.M.Bioorg.Med.Chem. Lett. 2014, 24, 2741.