Design, synthesis and anticancer activity of novel 6-(aminophenyl)-2,4-bismorpholino-1,3,5-triazine derivatives bearing arylmethylene hydrazine moiety

Abstract

In an attempt to develop potent and selective anticancer agents, we designed and synthesized a series of novel bis(morpholino-1,3,5-triazine) derivatives bearing aylmethylene hydrazine moiety and evaluated their cytotoxicity, in vitro, against H460(non-small-cell lung cancer), HT-29(human colorectal cancer) and MDA-MB-231(human breast cancer) cell lines. The pharmacological results indicate that all the compounds exhibit enhanced cytotoxicity than BMCL-200908069-1, and six target compounds(7e, 7h, 7j, 9a, 9b, 9c) were superior to PAC-1 against all the tested cancer cell lines. The most active compound 7j, with IC₅₀^(inhibitory concentration 50%) values of 0.75, 0.34 and 0.60 μmol/L against HT-29, H460 and MDA-MB-231 cancer cell lines, was 39-, 28-, and 60-fold more potent than BMCL-200908069-1(29.24, 9.52 and 36.21 μmol/L), respectively.

Keywords

Bis(morpholino-1,3,5-triazine) / Design / Anticancer activity

References

[1] Ma Z Y, Zhang X H, Li C N, Zheng Y J, Yang G L, Wang S K, He Y. Chem. Res. Chinese Universities, 2011, 27(5): 787.

[2] Maira S M, Pecchi S, Huang A, Burger M, Knapp M, Sterker D, Schnell C, Guthy D, Nagel T, Wiesmann M, Brachmann S, Fritsch C, Dorsch M, Chène P, Shoemaker K, Pover A D, Menezes D, Martiny-Baron G, Fabbro D, Wilson C J, Schlegel R, Hofmann F, García-Echeverría C, Sellers W R, Voliva C F. Mol. Cancer. Ther., 2012, 11: 317.

[3] Kong D, Yamori T. Cancer Sci., 2007, 98(10): 1638.

[4] Menear K A, Gomez S, Malagu K, Bailey C, Blackburn K, Cockcroft X L, Ewen S, Fundo A, Gall A L, Hermann G, Sebastian L, Sunose M, Presnot T, Torode E, Hickson I, Martin N M B, Smith G C M, Pike K G. Bioorg. Med. Chem. Lett., 2009, 19: 5898.

[5] Venkatesan A M, Chen Z, Santos O D, Dehnhardt C, Santos E D, Kaloustian S A, Mallon R, Hollander I, Feldberg L, Lucas J, Yu K, Chaudhary I, Mansour T S. Bioorg. Med. Chem. Lett., 2010, 20: 5869.

[6] Zhu W F, Liu Y J, Zhao Y F, Wang H Y, Tan L, Fan W J, Gong P. Arch. Pharm. Chem. Life Sci., 2012, 345: 812.

[7] Putt K S, Chen G W, Pearson J M, Sandhorst J S, Hoagland M S, Kwon J T, Hwang S K, Jin H, Churchwell M I, Cho M H, Doerge D R, Helferich W G, Hergenrother P J. Nat. Chem. Biol., 2006, 2(10): 543.

[8] Zhang G G, Liu Y J, Wang S B, Zhou C, Huang Q C, Gong P. Arch. Pharm. Chem. Life Sci., 2012, 345: 49.

[9] Zhang G G, Liu Y J, Ma X G, Dong H, Li J, Gong P. Chin. Chem. Lett., 2011, 22: 1223.

[10] Zhu W F, Zhai X, Fu Q Q, Guo F, Bai M, Wang J Q, Wang H Y, Gong P. Chem. Pharm. Bull., 2012, 60(8): 1037.

[11] Zhu W F, Zhai X, Li S, Cao Y Y, Gong P, Liu Y J. Chin. Chem. Lett., 2012, 23: 703.

[12] Peterson Q P, Hsu D C, Goode D R, Novotny C J, Totten R K, Hergenrother P J. J. Med. Chem., 2009, 52: 5721.

[13] Horiuchi T, Takeda Y, Haginoya N, Miyazaki M, Nagata M, Kitagawa M, Akahane K, Uoto K. Chem. Pharm. Bull., 2011, 59(8): 991.

[14] Horiuchi T, Chiba J, Uoto K, Soga T. Bioorg. Med. Chem. Lett., 2009, 19: 305.

[15] Horiuchi T, Nagata M, Kitagawa M, Akahane K, Uoto K. Bioorg. Med. Chem., 2009, 17: 7850.

[16] Xu S Y, Bian R L, Chen X. Method of Pharmacology, 2002, Beijing: Public Health Publishing House 1784.

[17] Chen S M, Liu J L, Wang X, Liang C, Ding J, Meng L H. Biochem. Pharm., 2012, 83: 1183.

[18] Garino C, Ghiani S, Gobetto R, Nervi C, Salassa L, Croce G, Milanesio M, Rosenberg E, Alexander Ross J B. Eur. J. Inorg. Chem., 2006, 2885.

[19] Zhu W F, Liu Y J, Zhai X, Wang X, Zhu Y, Wu D, Zhou H Y, Gong P, Zhao Y F. Eur. J. Med. Chem., 2012, 57: 162.