Synthesis and biological evaluation of novel uracil and 5-fluorouracil-1-yl acetic acid-colchicine conjugate

Abstract

A series of novel uracil and 5-fluorouracil-1-yl-acetic acid-colchicine derivatives(6a–6n) was synthesized via coupling uracil and 5-fluorouracil(5-FU) with C-10 analogues of colchicine. The antitumor activities of the target compounds against human hepatocellular carcinoma(BEL7402) cells, human ovary carcinoma(A2780) cells, human lung adenocarcinoma(A549) cells and human breast carcinoma(MCF7) cells were tested in vitro, and the structure-activity relationship(SAR) of the compounds was also studied. The bioassay results demonstrate that most of the tested compounds display significant activity and particularly, compounds 6a, 6e, 6h and 6l show more potent cytotoxic activities than 5-fluorouracil and colchicine. The results show that the new derivatives of colchicine are potential suppressors on human cancer.

Keywords

Colchicine / Uracil / 5-Fluorouracil / Antitumor activity

References

[1] Bhattacharyya B., Panda D., Gupta S., Banerjee M. Med. Res. Rev., 2008, 28(1): 155.

[2] Lu Y., Chen J., Xiao M., Li W., Miller D. D. Pharm. Res., 2012, 29(11): 2943.

[3] Yang B., Zhu Z. C., Goodson H. V., Miller M. J. Bioorg. Med. Chem. Lett., 2010, 20(11): 3831.

[4] Huzil J. T., Mane J., Tuszynski J. A. Interdiscip. Sci., 2010, 2(2): 169.

[5] Passarella D., Peretto B., Blascoy Y. R., Cappelletti G., Cartelli D., Ronchi C. Eur. J. Med. Chem., 2010, 45(1): 219.

[6] Larocque K., Ovadje P., Djurdjevic S., Mehdi M., Green J., Pandey S. PLoS One, 2014, 9(1): 87064.

[7] Kozaka T., Nakagawa-Goto K., Shi Q., Lai C. Y., Hamel E., Bastow K. F. Bioorg. Med. Chem. Lett., 2010, 20(14): 4091.

[8] Lee K. H., Wu Y. S., Iris H., Hall I. H. J. Med. Chem., 1977, 20(7): 911.

[9] Li S. S., Jiang X. N., Wang C. S. Chem. J. Chinese Universities, 2014, 35(11): 2403.

[10] Toriumi F., Kubota T., Saikawa Y., Yoshida M., Otani Y., Watanabe M., Kumai K., Kitajima M. Anticancer Res., 2004, 24(4): 2455.

[11] Longley D. B., Harkin D. P., Johnston P. G. Nat. Rev. Cancer, 2003, 3(5): 330.

[12] Scartozzi M., Maccaroni E., Giampieri R., Pistelli M., Bittoni A., del Prete M., Berardi R., Cascinu S. Pharmacogenomics, 2011, 12(4): 251.

[13] Wang W. B., Yang Y., Zhao Y. P., Zhang T. P., Liao Q., Shu H. World J. Gastroenterol., 2014, 20(42): 15682.

[14] Cheng M., Gao X., Wang Y., Chen H., He B., Xu H., Li Y., Han J., Zhang Z. Mar. Drugs, 2013, 11(9): 3517.

[15] Tong C. Y., Tang F. X., Liu B., Liao H. D., Liu X. M. Chem. J. Chinese Universities, 2014, 35(7): 1603.

[16] McCarthy O., Musso-Buendia A., Kaiser M., Brun R., Ruiz-Perez L. M., Johansson N. G., Pacanowska D. G., Gilbert I. H. Eur. J. Med. Chem., 2009, 44(2): 678.

[17] Udo K., Hokonohara K., Motoyama K., Arima H., Hirayama F., Uekama K. Int. J. Pharm, 2010, 388(1/2): 95.

[18] Wang B., Pan X. D., Liu H. Y., Yang J., Lü Z. Y., Zhao J. H. Acta Pharm. Sin., 2006, 41(11): 1057.

[19] Shen L. H., Zhang L., Wang H. X., Wang X., Zhang G. J. Asian J. Chem., 2014, 26(21): 7475.

[20] Tatsuzaki J., Taniguchi M., Bastow K. F., Nakagawa-Goto K., Morris-Natschke S. L., Itokawa H. Bioorg. Med. Chem., 2007, 15(18): 6193.