Abstract

Background: Cancer is a major health problem worldwide, the relative mortality rate caused by cancer is still very high even in developed countries. Although the remarkable success has been achieved: some small molecule anticancer agents have been approved by the U.S. Food and Drug Administration (FDA) in clinics and some are currently in clinical trials, cancer chemotherapy is still highly inadequate. It is essential to find novel structures, low side effect and more potent anticancer agents. Thieno[2,3-d]pyrimidine derivatives also exhibited a wide range of biological activities, especially thieno[2,3-d]pyrimidine derivatives exhibited potent anticancer activities. Based on our previous good results, we synthesized 21 new structures of thieno[2,3- d]pyrimidine derivatives in current work and evaluated their cytotoxicity to A549, HCT116 and MCF-7 cell lines.

Methods: The target compounds were prepared by the reaction of 5-substituted-4-chlorothieno[ 2,3-d]pyrimidine with (3-(substituted-phenyl]-isoxazole-5-yl)-methanol in dry iso-PrOH, catalyzed by Et3N. And then, the in vitro anticancer efficacy against A549, HCT116 and MCF-7 cell lines was evaluated using MTT method.

Results: The target compounds were characterized using NMR and MS. Most compounds exhibited good anticancer activity against A549, HCT116 and MCF-7 cell lines.

Conclusion: 6-Methyl-4-{[3-(4-chlorophenyl)-isoxazol-5-yl-]-methoxy-}-thieno[2,3-d]-pyrimidine (3e) exhibited the most potent cytotoxicity to A549, HCT116 and MCF-7 cell lines (IC50s: 2.79, 6.69 and 4.21×10-3 µM, respectively) than the reference drug gefitinib (IC50s: 17.90, 21.55 and 20.68 µM, respectively). 3e can be regarded as the best drug candidates for development of anticancer drugs.

Keywords: Isoxazole moiety, thieno[2, 3-d]pyrimidine derivatives, synthesis, anticancer activity, cell lines, anticancer drugs.

Graphical Abstract