Synthesis and antitumor activity of pyrido [2,3-d]pyrimidine and pyrido[2,3-d] [1,2,4]triazolo[4,3-a]pyrimidine derivatives that induce apoptosis through G1 cell-cycle arrest

• New pyridopyrimidine and pyridotriazolopyrimidine derivatives were synthesized.
• The new compounds displayed significant antitumor activity against PC-3 cancer cells.
• The most potent compound 15f was able to cause G1 cell cycle arrest at PC-3 cells.
• Also, 15f demonstrated activity as caspase-3 activator and apoptosis inducer.

New series of 2-(2-arylidenehydrazinyl)pyrido[2,3-d]pyrimidines 5a–e and pyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidines 6–15 were synthesized and evaluated for their cytotoxic activity against two cancer cell lines, namely PC-3 prostate cancer and A-549 lung cancer. Some of the tested compounds displayed high growth inhibitory activity against PC-3 cells. Whereas, compounds 5b and 15f showed relatively potent antitumor activity against PC-3 and A-549 cell lines. In particular, 4-(3-acetyl-5-oxo-6-phenyl-8-(thiophen-2-yl)pyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidin-1(5H)-yl)benzenesulfonamide 15f exhibited superior antitumor activity against both cell lines at submicromolar level (IC50 = 0.36, 0.41 μM, respectively). Moreover, the potential mechanisms of the cytotoxic activity of the promising compound 15f on the more sensitive cell line PC-3 were studied. The data indicated that 15f was able to cause cell cycle arrest at least partly through enhancing the expression level of the cell cycle inhibitor p21 and induced cancer cell apoptosis via caspase-3 dependent pathway.

New series of pyrido[2,3-d]pyrimidine and pyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidine derivatives were synthesized as antitumor agents. The most potent compound 15f caused cell cycle arrest and induced apoptosis in PC-3 cancer cell line. Figure optionsDownload as PowerPoint slide