Anticancer activity of new coumarin substituted hydrazide–hydrazone derivatives

• Sixteen coumarin hydrazide–hydrazone derivatives were synthesized.
• Bromocoumarins showed potent antitumor activity against Panc-1 cancer cell line.
• Bromocoumarins activated caspases 3/7 and they could induce apoptosis.
• Coumarin 7c induced the expression of cell cycle arrest (G2/M) genes.
• Coumarin 7c induced up- and down-regulation of several genes.

Drug resistance is a major impediment for cancer treatment, to overcome it we designed and synthesized sixteen coumarins bearing hydrazide–hydrazone moiety and evaluated them against human drug-resistant pancreatic carcinoma (Panc-1) cells and drug-sensitive (hepatic carcinoma; Hep-G2 and leukemia; CCRF) cell lines in vitro. The 6-brominated coumarin hydrazide–hydrazone derivatives (BCHHD) 7c, 8c and 10c were more potent than doxorubicin (DOX) against resistant Panc-1 cells. BCHHD 7c showed significant cytotoxicity against all tested cells (IC50: 3.60–6.50 μM) on comparison with all other coumarin hydrazide–hydrazone derivatives (CHHD), whereas BCHHD's 8c and 10c showed significant antiproliferative activity only against resistant Panc-1 cells with IC50 of 2.02 μM and 2.15 μM, respectively. All the investigated BCHHD's were able to activate caspases 3/7 and they could induce apoptosis in resistant Panc-1 cells. Microarray analysis showed that BCHHD 7c induced the expression of apoptotic- and cell cycle arrest (G2/M)- genes in resistant Panc-1 cells. Moreover, BCHHD 7c induced the up-regulation of CDKN1A, DDIT4, GDF-15 and down-regulation of CDC2, CDC20, CDK2 genes. Based on our results, we conclude that 7c could be a potent anticancer drug to overcome drug resistance in cancer and it could be highly beneficial for patients in the clinic.

New series of coumarins were synthesized and evaluated in vitro for their anticancer activity. Bromocoumarins were found to be the most active antitumor agent against drug-resistant pancreatic carcinoma cells. Figure optionsDownload as PowerPoint slide