Synthesis of new tricyclic thiolactams as potent antitumor agent for pancreatic cancer

Abstract

We synthesized the novel tricyclic thiolactams 2a–d, 3d–k, having a benzyl or substituted benzyl substituent on the nitrogen of indole subunit, and their preferential cytotoxicity under both nutrient-deprived medium (NDM) and Dulbecco’s modified Eagle’s medium (DMEM) was evaluated against a human pancreatic cancer cell line PANC-1. Among the tested compounds, the 4′-hydroxy derivative 3d showed the most potent cytotoxicity in NDM (PC50 1.68μM) although the moderate preferential cytotoxicity (PC50 1.68μM in NDM vs PC50 20μM in DMEM). The 3′-hydroxy derivative 3e exhibited the most preferential cytotoxicity (PC50 1.96μM in NDM vs less than 50% inhibition at 30μM in DMEM). The benzyl 2a and halogenated benzyl derivatives 2b,c showed no cytotoxicity in NDM. In addition, the indole (10, PC50 173.7μM), lactone (11, PC50 131.7μM), and lactam (12, PC50 44.8μM) derivatives showed week or moderate cytotoxicity in NDM. These results indicated that the hydroxy group on the benzyl substituent and tricyclic thiolactam ring were essential for the cytotoxicity in NDM against PANC-1 cell line. Moreover, 3′-hydroxy derivative 3e compound exhibited antitumor activity against the pancreatic ductal adenocarcinoma (PDAC) xenograft model in vivo.