Design, synthesis and biological evaluation of novel thiosemicarbazone-indole derivatives targeting prostate cancer cells

To discover novel anticancer agents with potent and low toxicity, we designed and synthesized a range of new thiosemicarbazone-indole analogues based on lead compound 4 we reported previously. Most compounds displayed moderate to high anticancer activities against five tested tumor cells (PC3, EC109, DU-145, MGC803, MCF-7). Specifically, the represented compound 16f possessed strong antiproliferative potency and high selectivity toward PC3 cells with the IC50 value of 0.054 mu M, compared with normal WPMY-1 cells with the IC50 value of 19.470 mu M. Preliminary mechanism research indicated that compound 16f could significantly suppress prostate cancer cells (PC3, DU-145) growth and colony formation in a dose-dependent manner. Besides, derivative 16f induced G1/S cycle arrest and apoptosis, which may be related to ROS accumulation due to the activation of MAPK signaling pathway. Furthermore, molecule 16f could effectively inhibit tumor growth through a xenograft model bearing PC3 cells and had no evident toxicity in vivo. Overall, based on the biological activity evaluation, analogue 16f can be viewed as a potential lead compound for further development of novel anti-prostate cancer drug. (C) 2020 Elsevier Masson SAS. All rights reserved.

Automated summary

Novel thiosemicarbazone-indole analogues were designed and synthesized based on lead compound 4, with compound 16f showing strong anticancer activity and selectivity towards PC3 cells. Its mechanism of action may involve inducing G1/S cycle arrest and apoptosis to inhibit cancer cell growth.