Synthesis and biological evaluation of prodrugs for nitroreductase based HSP90 inhibitor BIIB021as potential anticancer agents

Abstract

A series of prodrugs for nitroreductase (NTR) on the basis of BIIB021 as potential anticancer agents have been synthesized and tested in vitro for their cytotoxic effects. The results indicated that compounds 1c and 2c displayed promising antitumor activity, with IC50 values of 0.72 and 1.12 μM, respectively. Moreover, the two compounds were also accompanied by lower toxicity to normal WI-38 cells in comparison with positive agent BIIB021(IC50=495.51 and 570.27μM vs 261 μM). Cell cycle analysis revealed that both the compounds induced cell cycle arrest in the G2/M phase with a concomitant decrease in the population of G0/G1 phase in HeLa cells, which were accompanied by apoptosis. Together, the initial studies suggest that compounds 1c and 2c have the potential to be developed as promising lead compound for further optimization in structure and as well as for in vivo validation studies.