Design and synthesis of novel substituted indole-acrylamide derivatives and evaluation of their anti-cancer activity as potential tubulin-targeting agents

Novel compounds containing polar and nonpolar substitutions on the prop-2-en-1-on linker of the trans-indol-3-ylacrylamide scaffold were designed by modeling within the colchicine site of tubulin and then synthesized to determine the role of such substitutions on tubulin polymerization. We first determined the in vitro antiproliferation activities of the compounds against cancer cell lines with a particular focus on hepatocellular carcinoma. The results indicated that five of the compounds showed moderate antitumor activities. When the tubulin polymerization inhibitory effect of these compounds was evaluated, compound 13 was determined to be a tubulin polymerization inhibitor. Furthermore, cell cycle analysis for compound 13 resulted in G2/M-phase arrest in Huh7 cells. The results indicated that polar substitutions on the indole acrylamide scaffold enhance potency against tubulin polymerization. However, the substitution-related bioactivity shifting was not observed on the cancer cell lines since the inhibition mechanisms of the compounds may vary. (C) 2022 Elsevier B.V. All rights reserved.

Automated summary

In this study, novel compounds with polar and nonpolar substitutions on the prop-2-en-1-on linker of the trans-indol-3-ylacrylamide scaffold were designed and synthesized. The antiproliferative activities of these compounds against hepatocellular carcinoma were evaluated, and five of the compounds showed moderate antitumor activities. Compound 13 was identified as a tubulin polymerization inhibitor and induced G2/M-phase arrest in Huh7 cells. The results suggest that polar substitutions enhance the potency against tubulin polymerization.