Synthesis and Biological Evaluation of 2‑(Alkoxycarbonyl)-3-Anilinobenzo[<i>b</i>]thiophenes and Thieno[2,3‑<i>b</i>]pyridines as New Potent Anticancer Agents

Abstract

Two new series of inhibitors of tubulin polymerization based on the 2-(alkoxycarbonyl)-3-(3′,4′,5′-trimethoxyanilino)­benzo­[<i>b</i>]­thiophene and thieno­[2,3-<i>b</i>]­pyridine molecular skeletons were synthesized and evaluated for antiproliferative activity on a panel of cancer cell lines, inhibition of tubulin polymerization, cell cycle effects, and in vivo potency. Antiproliferative activity was strongly dependent on the position of the methyl group on the benzene portion of the benzo­[<i>b</i>]­thiophene nucleus, with the greatest activity observed when the methyl was located at the C-6 position. Also, in the smaller thieno­[2,3-<i>b</i>]­pyridine series, the introduction of the methyl group at the C-6 position resulted in improvement of antiproliferative activity to the nanomolar level. The most active compounds (<b>4i</b> and <b>4n</b>) did not induce cell death in normal human lymphocytes, suggesting that the compounds may be selective against cancer cells. Compound <b>4i</b> significantly inhibited in vivo the growth of a syngeneic hepatocellular carcinoma in Balb/c mice