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
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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