Studies on indolizines. Evaluation of their biological properties as microtubule-interacting agents and as melanoma targeting compounds

• Synthesis and biological screening of indolizine-containing inhibitors of tubulin polymerization.
• Evaluation of new indolizines for cytotoxicity on an NCI-60 human cancer cell lines panel.
• Discovery of indolizine derivatives with GI50 values in the nanomolar range on melanoma MDA-MB-435 cell lines.
• SAR study on indolizin-3-yl(3,4,5-trimethoxyphenyl) methanones as microtubule-interacting agents.

With the aim of investigating new analogues of phenstatin with an indolizin-3-yl unit, in particular as the B-ring, three new series of compounds (6–8, 9–34 and 54) were synthesized and tested for interactions with tubulin polymerization and evaluated for cytotoxicity on an NCI-60 human cancer cell lines panel. The replacement of the 3′-hydroxy-4′-methoxyphenyl B-ring of phenstatin with substituted indolizine unit results in the conservation of both antitubulin and cytotoxic effect. Indolizines 9 and 17 were the most effective in the present study and showed the highest antiproliferative effect on melanoma cell lines MDA-MB-435 (GI50 = 30 nM) and could serve as new lead compounds for the development of anti-cancer therapeutics.

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