Synthesis and biological evaluations of new analogs of 2-methoxyestradiol: Inhibitors of tubulin and angiogenesis

• Several new analogs of the anti-cancer agent 2-methoxyestradiol have been prepared.
• Improved inhibition against tubulin polymerization and angiogenesis were observed for some analogs.
• Some analogs displayed more potent cytotoxic effects against several cancer cell lines than 2-methoxyestradiol.
• New information on the structural–activity relationships for 2-methoxyestradiol has been gained.

The synthesis, cytotoxicity, inhibition of tubulin polymerization and anti-angiogenic effects of 15 analogs of 2-methoxyestradiol (1) are reported. The biological studies revealed that the position of nitrogen atom in the heterocyclic ring is important for inhibition of both tubulin polymerization and angiogenesis. The most potent inhibitors were compounds 11f and 13e, with a 6-substituted isoquinoline ring in the 17-position of the steroid skeleton. Moreover, low estrogen activity was observed for the analogs tested at 10 μM concentrations.

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