Synthesis of 2-alkoxy and 2-benzyloxy analogues of estradiol as anti-breast cancer agents through microtubule stabilization

• 2-Alkoxy and 2-benzyloxy analogues of an investigational drug, 2-methoxyestradiol.
• The best analogue 24 stabilized microtubule polymerisation and occupies bind pocket of taxol.
• Compound 24 induces apoptosis and was non-toxic up to 1000 mg/kg dose in Swiss-albino mice.

2-Methoxyestradiol (2ME2) is an investigational anticancer drug. In the present study, 2-alkoxyesters/acid and 2-benzyloxy analogues of estradiol have been synthesized as analogues of 2ME2. Three of the derivatives exhibited significant anticancer activity against human breast cancer cell lines. The best analogue of the series i.e. 24 showed stabilization of tubulin polymerisation process. It was substantiated by confocal microscopy and molecular docking studies where 24 occupied ‘paclitaxel binding pocket’ to stabilize the polymerisation process. Compound 24 significantly inhibited MDA-MB-231 cells (IC50: 7 μM) and induced arrest of cell cycle and apoptosis in MDA-MB-231 cells. In acute oral toxicity, 24 was found to be non-toxic and well tolerated in Swiss albino mice up to 1000 mg/kg dose.

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