Design, synthesis, and anti-proliferative activity of 1-(4-methoxyphenyl)-12-hydroxymethyl-p-carborane derivatives

• Methoxyphenyl-p-carborane derivatives were prepared.
• They were designed based on the structure of the potent estrogen receptor ligand.
• Tested compounds showed the cell growth inhibitory activity for human cancer cell lines.
• Panel screening against 39 human cancer cell lines were performed.
• Compound 2g induced an arrest of the cell cycle in the G2/M phase.

1-(4-Methoxyphenyl)-12-hydroxymethyl-p-carborane (2a), which is a precursor to the previously developed potent carborane-containing ER agonist BE120, exhibited weak cell growth inhibitory activity against four human cancer cell lines (MCF-7, MDA-MB-453, LNCaP, and PC-3). The biological evaluation of a series of derivatives of 2a revealed that an increased number of methoxy groups on the benzene ring of 2a enhanced the cell growth inhibitory activity. Trimethoxyphenyl derivative 2g afforded the most potent cell growth inhibitory activity (mean GI50 value: 5.8 μM) in a panel screening using 39 human cancer cell lines. Moreover, 2g induced for MDA-MB-453 breast cancer cell lines an arrest of the cell cycle in the G2/M phase and apoptosis mediated by caspase-3/7.

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