Boron Heterocycle High-Fidelity Estrogen Mimics as Novel Antiestrogens for the Treatment of Breast Cancer
Final rept. 1 Sep 2000-1 Sep 2001
SRI INTERNATIONAL MENLO PARK CA
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Through a careful de nova rational drug design process, we are developing a new class of high-fidelity estrogen mimics with intrinsic chemical properties conducive to potent binding to the estrogen receptor as well as to antiproliferation of human breast cancer cells. These mimics are constructed upon a stable boron heterocycle platform and can be made to bear a remarkable resemblance to the natural estrogens. Importantly, they can accommodate authentic A- and D-ring hydroxyl and ketone functionalities known to be essential to the intracellular recognition of estrogens by enzymes and receptor sites. The synthetic chemistry accomplishments made possible by this Award successfully removed all remaining obstacles to the facile generation of the boron heterocycle estrogen mimics. Accordingly, we are now in a position to easily and systematically produce analogs and examine them for bicactivities predictive of good breast cancer chemotherapeutic properties. The biological assay results obtained during this Award clearly reveal the covalently fused CD ring compounds as pure antagonists of the estrogen receptor, and we can now develop this subclass of compounds to produce potent lead candidates as novel boron heterocycle-based breast cancer chemotherapeutic agents.
- Medicine and Medical Research
- Organic Chemistry