The synthesis and evaluation of novel [2.2.1]-bicyclic aza-hydantoins as antagonists of the androgen receptor. Free

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The modulation of nuclear hormone function is a viable treatment option for many diseases including prostate cancer. The Androgen Receptor (AR) is a ligand binding transcription factor in the nuclear hormone receptor superfamily and is a key target for the growth and progression of prostate cancer. Chemical castration by treatment with an AR antagonist and an LHRH agonist is part of first-line therapy for prostate cancer patients. We wanted to find a novel non-steriodal, small molecule antagonist of AR that would show increased efficacy in the clinic compared to currently used antiandrogens. We utilized structural based methods to design a series of [2.2.1]-bicyclic aza-hydantoins that act as antagonists of AR. An 8-step synthsesis of both enantiomers of this series from D- and L-trans-hydroxyproline will be presented as well as a polymer-supported synthesis suitable for the creation of small libraries. The evaluation of in vitro activity against multiple cell lines expressing AR will also be presented.