Design and synthesis of novel tetrahydrofuran cyclic urea derivatives as androgen receptor antagonists
In order to improve the antiproliferative activity of androgen receptor (AR) antagonists, which used clinically for the treatment of prostate cancer that is a major cause of male death in worldwide, we report the design and synthesis of a series of tetrahydrofuran cyclic urea-based non-steroidal small molecule ARantagonists and exhibit potent AR antagonistic activity. These molecules with higher stereochemical aspects have been achieved by changing the hydantoin analogue antiandrogens to 4-(2-oxohexahydro-1H-furo[3,4-d] imidazol-1-yl)-2-(trifluoromethyl)benzonitrile analogues. Here, the thio-hydantoin pharmacophore of the recently reported antagonists is replaced by tetrahydrofuran cyclic urea. The antiproliferative properties ofthese molecules have been evaluated against androgen-dependent (LNCaP) cell line. Among the reported molecules, 4-(2-oxohexahydro-1H-furo[3,4-d]imidazol-1-yl)-2-(trifluoromethyl)benzonitrile (AR04) showed significantly improved in vitro activity, IC50 = 3.926 lM. Molecular structure-activity relationship studiesconfirm that the oxetane analogue AR04 is distinct from other synthesized AR antagonists. These results have suggested that AR04 exhibiting their potential as a lead compound for the alternative treatment of prostate cancer.
Volume 132, 2020
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