Abstract

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 AR antagonists 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 of these 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 µM. Molecular structure-activity relationship studies confirm 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.

Graphic abstract

To improve the antiproliferative activity of androgen receptor (AR) antagonists, various compounds with tetrahydrofuran cyclic urea ring system were designed and synthesized. Among the synthesized compounds, AR04 showed significantly improved in vitro activity, IC₅₀ = 3.926 µmol, which is almost equal to the commercially available drug, enzalutamide.

中文翻译：

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新型四氢呋喃环脲衍生物作为雄激素受体拮抗剂的设计与合成

摘要

为了提高雄激素受体（AR）拮抗剂的抗增殖活性，该拮抗剂在临床上用于治疗前列腺癌，而前列腺癌是全世界男性死亡的主要原因，我们报告了一系列基于四氢呋喃环脲的设计和合成非甾体小分子AR拮抗剂，并表现出强大的AR拮抗活性。这些具有更高立体化学方面的分子是通过将乙内酰脲类似物抗雄激素改变为4-（2-氧六氢-1H-呋喃[3,4-d]咪唑-1-基）-2-（三氟甲基）苄腈类似物而获得的。在这里，最近报道的拮抗剂的硫代乙内酰脲药效团被四氢呋喃环脲取代。这些分子的抗增殖特性已针对雄激素依赖性（LNCaP）细胞系进行了评估。在报告的分子中，AR04）表现出显着改善的体外活性，IC ₅₀ = 3.926 µM。分子结构-活性关系研究证实，氧杂环丁烷类似物AR04与其他合成的AR拮抗剂不同。这些结果表明，AR04显示出其作为替代性治疗前列腺癌的先导化合物的潜力。

图形摘要

为了提高雄激素受体（AR）拮抗剂的抗增殖活性，设计并合成了具有四氢呋喃环脲环系统的各种化合物。在合成的化合物中，AR04的体外活性显着提高，IC ₅₀ = 3.926 µmol，几乎等于市售药物enzalutamide。