Department of Chemistry and Biochemistry, California State University, Fresno, CA 93740, USA.
Department of Chemistry and RCMI Cancer Research Center, Xavier University of Louisiana, New Orleans, LA 70125, USA.
Molecules. 2021 Oct 24;26(21):6421. doi: 10.3390/molecules26216421.
To search for novel androgen receptor (AR) modulators for the potential treatment of castration-resistant prostate cancer (CRPC), naturally occurring silibinin was sought after as a lead compound because it possesses a moderate potency towards AR-positive prostate cancer cells and its chemical scaffold is dissimilar to all currently marketed AR antagonists. On the basis of the structure-activity relationships that we have explored, this study aims to incorporate carbamoyl groups to the alcoholic hydroxyl groups of silibinin to improve its capability in selectively suppressing AR-positive prostate cancer cell proliferation together with water solubility. To this end, a feasible approach was developed to regioselectively introduce a carbamoyl group to the secondary alcoholic hydroxyl group at C-3 without causing the undesired oxidation at C2-C3, providing an avenue for achieving 3--carbamoyl-5,7,20--trimethylsilybins. The application of the synthetic method can be extended to the synthesis of 3--carbamoyl-3',4',5,7--tetramethyltaxifolins. The antiproliferative potency of 5,7,20--trimethylsilybin and its nine 3-carbamoyl derivatives were assessed in an AR-positive LNCaP prostate cancer cell line and two AR-null prostate cancer cell lines (PC-3 and DU145). Our preliminary bioassay data imply that 5,7,20--trimethylsilybin and four 3--carbamoyl-5,7,20--trimethylsilybins emerge as very promising lead compounds due to the fact that they can selectively suppress AR-positive LNCaP cell proliferation. The IC values of these five 5,7,20--trimethylsilybins against the LNCaP cells fall into the range of 0.11-0.83 µM, which exhibit up to 660 times greater in vitro antiproliferative potency than silibinin. Our findings suggest that carbamoylated 5,7,20--trimethylsilybins could serve as a natural product-based scaffold for new antiandrogens for lethal castration-resistant prostate cancer.
为了寻找新型雄激素受体 (AR) 调节剂，用于治疗去势抵抗性前列腺癌 (CRPC)，我们以天然存在的水飞蓟宾作为先导化合物，因为它对 AR 阳性前列腺癌细胞具有中等效力，并且其化学结构与所有目前市售的 AR 拮抗剂都不同。基于我们已经探索的结构-活性关系，本研究旨在将氨基甲酰基引入水飞蓟宾的醇羟基中，以提高其选择性抑制 AR 阳性前列腺癌细胞增殖的能力，同时提高其水溶性。为此，开发了一种可行的方法，可在不引起 C2-C3 不必要氧化的情况下，在 C-3 上的仲醇羟基上区域选择性地引入氨基甲酰基，为实现 3--氨基甲酰基-5,7,20--三甲氧基水飞蓟宾提供了途径。该合成方法的应用可以扩展到 3--氨基甲酰基-3',4',5,7--四甲基紫杉林的合成。在 AR 阳性 LNCaP 前列腺癌细胞系和两个 AR 缺失的前列腺癌细胞系 (PC-3 和 DU145) 中，评估了 5,7,20--三甲氧基水飞蓟宾及其 9 种 3-氨基甲酰基衍生物的抗增殖活性。我们的初步生物测定数据表明，由于它们可以选择性地抑制 AR 阳性 LNCaP 细胞的增殖，因此 5,7,20--三甲氧基水飞蓟宾和 4 种 3--氨基甲酰基-5,7,20--三甲氧基水飞蓟宾是非常有前途的先导化合物。这五种 5,7,20--三甲氧基水飞蓟宾对 LNCaP 细胞的 IC 值在 0.11-0.83 µM 范围内，其体外抗增殖活性比水飞蓟宾高 660 倍。我们的研究结果表明，氨基甲酰化的 5,7,20--三甲氧基水飞蓟宾可以作为一种基于天然产物的新型抗雄激素骨架，用于治疗致命性去势抵抗性前列腺癌。
