Synthesis of Enantiospecific Androgen Receptor Antagonists of Enzalutamide-Resistant Human Prostate Cancer Cells

IF 3.9 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters Pub Date : 2026-08-13 Epub Date: 2026-06-25 DOI:10.1021/acsmedchemlett.6c00085

Chao Liu, Yuanye Sun, Pyone Myat Thwe, Glenn A. Harter, Sujatha Chilakala, Jonathan E. Katz, Ethan Canfield, Grzegorz Zapotoczny, Bethany Haliday, Elizabeth Elton, Boris A. Kashemirov, Katherin Patsch, David B. Agus, Charles E. McKenna

引用次数: 0

Abstract

Drugs targeting the androgen receptor (AR) are important therapeutics for castration-resistant prostate cancer (CRPC) but are vulnerable to resistance due to AR mutations. Previously, we reported that the (5R/5S) enantiomer pairs of four novel 3-pyrrolazole carboxamide derivatives 9ab–12ab are antagonists and agonists, respectively, of AR, as demonstrated by transcriptional assays supported by fluorescence microscopy and proliferation studies. Herein, we describe the synthesis and stereochemical characterization of these compounds and document their enantiospecific effect on enzalutamide-resistant AR.

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恩杂鲁胺耐药人前列腺癌细胞对映特异性雄激素受体拮抗剂的合成

靶向雄激素受体（AR）的药物是去势抵抗性前列腺癌（CRPC）的重要治疗方法，但由于AR突变而容易产生耐药性。在此之前，我们报道了四种新型3-吡咯唑类carboxamide衍生物9ab-12ab的（5R/5S）对映体对分别是AR的拮抗剂和激动剂，这是通过荧光显微镜和增殖研究支持的转录分析证实的。在此，我们描述了这些化合物的合成和立体化学表征，并记录了它们对恩杂鲁胺耐药AR的对映特异性作用。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

ACS Medicinal Chemistry Letters CHEMISTRY, MEDICINAL-

CiteScore

7.30

自引率

2.40%

发文量

328

审稿时长

1 months

期刊介绍： ACS Medicinal Chemistry Letters is interested in receiving manuscripts that discuss various aspects of medicinal chemistry. The journal will publish studies that pertain to a broad range of subject matter, including compound design and optimization, biological evaluation, drug delivery, imaging agents, and pharmacology of both small and large bioactive molecules. Specific areas include but are not limited to: Identification, synthesis, and optimization of lead biologically active molecules and drugs (small molecules and biologics) Biological characterization of new molecular entities in the context of drug discovery Computational, cheminformatics, and structural studies for the identification or SAR analysis of bioactive molecules, ligands and their targets, etc. Novel and improved methodologies, including radiation biochemistry, with broad application to medicinal chemistry Discovery technologies for biologically active molecules from both synthetic and natural (plant and other) sources Pharmacokinetic/pharmacodynamic studies that address mechanisms underlying drug disposition and response Pharmacogenetic and pharmacogenomic studies used to enhance drug design and the translation of medicinal chemistry into the clinic Mechanistic drug metabolism and regulation of metabolic enzyme gene expression Chemistry patents relevant to the medicinal chemistry field.