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睾酮和雌二醇头基杂化分子的合成及抗癌性能。

Synthesis and anticancer properties of a hybrid molecule with the testosterone and estradiol head-groups.

机构信息

Laboratoire de Recherche en Chimie Médicinale (LRCM) et Groupe de Recherche en Signalisation Cellulaire (GRSC), Département de Chimie, Biochimie et Physique, Université du Québec à Trois-Rivières, C.P. 500, Trois-Rivières, QC, G9A 5H7, Canada.

Centre de Recherche du CHU de Québec-Université Laval, Axe Oncologie, Hôpital Saint-François d'Assise, 10 rue de l'Espinay, Québec, Québec, G1L 3L5, Canada; Faculté de Pharmacie, Université Laval, Québec, Québec, G1V 0A6, Canada.

出版信息

Steroids. 2024 Sep;209:109469. doi: 10.1016/j.steroids.2024.109469. Epub 2024 Jul 9.

Abstract

This is the first report on a unique hybrid molecule made of estradiol and testosterone (TS). This distinctive hybrid molecule (1) was designed to interact with both the estrogen receptor (ER) and the androgen receptor (AR) found in hormone-dependent female and male cancer cells, and was synthesized using ethynylestradiol (17EE) as the estrogenic component and 7α-(4-azido-but-2-enyl)-4-androsten-17β-ol-3-one as the androgenic counterpart in a seven-step reaction with ∼ 26 % overall yield. We reasoned that the dual receptor binding ability could allow 1 to act as an antihormone. This was tested on hormone-dependent and hormone-independent breast cancer (BCa) and prostate cancer (PCa) cells. The antiproliferative activity was also assessed on colon and skin cancer cells. We found that 1 was active against MCF7 (ER + ) BCa cells (IC of 4.9 μM), had lower inhibitory potency on LNCaP (AR + ) PCa cells (IC > 5 μM) and no effect on PC3 and DU145 (AR-) PCa cells. This suggests that the estrogenic component of 1 can interact with the ER on MCF7 cells more effectively than the androgenic component with the AR on LNCaP PCa cells, possibly due to a suboptimal spacer or linkage site(s). Nonetheless, the hybrid 1 was active against colon (HT-29) and melanoma (M21) cancer cells (IC of 3.5 μM and 2.3 μM, respectively), and had low cross-reactivity with the drug- and androgen-metabolizing cytochrome P450 3A4 (CYP3A4, IC ≫ 5 µM). These findings demonstrate the anticancer potential of 1 and warrant further explorations on this new type of hybrids.

摘要

这是首个关于雌二醇和睾酮(TS)独特混合分子的报告。这种独特的混合分子(1)旨在与雌激素受体(ER)和雄激素受体(AR)相互作用,这些受体存在于依赖激素的女性和男性癌细胞中,是使用乙炔雌二醇(17EE)作为雌激素成分,7α-(4-叠氮基-2-烯基)-4-雄烯-17β-醇-3-酮作为雄激素对应物,通过七步反应合成的,总收率约为 26%。我们推断,双重受体结合能力可以使 1 发挥抗激素作用。这在依赖激素和非依赖激素的乳腺癌(BCa)和前列腺癌(PCa)细胞中进行了测试。还评估了其对结肠癌和皮肤癌细胞的抗增殖活性。我们发现,1 对 MCF7(ER+)BCa 细胞具有活性(IC 为 4.9 μM),对 LNCaP(AR+)PCa 细胞的抑制作用较弱(IC > 5 μM),对 PC3 和 DU145(AR-)PCa 细胞没有影响。这表明 1 的雌激素成分与 MCF7 细胞上的 ER 相互作用比雄激素成分与 LNCaP PCa 细胞上的 AR 相互作用更有效,这可能是由于空间位阻或连接位点不理想。尽管如此,混合分子 1 对结肠癌(HT-29)和黑色素瘤(M21)癌细胞具有活性(IC 分别为 3.5 μM 和 2.3 μM),并且与药物和雄激素代谢细胞色素 P450 3A4(CYP3A4,IC > 5 μM)的交叉反应性低。这些发现证明了 1 的抗癌潜力,并需要进一步探索这种新型混合体。

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