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首页> 外文期刊>International Journal of Molecular Sciences >Development of Androgen-Antagonistic Coumarinamides with a Unique Aromatic Folded Pharmacophore
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Development of Androgen-Antagonistic Coumarinamides with a Unique Aromatic Folded Pharmacophore

机译：用独特的芳香族折叠药物的雄激素拮抗香豆素酰胺的发展

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First-generation nonsteroidal androgen receptor (AR) antagonists, such as flutamide ( 2a ) and bicalutamide ( 3 ), are effective for most prostate cancer patients, but resistance often appears after several years due to the mutation of AR. Second-generation AR antagonists are effective against some of these castration-resistant prostate cancers, but their structural variety is still limited. In this study, we designed and synthesized 4-methyl-7-( N -alkyl-arylcarboxamido)coumarins as AR antagonist candidates and evaluated their growth-inhibitory activity toward androgen-dependent SC-3 cells. Coumarinamides with a secondary amide bond did not show inhibitory activity, but their N -methylated derivatives exhibited AR-antagonistic activity. Especially, 19b and 31b were more potent than the lead compound 7b , which was comparable to hydroxyflutamide ( 2b ). Conformational analysis showed that the inactive coumarinamides with a secondary amide bond have an extended structure with a trans -amide bond, while the active N -methylated coumarinamides have a folded structure with a cis -amide bond, in which the two aromatic rings are placed face-to-face. Docking study suggested that this folded structure is important for binding to AR. Selected coumarinamide derivatives showed AR-antagonistic activity toward LNCaP cells with T877A AR, and they had weak progesterone receptor (PR)-antagonistic activity. The folded coumarinamide structure appears to be a unique pharmacophore, different from those of conventional AR antagonists.
机译：第一代非甾体雄激素受体（AR）拮抗剂，例如氟胺（2A）和Bicaletamide（3），对大多数前列腺癌患者有效，但由于AR的突变，抗性通常在几年后出现。第二代AR拮抗剂对一些抗阉割的前列腺癌有效，但它们的结构品种仍然有限。在该研究中，我们设计和合成了4-甲基-7-（N-烷基 - 芳基羧酰基甲酰氨基）香豆素作为AR拮抗剂候选物，并评估其对雄激素依赖性SC-3细胞的生长抑制活性。香豆素酰胺与二次酰胺键没有显示出抑制活性，但它们的N-甲基化衍生物表现出AR-拮抗活性。特别是，19b和31b比铅化合物7b更有效，铅化合物7b与羟基氟胺（2b）相当。构象分析表明，具有仲酰胺键的无活性香豆素酰胺具有较延伸的结构，其具有反式 - 酰胺键，而活性N-甲基化香豆素酰胺具有折叠结构，其中两个芳环放置了一个芳香环-面对。对接研究表明，这种折叠的结构对于与AR结合很重要。选定的香豆素酰胺衍生物向具有T877A AR的LNCAP细胞显示Ar-拮抗活性，并且它们具有弱孕酮受体（PR）致法活性。折叠的香豆素酰胺结构似乎是一种独特的药效线，与常规Ar拮抗剂不同。

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