Discovery of methylpyrimidine ring-fused diterpenoid analogs as a novel testosterone synthesis promoter.
Discovery of methylpyrimidine ring-fused diterpenoid analogs as a novel testosterone synthesis promoter.
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发现甲基嘧啶环稠合二萜类似物作为新型睾酮合成促进剂
作者：
在此基础上，我们筛选了促进睾酮合成的二萜类似物的小合成文库，得到了甲基嘧啶环融合二萜类似物7作为hit化合物。在此基础上，设计、合成了一系列衍生物，并对其对小鼠Leydig TM3细胞睾酮分泌的影响进行了评价。大多数衍生物的促睾酮合成活性均优于阳性对照化合物淫羊藿苷，其中化合物17的促睾酮合成活性最佳，且细胞毒性较小。初步机制研究表明，17显著促进了睾酮合成相关标记基因（StAR、3β-HSD和CYP11A1）的表达。进一步研究表明，17通过刺激间质细胞的自噬，为睾酮合成提供了充足的类固醇物质。因此，化合物17成为进一步开发迟发性性腺功能减退（LOH）治疗药物的潜在先导化合物。
Herein we screened our small synthetic library of diterpenoid analogs for hit compounds on promoting testosterone synthesis and the methylpyrimidine ring-fused diterpenoid analog 7 was obtained as the hit. Based on the hit, a series of derivatives were designed, synthesized and evaluated for their effects on testosterone secretion in mouse Leydig TM3 cells. Most of the derivatives showed better activity in promoting testosterone synthesis than the positive control compound icariin, among which compound 17 has optimal activity and little cytotoxicity. Preliminary mechanism studies indicated that 17 significantly promoted the expression of testosterone synthesis-related marker genes (StAR, 3β-HSD and CYP11A1). Further studies showed that 17 provided sufficient steroid materials for testosterone synthesis by stimulating autophagy in Leydig cells. Thus compound 17 emerged as a potential lead compound for further development of therapeutics for late onset of hypogonadism (LOH).
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影响因子：
5.1
作者：
Dao, Trong-Tuan;Lee, Kwang-Youl;Oh, Won-Keun
通讯作者：
Oh, Won-Keun
DOI：
10.2174/138620712803901199
发表时间：
2012-12-01
影响因子：
1.8
作者：
Rao, Xiaoping;Huang, Xiuzhi;Shang, Shibin
通讯作者：
Shang, Shibin
影响因子：
15
作者：
STORK, G;BURGSTAHLER, AW
通讯作者：
BURGSTAHLER, AW
影响因子：
4.8
作者：
Lipina, Christopher;Hundal, Harinder S.
通讯作者：
Hundal, Harinder S.
影响因子：
3.5
作者：
Duarte, Noelia;Varga, Andras;Ferreira, Maria-Jose U.
通讯作者：
Ferreira, Maria-Jose U.