Synthesis and Biological Evaluation of Novel Olean-28, 13β-lactams as Potential Antiprostate Cancer Agents
Synthesis and Biological Evaluation of Novel Olean-28, 13β-lactams as Potential Antiprostate Cancer Agents
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新型 Olean-28,13β-内酰胺作为潜在抗前列腺癌药物的合成和生物学评价
DOI：
10.1021/jm5020023
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发表时间：
2015-06-11
影响因子：
7.3
通讯作者：
Zhang, Yihua
中科院分区：
文献类型：
--
作者：
Ai, Yong;Hu, Yang;Zhang, Yihua
γ-内酰胺是大量具有生物活性的天然产物和合成的小药物分子中的重要结构基序。然而，目前还没有直接从天然刚性多环酰胺构建γ-内酰胺环的有效方法。本文报道了一种以2，3-二氯-5，6-二氰基苯醌（DDQ）为催化剂，通过自由基离子机理的分子内缩合C-N偶联反应，从相应的酰胺出发合成一组新的β-28，13 β-内酰胺（10a-j）的简便方法。生物学评价表明，活性最高的内酰胺10 h对人癌细胞显示出有效的抗增殖活性，但对非癌细胞的体外抑制活性低13.84- 16.92倍。此外，10小时显著抑制体内植入的前列腺癌的生长。此外，10 h可诱导DU-145细胞周期阻滞和凋亡，并下调AKT/mTOR信号通路。最后，10 h在大鼠血浆和人肝微粒体中比CDDO-Me更稳定，并且几乎没有hERG通道抑制活性。因此，10 h可能是一种潜在的抗前列腺癌药物。
gamma-Lactam is an important structural motif in a large number of biologically active natural products and synthetic small pharmaceutical molecules. However, there is currently no effective approach to construct gamma-lactam ring directly from natural rigid polycyclic amides. Herein, we report a facile methodology for synthesis of a new group of olean-28,13 beta-lactams (10a-j) from their corresponding amides, promoted by an easily available reagent 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ), through an intramolecular dehydrogenative C-N coupling reaction via a radical ion mechanism. Biological evaluation indicated that the most active lactam 10h displayed potent antiproliferative activity against human cancer cells but 13.84- to 16.92-fold less inhibitory activity on noncancer cells in vitro. In addition, 10h significantly inhibited the growth of implanted prostate cancer in vivo. Furthermore, 10h induced cell cycle arrest and apoptosis and down-regulated the AKT/mTOR signaling in DU-145 cells. Finally, 10h was more stable in rat plasma and human liver microsomes than CDDO-Me and had little hERG channel inhibitory activity. Collectively, 10h may be a potential antiprostate cancer agent for further investigation.