通过抑制 TGFβ/Smad 通路发现马替瑞林噻二唑衍生物作为新型抗肝纤维化药物。
Discovery of Matrinic Thiadiazole Derivatives as a Novel Family of Anti-Liver Fibrosis Agents via Repression of the TGFβ/Smad Pathway.
机构信息
Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
出版信息
Molecules. 2018 Jul 5;23(7):1644. doi: 10.3390/molecules23071644.
A series of novel matrinic thiadiazole derivatives were designed, synthesized and evaluated for their inhibitory effect on COL1A1 promotor. The SAR indicated that: (i) the introduction of a thiadiazole on the 11-side chain was beneficial for activity; (ii) a 12--benzyl moiety was favorable for activity. Among them, compound displayed a high activity with an inhibitory rate of 39.7% at a concentration of 40 μM. It also effectively inhibited the expression of two representative collagen proteins (COL1A1 and α-SMA) on both the mRNA and protein levels and showed a high safety profile in vivo, indicating its great promise as an anti-liver fibrosis agent. Further study indicated that it might repress hepatic fibrogenesis via the TGFβ/Smad pathway. This study provided powerful information for further strategic optimization and the top compound was selected for further study as an ideal liver fibrosis lead for next investigation.
设计、合成了一系列新型马替林噻二唑衍生物，并评价了它们对 COL1A1 启动子的抑制作用。SAR 表明：（i）在 11-侧链上引入噻二唑有利于活性；（ii）12-苄基部分有利于活性。其中，化合物 显示出较高的活性，在 40 μM 浓度下抑制率为 39.7%。它还能有效抑制两种代表性胶原蛋白（COL1A1 和 α-SMA）在 mRNA 和蛋白水平上的表达，且在体内具有良好的安全性，表明其具有作为抗肝纤维化药物的巨大潜力。进一步的研究表明，它可能通过 TGFβ/Smad 途径抑制肝纤维化形成。该研究为进一步的战略优化提供了有力信息，选择顶级化合物 作为进一步研究的理想肝纤维化先导化合物，以进行下一步的研究。
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