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Molecules 2018, 23(7), 1644; https://doi.org/10.3390/molecules23071644

Discovery of Matrinic Thiadiazole Derivatives as a Novel Family of Anti-Liver Fibrosis Agents via Repression of the TGFβ/Smad Pathway

Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
These authors contributed equally to this work.
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Received: 14 June 2018 / Revised: 29 June 2018 / Accepted: 30 June 2018 / Published: 5 July 2018
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Abstract

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-N-benzyl moiety was favorable for activity. Among them, compound 6n 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 6n was selected for further study as an ideal liver fibrosis lead for next investigation. View Full-Text
Keywords: liver fibrosis; matrinic; thiadiazole; structure-activity relationship; COL1A1; TGFβ/Smad pathway liver fibrosis; matrinic; thiadiazole; structure-activity relationship; COL1A1; TGFβ/Smad pathway
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).
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Niu, T.; Niu, W.; Bao, Y.; Liu, T.; Song, D.; Li, Y.; He, H. Discovery of Matrinic Thiadiazole Derivatives as a Novel Family of Anti-Liver Fibrosis Agents via Repression of the TGFβ/Smad Pathway. Molecules 2018, 23, 1644.

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