Discovery of Matrinic Thiadiazole Derivatives as a Novel Family of Anti-Liver Fibrosis Agents via Repression of the TGFβ/Smad Pathway
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 acti...
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MDPI AG
2018-07-01
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| Series: | Molecules |
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| Online Access: | http://www.mdpi.com/1420-3049/23/7/1644 |
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doaj-5a5d9a85e2c64f8791a083588a88ef1d2020-11-24T20:48:23ZengMDPI AGMolecules1420-30492018-07-01237164410.3390/molecules23071644molecules23071644Discovery of Matrinic Thiadiazole Derivatives as a Novel Family of Anti-Liver Fibrosis Agents via Repression of the TGFβ/Smad PathwayTianyu Niu0Weixiao Niu1Yunyang Bao2Ting Liu3Danqing Song4Yinghong Li5Hongwei He6Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, ChinaInstitute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, ChinaInstitute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, ChinaInstitute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, ChinaInstitute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, ChinaInstitute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, ChinaInstitute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, ChinaA 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.http://www.mdpi.com/1420-3049/23/7/1644liver fibrosismatrinicthiadiazolestructure-activity relationshipCOL1A1TGFβ/Smad pathway |
| collection |
DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
Tianyu Niu Weixiao Niu Yunyang Bao Ting Liu Danqing Song Yinghong Li Hongwei He |
| spellingShingle |
Tianyu Niu Weixiao Niu Yunyang Bao Ting Liu Danqing Song Yinghong Li Hongwei He Discovery of Matrinic Thiadiazole Derivatives as a Novel Family of Anti-Liver Fibrosis Agents via Repression of the TGFβ/Smad Pathway Molecules liver fibrosis matrinic thiadiazole structure-activity relationship COL1A1 TGFβ/Smad pathway |
| author_facet |
Tianyu Niu Weixiao Niu Yunyang Bao Ting Liu Danqing Song Yinghong Li Hongwei He |
| author_sort |
Tianyu Niu |
| title |
Discovery of Matrinic Thiadiazole Derivatives as a Novel Family of Anti-Liver Fibrosis Agents via Repression of the TGFβ/Smad Pathway |
| title_short |
Discovery of Matrinic Thiadiazole Derivatives as a Novel Family of Anti-Liver Fibrosis Agents via Repression of the TGFβ/Smad Pathway |
| title_full |
Discovery of Matrinic Thiadiazole Derivatives as a Novel Family of Anti-Liver Fibrosis Agents via Repression of the TGFβ/Smad Pathway |
| title_fullStr |
Discovery of Matrinic Thiadiazole Derivatives as a Novel Family of Anti-Liver Fibrosis Agents via Repression of the TGFβ/Smad Pathway |
| title_full_unstemmed |
Discovery of Matrinic Thiadiazole Derivatives as a Novel Family of Anti-Liver Fibrosis Agents via Repression of the TGFβ/Smad Pathway |
| title_sort |
discovery of matrinic thiadiazole derivatives as a novel family of anti-liver fibrosis agents via repression of the tgfβ/smad pathway |
| publisher |
MDPI AG |
| series |
Molecules |
| issn |
1420-3049 |
| publishDate |
2018-07-01 |
| description |
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. |
| topic |
liver fibrosis matrinic thiadiazole structure-activity relationship COL1A1 TGFβ/Smad pathway |
| url |
http://www.mdpi.com/1420-3049/23/7/1644 |
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