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Discovery of 9O-Substituted Palmatine Derivatives as a New Class of Anti-COL1A1 Agents Via Repressing TGF-β1/Smads and JAK1/STAT3 Pathways

Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
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Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Molecules 2020, 25(4), 773; https://doi.org/10.3390/molecules25040773 (registering DOI)
Received: 13 January 2020 / Revised: 7 February 2020 / Accepted: 8 February 2020 / Published: 11 February 2020
(This article belongs to the Section Medicinal Chemistry)
Twenty 9O-substituted palmatine derivatives were prepared and tested for their biological effect against collagen α1 (I) (COL1A1) promotor in human hepatic stellate LX-2 cells. The structure−activity relationship (SAR) indicated that the introduction of a benzyl motif on the 9O atom was favorable for activity. Among them, compound 6c provided the highest inhibitory effect against COL1A1 with an IC50 value of 3.98 μM, and it also dose-dependently inhibited the expression of fibrogenic COL1A1, α-soomth muscle actin (α-SMA), matrix metalloprotein 2 (MMP2) in both mRNA and protein levels, indicating extensive inhibitory activity against fibrogenesis. A further primary mechanism study indicated that it might repress the hepatic fibrogenesis via inhibiting both canonical transforming growth factor-beta 1 (TGF-β1)/Smads and non-canonical janus-activated kinase 1 (JAK1)/singal transducer and activator of transcription 3 (STAT3) signaling pathways. Additionally, 6c owned a high safety profile with the LD50 value of over 1000 mg·kg−1 in mice. These results identified palmatine derivatives as a novel class of anti-fibrogenic agents, and provided powerful information for further structure optimization. View Full-Text
Keywords: hepatic fibrosis; palmatine; structure−activity relationship; COL1A1; TGF-β1/smads pathway; JAK1/STAT3 pathway hepatic fibrosis; palmatine; structure−activity relationship; COL1A1; TGF-β1/smads pathway; JAK1/STAT3 pathway
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MDPI and ACS Style

Fan, T.; Ge, M.; Guo, Z.; He, H.; Zhang, N.; Li, Y.; Song, D. Discovery of 9O-Substituted Palmatine Derivatives as a New Class of Anti-COL1A1 Agents Via Repressing TGF-β1/Smads and JAK1/STAT3 Pathways. Molecules 2020, 25, 773.

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