Discovery of 9O-Substituted Palmatine Derivatives as a New Class of Anti-COL1A1 Agents Via Repressing TGF-β1/Smads and JAK1/STAT3 Pathways
Discovery of 9O-Substituted Palmatine Derivatives as a New Class of Anti-COL1A1 Agents Via Repressing TGF-β1/Smads and JAK1/STAT3 Pathways
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通过抑制 TGF-β1/Smads 和 JAK1/STAT3 途径发现 9O 取代的巴马汀衍生物作为一类新型抗 COL1A1 药物
DOI：
10.3390/molecules25040773
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发表时间：
2020-02-02
期刊：
影响因子：
4.6
通讯作者：
Song, Danqing
中科院分区：
文献类型：
--
作者：
Fan, Tianyun;Ge, Maoxu;Song, Danqing
制备了20个90-取代巴马汀衍生物，并在人肝星状LX-2细胞中检测了它们对胶原α1(I)(COL1A1)启动子的生物学作用。结构-活性关系(SAR)表明，在9O原子上引入一个苄基基序有利于活性的提高。其中化合物6c对COL1A1的抑制作用最强，其IC50值为3.98µM，并且在mRNA和蛋白水平上均呈剂量依赖性抑制纤维化COL1A1、α-肌动蛋白(α-SMA)、基质金属蛋白2(MMP2)的表达，显示出广泛的抗纤维化作用。进一步的初步机制研究表明，它可能通过抑制规范性转化生长因子-β1(TGF-β1)/Smads和非典型性Janus激活的激酶1(JAK1)/信号转导和转录激活剂3(STAT3)信号通路来抑制肝纤维化的形成。此外，6c具有很高的安全性，在小鼠身上的LD50值超过1000毫克·公斤(-1)。这些结果证实了巴马汀衍生物是一类新型的抗纤维化药物，并为进一步的结构优化提供了有力的信息。
Twenty 9O-substituted palmatine derivatives were prepared and tested for their biological effect against collagen alpha 1 (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 mu M, and it also dose-dependently inhibited the expression of fibrogenic COL1A1, alpha-soomth muscle actin (alpha-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-beta 1)/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.