新型苦参碱衍生物WM130抑制肝纤维化的实验研究

Matrine, the main active ingredients of Sophora flavescens (S. flavescens Ait), possesses a biological activity of anti-liver fibrosis, and had been used for clinical treatment of acute/chronic liver diseases. However, the bioactivity of matrine was limited. From matrine, M19 (C16N3H27S) was figured out, it has better pharmacological activities than matrine and its other derivatives. It is confirmed that M19 could inhibit liver fibrosis and liver carcinogenesis by blocking AKt and EGFR signaling pathway. However, M19 is unstable and easily turns back into thiosulfate sophocarpine in aqueous solution. Currently, WM130 (C30N4H40SO5F), a novel matrine derivative based on M19, was synthesized in our laboratory. It exhibits more stable chemical properties and better pharmacological activities than M19. The proliferation of hepatic stellate cell (HSC) lines HSC-T6 and LX-2 could be inhibited by WM130. WM130 could also efficiently inhibit migration and induce apoptosis in HSC cells. The expression of TGF-β1 and p-Smad in HSC cells was suppressed by WM130. This experiment intends to study the effect of WM130 on the proliferation, migration, and apoptosis of HSC cells and liver fibrosis in rats, and investigates the possible molecular mechanism, hoping to provide an aggressive treatment for hepatic fibrosis.

苦参碱是中药苦参的有效成分，具有抗肝纤维化作用，临床上已用于急慢性肝病治疗，但药理作用不强。前期研究筛选出具有很强药效的苦参碱衍生物M19，其通过抑制AKt和EGFR信号通路的活性发挥抗肝纤维化和降低肝癌发生率的作用，但稳定性较差。进一步优化M19结构，我们筛选出具有强效作用的苦参碱马来酸盐衍生物WM130，其结构稳定，抗肝纤维化活性优良。预实验发现WM130对大鼠肝星状细胞HSC-T6和人肝星状细胞LX-2均具有增殖抑制作用，WM130可抑制肝星状细胞迁移并诱导其凋亡，且随WM130浓度的增加显著下调肝星状细胞中TGF-β1和p-Smad蛋白水平的表达。本研究拟着眼于WM130对TGF-β1和p-Smad信号传导途径的影响来阐明其对肝星状细胞增殖、迁移和凋亡的作用，以及对实验性大鼠肝纤维化及其癌变的抑制效果，探讨其可能的作用机制，希望能为肝纤维化疾病的治疗提供新型的治疗方案。

苦参碱是中药苦参的有效成分，具有抗肝纤维化作用，临床上已用于急慢性肝病治疗，但药理作用不强。前期研究筛选出具有很强药效的苦参碱衍生物M19，其通过抑制AKt和EGFR信号通路的活性发挥抗肝纤维化和降低肝癌发生率的作用，但稳定性较差。进一步优化M19结构，我们筛选出具有强效作用的苦参碱马来酸盐衍生物WM130，其结构稳定，抗肝纤维化活性优良。预实验发现WM130对大鼠肝星状细胞HSC-T6和人肝星状细胞LX-2均具有增殖抑制作用，WM130可抑制肝星状细胞迁移并诱导其凋亡，且随WM130浓度的增加显著下调肝星状细胞中TGF-β1和p-Smad蛋白水平的表达。WM130不但能够抑制肝纤维化，而且能够抑制肝癌的发生发展。我们已按计划完成全部研究内容，发表SCI论文2篇，申请并获得授权专利3项。