School of Life Sciences, Huzhou University, Huzhou, 313000, China.
State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China.
Eur J Med Chem. 2021 Oct 5;221:113522. doi: 10.1016/j.ejmech.2021.113522. Epub 2021 May 5.
Statins play an important role in the treatment of hyperlipidemia, but drug resistance and adverse effects greatly limits their application. To discover new lipid-lowering drugs, three different series of tetrahydroprotoberberine derivatives (THPBs) were designed and synthesized. These compounds were first tested for their effects on viability of HepG2 cells and 21 compounds with the percent of cell viability over 90% were further screened to evaluate their ability to reduce total cholesterol (TC) and triglyceride (TG) levels. Among these derivatives, two compounds displayed significant down-regulation both intracellular of TC and TG content, especially compound 49 exhibited the greatest efficacy. Mechanistically, compound 49 promoted proteasomal degradation of SREBPs. Importantly, compound 49 displayed superior bioavailability (F = 65.1%) and obvious efficacy in the treatment of high fat diet induced obesity in vivo. Therefore, compound 49 is a promising candidate to develop new treatment of hyperlipidemia.
他汀类药物在治疗高脂血症中发挥着重要作用，但药物耐药性和不良反应极大地限制了其应用。为了发现新的降脂药物，设计并合成了三种不同系列的四氢原小檗碱衍生物（THPBs）。首先测试了这些化合物对 HepG2 细胞活力的影响，有 21 种化合物的细胞活力百分比超过 90%，进一步筛选以评估它们降低总胆固醇（TC）和甘油三酯（TG）水平的能力。在这些衍生物中，两种化合物表现出显著降低细胞内 TC 和 TG 含量的作用，特别是化合物 49 表现出最大的功效。从机制上讲，化合物 49 促进了 SREBPs 的蛋白酶体降解。重要的是，化合物 49 在体内高脂饮食诱导肥胖的治疗中显示出优异的生物利用度（F=65.1%）和明显的疗效。因此，化合物 49 是开发治疗高脂血症的新药物的有前途的候选药物。
