文献类型：期刊文献

英文题名：Structure Optimization of Natural Product Catalpol to Obtain Novel and Potent Analogs against Heart Failure

作者：Liu, Hanfang[1];Guo, Xiaobo[1];Yang, Jin[1];Xia, Conglong[2];Yao, Yue[1];Li, Xiao[1];Liu, Xiaoyang[1];Yang, Junqi[1];Li, Xiaokang[1];Xu, Yixiang[1];Li, Jian[1,3,4];Wang, Manjiong[1]

机构：[1]East China Univ Sci & Technol, Shanghai Frontiers Sci Ctr Optogenet Tech Cell Met, Frontiers Sci Ctr Materiobiol & Dynam Chem, Sch Pharm,State Key Lab Bioreactor Engn,Shanghai K, Shanghai 200237, Peoples R China;[2]Dali Univ, Coll Pharm, Dali 671000, Peoples R China;[3]Shihezi Univ, Sch Pharm, Key Lab Xinjiang Phytomed Resource & Utilizat, Minist Educ, Shihezi 832003, Peoples R China;[4]Hainan Univ, Coll Pharm, Key Lab Trop Biol Resources, Minist Educ, Haikou 570228, Peoples R China

年份：2025

卷号：68

期号：4

起止页码：4540

外文期刊名：JOURNAL OF MEDICINAL CHEMISTRY

收录：;WOS:【SCI-EXPANDED(收录号:WOS:001417469900001)】；

基金：This work was supported by the National Natural Science Foundation of China (22307038, 22107030, 22437002, 22037002, 32121005), National key R&D Program of China (2021YFA0804904), Shanghai Frontier Science Center of Optogenetic Techniques for Cell Metabolism (2021 Sci & Tech 03-28), Innovation Program of Shanghai Municipal Education Commission (2021-01-07-00-02-E00104), Innovative Research Team of High-level Local Universities in Shanghai (SHSMU-ZDCX20212702), Chinese Special Fund for State Key Laboratory of Bioreactor Engineering (2060204), Shanghai Morning Light Program (20CG36).

语种：英文

摘要：Heart failure (HF) is a major global health threat, characterized by high morbidity and mortality. Targeting cardiac hypertrophy has been identified as a potential therapy for HF, with current treatments showing limited efficacy. Our research aims to address this limitation by exploring new structural classes of therapeutic agents. Starting from the natural product catalpol, we designed a series of novel catalpol analogs to break through the structural limitations of natural analogs, improve the anti-HF efficacy and metabolic properties. Among these, compound JZ19 exhibited remarkable efficacy in both myocardial cell injury assays and in an isoproterenol-induced murine HF model, outperforming catalpol. Our findings indicate that JZ19 potently reversed cardiac function by modulating the PI3K-AKT-GSK3 beta pathway, a key regulator of hypertrophy and apoptosis. Moreover, JZ19 showed favorable pharmacokinetic properties and safety. Overall, our results provide direct pharmacologic evidence supporting the further development of JZ19 as novel HF therapeutics by inhibiting cardiac hypertrophy and apoptosis.