title: 3,5-Dimethoxy-4-(3-(2-carbonyl-ethyldisulfanyl)-propionyl)-benzoic acid 4-guanidino-butyl ester: a novel twin drug that prevents primary cardiac myocytes from hypoxia-induced apoptosis.
abstract: Leonurine possesses cardioprotective effects in myocardial ischemia due to its anti-apoptotic properties. However, the process to isolate and purify leonurine is difficult, because of its low content in the Herb Leonuri and its impurity. Moreover, the high dosage used indicates low potency of leonurine. To overcome these defects, we had synthesized a novel twin drug of leonurine, 3,5-dimethoxy-4-(3-(2-carbonyl-ethyldisulfanyl)-propionyl)-benzoic acid 4-guanidino-butyl ester (compound 2). In this paper, we focused on investigating the cardioprotective effect and underlying mechanisms of compound 2. Our data showed that cell viability was significantly increased in a dose-dependent manner and the levels of lactate dehydrogenase (LDH) and creatine kinase (CK) were also significantly attenuated in the compound 2-treated group. In addition, we observed the cardioprotective effects by Hoechst 33258 nucleus staining, JC-1 staining, Annexin V-FITC/PI staining and transmission electron microscopy. Compound 2 inhibited apoptosis by reducing the ratio of Bcl-2/Bax, decreasing cleaved-caspase-3 expression and enhancing the phosphorylation of Akt. Furthermore, the phosphorylation effect of compound 2 was reversed by LY294002 the phosphatidylinositol-3-kinase (PI3K) inhibitor from happening. We concluded that compound 2 played a cardioprotective role in hypoxia-induced primary cardiac myocytes apoptosis partly via modulating the PI3K/Akt pathway at a 10-fold lower concentration than leonurine.
authors.affiliation: Department of Pharmacology, School of Pharmacy and Institute of Biomedical Sciences, Fudan University, Shanghai 201203, China.
authors.forename: Chunhua
authors.initials: C
authors.lastname: Liu
authors.forename: Wei
authors.initials: W
authors.lastname: Guo
authors.forename: Stefanie
authors.initials: S
authors.lastname: Maerz
authors.forename: Xianfeng
authors.initials: X
authors.lastname: Gu
authors.forename: Yizhun
authors.initials: Y
authors.lastname: Zhu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D019817:Benzoic Acid / Q000737:chemistry / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D015687:Cell Hypoxia / Q000187:drug effects; D003402:Creatine Kinase / Q000378:metabolism; D019610:Cytoprotection / Q000187:drug effects*; D004220:Disulfides / Q000737:chemistry / Q000494:pharmacology*; D005707:Gallic Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000187:drug effects* / Q000201:enzymology; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: C582661:3,5-dimethoxy-4-(3-(2-carbonyl-ethyldisulfanyl)-propionyl)benzoic acid 4-guanidinobutyl ester; D004220:Disulfides; D005707:Gallic Acid; D019817:Benzoic Acid; D007770:L-Lactate Dehydrogenase; D003402:Creatine Kinase