title: Design, synthesis, and preliminary cardioprotective effect evaluation of danshensu derivatives.
abstract: A series of (R)-3,4-dihydroxyphenyllactic acid Danshensu (DSS) derivatives were synthesized, and their cardioprotective effects were evaluated in vitro and in vivo. Among the new derivatives, compound 14 showed significant protective effects in cultured myocardial cells and in the rat model of myocardial ischemia. The therapeutic efficacy of compound 14 was significantly higher than that of its parent compound DSS, and amlodipine, a first-line treatment for angina pain. Compound 14 potently scavenged free radicals, significantly decreased the levels of LDH and MDA, and inhibited the leakage of CK in animal model of ischemia. We had previously found that compound 14 activated PI3K/Akt/GSK-3β and Nrf2//Keap1/heme oxygenase-1 (HO-1) signaling pathways in H9c2 cells. These results suggest that compound 14 has a unique mechanism of action, that is, multifunctional. Compound 14 may be a new potential therapy for ischemic heart diseases.
authors.affiliation: Institute of New Drug Research and Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine, Jinan University College of Pharmacy, Guangzhou, 510632, China.
authors.forename: Qingbin
authors.initials: Q
authors.lastname: Cui
authors.forename: Yonghong
authors.initials: Y
authors.lastname: Chen
authors.forename: Mingjuan
authors.initials: M
authors.lastname: Zhang
authors.forename: Luchen
authors.initials: L
authors.lastname: Shan
authors.forename: Yewei
authors.initials: Y
authors.lastname: Sun
authors.forename: Pei
authors.initials: P
authors.lastname: Yu
authors.forename: Gaoxiao
authors.initials: G
authors.lastname: Zhang
authors.forename: Dingyuan
authors.initials: D
authors.lastname: Wang
authors.forename: Zengchao
authors.initials: Z
authors.lastname: Zhao
authors.forename: Qian
authors.initials: Q
authors.lastname: Xu
authors.forename: Benhong
authors.initials: B
authors.lastname: Xu
authors.forename: Yuqiang
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000818:Animals; D002316:Cardiotonic Agents / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D003402:Creatine Kinase / Q000097:blood; D004195:Disease Models, Animal; D015195:Drug Design; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D051547:Heme Oxygenase-1 / Q000378:metabolism; D007511:Ischemia / Q000188:drug therapy; D007770:L-Lactate Dehydrogenase / Q000097:blood; D007773:Lactates / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D008315:Malondialdehyde / Q000097:blood; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D010666:Phenylpropionates / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011485:Protein Binding; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011719:Pyrazines / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D013237:Stereoisomerism
chemical_list: C000596359:(3,5,6-trimethylpyrazinyl)methyl 2-acetoxy-3-(3,4-diacetoxyphenyl)propanoate; D002316:Cardiotonic Agents; D007773:Lactates; D051267:NF-E2-Related Factor 2; D010666:Phenylpropionates; D011719:Pyrazines; C035055:3,4-dihydroxyphenyllactic acid; D008315:Malondialdehyde; D007770:L-Lactate Dehydrogenase; D051547:Heme Oxygenase-1; D019869:Phosphatidylinositol 3-Kinases; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D003402:Creatine Kinase
keywords: Danshensu derivatives; biological screening; chemical synthesis; drug design; myocardial ischemia