title: Discovery of a ring-opened derivative of 3-n-butylphthalide bearing NO/H2S-donating moieties as a potential anti-ischemic stroke agent.
abstract: To search for novel anti-ischemic stroke agents with higher potency than a known drug 3-n-butylphthalide (NBP), a series of ring-opened derivatives of NBP bearing both nitric oxide (NO) and hydrogen sulfide (H2S)-donating moieties (NO/H2S-NBP) (8a-8o) were designed, synthesized, and biologically evaluated. The most active compound 8d was more potent than NBP and the corresponding H2S-NBP 10 or NO-NBP 13 in inhibition of the ADP-induced platelet aggregation in vitro. In addition, 8d produced moderate levels of NO and H2S, which could be beneficial for improving cardiovascular and cerebral circulation. More importantly, in a rat model of transient focal cerebral ischemia, oral treatment with 8d improved neurobehavioral function, reduced the infarct brain size and brain-water content, and enhanced the levels of brain antioxidant SOD, GSH and GSH-Px but diminished the level of oxidant MDA. These protective effects of 8d against the ischemia/reperfusion (I/R)-related brain damage were greater than that of NBP, suggesting that 8d may be a promising agent for further investigation.
authors.affiliation: State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, PR China; Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, Nanjing 210009, PR China.
authors.forename: Wei
authors.initials: W
authors.lastname: Yin
authors.affiliation: State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, PR China.
authors.forename: Li
authors.initials: L
authors.lastname: Lan
authors.affiliation: State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, PR China; Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, Nanjing 210009, PR China.
authors.forename: Zhangjian
authors.initials: Z
authors.lastname: Huang
authors.affiliation: State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, PR China.
authors.forename: Jing
authors.initials: J
authors.lastname: Ji
authors.affiliation: State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, PR China; Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, Nanjing 210009, PR China.
authors.forename: Jiangen
authors.initials: J
authors.lastname: Fang
authors.affiliation: The Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, Lihu Avenue 1800, Wuxi 214122, PR China.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, PR China.
authors.forename: Hui
authors.initials: H
authors.lastname: Ji
authors.affiliation: State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, PR China; Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, Nanjing 210009, PR China.
authors.forename: Sixun
authors.initials: S
authors.lastname: Peng
authors.affiliation: State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, PR China.
authors.forename: Jinyi
authors.initials: J
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, PR China; Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, Nanjing 210009, PR China. Electronic address: zyhtgd@163.com.
authors.forename: Yihua
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D001572:Benzofurans / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D055808:Drug Discovery; D008297:Male; D051381:Rats; D020521:Stroke / Q000188:drug therapy*
chemical_list: D000975:Antioxidants; D001572:Benzofurans; C027125:3-n-butylphthalide
keywords: Anti-platelet aggregation; Hydrogen sulfide; Ischemic stroke; Nitric oxide