Synthesis And Anti-platelet Aggregation Activities Of Khellactone Derivatives

Objective:Khellactone coumarins in structure belonged to 7, 8-pyranocoumarin, occurring widely in umbelliferous plants. Khellactone coumarin derivatives have been reported to possess a wide range of biological activities, including dilating coronary arteries,improving cardiac function, reducing blood pressure, antibacterial activities, anti-HIV and calcium antagonist effects. In order to further explore and enrich the pharmacological application and structure-activity relationship of khellactone coumarin compounds.Methods:In this paper, the synthesis was started with resorcinol, followed by Pechmann reaction, hydrolysis, etherification to get 4-ethoxyl-7-hydroxycoumarin(A3). The4-ethoxyl seselin(A5) was furnished through nucleophilic substitution reaction with A3 and 3-chloro-3-methyl-1-butyne, and then followed by Claisen rearrangement. A5 via Sharpless asymmetrical dihydroxylation obtained 4-ethoxyl-dihydroseselin(A6). Finally,the esterification of A6 and organic acids were proceeded to afford the corresponding khellactone coumarin derivatives. We used 4-methyl coumarin as raw materials, followed by nucleophilic substitution and Claisen rearrangement reaction to generate 4-methyl seselin(B2). The intermediate 4-methyl-thiolactone seselin(B3) was synthesized by sulfuration reaction with B2 and Lawesson reagents. Then through Sharpless asymmetric hydroxylation, esterification reactions got 4-methyl-khelthiolactone derivatives. The anti-platelet aggregation activities of synthesized compounds were evaluated by microplate reader method(MP) in vitro.Results:sixteen 4-ethoxyl-khellactone derivatives and eight 4-methyl-khelthiolactone derivatives were synthesized. The structures of the target new compounds were confirmed by1H-NMR,13C-NMR, and MS spectra. The in vitro assay indicated that compounds4-ethoxyl-3’(S),4’(S)-di-O-(3,5-dinitrobenzoyl)-khellactone(A7i), 4-ethoxyl-3’(S),4’(S)-di-O-o-fluorinebenzoyl-khellactone(A7o), 4-methyl-3’(S),4’(S)-di-O-o-chlorobenzoyl khelthiolactone(B5q) and 4-methyl-3’(S),4’(S)-di-O-(2,4-dichlorobenzoyl)-khelthiolactone(B5n)showed higher activities than the positive control drug ozagrel sodium on the platelet aggregation inhibitory induced by ADP.Conclusions:The synthesized 4-ethoxyl-khellactone derivatives and 4-methyl-khelthiolactone have good anti-platelet aggregation activities with could be a valuable candidate for further development.