Synthesis and Evaluation of α‐Methylidene‐γ‐butyrolactone bearing flavone and xanthone moieties

Abstract

AbstractIn a search for inhibitors of platelet aggregation, a number of α‐methylidene‐γ‐butyrolactones 5 and 6 bearing flavone or xanthone moieties, respectively, were synthesized and evaluated for their antiplatelet activity against thrombin(Thr)‐, arachidonic‐acid(AA)‐, collagen(Col)−, and platelet‐activating‐factor(PAF)‐induced aggregation in washed rabbit platelets. These compounds were synthesized from 7‐hydroxyflavone (1) or 3‐hydroxyxanthone (2) via O‐alkylation (→ 3 and 4, resp.) and Reformatsky‐type condensation (Scheme). Most of the flavone‐containing α‐methylidene‐γ‐butyrolactones 5a–d showed potent antiplatelet effects on AA‐ and Col‐induced aggregation, while xanthone derivatives 6c–e were found to have the same pharmacological profile than aspirin in which only AA‐induced aggregation was inhibited (Table 1). However, 6c–e were approximately three to ten times more potent than aspirin (Table 2). For the vasorelaxing effects, 5a was the only compound which exhibited significant inhibitory activity on the high‐K+ medium, Ca2+‐induced vasoconstriction (Table3). Both 5a and 6a, with an aliphatic Me substituent at C(γ) of the lactone, were active against norepinephrine‐induced phasic and tonic constrictions while their γ‐aryl‐substituted counterparts 5b–f and 6b–f were inactive.