162. Synthesis and evaluation of α-methylidene-γ-butyrolactone bearing flavone and xanthone moieties

Article abstract of DOI:10.1002/hlca.19970800806

In a search for inhibitors of platelet aggregation, a number of α- methylidene-γ-butyrolactone 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 that 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 (Table 3). 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.