Synthesis and Cytotoxicity Evaluation of Certainα-Methylidene-γ-butyrolactones Bearing Coumarin, Flavone, Xanthone, Carbazole, and Dibenzofuran Moieties

Abstract

The cytotoxicities of α-methylidene-γ-butyrolactones, which are linked to coumarins (see 15 and 16) and to potential DNA-intercalating carriers such as flavones, xanthones, carbazole, and dibenzofuran (see 9a – e, 10a – e, 11, and 12), were studied. These compounds were synthesized via alkylation of their hydroxy precursors followed by a Reformatsky-type condensation (Scheme). These α-methylidene-γ-butyralactones were evaluated in vitro against 60 human tumor cell lines derived from nine cancer cell types and demonstrated a strong growth-inhibitory activity against leukemia cancer cells (Tables 1 and 2). For flavone- and xanthone-containing α-methylidene-γ-butyrolactones 9a – e and 10a – e, respectively, the overall potency (mean value) decreased on introduction of an electron-withdrawing substituent at the γ-phenyl substituent and increased with an electron-donating substituent. Comparing the different chromophores established the following order of decreasing potency (log GI50): dibenzofuran (12, −6.17) > flavone (9a, −5.96) > carbazole (11, −5.80) and xanthone (10a, −5.77) > coumarin (15, −5.60; 16, −5.65). Among them, the dibenzofuran derivative 12 showed not only strong inhibitory activities against leukemia cancer cell lines with an average log GI50 value of −7.22, but also good inhibitory activities against colon, melanoma, and breast cancer cells with average log GI50 values of −6.23, −6.31, and −6.39, respectively.