Synthesis and cytotoxicity evaluation of certain α-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.