Synthesis and Cytotoxic Activities of α‐Methylidene‐γ‐butyrolactones Bearing a Quinolin‐4(1H)‐one Moiety

The cytotoxicities of the α‐methylidene‐γ‐butyrolactones 4 , 5 , and 8 , which are linked to a quinolin‐4(1H)‐one moiety through a piperazine or O‐atom bridge were studied. These compounds were synthesized by alkylation of 1‐ethyl‐6‐fluoro‐1,4‐dihydro‐7‐hydroxy‐4‐oxoquinoline‐3‐carboxylic acid ( 6 ) followed by a Reformatsky‐type condensation. Compounds 4 , 5 , and 8 were evaluated in vitro against 60 human‐tumor cell lines derived from nine cancer‐cell types and demonstrated not only strong growth‐inhibitory activities against leukemia cancer cells, but also fairly good activities against the growth of certain solid tumors (see Table). The O‐bridged derivatives 8a and 8b exhibit both cytostatic (mean log GI₅₀=?5.20 and ?5.82, resp.) and cytocidal (mean log LC₅₀=?4.30 and ?4.93, resp.) effects, while the piperazine‐bridged analogues 4 and 5 possess only weak cytostatic (mean log GI₅₀=?5.19 and ?4.74, resp.; mean log LC₅₀>?4.00) capability. Among them, 8b is the most potent, with log GI₅₀=?6.47, ?6.72, ?6.53, and ?6.52 against leukemia, SW‐620 (colon), Lox IMV1, and SK‐MEL‐28 (melanoma) cancer cells, respectively.