Synthesis and cytotoxic activities of alpha-methylidene-gamma-butyrolactones bearing a quinolin-4(1H)-one moiety

The cytotoxicities of the u-methylidene-gamma -butyrolactones 4. 5. and 8. which are linked to a quinolin-4(1H)-one moiety through a piperazine or O-a tom 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 ev aluated in vitro against 60 human-tumor cell lines derived from nine cancer -cell types and demonstrated not only strong growth-inhibitory activities a gainst leukemia cancer cells. but also fairly good activities against the g rowth of certain solid tumors (see Table). The O-bridged derivatives 8a and 8b exhibit both cytostatic (mean log GI(50) = -5.20 and - 5.82, resp.) and cytocidal (mean log LC50 = - 4.30 and -4.93. resp.) effects, while the pip erazine-bridged analogues 4 and 5 possess only weak cytostatic (mean log GI (50) = - 5.20 and -5.82, resp. mean log LC50 > -4.00) capability, among the m. 8b is the most potent, with log GI(50) = -6.47. -6.72. -653, and 6.52 ag ainst leukemia. SW-620 (colon). Lox IMVI, and SK-MEL-28 (melanoma) cancer c ells. respectively.