Potential antitumor agents. Synthesis of bifunctional alpha-methylene-gamma-butyrolactones.
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Abstracto
A series of alkoxy-substituted di- and monolactones including the (E,E)-3,3'-(dioxaalkanediylidene)bis[dihydro-2(3H)-furanones] (17a-f), monolactones 6, 7, 8, 14, and 15, and dilactone 19 was synthesized by reaction of enolate 4 with appropriate alkyl halides (6, 7, 17a-f, 19), tosyl chloride (8), or acid chlorides (14, 15). Reaction of enolate 9 with tosyl chloride gave both Z and E isomers which allowed unequivocal assignment of stereochemistry to 8, 14, and 15. A series of open-chain bis(alpha-methylene-gamma-butyrolactones) (21a-d) was also prepared by a Reformatsky-type reaction between ethyl alpha-(bromomethyl)acrylate and appropriate dialdehydes. These compounds were tested for antitumor activity as part of a study of the influence of beta-substituents and distance between alkylating sites on the antitumor activity of alpha,beta-unsaturated lactones. The testing was carried out in standard NCI screens and selected compounds were tested against the Walker tumor. The alkoxy-substituted lactones were inactive in L1210 and were not cytotoxic. The open-chain bis(alpha-methylene-gamma-butyrolactones) showed borderline activity in 9KB and were inactive in L1210. Compound 21a gave a 45% inhibition of the Walker tumor at 18.75 mg/kg and was toxic at 37.5 mg/kg.