Potential antitumor agents. Synthesis of bifunctional alpha-methylene-gamma-butyrolactones.
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.
D015107:4-Butyrolactone / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000627:therapeutic use; D002279:Carcinoma 256, Walker / Q000188:drug therapy; D002460:Cell Line; D005663:Furans / Q000138:chemical synthesis*; D006801:Humans; D007939:Leukemia L1210 / Q000188:drug therapy; D051379:Mice; D051381:Rats; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D005663:Furans; D015107:4-Butyrolactone