Total synthesis of (+/-)-acetomycin and design of esterase-resistant analogs.
The synthesis of acetomycin and related analogs was investigated. Acetomycin was synthesized from diethyl allyl(methyl)malonate in 6.5% yield over 18 steps. The total number of steps was improved compared to our previous synthesis; i.e., four steps shorter, and the total yield was 4.5% greater than the previous synthesis. Acetomycin analogs with benzoyloxy and pivaloyloxy groups, instead of an acetoxy group at the 5-position of the gamma-butyrolactone ring were designed as esterase-resistant models and prepared similarly. Although they showed a similar level of cytotoxicity as acetomycin in vitro, they were not resistant to porcine liver esterase, and lost cytotoxicity in vivo.
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000138:chemical synthesis* / Q000378:metabolism* / Q000494:pharmacology; D004355:Drug Stability; D004950:Esterases / Q000378:metabolism*; D005663:Furans / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D006131:Growth Inhibitors / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D007624:KB Cells; D007939:Leukemia L1210; D051379:Mice; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013552:Swine