Cladinose analogues of sixteen-membered macrolide antibiotics. III. Efficient synthesis of 4-O-alkyl-L-cladinose analogues: improved antibacterial activities compatible with pharmacokinetics.
The synthesis and biological evaluation of sixteen-membered macrolides possessing a 4-O-alkyl-alpha-L-cladinosyl moiety as a neutral sugar are described. These potent novel derivatives have been efficiently synthesized avoiding glycosylations. Two hydroxyl groups in mycarose of the tri-(tert-butyldimethylsilyl) ether intermediate were successively alkylated. Sequential deprotections of silyl groups afforded 4-O-alkyl-L-cladinose analogues and 3,4-di-O-alkyl-L-mycarose analogues of leucomycin V. Some 4-O-alkyl-L-cladinose analogues exhibited potent antibacterial activities. The most active derivative, 3"-O-methyl-4"-O-(3-methylbutyl)leucomycin V, showed improved metabolic stability in rat plasma in vitro and extremely high concentrations in serum after oral administrations in mice and in hamsters.
Kurihara
K
K
Pharmaceutical Research Center, Meiji Seika Kaisha, Ltd., Yokohama, Japan.
Kikuchi
N
N
Ajito
K
K
D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D006224:Cricetinae; D005260:Female; D006601:Hexoses / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D018942:Macrolides; D008297:Male; D008647:Mesocricetus; D051379:Mice; D008813:Mice, Inbred ICR; D051381:Rats; D013329:Structure-Activity Relationship
D000900:Anti-Bacterial Agents; D006601:Hexoses; D018942:Macrolides; C013889:cladinose