Kurihara K, Kikuchi N, Ajito K
Pharmaceutical Research Center, Meiji Seika Kaisha, Ltd., Yokohama, Japan.
J Antibiot (Tokyo). 1997 Jan;50(1):32-44. doi: 10.7164/antibiotics.50.32.
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.
描述了具有4-O-烷基-α-L-克拉定糖部分作为中性糖的十六元大环内酯类化合物的合成及生物学评价。这些有效的新型衍生物已通过避免糖基化反应高效合成。三-（叔丁基二甲基甲硅烷基）醚中间体的霉糖中的两个羟基被依次烷基化。硅烷基的顺序脱保护得到了柱晶白霉素V的4-O-烷基-L-克拉定糖类似物和3,4-二-O-烷基-L-霉糖类似物。一些4-O-烷基-L-克拉定糖类似物表现出强效抗菌活性。活性最高的衍生物3″-O-甲基-4″-O-（3-甲基丁基）柱晶白霉素V在体外大鼠血浆中表现出改善的代谢稳定性，在小鼠和仓鼠口服给药后血清中浓度极高。
