124(P72) 4位がアルキル化されたクラジノースを有するロイコマイシン類縁化合物の合成と生物学的評価(ポスター発表の部)

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概要

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• Sixteen-membered macrolide antibiotics are safe and useful in treating infections caused by Gram-positive bacteria or Mycoplasma. However, one explanation concerning their unsatisfied efficiency involves a deacylation at a neutral sugar moiety in vivo. As part of our program in this area, we have designed novel 4-O-alkyl-L-cladinose analogues (1 and 2) of leucomycin in order to improve the pharmacokinetics. Compounds 1y were constructed via glycosylation. 4-O-Alkyl-L-cladinose was regioselectively introduced into a 4'-hydroxyl group of a glycosyl acceptor (3) using thioglycosides (10x). After reduction of N-oxide, biological transformation of 14 afforded desired 1y. On the other hand, compounds 2z were efficiently synthesized by direct alkylations. Leucomycin A_7 was protected with TBS groups and successive depropionylation prepared a stable diol (5). Sequential alkylations of 5 followed by deprotections gave another targets 2z smoothly. Compounds 1 g and 2g (4"-O-isoamyl derivatives) displayed similar activities in vitro to natural antibiotics, and their activities against Streptococcus pneumoniae were clearly enhanced. The maximum concentration in serum (Cmax) and urinary recovery of 1g were dramatically improved to be comparable to those of clarithromycin (CAM) in mice (200mg/kg, po). Moreover, Cmax and AUC of 2g were superior to those of rokitamycin or CAM in hamsters (500mg/kg, po). Compounds 1g and 2g also exhibited greatly improved therapeutic effects in mice. These excellent characters of 1g and 2g in vivo could be mainly explained by metabolic stability of their neutral sugar.

• 天然有機化合物討論会の論文
• 1996-09-02

著者

• 栗原 健一

  明菓創薬研

• 荒明 美奈子

  明菓創薬研

• 柴原 聖至

  明菓創薬研

• 原 修

  京大院工

• 味戸 慶一

  明菓創薬研

• 原 修

  明菓創薬研

• 五味 修一

  明菓創薬研

• 清水 明

  明菓創薬研

• 尾本 捷二

  明菓創薬研

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