No auxiliary, no byproduct strategy for water-soluble prodrugs of taxoids: Scope and limitation of O-N intramolecular acyl and acyloxy migration reactions

被引：43

作者：

Skwarczynski, M ^{[1
]}

Sohma, Y ^{[1
]}

Noguchi, M ^{[1
]}

Kimura, M ^{[1
]}

Hayashi, Y ^{[1
]}

Hamada, Y ^{[1
]}

Kimura, T ^{[1
]}

Kiso, Y ^{[1
]}

机构：

[1] Kyoto Pharmaceut Univ, Ctr Frontier Res Med Sci, Dept Med Chem, Yamashima Ku, Kyoto 6078412, Japan

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2005年 / 48卷 / 07期

关键词：

D O I：

10.1021/jm049344g

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Since numerous new taxoids active against multidrug resistant (MDR) tumors have been developed and their poor water-solubility is a very real problem in intravenous administration, we have designed and synthesized a series of novel water-soluble taxoid prodrugs (isotaxoids). These prodrugs, a 2'-O-isoform of taxoids, showed promising results with higher water solubility (0.8- 1.1 mg/mL) and proper kinetics for parent drug release by a simple pH-dependent chemical mechanism via O-N intramolecular acyl migration. No additional functional auxiliaries are released during the conversion to parent drugs, which would be an advantage in toxicology and general pharmacology, and the cost for the evaluations of auxiliary units in these fields could be saved in prodrug development. In addition, we demonstrate for the first time the successful application of the O-N intramolecular acyloxy migration reaction in the prodrug design, with the exception of the tert-butyloxycarbonyl group, and that this reaction can be provided with no organic solvent and no side products.

引用

页码：2655 / 2666

页数：12

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