Skwarczynski Mariusz, Sohma Youhei, Noguchi Mayo, Kimura Maiko, Hayashi Yoshio, Hamada Yoshio, Kimura Tooru, Kiso Yoshiaki
Department of Medicinal Chemistry, Center for Frontier Research in Medicinal Science, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8412, Japan.
J Med Chem. 2005 Apr 7;48(7):2655-66. doi: 10.1021/jm049344g.
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.
由于已经开发出许多对多药耐药（MDR）肿瘤有效的新型紫杉烷类化合物，并且它们的水溶性差在静脉给药中是一个非常现实的问题，我们设计并合成了一系列新型水溶性紫杉烷类前药（异紫杉烷类）。这些前药是紫杉烷类的2'-O-异构体，具有较高的水溶性（0.8-1.1mg/mL），并通过简单的pH依赖性化学机制（通过O-N分子内酰基迁移）实现母体药物释放的适当动力学，显示出有前景的结果。在转化为母体药物的过程中没有额外的功能性助剂释放，这在毒理学和一般药理学中将是一个优势，并且在开发前药时可以节省这些领域中助剂单元评估的成本。此外，我们首次证明了O-N分子内酰氧基迁移反应在除叔丁氧羰基以外的前药设计中的成功应用，并且该反应可以在无有机溶剂和无副产物的情况下进行。
