No Auxiliary, No Byproduct Strategy for Water-Soluble Prodrugs of Taxoids:  Scope and Limitation of O−N Intramolecular Acyl and Acyloxy Migration Reactions

• Published in: Journal of medicinal chemistry 2005-04, Vol.48 (7), p.2655-2666
• Main Authors: Skwarczynski, Mariusz, Sohma, Youhei, Noguchi, Mayo, Kimura, Maiko, Hayashi, Yoshio, Hamada, Yoshio, Kimura, Tooru, Kiso, Yoshiaki
• Format: Article
• Language: English
• Subjects: Alicyclic compounds, terpenoids, prostaglandins, steroids; Antineoplastic agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Biological and medical sciences; Chemistry; Drug Stability; Exact sciences and technology; General aspects; Hydrogen-Ion Concentration; Medical sciences; Organic chemistry; Pharmacology. Drug treatments; Preparations and properties; Prodrugs - chemical synthesis; Prodrugs - chemistry; Solubility; Structure-Activity Relationship; Taxoids - chemistry; Terpenoids; Water
• ISSN: 0022-2623; 1520-4804
• 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.