No auxiliary, no byproduct strategy for water-soluble prodrugs of taxoids: scope and limitation of O-N intramolecular acyl and acyloxy migration reactions.
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.
Skwarczynski
Mariusz
M
Department of Medicinal Chemistry, Center for Frontier Research in Medicinal Science, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8412, Japan.
Sohma
Youhei
Y
Noguchi
Mayo
M
Kimura
Maiko
M
Hayashi
Yoshio
Y
Hamada
Yoshio
Y
Kimura
Tooru
T
Kiso
Yoshiaki
Y
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry; D004355:Drug Stability; D006863:Hydrogen-Ion Concentration; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry; D012995:Solubility; D013329:Structure-Activity Relationship; D043823:Taxoids / Q000737:chemistry*; D014867:Water
D000970:Antineoplastic Agents; D011355:Prodrugs; D043823:Taxoids; D014867:Water