O-N intramolecular acyl migration strategy in water-soluble prodrugs of taxoids.
We synthesized a highly water-soluble canadensol prodrug 6 that formed canadensol 3 by a simple pH-dependent chemical mechanism via the O-N intramolecular acyl migration of the isobutyryl group. This prodrug, a 2'-O-isobutyryl isoform of 3, has no additional functional auxiliaries released during the conversion to 3. This is a significant advantage in toxicology and medical economics, since the potential side effects of reported water-soluble auxiliaries and the use of detergent for solubilization can be avoided. The solubility of 6 was 2.26 mg mL(-1) and only the parent drug 3 was released under physiological conditions (pH=7.4) while, in acidic medium, the release of 3 slowed until migration was completely obstructed at pH=2. In further consideration of this strategy, we elucidated the use of an 'O-N acyl-like' migration reaction of the Boc group in the design of a docetaxel prodrug. Both O-N migration and undesired hydrolysis of the Boc group occurred under physiological conditions, although no oxazolidinone formation was observed, suggesting the limitation of our water-soluble prodrug strategy to docetaxel.
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
Kimura
Maiko
M
Hayashi
Yoshio
Y
Kimura
Tooru
T
Kiso
Yoshiaki
Y
D000215:Acylation; D007202:Indicators and Reagents; D007700:Kinetics; D008958:Models, Molecular; D008968:Molecular Conformation; D009584:Nitrogen; D010100:Oxygen; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry*; D012995:Solubility; D013237:Stereoisomerism; D043823:Taxoids / Q000138:chemical synthesis* / Q000737:chemistry*; D014867:Water
D007202:Indicators and Reagents; D011355:Prodrugs; D043823:Taxoids; D014867:Water; D009584:Nitrogen; D010100:Oxygen