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.