BETA-GLUCURONYL CARBAMATE BASED PRO-MOIETIES DESIGNED FOR PRODRUGS IN ADEPT

A number of pro-moieties 8a - e designed for prodrug preparation have been synthesized (chart 2). The pro-moieties, containing a glucuronyl carbamate group linked to a spacer possessing a terminal carboxylic acid group, have been synthesized from isocyanates 6 and anomerically unprotected glucuronic acids 10 (chart 2). The requisite isocyanates had to be prepared using the Curtius rearrangement. Glucuronyl carbamates proved to be excellent substrates for human beta-glucuronidase. The pro-moieties 8a - e can be coupled to hydroxy- or amino group containing drugs. The resulting prodrugs are designed to be activated by beta-glucuronidase (chart 1) and to be used in ADEPT. Application is demonstrated with the synthesis of daunomycin prodrugs 12a - e (chart 3).