Synthesis of self-immolative glucuronide spacers based on aminomethylcarbamate. Application to 5-fluorouracil prodrugs for antibody-directed enzyme prodrug therapy

Abstract

The synthesis of three novel potential glucuronide-based prodrugs for antibody-directed enzyme prodrug therapy (ADEPT) is described. These prodrugs were designed to be activated at the tumour site by β-glucuronidase to afford the corrresponding anticancer agent, 5-FU. The structural pattern of these compounds includes a self-immolative spacer between the glucuronyl residue and the N¹ of 5-FU. Three types of spacers have been elaborated which, after enzymic hydrolysis, spontaneously decompose to deliver an unstable N¹ aminal 5-FU derivative and, from there, the cytotoxic drug. All potential prodrugs were stable and proved to be excellent substrates of E. coli in in vitro experiments.