Cancer Chemotherapy: A Paclitaxel Prodrug for ADEPT (Antibody-Directed Enzyme Prodrug Therapy)

A glucuronide‐based prodrug of paclitaxel (taxol®) has been synthesized for use in antibody‐directed enzyme prodrug therapy (ADEPT). This three‐component prodrug was obtained by coupling a glucuronyl derivative of N‐methylamino 4‐nitrophenol (10) to the 2′‐hydroxy group of the side‐chain of paclitaxel through an aromatic carbamate. Once deprotected, prodrug 2 was shown to be relatively stable in human serum, and to be significantly less cytotoxic (IC50 = 65 μM and 90 nM, respectively) than the parent drug. As expected, compound 2 efficiently releases taxol in the presence of β‐glucuronidase.