Synthesis and biological evaluations of a monomethylauristatin E glucuronide prodrug for selective cancer chemotherapy

• Synthesis of the first glucuronide prodrug of the potent monomethylauristatin E.
• Efficient release of the drug upon enzymatic activation.
• Subnanomolar cytotoxic activity against several cancer cell lines.
• Significant cytotoxic effect on primary cultures of patients with lung cancer.
• Significant antitumor effect without overt toxicity in vivo.

We developed a glucuronide prodrug of the potent monomethylauristatin E (MMAE). This prodrug is significantly less toxic than the parent drug. However, in the presence of β-glucuronidase the prodrug leads to the efficient release of MMAE thereby triggering a subnanomolar cytotoxic activity against several cancer cell lines. Preliminary in vivo experiments conducted in C57BL/6 mice bearing a subcutaneous murine Lewis Lung Carcinoma (LLC) demonstrated the potential of this targeting system for the selective treatment of solid tumors.

The glucuronide prodrug 1 of the potent monomethylauristatin E (MMAE) was synthesized and evaluated as a potential selective antitumor agent for the treatment of solid tumors.Figure optionsDownload as PowerPoint slide