Duocarmycin-based prodrugs for cancer prodrug monotherapy

The synthesis and biological evaluation of novel prodrugs based on the cytotoxic antibiotic duocarmycin SA (1) for a selective treatment of cancer using a prodrug monotherapy (PMT) are described. Transformation of the phenol 8 with the glucuronic acid benzyl ester trichloroacetimidate 9b followed by reaction with DMAI·HCl (10) gives the glucuronide 11b, which is deprotected to afford the desired prodrug 4a containing a glucuronic acid moiety. In addition, the prodrug 4b with a glucuronic methyl ester unit is prepared. The cytotoxicity of the glucuronides is determined using a HTCFA-assay with IC50 values of 610 nM for 4a and 3300 nM for 4b. In the presence of β-glucuronidase, 4a expresses an IC50 value of 0.9 nM and 4b of 2.1 nM resulting in QIC50 values of about 700 for 4a and 1600 for 4b.

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