Duocarmycin-based prodrugs for cancer prodrug monotherapy
- Bioorg Med Chem. 2008 Jun 15;16(12):6312-8. doi: 10.1016/j.bmc.2008.05.009.
- 1. Institute of Organic und Biomolecular Chemistry of the Georg-August-University Göttingen, D-37077 Göttingen, Germany. [email protected]
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 x 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 IC(50) values of 610 nM for 4a and 3300 nM for 4b. In the presence of beta-glucuronidase, 4a expresses an IC(50) value of 0.9 nM and 4b of 2.1 nM resulting in QIC(50) values of about 700 for 4a and 1600 for 4b.
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Cat. No.Product NameDescriptionTargetResearch Area
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Research Areas: Cancer