Asymmetric Synthesis and Biological Evaluation of Glycosidic Prodrugs for a Selective Cancer Therapy

Abstract

A severe limitation in cancer therapy is the often insufficient differentiation between malign and benign tissue using known chemotherapeutics. One approach to decrease side effects is antibody-directed enzyme prodrug therapy (ADEPT). We have developed new glycosidic prodrugs such as (−)-(1S)-26 b based on the antibiotic (+)-duocarmycin SA ((+)-1) with a QIC₅₀ value of 3500 (QIC₅₀=IC₅₀ of prodrug/IC₅₀ of prodrug+enzyme) and an IC₅₀ value for the corresponding drug (prodrug+enzyme) of 16 pM. The asymmetric synthesis of the precursor (−)-(1S)-19 was performed by arylation of the enantiomerically pure epoxide (+)-(S)-29 (≥98 % ee).