The structural basis for in situ activation of DNA alkylation by duocarmycin SA

Duocarmycin SA is a member of a growing class of interesting lead compounds for chemotherapy, distinguished by the manner in which they bind to and re act with DNA substrates. The first three-dimensional structure of a DNA add uct of an unnatural enantiomer from this family has been determined by H-1 NMR methods. Comparison to the previously determined structure of the natur al enantiomer bound in the same DNA-binding site provides unique insights i nto the similarities and critical distinctions producing the respective alk ylation products and site selectivities. The results also support the hypot hesis that the duocarmycin SA alkylation reaction is catalyzed by the bindi ng to DNA, and provide a deeper understanding of the structural basis for t his unique mode of activation. (C) 2000 Academic Press.