Altromycin B Threads the DNA Helix Interacting with Both the Major and the Minor Grooves To Position Itself for Site-Directed Alkylation of Guanine N7

The pluramycins are a class of antitumor antibiotics for which a detailed structural investigation of their interaction with DNA is lacking. Using altromycin B as a prototypical pluramycin, we have characterized the drug’s interaction with the self-complementary DNA duplex [d(GAAG*TACTTC)]2 diadduct (* denotes the site of covalent modification) by two-dimensional NMR and have gained considerable insight into the role played by the drug’s glycosidic substituents in sequence selectivity. The drug intercalates into the DNA molecule and stacks to the 5’ side of the modified guanine, thereby placing a disaccharide into the minor groove and a monosaccharide into the major groove. As a result of these interactions, the epoxide is positioned in the major groove of the DNA to perform electrophilic attack on N7 of guanine.