THE CARBOHYDRATE DOMAIN OF CALICHEAMICIN GAMMA-1(I) DETERMINES ITS SEQUENCE SPECIFICITY FOR DNA CLEAVAGE

We have investigated the DNA cleaving properties of calicheamicinone, the synthetic core aglycone of calicheamicin gamma-1I, a natural product with extremely potent antitumor activity. Our experiments have shown that the synthetic analog binds and cleaves DNA, albeit without any sequence selectivity and with less efficiency than the natural compound. We propose that a key element in the sequence recognition process is the thiobenzoate ring present in the natural compound. We have demonstrated by one-dimensional NMR that there is direct hydrogen abstraction from DNA by calicheamicinone, with enhanced binding affinity contributed by the carbohydrate domain. The reduced efficiency of hydrogen ion from DNA by bound calicheamicinone, compared with the natural compound, implicates the carbohydrate moiety in positioning the drug for hydrogen abstraction.