Calicheamicin gamma 1I is a recently discovered diyne-ene--containing antitumor antibiotic with considerable potency against murine tumors. In vitro, this drug interacts with double-helical DNA in the minor groove and causes site-specific double-stranded cleavage. It is proposed that the observed cleavage specificity is a result of a unique fit of the drug and DNA followed by the generation of a nondiffusible 1,4-dehydrobenzene--diradical species that initiates oxidative strand scission by hydrogen abstraction on the deoxyribose ring. The ability of calicheamicin gamma 1I to cause double-strand cuts at very low concentrations may account for its potent antitumor activity.

Calicheamicin gamma 1I is a recently discovered diyne-ene-containing antitumor antibiotic that cleaves DNA in a double-stranded fashion, a rarity among drugs, at specific sequences. It is proposed that the cutting specificity is due to a combination of the complementarity of the diyne-ene portion of the aglycone with DNA secondary structures and stabilization by association of the thiobenzoate-carbohydrate tail with the minor groove.

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Maduropeptin (MDP) is a recently isolated antitumor antibiotic, consisting of an enediyne-containing chromophore embedded in a highly acidic protein. This holoantibiotic damages duplex DNA in vitro, producing a mixture of single- and double-strand breaks at selected sites. The chromophore, isolated as the methanol adduct from the protein-containing holoantibiotic, exhibits the same selectivity and cleavage chemistry as the chromoprotein complex. Preliminary evidence suggests that the primary DNA breaks involve 4'-H abstraction from the deoxyribose sugars at the cleavage sites. Unlike most other enediyne antitumor antibiotics, DNA strand scission is not bioreductively induced by MDP or the methanol adduct of the chromophore. This was also observed for the C1027 chromophore. DNA cleavage is inhibited in the presence of certain cations (Ca2+, Mg2+) as was observed with the kedarcidin chromophore. 1H NMR spectroscopy studies on the methanol adduct of the maduropeptin chromophore in the presence of calcium chloride provide clues regarding its activation and give insight as to the regions of the chromophore important for DNA binding. Our results suggest that the solvent artifact of the chromophore may in essence be a prodrug and it regenerates the parent chromophore as in the holoantibiotic prior to cleaving DNA. As with kedarcidin and neocarzinostatin, maduropeptin exhibits a high affinity for histones, in vitro, cleaving them to low molecular mass peptides. Histone H1, the most opposite in net charge, is cleaved most readily. This latter activity may serve to disrupt the chromatin superstructure in vivo, prior to exposing the DNA to the chromophore.