Interaction of CC-1065 Analogs with DNA
Flynn, Jeffrey C.
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CC-l065 is a new antitumor antibiotic discovered within the last few years by The Upjohn Company (TUC). It was discovered as a fermentation product of Streptomyces zelensis, and is one of the most cytotoxic antitumor agents known. CC-l065 binds preferentially to A-T-rich DNA. It shows little or no affinity f:or heat-denatured DNA or RNA. Because of the strong binding of CC-l065, it has been postulated that this is a mechanism for its toxicity. Four structural analogs of CC-l065 were evaluated to compare their reactivity and binding characteristics with DNA. The reactivity of the cyclopropyl ring was pH-dependent and it hydrolyzed much quicker at pH 3.0 than pH 7.0. The extent of binding of the analogs with DNA was not as great as that of CC-l065, however. The analogs bound to double-stranded calf thymus DNA and poly d(A)·poly d(T), but not to poly d(G·C), thus showing the preference for A-T sites. These analogs also did not bind well to heat-denatured calf thymus or bovine serum albulmin. Hence, as with CC-l065, double-stranded DNA was the target for strong binding. Reactivity of the analogs may involve a non-covalent association of tne drug with the DNA, followed by nucleophilic attack of the cyclopropyl ring. It is proposed then that differences in reactivity are due to differences in the electron-donating ability of substituents attached to the reactive portion of the drug.