CC-1065/duocarmycin and bleomycin A2 hybrid agents: lack of enhancement of DNA alkylation by attachment to noncomplementary DNA binding subunits.

Hybrid agents 5-11 containing the C-terminus DNA binding domain of bleomycin A2 linked to the CBI analogue of the CC-1065 and duocarmycin DNA alkylation subunits were prepared and evaluated. The agents exhibited little or no enhancement of the DNA alkylation efficiency and in some cases the linkage resulted in diminished properties relative to the simple alkylation subunit itself. Moreover, the DNA alkylation selectivity (5'-AA > 5'-TA) of the resulting agents proved identical to that of simple derivatives of the CBI alkylation subunit, e.g. N-BOC-CBI. Thus, the linkage to the DNA binding domain of bleomycin A2 did not alter this inherent DNA alkylation selectivity to reflect a DNA binding or cleavage selectivity of bleomycin A2, nor did it reflect the greater 5- or 3.5-base-pair AT-rich selectivities observed with CC-1065 or the duocarmycins, respectively. Consistent with these observations, the cytotoxic properties of 5-11 were diminished relative to those of even simple derivatives of the CC-1065/duocarmycin alkylation subunits, e.g. N-BOC-CBI.