A Systematic Evaluation of the Bleomycin A2 l -Threonine Side Chain: Its Role in Preorganization of a Compact Conformation Implicated in Sequence-Selective DNA Cleavage

The preparation and examination of 3 − 7 are detailed and constitute analogues of deglycobleomycin A 2 ( 2 ) containing systematic modifications in the l -threonine side chain. The studies revealed a substantial impact of the substituent on the DNA cleavage efficiency and ratio of double strand/single strand (ds/ss) cleavage without affecting the characteristic 5‘-GPy selectivity. The results of the comparisons proved consistent with conformational effects of the substituent within the linker domain which restrict the number of accessible conformations (Φ ≅ −120°, Ψ = 60−180°) and favor adoption of a compact conformation (Φ ≅ −120°, Ψ ≅ 180°) implicated in sequence-selective DNA cleavage. The studies also identify one potential site that may adopt two nearly equivalent turn conformations. This site may constitute one swivel point in the structure that permits access to a class of related bound structures (Ψ = 60−180°) adaptable to variable conformational characteristics required of multiple cleavage sites, including access to both strands of duplex DNA from a single intercalation site important for both primary and secondary DNA cleavage.