A SYSTEMATIC EVALUATION OF THE BLEOMYCIN A(2) 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 ana logues of deglycobleomycin A(2) (2) containing systematic modification s in the L-threonine side chain. The studies revealed a substantial im pact of the substituent on the DNA cleavage efficiency and ratio of do uble strand/single strand (ds/ss) cleavage without affecting the chara cteristic 5'-GPy selectivity. The results of the comparisons proved co nsistent with conformational effects of the substituent within the lin ker domain which restrict the number of accessible conformations (Phi congruent to -120 degrees, Psi = 60-180 degrees) and favor adoption of a compact conformation (Phi congruent to -120 degrees, Psi congruent to 180 degrees) implicated in sequence-selective DNA cleavage. The stu dies also identify one potential site that may adopt two nearly equiva lent turn conformations. This site may constitute one swivel point in the structure that permits access to a class of related bound structur es (Psi = 60-180 degrees) adaptable to variable conformational charact eristics 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.