DEFINITION OF THE EFFECT AND ROLE OF THE BLEOMYCIN A(2) VALERATE SUBSTITUENTS - PREORGANIZATION OF A RIGID, COMPACT CONFORMATION IMPLICATEDIN SEQUENCE-SELECTIVE DNA CLEAVAGE

The synthesis and a comparative study of deglycobleomycin A(2) analogu es containing key modifications in the valerate subunit are described in efforts that define the role of the linker length and its substitue nts. In addition to demonstrating that the C3-hydroxy group exhibits o nly a modest effect (1-2x) that may be attributed to an intermolecular H-bond with DNA and that the length of the linker is important (C4 > C5 > C3 > C2), the studies illustrate that the substantial impact of t he C4-methyl group is linked to the presence of the C2-methyl group, w hile the modest impact of the C2-methyl group itself (ca. 2x) is not c oupled to the presence of the C4-methyl group. These effects may be ex plained by the conformational properties of the agents resulting from the substitutions and beautifully fit the models of DNA-bound Co(III)O OH bleomycin A(2) and deglycobleomycin A(2). The magnitude of the effe cts suggests that an important functional role of the linker region is to facilitate adoption of a rigid, compact conformation productive fo r DNA cleavage. The studies also identify a second potential site that may adopt two nearly equivalent conformations which may constitute a swivel point that permits access to a class of related bound structure s adaptable to the conformational characteristics of the multiple clea vage sites or access to both strands of DNA from a common intercalatio n site important for both primary (single strand) and secondary (doubl e strand) cleavage.