title: Biochemical evaluation of a 108-member deglycobleomycin library: viability of a selection strategy for identifying bleomycin analogues with altered properties.
abstract: The bleomycins (BLMs) are clinically used glycopeptide antitumor antibiotics that have been shown to mediate the sequence-selective oxidative damage of both DNA and RNA. Previously, we described the solid-phase synthesis of a library of 108 unique analogues of deglycoBLM A6, a congener that cleaves DNA analogously to BLM itself. Each member of the library was assayed for its ability to effect single- and double-strand nicking of duplex DNA, sequence-selective DNA cleavage, and RNA cleavage in the presence and absence of a metal ion cofactor. All of the analogues tested were found to mediate concentration-dependent plasmid DNA relaxation to some extent, and a number exhibited double-strand cleavage with an efficiency comparable to or greater than deglycoBLM A6. Further, some analogues having altered linker and metal-binding domains mediated altered sequence-selective cleavage, and a few were found to cleave a tRNA3Lys transcript both in the presence and in the absence of a metal cofactor. The results provide insights into structural elements within BLM that control DNA and RNA cleavage. The present study also permits inferences to be drawn regarding the practicality of a selection strategy for the solid-phase construction and evaluation of large libraries of BLM analogues having altered properties.
authors: Departments of Chemistry and Biology, University of Virginia, Charlottesville, Virginia 22904, USA.
authors: Qian
authors: Q
authors: Ma
authors: Zhidong
authors: Z
authors: Xu
authors: Benjamin R
authors: BR
authors: Schroeder
authors: Wenyue
authors: W
authors: Sun
authors: Fang
authors: F
authors: Wei
authors: Shigeki
authors: S
authors: Hashimoto
authors: Kazuhide
authors: K
authors: Konishi
authors: Christopher J
authors: CJ
authors: Leitheiser
authors: Sidney M
authors: SM
authors: Hecht
mesh_terms: D001761:Bleomycin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000145:classification / Q000378:metabolism; D020650:Combinatorial Chemistry Techniques; D004247:DNA / Q000235:genetics; D016208:Databases, Factual; D006031:Glycosylation; D015394:Molecular Structure; D010957:Plasmids / Q000235:genetics; D012313:RNA / Q000235:genetics
chemical_list: D001761:Bleomycin; D012313:RNA; C033284:deglycobleomycin; D004247:DNA