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Biochemical Evaluation of a 108-Member Deglycobleomycin Library:  Viability of a Selection Strategy for Identifying Bleomycin Analogues with Altered Properties

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journal contribution
posted on 17.10.2007, 00:00 by Qian Ma, Zhidong Xu, Benjamin R. Schroeder, Wenyue Sun, Fang Wei, Shigeki Hashimoto, Kazuhide Konishi, Christopher J. Leitheiser, Sidney M. Hecht
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.