Metallodesferals as a new class of DNA cleavers: Specificity, mechanism and targetting of DNA scission reactions |
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Authors: | R R Joshi and K N Ganesh |
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Institution: | (1) Bioorganic Unit, Division of Organic Chemistry-S, National Chemical Laboratory, 411008 Pune, India |
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Abstract: | Interaction of metal complexes with nucleic acids is currently attracting wide attention due to their potential utility as
drugs, regulators of gene expression and tools for molecular biology. Many metal complexes exhibit nucleolytic activity, the
most important examples being Cu(II)-OP, Fe(H)-BLM, Fe(II)-EDTA, metalloporphyrins, Ru and Co complexes of 4,7-diphenyl-l,10-phenanthroline
and more recently by Ni(II) complexes. Desferal, a well known siderophore and a highly effective drug in chelation therapy
of iron overload diseases, forms a stable octahedral co-ordination Fe(III) complex Eerrioxamine B. We have been interested
in the DNA damaging properties of metallodesferals and this paper describes the DNA cleaving ability of metallodesferals,
metal-dependent base selectively in DNA scission reactions, mechanistic studies on DNA cleavage by CuDFO and targetting of
DNA cutting by covalent MDFO conjugates. This paper reports the synthesis of Cu(II), Co (III) and Ni(II) complexes of a siderophore
chelating drug desferal, the studies on cleavage of plasmid DNA, the sequence preference of cleavage reactions, and C1’ as
the primary site of hydroxyl radical attack in the reactions. Oligonucleotides covalently linked with this molecular scissor
can direct the cleavage of either single or double strand DNA’s, mediated by duplex or triple helix structures respectively.
Such targetting of DNA cleavage reactions, mediated by oligonucleotide-Cu(II)/Co(III) desferal conjugates has demonstrated
reasonable site specificity and efficiency |
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Keywords: | DNA cleavers metallodesferals molecular scissor |
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