Oxidative damage of cellular DNA by metal chelates of the glycopeptide antitumor antibiotic bleomycin (BLM) is believed to be responsible for its antineoplastic activity. The DNA cleavage reaction is brought about by oxygen-based free radical(s) and/or hypervalent iron-oxo species formed in the vicinity of the DNA helix. In addition, recent research indicates that cobalt-BLMs cleave DNA under UV illumination. Elucidations of (a) the coordination structures of the metallobleomycins (M-BLMs) and (b) the mechanism(s) of the oxidative and photoinduced DNA damage are the goals of the proposed research. We plan to synthesize and structurally characterize metal complexes of designed ligands that mimic the metal-binding portion of BLM. The spectral parameters of these tailored metal complexes (called synthetic analogues) will be utilized to establish the structures of the corresponding M-BLMs under specific reaction conditions. Reactions of the analogues with dioxygen will be studied to elucidate the nature of the active intermediates. The photochemistry of the cobalt complexes will be explored to establish the mechanism of the light-induced DNA damage reaction. Attempts will be made to improve the DNA-affinity of the analogues by attaching various DNA-binding groups to them. The course of DNA cleavage reactions by these analogues will be monitored by gel electrophoretic studies. The MBRS students will participate in all phases of this research and contribute to the overall understanding of the drug action. They will take part in the synthesis of the organic ligands and their metal complexes. They will learn how to characterize unknown molecules by various state-of-the-art spectroscopic techniques and X-ray crystallography. Also, they will acquire expertise in various biochemical techniques like isotope labelling, DNA isolation and sequencing, chromatography, and electrophoresis. The MBRS students will be encouraged to design new molecules as well as alter the existing ones for better performances. They will use computers in such modelling pursuits. Participation in the proposed research will offer the MBRS students insight into drug-design and chemotherapy.
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