DNA damage by C1027 involves hydrogen atom abstraction and addition to nucleobases

C1027 is a potent antitumor agent that damages DNA. It has the unusual ability to produce double strand breaks and interstrand cross-links (ICLs) intracellularly, which enable it to initiate concurrent ataxia-telangiestasia mutated (ATM) and Rad-3 related (ATR) independent damage responses. The latt...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry 2012-08, Vol.20 (15), p.4744-4750
Main Authors: San Pedro, Joanna Maria N., Beerman, Terry A., Greenberg, Marc M.
Format: Article
Language:English
Subjects:
Aminoglycosides - chemistry
Aminoglycosides - pharmacology
Biological and medical sciences
DNA - drug effects
DNA Damage
Enediynes
Enediynes - chemistry
Enediynes - pharmacology
Hydrogen - chemistry
Interstrand cross-link
Medical sciences
Molecular Structure
Oxidized abasic sites
Pharmacology. Drug treatments
Plasmids
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Summary:C1027 is a potent antitumor agent that damages DNA. It has the unusual ability to produce double strand breaks and interstrand cross-links (ICLs) intracellularly, which enable it to initiate concurrent ataxia-telangiestasia mutated (ATM) and Rad-3 related (ATR) independent damage responses. The latter form of damage is not well characterized. We have examined the effect of DNA sequence on C1027 reactivity and found it to be more diverse than previously thought. In addition, analysis of the chemical stability of ICLs suggests that they result from reaction with the deoxyribose ring on one strand but direct addition to a nucleobase on the opposite strand.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2012.06.004