Site-specific synthesis and reactivity of oligonucleotides containing stereochemically defined 1,N2-deoxyguanosine adducts of the lipid peroxidation product trans-4-hydroxynonenal.
trans-4-Hydroxynonenal (HNE) is a major peroxidation product of omega-6 polyunsaturated fatty acids. The reaction of HNE with DNA gives four diastereomeric 1,N(2)-gamma-hydroxypropano adducts of deoxyguanosine; background levels of these adducts have been detected in animal tissue. Stereospecific syntheses of these four adducts at the nucleoside level have been accomplished. In addition, a versatile strategy for their site-specific incorporation into oligonucleotides has been developed. These adducts are destabilizing as measured by melting temperature when compared to an unadducted strand. The thermal destablization of the adducted 12-mers ranged from 5 to 16 degrees C and is dependent on the absolute stereochemistry of the adduct. The HNE adducts were also examined for their ability to form interstrand DNA-DNA cross-links when incorporated into a CpG sequence. We find that only one of the HNE stereoisomers formed interstrand DNA-DNA cross-links.
Department of Chemistry and Center in Molecular Toxicology, Vanderbilt University, Nashville, Tennessee 37235-1822, USA.
Hao
H
Wang
Ivan D
ID
Kozekov
Thomas M
TM
Harris
Carmelo J
CJ
Rizzo
D000447:Aldehydes / Q000737:chemistry*; D001665:Binding Sites; D002942:Circular Dichroism; D004247:DNA / Q000737:chemistry; D018736:DNA Adducts / Q000138:chemical synthesis / Q000737:chemistry*; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000737:chemistry*; D015227:Lipid Peroxidation; D019906:Nuclear Magnetic Resonance, Biomolecular; D009841:Oligonucleotides / Q000138:chemical synthesis / Q000737:chemistry*; D013237:Stereoisomerism; D013379:Substrate Specificity
C117629:8-nitro-2'-deoxyguanosine; D000447:Aldehydes; D018736:DNA Adducts; D009841:Oligonucleotides; D004247:DNA; D003849:Deoxyguanosine; C027576:4-hydroxy-2-nonenal