Synthesis, properties, and NMR studies of a C8-phenylguanine modified oligonucleotide that preferentially adopts the Z DNA conformation.
Carcinogenic aryl hydrazines produce C8-arylated purine adducts. The effect of these adducts on DNA conformation and their role in hydrazine carcinogenesis are unknown. Here, we describe a new synthetic route to produce these adducts that is also compatible with the synthesis of the corresponding phosphoramidites needed for oligonucleotide synthesis. Two oligonucleotides were prepared, an unmodified oligonucleotide, d((5)(')CGCGCGCGCG(3)(')), and a C8-phenylguanine modified oligonucleotide, d((5)(')CGCGCGCGCG(3)(')) (G = 8-phenylguanine). These oligonucleotides were compared using thermal denaturation, circular dichroism, NMR, and molecular modeling. The phenyl modification destabilizes the B DNA form and stabilizes the Z DNA form such that the B:Z ratio is near one under physiological conditions. In light of recent studies that show a role for Z DNA in gene expression and cell transformation, Z DNA stabilization by C8-arylguanine formation from aryl hydrazines may be relevant to their role in carcinogenesis.
Gannett
Peter M
PM
West Virginia University, P.O. Box 9530, Morgantown, West Virginia 26506, USA. pgannett@hsc.wvu.edu
Heavner
Sue
S
Daft
Jonathan R
JR
Shaughnessy
Kevin H
KH
Epperson
Jon D
JD
Greenbaum
Nancy L
NL
D020029:Base Pairing; D002942:Circular Dichroism; D043542:DNA, Z-Form / Q000138:chemical synthesis* / Q000737:chemistry*; D003849:Deoxyguanosine / Q000737:chemistry; D006147:Guanine / Q000031:analogs & derivatives* / Q000737:chemistry*; D006834:Hydrazines / Q000737:chemistry; D006860:Hydrogen Bonding; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D009690:Nucleic Acid Conformation; D009691:Nucleic Acid Denaturation; D009838:Oligodeoxyribonucleotides / Q000138:chemical synthesis* / Q000737:chemistry*; D011522:Protons; D013696:Temperature
D043542:DNA, Z-Form; D006834:Hydrazines; D009838:Oligodeoxyribonucleotides; D011522:Protons; C029424:hydrazine; D006147:Guanine; D003849:Deoxyguanosine