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J Org Chem. 2016 Jan 15;81(2):502-11. doi: 10.1021/acs.joc.5b02341. Epub 2016 Jan 4.

The N(2)-Furfuryl-deoxyguanosine Adduct Does Not Alter the Structure of B-DNA.

Author information

1
Department of Chemistry, Indian Institute of Technology Bombay , Mumbai-400076, India.
2
Department of Chemistry, University of Mumbai , Mumbai-400098, India.
3
Regional Centre for Biotechnology, NCR Biotech Science Cluster, Third Milestone, Faridabad-Gurgaon Expressway, Faridabad-121001, India.
4
Manipal University, Manipal-576104, India.
5
National Centre for Biological Sciences (NCBS-TIFR), GKVK Campus, Bellary Road, Bangalore-560065, India.

Abstract

N(2)-Furfuryl-deoxyguanosine (fdG) is carcinogenic DNA adduct that originates from furfuryl alcohol. It is also a stable structural mimic of the damage induced by the nitrofurazone family of antibiotics. For the structural and functional studies of this model N(2)-dG adduct, reliable and rapid access to fdG-modified DNAs are warranted. Toward this end, here we report the synthesis of fdG-modified DNAs using phosphoramidite chemistry involving only three steps. The functional integrity of the modified DNA has been verified by primer extension studies with DNA polymerases I and IV from E. coli. Introduction of fdG into a DNA duplex decreases the Tm by ∼1.6 °C/modification. Molecular dynamics simulations of a DNA duplex bearing the fdG adduct revealed that though the overall B-DNA structure is maintained, this lesion can disrupt W-C H-bonding, stacking interactions, and minor groove hydrations to some extent at the modified site, and these effects lead to slight variations in the local base pair parameters. Overall, our studies show that fdG is tolerated at the minor groove of the DNA to a better extent compared with other bulky DNA damages, and this property will make it difficult for the DNA repair pathways to detect this adduct.

PMID:
26650891
DOI:
10.1021/acs.joc.5b02341
[Indexed for MEDLINE]

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