Evaluation of the influence of compound structure on stacked-dimer formation in the DNA minor groove.
The Human Genome Project as well as sequencing of the genomes of other organisms offers a wealth of DNA targets for both therapeutic and diagnostic applications, and it is important to develop additional DNA binding motifs to fully exploit the potential of this new information. We have recently found that an aromatic dication, DB293, with an amidine-phenyl-furan-benzimidazole-amidine structure can recognize specific sequences of DNA by binding in the minor groove as a dimer [Wang, L., Bailly, C., Kumar, A., Ding, D., Bajic, M., Boykin, D. W., and Wilson, W. D. (2000) Proc. Natl. Acad. Sci. U.S.A. 97, 12-16]. The dimer binding is strong, highly cooperative and, in contrast to many closely related heterocyclic dications, has both GC and AT base pairs in the minor groove binding site. The aromatic heterocycle stacked dimer is quite different in structure from the polyamide-lexitropsin type compounds, and it is a dication while all lexitropsin dimers are monocations. The heterocyclic dimer represents only the second small molecule class that can recognize mixed sequences of DNA. To test the structural limits on the new type of complex, it is important to probe the influence of compound charge, chemical groups, and structural features. The effects of these compound molecular variations on DNA complex formation with several DNA sequences were evaluated by DNase I footprinting, CD and UV spectroscopy, thermal melting, and quantitative analysis with surface plasmon resonance biosensor methods. Conversion of the amidines to guanidinium groups does permit the cooperative dimer to form but removal of one amidine or addition of an alkyl group to the amidine strongly inhibited dimer formation. Changing the phenyl of DB293 to a benzimidazole or the benzimidazole to a phenyl or benzofuran also inhibited dimer formation. The results show that formation of the minor groove stacked-dimer complex is very sensitive to compound structure. The discovery of the aromatic dimer mode offers new opportunities to enhance the specificity and expand the range of applications of the compounds that target DNA.
Wang
L
L
Department of Chemistry, Georgia State University, Atlanta, Georgia 30303 USA.
Carrasco
C
C
Kumar
A
A
Stephens
C E
CE
Bailly
C
C
Boykin
D W
DW
Wilson
W D
WD
D000578:Amidines / Q000138:chemical synthesis / Q000737:chemistry*; D020029:Base Pairing; D001562:Benzimidazoles / Q000138:chemical synthesis; D001665:Binding Sites; D002227:Carbazoles / Q000138:chemical synthesis; D002412:Cations / Q000737:chemistry; D002942:Circular Dichroism; D004247:DNA / Q000737:chemistry*; D018983:DNA Footprinting; D005663:Furans / Q000138:chemical synthesis; D019791:Guanidine / Q000031:analogs & derivatives / Q000138:chemical synthesis; D009429:Netropsin / Q000031:analogs & derivatives* / Q000737:chemistry; D009690:Nucleic Acid Conformation; D009691:Nucleic Acid Denaturation; D009841:Oligonucleotides / Q000138:chemical synthesis; D011740:Pyrimidine Dimers / Q000737:chemistry*; D013056:Spectrophotometry, Ultraviolet; D020349:Surface Plasmon Resonance
D000578:Amidines; D001562:Benzimidazoles; D002227:Carbazoles; D002412:Cations; D005663:Furans; D009841:Oligonucleotides; D011740:Pyrimidine Dimers; C053654:lexitropsin; D009429:Netropsin; D004247:DNA; D019791:Guanidine