Structural selectivity of aromatic diamidines.
Competition dialysis was used to study the interactions of 13 substituted aromatic diamidine compounds with 13 nucleic acid structures and sequences. The results show a striking selectivity of these compounds for the triplex structure poly dA:(poly dT)2, a novel aspect of their interaction with nucleic acids not previously described. The triplex selectivity of selected compounds was confirmed by thermal denaturation studies. Triplex selectivity was found to be modulated by the location of amidine substituents on the core phenyl-furan-phenyl ring scaffold. Molecular models were constructed to rationalize the triplex selectivity of DB359, the most selective compound in the series. Its triplex selectivity was found to arise from optimal ring stacking on base triplets, along with proper positioning of its amidine substituents to occupy the minor and the major-minor grooves of the triplex. New insights into the molecular recognition of nucleic acid structures emerged from these studies, adding to the list of available design principles for selectively targeting DNA and RNA.
Chaires
Jonathan B
JB
James Graham Brown Cancer Center, Department of Medicine, Health Sciences Center, University of Louisville, 529 S. Jackson St., Louisville, Kentucky 40202, USA. jbchai01@gwise.louisville.edu
Ren
Jinsong
J
Hamelberg
Donald
D
Kumar
Arvind
A
Pandya
Vandna
V
Boykin
David W
DW
Wilson
W David
WD
D001550:Benzamidines / Q000737:chemistry*; D004247:DNA / Q000737:chemistry; D003956:Dialysis; D007536:Isomerism; D008958:Models, Molecular; D009690:Nucleic Acid Conformation; D011089:Polydeoxyribonucleotides / Q000737:chemistry; D011131:Polyribonucleotides / Q000737:chemistry; D013329:Structure-Activity Relationship
D001550:Benzamidines; D011089:Polydeoxyribonucleotides; D011131:Polyribonucleotides; C051802:triplex DNA; D004247:DNA