An experimental and computational analysis on the differential role of the positional isomers of symmetric bis-2-(pyridyl)-1H-benzimidazoles as DNA binding agents.
Three symmetrical positional isomers of bis-2-(n-pyridyl)-1H-benzimidazoles (n=2, 3, 4) were synthesized and DNA binding studies were performed with these isomeric derivatives. Like bisbenzimidazole compound Hoechst 33258, these molecules also demonstrate AT-specific DNA binding. The binding affinities of 3-pyridine (m-pyben) and 4-pyridine (p-pyben) derivatized bisbenzimidazoles to double-stranded DNA were significantly higher compared to 2-pyridine derivatized benzimidazole o-pyben. This has been established by combined experimental results of isothermal fluorescence titration, circular dichroism, and thermal denaturation of DNA. To rationalize the origin of their differential binding characteristics with double-stranded DNA, computational structural analyses of the uncomplexed ligands were performed using ab initio/Density Functional Theory. The molecular conformations of the symmetric head-to-head bisbenzimidazoles have been computed. The existence of intramolecular hydrogen bonding was established in o-pyben, which confers a conformational rigidity to the molecule about the bond connecting the pyridine and benzimidazole units. This might cause reduction in its binding affinity to double-stranded DNA compared to its para and meta counterparts. Additionally, the predicted stable conformations for p-, m-, and o-pyben at the B3LYP/6-31G* and RHF/6-31G* levels were further supported by experimental pKa determination. The results provide important information on the molecular recognition process of such symmetric head to head bisbenzimidazoles toward duplex DNA.
Chaudhuri
Padmaparna
P
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, India.
Ganguly
Bishwajit
B
Bhattacharya
Santanu
S
D001562:Benzimidazoles / Q000737:chemistry*; D001665:Binding Sites; D004247:DNA / Q000378:metabolism*; D006860:Hydrogen Bonding; D007536:Isomerism; D008958:Models, Molecular; D011725:Pyridines; D013329:Structure-Activity Relationship
D001562:Benzimidazoles; D011725:Pyridines; D004247:DNA; C023666:pyridine