Symmetrical bisbenzimidazoles with benzenediyl spacer: the role of the shape of the ligand on the stabilization and structural alterations in telomeric G-quadruplex DNA and telomerase inhibition.
The extremities of chromosomes end in a G-rich single-stranded overhang that has been implicated in the onset of the replicate senescence. The repeated sequence forming a G-overhang is able to adopt a four-stranded DNA structure called G-quadruplex, which is a poor substrate for the enzyme telomerase. Small molecule based ligands that selectively stabilize the telomeric G-quadruplex DNA, induce telomere shortening eventually leading to cell death. Herein, we have investigated the G-quadruplex DNA interaction with two isomeric bisbenzimidazole-based compounds that differ in terms of shape (V-shaped angular vs linear). While the linear isomer induced some stabilization of the intramolecular G-quadruplex structure generated in the presence of Na(+), the other, having V-shaped central planar core, caused a dramatic structural alteration of the latter, above a threshold concentration. This transition was evident from the pronounced changes observed in the circular dichroism spectra and from the gel mobility shift assay involving the G-quadruplex DNA. Notably, this angular isomer could also induce the G-quadruplex formation in the absence of any added cation. The ligand-quadruplex complexes were investigated by computational molecular modeling, providing further information on structure-activity relationships. Finally, TRAP (telomerase repeat amplification protocol) experiments demonstrated that the angular isomer is selective toward the inhibition of telomerase activity.
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, India. sb@orgchem.iisc.ernet.in
Santanu
S
Bhattacharya
Padmaparna
P
Chaudhuri
Akash K
AK
Jain
Ananya
A
Paul
D001562:Benzimidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006690:Bisbenzimidazole / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D003198:Computer Simulation; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D054856:G-Quadruplexes; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D019098:Telomerase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016615:Telomere / Q000737:chemistry*; D013696:Temperature
C553422:2,2'-(1,3-phenylene)-bis-(5-(4-(2-hydroxyethyl)-1-piperazinyl)-1H-benzimidazole); C553421:2,2'-(1,4-phenylene)-bis-(5-(4-(2-hydroxyethyl)-1-piperazinyl)-1H-benzimidazole); D001562:Benzimidazoles; D004791:Enzyme Inhibitors; D008024:Ligands; D010879:Piperazines; D019098:Telomerase; D006690:Bisbenzimidazole