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.
Bhattacharya
Santanu
S
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, India. sb@orgchem.iisc.ernet.in
Chaudhuri
Padmaparna
P
Jain
Akash K
AK
Paul
Ananya
A
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