Binding of gemini bisbenzimidazole drugs with human telomeric G-quadruplex dimers: effect of the spacer in the design of potent telomerase inhibitors.
The study of anticancer agents that act via stabilization of telomeric G-quadruplex DNA (G4DNA) is important because such agents often inhibit telomerase activity. Several types of G4DNA binding ligands are known. In these studies, the target structures often involve a single G4 DNA unit formed by short DNA telomeric sequences. However, the 3'-terminal single-stranded human telomeric DNA can form higher-order structures by clustering consecutive quadruplex units (dimers or n-mers). Herein, we present new synthetic gemini (twin) bisbenzimidazole ligands, in which the oligo-oxyethylene spacers join the two bisbenzimidazole units for the recognition of both monomeric and dimeric G4DNA, derived from d(T2AG3)4 and d(T2AG3)8 human telomeric DNA, respectively. The spacer between the two bisbenzimidazoles in the geminis plays a critical role in the G4DNA stability. We report here (i) synthesis of new effective gemini anticancer agents that are selectively more toxic towards the cancer cells than the corresponding normal cells; (ii) formation and characterization of G4DNA dimers in solution as well as computational construction of the dimeric G4DNA structures. The gemini ligands direct the folding of the single-stranded DNA into an unusually stable parallel-stranded G4DNA when it was formed in presence of the ligands in KCl solution and the gemini ligands show spacer length dependent potent telomerase inhibition properties.
Department of Organic Chemistry, Indian Institute of Science, Bangalore, India.
Ananya
A
Paul
Akash K
AK
Jain
Santosh K
SK
Misra
Basudeb
B
Maji
K
K
Muniyappa
Santanu
S
Bhattacharya
D000970:Antineoplastic Agents / Q000494:pharmacology; D006690:Bisbenzimidazole / Q000494:pharmacology*; D002942:Circular Dichroism; D004277:DNA, Single-Stranded / Q000235:genetics; D019281:Dimerization; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005456:Fluorescent Dyes / Q000494:pharmacology; D054856:G-Quadruplexes; D006358:Hot Temperature; D006801:Humans; D020128:Inhibitory Concentration 50; D008024:Ligands; D008958:Models, Molecular; D011189:Potassium Chloride / Q000737:chemistry; D017510:Protein Folding; D019098:Telomerase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D016615:Telomere / Q000648:ultrastructure*; D013696:Temperature
D000970:Antineoplastic Agents; D004277:DNA, Single-Stranded; D004791:Enzyme Inhibitors; D005456:Fluorescent Dyes; D008024:Ligands; D011189:Potassium Chloride; D019098:Telomerase; D006690:Bisbenzimidazole