Binding of Gemini Bisbenzimidazole Drugs with Human Telomeric G-Quadruplex Dimers: Effect of the Spacer in the Design of Potent Telomerase Inhibitors


Autoria(s): Paul, Ananya; Jain, AkashK; Misra, SantoshK; Maji, Basudeb; Muniyappa, K; Bhattacharya, Santanu
Data(s)

21/06/2012

Resumo

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 nmers). 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.

Formato

application/pdf

Identificador

http://eprints.iisc.ernet.in/44858/1/plos_one_7-6_2012.pdf

Paul, Ananya and Jain, AkashK and Misra, SantoshK and Maji, Basudeb and Muniyappa, K and Bhattacharya, Santanu (2012) Binding of Gemini Bisbenzimidazole Drugs with Human Telomeric G-Quadruplex Dimers: Effect of the Spacer in the Design of Potent Telomerase Inhibitors. In: PLOS ONE, 7 (6).

Publicador

PUBLIC LIBRARY SCIENCE

Relação

http://dx.doi.org/10.1371/journal.pone.0039467

http://eprints.iisc.ernet.in/44858/

Palavras-Chave #Biochemistry #Organic Chemistry #Others
Tipo

Journal Article

PeerReviewed