Targeting G-quadruplex DNA structures in the telomere and oncogene Promoter regions by benzimidazole-carbazole ligands

Kaulage, Mangesh H and Maji, Basudeb and Pasadi, Sanjeev and Ali, Asfa and Bhattacharya, Santanu and Muniyappa, K (2018) Targeting G-quadruplex DNA structures in the telomere and oncogene Promoter regions by benzimidazole-carbazole ligands. In: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 148 . pp. 178-194.

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Abstract

Recent studies support the idea that G-quadruplex structures in the promoter regions of oncogenes and telomere DNA can serve as potential therapeutic targets in the treatment of cancer. Accordingly, several different types of organic small molecules that stabilize G-quadruplex structures and inhibit telomerase activity have been discerned. Here, we describe the binding of benzimidazole-carbazole ligands to G-quadruplex structures formed in G-rich DNA sequences containing the promoter regions of human c-MYC, c-KIT1, c-KIT2, VEGF and BCL2 proto-oncogenes. The fluorescence spectroscopic data indicate that benzimidazole-carbazole ligands bind and stabilize the G-quadruplexes in the promoter region of oncogenes. The molecular docking studies provide insights into the mode and extent of binding of this class of ligands to the G-quadruplexes formed in oncogene promoters. The high stability of these G-quadruplex structures was validated by thermal denaturation and telomerase-catalyzed extension of the 3' end. Notably, benzimidazole-carbazole ligands suppress the expression of oncogenes in cancer cells in a dose-dependent manner. We anticipate that benzimidazole-carbazole ligands, by virtue of their ability to stabilize G-quadruplex structures in the promoter regions of oncogenes, might reduce the risk of cancer through the loss of function in the proteins encoded by these genes. (C) 2018 Elsevier Masson SAS. All rights reserved.

Item Type:	Journal Article
Publication:	EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Publisher:	ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER, 65 RUE CAMILLE DESMOULINS, CS50083, 92442 ISSY-LES-MOULINEAUX, FRANCE
Additional Information:	Copy right for this article belong to ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER, 65 RUE CAMILLE DESMOULINS, CS50083, 92442 ISSY-LES-MOULINEAUX, FRANCE
Department/Centre:	Division of Biological Sciences > Biochemistry Division of Chemical Sciences > Organic Chemistry
Date Deposited:	14 Apr 2018 18:49
Last Modified:	14 Apr 2018 18:49
URI:	http://eprints.iisc.ac.in/id/eprint/59574

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