Design, Synthesis and Biological Evaluation of New Substituted Diquinolinyl-Pyridine Ligands as Anticancer Agents by Targeting G-Quadruplex.

Rabindra Das,Edith Chevret,Vanessa Desplat,Sandra Rubio,Jean Guillon,Jean-Louis Mergny

doi:10.3390/molecules23010081

Abstract

G-quadruplexes (G4) are stacked non-canonical nucleic acid structures found in specific G-rich DNA or RNA sequences in the human genome. G4 structures are liable for various biological functions; transcription, translation, cell aging as well as diseases such as cancer. These structures are therefore considered as important targets for the development of anticancer agents. Small organic heterocyclic molecules are well known to target and stabilize G4 structures. In this article, we have designed and synthesized 2,6-di-(4-carbamoyl-2-quinolyl)pyridine derivatives and their ability to stabilize G4-structures have been determined through the FRET melting assay. It has been established that these ligands are selective for G4 over duplexes and show a preference for the parallel conformation. Next, telomerase inhibition ability has been assessed using three cell lines (K562, MyLa and MV-4-11) and telomerase activity is no longer detected at 0.1 μM concentration for the most potent ligand 1c. The most promising G4 ligands were also tested for antiproliferative activity against the two human myeloid leukaemia cell lines, HL60 and K562.

Highlights

Single stranded guanine-rich nucleic acid sequences may fold into non-canonical four-stranded secondary structures known as G-quadruplexes (G4) [1,2]
By considering previously reported G-quadruplex DNA binding ligands with a large flat aromatic considering previously reported G-quadruplex DNA binding ligands with a large flat aromatic surface and positively charged lipophilic lateral chains, we have designed pyridine di-quinoline surface and positively charged lipophilic lateral chains, we have designed pyridine dicore with the possibility to attach to various carboxamide side chains (Figure 1)
The results showed that the stabilizing abilities of the ligands 1a, c, d for G4 conformations are nearly unaffected in presence of ds-DNA competitor

Summary

Introduction

Single stranded guanine-rich nucleic acid sequences may fold into non-canonical four-stranded secondary structures known as G-quadruplexes (G4) [1,2]. These structures are formed through π-π stacking of G-quartets which involve four guanines organized in a plane via eight Hoogsteen type H-bonding [1,2]. G4-structures are mostly involved in regulating various biological processes such as maintenance of genetic information [9], replication [10], transcription [11], cell aging, translation, and diseases such as cancer [12,13]. Down-regulation of Molecules 2018, 23, 81; doi:10.3390/molecules23010081 www.mdpi.com/journal/molecules

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