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

• Main Authors: Rabindra Nath Das, Edith Chevret, Vanessa Desplat, Sandra Rubio, Jean-Louis Mergny, Jean Guillon
• Format: Article
• Language: English
• Published: MDPI AG 2017-12-01
• Series: Molecules
• Subjects: G-quadruplex; diquinolinyl-pyridine; G4 ligands; FRET-melting; circular dichroism; telomerase; antiproliferative activity; cancer
• Online Access: https://www.mdpi.com/1420-3049/23/1/81

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.