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

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.

Quadruplex Ligands in Cancer Therapy

“…In contrast, other novel ligands were reported to be selective compounds interacting not only with a unique G4, but also with a narrow-spectrum of G4s. Among them, new substituted diquinolinyl-pyridine ligands show a preference for the parallel conformation of telomeric, c-MYC and c-KIT G4s [59]. The same selectivity pattern was confirmed for APTO-253, a phenanthroline derivative that is in phase I clinical trials for the treatment of acute myeloid leukemia [41].…”

Targeting human telomeric DNA with azacyanines

“…The interactions of azacyanines with tel24 were first investigated using UV-Vis and circular dichroism (CD) spectroscopy in order to quickly survey and confirm the presence of interactions between the azacyanines and tel24. Such a survey also reveals changes in the secondary structure of tel24 upon azacyanine binding and the effect of azacyanine structure on tel24 binding [25,[28][29][30][31][32][33][34][35][36][37]. Our previous structural studies using NMR have shown that one azamethyl was binding to one tel24 G-quadruplex structure between the top quartet and the A-T base pairing in the loop region.…”

“…All samples were prepared in 25 mM potassium phosphate buffer (pH 7.0) and 70 mM KCl, unless otherwise stated. Samples were annealed by heating to 95 • C for 5 min in a water bath and then cooling overnight to room temperature prior to each experiment (19,25,33).…”

“…Several studies investigating the effect of the benzimidazole scaffold on telomeric DNA and oncogene promoters such as KRAS and VEGFR that are known to fold into quadruplex structures were recently reported [24][25][26][27][28][29][30]. In addition, several reports investigating the effect of such small molecules on different cancer lines and promoting G-quadruplexes as plausible targets in cancer therapy were also published [31][32][33][34][35][36]. Based on all these reported studies and our knowledge on azamethyl, we were inspired to explore a series of azacyanine compounds as potential G-quadruplex stabilizing compounds with the hope of finding a better candidate than azamethyl and understanding the effect of molecular structure on molecular recognition.…”

Syntheses and spectroscopic investigations of 2-pyridyl(N/N)spirocyclotriphosphazenes

“…In addition, the pyridine derivatives are quite essential compounds with the incredible biological applications (25,26). The new compounds, which contain a trimeric phosphazene ring with 2-pyridyl pendant arm, may be considered to have possibly antimicrobial, anticancer, antituberculosis, and antiproliferative activities.…”