Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

New (Iso)Quinolinyl-Pyridine-2,6-dicarboxamide G-Quadruplex Ligands. A Structure-Activity Relationship Study

Version 1 : Received: 29 May 2021 / Approved: 31 May 2021 / Online: 31 May 2021 (14:03:28 CEST)

How to cite: Cadoni, E.; Magalhães, P.R.; Emídio, R.M.; Mendes, E.; Vítor, J.B.; Carvalho, J.; Cruz, C.; Victor, B.L.; Paulo, A. New (Iso)Quinolinyl-Pyridine-2,6-dicarboxamide G-Quadruplex Ligands. A Structure-Activity Relationship Study. Preprints 2021, 2021050784 (doi: 10.20944/preprints202105.0784.v1). Cadoni, E.; Magalhães, P.R.; Emídio, R.M.; Mendes, E.; Vítor, J.B.; Carvalho, J.; Cruz, C.; Victor, B.L.; Paulo, A. New (Iso)Quinolinyl-Pyridine-2,6-dicarboxamide G-Quadruplex Ligands. A Structure-Activity Relationship Study. Preprints 2021, 2021050784 (doi: 10.20944/preprints202105.0784.v1).

Abstract

Quadruplex-interactive small molecules have a wide potential application, not only as drugs but also as sensors of quadruplexes structures. The purpose of this work is the synthesis of analogues of the bis-methylquinolinium-pyridine-2,6-dicarboxamide G4 ligand 360A, to identify relevant structure-activity relationships to apply to the design of other G4-interactive small molecules bearing bis-quinoline or bis-isoquinoline moieties. Thermal denaturation experiments revealed that non-methylated derivatives with a relative 1,4 position between the amide linker and the nitrogen of the quinoline ring are moderate G4 stabilizers, with a preference for the hybrid h-Telo G4. Insertion of a positive charge upon methylation of quinoline/isoquinoline nitrogen increases compounds capacity to selectively stabilize G4s compared to duplex DNA, with a preference for parallel structures. Among these, compounds having a relative 1,3-position between the charged methylquinolinium/isoquinolinium nitrogen and the amide linker are the best G4 stabilizers. More interestingly, these ligands showed different capacities to selectively block DNA polymer-ization in a PCR-stop assay and to induce G4 conformation switches of hybrid h-Telo G4. Mo-lecular dynamic simulations with the parallel k-RAS G4 structure showed that the relative spatial orientation of the two methylated quinoline/isoquinoline rings determines the ligands mode and strength of binding to G4s.

Subject Areas

Quinoline; Isoquinoline; G-Quadruplex ligands; k-RAS; c-MYC; telomere; SAR; pyri-dine-dicarboxamide; molecular dynamics

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