New (Iso)quinolinyl-pyridine-2,6-dicarboxamide G-Quadruplex Stabilizers. A Structure-Activity Relationship Study

G-quadruplex (G4)-interactive small molecules have a wide range of potential applications, not only as drugs, but also sensors quadruplex structures. The purpose this work is the synthesis analogues bis-methylquinolinium-pyridine-2,6-dicarboxamide G4 ligand 360A, to identify relevant structure–activity relationships apply design other G4-interactive bearing bis-quinoline or bis-isoquinoline moieties. Thermal denaturation experiments revealed that non-methylated derivatives with relative 1,4 position between amide linker and nitrogen quinoline ring are moderate stabilizers, preference for hybrid h-Telo G4, 21-nt sequence present in human telomeres. Insertion positive charge upon methylation quinoline/isoquinoline increases compounds’ ability selectively stabilize G4s compared duplex DNA, parallel Among these, compounds having 1,3-position charged methylquinolinium/isoquinolinium best stabilizers. More interestingly, these ligands showed different capacities block DNA polymerization PCR-stop assay induce conformation switches G4. Molecular dynamic simulations formed by k-RAS gene promoter, spatial orientation two methylated rings determines mode strength binding G4s.