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

Enrico Cadoni,Eduarda Mendes,Josué Carvalho,Alexandra Paulo,Bruno L Victor,Jorge Vítor,Rita M Emídio,Carla Cruz,Pedro R Magalhães

doi:10.3390/ph14070669

Enrico Cadoni, Eduarda Mendes + Show 7 more

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https://doi.org/10.3390/ph14070669

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Abstract

G-quadruplex (G4)-interactive small molecules have a wide range of potential applications, not only as drugs, but also as sensors of quadruplex 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, a 21-nt sequence present in human telomeres. Insertion of a positive charge upon methylation of quinoline/isoquinoline nitrogen increases compounds’ ability 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 polymerization in a PCR-stop assay and to induce G4 conformation switches of hybrid h-Telo G4. Molecular dynamic simulations with the parallel G4 formed by a 21-nt sequence present in k-RAS gene promoter, showed that the relative spatial orientation of the two methylated quinoline/isoquinoline rings determines the ligands mode and strength of binding to G4s.

Highlights

With the growing trend in the incidence of cancer [1], the need for developing effective and specific drugs to target cancer cells, for a less toxic and invasive therapy, is becoming increasingly important
Mutations and translocations occurring within certain protooncogenes, such as c-MYC [2,3], k-RAS [4,5], and c-KIT [6], have been frequently reported as a primary cause of cancer onset in several malignancies and for this reason, they have been widely studied as potential therapeutic targets [6,7,8]
Regarding compound 2a, we can see that both the top and regions of the k-RAS molecule, close to its 30 and 50 terminal, respectively, are the regions bottom regions of the k-RAS molecule, close to its 3′ and 5′ terminal, respectively, are the showing the highest number of contacts

Summary

Introduction

With the growing trend in the incidence of cancer [1], the need for developing effective and specific drugs to target cancer cells, for a less toxic and invasive therapy, is becoming increasingly important. The research efforts focused in small-molecules and oligonucleotide derivatives [21] that induce and stabilize G4-formation, has been seen as a promising approach to identify new therapeutic agents [19,22,23,24,25]. This is of utmost importance, considering the numerous evidences of G4-formation in vivo, which suggests a concrete physiological role of these structures in cells [26,27,28]

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