期刊
PHARMACEUTICALS
卷 14, 期 7, 页码 -出版社
MDPI
DOI: 10.3390/ph14070669
关键词
quinoline; isoquinoline; G-quadruplex ligands; k-RAS; c-MYC; telomere; SAR; pyridine-dicarboxamide; molecular dynamics
资金
- European Structural & Investment Funds through the COMPETE Program-Programa Operacional de Lisboa [LISBOA-01-0145FEDER-016405]
- Fundacao para a Ciencia e Tecnologia (FCT, Portugal) of iMed [SAICTPAC/0019/2015, UIDP/04138/2020]
- Fundacao para a Ciencia e Tecnologia (FCT, Portugal) of CICS [UIDB/00709/2020]
- Fundacao para a Ciencia e Tecnologia (FCT, Portugal) [PTDC/BIA-BFS/28419/2017, UIDB/04046/2020]
- Fundo Social Europeu e Programa Operacional Potencial Humano [IF/00959/2015]
- New England Biolabs, Inc. (Ipswich, MA, USA)
- Fundação para a Ciência e a Tecnologia [SAICTPAC/0019/2015, PTDC/BIA-BFS/28419/2017] Funding Source: FCT
The study aims to synthesize analogues of G4 ligand 360A, identify structure-activity relationships, and design other G4-interactive small molecules. Experimental results show that methylation affects the stability and selectivity of compounds towards G4, with compounds having a relative 1,3-position displaying the best G4 stabilization.
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.
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