Preferential targeting of i-motifs and G-quadruplexes by small molecules

• Published in: Chemical science (Cambridge) Vol. 8; no. 11; pp. 7448 - 7456
• Main Authors: Debnath, Manish, Ghosh, Shirsendu, Chauhan, Ajay, Paul, Rakesh, Bhattacharyya, Kankan, Dash, Jyotirmayee
• Format: Journal Article
• Language: English
• Published: CAMBRIDGE Royal Soc Chemistry 2017; Royal Society of Chemistry
• Subjects: Alkynes; Chemical synthesis; Chemistry; Chemistry, Multidisciplinary; Cycloaddition; Deoxyribonucleic acid; DNA; Gene expression; Ligands; Physical Sciences; Polymerase chain reaction; Science & Technology; TELOMERIC G-QUADRUPLEX; DNA-SEQUENCES; FLUORESCENCE SPECTROSCOPY; CLICK CHEMISTRY; GENE-EXPRESSION; PROMOTER REGION; RESONANCE ENERGY-TRANSFER; C-MYC TRANSCRIPTION; HNRNP LL; FOLDING DYNAMICS
• ISSN: 2041-6520; 2041-6539
• DOI: 10.1039/C7SC02693E

i-Motifs and G-quadruplexes are dynamic nucleic acid secondary structures, which are believed to play key roles in gene expression. We herein report two peptidomimetic ligands ( PBP1 and PBP2 ) that selectively target i-motifs and G-quadruplexes over double-stranded DNA. These peptidomimetics, regioisomeric with respect to the position of triazole/prolinamide motifs, have been synthesized using a modular method involving Cu( i )-catalyzed azide and alkyne cycloaddition. The para -isomer, PBP1 exhibits high selectivity for i-motifs while the meta -isomer PBP2 binds selectively to G-quadruplex structures. Interestingly, these ligands have the ability to induce G-quadruplex or i-motif structures from the unstructured single-stranded DNA conformations, as observed using single molecule Förster resonance energy transfer (smFRET) studies. The quantitative real-time polymerase chain reaction (qRT-PCR), western blot, and dual-luciferase assays indicate that PBP1 upregulates and PBP2 downregulates BCL-2 gene expression in cancer cells.