Specific Stabilization of c-MYC and c-KIT G-Quadruplex DNA Structures by Indolylmethyleneindanone Scaffolds

International audienceStabilization of G­quadruplex DNA structures by small molecules has emerged as a promising strategy for the development of anticancer drugs. Since G-quadruplex structures can adopt various topologies, attaining specific stabilization of a G­quadruplex topology to halt a particular biological process is daunting. To achieve this, we have designed and synthesized simple structural scaffolds based on indolylmethyleneindanone pharmacophore, which can specifically stabilize the parallel topology of promoter quadruplex DNAs (c­MYC, c­KIT1 and c­KIT2), when compared to various topologies of telomeric DNA and duplex DNAs. The lead ligands (InEt2 and InPr2) are water soluble and meet a number of desirable criteria for a small molecule drug. Highly specific induction and stabilization of the c-MYC and c-KITquadruplex DNAs (ΔT1/2 up to 24 °C) over telomeric and duplex DNAs (ΔT1/2 ~ 3.2 °C) by these ligands were further validated by ITC and ESI-MS experiments (Ka ~ 105­106 M−1). Low IC50 (~ 2 µM) values were emerged for these ligands from Taq DNA polymerase stop assay with the c-MYC quadruplex forming template, whereas the telomeric DNA template showed IC50 values >120 µM. Molecular modeling and dynamics studies demonstrated the 5'- and 3'- end stacking modes for these ligands. Overall, these results demonstrate that among the >1000 quadruplex stabilizing ligands reported so far, the indolylmethyleneindanone scaffolds stands out in terms of target specificity and structural simplicity, and therefore offers a new paradigm in topology specific G-quadruplex targeting for potential therapeutic and diagnostic applications

Light induced damage and repair in nucleic acids and proteins: general discussion Faraday Discussions

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Cationic red emitting fluorophore: a light up NIR fluorescent probe for G4-DNA

Guanine (G) quadruplexes (G4) are nucleic acid secondary structures formed by G-rich sequences, commonly found in human telomeric and oncogene-promoter regions, have emerged as targets for regulation of multiple biological processes. Considering their importance, targeting the G-quadruplex structure with small molecular binders is extremely pertinent. In this work, red emitting water soluble fluorophores bearing push-pull substituents were synthesized and examined for their interaction with human telomeric G4 and duplex (ds) -DNAs. The presence of a strong electron donating (dimethylamino) and electron withdrawing (cationic pyridinium) groups linked through a conjugated double bond helps in water solubility and enabling the emission in the near IR region (>700–nm). Binding of this cationic dye to the G4-DNA yields multiple-fold emission enhancement (~70 fold with G4-DNA vs. ~7 fold with ds-DNA) along with hypsochromic wavelength shifts (35 nm with G4-DNA and 8 nm with ds-DNA). The remarkable emission changes, ~2–4 fold enhanced binding efficiency noted with the antiparallel conformation of G4-DNA indicates preferential selectivity over ds-DNA. The molecular docking and dynamics studies of the ligands with duplex and G4-DNA were performed, and they provide insights into the mode of binding of these dyes with G4-DNA and supplement the experimental observations.by Beena Kumari, Akanksha Yadav, Sushree P. Pany, Pradeepkumar P. I. and Sriram Kanva