Mazzini, StefaniaGargallo Gómez, RaimundoMusso, LoanaDe Santis, FrancescaAviñó Andrés, AnnaScaglioni, LeonardoEritja i Casadellà, RamonDi Nicola, MassimoZunino, FrancoAmatulli, AnnabellaDallavalle, Sabrina2019-10-102019-10-102019-10-041661-6596https://hdl.handle.net/2445/142066The stabilization of G-quadruplex DNA structures by small molecules with affinity to oncogene promoters has emerged as a promising anticancer strategy, due to a potential role in gene expression regulation. We explored the ability of BMH-21 (1) and its analogue BA-41 (2) to bind the G-quadruplex structure present in the c-KIT promoter by biophysical methods and molecular modeling. We provide evidence that both compounds interact with the c-KIT 21-mer sequence. The stable monomeric intramolecular parallel G-quadruplex obtained by the mutation of positions 12 and 21 allowed the precise determination of the binding mode by NMR and molecular dynamics studies. Both compounds form a complex characterized by one ligand molecule positioned over the tetrad at the 30-end, stabilized by an extensive network of pi-pi interactions. The binding constants (Kb) obtained with fluorescence are similar for both complexes (around 10^6 M-1). Compound BA-41 (2) showed significant antiproliferative activity against a human lymphoma cell line, SU-DHL4, known to express substantial levels of c-KIT. However, the partial inhibition of c-KIT expression by Western blot analysis suggested that the interaction of compound 2 with the c-KIT promoter is not the primary event and that multiple e ects provide a contribution as determinants of biological activity.application/pdfengcc-by (c) Mazzini, Stefania et al., 2019http://creativecommons.org/licenses/by/3.0/esRessonància magnètica nuclearG-estructuresNuclear magnetic resonanceG-structuresinfo:eu-repo/semantics/article6919642019-10-10info:eu-repo/semantics/openAccess31590335