The 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 3'-end, stabilized by an extensive network of π-π interactions. The binding constants (Kb) obtained with fluorescence are similar for both complexes (around 106 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 effects provide a contribution as determinants of biological activity.
Stabilization of c-KIT G-quadruplex DNA structures by the RNA polymerase I inhibitors BMH-21 and BA-41 / S. Mazzini, R. Gargallo, L. Musso, F. De Santis, A. Avino, L. Scaglioni, R. Eritja, M. Di Nicola, F. Zunino, A. Amatulli, S. Dallavalle. - In: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES. - ISSN 1661-6596. - 20:19(2019), pp. 4927.1-4927.17.
|Titolo:||Stabilization of c-KIT G-quadruplex DNA structures by the RNA polymerase I inhibitors BMH-21 and BA-41|
MAZZINI, STEFANIA (Corresponding)
|Parole Chiave:||C-KIT; CD; G-quadruplex; NMR spectroscopy; Pyridoquinazolinone derivatives|
|Settore Scientifico Disciplinare:||Settore CHIM/08 - Chimica Farmaceutica|
Settore CHIM/06 - Chimica Organica
|Progetto:||PIANO DI SOSTEGNO ALLA RICERCA 2015-2017 - LINEA 2 "DOTAZIONE ANNUALE PER ATTIVITA' ISTITUZIONALE"|
|Data di pubblicazione:||2019|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.3390/ijms20194927|
|Appare nelle tipologie:||01 - Articolo su periodico|