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Title: Stabilization of c-KIT G-Quadruplex DNA structures by the RNA polymerase I inhibitors BMH-21 and BA-41
Author: Mazzini, Stefania
Gargallo Gómez, Raimundo
Musso, Loana
De Santis, Francesca
Aviñó Andrés, Anna
Scaglioni, Leonardo
Eritja i Casadellà, Ramon
Di Nicola, Massimo
Zunino, Franco
Amatulli, Annabella
Dallavalle, Sabrina
Keywords: Ressonància magnètica nuclear
Nuclear magnetic resonance
Issue Date: 4-Oct-2019
Publisher: MDPI
Abstract: 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 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.
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It is part of: International Journal of Molecular Sciences, 2019, vol. 20, num. 19, p. 4927
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ISSN: 1661-6596
Appears in Collections:Articles publicats en revistes (Enginyeria Química i Química Analítica)

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