Título:
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Stabilization of c-KIT G-Quadruplex DNA structures by the RNA polymerase I inhibitors BMH-21 and BA-41
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Autor/a:
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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
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Otros autores:
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Universitat de Barcelona |
Abstract:
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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. |
Materia(s):
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-Ressonància magnètica nuclear -G-estructures -Nuclear magnetic resonance -G-structures |
Derechos:
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cc-by (c) Mazzini, Stefania et al., 2019
http://creativecommons.org/licenses/by/3.0/es |
Tipo de documento:
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Artículo Artículo - Versión publicada |
Editor:
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MDPI
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