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 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.
| Original language | English |
|---|---|
| Article number | 4927 |
| Journal | International Journal of Molecular Sciences |
| Volume | 20 |
| Issue number | 19 |
| DOIs | |
| Publication status | Published - Oct 1 2019 |
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Keywords
- C-KIT
- CD
- G-quadruplex
- NMR spectroscopy
- Pyridoquinazolinone derivatives
ASJC Scopus subject areas
- Catalysis
- Molecular Biology
- Spectroscopy
- Computer Science Applications
- Physical and Theoretical Chemistry
- Organic Chemistry
- Inorganic Chemistry
Cite this
Stabilization of c-KIT G-quadruplex DNA structures by the RNA polymerase I inhibitors BMH-21 and BA-41. / Mazzini, Stefania; Gargallo, Raimundo; Musso, Loana; De Santis, Francesca; Aviñó, Anna; Scaglioni, Leonardo; Eritja, Ramon; Di Nicola, Massimo; Zunino, Franco; Amatulli, Annabella; Dallavalle, Sabrina.
In: International Journal of Molecular Sciences, Vol. 20, No. 19, 4927, 01.10.2019.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Stabilization of c-KIT G-quadruplex DNA structures by the RNA polymerase I inhibitors BMH-21 and BA-41
AU - Mazzini, Stefania
AU - Gargallo, Raimundo
AU - Musso, Loana
AU - De Santis, Francesca
AU - Aviñó, Anna
AU - Scaglioni, Leonardo
AU - Eritja, Ramon
AU - Di Nicola, Massimo
AU - Zunino, Franco
AU - Amatulli, Annabella
AU - Dallavalle, Sabrina
PY - 2019/10/1
Y1 - 2019/10/1
N2 - 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.
AB - 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.
KW - C-KIT
KW - CD
KW - G-quadruplex
KW - NMR spectroscopy
KW - Pyridoquinazolinone derivatives
UR - http://www.scopus.com/inward/record.url?scp=85072970361&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85072970361&partnerID=8YFLogxK
U2 - 10.3390/ijms20194927
DO - 10.3390/ijms20194927
M3 - Article
C2 - 31590335
AN - SCOPUS:85072970361
VL - 20
JO - International Journal of Molecular Sciences
JF - International Journal of Molecular Sciences
SN - 1661-6596
IS - 19
M1 - 4927
ER -