c-MYC G-quadruplex binding by the RNA polymerase I inhibitor BMH-21 and analogues revealed by a combined NMR and biochemical Approach

Musso, Loana; Mazzini, Stefania; Rossini, Anna; Castagnoli, Lorenzo; Scaglioni, Leonardo; Artali, Roberto; Nicola, Massimo Di; Zunino, Franco; Dallavalle, Sabrina

doi:10.1016/j.bbagen.2017.12.002

Cited by 31 publications

(41 citation statements)

References 45 publications

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“…This observation suggests that the interaction of the compound 2 with the c- KIT promoter is not the primary event and that multiple effects provide a contribution as determinants of biological activity. Indeed, the key role of c- KIT in controlling survival, proliferation and differentiation suggests the existence of a finely tuned network of molecular interactions, as documented by our present and previous results, which show the multitarget effects mediated by G-quadruplex stabilization [30]. Given the multitarget mechanism of action of these compounds and the different impacts of modulation of putative targets in tumor cells, no close correlations could be expected between the expression of each target and the effective concentration.…”

Section: Resultssupporting

confidence: 68%

“…We used the EQUISPEC program based on the multivariate analysis of all the spectra measured along the titration [44]. In both cases, the Kb values obtained for 1 and 2 with c-kit21T12T21 were in the order of 10 6 M -1 , which suggests a relatively strong interaction between both ligands and this sequence, higher than the interaction with Pu22T14T23 (Kb ca 10 5 M −1 ) [30].…”

Section: Resultsmentioning

confidence: 99%

“…We have recently explored the ability of BMH-21 ( 1 ) and its analogue BA-41 ( 2 ) (Scheme 1) to bind to G-quadruplexes. We have provided evidence that both compounds are not DNA intercalators but are effective binders of the human telomeric and c-MYC promoter G-quadruplexes [30].…”

Section: Introductionmentioning

confidence: 99%

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Stabilization of c-KIT G-Quadruplex DNA Structures by the RNA Polymerase I Inhibitors BMH-21 and BA-41

Mazzini

Gargallo

Musso

et al. 2019

IJMS

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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 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.

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Section: Resultssupporting

confidence: 68%

Section: Resultsmentioning

confidence: 99%

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Stabilization of c-KIT G-Quadruplex DNA Structures by the RNA Polymerase I Inhibitors BMH-21 and BA-41

Mazzini

Gargallo

Musso

et al. 2019

IJMS

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“…The analysis of the spectra at R=3.0 was performed starting from the attribution of the three tetrads by inter-residue NOE connectivities between the H1 imino and the aromatic protons H8 of guanine residues (following the procedure used for the study of other ligands. 28,52 The results reported in Table S6 show that the quadruplex structure is conserved. Also, for these complexes a significant shielding was observed for the H1 imino protons of the internal tetrad (δ = -0.30/-0.60 ppm) although lower than the values of the external tetrads (δ ≥-0.60 ppm).…”

Section: Determination Of Dna:ligand Stoichiometrymentioning

confidence: 98%

Naturally occurring quaternary benzo[c]phenanthridine alkaloids selectively stabilize G-quadruplexes

Jarošová

Paroulek

Rájecký

et al. 2018

Phys. Chem. Chem. Phys.

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In this work, the interaction of six natural benzo[c]phenanthridine alkaloids (macarpine, sanguilutine, sanguirubine, chelerythrine, sanguinarine and chelirubine) with parallel and antiparallel G-quadruplex DNA structures was studied. HT22 corresponding to the end of human telomeres and the modified promoter oncogene c-kit21 and Pu22 sequences have been used. Spectroscopically-monitored melting experiments and fluorescence titrations, competitive dialysis and nuclear magnetic resonance spectroscopy were used for this purpose. The results showed that these alkaloids stabilized G-quadruplex structures in terms of increments of Tm values (from 15 to 25 °C) with high selectivity over duplexes and unfolded DNA. The mode of binding was mainly by stacking on the terminal G-tetrads with stoichiometries of 1 : 2 (DNA : ligand). The presence of non-specific electrostatic interactions was also observed. Overall, the results pointed to a strong stabilization of G-quadruplex structures by these alkaloids.

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“…Together with single-molecule Förster resonance energy transfer (smFRET) data, the NMR data suggested that the G4 stabilization by BTC resulted from conformational selection and not an induced-fit process. The RNA polymerase I inhibitor BMH-21 was tested for c-MYC G4 (Pu22-T14/T23) binding [63]. The imino proton spectra of the G4 with increasing concentrations of the ligand clearly showed that the binding is an intermediate to slow exchange process, and the stoichiometry was also determined as 2:1 (drug: G4).…”

Section: G4-ligand Interactionmentioning

confidence: 99%

Dynamics Studies of DNA with Non-canonical Structure Using NMR Spectroscopy

Kim

Park

Lee

2020

IJMS

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The non-canonical structures of nucleic acids are essential for their diverse functions during various biological processes. These non-canonical structures can undergo conformational exchange among multiple structural states. Data on their dynamics can illustrate conformational transitions that play important roles in folding, stability, and biological function. Here, we discuss several examples of the non-canonical structures of DNA focusing on their dynamic characterization by NMR spectroscopy: (1) G-quadruplex structures and their complexes with target proteins; (2) i-motif structures and their complexes with proteins; (3) triplex structures; (4) left-handed Z-DNAs and their complexes with various Z-DNA binding proteins. This review provides insight into how the dynamic features of non-canonical DNA structures contribute to essential biological processes.

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c-MYC G-quadruplex binding by the RNA polymerase I inhibitor BMH-21 and analogues revealed by a combined NMR and biochemical Approach

Cited by 31 publications

References 45 publications

Stabilization of c-KIT G-Quadruplex DNA Structures by the RNA Polymerase I Inhibitors BMH-21 and BA-41

Stabilization of c-KIT G-Quadruplex DNA Structures by the RNA Polymerase I Inhibitors BMH-21 and BA-41

Naturally occurring quaternary benzo[c]phenanthridine alkaloids selectively stabilize G-quadruplexes

Dynamics Studies of DNA with Non-canonical Structure Using NMR Spectroscopy

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