Predicting the Three-Dimensional Structure of the c-<i>KIT</i> Proto-Oncogene Promoter and the Dynamics of Its Strongly Coupled Guanine Quadruplexes

Bignon, Emmanuelle; Spinello, Angelo; Miclot, Tom; D'Anna, Luisa; Ducani, Cosimo; Grandemange, Stéphanie; Barone, Giampaolo; Monari, Antonio; Terenzi, Alessio

doi:10.1021/acs.jpclett.3c00765

Cited by 6 publications

(3 citation statements)

References 59 publications

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“…41 In contrast, c-Kit1 is one of three G4-forming sequences located in the promoter region of the proto-oncogene KIT, which encodes a tyrosine kinase receptor known to be a clinically validated target for treating different tumors. 42,43 In this way, we can first assess whether our compounds exhibit a preference for G4s over B-DNA, and also determine if they have an affinity for a specific G4 topology.…”

Section: Catalytic Nadh Oxidationmentioning

confidence: 99%

Alloxazine-Based Ligands And Their Ruthenium Complexes As NADH Oxidation Catalysts And G4 Binders

Móran Plata,

Marretta,

Gaztelumendi

et al. 2024

Preprint

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Flavin-like ligands (L-1 and L-2) with extended π-conjugation were synthesized using microwave-assisted techniques. An N,N-chelating fragment was integrated into alloxazine units, providing binding sites for metal ions while retaining redox activity. The complexation capability of L-1 and L-2 with two prototypical Ru-scaffolds was examined to design Ru(II) complexes (M-1 and M-2), whose electronic properties were studied and compared with their corresponding ligands via absorption and emission spectroscopy, computational analysis (DFT and TD-DFT), and cyclic voltammetry (CV). The ability of L-1 and M-1 to undergo alloxazine/isoalloxazine tautomerization was demonstrated to play a crucial role in the photocatalytic oxidation of NADH, including under green and red wavelengths. Moreover, the interaction of M-1 and M-2 with B-DNA and G-quadruplex structures was investigated. M-2 showed high stabilization of Kit1 and h-Telo oligonucleotides. Meanwhile, M-1 demonstrated switchable emissive properties with B-DNA and induced conformational changes in the h-Telo G-quadruplex structure.

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Section: Catalytic Nadh Oxidationmentioning

confidence: 99%

Alloxazine-Based Ligands And Their Ruthenium Complexes As NADH Oxidation Catalysts And G4 Binders

Móran Plata,

Marretta,

Gaztelumendi

et al. 2024

Preprint

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“…Consequently, anticancer drugs that target G4 are actively being pursued with a number in clinical trials approved, , while there is also interest in developing diagnostic molecular probes to recognize these structures . The diversity of oncogene targets is further evidenced by their ability to form coupled ternary structures. , While, recent studies have revealed the presence of quadruplex forming sequences in Gram-negative bacteria suggesting a possible avenue to develop G4 targeting antibiotics to tackle antimicrobial resistance . Additionally, the presence of G4 structures in viral genomes, including RNA viruses and SARS-CoV-2 makes, further highlights its potential as a therapeutic target. , …”

Section: Introductionmentioning

confidence: 99%

“… 18 The diversity of oncogene targets is further evidenced by their ability to form coupled ternary structures. 19 , 20 While, recent studies have revealed the presence of quadruplex forming sequences in Gram-negative bacteria suggesting a possible avenue to develop G4 targeting antibiotics to tackle antimicrobial resistance. 21 Additionally, the presence of G4 structures in viral genomes, including RNA viruses and SARS-CoV-2 makes, further highlights its potential as a therapeutic target.…”

Section: Introductionmentioning

confidence: 99%

Good Vibrations Report on the DNA Quadruplex Binding of an Excited State Amplified Ruthenium Polypyridyl IR Probe

Stitch,

Avagliano,

Graczyk

et al. 2023

J. Am. Chem. Soc.

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The nitrile containing Ru(II)polypyridyl complex [Ru(phen) 2 (11,] 2+ (1) is shown to act as a sensitive infrared probe of G-quadruplex (G4) structures. UV−visible absorption spectroscopy reveals enantiomer sensitive binding for the hybrid htel(K) and antiparallel htel(Na) G4s formed by the human telomer sequence d[AG 3 (TTAG 3 ) 3 ]. Time-resolved infrared (TRIR) of 1 upon 400 nm excitation indicates dominant interactions with the guanine bases in the case of Λ-1/htel(K), Δ-1/htel(K), and Λ-1/htel(Na) binding, whereas Δ-1/htel(Na) binding is associated with interactions with thymine and adenine bases in the loop. The intense nitrile transient at 2232 cm −1 undergoes a linear shift to lower frequency as the solution hydrogen bonding environment decreases in DMSO/water mixtures. This shift is used as a sensitive reporter of the nitrile environment within the binding pocket. The lifetime of 1 in D 2 O (ca. 100 ps) is found to increase upon DNA binding, and monitoring of the nitrile and ligand transients as well as the diagnostic DNA bleach bands shows that this increase is related to greater protection from the solvent environment. Molecular dynamics simulations together with binding energy calculations identify the most favorable binding site for each system, which are in excellent agreement with the observed TRIR solution study. This study shows the power of combining the environmental sensitivity of an infrared (IR) probe in its excited state with the TRIR DNA "site effect" to gain important information about the binding site of photoactive agents and points to the potential of such amplified IR probes as sensitive reporters of biological environments.

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Alloxazine-Based Ligands and Their Ruthenium Complexes as NADH Oxidation Catalysts and G4 Binders

Móran Plata,

Marretta,

Gaztelumendi

et al. 2024

Inorg. Chem.

View full text Add to dashboard Cite

Flavin-like ligands (L-1 and L-2) with extended πconjugation were synthesized using microwave-assisted techniques. An N,N-chelating fragment was integrated into alloxazine units, providing binding sites for metal ions while retaining redox activity. The complexation capability of L-1 and L-2 with two prototypical Ru-scaffolds was examined to design Ru(II) complexes (M-1 and M-2), whose electronic properties were studied and compared with their corresponding ligands via absorption and emission spectroscopy, computational analysis (density functional theory (DFT) and time-dependent DFT (TD-DFT)), and cyclic voltammetry (CV). The ability of L-1 and M-1 to undergo alloxazine/isoalloxazine tautomerization was demonstrated to play a crucial role in the photocatalytic oxidation of NADH, including under green and red wavelengths. Moreover, the interaction of M-1 and M-2 with B-DNA and G-quadruplex structures was investigated. M-2 showed high stabilization of Kit1 and h-Telo oligonucleotides. Meanwhile, M-1 demonstrated switchable emissive properties with B-DNA and induced conformational changes in the h-Telo G-quadruplex structure.

show abstract

Predicting the Three-Dimensional Structure of the c-KIT Proto-Oncogene Promoter and the Dynamics of Its Strongly Coupled Guanine Quadruplexes

Cited by 6 publications

References 59 publications

Alloxazine-Based Ligands And Their Ruthenium Complexes As NADH Oxidation Catalysts And G4 Binders

Alloxazine-Based Ligands And Their Ruthenium Complexes As NADH Oxidation Catalysts And G4 Binders

Good Vibrations Report on the DNA Quadruplex Binding of an Excited State Amplified Ruthenium Polypyridyl IR Probe

Alloxazine-Based Ligands and Their Ruthenium Complexes as NADH Oxidation Catalysts and G4 Binders

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