Molecular Basis for Differential Recognition of G‐Quadruplex versus Double‐Helix DNA by Bis‐Phenanthroline Metal Complexes

Rigo, Riccardo; Bianco, Sara; Musetti, Caterina; Palumbo, Manlio; Sissi, Claudia

doi:10.1002/cmdc.201600129

Cited by 7 publications

(5 citation statements)

References 43 publications

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“…The ICD spectral features at pH 5.5 and 7.4 well overlap one to each other when normalized on the ligand concentration (Fig. S9C) and significantly resemble those previously reported for 042 in the presence of ctDNA or human telomeric G-quadruplex at low ionic strength 33 . S1 footprinting performed at pH 5.5 confirmed a different behaviour of the metal complex vs the free ligand.…”

Section: Resultssupporting

confidence: 84%

“…The use of some Phen derivatives as hit for this evaluation provided stimulating hints. We previously showed that G4 structures are preferentially recognized by systems comprising two Phen units organized around one coordinated metal ion according to a planar geometry 31,33 . Taking into account the reduced available surface area of the C-C + pair in comparison to the G4 tetrads, we expected that only one aromatic moiety should be sufficient to target an iM through stacking interactions.…”

Section: Resultsmentioning

confidence: 99%

“…As potential binders we tested some phenanthroline (Phen) derivatives that preferentially generate mono- or bis-Phen Ni(II) complexes according to the substitution pattern of the aromatic core. The interest in these systems derived by the fact that each single species was previously confirmed to be endowed with peculiar selectivity profiles towards different DNA conformations 30–33 . Overall, we confirmed that a single Phen unit is sufficient to obtain derivatives able to remarkably increase the stability of the iM folding of EGFR-272_C.…”

Section: Introductionmentioning

confidence: 99%

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pH-driven conformational switch between non-canonical DNA structures in a C-rich domain of EGFR promoter

Cristofari

Rigo

Greco

et al. 2019

Sci Rep

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EGFR is an oncogene that encodes for a trans-membrane tyrosine kinase receptor. Its mis-regulation is associated to several human cancers that, consistently, can be treated by selective tyrosine kinase inhibitors. The proximal promoter of EGFR contains a G-rich domain located at 272 bases upstream the transcription start site. We previously proved it folds into two main interchanging G-quadruplex structures, one of parallel and one of hybrid topology. Here we present the first evidences supporting the ability of the complementary C-rich strand (EGFR-272_C) to assume an intramolecular i-Motif (iM) structure that, according to the experimental conditions (pH, presence of co-solvent and salts), can coexist with a different arrangement we referred to as a hairpin. The herein identified iM efficiently competes with the canonical pairing of the two complementary strands, indicating it as a potential novel target for anticancer therapies. A preliminary screening for potential binders identified some phenanthroline derivatives as able to target EGFR-272_C at multiple binding sites when it is folded into an iM.

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Section: Resultssupporting

confidence: 84%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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pH-driven conformational switch between non-canonical DNA structures in a C-rich domain of EGFR promoter

Cristofari

Rigo

Greco

et al. 2019

Sci Rep

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Section: Introductionmentioning

confidence: 99%

“…Among the great variety of aromatic heterocycles that have been demonstrated interesting properties as potential quadruplex ligands, the 1,10-phenanthroline heterocyclic system deserves a mention. Several derivatives have been found to bind to quadruplexes with good affinity and selectivity, both in the form of organic ligands [35][36][37][38] or as metalloorganic derivatives [35,[39][40][41][42] On the other hand, natural and synthetic guanidine derivatives have been of great interest due to their pronounced biological activity [43]. Among their properties, it is worth mentioning their use in neurodegenerative disorders as anti-inflammatory agents, as inhibitors of the Na + /H + exchanger and blockers of the epithelial sodium channel, as inhibitors of F1F0-ATPase, as cardiovascular and as antidiabetic or chemotherapeutic agents.…”

Section: Introductionmentioning

confidence: 99%

PhenQE8, a Novel Ligand of the Human Telomeric Quadruplex

Gratal

Quero

Pérez‐Redondo

et al. 2021

IJMS

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A novel quadruplex ligand based on 1,10-phenanthroline and incorporating two guanyl hydrazone functionalities, PhenQE8, is reported herein. Synthetic access was gained in a two-step procedure with an overall yield of 61%. X-ray diffraction studies revealed that PhenQE8 can adopt an extended conformation that may be optimal to favor recognition of quadruplex DNA. DNA interactions with polymorphic G-quadruplex telomeric structures were studied by different techniques, such as Fluorescence resonance energy transfer (FRET) DNA melting assays, circular dichroism and equilibrium dialysis. Our results reveal that the novel ligand PhenQE8 can efficiently recognize the hybrid quadruplex structures of the human telomeric DNA, with high binding affinity and quadruplex/duplex selectivity. Moreover, the compound shows significant cytotoxic activity against a selected panel of cultured tumor cells (PC-3, HeLa and MCF-7), whereas its cytotoxicity is considerably lower in healthy human cells (HFF-1 and RPWE-1).

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Synthesis and Properties of 2,2′‐Oxybis(1,10‐phenanthroline) and 2,4‐Dioxa‐1,3(2,9)‐diphenanthrolinacyclobutaphane

Lü

Karim

Jahng

2018

Bulletin Korean Chem Soc

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Chemistry of 1,10-phenanthroline has long been of interest since first synthesis in 1898. 1 The importance of 1,10phenanthroline and its substituted analogues stems from their metal chelating properties and such ability has been widely applied in analytical chemistry for the analysis of metal cationic species. 2 The 1,10-phenanthroline moiety has been used not only as a single molecule but also as a part of macrocyclic ligand systems for molecular recognition, 3 cleavage of nucleic acids, 4 sensing agents, 5 catalysis for chemical reaction, 6 and photolysis, 7 and as therapeutic and bioanalytical applications, 8 which have been compiled in several reviews. 9 As the dimeric and cyclic 1,10-phenanthrolines are concerned, 2,2 0 -azabis(1,10-phenanthroline) (1b), 10 2,2 0 -thiobis(1,10-phenanthroline) (1c), 11 1,3(2,9)-diphenanthrolinacyclobutaphane (2a), 12 2,4-diaza-1,3(2,9)-diphenanthrolinacyclobutaphane (2b), 13 and 2,4-dithia-1,3(2,9)-diphenanthrolinacyclobutaphane (2c) 11c,14 were reported and have been attractive in variety of areas. 9c,10c,11c,13a,c However carbon-bridged di(1,10-phenanthrolin-2-yl)methane (1a) and the oxa-bridged 2,2 0 -oxybis (1,10-phenanthroline) (1d) and 2,4-dioxa-1,3(2,9)diphenanthrolinacyclobutaphane (2d), have not been reported. We herein described the preparation and properties of two new 1,10phenanthroline ethers, namely, 2,2 0 -oxybis(1,10-phenanthroline) (1d) and 2,4-dioxa-1,3(2,9)-diphenanthrolinacyclobutaphane (2d).Initial attempt for the synthesis of 1d involved a reaction of 1,10-phenanthrolin-2(1H)-one (3a) 15 and 2-chloro-1,10phenanthroline (4a) 16 in presence of KOH under the same condition for 1c. 11a,b The 1 H NMR spectrum of the product showed that it consisted of a mixture of 1d and 3a in a ratio of 1:4. To explain increased amount of 3a, we repeated the reaction with more reactive 2-bromo-1,10-phenanthroline 17 to give a 1.1:1 mixture of 1d and 3a. Formation of the same hydrolysis product, 3a, has also been reported in the reaction of 4a with 3c 18 reflecting that the low reactivity of 1a towards nucleophilic substitution and/or weak acidity of the amide proton of 3a might induce hydroxylation of 4a before it can undergo nucleophilic attack by the enolate anion. 19 Therefore, we used NaH to deprotonate 3a and the resulting enolate anion was then treated with excess of 4a, which led to 1d in 75% yield with a trace (7%) amount of 4a. 20 The 13 C NMR spectra of 1d showed resonances at δ 158.5 ppm for C2, which is comparable to those for C2 in 2c (δ 156.8) and in 3c (δ 181.0) 11a in CDCl 3 .For the preparation of cyclic diether 2d, 9-chloro-1,10phenanthrolin-2(1H)-one (3b) can be a good starting material, which can be prepared by hydrolysis of 2,9-dichloro-1,10-phenanthroline (4b) 13a with 36% (w/w) aqueous HCl. 21 The same reaction condition described above for 1d was applied to 3b to yield 2d in 44% yield. 22 1 H NMR spectrum of 2d showed two doublets at δ 8.00 and 6.65 (J = 9.5 Hz) for H3 and H4, respectively, and a singlet at δ 7.46 for H5, while 13 C NMR spectrum sho...

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Molecular Basis for Differential Recognition of G‐Quadruplex versus Double‐Helix DNA by Bis‐Phenanthroline Metal Complexes

Cited by 7 publications

References 43 publications

pH-driven conformational switch between non-canonical DNA structures in a C-rich domain of EGFR promoter

pH-driven conformational switch between non-canonical DNA structures in a C-rich domain of EGFR promoter

PhenQE8, a Novel Ligand of the Human Telomeric Quadruplex

Synthesis and Properties of 2,2′‐Oxybis(1,10‐phenanthroline) and 2,4‐Dioxa‐1,3(2,9)‐diphenanthrolinacyclobutaphane

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