Efficient Inhibition of Telomerase by Nickel–Salophen Complexes

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Telomeric regions containing G-quadruplex (G4) structures play a pivotal role in the development of cancers. The development of specific binders for G4s is thus of great interest in order to gain a deeper understanding of the role of these structures, and to ultimately develop new anticancer drug candidates. For several years, Ru complexes have been studied as efficient probes for DNA. Interest in these complexes stems mainly from the tunability of their structures and properties, and the possibility of using light excitation as a tool to probe their environment or to selectively trigger their reaction with a biological target. Herein, we report on the synthesis and thorough study of new Ru complexes based on a novel dipyrazino[2,3-a:2',3'-h]phenazine ligand (dph), obtained through a Chichibabin-like reaction. Luminescence experiments, surface plasmon resonance (SPR), and computational studies have demonstrated that these complexes behave as selective probes for G-quadruplex structures.

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

New Ruthenium‐Based Probes for Selective G‐Quadruplex Targeting

Piraux

Bar

Abraham

et al. 2017

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“…To explore the propensity of G4‐binding ligands to interact with the viral G4 structure formed by HIV‐PRO1 and to assess the selectivity of recognition, we collected six low molecular weight compounds, archetypes of important families of G4 ligands, and we studied, by SPR, their interactions with HIV conjugate 2 , telomeric conjugate 1 , and a control hairpin structure 9 (Supporting Information, Figure S42) (Table ). Template assembled DNA and RNA G4 model structures have been successfully exploited in the past, along with the hairpin structure 9 , to probe the interaction modes of several G4‐binding ligands –…”

Section: Resultsmentioning

confidence: 99%

Template‐Mediated Stabilization of a DNA G‐Quadruplex formed in the HIV‐1 Promoter and Comparative Binding Studies

Bonnat

Bar

Génnaro

et al. 2017

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G-rich DNA oligonucleotides derived from the promoter region of the HIV-1 long terminal repeat (LTR) were assembled onto an addressable cyclopeptide platform through sequential oxime ligation, a thiol-iodoacetamide SN2 reaction, and copper-catalyzed azide-alkyne cycloaddition reactions. The resulting conjugate was shown to fold into a highly stable antiparallel G4 architecture as demonstrated by UV, circular dichroism (CD), and NMR spectroscopic analysis. The binding affinities of six state-of-the-art G4-binding ligands toward the HIV-G4 structure were compared to those obtained with a telomeric G4 structure and a hairpin structure. Surface plasmon resonance binding analysis provides new insights into the binding mode of broadly exploited G4 chemical probes and further suggests that potent and selective recognition of viral G4 structures of functional significance might be achieved.

“…[8,9] Amongt he designedc ompounds, organic molecules based either on the acridine,p henanthroline or more recently quinazoline frameworkss howed good selectivities for G4; [18][19][20][21][22] whilei nt erms of metalc omplexes,m any metalloporphyrins and metal-salphens also revealed to possess high affinitiesand selectivities towards G4s. [23][24][25][26][27][28][29] In addition, mono and dinuclear ruthenium (II) complexesc arryingap olyazaaromatic and rigid planar extended ligandw ered eveloped and were shown to bind tightly to the G4 scaffold. [30][31][32][33][34][35][36] The high affinity of these compounds mainly arises from efficient p-stackingi nteractions with the G4 externalq uartet and additional interaction with the G4 grooves also appeared to play ap rominent role in the interaction of some complexes.…”

Section: Introductionmentioning

confidence: 99%

Flexible Ru^II Schiff Base Complexes: G‐Quadruplex DNA Binding and Photo‐Induced Cancer Cell Death

Gillard

Weynand

Bonnet

et al. 2020

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As eries of new Ru II Schiff base complexes built on the salphen moiety has been prepared. Thisi ncludes four flexible monometallic Ru II compounds and six rigid bimetallic analogues that contain Ni II ,P d II or Pt II cations into the salphen complexation site. Steadys tate luminescence titrations illustrated the capacity of the compounds to photoprobe Gquadruplex (G4) DNA.M oreover,t he vast array of the Schiff base structuralc hangesa llowed to extensivelya ssess the influenceo fthe ligand surface, flexibility and chargeont he interaction of the compounds with G4 DNA. This was achieved thanks to circulard ichroism melting assays and bio-layer interferometry studies that pointed up high affinities along with good selectivities of Ru II Schiff base complexes for G4 DNA. In cellulo studiesw ere carriedo ut with the most promising compounds. Cellular uptake with location of the compounds in the nucleus as well as in the nucleolus was observed. Cell viability experiments were performed with U2OS osteosarcomac ellsi nt he dark and under light irradiation which allowed the measurements of IC 50 values and photoindexes.T heys howedt he substantial role played by light irradiation in the activity of the drugsi na ddition to the low cytotoxicity of the molecules in the dark. Altogether,t he reportedr esults emphasize the promising propertieso fR u II Schiffbase complexesasanew class of candidates for developing potentialG 4D NA targeting diagnostic or therapeutic compounds.