Design and study of telomerase inhibitors based on G-quadruplex ligands

Negrutska, V. V.; Dubey, L. V.; Ya, Dubey I.; Ilchenko, Mykola; Dubey, I. Ya.

doi:10.7124/bc.000817

Cited by 12 publications

(12 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Imidazophenazine is known as DNA intercalator [26,27], and we supposed that the attached dye would improve the binding of porphyrin to G4 structures by intercalation into double-stranded regions of telomeric DNA or between guanine quartets. Indeed, TMPyP 3+ -imidazophenazine hybrids and their zinc(II) and manganese(III) complexes efficiently inhibited telomerase and demonstrated antiproliferative activity in vitro at micro-and submicromolar concentrations [28].…”

Section: Introductionmentioning

confidence: 99%

Spectroscopic Studies on Binding of Porphyrin-Phenazine Conjugate to Four-Stranded Poly(G)

et al. 2015

View full text Add to dashboard Cite

Binding of a novel cationic porphyrin-imidazophenazine conjugate, TMPyP(3+)-ImPzn, to four-stranded poly(G) was investigated in aqueous solutions of neutral pH under near physiological ionic conditions using absorption, polarized fluorescent spectroscopy and fluorescence titration techniques. In absence of the polymer the conjugate folds into stable internal heterodimer with stacking between the porphyrin and phenazine chromophores. Binding of TMPyP(3+)-ImPzn to poly(G) is realized by two competing ways. At low polymer-to-dye ratio (P/D < 6) outside electrostatic binding of the cationic porphyrin moieties of the conjugate to anionic polynucleotide backbone with their self-stacking is predominant. It is accompanied by heterodimer dissociation and distancing of phenazine moieties from the polymer. This binding mode is characterized by strong quenching of the conjugate fluorescence. Increase of P/D results in the disintegration of the porphyrin stacks and redistribution of the bound conjugate molecules along the polymer chain. At P/D > 10 another binding mode becomes dominant, embedding of TMPyP(3+)-ImPzn heterodimers into poly(G) groove as a whole is occurred.

show abstract

Section: Introductionmentioning

confidence: 99%

Spectroscopic Studies on Binding of Porphyrin-Phenazine Conjugate to Four-Stranded Poly(G)

et al. 2015

View full text Add to dashboard Cite

show abstract

“…This suggestion is in perfect agreement with our recent experimental data on biological activity of the conjugates. Zn(II) complex was found to be several times more efficient telomerase inhibitor [36] and antiproliferative agent [33,36] than non-metallated hybrid.…”

Section: Discussionmentioning

confidence: 99%

“…Imidazophenazine is known as DNA intercalating agent [34,35], and we supposed that the attached dye would improve the porphyrin binding to G4 structures by intercalation between guanine quartets. It was shown that both TMPyP 3+ -ImPzn conjugate and its Zn(II) and Mn(III) complexes at low micromolar concentrations inhibit telomerase in TRAP assay and demonstrate antiproliferative activity in vitro [33,36]. The binding of these conjugates to intramolecular antiparallel G-quadruplex formed by model 22-mer oligonucleotide 5′-d[AGGG(TTAGGG) 3 ]-3′, a fragment of human telomeric DNA (Tel22, PDB code 143D), was studied using spectroscopic techniques [37].…”

Section: Introductionmentioning

confidence: 99%

Binding of Metallated Porphyrin-Imidazophenazine Conjugate to Tetramolecular Quadruplex Formed by Poly(G): a Spectroscopic Investigation

et al. 2015

View full text Add to dashboard Cite

The binding of telomerase inhibitor ZnTMPyP(3+)-ImPzn, Zn(II) derivative of tricationic porphyrin-imidazophenazine conjugate, to tetramolecular quadruplex structure formed by poly(G) was studied in aqueous solutions at neutral pH and near physiological ionic strength using absorption and polarized fluorescent spectroscopy techniques. Three binding modes were determined from the dependences of the fluorescence intensity and polarization degree for the porphyrin and phenazine moieties of the conjugate on molar polymer-to-dye ratio (P/D). The first one is outside electrostatic binding of positively charged porphyrin fragments to anionic phosphate groups of the polymer which prevails only at very low P/D values and manifests itself by substantial fluorescence quenching. It is suggested that the formation of externally bound porphyrin dimers occurs. The other two binding modes observed at high P/D are embedding of the ZnTMPyP(3+) moiety into the groove of poly(G) quadruplex accompanied by more than 3-fold enhancement of the conjugate emission, and simultaneous intercalation of the phenazine fragment between the guanine bases accompanied by the increase of its fluorescence polarization degree up to 0.25. Thus Zn(II) conjugate seems to be promising ligand for the stabilization of G-quadruplex structures since porphyrin binding to poly(G) is strengthened by additional intercalation of phenazine moiety.

show abstract

“…They are considered as key regulatory elements in genome regions of biological significance, in particular, in human telomeres and promoter regions of some proto-oncogenes [10][11][12][13]. They are known as promising targets for anticancer therapy, since G-quadruplex binding ligands, including many porphyrin derivatives, are able to inhibit the telomerase, a tumor-associated enzyme responsible for telomere elongation [14][15][16]. We have recently found that CatPheo-a inhibits the telomerase in vitro at low micromolar concentrations being much more active than its precursor, anionic Pheo-a.…”

Section: Introductionmentioning

confidence: 99%

Spectroscopic study on binding of cationic Pheophorbide-ato antiparallel quadruplex Tel22

Ryazanova

Zozulya

Voloshin

et al. 2018

Preprint

View full text Add to dashboard Cite

Binding of water-soluble cationic Pheophorbide-a derivative (CatPheo-a) to Na + -stabilized antiparallel quadruplex formed by 22-mer oligonucleotide d[AG 3 (T 2 AG 3 ) 3 ], a fragment of human telomeric DNA (Tel22, PDB ID: 143D), has been examined using experimental techniques of absorption and polarized fluorescent spectroscopy as well as absorption melting. The binding affinity of CatPheo-a to Tel22 was studied in titration experiments registering the dependence of the dye fluorescence intensity and polarization degree on molar phosphate-to-dye ratio (P/D). CatPheo-a was found to bind effectively to the quadruplex, and two competitive binding modes were detected. The first one predominates at the dye excess and results in the fluorescence quenching, whereas the second one is preferential at the biopolymer excess and results in the enhancement of pheophorbide emission.The effect of CatPheo-a on thermodynamic parameters of Tel22 quadruplex unfolding was estimated using a two-state model. It was found that CatPheo-a destabilizes the quadruplex structure of Tel22 slightly decreasing its 4→1 transition midpoint temperature, gives destabilizing increment into Gibbs standard free energy and 2-fold decrease in the equilibrium quadruplex folding constant at 37°C. In ethanol CatPheo-a exhibits 15% higher efficiency of singlet oxygen generation as compared to the parent Pheo-a compound that makes it a promising photosensitizer for photodynamic therapy.

show abstract

Design and study of telomerase inhibitors based on G-quadruplex ligands

Cited by 12 publications

References 29 publications

Spectroscopic Studies on Binding of Porphyrin-Phenazine Conjugate to Four-Stranded Poly(G)

Spectroscopic Studies on Binding of Porphyrin-Phenazine Conjugate to Four-Stranded Poly(G)

Binding of Metallated Porphyrin-Imidazophenazine Conjugate to Tetramolecular Quadruplex Formed by Poly(G): a Spectroscopic Investigation

Spectroscopic study on binding of cationic Pheophorbide-ato antiparallel quadruplex Tel22

Contact Info

Product

Resources

About