Anthracene-terpyridine metal complexes as new G-quadruplex DNA binders

Gama, Sofia; Rodrigues, Isabelle; Mendes, Filipa; Santos, Isabel C.; Gabano, Elisabetta; Klejevskaja, Beata; González‐García, Jorge; Ravera, Mauro; Vilar, Ramón; Paulo, António

doi:10.1016/j.jinorgbio.2016.04.002

Cited by 43 publications

(32 citation statements)

References 53 publications

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“…11 and 12). [85][86][87][88] The central metal ion, the number of aromatic rings, as well as the number and position of the substituents on the terpyridine scaffold play critical roles for G4 recognition and stabilization. A series of comparative studies of metal-terpyridine complexes demonstrated that the binding affinity and selectivity for G4 DNA depend mainly dependent on the geometry of the complex.…”

Section: Metal-terpyridine Complexes and Derivativesmentioning

confidence: 99%

“…85 Another example is a group of Cu(II)-and Pt(II)-terpyridines 118-121 constructed by Gama et al, in which the terpyridine is tethered with a planar anthracene moiety via different linkers. 87 All these complexes are potent G4 stabilizers and telomerase inhibitors, exhibiting good affinity and selectivity for the G-quadruplex over duplex DNA. It is interesting to note that the strength of the ligand/G4 interactions increases with the linker size between the anthracenyl moiety and the terpyridine chelating unit.…”

Section: Metal-terpyridine Complexes and Derivativesmentioning

confidence: 99%

“…12 Platinum(II)-terpyridine complexes and derivatives reported as G4-ligands, the monodentate ligand is either a labile chloride or an alkynyl moiety. [85][86][87][88][90][91][92] Inorganic Chemistry Frontiers Review tives 150-151 bearing flexible cyclic amine-based side chains on the large planar aromatic ligand were also constructed by Chao et al 99 Measurements by using CD spectroscopy, FRET and PCR-stop assays proved that these complexes could effectively bind with and stabilize G-quadruplex structures (ΔT m = 5-15°C), thus exhibiting a concentration-dependent inhibitory effect on telomerase activity (IC 50 -TRAP = 100-500 nM), ultimately resulting in long-term anti-proliferation of cancer cells. Similarly, [Ru(dppz) 2 (bpy)] 2+ derivatives 153-154 bearing two dppz ligands and one modified bpy moiety with two quaternary ammonium pendants, again exhibited stronger interactions with G4 DNA than the classic [Ru(bpy) 2 (dppz)] 2+ and increased the melting temperature of G4 DNA by 7.0-9.4°C.…”

Section: Octahedral Metal Complexes With Planar Ligandsmentioning

confidence: 99%

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G-quadruplex DNA targeted metal complexes acting as potential anticancer drugs

Cao

Freisinger

et al. 2017

Inorg. Chem. Front.

228

158

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Section: Metal-terpyridine Complexes and Derivativesmentioning

confidence: 99%

Section: Metal-terpyridine Complexes and Derivativesmentioning

confidence: 99%

Section: Octahedral Metal Complexes With Planar Ligandsmentioning

confidence: 99%

See 1 more Smart Citation

G-quadruplex DNA targeted metal complexes acting as potential anticancer drugs

Cao

Freisinger

et al. 2017

Inorg. Chem. Front.

228

158

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“…Complex 1 was synthesized from [PtCl2( 4 -cod)] (cod = cycloocta-1,5-diene) and terpy according to literature procedures (see experimental section for details). 24,41,42 The following step of oxidation of complex 1 was performed with several oxidizing agents in order to prepare different Pt(IV) synthons, potentially useful for further coupling reactions (Scheme 1). 36,[43][44][45][46][47][48] Surprisingly, the most common reaction conditions failed to get the expected final products.…”

Section: Synthesis Of Pt(iv) Complexes Containing Terpyridinementioning

confidence: 99%

“…18,19 The Pt(II)-terpy complexes also interact with four-stranded Gquadruplex DNA. [20][21][22][23][24] G-quadruplex emerged as a promising anti-cancer target because their stabilization indirectly inhibits the telomerase enzyme. This enzyme is expressed in more than 85% of human tumors and compensates the loss of telomeres at each round of replication, thus contributing to cancer survival.…”

Section: Introductionmentioning

confidence: 99%

How to obtain Pt(iv) complexes suitable for conjugation to nanovectors from the oxidation of [PtCl(terpyridine)]⁺

et al. 2017

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Oxidation of [PtCl(terpy)] (terpy = 2,2':6',2''-terpyridine) has been attempted with several oxidizing agents and under different experimental conditions in order to obtain a Pt(iv) complex suitable for the conjugation to nanovectors to be used in drug delivery targeting for anticancer therapy. The best compromise in terms of yield and purity of the final complex was obtained by microwave-assisted reaction at 70 °C in 50% aqueous HO for 2 h. Under these conditions the quantitative formation of [PtCl(OH)(terpy)] was observed. The subsequent synthetic steps were, (i) functionalization of [PtCl(OH)(terpy)] in the axial position with succinic anhydride to obtain [PtCl(OH)(succinato)(terpy)] and (ii) reaction of the latter with nonporous silica nanoparticles (SNPs) with an external shell containing primary amino groups to obtain a nanovector able to transport the Pt(iv) antitumor prodrug in the form of a conjugate Pt-SNP. Finally, the antiproliferative activity and cell accumulation of [PtCl(terpy)], [PtCl(OH)(terpy)], and the Pt-SNP conjugate were measured on three cancer cell lines. Despite highly effective accumulation of Pt-SNP in cells, a modest increase in activity was observed with respect to the molecular species. Further experiments showed that the Pt-SNP conjugate can release [PtCl(terpy)] upon reduction, but this metabolite may undergo hydrolysis, and the resulting aquo complex could coordinate once again the free amino groups of the SNPs. In the resulting tetraamine form, the Pt(ii) complex conjugated to the SNPs cannot completely perform its antiproliferative activity.

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Gaining Insights on the Interactions of a Class of Decorated (2‐([2,2′‐Bipyridin]‐6‐yl)phenyl)platinum Compounds with c‐Myc Oncogene Promoter G‐Quadruplex and Other DNA Structures

Savva

Fossépré

Keramidas

et al. 2022

Chemistry A European J

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Organometallic molecules offer some of the most promising scaffolds for interaction with G-quadruplex nucleic acids. We report the efficient synthesis of a family of organoplatinum(II) complexes, featuring a 2-([2,2'-bipyridin]-6-yl)phenyl tridentate (N ∧ N ∧ C) ligand, that incorporates peripheral side-chains aiming at enhancing and diversifying its interaction capabilities. These include a di-isopropyl carbamoyl amide, a morpholine ethylenamide, two enantiomeric proline imides and an oxazole. The binding affinities of the Pt-complexes were evaluated via UV-vis and fluorescence titrations, against 5 topologically-distinct DNA structures, including c-myc G-quadruplex, two telomeric (22AG) Gquadruplexes, a duplex (ds26) and a single-stranded (polyT) DNA. All compounds exhibited binding selectivity in favour of c-myc, with association constants (K a ) in the range of 2-5 × 10 5 M À 1 , lower affinity for both folds of 22AG and for ds26 and negligible affinity for polyT. Remarkable emission enhancements (up to 200-fold) upon addition of excess DNA were demonstrated by a subset of the compounds with c-myc, providing a basis for optical selectivity, since optical response to all other tested DNAs was low. A c-myc DNAmelting experiment showed significant stabilizing abilities for all compounds, with the most potent binder, the morpholine-Pt-complex, exhibiting a ΔT m > 30 °C, at 1 : 5 DNA-to-ligand molar ratio. The same study implied contributions of the diverse side-chains to helix stabilization. To gain direct evidence of the nature of the interactions, mixtures of c-myc with the four most promising compounds were studied via UV Resonance Raman (UVRR) spectroscopy, which revealed end-stacking binding mode, combined with interactions of side-chains with loop nucleobase residues. Docking simulations were conducted to provide insights into the binding modes for the same four Pt-compounds, suggesting that the binding preference for two alternative orientations of the cmyc G-quadruplex thymine 'cap' ('open' vs. 'closed'), as well as the relative contributions to affinity from end-stacking and H-bonding, are highly dependent on the nature of the interacting Pt-complex side-chain.

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Anthracene-terpyridine metal complexes as new G-quadruplex DNA binders

Cited by 43 publications

References 53 publications

G-quadruplex DNA targeted metal complexes acting as potential anticancer drugs

G-quadruplex DNA targeted metal complexes acting as potential anticancer drugs

How to obtain Pt(iv) complexes suitable for conjugation to nanovectors from the oxidation of [PtCl(terpyridine)]⁺

Gaining Insights on the Interactions of a Class of Decorated (2‐([2,2′‐Bipyridin]‐6‐yl)phenyl)platinum Compounds with c‐Myc Oncogene Promoter G‐Quadruplex and Other DNA Structures

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Anthracene-terpyridine metal complexes as new G-quadruplex DNA binders

Cited by 43 publications

References 53 publications

G-quadruplex DNA targeted metal complexes acting as potential anticancer drugs

G-quadruplex DNA targeted metal complexes acting as potential anticancer drugs

How to obtain Pt(iv) complexes suitable for conjugation to nanovectors from the oxidation of [PtCl(terpyridine)]+

Gaining Insights on the Interactions of a Class of Decorated (2‐([2,2′‐Bipyridin]‐6‐yl)phenyl)platinum Compounds with c‐Myc Oncogene Promoter G‐Quadruplex and Other DNA Structures

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How to obtain Pt(iv) complexes suitable for conjugation to nanovectors from the oxidation of [PtCl(terpyridine)]⁺