Short Communication
Cluster dirhenium(III) cis-dicarboxylates with α-amino acids ligands as mighty selective G4s binders

https://doi.org/10.1016/j.jinorgbio.2021.111605Get rights and content

Highlights

  • The synthesis of dirhenium(III) complex compounds with Asp, Glu, Phe, Tyr is presented.

  • Fluorescence resonance energy transfer (FRET).

  • FRET – melting analysis showed strong stabilization activity with some G4 quadruplexes.

  • Specific binding to ckit1 and HTelo22 quadruplexes is shown.

  • Possible example of unique mechanism of molecular DNA recognition is proposed.

Abstract

The synthesis of four dirhenium(III) cis-dicarboxylates with the α-amino acids residues Asp (I), Glu (II), Phe (III) and Tyr (IV) is presented. The G–quadruplex stabilization potential was evaluated by fluorescence resonance energy transfer – melting analysis. All derivatives show specific binding to c-kit1 quadruplex, while II and IV have also strong stabilization activity to HTelo21 quadruplex. At the same time, the compounds do not show any stabilization activity for ds26 DNA, which suggests unique mechanisms of molecular DNA recognition for these complexes.

Graphical abstract

The first experimental evidence about specific molecular DNA recognition of G-quadruplexes by the quadruple-bonding dirhenium(III) compounds: a new type of G-quartet stacking: π−π,δ stacking and a new chemical type of G4-binders.

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Introduction

Quadruple bond is a unique bond not found in any natural molecule. Although the chemistry and biochemistry of compounds containing Resingle bondRe quadruple bonds have not been investigated in great detail so far, they offer interesting perspectives due to the unprecedented coordination chemistry and antiradical properties revealed in experiments in vitro and in vivo [1]. Dinuclear rhenium(III) compounds belong to the class of d4-d4 dimers with σ2π4δ2 electronic configuration in the ground state. According to quantum chemical calculations, the order 4 of the metal-metal bond is reduced to 3.5 in the case of an electron capture [2]. Quadruple bond (δ-bond) can be formed only by transition metal atoms. The δ → δ* electron transition component of the Resingle bondRe quadruple bond has much less energy than the π → π* and the other electron transitions [2]. This is the reason for the absorption band appearing in the long-waved visible area of the electronic absorption spectrum and for the antiradical, antioxidant properties of the quadruple-bonded dirhenium(III) compounds [1]. The cluster formation stabilizes the unusual 3+ oxidation state of rhenium; the dinuclear fragment Re26+ with the quadruple metal-metal bond behaves as a single central atom of a complex with an overall coordination number of 10. Therefore, compounds with novel properties can be prepared by changing the ligands attached to the dinuclear Re26+ fragment. As a matter of fact, synthetic procedures have been set up to obtain dirhenium(III) derivatives: octahalogenides; dihalogenotetra-μ-carboxylates; trihalohenotri-μ-carboxylates; cis-tetrahalogenodi-μ-carboxylates and trans-tetrahalogenodi-μ-carboxylates dirhenium(III) derivatives [1]. On the other hand, cluster dirhenium(III) compounds have shown anticancer activity in cancer cells in vitro and in in vivo in tumor-bearing animals [1]. These compounds being supplied together with cisplatin showed synergistic or additive anticancer effect [3]. But investigations of the interaction of these compounds with G-quadruplexes have not been explored so far. Nevertheless, this kind of interactions could make impact to understanding of mechanism of their biological activity.

Together with anticancer and DNA-binding activity, dirhenium(III) clusters revealed mighty antiradical activity in vitro [1] and antioxidant activity in vivo [4]. For example, while the introduction of any usual antioxidant (containing π-conjugated system, π-antioxidant) to tumor-bearing animals led a 1,5–2-fold decrease in the intensity of the process of peroxide oxidation of lipids (POL, the process accompanying any pathological state), the administration of quadruple-bonded rhenium compound decreases the intensity of POL in 4 or more times. Dirhenium(III) complexes interact with proteins [5], have superoxide dismutase [6] and catalase [7] activity in vitro and activate the enzymatic defense system in vivo [4]. We believe that these mighty antioxidant properties leading to nephro-, hepato- protection, supporting of the red blood system and bone marrow processing [8] of the tumor-bearing animals may be the result not only of the antiradical properties of the quadruple bond, but also of the interaction of the dirhenium(III) compounds with some regulatory systems of the living organism, for example, with repetitive G-rich sequences found in telomeric DNA at the ends of eukaryotic chromosomes and in certain gene-promoter regions [9,10].

Further elaboration of the synthetic methods may offer the possibility to synthesize dirhenium(III) quadruple-bonded complexes with non-protein amino acids and to evaluate their anticancer activity [11,12]. The possibility to coordinate specific or “biologically active” ligands around the metal core is a typical strategy for the generation of new medicines [13,14] that permit to move from ‘dirty’ drugs, killing not only diseased cells, to more specific targeting. The design of dirhenium(III) compounds with highly specific ligands for defined targets in cancer cells can lead to less-toxic chemicals (more tolerant) for non-tumor cells, and can permit to exploit both the redox regulation potential of the cluster fragment and the specific coordination ability of a ligand.

G4s (G-quadruplex secondary structures) are non-canonical nucleic acid structures formed in guanine-rich sequences, in which four guanine bases hold together by Hoogsteen hydrogen bonds form a G-quartet, and then two or more G-quartets stack to form the G-quadruplex structure retaining sodium or potassium ions in a central core channel. These DNA structures are becoming important targets for small-molecule drugs, which can stabilize the G4 structure promoting selective downregulation of gene expression [9,10]. Despite essential advances in the development of G4-binders of organic nature or metal complexes of gold, nickel, zinc, copper, platinum and ruthenium [14,15], there is still plenty of work to do in order to find improved selective G4s binders. There has been increasing interest in the development of small metal-containing molecules that can selectively bind to G-quadruplex DNA structures [[14], [15], [16], [17]]. Also, it was shown earlier that protein amino acids incremented G4-binding of some potential binders [18,19].

All above encouraged us to synthesize new dirhenium(III) complexes with α-amino acids and to explore their interaction with G4 structures.

Section snippets

Reagents and materials

All reagents were obtained from commercial sources. 1H NMR spectra were recorded with a Mercury 400 spectrometer (VARIAN) operating at 300 MHz. UV–Vis spectra were recorded with a Cary 300 spectrophotometer. Fluorescence resonance energy transfer (FRET) analysis was performed on a PCR Stratagene Mx3005P instrument (Agilent Technologies) with excitation at 450–495 nm and detection at 515–545 nm. Readings were taken in the temperature range 25–95 °C (intervals of 0.5 °C). Each measurement was

Synthesis and characterization

The dirhenium(III) target compounds were synthesized according to the Scheme 1.

Despite the synthetic scheme of compounds of I-IV is the usual one for obtaining cluster dirhenium(III) compounds [21], the inclusion of the different α-amino acids required some peculiarities, concerning time, pH, ratio of components etc., which are described in the experimental section.

The characterization of ІІV by elemental analysis, UV–Vis, IR and 1H NMR spectra is presented in the experimental section. All the

Conclusions

We reported the synthesis of four dirhenium(III) cis-dicarboxylates with the α-aminoacids. The G–quadruplex stabilization potential was evaluated by fluorescence resonance energy transfer – melting analysis. All derivatives show specific binding to c-kit1 quadruplex, while II and IV have also strong stabilization activity to HTelo21 quadruplex. At the same time, the compounds do not show any stabilization activity for ds26 DNA, which suggests unique mechanisms of molecular DNA recognition for

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgments

This work is funded partly by the Ministry of Education and Science of Ukraine. We would like to thank the University of Valencia for the Atracció al Talent grant for professors N. and A. Shtemenko. This work was partly supported by Spanish MICINN and MEC and FEDER funds from the European Union (Project CTQ2016-78499-C6-1-R, CTQ2017-90852-REDC, Unidad de Excelencia María de Maeztu CEX2019-000919-M and NECTAR CA18202 COST Action). I. P. and S. B want to thank Generalitat Valenciana and MICINN

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