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1.
Chemistry ; 30(15): e202304050, 2024 Mar 12.
Article in English | MEDLINE | ID: mdl-38197477

ABSTRACT

A low pKa (5.2), high polarizable volume (3.8 Å), and proneness to oxidation under ambient conditions make selenocysteine (Sec, U) a unique, natural reactive handle present in most organisms across all domains of life. Sec modification still has untapped potential for site-selective protein modification and probing. Herein we demonstrate the use of a cyclometalated gold(III) compound, [Au(bnpy)Cl2 ], in the arylation of diselenides of biological significance, with a scope covering small molecule models, peptides, and proteins using a combination of multinuclear NMR (including 77 Se NMR), and LC-MS. Diphenyl diselenide (Ph-Se)2 and selenocystine, (Sec)2 , were used for reaction optimization. This approach allowed us to demonstrate that an excess of diselenide (Au/Se-Se) and an increasing water percentage in the reaction media enhance both the conversion and kinetics of the C-Se coupling reaction, a combination that makes the reaction biocompatible. The C-Se coupling reaction was also shown to happen for the diselenide analogue of the cyclic peptide vasopressin ((Se-Se)-AVP), and the Bos taurus glutathione peroxidase (GPx1) enzyme in ammonium acetate (2 mM, pH=7.0). The reaction mechanism, studied by DFT revealed a redox-based mechanism where the C-Se coupling is enabled by the reductive elimination of the cyclometalated Au(III) species into Au(I).


Subject(s)
Cystine/analogs & derivatives , Organoselenium Compounds , Selenium , Animals , Cattle , Gold/chemistry , Peptides , Glutathione Peroxidase/metabolism , Selenocysteine/chemistry
2.
Angew Chem Int Ed Engl ; 62(38): e202305759, 2023 09 18.
Article in English | MEDLINE | ID: mdl-37338105

ABSTRACT

Artificial metallo-nucleases (AMNs) are promising DNA damaging drug candidates. Here, we demonstrate how the 1,2,3-triazole linker produced by the Cu-catalysed azide-alkyne cycloaddition (CuAAC) reaction can be directed to build Cu-binding AMN scaffolds. We selected biologically inert reaction partners tris(azidomethyl)mesitylene and ethynyl-thiophene to develop TC-Thio, a bioactive C3 -symmetric ligand in which three thiophene-triazole moieties are positioned around a central mesitylene core. The ligand was characterised by X-ray crystallography and forms multinuclear CuII and CuI complexes identified by mass spectrometry and rationalised by density functional theory (DFT). Upon Cu coordination, CuII -TC-Thio becomes a potent DNA binding and cleaving agent. Mechanistic studies reveal DNA recognition occurs exclusively at the minor groove with subsequent oxidative damage promoted through a superoxide- and peroxide-dependent pathway. Single molecule imaging of DNA isolated from peripheral blood mononuclear cells shows that the complex has comparable activity to the clinical drug temozolomide, causing DNA damage that is recognised by a combination of base excision repair (BER) enzymes.


Subject(s)
Click Chemistry , Copper , Copper/chemistry , Leukocytes, Mononuclear/metabolism , Ligands , DNA/chemistry , Azides/chemistry
3.
J Inorg Biochem ; 229: 111731, 2022 04.
Article in English | MEDLINE | ID: mdl-35131616

ABSTRACT

Metal complexes studied to date under the framework of metalloglycomics belong to the M-NH3 general motif (polynuclear platinum compounds; Werner's complex), acting mainly as cationic hydrogen bonding species toward glycosaminoglycans (GAGs), an interaction termed metalloshielding. In this paper, we expand our studies to substitution-inert octahedral cobalt(III) and ruthenium(II) complexes bearing the non­hydrogen-donor ligand 2,2'-bipyridine (bpy). We identified by NMR spectroscopy that [Co(bpy)3]3+ binds to the highly sulfated synthetic pentasaccharide, Fondaparinux (FPX), while no major perturbations are found in the presence of [Ru(bpy)3]2+. This result is of significance as both coordination compounds have analogous 3D structures. Although weakly binding to the model GAG, [Ru(bpy)3]2+ completely inhibits the enzymatic cleavage of FPX by the bacterial heparinase II (HepII) enzyme, which is not observed for the Co(III) analog. This observation suggests a direct inhibition of HepII by the Ru compound, through a mechanism that is unrelated to metalloshielding.


Subject(s)
2,2'-Dipyridyl/chemistry , Cobalt/chemistry , Coordination Complexes/chemistry , Ruthenium Compounds/chemistry , Fondaparinux/chemistry , Glycosaminoglycans/chemistry , Humans , Hydrogen Bonding , Ligands , Magnetic Resonance Spectroscopy/methods , Organometallic Compounds/chemistry , Polysaccharide-Lyases/chemistry , Ruthenium/chemistry
4.
Angew Chem Int Ed Engl ; 60(31): 17123-17130, 2021 07 26.
Article in English | MEDLINE | ID: mdl-34105220

ABSTRACT

Werner's Complex, as a cationic coordination complex (CCC), has hitherto unappreciated biological properties derived from its binding affinity to highly anionic biomolecules such as glycosaminoglycans (GAGs) and nucleic acids. Competitive inhibitor and spectroscopic assays confirm the high affinity to GAGs heparin, heparan sulfate (HS), and its pentasaccharide mimetic Fondaparinux (FPX). Functional consequences of this affinity include inhibition of FPX cleavage by bacterial heparinase and mammalian heparanase enzymes with inhibition of cellular invasion and migration. Werner's Complex is a very efficient condensing agent for DNA and tRNA. In proof-of-principle for translational implications, it is demonstrated to display antiviral activity against human cytomegalovirus (HCMV) at micromolar concentrations with promising selectivity. Exploitation of non-covalent hydrogen-bonding and electrostatic interactions has motivated the unprecedented discovery of these properties, opening new avenues of research for this iconic compound.


Subject(s)
Antiviral Agents/pharmacology , Coordination Complexes/pharmacology , Cytomegalovirus/drug effects , Fondaparinux/antagonists & inhibitors , Glycosaminoglycans/pharmacology , Antiviral Agents/chemistry , Coordination Complexes/chemistry , Glycosaminoglycans/chemistry , Humans , Microbial Sensitivity Tests
5.
Sci Rep ; 11(1): 4953, 2021 03 02.
Article in English | MEDLINE | ID: mdl-33654123

ABSTRACT

Invasion of periodontal tissues by Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans can be associated with aggressive forms of periodontitis. Oleoresins from different copaifera species and their compounds display various pharmacological properties. The present study evaluates the antibacterial and antivirulence activity of oleoresins obtained from different copaifera species and of ten isolated compounds against two causative agents of periodontitis. The following assays were performed: determination of the minimum inhibitory concentration (MIC), determination of the minimum bactericidal concentration (MBC), and determination of the antibiofilm activity by inhibition of biofilm formation and biofilm eradication tests. The antivirulence activity was assessed by hemagglutination, P. gingivalis Arg-X and Lis-X cysteine protease inhibition assay, and A. actinomycetemcomitans leukotoxin inhibition assay. The MIC and MBC of the oleoresins and isolated compounds 1, 2, and 3 ranged from 1.59 to 50 µg/mL against P. gingivalis (ATCC 33277) and clinical isolates and from 6.25 to 400 µg/mL against A. actinomycetemcomitans (ATCC 43717) and clinical isolates. About the antibiofilm activity, the oleoresins and isolated compounds 1, 2, and 3 inhibited biofilm formation by at least 50% and eradicated pre-formed P. gingivalis and A. actinomycetemcomitans biofilms in the monospecies and multispecies modes. A promising activity concerning cysteine protease and leucotoxin inhibition was also evident. In addition, molecular docking analysis was performed. The investigated oleoresins and their compounds may play an important role in the search for novel sources of agents that can act against periodontal pathogens.


Subject(s)
Aggregatibacter actinomycetemcomitans/physiology , Anti-Bacterial Agents/pharmacology , Biofilms/drug effects , Fabaceae/chemistry , Plant Extracts/pharmacology , Porphyromonas gingivalis/physiology , Anti-Bacterial Agents/chemistry , Biofilms/growth & development , Microbial Sensitivity Tests , Periodontitis/drug therapy , Periodontitis/microbiology , Plant Extracts/chemistry
6.
Dalton Trans ; 49(45): 16004-16033, 2020 Nov 25.
Article in English | MEDLINE | ID: mdl-33030464

ABSTRACT

In light of the Covid-19 outbreak, this review brings together historical and current literature efforts towards the development of antiviral metallodrugs. Classical compounds such as CTC-96 and auranofin are discussed in depth, as pillars for future metallodrug development. From the recent literature, both cell-based results and biophysical assays against potential viral biomolecule targets are summarized here. The comprehension of the biomolecular targets and their interactions with coordination compounds are emphasized as fundamental strategies that will foment further development of metal-based antivirals. We also discuss other possible and unexplored methods for unveiling metallodrug interactions with biomolecules related to viral replication and highlight the specific challenges involved in the development of antiviral metallodrugs.


Subject(s)
Antiviral Agents/therapeutic use , Betacoronavirus , Coordination Complexes/therapeutic use , Coronavirus Infections/drug therapy , Organometallic Compounds/therapeutic use , Pneumonia, Viral/drug therapy , Animals , Antiviral Agents/pharmacology , COVID-19 , Coordination Complexes/pharmacology , Coronavirus Infections/epidemiology , Disease Outbreaks , Humans , Organometallic Compounds/pharmacology , Pandemics , Pneumonia, Viral/epidemiology , SARS-CoV-2
7.
Dalton Trans ; 49(45): 16319-16328, 2020 Nov 25.
Article in English | MEDLINE | ID: mdl-32432260

ABSTRACT

Gold(i)-phosphine "auranofin-like" compounds have been extensively explored as anticancer agents in the past decade. Although potent cytotoxic agents, the lack of selectivity towards tumorigenic vs. non-tumorigenic cell lines often hinders further application. Here we explore the cytotoxic effects of a series of (R3P)AuL compounds, evaluating both the effect of the basicity and bulkiness of the carrier phosphine (R = Et or Cy), and the leaving group L (Cl-vs. dmap). [Au(dmap)(Et3P)]+ had an IC50 of 0.32 µM against the CEM cell line, with good selectivity in relation to HUVEC. Flow cytometry indicates reduced G1 population and slight accumulation in G2, as opposed to auranofin, which induces a high population of cells with fragmented DNA. Protein expression profile sets [Au(dmap)(Et3P)]+ further apart from auranofin, with proteolytic degradation of caspase-3 and poly(ADP-ribose)-polymerase (PARP), DNA strand-break induced phosphorylation of Chk2 Thr68 and increased p53 ser15 phosphorylation. The cytoxicity and observable biological effects correlate directly with the reactivity trend observed when using the series of gold(i)-phosphine compounds for targeting a model zinc finger, Sp1 ZnF3.


Subject(s)
Coordination Complexes/chemistry , Coordination Complexes/pharmacology , Gold/chemistry , Phosphines/chemistry , Precursor Cell Lymphoblastic Leukemia-Lymphoma/pathology , Zinc Fingers , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Humans , Phosphorylation/drug effects
8.
J Inorg Biochem ; 187: 85-96, 2018 10.
Article in English | MEDLINE | ID: mdl-30081333

ABSTRACT

The bis-(1,10-phenanthroline)copper(I) complex, [Cu(I)(phen)2]+, was the first copper-based artificial nuclease reported in the literature. The biological and ligand-like properties of sulfonamides make them good candidates for fine-tuning the reactivity of the [Cu(phen)2] motif with biomolecules. In this context, we developed three novel copper(II) complexes containing the sulfonamides sulfameter (smtrH) and sulfadimethoxine (sdmxH) and (N^N)-bidentate ligands (2,2'-biyridine or 1,10-phenantroline). The compounds were characterized by chemical and spectroscopic techniques and single-crystal X-ray crystallography. When targeting plasmid DNA, the phen-containing compounds [Cu(smtr-)2(phen)] (1) and [Cu(sdmx-)2(phen)] (2) demonstrated nuclease activity even in the absence of reducing agents. Addition of ascorbic acid resulted in a complete cleavage of DNA by 1 and 2 at concentrations higher than 10 µM. Experiments designed to evaluate the copper intermediates involved in the nuclease effect after reaction with ascorbic acid identified at least the [Cu(I)(N^N)2]+, [Cu(I)(sulfa)(N^N)]+ and [Cu(I)(sulfa)2]+ species. The compounds interact with DNA via groove binding and intercalation as verified by fluorescence spectroscopy, circular dichroism (CD) and molecular docking. The magnitude and preferred mode of binding are dependent on the nature of both N^N ligand and the sulfonamide. The potent nuclease activity of compounds 1 and 2 are well correlated with their antiproliferative and anti-M. tuberculosis profiles. The results presented here demonstrated the potential for further development of copper(II)-sulfonamide-(N^N) complexes as multipurpose metallodrugs.


Subject(s)
Antitubercular Agents , Cell Proliferation/drug effects , Coordination Complexes , Copper , Deoxyribonucleases , Mycobacterium tuberculosis/growth & development , Sulfonamides , Antitubercular Agents/chemical synthesis , Antitubercular Agents/chemistry , Antitubercular Agents/pharmacology , Coordination Complexes/chemical synthesis , Coordination Complexes/chemistry , Coordination Complexes/pharmacology , Copper/chemistry , Copper/pharmacology , DNA Cleavage/drug effects , Deoxyribonucleases/chemical synthesis , Deoxyribonucleases/chemistry , Deoxyribonucleases/pharmacology , Humans , K562 Cells , MCF-7 Cells , Molecular Docking Simulation , Sulfonamides/chemistry , Sulfonamides/pharmacology
9.
Angew Chem Int Ed Engl ; 57(30): 9305-9309, 2018 07 20.
Article in English | MEDLINE | ID: mdl-29870126

ABSTRACT

Reaction of the Au-C N chelate [Au(bnpy)Cl2 ] with the full-length zinc finger (ZnF; ZnCys3 His) of HIV nucleocapsid protein NCp7 results in C-S aryl transfer from the AuIII organometallic species to a cysteine of the ZnF. The reaction is general and occurs even for finger 3 of the transcription factor Sp1, containing a ZnCys2 His2 coordination sphere. This reaction is the first demonstration of group transfer from a coordination compound to biologically important zinc fingers, and is especially noteworthy for the ZnCys2 His2 transcription factors. The work expands the corpus of organometallic species which can efficiently modify biomolecules through C-atom transfer. The electronic features of the gold compound leading to this unexpected reaction were explored by X-ray absorption spectroscopy.


Subject(s)
CYS2-HIS2 Zinc Fingers , Carbon/chemistry , Gold/chemistry , HIV/chemistry , Nucleocapsid Proteins/chemistry , Sulfur/chemistry , Catalysis , Molecular Structure
10.
Inorg Chem ; 56(20): 12308-12318, 2017 Oct 16.
Article in English | MEDLINE | ID: mdl-28937773

ABSTRACT

In this work, we examined a series of thiophilic Au(I) compounds based on [Au(L)(PR3)] (L = Cl-, 4-dimethylaminopyridine (dmap); R= ethyl (Et), cyclohexyl (Cy)) for chemoselective auration of the C-terminal HIV nucleocapsid protein NCp7 F2 and the "full" HIV NCp7 (NC, zinc finger (ZnF)) as probes of nucleocapsid topography. The choice of phosphine allowed electronic and steric effects to be considered. The use of the heterocycle "leaving group" allowed us to study the effect of possible π-stacking with the essential tryptophan residue of NC on the reactivity and selectivity, mimicking the naturally occurring interaction between the zinc finger and nucleic acids. We also examined for comparison the "standard" gold-phosphine compound auranofin, which contains an S-bound glucose coordinated to the {Au(PEt3)} moiety. Both the nature of the phosphine and the nature of L affect the reactivity with the C-terminal NCp7 F2 and the "full" NC. 31P NMR spectroscopy showed the formation of long-lived {Au(PR3)}-ZnF species in all cases, but in the case of NCp7 F2, a selective interaction in the presence of the dmap ligand was observed. In the case of auranofin, an unusual Au-His (rather than Au-Cys) coordination was indicated on NC. The overall results suggest that it is useful to consider three aspects of zinc finger structure in considering the profile of chemical reactivity: (i) the zinc-bound cysteines as primary nucleophiles; (ii) the zinc-bound histidine as a "spectator" ligand; and (iii) ancillary groups not bound to Zn but essential for ZnF function such as the essential tryptophan in NCp7 F2 and NC. Modification of fully functional NC zinc finger by the Cy3P-containing species confirmed the inhibition of the NC-SL2 DNA interaction, as evaluated by fluorescence polarization.

11.
Angew Chem Int Ed Engl ; 56(16): 4464-4467, 2017 04 10.
Article in English | MEDLINE | ID: mdl-28319298

ABSTRACT

Traveling wave ion mobility (TWIM) mass spectrometry (MS) is a powerful method for the structural and conformational analysis of proteins and peptides, enabling the differentiation of isomeric peptides (or proteins) that have the same sequence but are modified at different residues. In this study, the TWIM-MS technique was used to separate isomeric AuI metallopeptide ions that were formed by ZnII displacement from the parent zinc fingers (ZFs). The synthetic gold finger peptides were derived from the C-terminus of the HIV nucleocapsid p7 protein (NCp7-F2) and finger 3 of the Sp1 transcription factor (Sp1-F3). TWIM-MS enabled the acquisition of distinct product ion spectra for each isomer, clearly indicating the binding sites for the major conformers in the presence of multiple coordination possibilities. Collision cross-section measurements showed that the aurated peptide has a slightly more compact structure than the parent zinc compound NCp7-F2, which showed only one conformation.

12.
Dalton Trans ; 45(21): 8712-6, 2016 Jun 07.
Article in English | MEDLINE | ID: mdl-27171123

ABSTRACT

cis-DDP presents reactivity towards the transcription factor Sp1-F3, as opposed to previous observations for Sp1-F2. Replacing the ammine ligands with the chelating ethylenediamine increases the reactivity giving a unique dinuclear {Pt(en)}2-bis(cysteine)-bridged product, confirmed by study of the binding sequence ACPECP.


Subject(s)
Coordination Complexes/chemistry , Platinum/chemistry , Sp1 Transcription Factor/chemistry , Amino Acid Sequence , Coordination Complexes/metabolism , Humans , Isomerism , Magnetic Resonance Spectroscopy , Mass Spectrometry , Protein Binding , Sp1 Transcription Factor/metabolism , Zinc Fingers
13.
Spectrochim Acta A Mol Biomol Spectrosc ; 122: 209-15, 2014 Mar 25.
Article in English | MEDLINE | ID: mdl-24316534

ABSTRACT

A new platinum(II) complex with the amino acid L-tryptophan (trp), named Pt-trp, was synthesized and characterized. Elemental, thermogravimetric and ESI-QTOF mass spectrometric analyses led to the composition [Pt(C11H11N2O2)2]⋅6H2O. Infrared spectroscopic data indicate the coordination of trp to Pt(II) through the oxygen of the carboxylate group and also through the nitrogen atom of the amino group. The (13)C CP/MAS NMR spectroscopic data confirm coordination through the oxygen atom of the carboxylate group, while the (15)N CP/MAS NMR data confirm coordination of the nitrogen of the NH2 group to the metal. Density functional theory (DFT) studies were applied to evaluate the cis and trans coordination modes of trp to platinum(II). The trans isomer was shown to be energetically more stable than the cis one. The Pt-trp complex was evaluated as a cytotoxic agent against SK-Mel 103 (human melanoma) and Panc-1 (human pancreatic carcinoma) cell lines. The complex was shown to be cytotoxic over the considered cells.


Subject(s)
Biological Assay/methods , Models, Molecular , Platinum/pharmacology , Quantum Theory , Tryptophan/chemical synthesis , Tryptophan/pharmacology , 3T3 Cells , Animals , Carbon-13 Magnetic Resonance Spectroscopy , Cell Death/drug effects , Cell Line, Tumor , Cell Survival/drug effects , Humans , Mass Spectrometry , Mice , Molecular Conformation , Platinum/chemistry , Spectrophotometry, Infrared , Thermogravimetry , Tryptophan/chemistry , Vibration
14.
Inorg Chem ; 52(19): 11280-7, 2013 Oct 07.
Article in English | MEDLINE | ID: mdl-24063530

ABSTRACT

The syntheses and the characterization by chemical analysis, (1)H and (31)P NMR spectroscopy, and mass spectrometry of a series of linear triphenylphosphine gold(I) complexes with substituted N-heterocycle ligands (L), [(PPh3)Au(I)(L)](+), is reported. The reaction of [(PPh3)Au(L)](+) (L = Cl(-) or substituted N- heterocyclic pyridine) with the C-terminal (Cys3His) finger of HIVNCp7 shows evidence by mass spectrometry (ESI-MS) and (31)P NMR spectroscopy of a long-lived {(PPh3)Au}-S-peptide species resulting from displacement of the chloride or pyridine ligand by zinc-bound cysteine with concomitant displacement of Zn(2+). In contrast, reactions with the Cys2His2 finger-3 of the Sp1 transcription factor shows significantly reduced intensities of {(PPh3)Au} adducts. The results suggest the possibility of systematic (electronic, steric) variations of "carrier" group PR3 and "leaving" group L as well as the nature of the zinc finger in modulation of biological activity. The cytotoxicity, cell cycle signaling effects, and cellular accumulation of the series are also reported. All compounds display cytotoxicity in the micromolar range upon 96 h continuous exposure to human tumor cells. The results may have relevance for the reported inhibition of viral load in simian virus by the gold(I) drug auranofin.


Subject(s)
Gold/chemistry , Heterocyclic Compounds/chemistry , Phosphines/chemistry , Zinc Fingers , gag Gene Products, Human Immunodeficiency Virus/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Circular Dichroism , Gold/pharmacology , Heterocyclic Compounds/pharmacology , Humans , Inhibitory Concentration 50 , Ligands , Magnetic Resonance Spectroscopy , Phosphines/pharmacology , Spectrometry, Mass, Electrospray Ionization , gag Gene Products, Human Immunodeficiency Virus/metabolism
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