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Multinuclear complexes are metal compounds featured by adjacent bound metal centers that can lead to unconventional reactivity. Some M2L4-type paddlewheel dinuclear complexes with monoanionic bridging ligands feature promising properties, including therapeutic ones. Molybdenum has been studied for the formation of multiple-bonded M2+ compounds due to their unique scaffold, redox, and spectroscopic properties as well as for applications in several fields including catalysis and biology. These latter are much less explored and only sporadic studies have been carried out. Here, a series of four dimolybdenum (II,II) carboxylate paddlewheel complexes were synthesized using different Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) as ligands. The reaction of (NH4)5[Mo2Cl9]·H2O with the selected NSAIDs in methanol produced the complexes Mo2(µ-O2CR)4 where RCO2 is ibuprofen (1), naproxen (2), aspirin (3) and indomethacin (4). The products were obtained in good yields and extensively characterized with integrated techniques. Stability and solution behaviour were studied using a mixed experimental and computational approach. Finally, the biological activity of 1 and 3 (i.e. the most reactive and the most stable compounds of the series, respectively) was preliminarily assessed confirming the disassembling of the molecules in the biological milieu. Overall, some very interesting results emerged for these unconventional compounds from a mechanistic point of view.
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The synthetic scope of 3-arylated tetrazo[1,2-b]indazoles is reported based on a Pd-catalyzed Liebeskind-Srogl cross-coupling reaction followed by an N-cyclisation process. The reactivity of the nitrogen atoms was used to further diversify these N-rich polyaromatic tetrazo[1,2-b]indazoles in a panel of reactions (protonation, selective oxidation, metallations). Selective ortho-C-H activation/functionalization on the heterocycle was also demonstrated with three transition metals (TM = Pd, Ir and Rh). The effects of all these molecular engineering strategies, particularly the N-modifications, on the optical and redox properties of the 3-arylated tetrazoindazoles were studied experimentally and theoretically. This study highlights the diversity of molecular structures and electronic properties offered by the tetrazo[1,2-b]indazole platform.
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Multiple medicinal strategies involve modifications of the structure of DNA or RNA, which disrupt their correct functioning. Metal complexes with medicinal effects, also known as metallodrugs, are among the agents intended specifically for the attack onto nucleosides. The diruthenium (II,III) and dirhodium (II,II) paddlewheel complexes constitute promising dual acting drugs due to their ability to release the therapeutically active bridging ligands upon their substitution by endogenous ligands. In this paper, we study the structure and the stability of the complexes formed by the diruthenium (II,III) and dirhodium (II,II) paddlewheel complexes coordinated in axial positions with the DNA/RNA nucleobases or base pairs, assuming the attainable metalation at all the accessible pyridyl nitrogens. Dirhodium complexes coordinate at the pyridyl nitrogens more strongly than the diruthenium complexes. On the other hand, we found that the diruthenium scaffold binds more selectively to nucleobase targets. Furthermore, we reveal a tighter coordination of diruthenium complex at the adenine-uracil base pair, compared to adenine-thymine, hence constituting a scarce instance of RNA-selectivity. We envision that the here reported computational outcomes may pace future experiments addressing the binding of diruthenium and dirhodium paddlewheel complexes at either single nucleobases or DNA/RNA fragments.
Assuntos
Pareamento de Bases , Complexos de Coordenação , DNA , RNA , Rutênio , DNA/química , RNA/química , Complexos de Coordenação/química , Rutênio/química , Ligantes , Modelos Moleculares , Ródio/químicaRESUMO
Metallodrugs are an important group of medicinal agents used for the treatment of various diseases ranging from cancers to viral, bacterial, and parasitic diseases. Their distinctive features include the availability of a metal centre, redox activity, as well as the ability to multitarget. Diruthenium paddlewheel complexes are an intensely developing group of metal scaffolds, which can securely coordinate bidentate xenobiotics and transport them to target tissues, releasing them by means of substitution reactions with biomolecular nucleophiles. It is of the utmost importance to gain a complete comprehension of which chemical reactions happen with them in physiological milieu to design novel drugs based on these bimetallic scaffolds. This review presents the data obtained in experiments and calculations, which clarify the chemistry these complexes undergo once administered in the proteic environment. This study demonstrates how diruthenium paddlewheel complexes may indeed embody a new paradigm in the design of metal-based drugs of dual-action by presenting and discussing the protein metalation by these complexes.
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Complexos de Coordenação , Proteínas , Rutênio , Complexos de Coordenação/química , Rutênio/química , Proteínas/química , Humanos , OxirreduçãoRESUMO
AS101 (Ammonium trichloro (dioxoethylene-O,O') tellurate) is an important hypervalent Te-based prodrug. Recently, we started a systematic investigation on AS101 with the aim to correlate its promising biological effects as a potent immunomodulator drug with multiple medicinal applications and its specific chemical properties. To date, a substantial agreement on the rapid conversion of the initial AS101 species into the corresponding TeOCl3- anion does exist, and this latter species is reputed as the pharmacologically active one. However, we realized that TeOCl3- could quickly undergo further steps of conversion in an aqueous medium, eventually producing the TeO2 species. Using a mixed experimental and theoretical investigation approach, we characterized the conversion process leading to TeO2 occurring both in pure water and in reference buffers at physiological-like pH. Our findings may offer a valuable "chemical tool" for a better description, interpretation -and optimization- of the mechanism of action of AS101 and Te-based compounds. This might be a starting point for improved AS101-based medicinal application.
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Pró-Fármacos , Pró-Fármacos/farmacologia , Pró-Fármacos/químicaRESUMO
Developing biocompatible nanocoatings is crucial for biomedical applications. Noble metal colloidal nanoparticles with biomolecular shells are thought to combine diverse chemical and optothermal functionalities with biocompatibility. Herein, we present nanoparticles with peptide hydrogel shells that feature an unusual combination of properties: the metal core possesses localized plasmon resonance, whereas a few-nanometer-thick shells open opportunities to employ their soft framework for loading and scaffolding. We demonstrate this concept with gold and silver nanoparticles capped by glutathione peptides stacked into parallel ß-sheets as they aggregate on the surface. A key role in the formation of the ordered structure is played by coinage metal(I) thiolates, i.e., Ag(I), Cu(I), and Au(I). The shell thickness can be controlled via the concentration of either metal ions or peptides. Theoretical modeling of the shell's molecular structure suggests that the thiolates have a similar conformation for all the metals and that the parallel ß-sheet-like structure is a kinetic product of the peptide aggregation. Using third-order nonlinear two-dimensional infrared spectroscopy, we revealed that the ordered secondary structure is similar to the bulk hydrogels of the coinage metal thiolates of glutathione, which also consist of aggregated stacked parallel ß-sheets. We expect that nanoparticles with hydrogel shells will be useful additions to the nanomaterial toolbox. The present method of nanogel coating can be applied to arbitrary surfaces where the initial deposition of the seed glutathione monolayer is possible.
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The targeting of human thioredoxin reductase is widely recognized to be crucially involved in the anticancer properties of several metallodrugs, including Au(I) complexes. In this study, the mechanism of reaction between a set of five N-heterocyclic carbene Au(I) complexes and models of the active Sec residue in human thioredoxin reductase was investigated by means of density functional theory approaches. The study was specifically addressed to the kinetics and thermodynamics of the tiled process by aiming at elucidating and explaining the differential inhibitory potency in this set of analogous Au(I) bis-carbene complexes. While the calculated free energy profile showed a substantially similar reactivity, we found that the binding of these Au(I) bis-carbene at the active CysSec dyad in the TrxR enzyme could be subjected to steric and orientational restraints, underlining both the approach of the bis-carbene scaffold and the attack of the selenol group at the metal center. A new and detailed mechanistic insight to the anticancer activity of these Au(I) organometallic complexes was thus provided by consolidating the TrxR targeting paradigm.
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Antineoplásicos , Complexos de Coordenação , Metano/análogos & derivados , Humanos , Selenocisteína , Tiorredoxina Dissulfeto Redutase/metabolismo , Antineoplásicos/farmacologia , Ouro/química , Complexos de Coordenação/químicaRESUMO
Ovarian cancer (OC) is a lethal gynecologic cancer in industrialized countries. Treatments for OC include the surgical removal and chemotherapy. In the last decades, improvements have been made in the surgery technologies, drug combinations and administration protocols, and in diagnosis. However, mortality from OC is still high owing to recurrences and insurgence of drug resistance. Accordingly, it is urgent the development of novel agents capable to effectively target OC. In this respect, tyrosine kinase inhibitors (TKIs) may play an important role. Most of TKIs developed and tested so far are organic. However, owing to their chemical versatility, also metals can be exploited to design selective and potent TKIs. We provide a short and easy-to-read overview on the main organic TKIs with a summary of those that entered clinical trials. Additionally, we describe the potential of metal-based TKIs, focusing on this overlooked family of compounds that may significantly contribute towards the concept of precision-medicine.
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Antineoplásicos , Neoplasias Ovarianas , Feminino , Humanos , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Neoplasias Ovarianas/tratamento farmacológicoRESUMO
Auranofin, a gold(I)-based complex, is under clinical trials for application as an anticancer agent for the treatment of nonsmall-cell lung cancer and ovarian cancer. In the past years, different derivatives have been developed, modifying gold linear ligands in the search for new gold complexes endowed with a better pharmacological profile. Recently, a panel of four gold(I) complexes, inspired by the clinically established compound auranofin, was reported by our research group. As described, all compounds possess an [Au{P(OMe)3}]+ cationic moiety, in which the triethylphosphine of the parent compound auranofin was replaced with an oxygen-rich trimethylphosphite ligand. The gold(I) linear coordination geometry was complemented by Cl-, Br-, I-, and the auranofin-like thioglucose tetraacetate ligand. As previously reported, despite their close similarity to auranofin, the panel compounds exhibited some peculiar and distinctive features, such as lower log P values which can induce relevant differences in the overall pharmacokinetic profiles. To get better insight into the P-Au strength and stability, an extensive study was carried out for relevant biological models, including three different vasopressin peptide analogues and cysteine, using 31P NMR and LC-ESI-MS. A DFT computational study was also carried out for a better understanding of the theoretical fundamentals of the disclosed differences with regard to triethylphosphine parent compounds.
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Antineoplásicos , Auranofina , Auranofina/farmacologia , Auranofina/química , Ligantes , Ouro/química , Antineoplásicos/farmacologia , Espectroscopia de Ressonância MagnéticaRESUMO
Recently, the well-characterized metallodrug auranofin has been demonstrated to restore the penicillin and cephalosporin sensitivity in resistant bacterial strains via the inhibition of the NDM-1 beta-lactamase, which is operated via the Zn/Au substitution in its bimetallic core. The resulting unusual tetrahedral coordination of the two ions was investigated via the density functional theory calculations. By assessing several charge and multiplicity schemes, coupled with on/off constraining the positions of the coordinating residues, it was demonstrated that the experimental X-ray structure of the gold-bound NDM-1 is consistent with either Au(I)-Au(I) or Au(II)-Au(II) bimetallic moieties. The presented results suggest that the most probable mechanism for the auranofin-based Zn/Au exchange in NDM-1 includes the early formation of the Au(I)-Au(I) system, superseded by oxidation yielding the Au(II)-Au(II) species bearing the highest resemblance to the X-ray structure.
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The straightforward access to a new class of aza-polyaromatics is reported. Starting from readily available fluorinated s-tetrazine, a cyclization process with azide leads to the formation of an unprecedented tetrazo[1,2-b]indazole or a bis-tetrazo[1,2-b]indazole (cis and trans conformers). Based on the new nitrogen core, further N-directed palladium-catalyzed ortho-C-H bond functionalization allows the introduction of halides or acetates. The physicochemical properties of these compounds were studied by a joint experimental/theoretical approach. The tetrazo[1,2-b]indazoles display solid-state π-stacking, low reduction potential, absorption in the visible range up to the near-infrared, and intense fluorescence, depending on the molecular structure.
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Inorganic drugs are capable of tight interactions with proteins through coordination towards aminoacidic residues, and this feature is recognized as a key aspect for their pharmacological action. However, the "protein metalation process" is exploitable for solving the phase problem and structural resolution. In fact, the use of inorganic drugs bearing specific metal centers and ligands capable to drive the binding towards the desired portions of the protein target could represent a very intriguing and fruitful strategy. In this context, a theoretical approach may further contribute to solve protein structures and their refinement. Here, we delineate the main features of a reliable experimental-theoretical integrated approach, based on the use of metallodrugs, for protein structure solving.
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Metais , Proteínas , Proteínas/química , Metais/químicaRESUMO
Recently, dirhodium and diruthenium paddlewheel complexes have drawn attention as perspective anticancer drugs. In this study, the kinetics of reaction of typical paddlewheel scaffolds Rh2(µ-O2CCH3)4(H2O)2, Ru2(µ-O2CCH3)4(H2O)Cl, and [Ru2(µ-O2CCH3)4(HO)Cl]- with protein nucleophiles were investigated by means of the density functional theory. The substitution of axial ligandsâwater and chlorideâby the models of protein residue side chains was analyzed, revealing the binding selectivity displayed by these paddlewheel metal scaffolds. The substitution of water is under a thermodynamic control, in which, although the Arg, Cys-, and Sec- residues are the most favorable, their binding is expected to be scarcely selective in a biological context. On the other hand, the replacement of the axial water with a more stable hydroxo ligand induces the chloride substitution in diRu complexes, which also targets Arg, Cys-, and Sec-, although with a moderately higher activation barrier for any examined protein residue. Additionally, the carried out characterization of the geometrical parameters of the transition states permitted determination of the impact of an increased steric hindrance of diRh and diRu complexes on their protein site selectivity. This study corroborates the idea of the substitution of the acetate ligands with biologically active, but more hindering, carboxylate ligands, in order to yield dual acting metallodrugs. This study allows us to assume that the delivery of diRu paddlewheel complexes in their monoanionic form [Ru2(µ-O2CR)4(OH)Cl]- decorated by the bulky substituents R may constitute an approach to augment the selectivity toward anticancer targets, such as TrxR in tumor cells, although under the condition that such a selectivity is operative only in high pH conditions.
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Antineoplásicos , Cloretos , Antineoplásicos/química , Antineoplásicos/farmacologia , Cinética , Ligantes , ÁguaRESUMO
The identification of novel therapeutics against the pandemic SARS-CoV-2 infection is an indispensable new address of current scientific research. In the search for anti-SARS-CoV-2 agents as alternatives to the vaccine or immune therapeutics whose efficacy naturally degrades with the occurrence of new variants, the salts of Bi3+ have been found to decrease the activity of the Zn2+-dependent non-structural protein 13 (nsp13) helicase, a key component of the SARS-CoV-2 molecular tool kit. Here, we present a multilevel computational investigation based on the articulation of DFT calculations, classical MD simulations, and MIF analyses, focused on the examination of the effects of Bi3+/Zn2+ exchange on the structure and molecular interaction features of the nsp13 protein. Our calculations confirmed that Bi3+ ions can replace Zn2+ in the zinc-finger metal centers and cause slight but appreciable structural modifications in the zinc-binding domain of nsp13. Nevertheless, by employing an in-house-developed ATOMIF tool, we evidenced that such a Bi3+/Zn2+ exchange may decrease the extension of a specific hydrophobic portion of nsp13, responsible for the interaction with the nsp12 protein. The present study provides for a detailed, atomistic insight into the potential anti-SARS-CoV-2 activity of Bi3+ and, more generally, evidences the hampering of the nsp13-nsp12 interaction as a plausible therapeutic strategy.
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COVID-19 , SARS-CoV-2 , Bismuto , Humanos , Íons , RNA Helicases/química , RNA Helicases/metabolismo , Sais , ZincoRESUMO
Ammonium trichloro (dioxoethylene-O,O') tellurate (AS101) is a potent immunomodulator prodrug that, in recent years, entered various clinical trials and was tested for a variety of potential therapeutic applications. It has been demonstrated that AS101 quickly activates in aqueous milieu, producing TeOCl3-, which likely represents the pharmacologically active species. Here we report on the study of the activation process of AS101 and of two its analogues. After the synthesis and characterization of AS101 and its derivatives, we have carried out a comparative study through a combined experimental and computational analysis. Based on the obtained results, we describe here, for the first time, the detailed reaction that AS101 and its bromido- and iodido-replaced analogues undergo in presence of water, allowing the conversion of the original molecule to the likely true pharmacophore. Interestingly, moving down in the halogens' group we observed a higher tendency to react, attributable to the ligands' effect. The chemical and mechanistic implications of these meaningful differences are discussed.
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Pró-Fármacos , Adjuvantes Imunológicos/uso terapêutico , Etilenos , Ligantes , Pró-Fármacos/farmacologia , TelúrioRESUMO
Auranofin (AF, hereafter) is an orally administered chrysotherapeutic agent approved for the treatment of rheumatoid arthritis that is being repurposed for various indications including bacterial infections. Its likely mode of action involves the impairment of the TrxR system through the binding of the pharmacophoric cation [AuPEt3]+. Accordingly, a reliable strategy to expand the medicinal profile of AF is the replacement of the thiosugar moiety with different ligands. Herein, we aimed to prepare the AF analogue bearing the acetylcysteine ligand (AF-AcCys, hereafter) and characterize its anti-staphylococcal activity. Biological studies revealed that AF-AcCys retains an antibacterial effect superimposable with that of AF against Staphylococcus aureus, whereas it is about 20 times less effective against Staphylococcus epidermidis. Bioinorganic studies confirmed that upon incubation with human serum albumin, AF-AcCys, similarly to AF, induced protein metalation through the [AuPEt3]+ fragment. Additionally, AF-AcCys appeared capable of binding the dodecapeptide Ac-SGGDILQSGCUG-NH2, corresponding to the tryptic C-terminal fragment (488-499) of hTrxR. To shed light on the pharmacological differences between AF and AF-AcCys, we carried out a comparative experimental stability study and a theoretical estimation of bond dissociation energies, unveiling the higher strength of the Au-S bond in AF-AcCys. From the results, it emerged that the lower lipophilicity of AF-AcCys with respect to AF could be a key feature for its different antibacterial activity. The differences and similarities between AF and AF-AcCys are discussed, alongside the opportunities and consequences that chemical structure modifications imply.
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Auranofina , Infecções Estafilocócicas , Acetilcisteína/farmacologia , Acetilcisteína/uso terapêutico , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Auranofina/química , Auranofina/farmacologia , Humanos , Infecções Estafilocócicas/tratamento farmacológico , Staphylococcus aureusRESUMO
Arsenoplatin-1 (AP-1) is a dual-action anticancer metallodrug with a promising pharmacological profile that features the simultaneous presence of a cisplatin-like center and an arsenite center. We investigated its interactions with proteins through a joint experimental and theoretical approach. The reactivity of AP-1 with a variety of proteins, including carbonic anhydrase (CA), superoxide dismutase (SOD), myoglobin (Mb), glyceraldehyde 3-phosphate dehydrogenase (GAPDH), and human serum albumin (HSA), was analyzed by means of electrospray ionization mass spectrometry (ESI MS) measurements. In accordance with previous observations, ESI MS experiments revealed that the obtained metallodrug-protein adducts originated from the binding of the [(AP-1)-Cl]+ fragment to accessible protein residues. Remarkably, in two cases, i.e., Mb and GAPDH, the formation of a bound metallic fragment that lacked the arsenic center was highlighted. The reactions of AP-1 with various nucleophiles side chains of neutral histidine, methionine, cysteine, and selenocysteine, in neutral form as well as cysteine and selenocysteine in anionic form, were subsequently analyzed through a computational approach. We found that the aquation of AP-1 is energetically disfavored, with a reaction free energy of +19.2 kcal/mol demonstrating that AP-1 presumably attacks its biological targets through the exchange of the chloride ligand. The theoretical analysis of thermodynamics and kinetics for the ligand-exchange processes of AP-1 with His, Met, Cys, Sec, Cys-, and Sec- side chain models unveils that only neutral histidine and deprotonated cysteine and selenocysteine are able to effectively replace the chloride ligand in AP-1.
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Trióxido de Arsênio/análogos & derivados , Cisplatino/análogos & derivadosRESUMO
The structure and the reactivity of four half-sandwich metal complexes of RuII, OsII, RhIII, and IrIII were investigated by means of density functional theory approaches. These piano-stool complexes, grouped in cym-bound complexes, RuII(cym)(dmb)Cl2, 1, and OsII(cym)(dmb)Cl2, 2, and Cp*-bound complexes, RhIII(Cp*)(dmb)Cl2, 3, and IrIII(Cp*)(dmb)Cl2, 4, with cym = η6-p-cymene, Cp* = η5-pentamethylcyclopentadienyl, and dmb = 1,3-dimethylbenzimidazol-2-ylidene, were recently proposed as anticancer metallodrugs that preferably target Cys- or Sec-containing proteins. Thus, density functional theory calculations were performed here to characterize in detail the thermodynamics and the kinetics underlining the targeting of these metallodrugs at either neutral or anionic Cys and Sec side chains. Calculations evidenced that all these complexes preferably target at Cys or Sec via chloro exchange, although cym-bound and Cp*-bound complexes resulted to be more prone to bind at neutral or anionic forms, respectively, of these soft protein sites. Further decomposition analyses of the activation free energies for the reaction between 1-4 complexes and either Cys or Sec, paralleled with the comparison among the optimized transition-state structures, allowed us to spotlight the significant role played by solvation in determining the overall reactivity and selectivity expected for these prototypical metallodrugs.
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Owing to the growing hardware capabilities and the enhancing efficacy of computational methodologies, computational chemistry approaches have constantly become more important in the development of novel anticancer metallodrugs. Besides traditional Pt-based drugs, inorganic and organometallic complexes of other transition metals are showing increasing potential in the treatment of cancer. Among them, Au(I)- and Au(III)-based compounds are promising candidates due to the strong affinity of Au(I) cations to cysteine and selenocysteine side chains of the protein residues and to Au(III) complexes being more labile and prone to the reduction to either Au(I) or Au(0) in the physiological milieu. A correct prediction of metal complexes' properties and of their bonding interactions with potential ligands requires QM computations, usually at the ab initio or DFT level. However, MM, MD, and docking approaches can also give useful information on their binding site on large biomolecular targets, such as proteins or DNA, provided a careful parametrization of the metal force field is employed. In this review, we provide an overview of the recent computational studies of Au(I) and Au(III) antitumor compounds and of their interactions with biomolecular targets, such as sulfur- and selenium-containing enzymes, like glutathione reductases, glutathione peroxidase, glutathione-S-transferase, cysteine protease, thioredoxin reductase and poly (ADP-ribose) polymerase 1.
Assuntos
Antineoplásicos , Complexos de Coordenação , Ouro , Proteínas de Neoplasias/antagonistas & inibidores , Neoplasias , Selenoproteínas/antagonistas & inibidores , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Complexos de Coordenação/química , Complexos de Coordenação/farmacocinética , Complexos de Coordenação/uso terapêutico , Ouro/química , Ouro/farmacocinética , Ouro/uso terapêutico , Humanos , Proteínas de Neoplasias/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Selenoproteínas/metabolismoRESUMO
Metal-based drugs represent a rich source of chemical substances of potential interest for the treatment of COVID-19. To this end, we have developed a small but representative panel of nine metal compounds, including both synthesized and commercially available complexes, suitable for medical application and tested them in vitro against the SARS-CoV-2 virus. The screening revealed that three compounds from the panel, i.e., the organogold(III) compound Aubipyc, the ruthenium(III) complex KP1019, and antimony trichloride (SbCl3), are endowed with notable antiviral properties and an acceptable cytotoxicity profile. These initial findings prompted us to perform a computational study to unveil the likely molecular basis of their antiviral actions. Calculations evidenced that the metalation of nucleophile sites in SARS-CoV-2 proteins or nucleobase strands, induced by Aubipyc, SbCl3, and KP1019, is likely to occur. Remarkably, we found that only the deprotonated forms of Cys and Sec residues can react favorably with these metallodrugs. The mechanistic implications of these findings are discussed.