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1.
Chempluschem ; 88(11): e202300303, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37610058

RESUMO

A series of four binuclear complexes of general formula [(C^C)Au(Cl)(L^L)(Cl)Au(C^C)], where C^C is 4,4'-diterbutylbiphenyl and L^L is either a bridging diphosphine or 4,4'-bipyridine, are synthetized with 52 to 72 % yield and structurally characterized by X-ray diffraction. The use of the chelating 1,2-diphenylphosphinoethane ligand in a 1 : 2 (P^P):Au stoichiometry leads to the near quantitative formation of a gold double-complex salt of general formula [(C^C)Au(P^P)][(C^C^)AuCl2 ]. The compounds display long-lived yellow-green phosphorescence with λem in the range of 525 to 585 nm in the solid state with photoluminescence quantum yields (PLQY) up to 10 %. These AuIII complexes are tested for their antiproliferative activity against lung adenocarcinoma cells A549 and results show that compounds 2 and 5 are the most promising candidates. The digold salt 5 shows anticancer activity between 66 and 200 nM on the tested cancer cell lines, whereas derivative 2 displays concentration values required to reduce by 50 % the cell viability (IC50 ) between 7 and 11 µM. Reactivity studies of compound 5 reveal that the [(C^C)Au(P^P)]+ cation is stable in the presence of relevant biomolecules including glutathione suggesting a structural mechanism of action.


Assuntos
Antineoplásicos , Antineoplásicos/química , Compostos Organoáuricos/química , Linhagem Celular Tumoral , Compostos de Bifenilo
2.
J Inorg Biochem ; 247: 112346, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37536162

RESUMO

The limited chemical stability of gold(III)-based compounds in physiological environment has been a challenge in drug discovery, and organometallic chemistry might provide the solution to overcome this issue. In this work, four novel cationic organogold(III)-dithiocarbamate complexes of general structure [(C^N)AuIIIDTC]PF6 (C1a - C4a, DTC = dithiocarbamate, L1 - L4, C^N = 2-anilinopyridine) are presented, and compared to their coordination gold(III)-dithiocarbamate analogues [AuIIIDTCCl2] (C1b - C4b), as potential anti-cancer and anti-leishmanial drugs. Most of the complexes effectively inhibited cancer cell growth, notably C3a presented anti-proliferative effect in the nanomolar range against breast cancer (MCF-7 and MDA-MB-231 cells with moderate selectivity. Pro-apoptotic studies on treated MCF-7 cells showed a high population of cells in early apoptosis. Reactivity studies of C3a towards model thiols (N-acetyl-L-cysteine) refer to a possible mode of action involving bonding between the organogold(III)-core and the thiolate. In the scope of neglected diseases, gold complexes are emerging as promising therapeutic alternatives against leishmaniasis. In this regard, all gold(III)-dithiocarbamate complexes presented anti-leishmanial activity against at least one Leishmania species. Complexes C1a, C4a, C1b, C4b were active against all tested parasites with IC50 values varying between 0.12 and 42 µM, and, overall, organometallic compounds presented more intriguing inhibition profiles. For C4a selectivity over 500-fold for L. braziliensis; even higher than the reference anti-leishmanial drug amphotericin B. Overall, our findings revealed that the organogold(III) moiety significantly amplified the anti-cancer and anti-leishmanial effects with respect to the coordination analogues; thus, showing the great potential of organometallic chemistry in metallodrug-based chemotherapy for cancer and leishmaniasis.


Assuntos
Antineoplásicos , Leishmania , Compostos Organometálicos , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/química , Compostos Organoáuricos/farmacologia , Compostos Organoáuricos/química , Ouro/química , Linhagem Celular Tumoral
3.
J Med Chem ; 66(12): 7868-7879, 2023 06 22.
Artigo em Inglês | MEDLINE | ID: mdl-37279147

RESUMO

The preparation of cyclometalated complexes offers a path to stable materials, catalysts, and therapeutic agents. Here, we explore the anticancer potential of novel biphenyl organogold(III) cationic complexes supported by diverse bisphosphine ligands, Au-1-Au-5, toward aggressive glioblastoma and triple negative breast cancer cells (TNBCs). The [C^C] gold(III) complex, Au-3, exhibits significant tumor growth inhibition in a metastatic TNBC mouse model. Remarkably, Au-3 displays promising blood serum stability over a relevant therapeutic window of 24 h and alteration in the presence of excess L-GSH. The mechanism-of-action studies show that Au-3 induces mitochondrial uncoupling, membrane depolarization, and G1 cell cycle arrest and prompts apoptosis. To the best of our knowledge, Au-3 is the first biphenyl gold-phosphine complex to uncouple mitochondria and inhibit TNBC growth in vivo.


Assuntos
Antineoplásicos , Neoplasias de Mama Triplo Negativas , Animais , Humanos , Camundongos , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Ouro/farmacologia , Mitocôndrias , Soro , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Compostos Organoáuricos/química , Compostos Organoáuricos/farmacologia
4.
Chem Commun (Camb) ; 58(36): 5526-5529, 2022 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-35420608

RESUMO

With the idea of exploiting metal templated C-S bond forming reactions to achieve modification of cysteines in bacterial proteins, a cyclometalated Au(III) compound was explored in a competitive chemoproteomic approach in S. aureus cell extracts. More than 100 ligandable cysteines were identified, of which more than 50% were not engaged by organic α-chloroacetamides in a previous study, indicating that organometallic compounds expand the ligandable space in bacteria. A selected interaction was validated using an enzyme activity assay, and intact protein mass spectrometry showed cysteine arylation of an unprecedented target. The obtained results demonstrate that this family of organogold compounds has potential for therapeutic protein targeting via selective, covalent modification of cysteine residues in bacteria.


Assuntos
Cisteína , Staphylococcus aureus , Cisteína/química , Compostos Organoáuricos/química
5.
J Inorg Biochem ; 229: 111726, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35065320

RESUMO

Leishmania amazonensis and L. braziliensis are the main etiological agents of the American Tegumentary Leishmaniasis (ATL). Taking into account the limited effectiveness and high toxicity of the current drug arsenal to treat ATL, novel options are urgently needed. Inspired by the fact that gold-based compounds are promising candidates for antileishmanial drugs, we studied the biological action of a systematic series of six (1)-(6) symmetric Au(I) benzyl and aryl-N-heterocyclic carbenes. All compounds were active at low micromolar concentrations with 50% effective concentrations ranging from 1.57 to 8.30 µM against Leishmania promastigotes. The mesityl derivative (3) proved to be the best candidate from this series, with a selectivity index ~13 against both species. The results suggest an effect of the steric and electronic parameters of the N-substituent in the activity. Intracellular infections were drastically reduced after 24h of (2)-(5) incubation in terms of infection rate and amastigote burden. Further investigations showed that our compounds induced significant parasites' morphological alterations and membrane permeability. Also, (3) and (6) were able to reduce the residual activity of three Leishmania recombinant cysteine proteases, known as possible targets for Au(I) complexes. Our promising results open the possibility of exploring gold complexes as leishmanicidal molecules to be further screened in in vivo models of infection.


Assuntos
Imidazóis/farmacologia , Compostos Organoáuricos/farmacologia , Tripanossomicidas/farmacologia , Animais , Membrana Celular/efeitos dos fármacos , Inibidores de Cisteína Proteinase/síntese química , Inibidores de Cisteína Proteinase/farmacologia , Feminino , Ouro/química , Imidazóis/síntese química , Leishmania braziliensis/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Estrutura Molecular , Compostos Organoáuricos/síntese química , Testes de Sensibilidade Parasitária , Relação Estrutura-Atividade , Tripanossomicidas/síntese química
6.
Biomolecules ; 11(12)2021 12 10.
Artigo em Inglês | MEDLINE | ID: mdl-34944502

RESUMO

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.


Assuntos
2,2'-Dipiridil/análogos & derivados , Antimônio/farmacologia , Antivirais/farmacologia , Tratamento Farmacológico da COVID-19 , Cloretos/farmacologia , Indazóis/farmacologia , Compostos Organoáuricos/farmacologia , Compostos Organometálicos/farmacologia , Compostos de Rutênio/farmacologia , SARS-CoV-2/efeitos dos fármacos , 2,2'-Dipiridil/química , 2,2'-Dipiridil/farmacologia , Animais , Antimônio/química , Antivirais/química , Linhagem Celular , Cloretos/química , Chlorocebus aethiops , Descoberta de Drogas , Humanos , Indazóis/química , Compostos Organoáuricos/química , Compostos Organometálicos/química , Compostos de Rutênio/química , Células Vero
7.
Dalton Trans ; 50(47): 17487-17490, 2021 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-34796892

RESUMO

The reactions of the medicinal gold(I) compound auranofin and its close analogues with vasopressin and the diselenide analogue were comparatively investigated by LC-electrospray MS/MS. Evidence is gained of the possible cleavage of the S-S and Se-Se bridges induced by Au(I). Notably, we found that, in the absence of reducing agents, the sulfur and selenium atoms are metallated only at high temperature (70 °C) with the preferential binding of gold to selenium. The reaction with the S-S bridge can take place at physiological temperature (37 °C) under reducing conditions. The implications of these results are discussed in the general frame of the reactivity of biologically relevant soft Lewis acids with peptides and proteins.


Assuntos
Neurofisinas/antagonistas & inibidores , Compostos Organoáuricos/farmacologia , Compostos Organosselênicos/farmacologia , Precursores de Proteínas/antagonistas & inibidores , Vasopressinas/antagonistas & inibidores , Humanos , Neurofisinas/metabolismo , Compostos Organoáuricos/química , Compostos Organosselênicos/química , Precursores de Proteínas/metabolismo , Vasopressinas/metabolismo
8.
Dalton Trans ; 50(47): 17413-17437, 2021 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-34693422

RESUMO

This tutorial review highlights key principles underpinning the design of selected metallodrugs to target specific biological macromolecules (DNA and proteins). The review commences with a descriptive overview of the eukaryotic cell cycle and the molecular biology of cancer, particularly apoptosis, which is provided as a necessary foundation for the discovery, design, and targeting of metal-based anticancer agents. Drugs which target DNA have been highlighted and clinically approved metallodrugs discussed. A brief history of the development of mainly gold-based metallodrugs is presented prior to addressing ligand systems for stabilizing and adding functionality to bio-active gold(I) and gold(III) complexes, particularly in the burgeoning field of anticancer metallodrugs. Concepts such as multi-modal and selective cytotoxic agents are covered where necessary for selected compounds. The emerging role of carbenes as the ligand system of choice to achieve these goals for gold-based metallodrug candidates is highlighted prior to closing the review with comments on some future directions that this research field might follow. The latter section ultimately emphasizes the importance of understanding the fate of metal complexes in cells to garner key mechanistic insights.


Assuntos
Antineoplásicos/farmacologia , Neoplasias/tratamento farmacológico , Compostos Organoáuricos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Humanos , Neoplasias/patologia , Compostos Organoáuricos/síntese química , Compostos Organoáuricos/química
9.
Dalton Trans ; 50(40): 14444-14452, 2021 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-34585201

RESUMO

A few gold compounds were recently found to show antimicrobial properties in vitro, holding great promise for the discovery of new drugs to overcome antibiotic resistance. Here, the inhibition of the bacterial virulence factor urease by four Au(I)-compounds, namely Au(PEt3)Cl, Au(PEt3)Br, Au(PEt3)I and [Au(PEt3)2]Cl, obtained from the antiarthritic Au(I)-drug Auranofin and earlier reported to act as antimicrobials, is investigated. The three monophosphino Au(I) complexes showed IC50 values in the 30-100 nM range, while the diphosphino Au(I) complex, though being less active, still showed a IC50 value of 7 µM. The structural basis for this inhibition was provided by solving the crystal structures of urease co-crystallized with Au(PEt3)I and [Au(PEt3)2]Cl: at least two Au(I) ions bind the enzyme in a flap domain involved in the catalysis, thus obliterating enzyme activity. Peculiar changes observed in the two structures reveal implications for the mechanism of soft metal binding and enzyme inactivation.


Assuntos
Antibacterianos/farmacologia , Inibidores Enzimáticos/farmacologia , Compostos Organoáuricos/farmacologia , Sporosarcina/efeitos dos fármacos , Urease/antagonistas & inibidores , Antibacterianos/síntese química , Antibacterianos/química , Cristalografia por Raios X , Teoria da Densidade Funcional , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Molecular , Compostos Organoáuricos/síntese química , Compostos Organoáuricos/química , Sporosarcina/enzimologia , Urease/metabolismo
10.
Sci Rep ; 11(1): 17523, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34471155

RESUMO

Exposure to arsenic, a ubiquitous metalloid on Earth, results in human cancers. Skin cancer is the most common arsenical cancers. Both autophagy and aquaporin pathway are known to promote carcinogenesis. However, the mechanisms by which arsenic regulates aquaporin and autophagy in arsenical skin cancers remain elusive. This study aims to address how arsenic regulates aquaporin-3, the predominant aquaporin in epidermal keratinocytes, and how this process would induce autophagy. Quantitative real-time PCR and immunofluorescence were used to measure the expression of aquaporin 3 in arsenical skin cancers and arsenic-treated keratinocytes. Beclin-1 expression and autophagy were measured. We examined if blocking aquaporin 3 could interfere arsenic-induced autophagy in keratinocytes. Expression of aquaporin 3 is increased in arsenical cancers and in arsenic-treated keratinocytes. Arsenic induced autophagy in primary human keratinocytes. Notably, the arsenic-induced autophagy was inhibited by pretreatment of keratinocytes with aquaporin inhibitors Auphen or AgNO3, or RNA interference against aquaporin 3. The data indicates that the aquaporin 3 is an important cell membrane channel to mediate arsenic uptake and contributes to the arsenic-induced autophagy.


Assuntos
Aquaporina 3/metabolismo , Arsênio/farmacologia , Autofagia/efeitos dos fármacos , Queratinócitos/efeitos dos fármacos , Idoso , Idoso de 80 Anos ou mais , Proteína Beclina-1/metabolismo , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Feminino , Humanos , Queratinócitos/metabolismo , Masculino , Pessoa de Meia-Idade , Compostos Organoáuricos/farmacologia
11.
Metallomics ; 13(9)2021 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-34468767

RESUMO

The inhibition of glycerol permeation via human aquaporin-10 (hAQP10) by organometallic gold complexes has been studied by stopped-flow fluorescence spectroscopy, and its mechanism has been described using molecular modelling and atomistic simulations. The most effective hAQP10 inhibitors are cyclometalated Au(III) C^N compounds known to efficiently react with cysteine residues leading to the formation of irreversible C-S bonds. Functional assays also demonstrate the irreversibility of the binding to hAQP10 by the organometallic complexes. The obtained computational results by metadynamics show that the local arylation of Cys209 in hAQP10 by one of the gold inhibitors is mapped into a global change of the overall free energy of glycerol translocation across the channel. Our study further pinpoints the need to understand the mechanism of glycerol and small molecule permeation as a combination of local structural motifs and global pore conformational changes, which are taking place on the scale of the translocation process and whose study, therefore, require sophisticated molecular dynamics strategies.


Assuntos
Aquaporinas/antagonistas & inibidores , Compostos Organoáuricos/farmacologia , Fenômenos Biofísicos , Humanos , Simulação de Dinâmica Molecular , Espectrometria de Fluorescência/métodos
12.
Chemistry ; 27(63): 15773-15785, 2021 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-34436799

RESUMO

A library of eleven cationic gold(III) complexes of the general formula [(C C)Au(N N)]+ when C C is either biphenyl or 4,4'-ditertbutyldiphenyl and N N is a bipyridine, phenanthroline or dipyridylamine derivative have been synthesized and characterized. Contrasting effects on the viability of the triple negative breast cancer cells MDA-MB-231 was observed from a preliminary screening. The antiproliferative activity of the seven most active complexes were further assayed on a larger panel of human cancer cells as well as on non-cancerous cells for comparison. Two complexes stood out for being either highly active or highly selective. Eventually, reactivity studies with biologically meaningful amino acids, glutathione, higher order DNA structures and thioredoxin reductase (TrxR) revealed a markedly different behavior from that of the well-known coordinatively isomeric [(C N C)Au(NHC)]+ structure. This makes the [(C C)Au(N N)]+ complexes a new class of organogold compounds with an original mode of action.


Assuntos
Antineoplásicos , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células , Ouro/farmacologia , Humanos , Compostos Organoáuricos/farmacologia , Tiorredoxina Dissulfeto Redutase
13.
ChemMedChem ; 16(20): 3222-3230, 2021 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-34159760

RESUMO

Chemical control of mitochondrial dynamics and bioenergetics can unravel fundamental biological mechanisms and therapeutics for several diseases including, diabetes and cancer. We synthesized stable, water-soluble gold(III) complexes (Auraformin) supported by biguanide metformin or phenylmetformin for efficacious inhibition of mitochondrial respiration. The new compounds were characterized following the reaction of [C N]-cyclometalated gold(III) compounds with respective biguanides. Auraformin is solution stable in a physiologically relevant environment. We show that auraformin decreases mitochondrial respiration efficiently in comparison to the clinically used metformin by 100-fold. The compound displays significant mitochondrial uptake and induces antiproliferative activity in the micromolar range. Our results shed light on the development of new scaffolds as improved inhibitors of mitochondrial respiration.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Ouro/farmacologia , Metformina/farmacologia , Mitocôndrias/efeitos dos fármacos , Compostos Organoáuricos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Ouro/química , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Metformina/química , Mitocôndrias/metabolismo , Estrutura Molecular , Compostos Organoáuricos/síntese química , Compostos Organoáuricos/química , Solubilidade , Relação Estrutura-Atividade , Células Tumorais Cultivadas , Água/química
14.
ChemMedChem ; 16(19): 3060-3070, 2021 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-34181818

RESUMO

The rise of antimicrobial resistance has necessitated novel strategies to efficiently combat pathogenic bacteria. Metal-based compounds have been proven as a possible alternative to classical organic drugs. Here, we have assessed the antibacterial activity of seven gold complexes of different families. One compound, a cyclometalated Au(III) C^N complex, showed activity against Gram-positive bacteria, including multi-drug resistant clinical strains. The mechanism of action of this compound was studied in Bacillus subtilis. Overall, the studies point towards a complex mode of antibacterial action, which does not include induction of oxidative stress or cell membrane damage. A number of genes related to metal transport and homeostasis were upregulated upon short treatment of the cells with gold compound. Toxicity tests conducted on precision-cut mouse tissue slices ex vivo revealed that the organogold compound is poorly toxic to mouse liver and kidney tissues, and may thus, be treated as an antibacterial drug candidate.


Assuntos
Antibacterianos/farmacologia , Bactérias Gram-Positivas/efeitos dos fármacos , Compostos Organoáuricos/farmacologia , Animais , Antibacterianos/síntese química , Antibacterianos/química , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Camundongos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Compostos Organoáuricos/síntese química , Compostos Organoáuricos/química , Relação Estrutura-Atividade
15.
Biometals ; 34(4): 867-879, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33907910

RESUMO

Chloro(triethylphosphine)gold(I), (Et3PAuCl hereafter), is an Auranofin (AF)-related compound showing very similar biological and pharmacological properties. Like AF, Et3PAuCl exhibits potent antiproliferative properties in vitro toward a variety of cancer cell lines and is a promising anticancer drug candidate. We wondered whether Et3PAuCl encapsulation might lead to an improved pharmacological profile also considering the likely reduction of unwanted side-reactions that are responsible for adverse effects and for drug inactivation. Et3PAuCl was encapsulated in biocompatible PLGA-PEG nanoparticles (NPs) and the new formulation evaluated in colorectal HCT-116 cancer cells in comparison to the free gold complex. Notably, encapsulated Et3PAuCl (nano-Et3PAuCl hereafter) mostly retains the cellular properties of the free gold complex and elicits even greater cytotoxic effects in colorectal cancer (CRC) cells, mediated by apoptosis and autophagy. Moreover, a remarkable inhibition of two crucial signaling pathways, i.e. ERK and AKT, by nano-Et3PAuCl, was clearly documented. The implications of these findings are discussed.


Assuntos
Antineoplásicos/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Nanopartículas/química , Compostos Organoáuricos/farmacologia , Poliésteres/química , Polietilenoglicóis/química , Antineoplásicos/síntese química , Antineoplásicos/química , Cápsulas , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Compostos Organoáuricos/síntese química , Compostos Organoáuricos/química , Células Tumorais Cultivadas
16.
Inorg Chem ; 60(7): 5054-5062, 2021 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-33739101

RESUMO

Organometallic complexes have recently gained attention as competent bioconjugation reagents capable of introducing a diverse array of substrates to biomolecule substrates. Here, we detail the synthesis and characterization of an aminophosphine-supported Au(III) platform that provides rapid and convenient access to a wide array of peptide-based assemblies via cysteine S-arylation. This strategy results in the formation of robust C-S covalent linkages and is an attractive method for the modification of complex biomolecules due to the high functional group tolerance, chemoselectivity, and rapid reaction kinetics associated with these arylation reactions. This work expands upon existing metal-mediated cysteine arylation by introducing a class of air-stable organometallic complexes that serve as robust bioconjugation reagents enabling the synthesis of conjugates of higher structural complexity including macrocyclic stapled and bicyclic peptides as well as a peptide-functionalized multivalent hybrid nanocluster. This organometallic-based approach provides a convenient, one-step method of peptide functionalization and macrocyclization, and has the potential to contribute to efforts directed toward developing efficient synthetic strategies of building new and diverse hybrid peptide-based assemblies.


Assuntos
Cisteína/química , Indicadores e Reagentes/química , Compostos Organoáuricos/química , Peptídeos/síntese química , Estrutura Molecular , Peptídeos/química
18.
ChemMedChem ; 16(11): 1681-1695, 2021 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-33615725

RESUMO

Leishmaniasis is one of the most neglected diseases worldwide and is considered a serious public health issue. The current therapeutic options have several disadvantages that make the search for new therapeutics urgent. Gold compounds are emerging as promising candidates based on encouraging in vitro and limited in vivo results for several AuI and AuIII complexes. The antiparasitic mechanisms of these molecules remain only partially understood. However, a few studies have proposed the trypanothione redox system as a target, similar to the mammalian thioredoxin system, pointed out as the main target for several gold compounds with significant antitumor activity. In this review, we present the current status of the investigation and design of gold compounds directed at treating leishmaniasis. In addition, we explore potential targets in Leishmania parasites beyond the trypanothione system, taking into account previous studies and structure modulation performed for gold-based compounds.


Assuntos
Antiprotozoários/farmacologia , Descoberta de Drogas , Glutationa/análogos & derivados , Leishmania/efeitos dos fármacos , Leishmaniose/tratamento farmacológico , Compostos Organoáuricos/farmacologia , Espermidina/análogos & derivados , Animais , Antiprotozoários/química , Glutationa/antagonistas & inibidores , Glutationa/metabolismo , Humanos , Leishmania/metabolismo , Leishmaniose/metabolismo , Compostos Organoáuricos/química , Oxirredução , Testes de Sensibilidade Parasitária , Espermidina/antagonistas & inibidores , Espermidina/metabolismo
19.
Naunyn Schmiedebergs Arch Pharmacol ; 394(6): 1133-1142, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33464387

RESUMO

Apparently, both a decrease in beta cell function and in beta cell mass contribute to the progressive worsening of type 2 diabetes. So, it is of particular interest to define factors which are relevant for the regulation of insulin secretion and at the same time for the maintenance of beta cell mass. The NADPH-thioredoxin system has a candidate role for such a dual function. Here, we have characterized the effects of a highly specific inhibitor of thioredoxin reductase, AM12, on the viability and function of insulin-secreting MIN6 cells and isolated NMRI mouse islets. Viability was checked by MTT testing and the fluorescent live-dead assay. Apoptosis was assessed by annexin V assay. Insulin secretion of perifused islets was measured by ELISA. The cytosolic Ca2+ concentration was measured by the Fura technique. Acute exposure of perifused pancreatic islets to 5 µM AM12 was without significant effect on insulin secretion. Islets cultured for 24 h in 0.5 or 5 µM AM12 showed unchanged basal secretion during perifusion, but the response to 30 mM glucose was significantly enhanced by 5 µM. Twenty-four-hour exposure to 5 µM AM12 proved to be without effect on the viability of MIN6 cells, whereas longer exposure was clearly toxic. Islets were more susceptible, showing initial signs of apoptosis after 24-h exposure to 5 µM AM12. The activity of the NADPH-thioredoxin system is indispensable for beta cell viability but may have a limiting effect on glucose-induced insulin secretion.


Assuntos
Secreção de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/efeitos dos fármacos , Ilhotas Pancreáticas/efeitos dos fármacos , Tiorredoxina Dissulfeto Redutase/antagonistas & inibidores , Animais , Apoptose/efeitos dos fármacos , Derivados de Benzeno/farmacologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Feminino , Glucose/metabolismo , Células Secretoras de Insulina/metabolismo , Ilhotas Pancreáticas/metabolismo , Camundongos , Compostos Organoáuricos/farmacologia , Tiorredoxina Dissulfeto Redutase/metabolismo , Fatores de Tempo
20.
Cell Mol Life Sci ; 78(6): 3073-3085, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33231721

RESUMO

Inflammasomes are large immune multiprotein complexes that tightly regulate the production of the pro-inflammatory cytokines, being dependent on cell regulatory volume mechanisms. Aquaporins (AQPs) are protein channels that facilitate the transport of water and glycerol (aquaglyceroporins) through membranes, essential for cell volume regulation. Although these membrane proteins are highly expressed in monocytes and macrophages, their role in the inflammatory process is still unclear. Here, we investigated the role of aquaglyceroporin AQP3 in NLRP3-inflammasome activation by complementary approaches based either on shRNA silencing or on AQP3 selective inhibition. The latter has been achieved using a reported potent gold-based inhibitor, Auphen. AQP3 inhibition or silencing partially blocked LPS-priming and decreased production of IL-6, proIL-1ß, and TNF-α, suggesting the possible involvement of AQP3 in macrophage priming by Toll-like receptor 4 engagement. Moreover, AQP3-dependent cell reswelling increased IL-1ß release through caspase-1 activation. NLRP3-inflammasome activation induced by reswelling, nigericin, and ATP was also blocked when AQP3 was inhibited or silenced. Altogether, these data point towards AQPs as potential players in the setting of the inflammatory response.


Assuntos
Aquaporina 3/metabolismo , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Aquaporina 3/antagonistas & inibidores , Aquaporina 3/genética , Caspase 1/deficiência , Caspase 1/genética , Caspase 1/metabolismo , Linhagem Celular , Citocinas/metabolismo , Glicerol/metabolismo , Humanos , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Lipopolissacarídeos/farmacologia , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Nigericina/farmacologia , Compostos Organoáuricos/química , Compostos Organoáuricos/metabolismo , Potássio/metabolismo , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Receptor 4 Toll-Like/metabolismo , Regulação para Cima/efeitos dos fármacos
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