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1.
Inorg Chem ; 60(18): 14174-14189, 2021 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-34477373

RESUMO

Ruthenium(II) complexes (Ru1-Ru5), with the general formula [Ru(N-S)(dppe)2]PF6, bearing two 1,2-bis(diphenylphosphino)ethane (dppe) ligands and a series of mercapto ligands (N-S), have been developed. The combination of these ligands in the complexes endowed hydrophobic species with high cytotoxic activity against five cancer cell lines. For the A549 (lung) and MDA-MB-231 (breast) cancer cell lines, the IC50 values of the complexes were 288- to 14-fold lower when compared to cisplatin. Furthermore, the complexes were selective for the A549 and MDA-MB-231 cancer cell lines compared to the MRC-5 nontumor cell line. The multitarget character of the complexes was investigated by using calf thymus DNA (CT DNA), human serum albumin, and human topoisomerase IB (hTopIB). The complexes potently inhibited hTopIB. In particular, complex [Ru(dmp)(dppe)2]PF6 (Ru3), bearing the 4,6-diamino-2-mercaptopyrimidine (dmp) ligand, effectively inhibited hTopIB by acting on both the cleavage and religation steps of the catalytic cycle of this enzyme. Molecular docking showed that the Ru1-Ru5 complexes have binding affinity by active sites on the hTopI and hTopI-DNA, mainly via π-alkyl and alkyl hydrophobic interactions, as well as through hydrogen bonds. Complex Ru3 displayed significant antitumor activity against murine melanoma in mouse xenograph models, but this complex did not damage DNA, as revealed by Ames and micronucleus tests.


Assuntos
Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , DNA Topoisomerases Tipo I/metabolismo , Fosfinas/farmacologia , Rutênio/farmacologia , Inibidores da Topoisomerase I/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Ligantes , Fosfinas/química , Rutênio/química , Inibidores da Topoisomerase I/síntese química , Inibidores da Topoisomerase I/química , Células Tumorais Cultivadas
2.
Molecules ; 26(9)2021 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-33923006

RESUMO

Phosphine-borane complexes are novel chemical entities with preclinical efficacy in neuronal and ophthalmic disease models. In vitro and in vivo studies showed that the metabolites of these compounds are capable of cleaving disulfide bonds implicated in the downstream effects of axonal injury. A difficulty in using standard in silico methods for studying these drugs is that most computational tools are not designed for borane-containing compounds. Using in silico and machine learning methodologies, the absorption-distribution properties of these unique compounds were assessed. Features examined with in silico methods included cellular permeability, octanol-water partition coefficient, blood-brain barrier permeability, oral absorption and serum protein binding. The resultant neural networks demonstrated an appropriate level of accuracy and were comparable to existing in silico methodologies. Specifically, they were able to reliably predict pharmacokinetic features of known boron-containing compounds. These methods predicted that phosphine-borane compounds and their metabolites meet the necessary pharmacokinetic features for orally active drug candidates. This study showed that the combination of standard in silico predictive and machine learning models with neural networks is effective in predicting pharmacokinetic features of novel boron-containing compounds as neuroprotective drugs.


Assuntos
Boranos/química , Aprendizado de Máquina , Fármacos Neuroprotetores/química , Fosfinas/química , Barreira Hematoencefálica/efeitos dos fármacos , Boranos/farmacologia , Simulação por Computador , Humanos , Neuroproteção/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Fosfinas/farmacologia , Ligação Proteica/efeitos dos fármacos
3.
Inorg Chem ; 60(5): 2914-2930, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33570919

RESUMO

Ruthenium(II) complexes are currently considered attractive alternatives to the widely used platinum-based drugs. We present herein the synthesis and characterization of half-sandwich ruthenium compounds formulated as [Ru(p-cymene)(L)Cl][CF3SO3] (L = 1,1-bis(methylenediphenylphosphano)ethylene, 1; L = 1,1-bis(diphenylphosphano)ethylene, 2), which were characterized by elemental analysis, mass spectrometry, 1H and 31P{1H} NMR, UV-vis and IR spectroscopy, conductivity measurements and cyclic voltammetry. The molecular structures for both complexes were determined by single-crystal X-ray diffraction. Their cytotoxic activity was evaluated using the MTT assay against human tumor cells, namely ovarian (A2780) and breast (MCF7 and MDA-MB-231). Both complexes were active against breast adenocarcinoma cells, with complex 1 exhibiting a quite remarkable cytotoxicity in the submicromolar range. Interestingly, at concentrations equivalent to the IC50 values in the MCF7 cancer cells, complexes 1 and 2 presented lower cytotoxicity in normal human primary fibroblasts. The antiproliferative effects of 1 and 2 in MCF7 cells might be associated with the induction of reactive oxygen species (ROS), leading to a combined cell death mechanism via apoptosis and autophagy. Despite the fact that in vitro a partial intercalation between complexes and DNA was observed, no MCF7 cell cycle delay or arrest was observed, indicating that DNA might not be a direct target. Complexes 1 and 2 both exhibited a moderate to strong interaction with human serum albumin, suggesting that protein targets may be involved in their mode of action. Their acute toxicity was evaluated in the zebrafish model. Complex 1 (the most toxic of the two) exhibited a lethal toxicity LC50 value about 1 order of magnitude higher than any IC50 concentrations found for the cancer cell models used, highlighting its therapeutic relevance as a drug candidate in cancer chemotherapy.


Assuntos
Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Fosfinas/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Antineoplásicos/toxicidade , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Complexos de Coordenação/síntese química , Complexos de Coordenação/metabolismo , Complexos de Coordenação/toxicidade , DNA/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais , Fibroblastos/efeitos dos fármacos , Humanos , Fosfinas/síntese química , Fosfinas/metabolismo , Fosfinas/toxicidade , Ligação Proteica , Espécies Reativas de Oxigênio/metabolismo , Rutênio/química , Albumina Sérica Humana/metabolismo , Peixe-Zebra
5.
Biochem Biophys Res Commun ; 539: 15-19, 2021 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-33412416

RESUMO

BACKGROUND: Treatment of neurodegenerative diseases, such as Parkinson's disease, Huntington's chorea, Alzheimer's disease, is one of the priority directions in modern medicine. Thus, search and production of new physiologically active substances for the treatment of neurodegenerative disorders is one of the most important tasks for organic chemistry. The approach based on the replacement of a peptide bond in a peptide molecule with a structural isostere, non-hydrolyzable methylene phosphoryl fragment makes it possible to increase the metabolic stability of peptide molecules to the destructive action of peptidases. METHODS: This work is devoted to the approbation of a new synthetic approach to the production of physiologically active substances in a series of peptide-type compounds with activity by replacing the peptide bond with isosteric methylene-phosphoryl fragment with the preservation of the original amino acid sequence. RESULTS: A phosphine analog of the known physiologically active tripeptide proline-glycine-proline was obtained, cytotoxicity and neuroprotective properties of the initial tripeptide and its phosphine analog were studied. CONCLUSION: Preliminary biological tests have shown that the obtained phosphine analog of the proline-glycine-proline tripeptide is involved in modulating the formation of sediments in the cellular system of proteinopathy, which may indicate their potential antiaggregatory properties.


Assuntos
Doenças Neurodegenerativas/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Oligopeptídeos/farmacologia , Fosfinas/química , Prolina/análogos & derivados , Agregação Patológica de Proteínas/tratamento farmacológico , Linhagem Celular Tumoral , Humanos , Doenças Neurodegenerativas/metabolismo , Fármacos Neuroprotetores/química , Oligopeptídeos/química , Fosfinas/farmacologia , Prolina/química , Prolina/farmacologia , Agregação Patológica de Proteínas/metabolismo
6.
Angew Chem Int Ed Engl ; 60(12): 6704-6709, 2021 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-33274606

RESUMO

We report the anti-breast cancer stem cell (CSC) properties of a series of Group 10-bis(azadiphosphine) complexes 1-3 under exclusively three-dimensional cell culture conditions. The breast CSC mammosphere potency of 1-3 is dependent on the Group 10 metal present, increasing in the following order: 1 (nickel complex) <2 (palladium complex) <3 (platinum complex). Notably, 3 reduces the formation and size of mammospheres to a greater extent than salinomycin, an established CSC-active compound, or any reported anti-CSC metal complex tested under similar conditions. Mechanistic studies suggest that the most effective complexes 2 and 3 readily penetrate CSC mammospheres, enter CSC nuclei, induce genomic DNA damage, and trigger caspase-dependent apoptosis. To the best of our knowledge, this is the first study to systematically probe the anti-CSC activity of a series of structurally related Group 10 complexes and to be conducted entirely using three-dimensional CSC culture conditions.


Assuntos
Antineoplásicos/farmacologia , Compostos Aza/farmacologia , Neoplasias da Mama/tratamento farmacológico , Complexos de Coordenação/farmacologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Fosfinas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Compostos Aza/química , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Dano ao DNA , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Tamanho da Partícula , Fosfinas/química , Relação Estrutura-Atividade , Células Tumorais Cultivadas
7.
Pestic Biochem Physiol ; 171: 104717, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33357567

RESUMO

The rusty grain beetle, Cryptolestes ferrugineus, a major pest of stored commodities, has developed very high levels (>1000×) of resistance to the fumigant phosphine. Resistance in this species is remarkably stronger than reported in any other stored product pests demanding the need to understand the molecular basis of this trait. Previous genetic studies in other grain insect pests identified specific variants in two major genes, rph1 and rph2 in conferring the strong resistance trait. However, in C. ferrugineus, although the gene, rph1 was identified as cytochrome-b5-fatty acid desaturase, the rph2 gene has not been reported so far. We tested the candidate gene for rph2, dihydrolipoamide dehydrogenase (dld) using the recently published transcriptome of C. ferrugineus and identified three variants, L73N and A355G + D360H, a haplotype, conferring resistance in this species. Our sequence analysis in resistant strain and phosphine selected resistant survivors indicates that these variants occur either alone as a homozygote or a mixture of heterozygotes (i.e complex heterozygotes) both conferring strong resistance. We also found that one of the three variants, possibly L73N expressing "dominant" trait at low frequency in resistant insects. Comparison of dld sequences between Australian and Chinese resistant strain of this species confirmed that the identified variants are highly conserved. Our fitness analysis indicated that resistant insects may not incur significant biological costs in the absence of phosphine selection for 19 generations. Thus, we propose that the observed high levels of resistance in C. ferrugineus could be primarily due to the characteristics of three unique variants, L73N and A355G + D360H within dld.


Assuntos
Besouros , Inseticidas , Fosfinas , Animais , Austrália , Besouros/genética , Di-Hidrolipoamida Desidrogenase/genética , Resistência a Inseticidas/genética , Inseticidas/farmacologia , Fosfinas/farmacologia
8.
Inorg Chem ; 59(20): 15004-15018, 2020 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-32997499

RESUMO

In this paper, a series of new ruthenium complexes of the general formula [Ru(NS)(dpphpy)(dppb)]PF6 (Ru1-Ru3), where dpphpy = diphenyl-2-pyridylphosphine, NS ligands = 2-thiazoline-2-thiol (tzdt, Ru1), 2-mercaptopyrimidine (pySm, Ru2), and 4,6-diamino-2-mercaptopyrimidine (damp, Ru3), and dppb = 1,4-bis(diphenylphosphino)butane, were synthesized and characterized by elemental analysis, spectroscopic techniques (IR, UV/visible, and 1D and 2D NMR), and X-ray diffraction. In the characterization, the correlation between the phosphorus atoms and their respective aromatic hydrogen atoms of the compounds in the assignment stands outs, by 1H-31P HMBC experiments. The compounds show anticancer activities against A549 (lung) and MDA-MB-231 (breast) cancer cell lines, higher than the clinical drug cisplatin. All of the complexes are more cytotoxic against the cancer cell lines than against the MRC-5 (lung) and MCF-10A (breast) nontumorigenic human cell lines. For A549 tumor cells, cell cycle analysis upon treatment with Ru2 showed that it inhibits the mitotic phase because arrest was observed in the Sub-G1 phase. Additionally, the compound induces cell death by an apoptotic pathway in a dose-dependent manner, according to annexin V-PE assay. The multitargeted character of the compounds was investigated, and the biomolecules were DNA, topoisomerase IB, and proteasome, as well as the fundamental biomolecule in the pharmacokinetics of drugs, human serum albumin. The experimental results indicate that the complexes do not target DNA in the cells. At low concentrations, the compounds showed the ability to partially inhibit the catalytic activity of topoisomerase IB in the process of relaxation of the DNA plasmid. Among the complexes assayed in cultured cells, complex Ru3 was able to diminish the proteasomal chymotrypsin-like activity to a greater extent.


Assuntos
Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , DNA Topoisomerases Tipo I/metabolismo , Inibidores de Proteassoma/farmacologia , Inibidores da Topoisomerase I/farmacologia , Antineoplásicos/síntese química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Complexos de Coordenação/síntese química , Ensaios de Seleção de Medicamentos Antitumorais , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Humanos , Fosfinas/síntese química , Fosfinas/farmacologia , Inibidores de Proteassoma/síntese química , Rutênio/química , Compostos de Sulfidrila/síntese química , Compostos de Sulfidrila/farmacologia , Inibidores da Topoisomerase I/síntese química
9.
Eur J Med Chem ; 204: 112613, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32784095

RESUMO

Herein, we review developments in synthesis, structure, and biological (anti-cancer) activities of 1,1-bis(diphenylphosphino)methane (dppm) bridged homo- and heterobimetallic systems of the type LmM(µ2-dppm)M'Ln (M and M' are transition metals which may be different or the same and Ln,m are co-ligands) since the first such reported bimetallic system in 1987 until the present time (2020). As the simplest diphosphine, dppm enables facile formation of bimetallic complexes, where, given the short spacer between the PPh2 groups, close spatial proximity of the metal centres is ensured. We concentrate on complexes bearing no M-M interaction and contrast biological activities of these complexes with mononuclear counterparts and positive control agents such as cisplatin, in an attempt to elucidate patterns in the biological activities of these complexes.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Metais/química , Fosfinas/química , Fosfinas/farmacologia , Antibacterianos/farmacologia , Antineoplásicos/síntese química , Linhagem Celular Tumoral , Complexos de Coordenação/síntese química , Cristalografia por Raios X , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Ligantes , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Fosfinas/síntese química , Salmonella typhimurium/efeitos dos fármacos , Espectrofotometria Ultravioleta , Staphylococcus aureus/efeitos dos fármacos , Relação Estrutura-Atividade
10.
Bioorg Med Chem Lett ; 30(20): 127492, 2020 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-32791194

RESUMO

The development of both chemotherapeutic drug resistance as well as adverse side effects suggest that the current chemotherapeutic drugs remain ineffective in treating the various types of cancers. The development of new metallodrugs presenting anti-cancer activity is therefore needed. Ruthenium complexes have gained a great deal of interest due to their promising anti-tumour properties and reduced toxicity in vivo. This study highlighted the effective induction of cell death in a malignant melanoma cell by two novel bis-amino-phosphine ruthenium(II) complexes referred to as GA105 and GA113. The IC50 concentrations were determined for both the complexes, the ligand and cisplatin, for comparison. Both complexes GA105 and GA113 displayed a high anti-cancer selectivity profile as they exhibited low IC50 values of 6.72 µM and 8.76 µM respectively, with low toxicity towards a non-malignant human cell line. The IC50 values obtained for both complexes were lower than that of cisplatin. The new complexes were more effective compared to the free ligand, GA103 (IC50 = >20 µM). Morphological studies on treated cells induced apoptotic features, which with further studies could indicate an intrinsic cell death pathway. Additionally, flow cytometric analysis revealed that the mode of cell death of complex GA113 was apoptosis. The outcomes herein give further insight into the potential use of selected Ru(II) complexes as alternative chemotherapeutic drugs in the future.


Assuntos
Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Diaminas/farmacologia , Fosfinas/farmacologia , Rutênio/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Diaminas/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células HEK293 , Humanos , Ligantes , Estrutura Molecular , Fosfinas/química , Rutênio/química , Relação Estrutura-Atividade
11.
Inorg Chem ; 59(15): 10557-10568, 2020 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-32657125

RESUMO

A series of silver(I) camphorsulfonato complexes containing various phosphine ligands having the stoichiometry [Ag(camphSO3)(PR3)] [PR3 = PTA (1,3,5-triaza-7-phosphaadamantane), PASO2 (2-thia-1,3,5-triaza-7-phosphaadamantane-2,2-dioxide), PPh3, PCy3, P(CH2CH2CN)3, PPyPh2, or P(o-tol)3] were prepared and fully characterized by NMR spectroscopic methods and X-ray crystallography. Depending on the nature of the phosphine, a variety of different supramolecular structures, including dimers, macrocycles, and coordination polymers, were observed in the solid state. The in vitro antimicrobial activity in seven different pathogens (Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Acinetobacter baumannii, Candida albicans, and Cryptococcus neoformans var. grubii) as well as toxicity in human cells was also examined. While all compounds show some activity against the bacteria, they were especially active against the fungus C. neoformans. The most active and at the same time least toxic compound was found to be the water-soluble complex [Ag(camphSO3)(PTA)2].


Assuntos
Antibacterianos/farmacologia , Antifúngicos/farmacologia , Complexos de Coordenação/farmacologia , Compostos Organofosforados/farmacologia , Fosfinas/farmacologia , Prata/farmacologia , Acinetobacter baumannii/efeitos dos fármacos , Antibacterianos/síntese química , Antibacterianos/química , Antifúngicos/síntese química , Antifúngicos/química , Candida albicans/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Cryptococcus neoformans/efeitos dos fármacos , Cristalografia por Raios X , Eritrócitos/efeitos dos fármacos , Escherichia coli/efeitos dos fármacos , Células HEK293 , Humanos , Klebsiella pneumoniae/efeitos dos fármacos , Ligantes , Modelos Moleculares , Compostos Organofosforados/química , Fosfinas/química , Pseudomonas aeruginosa/efeitos dos fármacos , Prata/química , Staphylococcus aureus/efeitos dos fármacos
12.
J Inorg Biochem ; 210: 111102, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32574870

RESUMO

Aiming at obtaining new copper complexes with good cytotoxicity against cancer cells, triphenylphosphine (TPP) was introduced to obtain insight into the influence of the co-ligands. In this paper, two copper complexes, Cu(2-pbmq)(CH3OH)Br2 (1) and [Cu(2-pbmq)(TPP)Br]2 (2) were designed, synthesized, and characterized by X-ray crystallography, 2-((2-(pyrazin-2-yl)-1H-benzo[d]imidazol-1-yl)methyl))quinolone (2-pbmq), to investigate the influence of the TPP group on the anticancer activity of the metal complex. Although the presence of the TPP group diminished the intensity of the interaction properties of the complex with DNA, the in vitro anticancer activity and cellular uptake of the TPP-containing complex were markedly superior to those of its TPP-lacking counterpart. Detailed studies on the more potently cytotoxic complex 2 revealed that it accumulated in nucleus, arrested the cell cycle at the G0-G1 phase, causing mitochondrial dysfunction, involving the potential simultaneous mitochondrial membrane collapse, cellular ATP level depletion, and Ca2+ leakage, eventually inducing cell apoptosis. In summary, the introduction of a TPP group enhances the biological activity and cytotoxicity of the complex.


Assuntos
Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Fosfinas/farmacologia , Trifosfato de Adenosina/metabolismo , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Cálcio/metabolismo , Linhagem Celular Tumoral , Complexos de Coordenação/química , Cobre/química , Ensaios de Seleção de Medicamentos Antitumorais , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Fosfinas/química
13.
J Inorg Biochem ; 210: 111124, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32534287

RESUMO

Biological activity against reference and multi-drug resistant (MDR) clinical strains of fluoroquinolones (FQs): ciprofloxacin (HCp), norfloxacin (HNr), lomefloxacin (HLm) and sparfloxacin (HSf), phosphine ligands derived from those antibiotics and 14 phosphino copper(I) and copper(II) complexes with 2,9-dimethyl-1,10-phenanthroline, 1,10-phenanthroline or 2,2'-biquinoline have been determined. Almost all phosphines showed excellent antibacterial activity relative to reference strains (S. aureus ATCC 6538, E. coli ATCC 25922, K. pneumoniae ATCC 4352, and P. aeruginosa ATCC 27853). In rare cases P. aeruginosa rods showed natural insensitivity to oxides, and their copper(II) complexes. Most of the studied compounds showed weak antibacterial activity against clinical multi-drug resistant strains (MDR P. aeruginosa 16, 46, 325, 355, MRD A. baumanii 483 and MDR S. aureus 177). However, phosphines Ph2PCH2Sf (PSf), Ph2PCH2Lm (PLm) and their copper(I) complexes were characterized by the best antibacterial activity. In addition, PSf compounds, in which the activities relative to P. aeruginosa MDRs were relatively diverse, paid particular attention in our studies. Genetic and phenotypic studies of these strains showed significant differences between the strains, indicating different profiles of FQs resistance mechanisms. This may prove that a change in the spatial conformation of the PSf derivatives relative to the native form of HSf increased its affinity for the target site of action in gyrase, leading to selective inhibition of the multiplication of MDR strains. In conclusion, differences in PSf activity within closely related P. aeruginosa strains may indicate its diagnostic and therapeutic potential.


Assuntos
Antibacterianos/farmacologia , Complexos de Coordenação/farmacologia , Fluoroquinolonas/farmacologia , Fosfinas/farmacologia , Antibacterianos/química , Bactérias/efeitos dos fármacos , Complexos de Coordenação/química , Cobre/química , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Fluoroquinolonas/química , Testes de Sensibilidade Microbiana , Estrutura Molecular , Fosfinas/química , Relação Estrutura-Atividade
14.
Dalton Trans ; 49(25): 8528-8539, 2020 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-32525156

RESUMO

The search for new antifungals is very important because the large genetic variation of pathogenic organisms has resulted in the development of increasingly effective defense mechanisms by microorganisms. Metal complexes as potential drugs are nowadays gaining interest, because they are characterized by accessible redox states of metal centers and a plethora of easily modifiable geometries. In this work we present two new copper(i) iodide or thiocyanide complexes with 2,9-dimethyl-1,10-phenanthroline (dmp) and a diphenylphosphane derivative of ketoconazole (KeP), where a ketoconazole acetyl group is replaced by the -CH2PPh2 unit, [CuI(dmp)KeP] (1-KeP) and [CuNCS(dmp)KeP] (2-KeP) - their synthesis and structural characteristics. The analysis of the intrinsic fluorescence of the ketoconazole moiety in the coordinated KeP molecule revealed that the copper(i) central atom does not act as a quencher and the observed decrease of fluorescence intensity is a result of a strong inner filter effect caused by the presence of the CuXdmp unit. Moreover, the complexes exhibit a remarkable MLCT (metal-ligand charge transfer) based phosphorescence with the emission maximum at 600-615 nm in aqueous media, which probably results from the formation of dimers and higher order oligomers in the most polar solutions. Both complexes proved to be promising antifungal agents towards Candida albicans, showing a relatively high efficiency towards the fluconazole resistant strains with -CDR1 and CDR2 or MDR1 efflux pump overexpression, which suggests that they overcome at least partially these defense mechanisms. Simulations of docking to the cytochrome P450 14α-demethylase (the azoles' primary molecular target) suggested that the compounds studied were rather incapable of competitively inhibiting this enzyme, unlike ketoconazole and the KeP ligand. On the other hand, the phosphorescence in aqueous solutions allowed recording the confocal micrographs of the complexes which showed that both of them are situated in spherical structures inside the cells, most likely in the vacuoles.


Assuntos
Antifúngicos/farmacologia , Candida albicans/efeitos dos fármacos , Complexos de Coordenação/farmacologia , Inibidores das Enzimas do Citocromo P-450/farmacologia , Sistema Enzimático do Citocromo P-450/metabolismo , Imagem Óptica , Adulto , Antifúngicos/síntese química , Antifúngicos/química , Candida albicans/citologia , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Cobre/química , Cobre/farmacologia , Inibidores das Enzimas do Citocromo P-450/síntese química , Inibidores das Enzimas do Citocromo P-450/química , Humanos , Cetoconazol/química , Cetoconazol/farmacologia , Medições Luminescentes , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Estrutura Molecular , Fenantrolinas/química , Fenantrolinas/farmacologia , Fosfinas/química , Fosfinas/farmacologia
15.
Dalton Trans ; 49(23): 7852-7861, 2020 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-32463416

RESUMO

This work describes the synthesis of the gold(i) complexes of phosphine sulphides. The formation of these new derivatives has been confirmed by X-ray crystallography. The coordination of gold(i) with the sulphur atom of the phosphine sulphides favors the inhibition of topoisomerase I as well as a high cytotoxicity of the gold(i)-complexed compounds against the cancer line A549 with IC50 values in the nanomolar range and IC50 values below 5 µM against the SKOV3 cell line. It should be noted that the cytotoxicities observed for the new gold(i) complexes are higher than those observed for phosphine sulphide ligands before binding to gold. Furthermore, the results also indicate that the presence of a nitrogenated heterocycle, such as tetrahydroquinoline or quinoline, is also necessary for the TopI inhibition to be maintained. In addition, no toxicity was observed when the non-cancerous lung fibroblast cell line (MRC5) was treated with the new phosphine sulphide gold(i) complexes prepared.


Assuntos
Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , DNA Topoisomerases Tipo I/metabolismo , Inibidores da Topoisomerase I/farmacologia , Células A549 , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Cristalografia por Raios X , Teoria da Densidade Funcional , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Ouro/química , Ouro/farmacologia , Humanos , Modelos Moleculares , Estrutura Molecular , Fosfinas/química , Fosfinas/farmacologia , Relação Estrutura-Atividade , Sulfetos/química , Sulfetos/farmacologia , Inibidores da Topoisomerase I/síntese química , Inibidores da Topoisomerase I/química
16.
Dalton Trans ; 49(22): 7355-7363, 2020 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-32432621

RESUMO

Ovarian cancer is a highly aggressive disease which is treated by surgery and platinum chemotherapy. However, a significant proportion of treated patients develop resistance to platinum treatment resulting in tumor relapse. Acquired platinum resistance has been recently correlated with activation of pro-survival endoplasmic reticulum (ER) stress responses. We hypothesized that Au complexes that induce severe ER stress might counteract pro-survival cellular attempts leading to the ER stress-mediated apoptosis and reduced platinum resistance. In this work, we prepared a series of highly cytotoxic AuI-dialkyldithiocarbamate complexes and investigated their anticancer potential in ovarian cancer cells. Complexes demonstrated surprisingly low stability in chloroform, resulting in the formation of an Au chain polymer, which also displayed excellent cytotoxicity. Lead complex 2 induced oxidative stress and ER stress-mediated p53-independent apoptosis associated with PARP cleavage and cell cycle arrest at G2/M phase. Importantly, 2 caused the surface exposure of calreticulin (CRT), which is the first step in the activation of cellular immunogenic response.


Assuntos
Antineoplásicos/farmacologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Estresse do Retículo Endoplasmático/imunologia , Compostos Organoáuricos/farmacologia , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/imunologia , Fosfinas/farmacologia , Tiocarbamatos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Estrutura Molecular , Compostos Organoáuricos/síntese química , Compostos Organoáuricos/química , Neoplasias Ovarianas/patologia , Estresse Oxidativo/efeitos dos fármacos , Fosfinas/química , Tiocarbamatos/química , Células Tumorais Cultivadas
17.
Molecules ; 25(7)2020 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-32235326

RESUMO

Phosphine resistance is a worldwide issue threatening the grain industry. The cuticles of insects are covered with a layer of lipids, which protect insect bodies from the harmful effects of pesticides. The main components of the cuticular lipids are hydrocarbon compounds. In this research, phosphine-resistant and -susceptible strains of two main stored-grain insects, T. castaneum and R. dominica, were tested to determine the possible role of their cuticular hydrocarbons in phosphine resistance. Direct immersion solid-phase microextraction followed by gas chromatography-mass spectrometry (GC-MS) was applied to extract and analyze the cuticular hydrocarbons. The results showed significant differences between the resistant and susceptible strains regarding the cuticular hydrocarbons that were investigated. The resistant insects of both species contained higher amounts than the susceptible insects for the majority of the hydrocarbons, sixteen from cuticular extraction and nineteen from the homogenized body extraction for T. castaneum and eighteen from cuticular extraction and twenty-one from the homogenized body extraction for R. dominica. 3-methylnonacosane and 2-methylheptacosane had the highest significant difference between the susceptible and resistant strains of T. castaneum from the cuticle and the homogenized body, respectively. Unknown5 from the cuticle and 3-methylhentriacontane from the homogenized body recorded the highest significant differences in R. dominica. The higher hydrocarbon content is a key factor in eliminating phosphine from entering resistant insect bodies, acting as a barrier between insects and the surrounding phosphine environment.


Assuntos
Alcanos/isolamento & purificação , Besouros/efeitos dos fármacos , Resistência a Inseticidas/fisiologia , Inseticidas/farmacologia , Fosfinas/farmacologia , Tribolium/efeitos dos fármacos , Alcanos/química , Alcanos/classificação , Animais , Besouros/química , Besouros/fisiologia , Misturas Complexas/química , Grão Comestível/parasitologia , Cromatografia Gasosa-Espectrometria de Massas , Tegumento Comum/fisiologia , Microextração em Fase Sólida , Tribolium/química , Tribolium/fisiologia , Triticum/parasitologia
18.
Bioorg Med Chem ; 28(4): 115310, 2020 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-31980362

RESUMO

Increasing structural options in medicinal chemistry is important for the development of novel and distinctive drug candidates. In this study, we focused on phosphorus-containing functionalities. We designed and synthesized a series of phosphinophenol derivatives and determined their physicochemical properties, including hydrophobicity parameter LogP, and their biological activity toward estrogen receptor (ER). Notably, the phosphine borane derivatives (9 and 14) exhibited potent ER-antagonistic activity, exceeding the potency of the corresponding alkane (15) and silane (16) derivatives, despite having a less hydrophobic nature. The determined physicochemical parameters will be helpful for the rational design of phosphorus-containing biologically active compounds. Our results indicate that phosphine boranes are a promising new chemical entry in the range of structural options for drug discovery.


Assuntos
Boranos/farmacologia , Moduladores de Receptor Estrogênico/farmacologia , Fenóis/farmacologia , Fosfinas/farmacologia , Receptores de Estrogênio/antagonistas & inibidores , Alcanos/química , Boranos/química , Relação Dose-Resposta a Droga , Moduladores de Receptor Estrogênico/síntese química , Moduladores de Receptor Estrogênico/química , Humanos , Interações Hidrofóbicas e Hidrofílicas , Estrutura Molecular , Fenóis/síntese química , Fenóis/química , Fosfinas/química , Receptores de Estrogênio/metabolismo , Silanos/química , Relação Estrutura-Atividade
19.
Redox Biol ; 28: 101310, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31514052

RESUMO

Multiple myeloma (MM), the second most common haematological malignancy, is a clonal plasma B-cell neoplasm that forms within the bone marrow. Despite recent advancements in treatment, MM remains an incurable disease. Auranofin, a linear gold(I) phosphine compound, has previously been shown to exert a significant anti-myeloma activity by inhibiting thioredoxin reductase (TrxR) activity. A bis-chelated tetrahedral gold(I) phosphine complex [Au(d2pype)2]Cl (where d2pype is 1,2-bis(di-2-pyridylphosphino)ethane) was previously designed to improve the gold(I) compound selectivity towards selenol- and thiol-containing proteins, such as TrxR. In this study, we show that [Au(d2pype)2]Cl significantly inhibited TrxR activity in both bortezomib-sensitive and resistant myeloma cells, which led to a significant reduction in cell proliferation and induction of apoptosis, both of which were dependent on ROS. In clonogenic assays, treatment with [Au(d2pype)2]Cl completely abrogated the tumourigenic capacity of MM cells, whereas auranofin was less effective. We also show that [Au(d2pype)2]Cl exerted a significant anti-myeloma activity in vivo in human RPMI8226 xenograft model in immunocompromised NOD/SCID mice. The MYC oncogene, known to drive myeloma progression, was downregulated in both in vitro and in vivo models when treated with [Au(d2pype)2]Cl. This study highlights the "proof of concept" that improved gold(I)-based compounds could potentially be used to not only treat MM but as an alternative tool to understand the role of the Trx system in the pathogenesis of this blood disease.


Assuntos
Ouro/química , Mieloma Múltiplo/tratamento farmacológico , Fosfinas/administração & dosagem , Tiorredoxina Dissulfeto Redutase/antagonistas & inibidores , Animais , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Regulação para Baixo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Mieloma Múltiplo/enzimologia , Mieloma Múltiplo/genética , Fosfinas/química , Fosfinas/farmacologia , Proteínas Proto-Oncogênicas c-myc/genética , Ensaios Antitumorais Modelo de Xenoenxerto
20.
J Med Chem ; 63(5): 2455-2469, 2020 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-31841324

RESUMO

Fungi cause serious nosocomial infections including candidiasis and aspergillosis, some of which display reduced susceptibility to current antifungals. Inorganic compounds have been found to be beneficial against various medical ailments but have yet to be applied to fungal infections. Here, we explore the activity of linear and square-planar gold(I)-phosphine complexes against a panel of 28 fungal strains including Candida spp., Cryptococcus spp., Aspergillus spp., and Fusarium spp. Notably, two square-planar gold(I) complexes with excellent broad-spectrum activity display potent antifungal effects against strains of Candida auris, an emerging multidrug-resistant fungus that presents a serious global health threat. To characterize the biological activity of these gold(I) complexes, we used a series of time-kill studies, cytotoxicity and hemolysis assays, as well as whole-cell uptake and development of resistance studies.


Assuntos
Antifúngicos/farmacologia , Complexos de Coordenação/farmacologia , Fungos/efeitos dos fármacos , Ouro/farmacologia , Fosfinas/farmacologia , Antifúngicos/química , Complexos de Coordenação/química , Ouro/química , Humanos , Testes de Sensibilidade Microbiana , Modelos Moleculares , Micoses/tratamento farmacológico , Fosfinas/química
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