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1.
Theriogenology ; 140: 188-200, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31479835

RESUMO

Despite conflicting data on doxorubicin (DOX) reproductive toxicity, its chemotherapeutic potential sustains its use to treat different types of cancer. This work was designed to study the protective effect of a newly synthesized thiocyanoacetamide (TA), in comparison with selenium (Se), against doxorubicin-induced in vitro toxicity in rat Sertoli cells (SCs). DOX was administered alone or in combination with Se or TA. The possible protective role of increased concentrations of TA (0.25, 0.5 and 1 mM) or Se (12, 25 and 50 µM) on SCs was tested against 1 µM of DOX. From this screening, only the least toxic doses of TA and Se were used for further analysis. DOX cytotoxicity, as well as its impact on SCs viability, mitochondrial membrane potential (ΔΨm), oxidative stress biomarkers, apoptosis and autophagy were assessed. Our results showed that DOX exerted its cytotoxic effect through a significant increase in cell death. DOX-mediated cell death was not related to autophagy nor to an overproduction of reactive oxygen species. It was rather due to apoptosis, as shown by the increased number of apoptotic cells and increased activity of caspase-3, or due to necrosis, as shown by the increase in lactate dehydrogenase (LDH) extracellular activity. Still, Bax and Bcl-2 protein expression levels, as well as ΔΨm were not altered by the different treatments. Some individual doses of Se or TA induced a significant toxicity in SCs, however, when combined with DOX, there was a decrease in cell death, LDH extracellular activity, number of apoptotic cells and caspase-3 activity. Overall, our results indicate that DOX-mediated apoptosis in cultured SCs can possibly be averted through its association with specific doses of Se or TA. Nevertheless, TA showed a higher efficiency than Se in reducing DOX-induced toxicity in SCs by decreasing not only apoptosis, but also necrosis and autophagy.


Assuntos
Antibióticos Antineoplásicos/toxicidade , Doxorrubicina/toxicidade , Substâncias Protetoras/farmacologia , Células de Sertoli/efeitos dos fármacos , Tioamidas/farmacologia , Animais , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Biomarcadores/metabolismo , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Estresse Oxidativo , Ratos , Tioamidas/química
2.
ACS Chem Biol ; 14(8): 1819-1828, 2019 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-31365229

RESUMO

Thioviridamide, prethioviridamide, and JBIR-140, which are ribosomally synthesized and post-translationally modified peptides (RiPPs) possessing five thioamide bonds, induce selective apoptosis in various cancer cells, especially those expressing the adenovirus oncogene E1A. However, the target protein of this unique family of bioactive compounds was previously unknown. To investigate the mechanism of action, we adopted a combined approach of genome-wide shRNA library screening, transcriptome profiling, and biochemical identification of prethioviridamide-binding proteins. An shRNA screen identified 63 genes involved in cell sensitivity to prethioviridamide, which included translation initiation factors, aminoacyl tRNA synthetases, and mitochondrial proteins. Transcriptome profiling and subsequent analysis revealed that prethioviridamide induces the integrated stress response (ISR) through the GCN2-ATF4 pathway, which is likely to cause cell death. Furthermore, we found that prethioviridamide binds and inhibits respiratory chain complex V (F1Fo-ATP synthase) in mitochondria, suggesting that inhibition of complex V leads to activation of the GCN2-ATF4 pathway. These results imply that the members of a unique family of RiPPs with polythioamide structure target mitochondria to induce the ISR.


Assuntos
Antineoplásicos/farmacologia , Oligopeptídeos/farmacologia , Tioamidas/farmacologia , Fator 4 Ativador da Transcrição/metabolismo , Animais , Antineoplásicos/química , Perfilação da Expressão Gênica , Células HeLa , Humanos , Mitocôndrias/metabolismo , Oligopeptídeos/química , Proteínas Quinases/metabolismo , Processamento de Proteína Pós-Traducional , ATPases Translocadoras de Prótons/antagonistas & inibidores , RNA/metabolismo , Ratos , Transdução de Sinais/fisiologia , Tioamidas/química
3.
Bioorg Chem ; 88: 102941, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31039470

RESUMO

Hydrogen sulfide (H2S) is a biologically important gaseous molecule that exhibits promising protective effects against a variety of pathological processes. For example, it was recognized as a blood pressure lowering agent. Aligned with the need for easily modifiable platforms for the H2S supply, we report here the preparation and the H2S release kinetics from a series of structurally diversified thioamides, thiolactams and thioureas. Three different thionation methods based on the usage of a phosphorus pentasulfide and Lawesson reagent were applied to prepare the target thioamides and thiolactams. Furthermore, obtained H2S donors were evaluated both in in vivo and in vitro studies. The kinetic parameters of the liberating H2S was determined and compared with NaHS and GYY4137 using two different detection technics i.e.; fluorescence labeling 7-azido-4-methyl-2H-chromen-2-one and 5,5'-dithiobis (2-nitrobenzoic acid), sulfhydryl probe, also known as the Ellman's reagent. We have proved that the amount of releasing H2S from these compounds is controllable through structural modifications. Finally, the present study shows a hypotensive response to an intravenous administration of the developed donors in the anesthetized rats.


Assuntos
Pressão Sanguínea/efeitos dos fármacos , Sulfeto de Hidrogênio/análise , Lactamas/farmacologia , Tioamidas/farmacologia , Tioureia/farmacologia , Administração Intravenosa , Animais , Cinética , Lactamas/administração & dosagem , Lactamas/química , Masculino , Ratos , Ratos Sprague-Dawley , Tioamidas/administração & dosagem , Tioamidas/química , Tioureia/administração & dosagem , Tioureia/química
4.
Chembiochem ; 20(16): 2059-2062, 2019 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-30950552

RESUMO

Thioamide substitutions of the peptide backbone have been shown to reduce proteolytic degradation, and this property can be used to generate competitive protease inhibitors and to stabilize peptides toward degradation in vivo. Here, we present a straightforward sensor design that allows a systematic study of the positional effects of thioamide substitution by using real-time fluorescence. Thioamide scanning in peptide substrates of five papain family cysteine proteases demonstrates that a thioamide at or near the scissile bond can slow proteolysis in all cases, but that the magnitude of the effects varies with position and protease in spite of high sequence homology. Mechanistic investigation of papain proteolysis reveals that the thioamide effects derive from reductions in both affinity (KM ) and turnover number (kcat ). Computational modeling allows these effects to be understood based on disruption of key enzyme-substrate hydrogen bonds, providing a model for future rational use of thioamides to confer cysteine protease resistance.


Assuntos
Cisteína Proteases/metabolismo , Corantes Fluorescentes/química , Peptídeos/farmacologia , Inibidores de Proteases/farmacologia , Proteólise/efeitos dos fármacos , Tioamidas/farmacologia , Corantes Fluorescentes/síntese química , Peptídeos/síntese química , Peptídeos/química , Inibidores de Proteases/síntese química , Inibidores de Proteases/química , Tioamidas/química
5.
Ann Pharm Fr ; 77(2): 126-135, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30709547

RESUMO

OBJECTIVES: This work aims at getting more insights into the distinct behavior of S-oxide derivatives of thiocarbonyl-containing antitubercular drugs, in order to better understand their mechanism of action and toxicity. METHODS: Computational calculation of relative free energy (ΔΔG) of S-oxide tautomers (sulfine R-C [SO]NH2), sulfenic acid (R-C [S-OH]NH) and sulfoxide (R-C [SHO]NH) derived from thioamide and thiourea antitubercular drugs and an update of the literature data with a new point of view about how the structural features of oxidized primary metabolites (S-oxide) can influence the outcome of the reactions and be determinant for the mechanisms of action and of toxicity of these drugs. RESULTS: The calculated free energy of S-oxide tautomers, derived from thioamide and thiourea-type antitubercular drugs, supported by some experimental results, revealed that S-oxide derivatives could be found under sulfine and sulfenic acid forms depending on their chemical structures. Thiocarbonyl compounds belonging to the thioamide series are firstly oxidized, in the presence of H2O2, into the corresponding S-oxide derivatives that are more stable under the sulfine tautomeric form. Otherwise, S-oxides of thiourea-type (acyclic and cyclic) compounds tend to adopt the sulfenic acid tautomeric form preferentially. While the intermediate ethionamide-SO under sulfine form can be isolated and in the presence of H2O2 can undergo further oxidation by a mechanism yielding radical species that are toxic for Mycobacterium tuberculosis and human, thioacetazone-SO, found mainly into sulfenic acid form, is unstable and sufficiently reactive in biological conditions to intercept different biochemical pathways and manifests thus its toxicity. CONCLUSION: Based on experimental and theoretical data, we propose that S-oxide derivatives of thioamide and thiourea-type antitubercular drugs have preference for distinct tautomeric forms. S-oxide of ethioamide is preferentially under sulfine form whereas S-oxide of thiourea compound as thioacetazone is mainly found under sulfenic acid form. These structural features lead to individual chemical reactivities that might explain the distinct mechanism of action and toxicity observed for the thioamide and thiourea antitubercular drugs.


Assuntos
Antituberculosos/química , Antituberculosos/farmacologia , Óxidos/química , Óxidos/farmacologia , Antituberculosos/toxicidade , Cromatografia Líquida de Alta Pressão , Óxidos/toxicidade , Estereoisomerismo , Ácidos Sulfênicos/química , Tioamidas/química , Tioamidas/farmacologia , Tioamidas/toxicidade , Tioureia/química , Tioureia/farmacologia , Tioureia/toxicidade
6.
J Antibiot (Tokyo) ; 72(5): 260-270, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30755737

RESUMO

A new thiourea ligand (HL), namely N-(4-chlorophenyl)morpholine-4-carbothioamide and its Co(III), Ni(II) and Ag(I) complexes (1a, 1b and 1c) were synthesized and investigated by Fourier-transform infrared, 1H NMR and UV-visible spectroscopies. The compounds HL and 1c were characterized by single-crystal X-ray crystallography revealing the triclinic space group P[Formula: see text] for both compounds. The inhibitory effect of HL ligand, 1a, 1b, and 1c complexes was investigated with in vitro tests on Gram-positive and Gram-negative bacteria. For the 1c complex, the results showed that the coordination of the HL to Ag(I) ion increased its antibacterial effect especially against E. coli. The assays also indicated that for the same bacteria strains, the new complexes showed higher activity than the ligand, with the relative activity 1c > 1b > 1a > HL. Moreover, all samples were more suitable antimicrobial agents against the Gram-negative than those of the Gram-positive bacteria. Eventually, the relationship between the structure and bactericidal activities of these specimens was examined by calculating frontier molecular orbital (HOMO and LUMO) energies using density functional theory method at the 6-31 G*/LANL2DZ level of theory.


Assuntos
Antibacterianos/farmacologia , Complexos de Coordenação/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Morfolinas/farmacologia , Tioamidas/farmacologia , Tioureia/metabolismo , Antibacterianos/síntese química , Antibacterianos/química , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Cristalografia por Raios X , Espectroscopia de Ressonância Magnética , Testes de Sensibilidade Microbiana , Estrutura Molecular , Morfolinas/síntese química , Morfolinas/química , Espectrofotometria Ultravioleta , Espectroscopia de Infravermelho com Transformada de Fourier , Tioamidas/síntese química , Tioamidas/química
7.
Curr Org Synth ; 16(7): 1055-1066, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31984886

RESUMO

BACKGROUND: Oxidative stress due to high levels of reactive organic species is the cause of the progression of inflammation in various diseases. The molecules possessing both anti-inflammatory and antioxidant activity can be the promising key to treat inflammatory diseases. Phthalimide and hydrazinecarbothioamide are anti-inflammatory and anti-oxidant pharmacophores. OBJECTIVE: Molecular hybrids possessing above two pharmacophores were designed. A series of N-phenyl substituted 2-(2-(1,3-dioxoisoindolin-2-yl)acetyl)-N-phenylhydrazine-1-carbothioamide (CGS compounds) was synthesized and evaluated for biological activities. METHODS: N-phthaloylglycyl hydrazide was reacted with unsubstituted/substituted phenyl isothiocyanates to yield CGS compounds. Synthesized compounds were evaluated for in vivo anti-inflammatory activity in carrageenan rat paw edema model, and in vitro anti-oxidant activity by DPPH assay. Levels of TNF-α and oxidative stress at the site of inflammation were measured. The genetic algorithm-PLS regression based QSAR model correlating the effect of N-phenyl substituent on the anti-inflammatory activity was developed. Further, the interaction of the active compound in the TNF-α binding pocket was studied by in silico docking. RESULTS: Compound containing the 2-OCH3, 4-NO2 (CGS-5); 4-CF3 (CGS-9); 4-NO2 (CGS-3) showed significant anti-inflammatory activity (percentage inhibition of paw edema after 3 hour = 58.24, 50.38, 40.05, respectively) and potent anti-oxidant activity (IC50 =0.045, 0.998, 0.285 µg/ml, respectively). Reduced levels of TNF- α and increased levels of GSH were observed for the above three compounds. Descriptors for QSAR model identified by GA-PLS were WPSA1, Weta1unity, WDunity, SC3, VC5, MlogP, and WTPT3. The identified model was highly predictive, and value of root mean square error of prediction for internal (leave one out) and external validation was: 1.579, 1.325. CONCLUSION: Molecular hybrids of phthalimide and hydrazinecarbothioamide were synthesized. Some of the compounds possessed promising anti-inflammatory and anti-oxidant activities.


Assuntos
Anti-Inflamatórios/química , Antioxidantes/química , Hidrazinas/química , Ftalimidas/química , Tioamidas/química , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/farmacologia , Antioxidantes/síntese química , Antioxidantes/farmacologia , Técnicas de Química Sintética , Desenho de Fármacos , Edema/tratamento farmacológico , Hidrazinas/síntese química , Hidrazinas/farmacologia , Modelos Moleculares , Estresse Oxidativo/efeitos dos fármacos , Ftalimidas/síntese química , Ftalimidas/farmacologia , Ratos Wistar , Tioamidas/síntese química , Tioamidas/farmacologia
8.
Biochem Biophys Res Commun ; 509(1): 209-215, 2019 01 29.
Artigo em Inglês | MEDLINE | ID: mdl-30579605

RESUMO

Melanin plays an important role in the protection of the skin from ultraviolet irradiation. However, excessive melanin deposition leads to hyperpigmentation and freckles, which are recognized as skin problems, and signs of aging. Tyrosinase, a copper-containing protein, is the rate-limiting enzyme in melanin biosynthesis and first catalyzes the hydroxylation of l-tyrosine to 3,4-dihydroxyphenylalanine (DOPA) and the further oxidization to dopaquinone. To assist the proper regulation of melanin production, we screened compounds and found that 5,6,7,8-tetrahydro-4H-furo[3,2-c]azepine-4-thione (T4FAT), a thioamide derivative, inhibited melanogenesis in B16F10 mouse melanoma cells. T4FAT was not toxic to cells and was stable in water; in addition, it inhibited the activity of tyrosinase derived from mushroom and B16F10 cells in a non-competitive manner. T4FAT downregulated tyrosinase protein expression in B16F10 cells without affecting mRNA expression. As copper binding to the tyrosinase protein is required for both enzymatic activity, correct folding, and maturation, we examined the metal-chelating activities of T4FAT. Equimolar amount of T4FAT resulted in almost complete chelation of copper ions. The thioamide group of T4FAT is essential for copper chelation and tyrosinase inhibition, which subsequently resulted in melanogenesis inhibition in B16F10 cells. Although T4FAT has similar in vitro properties to kojic acid, which is also a copper chelator and approved as a component of cosmetic formulations, T4FAT inhibited melanogenesis in B16F10 cells 30 times more efficiently than kojic acid. These results suggested that T4FAT, a novel copper chelator, may be helpful for the development of new cosmetics for skin whitening.


Assuntos
Azepinas/química , Azepinas/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Melaninas/metabolismo , Monofenol Mono-Oxigenase/antagonistas & inibidores , Agaricales/enzimologia , Animais , Linhagem Celular Tumoral , Quelantes/química , Quelantes/farmacologia , Cobre/metabolismo , Melaninas/antagonistas & inibidores , Melanoma Experimental/enzimologia , Melanoma Experimental/metabolismo , Camundongos , Monofenol Mono-Oxigenase/metabolismo , Tioamidas/química , Tioamidas/farmacologia
9.
Invest New Drugs ; 37(5): 849-864, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-30498945

RESUMO

It has been shown previously that molecules built on benzanilide and thiobenzanilide scaffolds possess differential biological properties including selective anticancer activity. In our previous study, we examined the cytotoxic activity and mechanism of action of the thiobenzanilide derivative N,N'-(1,2-phenylene)bis3,4,5-trifluorobenzothioamide (63 T) as a potential chemotherapeutic compound in an experimental model employing A549 lung adenocarcinoma cells and CCD39Lu non-tumorigenic lung fibroblasts. Since the results suggested oxidative stress as a co-existing mechanism of the cytotoxic effect exerted by 63 T on tested cells, studies involving the analysis of reactive oxygen species (ROS) generation and markers of oxidative stress in cells incubated with 63 T were carried out. It may be concluded that the selective activity of 63 T against cancer cells shown in our experiments is caused, at least in part, by the response of the tested cells to 63 T mediated oxidative stress in both tested cell lines.


Assuntos
Adenocarcinoma de Pulmão/patologia , Antineoplásicos/farmacologia , Derivados de Benzeno/farmacologia , Fibroblastos/patologia , Neoplasias Pulmonares/patologia , Pulmão/patologia , Estresse Oxidativo/efeitos dos fármacos , Tioamidas/farmacologia , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/metabolismo , Apoptose , Proliferação de Células , Células Cultivadas , Dano ao DNA/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Humanos , Peroxidação de Lipídeos/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Espécies Reativas de Oxigênio/metabolismo
10.
Angew Chem Int Ed Engl ; 57(43): 14080-14084, 2018 10 22.
Artigo em Inglês | MEDLINE | ID: mdl-30193003

RESUMO

Closthioamide (CTA) is a unique symmetric nonribosomal peptide with six thioamide moieties that is produced by the Gram-positive obligate anaerobe Ruminiclostridium cellulolyticum. CTA displays potent inhibitory activity against important clinical pathogens, making it a promising drug candidate. Yet, the biosynthesis of this DNA gyrase-targeting antibiotic has remained enigmatic. Using a combination of genome mining, genome editing (targeted group II intron, CRISPR/Cas9), and heterologous expression, we show that CTA biosynthesis involves specialized enzymes for starter unit biosynthesis, amide bond formation, thionation, and dimerization. Surprisingly, CTA biosynthesis involves a novel thiotemplated peptide assembly line that markedly differs from known nonribosomal peptide synthetases. These findings provide the first insights into the biosynthesis of thioamide-containing nonribosomal peptides and offer a starting point for the discovery of related natural products.


Assuntos
Antibacterianos/química , Bactérias Anaeróbias/química , Clostridiales/química , Edição de Genes , Tioamidas/química , Antibacterianos/farmacologia , Bactérias Anaeróbias/genética , Sistemas CRISPR-Cas , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Cromatografia Líquida de Alta Pressão , Clostridiales/genética , DNA Girase/efeitos dos fármacos , Genes Bacterianos , Íntrons , Espectrometria de Massas , Família Multigênica , Peptídeo Sintases/química , Espectroscopia de Prótons por Ressonância Magnética , Tioamidas/farmacologia
11.
Eur J Med Chem ; 159: 35-46, 2018 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-30268015

RESUMO

Ethionamide is a key antibiotic prodrug of the second-line chemotherapy regimen to treat tuberculosis. It targets the biosynthesis of mycolic acids thanks to a mycobacterial bioactivation carried out by the Baeyer-Villiger monooxygenase EthA, under the control of a transcriptional repressor called EthR. Recently, the drug-like molecule SMARt-420, which triggers a new transcriptional regulator called EthR2, allowed the derepression a cryptic alternative bioactivation pathway of ethionamide. In order to study the bioactivation of a collection of thioisonicotinamides through the two bioactivation pathways, we developed a new two-step chemical pathway that led to the efficient synthesis of eighteen ethionamide analogues. Measurements of the antimycobacterial activity of these derivatives, used alone and in combination with boosters BDM41906 or SMARt-420, suggest that the two different bioactivation pathways proceed via the same mechanism, which implies the formation of similar metabolites. In addition, an electrochemical study of the aliphatic thioisonicotinamide analogues was undertaken to see whether their oxidation potential correlates with their antitubercular activity measured in the presence or in the absence of the two boosters.


Assuntos
Antituberculosos/farmacologia , Etionamida/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Tioamidas/farmacologia , Antituberculosos/síntese química , Antituberculosos/química , Relação Dose-Resposta a Droga , Etionamida/química , Testes de Sensibilidade Microbiana , Estrutura Molecular , Relação Estrutura-Atividade , Tioamidas/química
12.
Bioorg Chem ; 81: 79-87, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30118988

RESUMO

A series of N-aryl-2-phenyl-hydrazinecarbothioamides have been investigated as possible inhibitors of tyrosinase, an enzyme involved in the development of melanomas. The hydrazinecarbothioamides 1-6 were synthesized from the reaction between phenylhydrazine and isothiocyanates, for which three different methods have been employed, namely stirring at room temperature, by microwave irradiation or by mechanochemical grinding. Quantitative yields were obtained for the later technique. Compound 4 showed the best value for tyrosinase inhibition (IC50 = 22.6 µM), which occurs through an uncompetitive mechanism. Molecular docking results suggested that 4 can interact via T-stacking with the substrate L-DOPA and via hydrogen bonding and hydrophobic forces with the amino acid residues Ala-79, His-243, Val-247, Phe-263, Val-282, and Glu-321. The interaction between human serum albumin (HSA) and compound 4 occurs through a ground state association and does not perturb the secondary structure of the albumin as well as the microenvironment around Tyr and Trp residues. The binding is spontaneous, moderate and occurs mainly in the Sudlow's site I. Molecular docking results suggested hydrogen bonding, hydrophobic and electrostatic interactions as the main binding forces between the compound 4 and the amino acid residues Lys-198, Trp-214, Glu-449, Leu-452, and Leu-480.


Assuntos
Inibidores Enzimáticos/farmacologia , Hidrazinas/farmacologia , Monofenol Mono-Oxigenase/antagonistas & inibidores , Albumina Sérica Humana/antagonistas & inibidores , Tioamidas/farmacologia , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Hidrazinas/síntese química , Hidrazinas/química , Simulação de Acoplamento Molecular , Estrutura Molecular , Monofenol Mono-Oxigenase/metabolismo , Albumina Sérica Humana/química , Relação Estrutura-Atividade , Tioamidas/síntese química , Tioamidas/química
13.
ACS Infect Dis ; 4(8): 1257-1263, 2018 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-29750860

RESUMO

In response to the urgent need for new antibiotic development strategies, antimicrobial peptides and their synthetic mimetics are being investigated as promising alternatives to traditional antibiotics. To facilitate their development into clinically viable candidates, we need to understand what molecular features and physicochemical properties are needed to induce cell death. Within the context of sequence-defined oligothioetheramides (oligoTEAs), we explore the impact of the cationic pendant group and backbone hydrophobicity on the potency and selectivity of antibacterial oligoTEAs. Through antibacterial, cytotoxicity, membrane destabilization, and membrane depolarization assays, we find a strong dependency on the nature of the cationic group and improved selectivity toward bacteria by tuning backbone hydrophobicity. In particular, compounds with the guanidinium headgroup are more potent than those with amines. Finally, we identify a promising oligoTEA, PDT-4G, with enhanced activity in vitro (minimum inhibitory concentration (MIC) ∼ 0.78 µM) and moderate activity in a mouse thigh infection model of methicillin-resistant Staphylococcus aureus. The studies outlined in this work provide insights into the effect of macromolecular physicochemical properties on antibacterial potency. This knowledge base will be vital for researchers engaged in the ongoing development of clinically viable antibacterial agents.


Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Tioamidas/química , Tioamidas/farmacologia , Animais , Antibacterianos/administração & dosagem , Cátions/administração & dosagem , Cátions/química , Cátions/farmacologia , Modelos Animais de Doenças , Interações Hidrofóbicas e Hidrofílicas , Camundongos , Testes de Sensibilidade Microbiana , Infecções Estafilocócicas/tratamento farmacológico , Tioamidas/administração & dosagem , Resultado do Tratamento
14.
Bioorg Chem ; 77: 56-67, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29331765

RESUMO

Even after considerable advances in the field of epilepsy treatment, convulsions are inefficiently controlled by standard drug therapy. Herein, a series of pyrimidine-carbothioamide derivatives 4(a-t) was designed as anticonvulsant agents by doing some important structural modifications in well-known anticonvulsant drugs. Two classical animal models were used for the in vivo anticonvulsant screening, maximum electroshock seizure (MES) and subcutaneous pentylenetetrazole (scPTZ) models; followed by motor impairment study by rotarod method. The most active compound 4g effectively suppressed seizure effect in both the animal models with median doses of 15.6 mg/kg (MES ED50), 278.4 mg/kg (scPTZ ED50) and 534.4 mg/kg (TD50) with no sign of neurotoxicity. Furthermore, in vitro GABA-AT enzyme activity assay of 4g showed inhibitory potency (IC50) of 12.23 µM. The docking study also favored the animal studies.


Assuntos
4-Aminobutirato Transaminase/antagonistas & inibidores , Anticonvulsivantes/farmacologia , Inibidores Enzimáticos/farmacologia , Pirimidinas/farmacologia , Convulsões/tratamento farmacológico , Tioamidas/farmacologia , 4-Aminobutirato Transaminase/metabolismo , Animais , Anticonvulsivantes/síntese química , Anticonvulsivantes/química , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Eletrochoque , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Masculino , Camundongos , Modelos Moleculares , Estrutura Molecular , Pentilenotetrazol , Pirimidinas/síntese química , Pirimidinas/química , Convulsões/induzido quimicamente , Relação Estrutura-Atividade , Tioamidas/síntese química , Tioamidas/química
15.
ACS Chem Biol ; 12(11): 2815-2822, 2017 11 17.
Artigo em Inglês | MEDLINE | ID: mdl-28968491

RESUMO

Thioviridamide is a structurally novel ribosomally synthesized and post-translational modified peptide (RiPP) produced by Streptomyces olivoviridis NA005001. It is characterized by a structure that features a series of thioamide groups and possesses potent antiproliferative activity in cancer cell lines. Its unusual structure allied to its promise as an anticancer compound led us to investigate the diversity of thioviridamide-like pathways across sequenced bacterial genomes. We have isolated and characterized three diverse members of this family of natural products. This characterization is supported by transformation-associated recombination cloning and heterologous expression of one of these compounds, thiostreptamide S4. Our work provides an insight into the diversity of this rare class of compound and indicates that the unusual N-terminus of thioviridamide is not introduced biosynthetically but is instead introduced during acetone extraction. A detailed analysis of the biological activity of one of the newly discovered compounds, thioalbamide, indicates that it is highly cytotoxic to cancer cells, while exhibiting significantly less activity toward a noncancerous epithelial cell line.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Família Multigênica , Peptídeos Cíclicos/química , Peptídeos Cíclicos/farmacologia , Streptomyces/genética , Tioamidas/química , Tioamidas/farmacologia , Antineoplásicos/metabolismo , Vias Biossintéticas , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Genômica , Humanos , Neoplasias/tratamento farmacológico , Peptídeos Cíclicos/genética , Streptomyces/química , Streptomyces/metabolismo
16.
ACS Chem Biol ; 12(11): 2837-2841, 2017 11 17.
Artigo em Inglês | MEDLINE | ID: mdl-28981254

RESUMO

Thioviridamide is a structurally unique ribosomally synthesized and post-translationally modified peptide that contains several thioamide bonds and is active against a number of cancer cell lines. In the search for naturally occurring thioviridamide analogs, we employed genome mining that led to the identification of several related gene clusters. Chemical screening followed by cultivation and isolation yielded thioholgamides A and B, two new additions to the thioviridamide family with several amino acid substitutions, a different N-capping moiety, and with one less thioamide bond. Thioholgamides display improved cytotoxicity in the submicromolar range against a range of cell lines and an IC50 of 30 nM for thioholgamide A against HCT-116 cells. Herein, we report the isolation and structural elucidation of thioholgamides A and B, a proposed biosynthetic cluster for their production, and their bioactivities against a larger panel of microorganisms and cancer cell lines.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Peptídeos Cíclicos/química , Peptídeos Cíclicos/farmacologia , Streptomyces/metabolismo , Tioamidas/química , Tioamidas/farmacologia , Antineoplásicos/metabolismo , Produtos Biológicos/química , Produtos Biológicos/metabolismo , Produtos Biológicos/farmacologia , Vias Biossintéticas , Linhagem Celular Tumoral , Células HCT116 , Humanos , Família Multigênica , Peptídeos Cíclicos/genética , Peptídeos Cíclicos/metabolismo , Processamento de Proteína Pós-Traducional , Streptomyces/química , Streptomyces/genética , Tioamidas/metabolismo
17.
J Inorg Biochem ; 177: 395-401, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28916262

RESUMO

Ru(II) and Os(II) complexes of 2-pyridinecarbothioamide ligands were introduced as orally administrable anticancer agents (S.M. Meier, M. Hanif, Z. Adhireksan, V. Pichler, M. Novak, E. Jirkovsky, M.A. Jakupec, V.B. Arion, C.A. Davey, B.K. Keppler, C.G. Hartinger, Chem. Sci., 2013, 4, 1837-1846). In order to identify structure-activity relationships, a series of N-phenyl substituted pyridine-2-carbothiamides (PCAs) were obtained by systematically varying the substituents at the phenyl ring. The PCAs were then converted to their corresponding RuII(η6-p-cymene) complexes and characterized spectroscopically and by X-ray diffraction as well as in terms of stability in water and HCl. The cytotoxic activity of the PCA ligands and their respective organoruthenium compounds was evaluated in a panel of cell lines (HCT116, H460, SiHa and SW480). The lipophilic PCAs 1-4 showed cytotoxicity in the low micromolar range and 6 was the most potent compound of the series with an IC50 value of 1.1µM against HCT116 colon cancer cells. These observations were correlated with calculated octanol/water partition coefficient (clogP) data and quantitative estimated druglikeness. A similar trend as for the PCAs was found in their Ru complexes, where the complexes with more lipophilic ligands proved to be more cytotoxic in all tested cell lines. In general, the PCAs and their organoruthenium derivatives demonstrated excellent drug-likeness and cytotoxicity with IC50 values in the low micromolar range, making them interesting candidates for further development as orally active anticancer agents.


Assuntos
Antineoplásicos/química , Complexos de Coordenação/química , Piridinas/química , Rutênio/química , Tioamidas/química , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Complexos de Coordenação/síntese química , Complexos de Coordenação/farmacologia , Humanos , Interações Hidrofóbicas e Hidrofílicas , Ligantes , Piridinas/síntese química , Piridinas/farmacologia , Relação Estrutura-Atividade , Tioamidas/síntese química , Tioamidas/farmacologia
18.
Pathog Dis ; 75(6)2017 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-28859311

RESUMO

In the continuous effort to identify new HIV-1 inhibitors endowed with innovative mechanisms, the dual inhibition of different viral functions would provide a significant advantage against drug-resistant variants. The HIV-1 reverse transcriptase (RT)-associated ribonuclease H (RNase H) is the only viral-encoded enzymatic activity that still lacks an efficient inhibitor. We synthesized a library of 3,5-diamino-N-aryl-1H-pyrazole-4-carbothioamide and 4-amino-5-benzoyl-N-phenyl-2-(substituted-amino)-1H-pyrrole-3-carbothioamide derivatives and tested them against RNase H activity. We identified the pyrazolecarbothioamide derivative A15, able to inhibit viral replication and both RNase H and RNA-dependent DNA polymerase (RDDP) RT-associated activities in the low micromolar range. Docking simulations hypothesized its binding to two RT pockets. Site-directed mutagenesis experiments showed that, with respect to wt RT, V108A substitution strongly reduced A15 IC50 values (12.6-fold for RNase H inhibition and 4.7-fold for RDDP), while substitution A502F caused a 9.0-fold increase in its IC50 value for RNase H, not affecting the RDDP inhibition, reinforcing the hypothesis of a dual-site inhibition. Moreover, A15 retained good inhibition potency against three non-nucleoside RT inhibitor (NNRTI)-resistant enzymes, confirming a mode of action unrelated to NNRTIs and suggesting its potential as a lead compound for development of new HIV-1 RT dual inhibitors active against drug-resistant viruses.


Assuntos
Fármacos Anti-HIV/farmacologia , Inibidores Enzimáticos/farmacologia , Transcriptase Reversa do HIV/antagonistas & inibidores , Pirazóis/farmacologia , Ribonuclease H/antagonistas & inibidores , Bibliotecas de Moléculas Pequenas/farmacologia , Tioamidas/farmacologia , Substituição de Aminoácidos , Fármacos Anti-HIV/química , Fármacos Anti-HIV/isolamento & purificação , Sítios de Ligação , Linhagem Celular , Clonagem Molecular , Desenho de Fármacos , Farmacorresistência Viral/efeitos dos fármacos , Farmacorresistência Viral/genética , Inibidores Enzimáticos/química , Inibidores Enzimáticos/isolamento & purificação , Escherichia coli/genética , Escherichia coli/metabolismo , Regulação da Expressão Gênica , Transcriptase Reversa do HIV/química , Transcriptase Reversa do HIV/genética , Transcriptase Reversa do HIV/metabolismo , HIV-1/efeitos dos fármacos , HIV-1/enzimologia , HIV-1/crescimento & desenvolvimento , Humanos , Simulação de Acoplamento Molecular , Mutagênese Sítio-Dirigida , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Estrutura Secundária de Proteína , Pirazóis/síntese química , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Ribonuclease H/química , Ribonuclease H/genética , Ribonuclease H/metabolismo , Bibliotecas de Moléculas Pequenas/síntese química , Linfócitos T/efeitos dos fármacos , Linfócitos T/virologia , Tioamidas/síntese química
19.
Artigo em Inglês | MEDLINE | ID: mdl-28784667

RESUMO

Neisseria gonorrhoeae is one of the leading antimicrobial resistance threats worldwide. This study determined the MICs of closthioamide to be 0.008 to 0.5 mg/liter for clinical N. gonorrhoeae strains and related species. Cross-resistance with existing antimicrobial resistance was not detected, indicating that closthioamide could be used to treat drug-resistant N. gonorrhoeae.


Assuntos
Antibacterianos/farmacologia , Neisseria gonorrhoeae/efeitos dos fármacos , Tioamidas/farmacologia , Resistência Microbiana a Medicamentos/fisiologia , Gonorreia/tratamento farmacológico , Humanos , Testes de Sensibilidade Microbiana
20.
J Med Chem ; 60(4): 1591-1597, 2017 02 23.
Artigo em Inglês | MEDLINE | ID: mdl-28085281

RESUMO

Given the putative role of PHGDH in cancer, development of inhibitors is required to explore its function. In this context, we established and validated a straightforward enzymatic assay suitable for high-throughput screening and we identified inhibitors with similar chemical scaffolds. Through a convergent pharmacophore approach, we synthesized α-ketothioamides that exhibit interesting in vitro PHGDH inhibition and encouraging cellular results. These novel probes may be used to understand the emerging biology of this metabolic target.


Assuntos
Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Fosfoglicerato Desidrogenase/antagonistas & inibidores , Tioamidas/química , Tioamidas/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Ensaios de Triagem em Larga Escala , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/enzimologia , Fosfoglicerato Desidrogenase/metabolismo
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