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1.
Nanoscale ; 12(31): 16451-16461, 2020 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-32790812

RESUMO

Multidrug resistance (MDR) remains a huge obstacle during cancer treatment. One of the most studied MDR mechanisms is P-glycoprotein (P-gp) mediated drug efflux. Based on the three-dimensional structural characteristics of P-gp, gold nanoparticles (AuNPs) with average sizes of 4.1 nm and 5.4 nm were designed for the construction of nanodrug delivery systems (NanoDDSs), with the anticancer molecules 2-(9-anthracenylmethylene)-hydrazinecarbothioamide (ANS) and 6-mercaptopurine (6-MP) modified on the AuNP surfaces through the thiol group. In vitro cytotoxicity results suggested that the larger sized AuNPs can effectively decrease the drug resistance index of MCF-7/ADR cells to ∼2. Verapamil and P-gp antibody competitive experiments, combined with the cellular uptake of AuNPs, indicated that larger NanoDDSs were more conducive to intracellular drug accumulation and thus had improved anticancer activities, due to a size mismatch between the nanoparticles and the active site of P-gp, and, therefore, reduced drug efflux was seen. Measurements of ATPase activity and intracellular ATP levels indicated that the larger nanoparticles do not bind well to P-gp, thus avoiding effective recognition by P-gp. This was further evidenced by the observation that 4.1 nm and 5.4 nm NanoDDS-treated MCF-7/ADR cells showed remarkable differences in energy-related metabolic pathways. Therefore, the critical size of AuNPs for overcoming MDR was identified to be between 4.1 nm and 5.4 nm. This provides a more accurate description of the composite dimension requirements for NanoDDSs that are designed to overcome MDR.


Assuntos
Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Ouro/química , Nanopartículas Metálicas/química , Subfamília B de Transportador de Cassetes de Ligação de ATP/antagonistas & inibidores , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Trifosfato de Adenosina/metabolismo , Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Peptídeos Penetradores de Células/química , Sistemas de Liberação de Medicamentos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Ouro/metabolismo , Humanos , Hidrazinas/química , Hidrazinas/farmacologia , Células MCF-7 , Mercaptopurina/química , Mercaptopurina/farmacologia , Tamanho da Partícula , Tioamidas/química , Tioamidas/farmacologia , Verapamil/farmacologia
2.
Chem Biol Interact ; 329: 109220, 2020 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-32763245

RESUMO

The sepsis is considered as serious clinic-pathological condition related with high rate of morbidity and mortality in critical care settings. In the proposed study, the hydrazides derivatives N-(benzylidene)-2-((2-hydroxynaphthalen-1-yl)diazenyl)benzohydrazides (1-2) (NCHDH and NTHDH) were investigated against the LPS-induced sepsis in rodents. The NCHDH and NTHDH markedly improved the physiological sign and symptoms associated with the sepsis such as mortality, temperature, and clinical scoring compared to negative control group, which received only LPS (i.p.). The NCHDH and NTHDH also inhibited the production of the NO and MPO compared to the negative control. Furthermore, the treatment control improved the histological changes markedly of all the vital organs. Additionally, the Masson's trichrome and PAS (Periodic Acid Schiff) staining also showed improvement in the NCHDH and NTHDH treated group in contrast to LPS-induced group. The antioxidants were enhanced by the intervention of the NCHDH and NTHDH and the level of the MDA and POD were attenuated marginally compared to the LPS-induced group. The hematology study showed marked improvement and the reversal of the LPS-induced changes in blood composition compared to the negative control. The synthetic function of the liver and kidney were preserved in the NCHDH and NTHDH treated group compared to the LPS-induced group. The NCHDH and NTHDH markedly enhanced the Nrf2, HO-1 (Heme oxygenase-1), while attenuated the Keap1 and TRPV1 expression level as compared to LPS treated group. Furthermore, the NCHDH and NTHDH treatment showed marked increased in the mRNA expression level of the HSP70/90 proteins compared to the negative control.


Assuntos
Hidrazinas/farmacologia , Insuficiência de Múltiplos Órgãos/etiologia , Sepse/etiologia , Transdução de Sinais/efeitos dos fármacos , Animais , Sobrevivência Celular/efeitos dos fármacos , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/metabolismo , Heme Oxigenase-1/metabolismo , Hidrazinas/química , Hidrazinas/uso terapêutico , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Lipopolissacarídeos/toxicidade , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Insuficiência de Múltiplos Órgãos/tratamento farmacológico , Insuficiência de Múltiplos Órgãos/mortalidade , Fator 2 Relacionado a NF-E2/metabolismo , Óxido Nítrico/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Peroxidase/metabolismo , Sepse/tratamento farmacológico , Sepse/mortalidade , Canais de Cátion TRPV/genética , Canais de Cátion TRPV/metabolismo
3.
Am J Respir Cell Mol Biol ; 63(5): 690-698, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32706610

RESUMO

Impaired sphingolipid synthesis is linked genetically to childhood asthma and functionally to airway hyperreactivity (AHR). The objective was to investigate whether sphingolipid synthesis could be a target for asthma therapeutics. The effects of GlyH-101 and fenretinide via modulation of de novo sphingolipid synthesis on AHR was evaluated in mice deficient in SPT (serine palmitoyl-CoA transferase), the rate-limiting enzyme of sphingolipid synthesis. The drugs were also used directly in human airway smooth-muscle and epithelial cells to evaluate changes in de novo sphingolipid metabolites and calcium release. GlyH-101 and fenretinide increased sphinganine and dihydroceramides (de novo sphingolipid metabolites) in lung epithelial and airway smooth-muscle cells, decreased the intracellular calcium concentration in airway smooth-muscle cells, and decreased agonist-induced contraction in proximal and peripheral airways. GlyH-101 also decreased AHR in SPT-deficient mice in vivo. This study identifies the manipulation of sphingolipid synthesis as a novel metabolic therapeutic strategy to alleviate AHR.


Assuntos
Hiper-Reatividade Brônquica/metabolismo , Esfingolipídeos/biossíntese , Células Epiteliais Alveolares/efeitos dos fármacos , Células Epiteliais Alveolares/metabolismo , Bradicinina/farmacologia , Cálcio/metabolismo , Sinalização do Cálcio/efeitos dos fármacos , Fenretinida/farmacologia , Glicina/análogos & derivados , Glicina/farmacologia , Humanos , Hidrazinas/farmacologia , Metaboloma/efeitos dos fármacos , Cloreto de Metacolina/farmacologia , Contração Muscular/efeitos dos fármacos , Serina C-Palmitoiltransferase/metabolismo
4.
J Virol ; 94(19)2020 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-32699090

RESUMO

Lysine-specific demethylase 1 (LSD1) targets cellular proteins, including histone H3, p53, E2F, and Dnmt1, and is involved in the regulation of gene expression, DNA replication, the cell cycle, and the DNA damage response. LSD1 catalyzes demethylation of histone H3K9 associated with herpes simplex virus 1 (HSV-1) immediate early (IE) promoters and is necessary for IE gene expression, viral DNA replication, and reactivation from latency. We previously found that LSD1 associates with HSV-1 replication forks and replicating viral DNA, suggesting that it may play a direct role in viral replication or coupled processes. We investigated the effects of the LSD1 inhibitor SP-2509 on the HSV-1 life cycle. Unlike previously investigated LSD1 inhibitors tranylcypromine (TCP) and OG-L002, which covalently attach to the LSD1 cofactor flavin adenine dinucleotide (FAD) to inhibit demethylase activity, SP-2509 has previously been shown to inhibit LSD1 protein-protein interactions. We found that SP-2509 does not inhibit HSV-1 IE gene expression or transcription factor and RNA polymerase II (Pol II) association with viral DNA prior to the onset of replication. However, SP-2509 does inhibit viral DNA replication, late gene expression, and virus production. We used EdC labeling of nascent viral DNA to image aberrant viral replication compartments that form in the presence of SP-2509. Treatment resulted in the formation of small replication foci that colocalize with replication proteins but are defective for Pol II recruitment. Taken together, these data highlight a potential new role for LSD1 in the regulation of HSV-1 DNA replication and gene expression after the onset of DNA replication.IMPORTANCE Treatment of HSV-1-infected cells with SP-2509 blocked viral DNA replication, gene expression after the onset of DNA replication, and virus production. These data support a potential new role for LSD1 in the regulation of viral DNA replication and successive steps in the virus life cycle, and further highlight the promising potential to utilize LSD1 inhibition as an antiviral approach.


Assuntos
Antivirais/farmacologia , Herpesvirus Humano 1/efeitos dos fármacos , Herpesvirus Humano 1/fisiologia , Histona Desmetilases/efeitos dos fármacos , Hidrazinas/farmacologia , Sulfonamidas/farmacologia , Replicação Viral/efeitos dos fármacos , Animais , Linhagem Celular , Chlorocebus aethiops , Replicação do DNA/efeitos dos fármacos , DNA Viral , Regulação Viral da Expressão Gênica/efeitos dos fármacos , Genes Precoces , Herpes Simples/tratamento farmacológico , Histonas/metabolismo , Humanos , Regiões Promotoras Genéticas , Células Vero
5.
Chemosphere ; 259: 127499, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32629314

RESUMO

Soybean looper (SBL), Chrysodeixis includens (Walker), is an economically important soybean and cotton pest in Brazil. Here, we selected an SBL strain resistant to teflubenzuron using F2 screening, estimated the resistance allele frequency, characterized the inheritance of resistance, investigated fitness costs, evaluated patterns of cross-resistance, and determined the magnitude of resistance. The teflubenzuron-resistant strain (Teflu-R) was selected from field-collected populations with an estimated allele frequency of 0.1700. Estimated LC50 values were 0.010 and 363.61 µg a.i. cm-2 for the susceptible (Sus) and Teflu-R strains, respectively, representing a 36,361-fold resistance ratio (RR). The LC50 values of reciprocal crosses were 1.02 and 0.59 µg a.i. cm-2, suggesting that resistance is autosomally inherited. The low survival of reciprocal crosses (16 and 20%) on teflubenzuron-sprayed leaves indicates incomplete recessive resistance. The number of segregations influencing resistance was 2.72, suggesting a polygenic effect. The Teflu-R strain showed longer development periods as well as lower survival and population growth than the Sus strain, revealing fitness costs. The Teflu-R strain also showed high cross-resistancesto other chitin inhibitor insecticides, such as novaluron (RR = 6147-fold) and lufenuron (RR = 953-fold), but low cross-resistance to methoxyfenozide, flubendiamide, and indoxacarb (RR < 3.45-fold). On discriminatory concentrations of teflubenzuron and novaluron, populations of SBL showed survival rates from 15 to 52%, indicating field resistance to these insecticides. Our findings indicated that resistance to teflubenzuron in SBL is autosomal, recessive, polygenic, and associated with fitness cost. We also found a high cross-resistance to other benzoylphenylureas and a high frequency of resistance to this mode-of-action in SBL in Brazil.


Assuntos
Quitina/antagonistas & inibidores , Resistência a Inseticidas , Inseticidas , Mariposas/efeitos dos fármacos , Soja/parasitologia , Animais , Benzamidas/farmacologia , Brasil , Quitina/biossíntese , Quitina/farmacologia , Hidrazinas/farmacologia , Inseticidas/farmacologia , Hormônios Juvenis/farmacologia , Larva/efeitos dos fármacos , Lepidópteros/efeitos dos fármacos , Compostos de Fenilureia/farmacologia , Doenças das Plantas/parasitologia , Soja/efeitos dos fármacos , Sulfonas/farmacologia
6.
Infect Genet Evol ; 85: 104419, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32540428

RESUMO

The COVID-19 pandemic, caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), is a current global threat for which there is an urgent need to search for an effective therapy. The transmembrane spike (S) glycoprotein of SARS-CoV-2 directly binds to the host angiotensin-converting enzyme 2 (ACE2) and mediates viral entrance, which is therefore considered as a promising drug target. Considering that new drug development is a time-consuming process, drug repositioning may facilitate rapid drug discovery dealing with sudden infectious diseases. Here, we compared the differences between the virtual structural proteins of SARS-CoV-2 and SARS-CoV, and selected a pocket mainly localizing in the fusion cores of S2 domain for drug screening. A virtual drug design algorithm screened the Food and Drug Administration-approved drug library of 1234 compounds, and 13 top scored compounds were obtained through manual screening. Through in vitro molecular interaction experiments, eltrombopag was further verified to possess a high binding affinity to S protein plus human ACE2 and could potentially affect the stability of the ACE2-S protein complex. Hence, it is worth further exploring eltrombopag as a potential drug for the treatment of SARS-CoV-2 infection.


Assuntos
/metabolismo , Benzoatos/farmacologia , Hidrazinas/farmacologia , Pirazóis/farmacologia , Vírus da SARS/metabolismo , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/metabolismo , Algoritmos , Benzoatos/química , Simulação por Computador , Desenho de Fármacos , Reposicionamento de Medicamentos , Humanos , Hidrazinas/química , Modelos Moleculares , Ligação Proteica , Estabilidade Proteica , Pirazóis/química , Vírus da SARS/efeitos dos fármacos , Relação Estrutura-Atividade
7.
Int J Hematol ; 112(5): 725-727, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32557126

RESUMO

Chemotherapy is the mainstay of treatment for advanced pancreatic cancer however, due to possible myelotoxicity, it is used with caution in patients with thrombocytopenia, especially when severe. TPO-receptor agonists have been employed for chemotherapy-induced thrombocytopenia, however treatment with TPO-receptor agonists to allow chemotherapy in patients with inherited thrombocytopenia has not been reported so far. We report the first successful use of eltrombopag to prevent chemotherapy-induced thrombocytopenia in a patient with MHY9-related disorder and pancreatic cancer. Treatment with eltrombopag allowed to attain a safe and stable platelet count for several months sufficient to permit chemotherapy and to allow the patient to undergo endoscopic placement of a biliary stent with no bleeding complications.


Assuntos
Benzoatos/uso terapêutico , Hidrazinas/uso terapêutico , Cadeias Pesadas de Miosina , Neoplasias Pancreáticas/tratamento farmacológico , Pirazóis/uso terapêutico , Trombocitopenia/tratamento farmacológico , Trombocitopenia/genética , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Benzoatos/farmacologia , Perda Sanguínea Cirúrgica/prevenção & controle , Endoscopia do Sistema Digestório , Feminino , Humanos , Hidrazinas/farmacologia , Neoplasias Pancreáticas/cirurgia , Contagem de Plaquetas , Pirazóis/farmacologia , Receptores de Trombopoetina/agonistas , Trombocitopenia/sangue , Trombocitopenia/congênito
8.
PLoS One ; 15(6): e0233993, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32484843

RESUMO

Multidrug resistance (MDR) to chemotherapeutic drugs remains one of the major impediments to the treatment of cancer. Discovery and development of drugs that can prevent and reverse the acquisition of multidrug resistance constitute a foremost challenge in cancer therapeutics. In this work, we screened a library of 1,127 compounds with known targets for their ability to overcome Pgp-mediated multidrug resistance in cancer cell lines. We identified four compounds (CHIR-124, Elesclomol, Tyrphostin-9 and Brefeldin A) that inhibited the growth of two pairs of parental and Pgp-overexpressing multidrug-resistant cell lines with similar potency irrespective of their Pgp status. Mechanistically, CHIR-124 (a potent inhibitor of Chk1 kinase) inhibited Pgp activity in both multidrug-resistant cell lines (KB-V1 and A2780-Pac-Res) as determined through cell-based Pgp-efflux assays. Other three inhibitors on the contrary, were effective in Pgp-overexpressing resistant cells without increasing the cellular accumulation of a Pgp substrate, indicating that they overcome resistance by avoiding efflux through Pgp. None of these compounds modulated the expression of Pgp in resistant cell lines. PIK-75, a PI3 Kinase inhibitor, was also determined to inhibit Pgp activity, despite being equally potent in only one of the two pairs of resistant and parental cell lines. Strong binding of both CHIR-124 and PIK-75 to Pgp was predicted through docking studies and both compounds inhibited Pgp in a biochemical assay. The inhibition of Pgp causes accumulation of these compounds in the cells where they can modulate the function of their target proteins and thereby inhibit cell proliferation. In conclusion, we have identified compounds with various cellular targets that overcome multidrug resistance in Pgp-overexpressing cell lines through mechanisms that include Pgp inhibition and efflux evasion. These compounds, therefore, can avoid challenges associated with the co-administration of Pgp inhibitors with chemotherapeutic or targeted drugs such as additive toxicities and differing pharmacokinetic properties.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Ensaios de Triagem em Larga Escala , Neoplasias/tratamento farmacológico , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Brefeldina A/farmacologia , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Hidrazinas/farmacologia , Hidrazonas/farmacologia , Neoplasias/genética , Neoplasias/patologia , Quinolinas/farmacologia , Quinuclidinas/farmacologia , Sulfonamidas/farmacologia , Tirfostinas/farmacologia
9.
Science ; 368(6491): 620-625, 2020 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-32381719

RESUMO

Loss-of-function mutations in the copper (Cu) transporter ATP7A cause Menkes disease. Menkes is an infantile, fatal, hereditary copper-deficiency disorder that is characterized by progressive neurological injury culminating in death, typically by 3 years of age. Severe copper deficiency leads to multiple pathologies, including impaired energy generation caused by cytochrome c oxidase dysfunction in the mitochondria. Here we report that the small molecule elesclomol escorted copper to the mitochondria and increased cytochrome c oxidase levels in the brain. Through this mechanism, elesclomol prevented detrimental neurodegenerative changes and improved the survival of the mottled-brindled mouse-a murine model of severe Menkes disease. Thus, elesclomol holds promise for the treatment of Menkes and associated disorders of hereditary copper deficiency.


Assuntos
Cobre/metabolismo , Hidrazinas/uso terapêutico , Síndrome dos Cabelos Torcidos/tratamento farmacológico , Animais , Transporte Biológico/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Linhagem Celular , Transportador de Cobre 1/genética , Modelos Animais de Doenças , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Hidrazinas/farmacologia , Masculino , Síndrome dos Cabelos Torcidos/metabolismo , Síndrome dos Cabelos Torcidos/patologia , Camundongos , Camundongos Knockout , Mitocôndrias/metabolismo , Doenças Neurodegenerativas/prevenção & controle , Ratos
10.
Insect Biochem Mol Biol ; 121: 103372, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32276112

RESUMO

Insecticide based vector control tools such as insecticide treated bednets and indoor residual spraying represent the cornerstones of malaria control programs. Resistance to chemistries used in these programs is now widespread and represents a significant threat to the gains seen in reducing malaria-related morbidity and mortality. Recently, disruption of the 20-hydroxyecdysone steroid hormone pathway was shown to reduce Plasmodium development and significantly reduce both longevity and egg production in a laboratory susceptible Anopheles gambiae population. Here, we demonstrate that disruption of this pathway by application of the dibenzoylhydrazine, methoxyfenozide (DBH-M), to insecticide resistant An. coluzzii, An. gambiae sl and An. funestus populations significantly reduces egg production in both topical and tarsal application. Moreover, DBH-M reduces adult longevity when applied topically, and tarsally after blood feeding. As the cytochrome p450s elevated in pyrethroid resistant Anopheles only bind DBH-M very weakly, this compound is unlikely to be subject to cross-resistance in a field-based setting. Manipulation of this hormonal signalling pathway therefore represents a potential complementary approach to current malaria control strategies, particularly in areas where high levels of insecticide resistance are compromising existing tools.


Assuntos
Anopheles/genética , Ecdisterona/agonistas , Aptidão Genética/efeitos dos fármacos , Hidrazinas/farmacologia , Resistência a Inseticidas/genética , Inseticidas/farmacologia , Hormônios Juvenis/farmacologia , Mosquitos Vetores/genética , Animais , Anopheles/efeitos dos fármacos , Feminino , Mosquitos Vetores/efeitos dos fármacos
12.
Dalton Trans ; 49(14): 4404-4415, 2020 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-32175553

RESUMO

In this study, two novel organic ligands, bis(salicylaldehyde)pyrazino-1,10-phenanthroline-7,10-dicarbohydrazide (L) and bis(salicylaldehyde)-1,10-phenanthroline-7,10-dicarbohydrazide (L1), were synthesized. These ligands were used to react with lanthanide(iii) acetate to obtain complexes 1-6, namely, [Dy5(L)2(CH3COO)5(CH3OH)(µ3-OH)(µ2-OH)(H2O)]·2CH3OH (1), [Tb5(L)2(CH3COO)5(CH3OH)(µ3-OH)(µ2-OH)(H2O)]·3CH3OH (2), [Gd5(L)2(CH3COO)5(CH3OH)(µ3-OH)(µ2-OH)(H2O)]·3CH3OH (3), [Dy5(L1)2(µ2-OH)(µ3-OH)(CH3COO)5(CH3OH)(H2O)2]·2H2O (4), [Dy5(L1)2(µ3-OH)(CH3COO)6(CH3OH)3]·CH3OH (5), and [Dy5(L1)2(µ2-OH)2(µ3-OH)(CH3COO)4(CH3OH)(H2O)2]·CH3OH (6). Fluorescence studies demonstrated that complexes 1-6 show appreciable fluorescence in the yellow-green region. In vitro antitumor screening revealed that complex 1 exhibits better inhibitory activities than the commercial anticancer drug cisplatin against SK-OV-3 and A549 tumor cell lines, with IC50 values of 8.09 ± 1.25 and 13.26 ± 0.39 µM, respectively. All six complexes showed low cytotoxicity toward normal human liver HL-7702 cells compared with cisplatin. Complexes 1 and 3 induced the highest apoptosis rate of SK-OV-3/DDP cells. They also bind to DNA via an intercalative mode with the binding constant Kq values of 1.6 × 104 and 1.19 × 104 L mol-1, respectively. Confocal fluorescence imaging ascertained that complexes 1 and 3 are primarily localized in the mitochondria. Further studies revealed that these complexes trigger SK-OV-3/DDP cell apoptosis via a mitochondrial dysfunction pathway, which is probably caused by the reduction of the mitochondrial membrane potential and the induction of reactive oxygen species production.


Assuntos
Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Hidrazinas/farmacologia , Elementos da Série dos Lantanídeos/farmacologia , Mitocôndrias/efeitos dos fármacos , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , DNA de Neoplasias/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Hidrazinas/química , Elementos da Série dos Lantanídeos/química , Mitocôndrias/metabolismo , Estrutura Molecular , Relação Estrutura-Atividade
13.
J Med Chem ; 63(9): 4655-4684, 2020 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-32118427

RESUMO

A high-throughput screen designed to discover new inhibitors of histone acetyltransferase KAT6A uncovered CTX-0124143 (1), a unique aryl acylsulfonohydrazide with an IC50 of 1.0 µM. Using this acylsulfonohydrazide as a template, we herein disclose the results of our extensive structure-activity relationship investigations, which resulted in the discovery of advanced compounds such as 55 and 80. These two compounds represent significant improvements on our recently reported prototypical lead WM-8014 (3) as they are not only equivalently potent as inhibitors of KAT6A but are less lipophilic and significantly more stable to microsomal degradation. Furthermore, during this process, we discovered a distinct structural subclass that contains key 2-fluorobenzenesulfonyl and phenylpyridine motifs, culminating in the discovery of WM-1119 (4). This compound is a highly potent KAT6A inhibitor (IC50 = 6.3 nM; KD = 0.002 µM), competes with Ac-CoA by binding to the Ac-CoA binding site, and has an oral bioavailability of 56% in rats.


Assuntos
Antineoplásicos/farmacologia , Histona Acetiltransferases/antagonistas & inibidores , Hidrazinas/farmacologia , Sulfonamidas/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Descoberta de Drogas , Estabilidade de Medicamentos , Humanos , Hidrazinas/síntese química , Hidrazinas/metabolismo , Masculino , Camundongos , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/metabolismo
14.
Spectrochim Acta A Mol Biomol Spectrosc ; 231: 118123, 2020 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-32058916

RESUMO

There is an urgent need to eliminate the era of superbugs through design and development of novel and sustainable drugs. Transition metal complexes can be one of the hopes for tackling drug resistant pathogens. In this view, we have developed a manganese complex appended with an ON donor ligand which has shown excellent activity against one of the prominent fungal species. The Mn (II) complex, [MnII(OH2)2(Hhpdbal-sbdt)2] (1) was synthesized using a Schiff base ligand derived from an azo aldehyde and S-benzyldithiocarbazate. The complex was characterized with the help of analytical techniques such as elemental analysis, FT-IR, EDAX, EPR and TGA. The solution behavior in physiological conditions and in biological media was preliminarily evaluated by studying the behavior of complex in varied pH conditions and in the presence of protein, BSA. The effect of the compound on few drug resistant pathogenic species of bacteria and fungi and on the uptake of glucose by insulin resistant cells was evaluated using whole cell inhibition assay and NBDG assay respectively. The study gave a noteworthy result with respect to the manganese compound's biological activity, with an inhibitory activity of 93% towards a fungi species, Cryptococcus neoformans and with a relatively good glucose uptake inducing capacity. The manganese complex, which maintains its stability over a wide range of pH conditions and interacts with serum protein, BSA in a facile manner can be an excellent drug candidate and eventually be added to the library of compounds being screened for in vivo activity studies.


Assuntos
Anti-Infecciosos/química , Complexos de Coordenação/química , Hidrazinas/química , Manganês/química , Bases de Schiff/química , Animais , Anti-Infecciosos/síntese química , Anti-Infecciosos/farmacologia , Bactérias/efeitos dos fármacos , Bovinos , Complexos de Coordenação/síntese química , Complexos de Coordenação/farmacologia , Fungos/efeitos dos fármacos , Glucose/metabolismo , Células Hep G2 , Humanos , Hidrazinas/síntese química , Hidrazinas/farmacologia , Manganês/farmacologia , Bases de Schiff/síntese química , Bases de Schiff/farmacologia , Soroalbumina Bovina/metabolismo
15.
J Enzyme Inhib Med Chem ; 35(1): 622-628, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32037900

RESUMO

A series of bio-organometallic-hydrazones of the general formula [{(η5-C5H4)-C(R)=N-N(H)-C6H4-4-SO2NH2}]MLn(MLn = Re(CO)3, Mn(CO)3, FeCp; R=H, CH3) were prepared by reaction of formyl/acetyl organometallic precursors with 4-hydrazino-benzenesulphonamide. All compounds were characterized by conventional spectroscopic techniques (infra-red, 1H and 13C NMR, mass spectrometry and elemental analysis). Biological evaluation as carbonic anhydrase (CA, EC 4.2.1.1) inhibitors agents was carried out using four human/h) isoforms, hCA I, II, IX and XII. The cytosolic isoforms hCA I and II were effectively inhibited by almost all derivatives with inhibition constants of 1.7-22.4 nM. Similar effects were observed for the tumour-associated transmembrane isoform hCA XII (KIs of 1.9-24.4 nM). hCA IX was less sensitive to inhibition with these compounds. The presence of bio-organometallic or metallo-carbonyl moieties in the molecules of these CAIs makes them amenable for interesting pharmacologic applications, for example for compounds with CO donating properties.


Assuntos
Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/metabolismo , Hidrazinas/farmacologia , Compostos Organometálicos/farmacologia , Sulfonamidas/farmacologia , Dióxido de Carbono/antagonistas & inibidores , Dióxido de Carbono/química , Dióxido de Carbono/metabolismo , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Relação Dose-Resposta a Droga , Humanos , Hidrazinas/química , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Estrutura Molecular , Compostos Organometálicos/síntese química , Compostos Organometálicos/química , Relação Estrutura-Atividade , Sulfonamidas/química
16.
J Sci Food Agric ; 100(7): 3078-3086, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32077490

RESUMO

BACKGROUND: Nitric oxide (NO) donors have been used to control biofilm formation. Nitric oxide can be delivered in situ using organic carriers and acts as a signaling molecule. Cells exposed to NO shift from biofilm to the planktonic state and are better exposed to the action of disinfectants. In this study, we investigate the capability of the NO donors molsidomine, MAHAMA NONOate, NO-aspirin and diethylamine NONOate to act as anti-adhesion agents on ready-to-eat vegetables, as well as dispersants for a number of pathogenic biofilms on plastic. RESULTS: Our results showed that 10 pM molsidomine reduced the attachment of Salmonella enterica sv Typhimurium 14 028 to pea shoots and coriander leaves of about 0.5 Log(CFU/leaf) when compared with untreated control. The association of 10 pmol L-1 molsidomine with 0.006% H2 O2 showed a synergistic effect, leading to a significant reduction in cell collection on the surface of the vegetable of about 1 Log(CFU/leaf). Similar results were obtained for MAHMA NONOate. We also showed that the association of diethylamine NONOate at 10 mmol L-1 and 10 pmol L-1 with the quaternary ammonium compound diquat bromide improved the effectiveness of biofilm dispersal by 50% when compared with the donor alone. CONCLUSIONS: Our findings reveal a dual role of NO compounds in biofilm control. Molsidomine, MAHMA NONOate, and diethylamine NONOate are good candidates for either preventing biofilm formation or dispersing biofilm, especially when used in conjunction with disinfectants. Nitric oxide compounds have the potential to be developed into a toolkit for pro-active practices for good agricultural practices (GAPs), hazard analysis and critical control points (HACCP), and cleaning-in-place (CIP) protocols in industrial settings where washing is routinely applied. © 2020 Society of Chemical Industry.


Assuntos
Aderência Bacteriana/efeitos dos fármacos , Fenômenos Fisiológicos Bacterianos/efeitos dos fármacos , Biofilmes/efeitos dos fármacos , Fast Foods/microbiologia , Doadores de Óxido Nítrico/farmacologia , Salmonella typhimurium/efeitos dos fármacos , Verduras/microbiologia , Coriandrum/microbiologia , Desinfetantes/farmacologia , Fast Foods/análise , Hidrazinas/farmacologia , Molsidomina/farmacologia , Ervilhas/microbiologia , Plásticos/análise , Polipropilenos/análise , Salmonella typhimurium/fisiologia
18.
J Hazard Mater ; 388: 122029, 2020 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-31954303

RESUMO

Hypochlorous acid (HOCl)/hypochlorite (ClO-) was a biologically important component of reactive oxygen species (ROS) and plays a key role in human immune function systems. HOCl/ClO- can destroy invasive bacteria and pathogens, and mediate the physiological balance of the organism with low concentrations, and cause oxidation of the biomolecules such as proteins, cholesterol and nucleic acid in biological cells, leading to a series of diseases with over capacity. Therefore, quantifying the content of HOCl/ClO- in organisms are extremely urgent. In this work, coumarin-salicylic hydrazide Schiff base (CMSH), a ratiometric and colorimetric fluorescent probe for ClO- detection based on coumarin as the fluorophore unit was rationally designed and synthesized. The results indicated that CMSH exhibits high selectivity and sensitivity for ClO- identification. Additionally, the ratios (I470/I532) displayed brilliant ClO--dependent quick and sensitive performance within 40 s and limitation of 128 nM, respectively. As well as the color of the solution changes from green to colorless accompanied by the fluorescence form green turns into blue with addition of ClO-. Totally, CMSH has been successfully employed as ratiometric sensor to image in living cells, bacteria and zebrafish with low cytotoxicity and good permeability.


Assuntos
Cumarínicos/farmacologia , Corantes Fluorescentes/farmacologia , Hidrazinas/farmacologia , Ácido Hipocloroso/metabolismo , Bases de Schiff/farmacologia , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Colorimetria , Escherichia coli/metabolismo , Humanos , Imagem Óptica , Peixe-Zebra/metabolismo
20.
Mol Biol Rep ; 47(3): 1637-1647, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31933263

RESUMO

Gastric cancer is one of the common types of cancer around the world which has few therapeutic options. Nitrogen heterocyclic derivatives such as thiazoles are used as the basis for the progression of the drugs. The objective of this study was to synthesize the 1-((3-(4-chlorophenyl)-1-phenyl-1H-pyrazol-4-yl) methylene)-2-(4-phenylthiazol-2-yl) hydrazine (TP) conjugating with (3-Chloropropyl) trimethoxysilane (CPTMOS)-coated Fe3O4 nanoparticles (NPs) for anti-cancer activities against gastric AGS cancer cell line. The synthesized Fe3O4@CPTMOS/TP NPs were characterized by FT-IR, XRD, EDX, SEM, TEM and Zeta potential analyses. To evaluate the toxicity of the above compound after AGS cell culture in RPMI1640 medium, the cells were treated at different concentrations for 24 h. The viability of the cells was investigated by MTT assay. Moreover, apoptosis induced by Fe3O4@CPTMOS/TP NPs was assessed by Hoechst 33432 staining, oxygen activity specification evaluation, caspase-3 activity assay, cell cycle analysis and annexin V/PI staining followed by flow cytometry analysis. The IC50 value in AGS cells was estimated to be 95.65 µg/ml. The flow cytometry results of Fe3O4@CPTMOS/TP NPs revealed a large number of cells in the apoptotic regions compared to the control cells and the cells treated with TP. In addition, the amount of ROS production and caspase-3 activity increased in the treated cells with Fe3O4@CPTMOS/TP NPs. The percentage of inhibited cancer cells in the G0/G1 phase increased under the treatment in the binding state to the nonionic iron oxide nanoparticles. Overall, this study showed that Fe3O4@CPTMOS/TP NP had effect on induction of apoptosis and inhibiting the growth of AGS cancer cells. Thus, Fe3O4@CPTMOS/TP NP can be considered as a new anti-cancer candid for next phase of studies on mouse models.


Assuntos
Antineoplásicos/química , Compostos Férricos/química , Hidrazinas/química , Nanopartículas/química , Silanos/química , Neoplasias Gástricas/patologia , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Hidrazinas/farmacologia , Microscopia Eletrônica , Modelos Químicos , Estrutura Molecular , Nanopartículas/administração & dosagem , Nanopartículas/ultraestrutura , Necrose , Espécies Reativas de Oxigênio/metabolismo , Espectroscopia de Infravermelho com Transformada de Fourier , Neoplasias Gástricas/metabolismo , Difração de Raios X
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