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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.
Nat Chem Biol ; 16(11): 1199-1207, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32747809

RESUMO

Targeted protein degradation is a new therapeutic modality based on drugs that destabilize proteins by inducing their proximity to E3 ubiquitin ligases. Of particular interest are molecular glues that can degrade otherwise unligandable proteins by orchestrating direct interactions between target and ligase. However, their discovery has so far been serendipitous, thus hampering broad translational efforts. Here, we describe a scalable strategy toward glue degrader discovery that is based on chemical screening in hyponeddylated cells coupled to a multi-omics target deconvolution campaign. This approach led us to identify compounds that induce ubiquitination and degradation of cyclin K by prompting an interaction of CDK12-cyclin K with a CRL4B ligase complex. Notably, this interaction is independent of a dedicated substrate receptor, thus functionally segregating this mechanism from all described degraders. Collectively, our data outline a versatile and broadly applicable strategy to identify degraders with nonobvious mechanisms and thus empower future drug discovery efforts.


Assuntos
Acetamidas/química , Antibacterianos/farmacologia , Quinases Ciclina-Dependentes/metabolismo , Ciclinas/metabolismo , Doxiciclina/farmacologia , Hidrazinas/química , Indóis/química , Proteólise/efeitos dos fármacos , Proteína 7 de Ligação ao Retinoblastoma/metabolismo , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Regulação da Expressão Gênica , Humanos , Estrutura Molecular , Ligação Proteica , Conformação Proteica , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/química , Relação Estrutura-Atividade , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinação/efeitos dos fármacos
3.
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
4.
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
5.
Nat Commun ; 11(1): 2423, 2020 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-32415069

RESUMO

Ewing sarcoma (EwS) is an aggressive childhood cancer likely originating from mesenchymal stem cells or osteo-chondrogenic progenitors. It is characterized by fusion oncoproteins involving EWSR1 and variable members of the ETS-family of transcription factors (in 85% FLI1). EWSR1-FLI1 can induce target genes by using GGAA-microsatellites as enhancers.Here, we show that EWSR1-FLI1 hijacks the developmental transcription factor SOX6 - a physiological driver of proliferation of osteo-chondrogenic progenitors - by binding to an intronic GGAA-microsatellite, which promotes EwS growth in vitro and in vivo. Through integration of transcriptome-profiling, published drug-screening data, and functional in vitro and in vivo experiments including 3D and PDX models, we discover that constitutively high SOX6 expression promotes elevated levels of oxidative stress that create a therapeutic vulnerability toward the oxidative stress-inducing drug Elesclomol.Collectively, our results exemplify how aberrant activation of a developmental transcription factor by a dominant oncogene can promote malignancy, but provide opportunities for targeted therapy.


Assuntos
Regulação Neoplásica da Expressão Gênica , Proteínas de Fusão Oncogênica/metabolismo , Estresse Oxidativo , Sarcoma de Ewing/patologia , Adulto , Animais , Neoplasias Ósseas/patologia , Linhagem Celular Tumoral , Proliferação de Células , Criança , Condrócitos/metabolismo , Metilação de DNA , Elementos Facilitadores Genéticos , Perfilação da Expressão Gênica , Células HEK293 , Humanos , Hidrazinas/química , Células-Tronco Mesenquimais/metabolismo , Camundongos , Repetições de Microssatélites , Mitocôndrias/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Oncogenes , Interferência de RNA , Fatores de Transcrição SOXD/metabolismo , Sarcoma/genética
6.
Chem Commun (Camb) ; 56(41): 5524-5527, 2020 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-32296787

RESUMO

A cobalt-catalyzed direct C-H/N-H functionalization of thiophene-2-carbohydrazides with maleimides by utilizing 2-(1-methylhydrazinyl)pyridine (MHP) as an easily removable bidentate directing group has been developed. This formal [4+2] cycloaddition has been achieved for the first time, and it provides an alternative and versatile approach to construct thiophene-fused pyridones using an inexpensive cobalt catalyst. The C-H/N-H activation cascade protocol showed a high efficiency and a broad substrate scope, and the products were obtained in good to excellent yields.


Assuntos
Cobalto/química , Hidrazinas/química , Maleimidas/química , Piridinas/química , Piridonas/síntese química , Tiofenos/química , Catálise , Ciclização , Estrutura Molecular , Piridonas/química , Estereoisomerismo
7.
J Med Chem ; 63(8): 3881-3895, 2020 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-32223194

RESUMO

Exportin-1 (also named as CRM1) plays a prominent role in autoimmune disorders and has emerged as a potential therapeutic target for colitis. Here we report on the rational structure-based discovery of a small-molecule antagonist of exportin-1, LFS-829, with low-range nanomolar activities. The co-crystallographic structure, surface plasmon resonance binding assay, and cell-based phenotypic nuclear export functional assay validated that exportin-1 is a key target of LFS-829. Moreover, we demonstrated that the C528S mutation or the knockdown on exportin-1 can abolish the cellular activities of LFS-829. Strikingly, oral administration of LFS-829 can significantly reverse the pathological features of colitis model mice. We revealed that LFS-829 can attenuate dual NF-κB signaling and the Nrf2 cytoprotection pathway via targeting exportin-1 in colitis mice. Moreover, LFS-829 has a very low risk of cardiotoxicity and acute toxicity. Therefore, LFS-829 holds great promise for the treatment of colitis and may warrant translation for use in clinical trials.


Assuntos
Colite/tratamento farmacológico , Sistemas de Liberação de Medicamentos/métodos , Descoberta de Drogas/métodos , Hidrazinas/administração & dosagem , Carioferinas/antagonistas & inibidores , Receptores Citoplasmáticos e Nucleares/antagonistas & inibidores , Triazóis/administração & dosagem , Sequência de Aminoácidos , Animais , Colite/metabolismo , Colite/patologia , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Hidrazinas/química , Carioferinas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Receptores Citoplasmáticos e Nucleares/metabolismo , Triazóis/química
8.
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
9.
Spectrochim Acta A Mol Biomol Spectrosc ; 233: 118165, 2020 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-32120288

RESUMO

In the present paper, the kinetics of a reaction between bovine serum albumin (BSA) and pyridoxal, pyridoxal 5'-phosphate was studied, apparent rate constant of product formation and dissociation as well as binding constants were determined. Pyridoxal 5'-phosphate hydrazones of isonicotinic, picolinic, 2-furoic, thiophene-2-carboxylic, pyrazinoic acids binding to BSA was studied by spectrofluorimetry, stability constants of the associates were calculated from experimental data using maximal likelihood approach. The changes in the secondary structure of BSA induced by hydrazones addition were studied by IR spectroscopy. New freely available software for curve fitting was developed as a part of the software kit designed for the solution chemistry and used for a specific problem of this study, IR spectra processing.


Assuntos
Hidrazinas/química , Fosfato de Piridoxal/química , Soroalbumina Bovina/química , Animais , Bovinos , Estrutura Secundária de Proteína
10.
Anal Bioanal Chem ; 412(12): 2841-2849, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32078005

RESUMO

Free fatty acid (FFA) and acylcarnitine (AcCar) are key elements of energy metabolism. Dysregulated levels of FFA and AcCar are associated with genetic defects and other metabolic disorders. Due to differences in the physicochemical properties of these two classes of compounds, it is challenging to quantify FFA and AcCar in human plasma using a single method. In this work, we developed a chemical isotope labeling (CIL)-based liquid chromatography-multiple reaction monitoring (LC-MRM) method to simultaneously quantify FFA and AcCar. Dansylhydrazine (DnsHz) was used to label the carboxylic acid moiety on FFA and AcCar. This resulted in the formation of a permanently charged ammonium ion for facile ionization in positive ionization mode and higher hydrophobicity for enhanced retention of short-chain analogs on reversed-phase LC columns and enabled absolute quantification by using heavy labeled DnsHz analogs as internal standards. Labeling conditions including the concentration and freshness of cross-linker, reaction time, and temperature were optimized. This method can successfully quantify all short-, medium- and long-chain FFAs and AcCars with greatly enhanced sensitivity. Using this method, 25 FFAs and 13 AcCars can be absolutely quantified and validated in human plasma samples within 12 min. Simultaneous quantification of FFA and AcCar enabled by this CIL-based LC-MRM method facilitates the investigation of fatty acid metabolism and has potential in clinical applications.


Assuntos
Isótopos de Carbono/análise , Carnitina/análogos & derivados , Cromatografia Líquida/métodos , Compostos de Dansil/química , Hidrazinas/química , Marcação por Isótopo/métodos , Espectrometria de Massas em Tandem/métodos , Carnitina/sangue , Humanos
11.
PLoS One ; 15(2): e0228543, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32045426

RESUMO

Two molecules, 7-(diethylamino)coumarin-3-carbohydrazide (DCCH) and fluorescein-5-thiosemicarbazide (FTSC) were investigated in different solvents, under varying pH conditions regarding their spectroscopic properties for the usage as a Förster Resonance Energy Transfer (FRET) pair to study the molecular interaction between cellulosic surfaces. All the relevant spectroscopic properties to determine the Förster distance were measured and the performance as a FRET system was checked. From the results, it is clear that the environmental conditions need to be accurately controlled as both, but especially the FTSC dyes are sensitive to changes. For high enough concentrations positive FRET systems were observed in DMF, DMSO, H2O, THF and alkaline DMF. However due to the low quantum yield of the unmodified DCCH throughout the investigated parameter range and the strong environmental dependency of FTSC, both dyes are not preferable for being used in a FRET system for studying interaction between cellulosic surfaces.


Assuntos
Cumarínicos/química , Fluoresceínas/química , Transferência Ressonante de Energia de Fluorescência/métodos , Hidrazinas/química , Solventes/química , Análise Espectral/métodos , Transferência de Energia/efeitos dos fármacos , Concentração de Íons de Hidrogênio , Solventes/farmacologia , Espectrometria de Fluorescência/métodos , Espectrofotometria Ultravioleta/métodos
12.
Org Biomol Chem ; 18(10): 1881-1885, 2020 03 14.
Artigo em Inglês | MEDLINE | ID: mdl-32100807

RESUMO

A convenient two-step method is reported for the ligation of alkoxyamine- or hydrazine-bearing cargo to proline N-termini. Using this approach, bifunctional proline N-terminal bioconjugates are constructed and proline N-terminal proteins are immobilized.


Assuntos
Aminas/química , Hidrazinas/química , Prolina/química , Proteínas/síntese química , Hidrazonas/síntese química , Cetonas/síntese química , Oxirredução , Oximas/síntese química , Pyrococcus furiosus/química , Vírus do Mosaico do Tabaco/química
13.
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
14.
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.
Nanoscale ; 12(9): 5501-5506, 2020 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-32091054

RESUMO

In order to improve the cell-imaging ability, and particularly, to extend the bio-application of AIEgen, human papillomavirus (HPV) capsid protein L1 was assembled with the complex of DNA and aggregation-induced emission fluorogen 9,10-distyrylhydrazine (DSAI), where the virus-like particles (VLPs) of HPV encapsulate the complex via electrostatic interaction. The co-assembled nanoparticles, DSAI-DNA@VLPs, showed homogeneous size (∼53 nm), enhanced fluorescence (8 × 2.5-fold), considerable stability (anti-DNase digestion), improved biocompatibility and commendable protection for the DSAI-DNA complex, ensuring virtual brighter imaging in live cells, both for HeLa and normal 293T cell lines.


Assuntos
Proteínas do Capsídeo/química , Corantes Fluorescentes/química , Hidrazinas/química , Proteínas Oncogênicas Virais/química , Proteínas do Capsídeo/metabolismo , DNA/química , Células HEK293 , Células HeLa , Humanos , Microscopia Confocal , Nanopartículas/química , Proteínas Oncogênicas Virais/metabolismo , Tamanho da Partícula
17.
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
18.
Carbohydr Polym ; 231: 115727, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31888849

RESUMO

Carbazate groups were grafted on the commercial cellulose membrane (CM) to specifically scavenge the carbonylated proteins for hemodialysis. It confirmed that carbazate groups were successfully covalently attached on the CMs by XPS and EDS, and the modified CMs still saved their original morphology and crystalline structures by SEM and XRD. Furthermore, the modified CMs presented favorable physicochemical stability at wide pH range from 2.5 to 7.4. It was also found that the carbazate modified CMs could selectively remove carbonylated proteins from acrolein treated bovine serum albumin (BSA) or ESRD patient's blood serum in PBS buffer. The modified CMs showed the potential to be utilized as the substitute of dialysis membranes in hemodialysis.


Assuntos
Celulose/química , Hidrazinas/química , Falência Renal Crônica/terapia , Membranas Artificiais , Acroleína/farmacologia , Celulose/uso terapêutico , Humanos , Hidrazinas/uso terapêutico , Falência Renal Crônica/sangue , Polissacarídeos/química , Carbonilação Proteica/efeitos dos fármacos , Diálise Renal/instrumentação , Soroalbumina Bovina/química
19.
Carbohydr Polym ; 232: 115802, 2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-31952601

RESUMO

A series of biocompatible and non- toxic polysaccharide molecules have been successfully fabricated and explored their potential application for scavenging the carbonyl species in vitro. These macromolecules were dextrans with different hydrazide substitution ratios determined by TNBS assay, NMR and FTIR characterization. The colorimetric assay had demonstrated that these macromolecules could effectively scavenge acrolein, oxidized bovine serum albumin (BSA) in buffer solutions as well as carbonyl proteins from serum. The scavengers could achieve twice more scavenging effects for modified dextrans with high molecular weight (Mw = 100,000) than those of low ones (Mw = 40,000) with the same substitution ratio. Protein gel electrophoresis confirmed that the formation of the complex between carbonyls and modified dextrans resulted in appearance of slower bands. It also revealed that such macromolecules could protect cultured cells against the toxicity of acrolein or its derivatives. The proposed macromolecules indicated a very promising capability as scavengers for oxidative stress plus its derivatives without side effects.


Assuntos
Dextranos/metabolismo , Depuradores de Radicais Livres/metabolismo , Hidrazinas/metabolismo , Soroalbumina Bovina/metabolismo , Animais , Bovinos , Dextranos/química , Depuradores de Radicais Livres/química , Hidrazinas/química , Estrutura Molecular , Carbonilação Proteica , Soroalbumina Bovina/química
20.
Lasers Med Sci ; 35(8): 1729-1740, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31965353

RESUMO

Despite of high in vitro anticancer efficacy of many chemotherapeutics, their in vivo use is limited due to lack of biocompatibility and tumor targeting. Near-infrared (NIR) photothermally induced phase transition of PLGA-PEG regime was utilized for developing highly efficient photoresponsive drug delivery systems. Co-encapsulation of plasmonic gold nanorods (GNRs), as NIR-trigger, with the novel and highly efficient anticancer drug N'-(2-Methoxybenzylidene)-3-methyl-1-phenyl-H-Thieno[2,3-c]Pyrazole-5-Carbohyd-razide (MTPC) produced NIR-responsive biodegradable polymeric (PLGA-b-PEG) nanocapsules. This remotely controllable drug release significantly enhanced both biodistribution and pharmacokinetics of the hydrophobic drug. Intravenous (IV) injection of the prepared nanocapsules (MTPC/GNRs@PLGA-PEG) to tumor-bearing mice followed by extracorporeal exposure of the tumor to NIR light resulted in highly selective drug accumulation at the tumor sites. In vivo biodistribution and pharmacokinetics utilizing iodine-131 drug-radiolabelling technique revealed a maximum target to non-target ratio (T/NT) of 5.8, 4 h post-injection with maximum drug level in the tumor (6.3 ± 0.6% of the injected dose). Graphical abstract.


Assuntos
Antineoplásicos/uso terapêutico , Ouro/química , Nanotubos/química , Polietilenoglicóis/química , Poliglactina 910/química , Espectroscopia de Luz Próxima ao Infravermelho , Animais , Preparações de Ação Retardada , Liberação Controlada de Fármacos , Feminino , Humanos , Hidrazinas/química , Hidrazinas/farmacocinética , Hidrazinas/uso terapêutico , Radioisótopos do Iodo/química , Células MCF-7 , Camundongos , Nanocápsulas/química , Nanotubos/ultraestrutura , Distribuição Tecidual
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