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1.
Eur J Med Chem ; 178: 13-29, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31173968

RESUMO

The oncogenic Epstein-Barr virus (EBV) evades the immune system through limiting the expression of its highly antigenic and essential genome maintenance protein, EBNA1, to the minimal level to ensure viral genome replication, thereby also minimizing the production of EBNA1-derived antigenic peptides. This regulation is based on inhibition of translation of the virally-encoded EBNA1 mRNA, and involves the interaction of host protein nucleolin (NCL) with G-quadruplex (G4) structures that form in the glycine-alanine repeat (GAr)-encoding sequence of the EBNA1 mRNA. Ligands that bind to these G4-RNA can prevent their interaction with NCL, leading to disinhibition of EBNA1 expression and antigen presentation, thereby interfering with the immune evasion of EBNA1 and therefore of EBV (M.J. Lista et al., Nature Commun., 2017, 8, 16043). In this work, we synthesized and studied a series of 20 cationic bis(acylhydrazone) derivatives designed as G4 ligands. The in vitro evaluation showed that most derivatives based on central pyridine (Py), naphthyridine (Naph) or phenanthroline (Phen) units were efficient G4 binders, in contrast to their pyrimidine (Pym) counterparts, which were poor G4 binders due to a significantly different molecular geometry. The influence of lateral heterocyclic units (N-substituted pyridinium or quinolinium residues) on G4-binding properties was also investigated. Two novel compounds, namely PyDH2 and PhenDH2, used at a 5 µM concentration, were able to significantly enhance EBNA1 expression in H1299 cells in a GAr-dependent manner, while being significantly less toxic than the prototype drug PhenDC3 (GI50 > 50 µM). Antigen presentation, RNA pull-down and proximity ligation assays confirmed that the effect of both drugs was related to the disruption of NCL-EBNA1 mRNA interaction and the subsequent promotion of GAr-restricted antigen presentation. Our work provides a novel modular scaffold for the development of G-quadruplex-targeting drugs acting through interference with G4-protein interaction.


Assuntos
Hidrazonas/farmacologia , Evasão da Resposta Imune/efeitos dos fármacos , Fatores Imunológicos/farmacologia , Fosfoproteínas/metabolismo , Ligação Proteica/efeitos dos fármacos , RNA Mensageiro/metabolismo , Proteínas de Ligação a RNA/metabolismo , Animais , Linhagem Celular Tumoral , Antígenos Nucleares do Vírus Epstein-Barr/genética , Antígenos Nucleares do Vírus Epstein-Barr/metabolismo , Quadruplex G , Herpesvirus Humano 4/genética , Humanos , Hidrazonas/síntese química , Hidrazonas/química , Fatores Imunológicos/síntese química , Fatores Imunológicos/química , Ligantes , Camundongos , RNA Mensageiro/genética
2.
Curr Top Med Chem ; 19(14): 1241-1251, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31223088

RESUMO

BACKGROUND: Schistosomiasis is a neglected disease, which affects millions of people in developing countries. Its treatment relies on a single therapeutic alternative, the praziquantel. This situation may lead to drug resistance which, in turn, made urgent the need for new antischistosomal agents. Nacylhydrazones are usually explored as good antimicrobial agents, but the vanillin-related N-acylhydrazones have never been tested by their antiparasitic potential. OBJECTIVE: Herein, we report the synthesis of seven analogues, three of them unpublished, their biological investigation against Schistosoma mansoni and Target Fishing studies. METHODS: The compounds were synthesized following classical synthetical approaches. The anthelmintic potential was assessed as well as their cytotoxicity profile. Confocal laser scanning microscopy and target fishing study were performed to better understand the observed antischistosomal activity. RESULTS: Compound GPQF-407 exhibited good antischistosomal activity (47.91 µM) with suitable selectivity index (4.14). Confocal laser scanning microscopy revealed that it triggered severe tegumental destruction and tubercle disintegration. Target fishing studies pointed out some probable targets, such as the serine-threonine kinases, dihydroorotate dehydrogenases and carbonic anhydrase II. CONCLUSION: The GPQF-407 was revealed to be a promising antischistosomal agent which, besides presenting the N-acylhydrazone privileged scaffold, also could be easily synthesized on large scales from commercially available materials.


Assuntos
Benzaldeídos/farmacologia , Hidrazonas/farmacologia , Schistosoma mansoni/efeitos dos fármacos , Esquistossomicidas/farmacologia , Animais , Benzaldeídos/química , Sobrevivência Celular/efeitos dos fármacos , Cercopithecus aethiops , Relação Dose-Resposta a Droga , Hidrazonas/síntese química , Hidrazonas/química , Estrutura Molecular , Esquistossomicidas/síntese química , Esquistossomicidas/química , Relação Estrutura-Atividade , Células Vero
3.
Inorg Chem ; 58(13): 8800-8819, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31247881

RESUMO

Very few inorganic antineoplastic drugs have entered the clinic in the last decades, mainly because of toxicity issues. Because copper is an essential trace element of ubiquitous occurrence, decreased side effects could be expected in comparison with the widely used platinum anticancer compounds. In the present work, two novel hydrazonic binucleating ligands and their µ-hydroxo dicopper(II) complexes were prepared and fully characterized. They differ by the nature of the aromatic group present in their aroylhydrazone moieties: while H3L1 and its complex, 1, possess a thiophene ring, H3L2 and 2 contain the more polar furan heterocycle. X-ray diffraction indicates that both coordination compounds are very similar in structural terms and generate dimeric arrangements in the solid state. Positive-ion electrospray ionization mass spectrometry analyses confirmed that the main species present in a 10% dimethyl sulfoxide (DMSO)/water solution should be [Cu2(HL)(OH)]+ and the DMSO-substituted derivative [Cu2(L)(DMSO)]+. Scattering techniques [dynamic light scattering (DLS) and small-angle X-ray scattering] suggest that the complexes and their free ligands interact with bovine serum albumin (BSA) in a reversible manner. The binding constants to BSA were determined for the complexes through fluorescence spectroscopy. Moreover, to gain insight into the mechanism of action of the compounds, calf thymus DNA binding studies by UV-visible and DLS measurements using plasmid pBR322 DNA were also performed. For the complexes, DLS data seem to point to the occurrence of DNA cleavage to Form III (linear). Both ligands and their dicopper(II) complexes display potent antiproliferative activity in a panel of four cancer cell lines, occasionally even in the submicromolar range, with the complexes being more potent than the free ligands. Our data on cellular models correlate quite well with the DNA interaction experiments. The results presented herein show that aroylhydrazone-derived binucleating ligands, as well as their dinuclear µ-hydroxodicopper(II) complexes, may represent a promising structural starting point for the development of a new generation of highly active potential antitumor agents.


Assuntos
Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Hidrazonas/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/toxicidade , Bovinos , Linhagem Celular Tumoral , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Complexos de Coordenação/toxicidade , Cobre/química , DNA/química , Clivagem do DNA/efeitos dos fármacos , Cães , Humanos , Hidrazonas/síntese química , Hidrazonas/química , Hidrazonas/toxicidade , Isomerismo , Ligantes , Células Madin Darby de Rim Canino , Camundongos , Plasmídeos/química , Multimerização Proteica/efeitos dos fármacos , Soroalbumina Bovina/metabolismo
4.
Eur J Med Chem ; 177: 153-170, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31132531

RESUMO

The eukaryotic initiation factor 4E (eIF4E) is an emerging anticancer drug target for specific anticancer therapy as a promising approach to overcome drug resistance and promote chemotherapy antitumor efficacy. A series of bromophenol-thiazolylhydrazone hybrids were designed, synthesized and evaluated for their antitumor activities. Among of them, the most potent compound 3e (EGPI-1) could inhibit the eIF4E/eIF4G interaction. Further mechanism study demonstrated EGPI-1 played an antitumor role in multiple modes of action including regulating the activity of eIF4E by inhibiting the phosphorylation of eIF4E and 4EBP1, disrupting mitochondrial function through the mTOR/4EBP1 signaling pathway, and inducing autophagy, apoptosis and ROS generation. Moreover, EGPI-1 showed good safety and favorable pharmacokinetic properties in vivo. These observations demonstrate that EGPI-1 may serve as an excellent lead compound for the development of new anticancer drugs that target the eIF4E/eIF4G interface and as a chemical genetic probe to investigate the role of the eIF4E in biological processes and human diseases.


Assuntos
Antineoplásicos/farmacologia , Fator de Iniciação 4E em Eucariotos/antagonistas & inibidores , Fator de Iniciação 4G em Eucariotos/antagonistas & inibidores , Hidrazonas/farmacologia , Tiazóis/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacocinética , Antineoplásicos/toxicidade , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Sítios de Ligação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Desenho de Drogas , Fator de Iniciação 4E em Eucariotos/química , Fator de Iniciação 4E em Eucariotos/metabolismo , Fator de Iniciação 4G em Eucariotos/metabolismo , Feminino , Células Endoteliais da Veia Umbilical Humana , Humanos , Hidrazonas/síntese química , Hidrazonas/farmacocinética , Hidrazonas/toxicidade , Masculino , Camundongos , Simulação de Acoplamento Molecular , Fosforilação , Ligação Proteica , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Tiazóis/síntese química , Tiazóis/farmacocinética , Tiazóis/toxicidade , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Cell Prolif ; 52(4): e12611, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31054182

RESUMO

OBJECTIVES: Epigenetic modifiers were important players in the development of haematological malignancies and sensitivity to therapy. Mutations of SET domain-containing 2 (SETD2), a methyltransferase that catalyses the trimethylation of histone 3 on lysine 36 (H3K36me3), were found in various myeloid malignancies. However, the detailed mechanisms through which SETD2 confers chronic myeloid leukaemia progression and resistance to therapy targeting on BCR-ABL remain unclear. MATERIALS AND METHODS: The level of SETD2 in imatinib-sensitive and imatinib-resistant chronic myeloid leukaemia (CML) cells was examined by immunoblotting and quantitative real-time PCR. We analysed CD34+ CD38- leukaemic stem cells by flow cytometry and colony formation assays upon SETD2 knockdown or overexpression. The impact of SETD2 expression alterations or small-molecule inhibitor JIB-04 targeting H3K36me3 loss on imatinib sensitivity was assessed by IC50, cell apoptosis and proliferation assays. Finally, RNA sequencing and ChIP-quantitative PCR were performed to verify putative downstream targets. RESULTS: SETD2 was found to act as a tumour suppressor in CML. The novel oncogenic targets MYCN and ERG were shown to be the direct downstream targets of SETD2, where their overexpression induced by SETD2 knockdown caused imatinib insensitivity and leukaemic stem cell enrichment in CML cell lines. Treatment with JIB-04, an inhibitor that restores H3K36me3 levels through blockade of its demethylation, successfully improved the cell imatinib sensitivity and enhanced the chemotherapeutic effect. CONCLUSIONS: Our study not only emphasizes the regulatory mechanism of SETD2 in CML, but also provides promising therapeutic strategies for overcoming the imatinib resistance in patients with CML.


Assuntos
Regulação para Baixo/genética , Resistencia a Medicamentos Antineoplásicos/genética , Histona Metiltransferases/genética , Histona-Lisina N-Metiltransferase/genética , Mesilato de Imatinib/farmacologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Aminopiridinas/farmacologia , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Apoptose/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Regulação para Baixo/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Proteínas de Fusão bcr-abl/genética , Humanos , Hidrazonas/farmacologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia
6.
Virol J ; 16(1): 37, 2019 03 25.
Artigo em Inglês | MEDLINE | ID: mdl-30909932

RESUMO

BACKGROUND: Porcine sapelovirus (PSV), a species of the genus Sapelovirus within the family Picornaviridae, are a significant cause of enteritis, pneumonia, polioencephalomyelitis and reproductive disorders in pigs. However, the life cycle of PSV on the molecular level is largely unknown. METHODS: Here, we used chemical inhibitors, RNA interference, and overexpression of dominant negative (DN) mutant plasmids to verify the roles of distinct endocytic pathways involved in PSV entry into porcine small intestinal epithelial cell line (IPEC-J2). RESULTS: Our experiments indicated that PSV infection was inhibited when cells were pre-treated with NH4Cl or chloroquine. Inhibitors nystatin, methyl-ß-cyclodextrin, dynasore and wortmannin dramatically reduced PSV entry efficiency, whereas the inhibitors chlorpromazine and EIPA had no effect. Furthermore, overexpression caveolin DN mutant and siRNA against caveolin also decreased virus titers and VP1 protein synthesis, whereas overexpression EPS15 DN mutant and siRNA against EPS15 did not reduce virus infection. CONCLUSIONS: Our findings suggest that PSV entry into IPEC-J2 cells depends on caveolae/lipid raft mediated-endocytosis, that is pH-dependent and requires dynamin and PI3K but is independent of clathrin and macropinocytosis.


Assuntos
Cavéolas/virologia , Endocitose , Células Epiteliais/virologia , Picornaviridae/fisiologia , Internalização do Vírus/efeitos dos fármacos , Cloreto de Amônio/farmacologia , Animais , Linhagem Celular , Cloroquina/farmacologia , Clatrina/metabolismo , Dinaminas/metabolismo , Hidrazonas/farmacologia , Nistatina/farmacologia , Picornaviridae/efeitos dos fármacos , Interferência de RNA , RNA Interferente Pequeno , Suínos
7.
Pak J Pharm Sci ; 32(1): 15-19, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30772785

RESUMO

This research based on the anti-inflammatory and antiplatelet aggregation properties of some new thiazolyl hydrazone derivatives of 1-indanone. In this regard a thiosemicabazone and twelve thiazolyl derivatives of 1-indanone have been synthesized. Out of these synthetic compounds seven derivatives 1-3, 6, 11-13 exhibited varying degree of anti-inflammatory action with IC50 esteems going from 5.1±1.3 - 78.8±4.6µM/mL. Compound 1 (IC50 =5.1±1.9µM) displayed potent result than standard ibuprofen (IC50 = 11.2±1.9 µM). In antiplatelet aggregation assay, five compounds 1, 5, 6, 8 and 11 were observed to be dynamic with IC50 esteems observed in the range of 38.34-255.7±4.1µM, wher eas, aspirin (IC50 = 30.3±2.6 µM) was used as standard. However, compound 11 was found to be good active for both anti-inflammatory and antiplatelet aggregation activities (IC50 = 13.9±4.9µg/mL) (IC50 = 38.60±3.1µM), respectively.


Assuntos
Anti-Inflamatórios/farmacologia , Hidrazonas/farmacologia , Indanos/farmacologia , Inibidores da Agregação de Plaquetas/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Explosão Respiratória/efeitos dos fármacos , Anti-Inflamatórios/síntese química , Relação Dose-Resposta a Droga , Humanos , Hidrazonas/síntese química , Ibuprofeno/farmacologia , Indanos/síntese química , Estrutura Molecular , Inibidores da Agregação de Plaquetas/síntese química , Relação Estrutura-Atividade , Tiossemicarbazonas/síntese química
8.
Pak J Pharm Sci ; 32(1): 103-108, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30772797

RESUMO

New series of Co+2, Ni+2, Cu+2 and Zn+2 complexes have been synthesized using a bio-active hydrazone compound 4-hydroxybenzaldehyde-N-(5-chloro-2-oxo-1,2-dihydro-3H-indol-3-ylidene), abbreviated as [HL]. Complexes were characterized using elemental analysis, FT-IR, UV-visible spectroscopy conductivity and magnetic susceptibility measurements. Results showed that the bi-dentate [HL] coordinated in a square planner manner with Cu+2 while for the rest of the M+2 ions, it coordinated in a octahedral fashion. Free ligand and its metal complexes were also studied for their antioxidant potential by employing two methods i.e. DPPH radical scavenging and reducing power assay. It was observed that the metal complexes were considerably more potent free radical scavenger and had better reducing abilities compared to the free ligand, furthermore, for both in vitro assays, metal complexes turned out to be better DPPH scavengers and had better reducing abilities than the standards used during biological assays.


Assuntos
Complexos de Coordenação/síntese química , Complexos de Coordenação/farmacologia , Depuradores de Radicais Livres/síntese química , Depuradores de Radicais Livres/farmacologia , Hidrazonas/síntese química , Hidrazonas/farmacologia , Compostos de Bifenilo/química , Ferro/química , Estrutura Molecular , Oxirredução , Picratos/química , Espectroscopia de Prótons por Ressonância Magnética , Espectrofotometria Ultravioleta , Espectroscopia de Infravermelho com Transformada de Fourier , Relação Estrutura-Atividade , Tiocianatos/química
9.
J Enzyme Inhib Med Chem ; 34(1): 597-612, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30727777

RESUMO

A new series of 4-(3-nitrophenyl)thiazol-2-ylhydrazone derivatives were designed, synthesised, and evaluated to assess their inhibitory effect on the human monoamine oxidase (hMAO) A and B isoforms. Different (un)substituted (hetero)aromatic substituents were linked to N1 of the hydrazone in order to establish robust structure-activity relationships. The results of the biological testing demonstrated that the presence of the hydrazothiazole nucleus bearing at C4 a phenyl ring functionalised at the meta position with a nitro group represents an important pharmacophoric feature to obtain selective and reversible human MAO-B inhibition for the treatment of neurodegenerative disorders. In addition, the most potent and selective MAO-B inhibitors were evaluated in silico as potential cholinesterase (AChE/BuChE) inhibitors and in vitro for antioxidant activities. The results obtained from molecular modelling studies provided insight into the multiple interactions and structural requirements for the reported MAO inhibitory properties.


Assuntos
Antioxidantes/farmacologia , Hidrazonas/farmacologia , Inibidores da Monoaminoxidase/farmacologia , Monoaminoxidase/metabolismo , Tiazóis/farmacologia , Acetilcolinesterase/metabolismo , Antioxidantes/síntese química , Antioxidantes/química , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Humanos , Hidrazonas/síntese química , Hidrazonas/química , Modelos Moleculares , Estrutura Molecular , Inibidores da Monoaminoxidase/síntese química , Inibidores da Monoaminoxidase/química , Tiazóis/síntese química , Tiazóis/química
10.
J Enzyme Inhib Med Chem ; 34(1): 451-458, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30734605

RESUMO

A series of organometallic acylhydrazones was prepared, incorporating Re(CO)3, Mn(CO)3 and ferrocenyl moieties, which were subsequently reacted with amino-sulfonamides in order to obtain carbonic anhydrase (CA, EC 4.2.1.1) inhibitors possessing organometallic moieties in their molecules. The new derivatives were investigated as inhibitors of four human (h) CA isoforms with pharmaceutical applications, such as the cytosolic hCA I, II and VII and the mitochondrial hCA VA. An interesting inhibitory profile against these isoforms was obtained, with some of these metal complexes acting as subnanomolar or low nanomolar inhibitors. They were also thoroughly characterised from the chemical point of view, making them of interest for further developments in the field of metal complexes of sulfonamides with CA inhibitory action.


Assuntos
Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/metabolismo , Hidrazonas/farmacologia , Compostos Organometálicos/farmacologia , Sulfonamidas/farmacologia , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Relação Dose-Resposta a Droga , Humanos , Hidrazonas/química , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Estrutura Molecular , Compostos Organometálicos/química , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química
11.
Molecules ; 24(1)2019 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-30621322

RESUMO

In the context of an increased incidence of invasive fungal diseases, there is an imperative need of new antifungal drugs with improved activity and safety profiles. A novel series of acylhydrazones bearing a 1,4-phenylene-bisthiazole scaffold was designed based on an analysis of structures known to possess anti-Candida activity obtained from a literature review. Nine final compounds were synthesized and evaluated in vitro for their inhibitory activity against various strains of Candida spp. The anti-Candida activity assay revealed that some of the new compounds are as active as fluconazole against most of the tested strains. A molecular docking study was conducted in order to evaluate the binding poses towards lanosterol 14α-demethylase. An in silico ADMET analysis showed that the compounds possess drug-like properties and represent a biologically active framework that should be further optimized as potential hits.


Assuntos
Antifúngicos/farmacologia , Candida/efeitos dos fármacos , Hidrazonas/farmacologia , Antifúngicos/síntese química , Desenho de Drogas , Fluconazol/farmacologia , Hidrazonas/síntese química , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Estrutura Molecular , Ligação Proteica , Relação Estrutura-Atividade
12.
Eur J Med Chem ; 164: 273-281, 2019 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-30597328

RESUMO

N,N'-Diaryl-bishydrazones of [1,1'-biphenyl]-3,4'-dicarboxaldehyde, [1,1'-biphenyl]-4,4'-dicarboxaldehyde, and 4,4'-bisacetyl-1,1-biphenyl exhibited excellent antifungal activity against a broad spectrum of filamentous and non-filamentous fungi. These N,N'-diaryl-bishydrazones displayed no antibacterial activity in contrast to previously reported N,N'-diamidino-bishydrazones and N-amidino-N'-aryl-bishydrazones. The leading candidate, 4,4'-bis((E)-1-(2-(4-fluorophenyl)hydrazono)ethyl)-1,1'-biphenyl, displayed less hemolysis of murine red blood cells at concentrations at or below that of a control antifungal agent (voriconazole), was fungistatic in a time-kill study, and possessed no mammalian cytotoxicity and no toxicity with respect to hERG inhibition.


Assuntos
Antifúngicos/química , Compostos de Bifenilo/farmacologia , Hidrazonas/farmacologia , Animais , Antifúngicos/farmacologia , Compostos de Bifenilo/química , Compostos de Bifenilo/uso terapêutico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Eritrócitos/efeitos dos fármacos , Fungicidas Industriais , Hemólise/efeitos dos fármacos , Hidrazonas/química , Hidrazonas/uso terapêutico , Camundongos
13.
Eur J Med Chem ; 163: 840-852, 2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30579124

RESUMO

Microtubule affinity-regulating kinase 4 (MARK4) is a potential drug target as the same is found to be over expressed in several types of cancers. In search of effective MARK4 inhibitors, we have synthesized and characterized Isatin-triazole hydrazones (9a-i) and evaluated their inhibitory potential. Of all the compounds, 9g showed better binding affinity and enzyme inhibition potential in sub micromolar range. Human serum albumin (HSA) binding assay suggested an easy transportation of 9g in blood stream due to its binding affinity. In vitro anticancer studies performed on MCF-7, MDA-MB-435s and HepG2 cells using 9g showed inhibition of cell proliferation and cell migration. Further, 9g induces apoptosis in these cancerous cells, with IC50 values of 6.22, 9.94 and 8.14 µM, respectively. Putatively, 9g seems to cause oxidative stress resulting in apoptosis. Functional assay of 9g with a panel of 26 kinases showed MARK4 specific profile. In conclusion, 9g seems to possess an effective inhibitory potential towards MARK4 adding an additional repertoire to anticancer therapeutics.


Assuntos
Hidrazonas/uso terapêutico , Isatina/uso terapêutico , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Triazóis/uso terapêutico , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Células Hep G2 , Humanos , Hidrazonas/química , Hidrazonas/farmacologia , Isatina/química , Isatina/farmacologia , Células MCF-7 , Metástase Neoplásica/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Ligação Proteica , Inibidores de Proteínas Quinases/farmacologia , Triazóis/química , Triazóis/farmacologia
14.
Colloids Surf B Biointerfaces ; 175: 671-679, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30590328

RESUMO

In this research we report the biological synthesis of electrically conducting polymer - Polypyrrole (Ppy). Cell-assisted enzymatic polymerization/oligomerization of Ppy was achieved using whole cell culture and cell-free crude enzyme extract from two white-rot fungal cultures. The selected fungal strains belong to Trametes spp., known laccase producers, commonly applied in bioremediation and bioelectrochemical fields. The biocatalytic reaction was initiated in situ through the copper-containing enzymes biosynthesized within the cell cultures under submerged aerobe cultivation conditions. The procedure was inspired by successful reports of laccase-catalyzed pyrrole polymerization. The usage of whole culture and/or crude enzyme extract has the advantage of overcoming enzyme purification and minimizing the liability of enzyme inactivation through improved stability of enzymes in their natural environment. Spectral and electrochemical techniques (UV-vis spectroscopy, infrared spectroscopy; cyclic voltammetry (CV)) and pH measurements provided insight into the evolution of pyrrole polymerization/oligomerization and the electrochemical features of the final product. Microscopy techniques (optical microscopy and scanning electron microscopy (SEM)) were primary tools for visualization of the formed Ppy particles. The relevance of our research is twofold: Ppy prepared in crude enzyme extract results in enzyme encapsulated within Ppy and/or Ppy-modified fungal cells can be formed when polymerization occurs in whole cell culture. The route of biocatalysis can be chosen according to the desired bioelectrochemical application. The reported study focuses on the improvement of charge transfer through the fungal cell membrane and/or cell wall by modification of the fungal cells with conducting polymer - polypyrrole.


Assuntos
Proteínas Fúngicas/metabolismo , Monofenol Mono-Oxigenase/metabolismo , Polímeros/metabolismo , Pirróis/metabolismo , Trametes/metabolismo , Benzotiazóis/metabolismo , Benzotiazóis/farmacologia , Biocatálise , Parede Celular/efeitos dos fármacos , Parede Celular/metabolismo , Meios de Cultura/química , Meios de Cultura/farmacologia , Condutividade Elétrica , Técnicas Eletroquímicas , Fermentação/efeitos dos fármacos , Guaiacol/metabolismo , Guaiacol/farmacologia , Hidrazonas/metabolismo , Hidrazonas/farmacologia , Concentração de Íons de Hidrogênio , Polímeros/química , Pirróis/química , Ácidos Sulfônicos/metabolismo , Ácidos Sulfônicos/farmacologia , Trametes/efeitos dos fármacos
15.
Biosci Rep ; 39(1)2019 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-30538170

RESUMO

The tetracycline repressor (TetR)-regulated system is a widely used tool to study gene functions through control of its expression. Various effectors such as tetracycline (Tc) and doxycycline (Dox) quickly induce or shut down gene expression, but reversing gene expression has not been eligible due to long half-lives of such effectors. Here, we found that procaspase activating compound 1 (PAC-1) rapidly reduces transient expression of TetR-regulated green fluorescent protein (GFP) in mammalian cells. Next, we applied PAC-1 to control of expression of transient receptor potential melastatin 7 (TRPM7) protein, whose downstream cellular events can be monitored by cell morphological changes. We observed that PAC-1 quickly reduces TRPM7 expression, consequently affecting cell morphology regulated by TRPM7. The present study demonstrates the first small molecule that efficiently turns off the TetR-regulated gene expression in mammalian cells, thereby precisely regulating the expression level of target gene.


Assuntos
Regulação da Expressão Gênica/efeitos dos fármacos , Hidrazonas/farmacologia , Piperazinas/farmacologia , Proteínas Repressoras/genética , Tetraciclina/farmacologia , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/genética , Regulação da Expressão Gênica/genética , Proteínas de Fluorescência Verde/genética , Células HEK293 , Humanos , Canais de Cátion TRPM/genética
16.
Nat Commun ; 9(1): 5230, 2018 12 07.
Artigo em Inglês | MEDLINE | ID: mdl-30531796

RESUMO

Left ventricular hypertrophy (LVH) is a major risk factor for cardiovascular morbidity and mortality. Pathological LVH engages transcriptional programs including reactivation of canonical fetal genes and those inducing fibrosis. Histone lysine demethylases (KDMs) are emerging regulators of transcriptional reprogramming in cancer, though their potential role in abnormal heart growth and fibrosis remains little understood. Here, we investigate gain and loss of function of an H3K9me2 specific demethylase, Kdm3a, and show it promotes LVH and fibrosis in response to pressure-overload. Cardiomyocyte KDM3A activates Timp1 transcription with pro-fibrotic activity. By contrast, a pan-KDM inhibitor, JIB-04, suppresses pressure overload-induced LVH and fibrosis. JIB-04 inhibits KDM3A and suppresses the transcription of fibrotic genes that overlap with genes downregulated in Kdm3a-KO mice versus WT controls. Our study provides genetic and biochemical evidence for a pro-hypertrophic function of KDM3A and proof-of principle for pharmacological targeting of KDMs as an effective strategy to counter LVH and pathological fibrosis.


Assuntos
Cardiomegalia/genética , Regulação da Expressão Gênica/genética , Histona Desmetilases/genética , Miocárdio/metabolismo , Aminopiridinas/farmacologia , Animais , Animais Recém-Nascidos , Cardiomegalia/enzimologia , Células Cultivadas , Fibrose/genética , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/efeitos dos fármacos , Histona Desmetilases/antagonistas & inibidores , Histona Desmetilases/metabolismo , Humanos , Hidrazonas/farmacologia , Camundongos Knockout , Camundongos Transgênicos , Miocárdio/enzimologia , Miocárdio/patologia , Miócitos Cardíacos/metabolismo , Ratos Sprague-Dawley
17.
Eur J Med Chem ; 158: 247-258, 2018 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-30218910

RESUMO

A series of linezolid analogues containing a hydrazone moiety were designed, synthesized and evaluated for their antibacterial activity. Most compounds exhibited more potent antibacterial activity against S.aureus, MRSA, MSSA, LREF and VRE pathogens as compared with linezolid and radezolid. Compounds 9a, 9c, 9f, 9g, 10m and 10t were more potent against tested clinical isolates of MRSA, MSSA, VRE and LREF as compared to linezolid. Compound 9a exhibited comparable activity with linezolid against human MAO-A for safety evaluation and showed moderate metabolism in human liver microsome. The most promising compound 9a showed remarkable antibacterial activity against S.aureus, MRSA, MSSA, LREF and VRE pathogens with MIC value of 0.0675 mg/mL, respectively, which was 15- to 30-fold more potent than linezolid.


Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Bactérias Gram-Positivas/efeitos dos fármacos , Hidrazonas/química , Hidrazonas/farmacologia , Oxazolidinonas/química , Oxazolidinonas/farmacologia , Antibacterianos/síntese química , Antibacterianos/metabolismo , Infecções por Bactérias Gram-Positivas/tratamento farmacológico , Células Hep G2 , Humanos , Hidrazonas/síntese química , Hidrazonas/metabolismo , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Simulação de Acoplamento Molecular , Oxazolidinonas/síntese química , Oxazolidinonas/metabolismo
18.
Life Sci ; 209: 85-96, 2018 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-30076923

RESUMO

AIMS: Double stranded protein kinase R cellular response is associated with various stress signals such as nutrients, endoplasmic stress, cytokines and mechanical stress. Increased PKR activity has been observed under diabetic and cardiovascular disease conditions. Most of the currently available PKR inhibitors are non-specific and have other effects as well. Thus, the aim of the present study was to examine the effect of novel PKR inhibitor indirubin-3-hydrazone (IHZ) in cultured rat H9C2 cardiomyocytes and wistar rats. MATERIALS AND METHODS: PKR expression was determined by Q-PCR, immunofluorescence and immunoblotting. The expression of different gene markers for apoptosis was measured by RT-PCR. Apoptosis and oxidative stress were determined by flow cytometry. KEY FINDINGS: High glucose (HG) treated H9C2 cardiomyocytes and high fructose (HF) treated wistar rats developed a significant increase in PKR expression. A significant increase in apoptosis and generation of reactive oxygen species was also observed in HG treated H9C2 cells and HF treated rats. Reduced vacuole formation and prominent nuclei were also observed in high glucose treated cells. Cardiac hypertrophy and increased fibrosis were observed in HF treated rats. All these effects of HG and HF were attenuated by novel PKR inhibitor, indirubin-3-hydrazone. SIGNIFICANCE: Our results indicate IHZ as an effective inhibitor of PKR in vitro and in-vivo, thus it may prove very useful in blocking the multiple harmful effects of PKR.


Assuntos
Hidrazonas/farmacologia , Miócitos Cardíacos/efeitos dos fármacos , eIF-2 Quinase/antagonistas & inibidores , Animais , Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Células Cultivadas , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Hidrazonas/química , Hiperglicemia/tratamento farmacológico , Hiperglicemia/metabolismo , Hiperglicemia/patologia , Técnicas In Vitro , Indóis/química , Indóis/farmacologia , Masculino , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos
19.
J Enzyme Inhib Med Chem ; 33(1): 1181-1193, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30044647

RESUMO

In this study, we synthesized a new congener series of N-sulphonylhydrazones designed as candidate ROCK inhibitors using the molecular hybridization of the clinically approved drug fasudil (1) and the IKK-ß inhibitor LASSBio-1524 (2). Among the synthesized compounds, the N-methylated derivative 11 (LASSBio-2065) showed the best inhibitory profile for both ROCK isoforms, with IC50 values of 3.1 and 3.8 µM for ROCK1 and ROCK2, respectively. Moreover, these compounds were also active in the scratch assay performed in human breast cancer MDA-MB 231 cells and did not display toxicity in MTT and LDH assays. Molecular modelling studies provided insights into the possible binding modes of these N-sulphonylhydrazones, which present a new molecular architecture capable of being optimized and developed as therapeutically useful ROCK inhibitors.


Assuntos
Hidrazonas/química , Isoquinolinas/química , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Quinases Associadas a rho/antagonistas & inibidores , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/análogos & derivados , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/química , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/farmacologia , Animais , Linhagem Celular Tumoral , Feminino , Humanos , Hidrazonas/síntese química , Hidrazonas/farmacologia , Modelos Moleculares , Difração de Pó , Análise Espectral/métodos
20.
Exp Parasitol ; 192: 25-35, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30028986

RESUMO

Perkinsus protozoan parasites have been associated with high mortality of bivalves worldwide, including Brazil. The use of antiproliferative drugs to treat the Perkinsosis is an unusual prophylactic strategy. However, because of their environment impact it could be used to control parasite proliferation in closed system, such as hatchery. This study evaluated the anti-Perkinsus activity potential of synthesized and commercial compounds. Viability of hypnospores of Perkinsus spp. was assessed in vitro. Cells were incubated with three 2-amino-thiophene (6AMD, 6CN, 5CN) and one acylhydrazone derivatives (AMZ-DCL), at the concentrations of 31.25; 62.5; 125; 250 and 500 µM and one commercial chlorinated phenoxy phenol derivative, triclosan (2, 5, 10 and 20 µM), for 24-48 h. Two synthetic molecules (6CN and AMZ-DCL) caused a significant decline (38 and 39%, respectively) in hypnospores viability, at the highest concentration (500 µM), after 48 h. Triclosan was the most cytotoxic compound, causing 100% of mortality at 20 µM after 24 h and at 10 µM after 48 h. Cytotoxic effects of the compounds 6CN, AMZ-DCL, and triclosan were investigated by measuring parasite's zoosporulation, morphological changes and metabolic activities (esterase activity, production of reactive oxygen species and lipid content). Results showed that zoosporulation occurred in few cell. Triclosan caused changes in the morphology of hypnospores. The 6CN and AMZ-DCL did not alter the metabolic activities studied whilst Triclosan significantly increased the production of reactive oxygen species and changed the amount and distribution of lipids in the hypnospores. These results suggest that three compounds had potential to be used as antiprotozoal drugs, although further investigation of their mechanism of action must be enlightened.


Assuntos
Alveolados/efeitos dos fármacos , Antiprotozoários/farmacologia , Ostreidae/parasitologia , Alveolados/patogenicidade , Alveolados/fisiologia , Análise de Variância , Animais , Antiprotozoários/uso terapêutico , Aquicultura , Bivalves/parasitologia , Brasil , Carboxilesterase/efeitos dos fármacos , Carboxilesterase/metabolismo , Estuários , Proteínas de Fluorescência Verde , Hidrazonas/química , Hidrazonas/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Substâncias Luminescentes , Espécies Reativas de Oxigênio/metabolismo , Água do Mar , Esporos de Protozoários/efeitos dos fármacos , Tiofenos/química , Tiofenos/farmacologia , Triclosan/farmacologia
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