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1.
Int J Mol Sci ; 22(17)2021 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-34502297

RESUMO

Hydrazide-hydrazones possess a wide spectrum of bioactivity, including antibacterial, antitubercular, antifungal, anticancer, anti-inflammatory, anticonvulsant, antidepressant, antiviral, and antiprotozoal properties. This review is focused on the latest scientific reports regarding antibacterial, antimycobacterial, and antifungal activities of hydrazide-hydrazones published between 2017 and 2021. The molecules and their chemical structures presented in this article are the most active derivatives, with discussed activities having a hydrazide-hydrazone moiety as the main scaffold or as a side chain. Presented information constitute a concise summary, which may be used as a practical guide for further design of new molecules with antimicrobial activity.


Assuntos
Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Hidrazonas/farmacologia , Animais , Bactérias/crescimento & desenvolvimento , Humanos
2.
Molecules ; 26(16)2021 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-34443416

RESUMO

Acylhydrazones are still an important framework to the design of new bioactive compounds. As treatment of chronic pain represents a clinical challenge, we decided to modify the structure of LASSBio-1514 (1), previously described as anti-inflammatory and analgesic prototype. Applying the homologation as a strategy for molecular modification, we designed a series of cyclopentyl- (2a-e), cyclobutyl- (3a-e), and cyclopropylacylhydrazones (4a-e) that were synthetized and evaluated in murine models of inflammation and pain. A comparison of their in silico physicochemical and drug-like profile was conducted, as well as their anti-inflammatory and analgesic effect. Compounds 4a (LASSBio-1755) and 4e (LASSBio-1757) displayed excellent in silico drug-like profiles and were identified as new analgesic lead-candidates in acute and chronic model of pain, through oral administration.


Assuntos
Simulação por Computador , Desenho de Fármacos , Hidrazonas/síntese química , Hidrazonas/farmacologia , Preparações Farmacêuticas/síntese química , Analgésicos/farmacologia , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Aspirina/farmacologia , Células CACO-2 , Humanos , Hidrazonas/química , Hiperalgesia/patologia , Indometacina/farmacologia , Masculino , Camundongos , Conformação Molecular , Peso Molecular , Preparações Farmacêuticas/química , Ratos Wistar
3.
Int J Mol Sci ; 22(13)2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-34281197

RESUMO

Psoriasis, a long-lasting and multifactorial skin disease, is related to comorbidities such as metabolic disease, depression, and psoriatic arthritis. Psoriasis occurs due to a variety of factors including keratinocyte hyperproliferation, inflammation, and abnormal differentiation. Proinflammatory cytokines upregulated by increased activation of keratinocytes and immune cells in the skin trigger progression of psoriasis. This study aimed to investigate the effects of anoctamin1 (ANO1) on psoriasis development in vitro and in vivo. We analyzed the proliferation of HaCaT keratinocytes and ANO1-related ERK and AKT signaling pathways after ANO1 inhibitor (T16Ainh-A01 and Ani9) treatment and knock-down of ANO1. Furthermore, after applying imiquimod (IMQ) cream or coapplying IMQ cream and T16Ainh-A01 on mouse ears, we not only observed psoriatic symptoms, including ear thickening, but also quantified the effects of treatment on ERK and AKT signaling-involved proteins and proinflammatory cytokines. Inhibition of ANO1 attenuated the proliferation of HaCaT cells and induced reduction of pERK1/2. Coapplication of IMQ and T16Ainh-A01 on ears of mice reduced not only symptoms of IMQ-induced psoriasis such as thickening and erythema, but also expression of ANO1 and pERK1/2 compared to that of application of IMQ alone. In addition, the expression levels of IL-17A, IL-17F, IL-22, IL-23, IL-6, IL-1ß, and TNF-α increased after applying IMQ and were significantly reduced by coapplying IMQ and T16Ainh-A01. These results aid in understanding the underlying mechanisms of ANO1 in epidermal layer keratinocyte hyperproliferation and suggest the potential of ANO1 as a target to treat psoriasis.


Assuntos
Anoctamina-1/farmacologia , Queratinócitos/efeitos dos fármacos , Psoríase/induzido quimicamente , Acetamidas/farmacologia , Animais , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Células HaCaT , Humanos , Hidrazonas/farmacologia , Imiquimode/efeitos adversos , Imiquimode/farmacologia , Inflamação/metabolismo , Inflamação/patologia , Interleucinas/metabolismo , Queratinócitos/metabolismo , Queratinócitos/patologia , Sistema de Sinalização das MAP Quinases , Camundongos , Camundongos Endogâmicos BALB C , Psoríase/metabolismo , Psoríase/patologia , Pirimidinas/farmacologia , Tiazóis/farmacologia
4.
J Enzyme Inhib Med Chem ; 36(1): 1521-1539, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34266349

RESUMO

Hydrazone is a bioactive pharmacophore that can be used to design antitumor agents. We synthesised a series of hydrazones (compounds 4-24) incorporating a 4-methylsulfonylbenzene scaffold and analysed their potential antitumor activity. Compounds 6, 9, 16, and 20 had the most antitumor activity with a positive cytotoxic effect (PCE) of 52/59, 27/59, 59/59, and 59/59, respectively, while compounds 5, 10, 14, 15, 18, and 19 had a moderate antitumor activity with a PCE of 11/59-14/59. Compound 20 was the most active and had a mean 50% cell growth inhibition (GI50) of 0.26 µM. Compounds 9 and 20 showed the highest inhibitory activity against COX-2, with a half-maximal inhibitory concentration (IC50) of 2.97 and 6.94 µM, respectively. Compounds 16 and 20 significantly inhibited EGFR (IC50 = 0.2 and 0.19 µM, respectively) and HER2 (IC50 = 0.13 and 0.07 µM, respectively). Molecular docking studies of derivatives 9, 16, and 20 into the binding sites of COX-2, EGFR, and HER2 were carried out to explore the interaction mode and the structural requirements for antitumor activity.


Assuntos
Antineoplásicos/farmacologia , Hidrazonas/farmacologia , Simulação de Acoplamento Molecular , Sulfonamidas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Hidrazonas/química , Estrutura Molecular , Relação Estrutura-Atividade , Sulfonamidas/química
5.
Chem Biol Interact ; 345: 109540, 2021 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-34139148

RESUMO

In the present study, fifteen benzimidazolyl-2-hydrazones 7a-7o of fluoro-, hydroxy- and methoxy-substituted benzaldehydes and 1,3-benzodioxole-5-carbaldehyde were synthesized and their structure was identified by IR, NMR, and elemental analysis. The compounds 7j 2-(3-hydroxybenzylidene)-1-(5(6)-methyl-1H-benzimidazol-2-yl)hydrazone and 7i 2-(3-hydroxybenzylidene)-1-(1H-benzimidazol-2-yl)hydrazone have exerted the strongest anthelmintic activity (100% after 24 h incubation period at 37 °C) against isolated muscle larvae of Trichinella spiralis in an in vitro experiment. The in vitro cytotoxicity assay towards MCF-7 breast cancer cells and mouse embryo fibroblasts 3T3 showed that the studied benzimidazolyl-2-hydrazones exhibit low to moderate cytotoxic effects. The ability of the studied benzimidazolyl-2-hydrazones to modulate microtubule polymerization was confirmed and suggested that their anthelmintic action is mediated through inhibition of the tubulin polymerization likewise the other known benzimidazole anthelmitics. It was also shown that the four most promising benzimidazolyl-2-hydrazones do not affect significantly the AChE activity even at high tested concentration, thus indicating that they do not have the potential for neurotoxic effects. The binding mode of compounds 7j and 7n in the colchicine-binding site of tubulin were clarified by molecular docking simulations. Taken together, these results demonstrate that for the synthesized benzimidazole derivatives the anthelmintic activity against T. spiralis and the inhibition of tubulin polymerization are closely related.


Assuntos
Benzimidazóis/química , Hidrazonas/química , Hidrazonas/farmacologia , Simulação de Acoplamento Molecular , Tubulina (Proteína)/metabolismo , Anti-Helmínticos/síntese química , Anti-Helmínticos/química , Anti-Helmínticos/metabolismo , Anti-Helmínticos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Técnicas de Química Sintética , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Hidrazonas/síntese química , Hidrazonas/metabolismo , Células MCF-7 , Conformação Proteica , Relação Estrutura-Atividade , Tubulina (Proteína)/química , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/química , Moduladores de Tubulina/metabolismo , Moduladores de Tubulina/farmacologia
6.
Molecules ; 26(10)2021 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-34069070

RESUMO

A series of novel thiochromanone derivatives containing a sulfonyl hydrazone moiety were designed and synthesized. Their structures were determined by 1H-NMR, 13C-NMR, and HRMS. Bioassay results showed that most of the target compounds revealed moderate to good antibacterial activities against Xanthomonas oryzae pv. oryzae, Xanthomonas oryzae pv. oryzicolaby, and Xanthomonas axonopodis pv. citri. Compound 4i had the best inhibitory activity against Xanthomonas oryzae pv. oryzae, Xanthomonas oryzae pv. oryzicolaby, and Xanthomonas axonopodis pv. citri, with the EC50 values of 8.67, 12.65, and 10.62 µg/mL, which were superior to those of Bismerthiazol and Thiodiazole-copper. Meanwhile, bioassay results showed that all of the target compounds proved to have lower antifungal activities against Sclerotinia sclerotiorum, Fusarium oxysporum, Gibberella zeae, Rhizoctonia solani, Verticillium dahlia, and Botrytis cinerea than those of Carbendazim.


Assuntos
Cromanos/síntese química , Cromanos/farmacologia , Hidrazonas/síntese química , Hidrazonas/farmacologia , Sulfonas/síntese química , Sulfonas/farmacologia , Antibacterianos/farmacologia , Antifúngicos/farmacologia , Cromanos/química , Fungos/efeitos dos fármacos , Hidrazonas/química , Testes de Sensibilidade Microbiana , Relação Estrutura-Atividade , Xanthomonas/efeitos dos fármacos
7.
Theranostics ; 11(13): 6491-6506, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33995670

RESUMO

Rationale: TGFß signaling pathway controls tissue fibrotic remodeling, a hallmark in many diseases leading to organ injury and failure. In this study, we address the role of Apilimod, a pharmacological inhibitor of the lipid kinase PIKfyve, in the regulation of cardiac pathological fibrotic remodeling and TGFß signaling pathway. Methods: The effects of Apilimod treatment on myocardial fibrosis, hypertrophy and cardiac function were assessed in vivo in a mouse model of pressure overload-induced heart failure. Primary cardiac fibroblasts and HeLa cells treated with Apilimod as well as genetic mutation of PIKfyve in mouse embryonic fibroblasts were used as cell models. Results: When administered in vivo, Apilimod reduced myocardial interstitial fibrosis development and prevented left ventricular dysfunction. In vitro, Apilimod controlled TGFß-dependent activation of primary murine cardiac fibroblasts. Mechanistically, both Apilimod and genetic mutation of PIKfyve induced TGFß receptor blockade in intracellular vesicles, negatively modulating its downstream signaling pathway and ultimately dampening TGFß response. Conclusions: Altogether, our findings propose a novel function for PIKfyve in the control of myocardial fibrotic remodeling and the TGFß signaling pathway, therefore opening the way to new therapeutic perspectives to prevent adverse fibrotic remodeling using Apilimod treatment.


Assuntos
Insuficiência Cardíaca/tratamento farmacológico , Hidrazonas/uso terapêutico , Morfolinas/uso terapêutico , Fosfatidilinositol 3-Quinases/fisiologia , Pirimidinas/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Fator de Crescimento Transformador beta/fisiologia , Animais , Células Cultivadas , Avaliação Pré-Clínica de Medicamentos , Fibroblastos/efeitos dos fármacos , Fibrose , Células HEK293 , Células HeLa , Insuficiência Cardíaca/patologia , Humanos , Hidrazonas/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Morfolinas/farmacologia , Miocárdio/patologia , Pirimidinas/farmacologia , Ratos , Receptor do Fator de Crescimento Transformador beta Tipo II/efeitos dos fármacos , Método Simples-Cego , Disfunção Ventricular Esquerda/prevenção & controle , Remodelação Ventricular/efeitos dos fármacos
8.
Acta Chim Slov ; 68(1): 65-71, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34057532

RESUMO

Two newly synthesized nicotinohydrazones, 6-bromo-2'-(2-chlorobenzylidene)nicotinohydrazide (1) and 6-bromo-2'-(3-bromo-5-chloro-2-hydroxybenzylidene)nicotinohydrazide methanol solvate (2), have been obtained and structurally characterized by spectroscopic method and single crystal X-ray determination. The molecules in both compounds are in E configuration regarding to the azomethine groups. The molecules of compound 1 are linked via hydrogen bonds of N?H∙∙∙O, generating one dimensional chains running along the c-axis direction. The hydrazone molecules of compound 2 are linked by methanol molecules via hydrogen bonds of N?H∙∙∙O and O?H∙∙∙N, generating dimers. The in vitro antimicrobial activities of these compounds indicate that they are interesting antibacterial agents.


Assuntos
Antibacterianos/farmacologia , Hidrazonas/farmacologia , Niacinamida/análogos & derivados , Niacinamida/farmacologia , Antibacterianos/síntese química , Bactérias/efeitos dos fármacos , Cristalografia por Raios X , Hidrazonas/síntese química , Testes de Sensibilidade Microbiana , Estrutura Molecular , Niacinamida/síntese química
9.
J Agric Food Chem ; 69(21): 5804-5817, 2021 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-34008970

RESUMO

A series of novel 2,6-dimethyl-4-aminopyrimidine hydrazones 5 were rationally designed and synthesized as pyruvate dehydrogenase complex E1 (PDHc-E1) inhibitors. Compounds 5 strongly inhibited Escherichia coli (E. coli) PDHc-E1 (IC50 values 0.94-15.80 µM). As revealed by molecular docking, site-directed mutagenesis, enzymatic, and inhibition kinetic analyses, compounds 5 competitively inhibited PDHc-E1 and bound in a "straight" pattern at the E. coli PDHc-E1 active site, which is a new binding mode. In in vitro antifungal assays, most compounds 5 at 50 µg/mL showed more than 80% inhibition against the mycelial growth of six tested phytopathogenic fungi, including Botrytis cinerea, Monilia fructigena, Colletotrichum gloeosporioides, andBotryosphaeria dothidea. Notably, 5f and 5i were 1.8-380 fold more potent against M. fructigena than the commercial fungicides captan and chlorothalonil. In vivo, 5f and 5i controlled the growth of M. fructigena comparably to the commercial fungicide tebuconazole. Thus, 5f and 5i have potential commercial value for the control of peach brown rot caused by M. fructigena.


Assuntos
Piruvato Desidrogenase (Lipoamida) , Complexo Piruvato Desidrogenase , Antifúngicos/farmacologia , Botrytis , Candida , Colletotrichum , Inibidores Enzimáticos , Escherichia coli , Hidrazonas/farmacologia , Simulação de Acoplamento Molecular , Pirimidinas
10.
Molecules ; 26(7)2021 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-33917290

RESUMO

This paper reports on the synthesis and characterization of two new polypyridyl-hydrazone Schiff bases, (E)-N'-(6-oxo-1,10-phenanthrolin-5(6H)-ylidene)thiophene-2-carbohydrazide (L1) and (E)-N'-(6-oxo-1,10-phenanthrolin-5(6H)-ylidene)furan-2-carbohydrazide (L2), and their two Ru(II) complexes of the general formula [RuCl(DMSO)(phen)(Ln)](PF6). Considering that hydrazides are a structural part of severa l drugs and metal complexes containing phenanthroline derivatives are known to interact with DNA and to exhibit antitumor activity, more potent anticancer agents can be obtained by covalently linking the thiophene acid hydrazide or the furoic acid hydrazide to a 1,10-phenanthroline moiety. These ligands and the Ru(II) complexes were characterized by elemental analyses, electronic, vibrational, 1H NMR, and ESI-MS spectroscopies. Ru is bound to two different N-heterocyclic ligands. One chloride and one S-bonded DMSO in cis-configuration to each other complete the octahedral coordination sphere around the metal ion. The ligands are very effective in inhibiting cellular growth in a chronic myelogenous leukemia cell line, K562. Both complexes are able to interact with DNA and present moderate cytotoxic activity, but 5 min of UV-light exposure increases cytotoxicity by three times.


Assuntos
Complexos de Coordenação/farmacologia , Hidrazonas/farmacologia , Luz , Fenantrolinas/farmacologia , Rutênio/farmacologia , Animais , Bovinos , Morte Celular/efeitos dos fármacos , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , DNA/metabolismo , Dimetil Sulfóxido/química , Humanos , Hidrazonas/síntese química , Hidrazonas/química , Células K562 , Ligantes , Fenantrolinas/síntese química , Fenantrolinas/química , Espectroscopia de Prótons por Ressonância Magnética , Espectrometria de Massas por Ionização por Electrospray
11.
Bioorg Med Chem Lett ; 40: 127926, 2021 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-33705902

RESUMO

This work presents the design and synthesis of camphor, fenchone, and norcamphor N-acylhydrazone derivatives as a new class of inhibitors of the Hantaan virus, which causes haemorrhagic fever with renal syndrome (HFRS). A cytopathic model was developed for testing chemotherapeutics against the Hantaan virus, strain 76-118. In addition, a study of the antiviral activity was carried out using a pseudoviral system. It was found that the hit compound possesses significant activity (IC50 = 7.6 ± 2 µM) along with low toxicity (CC50 > 1000 µM). Using molecular docking procedures, the binding with Hantavirus nucleoprotein was evaluated and the correlation between the structure of the synthesised compounds and the antiviral activity was established.


Assuntos
Antivirais/farmacologia , Canfanos/farmacologia , Vírus Hantaan/efeitos dos fármacos , Hidrazonas/farmacologia , Isoindóis/farmacologia , Norbornanos/farmacologia , Animais , Antivirais/síntese química , Antivirais/metabolismo , Canfanos/síntese química , Canfanos/metabolismo , Proteínas do Capsídeo/metabolismo , Cães , Desenho de Fármacos , Células HEK293 , Humanos , Hidrazonas/síntese química , Hidrazonas/metabolismo , Isoindóis/síntese química , Isoindóis/metabolismo , Células Madin Darby de Rim Canino , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Norbornanos/síntese química , Norbornanos/metabolismo , Ligação Proteica , Proteínas do Core Viral/metabolismo
12.
Bioorg Med Chem Lett ; 40: 127962, 2021 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-33741463

RESUMO

Osthole, a coumarin-type natural product, is isolated from Chinese traditional herbal medicine Cnidium monnieri. In order to improve the pesticidal activity of osthole, and high value-added application of the plant Cnidium monnieri, a series of new derivatives containing hydrazone/acylhydrazone/sulfonylhydrazone skeletons at the C-8 position of osthole were regioselectively semi-prepared. The steric structure of 3c was determined by the X-ray crystal structure. Against Mythimna separata Walker, benzoylhydrazone 3b (R1 = 4-CH3Ph) showed 1.6 folds potent insecticidal activity of the precursor osthole. Introduction of the acylhydrazones on the 3'-methyl-2'-butylenyl fragment at the C-8 position of osthole can improve the insecticidal activity. These will provide a foundation for future structural modifications of osthole as pesticidal agents.


Assuntos
Cumarínicos/farmacologia , Hidrazonas/farmacologia , Inseticidas/farmacologia , Animais , Cumarínicos/síntese química , Hidrazonas/síntese química , Inseticidas/síntese química , Estrutura Molecular , Mariposas/efeitos dos fármacos , Testes de Toxicidade
13.
Bioorg Med Chem ; 37: 116097, 2021 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-33743356

RESUMO

Naproxen is a common non-steroidal anti-inflammatory drug, which is the most usually used propionic acid derivative for the treatment of many types of diseases. In this study, a series of novel (S)-Naproxen derivatives bearing hydrazide-hydrazone moiety were designed, synthesized, and evaluated for anticancer activity. The structures of these compounds were characterized by spectral (1H-13C NMR, FT-IR, and HR-MS analyses) methods. All synthesized compounds were screened for anticancer activity against two different human breast cancer cell lines (MDA-MB-231 and MCF-7). Among them, (S)-2-(6-methoxynaphthalen-2-yl)-N'-{(E)-[2-(trifluoromethoxy)phenyl]methylidene} propanehydrazide (3a) showed the most potent anticancer activity against both cancer cell lines with a good selectivity (IC50 = 22.42 and 59.81 µM, respectively). Furthermore, the molecular modeling of these compounds was studied on Vascular Endothelial Growth Factor Receptor 2. Inhibition of VEGFR-2 and apoptotic protein Bcl-2 was investigated in MDA-MB-231 cells treated with compound 3a by using Western Blotting. Apoptosis was also detected by staining with DAPI in fluorescence microscopy. Flow Cytometry analyses related to cell cycle phases showed that a dramatic increase in S and M phases was established compared to untreated control cells indicating the cancer cell cycle arrest. The anticancer activity of compound 3a was investigated in the Ehrlich acid tumor model, a well-validated in vivo ectopic breast cancer model, in mice. Our results showed that compound 3a had anticancer activity and decreased the tumor volume in both low (60 mg/kg) and high (120 mg/kg) doses in mice.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Hidrazonas/uso terapêutico , Naproxeno/análogos & derivados , Naproxeno/uso terapêutico , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Animais , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Humanos , Hidrazonas/síntese química , Hidrazonas/metabolismo , Hidrazonas/farmacologia , Camundongos Endogâmicos BALB C , Simulação de Acoplamento Molecular , Naproxeno/metabolismo , Naproxeno/farmacologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
14.
J Nanobiotechnology ; 19(1): 71, 2021 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-33685469

RESUMO

BACKGROUND: siRNAs hold a great potential for cancer therapy, however, poor stability in body fluids and low cellular uptake limit their use in the clinic. To enhance the bioavailability of siRNAs in tumors, novel, safe, and effective carriers are needed. RESULTS: Here, we developed cationic solid lipid nanoparticles (cSLNs) to carry siRNAs targeting EphA2 receptor tyrosine kinase (siEphA2), which is overexpressed in many solid tumors including prostate cancer. Using DDAB cationic lipid instead of DOTMA reduced nanoparticle size and enhanced both cellular uptake and gene silencing in prostate cancer cells. DDAB-cSLN showed better cellular uptake efficiency with similar silencing compared to commercial transfection reagent (Dharmafect 2). After verifying the efficacy of siEphA2-loaded nanoparticles, we further evaluated a potential combination with a histone lysine demethylase inhibitor, JIB-04. Silencing EphA2 by siEphA2-loaded DDAB-cSLN did not affect the viability (2D or 3D culture), migration, nor clonogenicity of PC-3 cells alone. However, upon co-administration with JIB-04, there was a decrease in cellular responses. Furthermore, JIB-04 decreased EphA2 expression, and thus, silencing by siEphA2-loaded nanoparticles was further increased with co-treatment. CONCLUSIONS: We have successfully developed a novel siRNA-loaded lipid nanoparticle for targeting EphA2. Moreover, preliminary results of the effects of JIB-04, alone and in combination with siEphA2, on prostate cancer cells and prostate cancer tumor spheroids were presented for the first time. Our delivery system provides high transfection efficiency and shows great promise for targeting other genes and cancer types in further in vitro and in vivo studies.


Assuntos
Histona Desmetilases/efeitos dos fármacos , Lipídeos/química , Nanopartículas/química , Neoplasias da Próstata/tratamento farmacológico , RNA Interferente Pequeno/farmacologia , Receptor EphA2/metabolismo , Aminopiridinas/farmacologia , Cátions , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Inativação Gênica/efeitos dos fármacos , Humanos , Hidrazonas/farmacologia , Masculino , Nanopartículas/uso terapêutico , Tamanho da Partícula , Próstata , RNA Interferente Pequeno/genética , Receptor EphA2/genética , Transfecção
15.
Neurochem Res ; 46(6): 1502-1513, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33704649

RESUMO

Alpha-synuclein plays a vital role in the pathology of Parkinson's disease (PD). Spreading of α-synuclein in neighboring cells was believed to contribute to progression in PD. How α-synuclein transmission affects adjacent cells is not full elucidated. Here, we used recombinant α-synuclein to mimic intercellular transmitted α-synuclein in MES23.5 dopaminergic cells, to investigate whether and how it could modulate iron metabolism. The results showed that α-synuclein treatment up-regulated divalent metal transporter 1 (DMT1) and down-regulated iron transporter (FPN), also up-regulated iron regulatory protein 1 (IRP1) protein levels and hepcidin mRNA levels. Endocytosis inhibitor dynasore pretreatment completely abolished and even reversed the upregulation of DMT1 and IRP1 induced by α-synuclein, however, FPN down-regulation was partially blocked by dynasore. Autophagy-inducing agent rapamycin reversed DMT1 up-regulation and FPN down-regulation, and fully blocked the upregulation of IRP1. Elevated hepcidin levels induced by α-synuclein was fully blocked by dynasore pretreatment, however, even higher with rapamycin pretreatment. Alpha-synuclein treatment triggered endoplasmic reticulum (ER) stress. ER stress inducer thapsigargin induced similar responses elicited by α-synuclein. ER stress inhibitor salubrinal blocked the up-regulation of IRP1 and hepcidin, as well as DMT1 up-regulation and FPN down-regulation, also dramatically abolished cAMP-response elements binding protein phosphorylation induced by α-synuclein. Taken together, these finding indicated that extracellular α-synuclein could regulate cellular iron metabolism, probably mediated by ER stress. It provides novel evidence to elucidate the relationships between transmitted α-synuclein and iron metabolism disturbance in PD.


Assuntos
Proteínas de Transporte de Cátions/metabolismo , Estresse do Retículo Endoplasmático/fisiologia , Proteína 1 Reguladora do Ferro/metabolismo , alfa-Sinucleína/farmacologia , Animais , Autofagia/efeitos dos fármacos , Linhagem Celular Tumoral , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/química , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Regulação para Baixo/efeitos dos fármacos , Endocitose/efeitos dos fármacos , Hepcidinas/metabolismo , Hidrazonas/farmacologia , Camundongos , Fosforilação/efeitos dos fármacos , Ratos , Sirolimo/farmacologia , Regulação para Cima/efeitos dos fármacos
16.
BMC Cancer ; 21(1): 237, 2021 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-33676427

RESUMO

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC), one of the most lethal cancers, is driven by oncogenic KRAS mutations. Farnesyl thiosalicylic acid (FTS), also known as salirasib, is a RAS inhibitor that selectively dislodges active RAS proteins from cell membrane, inhibiting downstream signaling. FTS has demonstrated limited therapeutic efficacy in PDAC patients despite being well tolerated. METHODS: To improve the efficacy of FTS in PDAC, we performed a genome-wide CRISPR synthetic lethality screen to identify genetic targets that synergize with FTS treatment. Among the top candidates, multiple genes in the endoplasmic reticulum-associated protein degradation (ERAD) pathway were identified. The role of ERAD inhibition in enhancing the therapeutic efficacy of FTS was further investigated in pancreatic cancer cells using pharmaceutical and genetic approaches. RESULTS: In murine and human PDAC cells, FTS induced unfolded protein response (UPR), which was further augmented upon treatment with a chemical inhibitor of ERAD, Eeyarestatin I (EerI). Combined treatment with FTS and EerI significantly upregulated the expression of UPR marker genes and induced apoptosis in pancreatic cancer cells. Furthermore, CRISPR-based genetic ablation of the key ERAD components, HRD1 and SEL1L, sensitized PDAC cells to FTS treatment. CONCLUSION: Our study reveals a critical role for ERAD in therapeutic response of FTS and points to the modulation of UPR as a novel approach to improve the efficacy of FTS in PDAC treatment.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carcinoma Ductal Pancreático/tratamento farmacológico , Degradação Associada com o Retículo Endoplasmático/efeitos dos fármacos , Neoplasias Pancreáticas/tratamento farmacológico , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Apoptose/efeitos dos fármacos , Apoptose/genética , Sistemas CRISPR-Cas/genética , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Degradação Associada com o Retículo Endoplasmático/genética , Farneseno Álcool/análogos & derivados , Farneseno Álcool/farmacologia , Farneseno Álcool/uso terapêutico , Técnicas de Inativação de Genes , Humanos , Hidrazonas/farmacologia , Hidrazonas/uso terapêutico , Hidroxiureia/análogos & derivados , Hidroxiureia/farmacologia , Hidroxiureia/uso terapêutico , Camundongos , Neoplasias Pancreáticas/patologia , Proteínas/genética , Salicilatos/farmacologia , Salicilatos/uso terapêutico , Mutações Sintéticas Letais , Ubiquitina-Proteína Ligases/genética , Resposta a Proteínas não Dobradas/efeitos dos fármacos
17.
Molecules ; 26(4)2021 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-33671247

RESUMO

In the present study, naphthyl acetohydrazide (HL) ligand was prepared and used for the synthesis of new six amorphous transition metal (Co(II), Ni(II), Cu(II), Zn(II), Pb(II), Cd(II)) complexes. All the compounds were characterized by elemental analysis, UV-vis, FT-IR, 1H- and 13C-NMR, and Matrix-Assisted Laser Desorption Ionization (MALDI). The solubilization study was carried out by estimating the interaction between the metal complexes with surfactants viz. sodium stearate (SS) and Cetyltrimethylammonium bromide (CTAB). UV-Visible spectroscopy was employed to determine partitioning and binding parameters, whereas electrical conductivity measurements were employed to estimate critical micellar concentration (CMC), the extent of dissociation, and free energy of micellization. The CT-DNA interaction of synthesized compounds with DNA represents the major groove binding. The synthesized ligand and metal complexes were also tested against bacterial and fungal strains and it has been observed that Cu(II) complex is active against all the strains except Candida albicans, while Cd(II) complex is active against all bacterial and fungal strains except Pseudomonas. Among all compounds, only the Pd(II) complex shows reasonable activity against cervical cancer HeLa cell lines, representing 97% inhibition.


Assuntos
Anti-Infecciosos/farmacologia , Complexos de Coordenação/síntese química , DNA/metabolismo , Hidrazonas/síntese química , Hidrazonas/farmacologia , Metais/química , Micelas , Neoplasias/patologia , Bactérias/efeitos dos fármacos , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Sobrevivência Celular/efeitos dos fármacos , Condutividade Elétrica , Células HeLa , Humanos , Hidrazonas/química , Ligantes , Testes de Sensibilidade Microbiana , Espectroscopia de Prótons por Ressonância Magnética , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Espectrofotometria Ultravioleta , Espectroscopia de Infravermelho com Transformada de Fourier , Tensoativos/química
18.
Molecules ; 26(4)2021 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-33668452

RESUMO

Based on the broad spectrum of biological activity of hydrazide-hydrazones, trifluoromethyl compounds, and clinical usage of cholinesterase inhibitors, we investigated hydrazones obtained from 4-(trifluoromethyl)benzohydrazide and various benzaldehydes or aliphatic ketones as potential inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). They were evaluated using Ellman's spectrophotometric method. The hydrazide-hydrazones produced a dual inhibition of both cholinesterase enzymes with IC50 values of 46.8-137.7 µM and 19.1-881.1 µM for AChE and BuChE, respectively. The majority of the compounds were stronger inhibitors of AChE; four of them (2-bromobenzaldehyde, 3-(trifluoromethyl)benzaldehyde, cyclohexanone, and camphor-based 2o, 2p, 3c, and 3d, respectively) produced a balanced inhibition of the enzymes and only 2-chloro/trifluoromethyl benzylidene derivatives 2d and 2q were found to be more potent inhibitors of BuChE. 4-(Trifluoromethyl)-N'-[4-(trifluoromethyl)benzylidene]benzohydrazide 2l produced the strongest inhibition of AChE via mixed-type inhibition determined experimentally. Structure-activity relationships were identified. The compounds fit physicochemical space for targeting central nervous systems with no apparent cytotoxicity for eukaryotic cell line together. The study provides new insights into this CF3-hydrazide-hydrazone scaffold.


Assuntos
Acetilcolinesterase/metabolismo , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Hidrazinas/química , Hidrazonas/farmacologia , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/patologia , Sistema Nervoso Central/efeitos dos fármacos , Humanos , Hidrazonas/química , Cinética
19.
PLoS Biol ; 19(2): e3001091, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33630831

RESUMO

The recent emergence of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the underlying cause of Coronavirus Disease 2019 (COVID-19), has led to a worldwide pandemic causing substantial morbidity, mortality, and economic devastation. In response, many laboratories have redirected attention to SARS-CoV-2, meaning there is an urgent need for tools that can be used in laboratories unaccustomed to working with coronaviruses. Here we report a range of tools for SARS-CoV-2 research. First, we describe a facile single plasmid SARS-CoV-2 reverse genetics system that is simple to genetically manipulate and can be used to rescue infectious virus through transient transfection (without in vitro transcription or additional expression plasmids). The rescue system is accompanied by our panel of SARS-CoV-2 antibodies (against nearly every viral protein), SARS-CoV-2 clinical isolates, and SARS-CoV-2 permissive cell lines, which are all openly available to the scientific community. Using these tools, we demonstrate here that the controversial ORF10 protein is expressed in infected cells. Furthermore, we show that the promising repurposed antiviral activity of apilimod is dependent on TMPRSS2 expression. Altogether, our SARS-CoV-2 toolkit, which can be directly accessed via our website at https://mrcppu-covid.bio/, constitutes a resource with considerable potential to advance COVID-19 vaccine design, drug testing, and discovery science.


Assuntos
Vacinas contra COVID-19 , COVID-19/diagnóstico , COVID-19/virologia , Genética Reversa , SARS-CoV-2/genética , Células A549 , Enzima de Conversão de Angiotensina 2/metabolismo , Animais , Chlorocebus aethiops , Códon , Humanos , Hidrazonas/farmacologia , Camundongos , Morfolinas/farmacologia , Fases de Leitura Aberta , Plasmídeos/genética , Pirimidinas/farmacologia , Serina Endopeptidases/metabolismo , Células Vero , Proteínas Virais/metabolismo
20.
J Med Chem ; 64(4): 2024-2045, 2021 02 25.
Artigo em Inglês | MEDLINE | ID: mdl-33538587

RESUMO

We identified a set of thiosemicarbazone (TSC) metal ion chelators that reactivate specific zinc-deficient p53 mutants using a mechanism called zinc metallochaperones (ZMCs) that restore zinc binding by shuttling zinc into cells. We defined biophysical and cellular assays necessary for structure-activity relationship studies using this mechanism. We investigated an alternative class of zinc scaffolds that differ from TSCs by substitution of the thiocarbamoyl moiety with benzothiazolyl, benzoxazolyl, and benzimidazolyl hydrazones. Members of this series bound zinc with similar affinity and functioned to reactivate mutant p53 comparable to the TSCs. Acute toxicity and efficacy assays in rodents demonstrated C1 to be significantly less toxic than the TSCs while demonstrating equivalent growth inhibition. We identified C85 as a ZMC with diminished copper binding that functions as a chemotherapy and radiation sensitizer. We conclude that the benzothiazolyl, benzoxazolyl, and benzimidazolyl hydrazones can function as ZMCs to reactivate mutant p53 in vitro and in vivo.


Assuntos
Benzotiazóis/uso terapêutico , Benzoxazóis/uso terapêutico , Quelantes/uso terapêutico , Hidrazonas/uso terapêutico , Proteína Supressora de Tumor p53/metabolismo , Zinco/metabolismo , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Benzotiazóis/síntese química , Benzotiazóis/farmacologia , Benzoxazóis/síntese química , Benzoxazóis/farmacologia , Linhagem Celular Tumoral , Quelantes/síntese química , Quelantes/farmacologia , Humanos , Hidrazonas/síntese química , Hidrazonas/farmacologia , Camundongos Nus , Estrutura Molecular , Neoplasias/tratamento farmacológico , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/uso terapêutico , Relação Estrutura-Atividade , Proteína Supressora de Tumor p53/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
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