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1.
Int J Mol Sci ; 22(19)2021 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-34638861

RESUMO

Among organic-inorganic hybrid molecules consisting of organic structure(s) and metal(s), only few studies are available on the cytotoxicity of nucleophilic molecules. In the present study, we investigated the cytotoxicity of a nucleophilic organotellurium compound, diphenyl ditelluride (DPDTe), using a cell culture system. DPDTe exhibited strong cytotoxicity against vascular endothelial cells and fibroblasts along with high intracellular accumulation but showed no cytotoxicity and had less accumulation in vascular smooth muscle cells and renal epithelial cells. The cytotoxicity of DPDTe decreased when intramolecular tellurium atoms were replaced with selenium or sulfur atoms. Electronic state analysis revealed that the electron density between tellurium atoms in DPDTe was much lower than those between selenium atoms of diphenyl diselenide and sulfur atoms of diphenyl disulfide. Moreover, diphenyl telluride did not accumulate and exhibit cytotoxicity. The cytotoxicity of DPDTe was also affected by substitution. p-Dimethoxy-DPDTe showed higher cytotoxicity, but p-dichloro-DPDTe and p-methyl-DPDTe showed lower cytotoxicity than that of DPDTe. The subcellular distribution of the compounds revealed that the compounds with stronger cytotoxicity showed higher accumulation rates in the mitochondria. Our findings suggest that the electronic state of tellurium atoms in DPDTe play an important role in accumulation and distribution of DPDTe in cultured cells. The present study supports the hypothesis that nucleophilic organometallic compounds, as well as electrophilic organometallic compounds, exhibit cytotoxicity by particular mechanisms.


Assuntos
Derivados de Benzeno/farmacologia , Células Endoteliais/efeitos dos fármacos , Compostos Organometálicos/farmacologia , Compostos Organosselênicos/farmacologia , Telúrio/farmacologia , Animais , Derivados de Benzeno/química , Derivados de Benzeno/metabolismo , Bovinos , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Células Endoteliais/citologia , Células Endoteliais/metabolismo , Células Epiteliais/citologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Humanos , Células LLC-PK1 , Modelos Químicos , Estrutura Molecular , Miócitos de Músculo Liso/citologia , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Compostos Organometálicos/química , Compostos Organometálicos/metabolismo , Compostos Organosselênicos/química , Compostos Organosselênicos/metabolismo , Suínos , Telúrio/química
2.
Cells ; 10(8)2021 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-34440916

RESUMO

Defects in mitochondrial dynamics, fission, fusion, and motility have been implicated in the pathogenesis of multiple neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease, Huntington's disease, and Charcot-Marie-Tooth disease. Another key feature of neurodegeneration is the increase in reactive oxygen species (ROS). Previous work has shown that the cytoskeleton, in particular the microtubules, and ROS generated by rotenone significantly regulate mitochondrial dynamics in Dictyostelium discoideum. The goal of this project is to study the effects of ROS on mitochondrial dynamics within our model organism D. discoideum to further understand the underlying issues that are the root of neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. We chose three likely ROS inducers, cumene hydroperoxide, hydroxylamine hydrochloride, and Antimycin A. Our work demonstrates that alteration of the microtubule cytoskeleton is not required to alter dynamics in response to ROS and there is no easy way to predict how mitochondrial dynamics will be altered based on which ROS generator is used. This research contributes to the better understanding of the cellular mechanisms that induce the pathogenesis of incurable neurodegenerative diseases with the hope that it will translate into developing new and more effective treatments for patients afflicted by them.


Assuntos
Citoesqueleto/metabolismo , Dictyostelium/metabolismo , Microtúbulos/metabolismo , Mitocôndrias/metabolismo , Dinâmica Mitocondrial , Espécies Reativas de Oxigênio/metabolismo , Doença de Alzheimer/metabolismo , Antimicina A/farmacologia , Derivados de Benzeno/farmacologia , Doença de Charcot-Marie-Tooth/metabolismo , Citoesqueleto/efeitos dos fármacos , Dictyostelium/citologia , Dictyostelium/efeitos dos fármacos , Humanos , Doença de Huntington/metabolismo , Hidroxilamina/farmacologia , Microtúbulos/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Modelos Biológicos , Doença de Parkinson/metabolismo
3.
Molecules ; 26(12)2021 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-34198585

RESUMO

The present investigation informs a descriptive study of 1-(4-Hydroxyphenyl) -3-phenylprop-2-en-1-one compound, by using density functional theory at B3LYP method with 6-311G** basis set. The oxygen atoms and π-system revealed a high chemical reactivity for the title compound as electron donor spots and active sites for an electrophilic attack. Quantum chemical parameters such as hardness (η), softness (S), electronegativity (χ), and electrophilicity (ω) were yielded as descriptors for the molecule's chemical behavior. The optimized molecular structure was obtained, and the experimental data were matched with geometrical analysis values describing the molecule's stable structure. The computed FT-IR and Raman vibrational frequencies were in good agreement with those observed experimentally. In a molecular docking study, the inhibitory potential of the studied molecule was evaluated against the penicillin-binding proteins of Staphylococcus aureus bacteria. The carbonyl group in the molecule was shown to play a significant role in antibacterial activity, four bonds were formed by the carbonyl group with the key protein of the bacteria (three favorable hydrogen bonds plus one van der Waals bond) out of six interactions. The strong antibacterial activity was also indicated by the calculated high binding energy (-7.40 kcal/mol).


Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Derivados de Benzeno/química , Derivados de Benzeno/farmacologia , Cetonas/química , Cetonas/farmacologia , Alcenos/química , Alcenos/farmacologia , Domínio Catalítico , Teoria da Densidade Funcional , Modelos Moleculares , Simulação de Acoplamento Molecular , Teoria Quântica , Espectroscopia de Infravermelho com Transformada de Fourier/métodos , Análise Espectral Raman/métodos , Eletricidade Estática
4.
J Med Chem ; 64(14): 10418-10428, 2021 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-34232641

RESUMO

Tegumental carbonic anhydrase from the worm Schistosoma mansoni (SmCA) is considered a new anti-parasitic target because suppressing its expression interferes with schistosome metabolism and virulence. Here, we present the inhibition profiles of selenoureido compounds on recombinant SmCA and resolution of the first X-ray crystal structures of SmCA in adduct with a selection of such inhibitors. The key molecular features of such compounds in adduct with SmCA were obtained and compared to the human isoform hCA II, in order to understand the main structural factors responsible for enzymatic affinity and selectivity. Compounds that more specifically inhibited the schistosome versus human enzymes were identified. The results expand current knowledge in the field and pave the way for the development of more potent antiparasitic agents in the near future.


Assuntos
Derivados de Benzeno/farmacologia , Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/metabolismo , Compostos Organosselênicos/farmacologia , Schistosoma mansoni/enzimologia , Sulfonamidas/farmacologia , Animais , Derivados de Benzeno/síntese química , Derivados de Benzeno/química , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Modelos Moleculares , Estrutura Molecular , Compostos Organosselênicos/síntese química , Compostos Organosselênicos/química , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química
5.
Eur J Med Chem ; 223: 113601, 2021 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-34153575

RESUMO

Syntenin stimulates exosome production and its expression is upregulated in many cancers and implicated in the spread of metastatic tumor. These effects are supported by syntenin PDZ domains interacting with syndecans. We therefore aimed to develop, through a fragment-based drug design approach, novel inhibitors targeting syntenin-syndecan interactions. We describe here the optimization of a fragment, 'hit' C58, identified by in vitro screening of a PDZ-focused fragment library, which binds specifically to the syntenin-PDZ2 domain at the same binding site as the syndecan-2 peptide. X-ray crystallographic structures and computational docking were used to guide our optimization process and lead to compounds 45 and 57 (IC50 = 33 µM and 47 µM; respectively), two representatives of syntenin-syndecan interactions inhibitors, that selectively affect the syntenin-exosome release. These findings demonstrate that it is possible to identify small molecules inhibiting syntenin-syndecan interaction and exosome release that may be useful for cancer therapy.


Assuntos
Aminoácidos/farmacologia , Antineoplásicos/farmacologia , Derivados de Benzeno/farmacologia , Exossomos/metabolismo , Sinteninas/metabolismo , Aminoácidos/síntese química , Aminoácidos/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Derivados de Benzeno/síntese química , Derivados de Benzeno/metabolismo , Desenho de Fármacos , Humanos , Células MCF-7 , Simulação de Acoplamento Molecular , Estrutura Molecular , Domínios PDZ , Ligação Proteica/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/metabolismo , Bibliotecas de Moléculas Pequenas/farmacologia , Relação Estrutura-Atividade , Sindecanas/metabolismo , Sinteninas/química
6.
Future Med Chem ; 13(13): 1091-1103, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34080888

RESUMO

Aim: This study investigated our Enzymelinks, COX-2-10aa-mPGES-1 and COX-2-10aa-PGIS, as cellular cross-screening targets for quick identification of lead compounds to inhibit inflammatory PGE2 biosynthesis while maintaining prostacyclin synthesis. Methods: We integrated virtual and wet cross-screening using Enzymelinks to rapidly identify lead compounds from a large compound library. Results: From 380,000 compounds virtually cross-screened with the Enzymelinks, 1576 compounds were identified and used for wet cross-screening using HEK293 cells that overexpressed individual Enzymelinks as targets. The top 15 lead compounds that inhibited mPGES-1 activity were identified. The top compound that specifically inhibited inflammatory PGE2 biosynthesis alone without affecting COX-2 coupled to PGI2 synthase (PGIS) for PGI2 biosynthesis was obtained. Conclusion: Enzymelink technology could advance cyclooxygenase pathway-targeted drug discovery to a significant degree.


Assuntos
Derivados de Benzeno/farmacologia , Ciclo-Oxigenase 1/metabolismo , Sistema Enzimático do Citocromo P-450/metabolismo , Oxirredutases Intramoleculares/metabolismo , Engenharia de Proteínas , Derivados de Benzeno/química , Avaliação Pré-Clínica de Medicamentos , Células HEK293 , Humanos , Microssomos/efeitos dos fármacos , Microssomos/enzimologia
7.
Bioorg Chem ; 112: 104940, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33965780

RESUMO

A series of novel substituted bisurea 1,4-Diisocyanatobenzene compounds were designed, synthesized and introduced as potent anticancer compounds and screened for their in vitro anti-proliferative activities in human cancer cell lines. The structures of all titled compounds were characterized using Fourier-transform infrared mass spectra, nuclear magnetic resonance spectroscopy, elemental analysis and evaluated their sustainability using biological experiments. A selected group of ten derivatives were apprised for their anti-proliferative activity. The compounds 3d and 3e displayed potent anticancer activity with low IC50 value of 5.40, and 5.89 µM against HeLa cancer cell lines. The observed apoptosis data has demonstrated that compounds 3d and 3e induce the activaties of caspase-9 and caspase-3, the compounds 3d and 3e regulated fungal zone inhibition. Due to promising growth inhibitions, the all synthesized compounds were allowed to campaign includes quantum-polarized-ligand, quantum mechanical and molecular mechanical, docking experiments. The compounds 3d and 3e have exhibited a higher affinity for ERK/MAP kinase and CDK2 proteins. The molecular docking interactions have demonstrated two stage inhibition of cancer cells by binding with ERK/MAP kinase and CDK2 leads to inactivation of cell proliferation,cell cycle progression,cell divisionanddifferentiation, and hypo-phosphorylation of ribosome leading cells to restricts at point boundary of the G1/S phase. The long-range molecular dynamics, 150 ns, simulations were also revealed more consistency by 3d. Our study conclude good binding propensity for active-tunnel of ERK/MAP kinase and CDK2 proteins, by 3d (1,1'-(1,4-phenylene) bis(3-(2-chlorobenzyl)urea)), to suggest that the designed and synthesized 3d is to use as selective novel nuclei in anti-cancer chemotherapeutics.


Assuntos
Antifúngicos/farmacologia , Antineoplásicos/farmacologia , Derivados de Benzeno/farmacologia , Isocianatos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Ureia/farmacologia , Animais , Antifúngicos/síntese química , Antifúngicos/química , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Derivados de Benzeno/síntese química , Derivados de Benzeno/química , Proliferação de Células/efeitos dos fármacos , Ciclina E/antagonistas & inibidores , Ciclina E/metabolismo , Quinase 2 Dependente de Ciclina/antagonistas & inibidores , Quinase 2 Dependente de Ciclina/deficiência , Quinase 2 Dependente de Ciclina/metabolismo , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Isocianatos/síntese química , Isocianatos/química , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Testes de Sensibilidade Microbiana , Simulação de Dinâmica Molecular , Estrutura Molecular , Proteínas Oncogênicas/antagonistas & inibidores , Proteínas Oncogênicas/metabolismo , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Saccharomyces cerevisiae/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-Atividade , Ureia/análogos & derivados , Ureia/química
8.
Front Immunol ; 12: 664425, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34054833

RESUMO

Antrodia cinnamomea exhibits anti-inflammatory, antioxidant, and immunomodulatory activities. We aimed to explore the antipsoriatic potential of 2,4-dimethoxy-6-methylbenzene-1,3-diol (DMD) derived from A. cinnamomea. The macrophages activated by imiquimod (IMQ) were used as the cell model for examining the anti-inflammatory effect of DMD in vitro. A significantly high inhibition of IL-23 and IL-6 by DMD was observed in THP-1 macrophages and bone marrow-derived mouse macrophages. The conditioned medium of DMD-treated macrophages could reduce neutrophil migration and keratinocyte overproliferation. DMD could downregulate cytokine/chemokine by suppressing the phosphorylation of mitogen-activated protein kinases (MAPKs) and NF-κB. We also observed inhibition of GDAP1L1/Drp1 translocation from the cytoplasm to mitochondria by DMD intervention. Thus, mitochondrial fission could be a novel target for treating psoriatic inflammation. A psoriasiform mouse model treated by IMQ showed reduced scaling, erythema, and skin thickening after topical application of DMD. Compared to the IMQ stimulation only, the active compound decreased epidermal thickness by about 2-fold. DMD diminished the number of infiltrating macrophages and neutrophils and their related cytokine/chemokine production in the lesional skin. Immunostaining of the IMQ-treated skin demonstrated the inhibition of GDAP1LI and phosphorylated Drp1 by DMD. The present study provides insight regarding the potential use of DMD as an effective treatment modality for psoriatic inflammation.


Assuntos
Derivados de Benzeno/farmacologia , Dinaminas/metabolismo , Proteínas Quinases Ativadas por Mitógeno/metabolismo , NF-kappa B/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Polyporales/química , Animais , Citocinas/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Humanos , Imuno-Histoquímica , Ativação de Macrófagos/genética , Ativação de Macrófagos/imunologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Fosforilação/efeitos dos fármacos , Transporte Proteico/efeitos dos fármacos , Psoríase/etiologia , Psoríase/metabolismo , Psoríase/patologia , Transdução de Sinais/efeitos dos fármacos
9.
J Med Chem ; 64(9): 5667-5688, 2021 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-33949859

RESUMO

Multiple sclerosis (MS) is an autoimmune demyelinating disease of the central nervous system (CNS) that causes severe motor, sensory, and cognitive impairments. Kallikrein-related peptidase (KLK)6 is the most abundant serine protease secreted in the CNS, mainly by oligodendrocytes, the myelin-producing cells of the CNS, and KLK6 is assumed to be a robust biomarker of MS, since it is highly increased in the cerebrospinal fluid (CSF) of MS patients. Here, we report the design and biological evaluation of KLK6's low-molecular-weight inhibitors, para-aminobenzyl derivatives. Interestingly, selected hit compounds were selective of the KLK6 proteolytic network encompassing KLK1 and plasmin that also participate in the development of MS physiopathology. Moreover, hits were found noncytotoxic on primary cultures of murine neurons and oligodendrocyte precursor cells (OPCs). Among them, two compounds (32 and 42) were shown to promote the differentiation of OPCs into mature oligodendrocytes in vitro constituting thus emerging leads for the development of regenerative therapies.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Calicreínas/antagonistas & inibidores , Inibidores de Serino Proteinase/farmacologia , Animais , Derivados de Benzeno/química , Derivados de Benzeno/metabolismo , Derivados de Benzeno/farmacologia , Sítios de Ligação , Domínio Catalítico , Células Cultivadas , Desenho de Fármacos , Fibrinolisina/antagonistas & inibidores , Fibrinolisina/metabolismo , Humanos , Calicreínas/metabolismo , Cinética , Camundongos , Simulação de Acoplamento Molecular , Esclerose Múltipla/metabolismo , Esclerose Múltipla/patologia , Neurônios/citologia , Neurônios/metabolismo , Oligodendroglia/citologia , Oligodendroglia/metabolismo , Inibidores de Serino Proteinase/química , Inibidores de Serino Proteinase/metabolismo , Células-Tronco/citologia , Células-Tronco/metabolismo , Relação Estrutura-Atividade
10.
Molecules ; 26(5)2021 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-33800893

RESUMO

In order to replace the huge amounts of copper salts used in citrus orchards, alternatives have been sought in the form of organic compounds of natural origin with activity against the causative agent of citrus canker, the phytopathogen Xanthomonas citri subsp. Citri. We synthesized a series of 4-alkoxy-1,2-benzene diols (alkyl-BDOs) using 1,2,4-benzenetriol (BTO) as a starting material through a three-step synthesis route and evaluated their suitability as antibacterial compounds. Our results show that alkyl ethers derived from 1,2,4-benzenetriol have bactericidal activity against X. citri, disrupting the bacterial cell membrane within 15 min. Alkyl-BDOs were also shown to remain active against the bacteria while in solution, and presented low toxicity to (human) MRC-5 cells. Therefore, we have demonstrated that 1,2,4-benzenetriol-a molecule that can be obtained from agricultural residues-is an adequate precursor for the synthesis of new compounds with activity against X. citri.


Assuntos
Antibacterianos/farmacologia , Derivados de Benzeno/farmacologia , Citrus/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Doenças das Plantas/microbiologia , Folhas de Planta/efeitos dos fármacos , Xanthomonas/patogenicidade , Antibacterianos/química , Derivados de Benzeno/química , Proliferação de Células , Citrus/microbiologia , Fibroblastos/citologia , Humanos , Folhas de Planta/microbiologia
11.
Int J Mol Sci ; 22(7)2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33915826

RESUMO

Six kuwanon derivatives (A/B/C/E/H/J) extracted from the roots of Morus alba L. were evaluated to determine their cyclooxygenase (COX)-1 and 2 inhibitory effects. Cyclooxygenase (COX) is known as the target enzyme of nonsteroidal anti-inflammatory drugs (NSAIDs), which are the most widely used therapeutic agents for pain and inflammation. Among six kuwanon derivatives, kuwanon A showed selective COX-2 inhibitory activity, almost equivalent to that of celecoxib, a known COX inhibitor. Kuwanon A showed high COX-2 inhibitory activity (IC50 = 14 µM) and a selectivity index (SI) range of >7.1, comparable to celecoxib (SI > 6.3). To understand the mechanisms underlying this effect, we performed docking simulations, fragment molecular orbital (FMO) calculations, and pair interaction energy decomposition analysis (PIEDA) at the quantum-mechanical level. As a result, kuwanon A had the strongest interaction with Arg120 and Tyr355 at the gate of the COX active site (-7.044 kcal/mol) and with Val89 in the membrane-binding domain (-6.599 kcal/mol). In addition, kuwanon A closely bound to Val89, His90, and Ser119, which are residues at the entrance and exit routes of the COX active site (4.329 Å). FMO calculations and PIEDA well supported the COX-2 selective inhibitory action of kuwanon A. It showed that the simulation and modeling results and experimental evidence were consistent.


Assuntos
Derivados de Benzeno/farmacologia , Inibidores de Ciclo-Oxigenase 2/isolamento & purificação , Flavonoides/farmacologia , Morus/química , Derivados de Benzeno/isolamento & purificação , Flavonoides/isolamento & purificação , Simulação de Acoplamento Molecular , Extratos Vegetais/química
12.
J Med Chem ; 64(8): 4762-4786, 2021 04 22.
Artigo em Inglês | MEDLINE | ID: mdl-33835811

RESUMO

A benzo[6]annulene, 4-(tert-butyl)-N-(3-methoxy-5,6,7,8-tetrahydronaphthalen-2-yl) benzamide (1a), was identified as an inhibitor against Chikungunya virus (CHIKV) with antiviral activity EC90 = 1.45 µM and viral titer reduction (VTR) of 2.5 log at 10 µM with no observed cytotoxicity (CC50 = 169 µM) in normal human dermal fibroblast cells. Chemistry efforts to improve potency, efficacy, and drug-like properties of 1a resulted in a novel lead compound 8q, which possessed excellent cellular antiviral activity (EC90 = 270 nM and VTR of 4.5 log at 10 µM) and improved liver microsomal stability. CHIKV resistance to an analog of 1a, compound 1c, tracked to a mutation in the nsP3 macrodomain. Further mechanism of action studies showed compounds working through inhibition of human dihydroorotate dehydrogenase in addition to CHIKV nsP3 macrodomain. Moderate efficacy was observed in an in vivo CHIKV challenge mouse model for compound 8q as viral replication was rescued from the pyrimidine salvage pathway.


Assuntos
Antivirais/farmacologia , Derivados de Benzeno/química , Vírus Chikungunya/fisiologia , Replicação Viral/efeitos dos fármacos , Animais , Antivirais/química , Antivirais/farmacocinética , Antivirais/uso terapêutico , Derivados de Benzeno/metabolismo , Derivados de Benzeno/farmacologia , Derivados de Benzeno/uso terapêutico , Sítios de Ligação , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Febre de Chikungunya/tratamento farmacológico , Modelos Animais de Doenças , Feminino , Meia-Vida , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microssomos Hepáticos/metabolismo , Simulação de Acoplamento Molecular , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/antagonistas & inibidores , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/metabolismo , Relação Estrutura-Atividade
13.
J Mater Chem B ; 9(14): 3136-3142, 2021 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-33656045

RESUMO

Antibiotic vancomycin (Van) is often used as the drug of last resort to treat methicillin resistant Staphylococcus aureus. Due to the emergence of Van-resistant microbes, it is necessary to continuously design strategies to increase the efficacy of Van against resistant cells. In this study, an efficient method of bio-conjugating Van to bacteria is proposed using near-infrared (NIR)-light activation. A Nd3+-sensitized upconversion nanocrystal (UCNC) decorated with toluidine blue O (TB) on its surface undergoes upconverted energy transfer from the UCNC to TB when excited by 808 nm light. The photoexcited TB then catalyses the conversion of the dihydrotetrazine (dHTz) moiety in a Van-dHTz conjugate system to tetrazine which undergoes an efficient inverse electron demand Diels-Alder reaction with prior attached norbornene molecules on bacterial cell walls. The enhanced affinity of Van to bacteria by covalent bonding improves the activity of the drug against drug-resistant Enterococci, and the MIC is reduced by 6- to 7-fold as compared to neat Van. We demonstrate that the mode of action is due to increased inhibition of peptidoglycan cell wall biosynthesis. The findings in this study demonstrate that on-demand NIR-light activated bioorthogonal conjugation of Van to microbes is a viable alternative treatment in combating drug-resistant bacteria.


Assuntos
Antibacterianos/farmacologia , Compostos Aza/farmacologia , Derivados de Benzeno/farmacologia , Farmacorresistência Bacteriana/efeitos dos fármacos , Enterococcus/efeitos dos fármacos , Raios Infravermelhos , Vancomicina/farmacologia , Antibacterianos/química , Compostos Aza/química , Derivados de Benzeno/química , Catálise , Testes de Sensibilidade Microbiana , Processos Fotoquímicos , Vancomicina/química
14.
Chem Biodivers ; 18(4): e2000949, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33645910

RESUMO

Three new eremophilane sesquiterpenes phomadecalins G-I (1-3) and two new benzene derivatives microdiplzenes A and B (12 and 13), together with nine known eremophilane sesquiterpenes (4-11 and 14) were isolated from an endophytic fungus, Microdiplodia sp. WGHS5. Their structures were elucidated by the interpretation of HR-ESI-MS and NMR data; meanwhile, the absolute configurations of new compounds were determined on the base of ECD calculations. All compounds were evaluated for the antimicrobial activities and antiproliferative effect on human gastric cancer cell lines (BGC-823).


Assuntos
Antibacterianos/farmacologia , Antifúngicos/farmacologia , Antineoplásicos/farmacologia , Endófitos/química , Sesquiterpenos Policíclicos/farmacologia , Antibacterianos/química , Antibacterianos/isolamento & purificação , Antifúngicos/química , Antifúngicos/isolamento & purificação , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Bactérias/efeitos dos fármacos , Derivados de Benzeno/química , Derivados de Benzeno/isolamento & purificação , Derivados de Benzeno/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Fungos/efeitos dos fármacos , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Sesquiterpenos Policíclicos/química , Sesquiterpenos Policíclicos/isolamento & purificação , Sesquiterpenos/química , Sesquiterpenos/isolamento & purificação , Sesquiterpenos/farmacologia
15.
Angew Chem Int Ed Engl ; 60(21): 11758-11762, 2021 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-33724623

RESUMO

Extensive recent efforts have been put on the design of high-performance organic near-infrared (NIR) photothermal agents (PTAs), especially over NIR-II bio-window (1000-1350 nm). So far, the development is mainly limited by the rarity of molecules with good NIR-II response. Here, we report organic nanoparticles of intermolecular charge-transfer complexes (CTCs) with easily programmable optical absorption. By employing different common donor and acceptor molecules to form CTC nanoparticles (CT NPs), absorption peaks of CT NPs can be controllably tuned from the NIR-I to NIR-II region. Notably, CT NPs formed with perylene and TCNQ have a considerably red-shifted absorption peak at 1040 nm and achieves a good photothermal conversion efficiency of 42 % under 1064 nm excitation. These nanoparticles were used for antibacterial application with effective activity towards both Gram-negative and Gram-positive bacteria. This work opens a new avenue into the development of efficient PTAs.


Assuntos
Antibacterianos/farmacologia , Nanopartículas/química , Antibacterianos/química , Antibacterianos/efeitos da radiação , Derivados de Benzeno/química , Derivados de Benzeno/farmacologia , Derivados de Benzeno/efeitos da radiação , Escherichia coli/efeitos dos fármacos , Raios Infravermelhos , Testes de Sensibilidade Microbiana , Nanopartículas/efeitos da radiação , Nitrilas/química , Nitrilas/farmacologia , Nitrilas/efeitos da radiação , Perileno/química , Perileno/farmacologia , Perileno/efeitos da radiação , Compostos Policíclicos/química , Compostos Policíclicos/farmacologia , Compostos Policíclicos/efeitos da radiação , Solubilidade , Staphylococcus aureus/efeitos dos fármacos , Eletricidade Estática/efeitos adversos , Compostos de Sulfidrila/química , Compostos de Sulfidrila/farmacologia , Compostos de Sulfidrila/efeitos da radiação , Água/química
16.
Life Sci ; 275: 119334, 2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-33711391

RESUMO

AIMS: We examined the effects of treatment with 1-nitro-2-phenylethane (NP), a novel soluble guanylate cyclase stimulator, on monocrotaline (MCT)-induced PAH in rats. MAIN METHODS: At day 0, male adult rats were injected with a single subcutaneous (s.c.) dose of monocrotaline (60 mg/kg). Control (CNT) rats received an equal volume of monocrotaline's vehicle only (s.c.). Four weeks later, MCT-treated rats were treated orally for 14 days with NP (50 mg/kg/day) (MCT-NP group) or its vehicle (Tween 2%) (MCT-V group). At the end of the treatment period and before invasive hemodynamic study, rats of all experimental groups were examined by echocardiography. KEY FINDINGS: With respect to CNT rats, MCT-V rats showed significant; (1) increases in pulmonary artery (PA) diameter, RV free wall thickness and end-diastolic RV area, and increase of Fulton index; (2) decreases in maximum pulmonary flow velocity, PA acceleration time (PAAT), PAAT/time of ejection ratio, and velocity-time integral; (3) increases in estimated mean pulmonary arterial pressure; (4) reduction of maximal relaxation to acetylcholine in aortic rings, and (5) increases in wall thickness of pulmonary arterioles. All these measured parameters were significantly reduced or even abolished by oral treatment with NP. SIGNIFICANCE: NP reversed endothelial dysfunction and pulmonary vascular remodeling, which in turn reduced ventricular hypertrophy. NP reduced pulmonary artery stiffness, normalized the pulmonary artery diameter and alleviated RV enlargement. Thus, NP may represent a new therapeutic or a complementary approach to treatment of PAH.


Assuntos
Derivados de Benzeno/farmacologia , Hipertensão Arterial Pulmonar/tratamento farmacológico , Animais , Ecocardiografia , Endotélio Vascular/efeitos dos fármacos , Hemodinâmica/efeitos dos fármacos , Masculino , Monocrotalina/antagonistas & inibidores , Monocrotalina/farmacologia , Hipertensão Arterial Pulmonar/induzido quimicamente , Hipertensão Arterial Pulmonar/diagnóstico por imagem , Artéria Pulmonar/efeitos dos fármacos , Ratos , Ratos Wistar , Guanilil Ciclase Solúvel/efeitos dos fármacos , Remodelação Vascular/efeitos dos fármacos
17.
J Pharm Pharm Sci ; 24: 23-36, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33735604

RESUMO

BACKGROUND: Current therapies for acute leukemias (ALs) are associated with severe adverse reactions and high relapse rates, which makes the search for new antileukemic agents a necessity. Therefore, the aim of this study was to evaluate the effects of a new sulfonamide, S1, in AL cells K562 and Jurkat. METHODS: The cytotoxic activity of S1 was assessed using MTT method. The involvement of apoptosis in the mechanism of cell death was assessed by flow cytometry and fluorescence microscopy. RESULTS: Our results demonstrated that S1 induced morphological changes suggestive of apoptosis in both K562 and Jurkat cells. Additionally, S1 was not cytotoxic to normal erythrocytes and mononuclear cells and had a highly selective cytotoxicity for AL lineages. The mechanisms of cell death induced by S1 in K562 cells involves cell cycle arrest at G2/M phase and the activation of both extrinsic and intrinsic apoptosis, with an increased FasR and AIF expression and the loss of mitochondrial potential. As for Jurkat, we observed cell cycle blockade at G0/G1 phase, phosphatidylserine exposure and the involvement of intrinsic apoptosis only, with mitochondrial potential loss and a reduced expression of Survivin.  Although sulfonamide S1 did not altered Bcl-2 and Bax expression in AL cell lines, it was able to activate caspase-3 in K562 cells. CONCLUSION: Our results suggest that sulfonamide S1 may be a promising candidate for the development of new drugs for the treatment of ALs.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Derivados de Benzeno/farmacologia , Leucemia Mieloide Aguda/tratamento farmacológico , Sulfonamidas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Derivados de Benzeno/síntese química , Derivados de Benzeno/química , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Células Jurkat , Células K562 , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Estrutura Molecular , Sulfonamidas/síntese química , Sulfonamidas/química
18.
Chem Biol Interact ; 338: 109427, 2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33639173

RESUMO

Oxidative stress and inflammation are implicated in the occurrence and progression of diabetic nephropathy (DN). Diphenyl diselenide (DPDS) is a stable and simple diaryl diselenide with anti-hyperglycemic, anti-inflammatory, and antioxidant activities. However, the effects of DPDS on DN are still unclear to date. Herein, we aimed to explore whether DPDS could improve renal dysfunction in streptozotocin (STZ)-induced diabetic rats and its underlying mechanisms. STZ-induced DN rats were administered with DPDS (5 or 15 mg/kg) or metformin (200 mg/kg) once daily by intragastric gavage for 12 weeks. DPDS supplementation significantly improved hyperglycemia, glucose intolerance, dyslipidemia, and the renal pathological abnormalities, concurrent with significantly reduced serum levels of creatinine, urea nitrogen, urine volume, and urinary levels of micro-albumin, ß2-microglobulin and N-acetyl-glucosaminidase activities. Moreover, DPDS effectively promoted the activities of antioxidant enzymes, and reduced the levels of MDA and pro-inflammatory factors in serum and the kidney. Furthermore, DPDS supplementation activated the renal Nrf2/Keap1 signaling pathway, but attenuated the high phosphorylation levels of NFκB, JNK, p38 and ERK1/2. Altogether, the current study indicated for the first time that DPDS ameliorated STZ-induced renal dysfunction in rats, and its mechanism of action may be attributable to suppressing oxidative stress via activating the renal Nrf2/Keap1 signaling pathway and mitigating inflammation by suppressing the renal NFκB/MAPK signaling pathways, suggesting a potential therapeutic approach for DN.


Assuntos
Derivados de Benzeno/uso terapêutico , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/patologia , Nefropatias Diabéticas/tratamento farmacológico , Inflamação/tratamento farmacológico , Compostos Organosselênicos/uso terapêutico , Estresse Oxidativo , Animais , Antioxidantes/metabolismo , Derivados de Benzeno/farmacologia , Citocinas/metabolismo , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/fisiopatologia , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/fisiopatologia , Nefropatias Diabéticas/complicações , Nefropatias Diabéticas/patologia , Nefropatias Diabéticas/fisiopatologia , Dislipidemias/complicações , Dislipidemias/tratamento farmacológico , Dislipidemias/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Glucose/metabolismo , Inflamação/complicações , Inflamação/genética , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Rim/patologia , Rim/fisiopatologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Modelos Biológicos , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Compostos Organosselênicos/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Ratos Sprague-Dawley , Estreptozocina
19.
Eur J Med Chem ; 214: 113230, 2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33581553

RESUMO

To continue our ongoing studies on discovery of new potent antifungal leads, 43 novel pyrazole-aromatic containing carboxamides were rationally designed and synthesized. Bioassays indicated that most target compounds displayed good in vitro antifungal activities against Botrytis cinerea, Rhizoctonia cerealis and Sclerotinia sclerotiorum and in vivo antifungal activity against R. solani. Compound 11ea exhibited the most significant in vitro activity against R. cerealis (EC50 = 0.93 µg/mL) with about 2-fold more potent than a previously reported lead compound A1 (EC50 = 2.01 µg/mL), and about 11-fold more potent than the positive control/commercial succinate dehydrogenase inhibitor thifluzamide (EC50 = 23.09 µg/mL). Structure-activity relationship analysis and molecular docking simulations indicated that the presence of difluoromethyl pyrazole-(m-benzene) carboxamide scaffold obviously increased the antifungal activity. The further enzymatic bioassay showed that both thifluzamide and compound 11ea displayed excellent SDH inhibitory effects, and fluorescence quenching analysis suggested that they may share the same target SDH.


Assuntos
Antifúngicos/farmacologia , Basidiomycota/enzimologia , Derivados de Benzeno/farmacologia , Inibidores Enzimáticos/farmacologia , Pirazóis/farmacologia , Succinato Desidrogenase/antagonistas & inibidores , Antifúngicos/síntese química , Antifúngicos/química , Ascomicetos/efeitos dos fármacos , Basidiomycota/efeitos dos fármacos , Derivados de Benzeno/síntese química , Derivados de Benzeno/química , Botrytis/efeitos dos fármacos , Relação Dose-Resposta a Droga , Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Estrutura Molecular , Pirazóis/síntese química , Pirazóis/química , Relação Estrutura-Atividade , Succinato Desidrogenase/metabolismo
20.
Int J Mol Sci ; 22(3)2021 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-33572814

RESUMO

Although multiple myeloma (MM) patients benefit from standard bortezomib (BTZ) chemotherapy, they develop drug resistance, resulting in relapse. We investigated whether histone deacetylase 6 (HDAC6) inhibitor A452 overcomes bortezomib resistance in MM. We show that HDAC6-selective inhibitor A452 significantly decreases the activation of BTZ-resistant markers, such as extracellular signal-regulated kinases (ERK) and nuclear factor kappa B (NF-κB), in acquired BTZ-resistant MM cells. Combination treatment of A452 and BTZ or carfilzomib (CFZ) synergistically reduces BTZ-resistant markers. Additionally, A452 synergizes with BTZ or CFZ to inhibit the activation of NF-κB and signal transducer and activator of transcription 3 (STAT3), resulting in decreased expressions of low-molecular-mass polypeptide 2 (LMP2) and LMP7. Furthermore, combining A452 with BTZ or CFZ leads to synergistic cancer cell growth inhibition, viability decreases, and apoptosis induction in the BTZ-resistant MM cells. Overall, the synergistic effect of A452 with CFZ is more potent than that of A452 with BTZ in BTZ-resistant U266 cells. Thus, our findings reveal the HDAC6-selective inhibitor as a promising therapy for BTZ-chemoresistant MM.


Assuntos
Antineoplásicos/farmacologia , Derivados de Benzeno/farmacologia , Bortezomib/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Mieloma Múltiplo/tratamento farmacológico , Linhagem Celular Tumoral , Desacetilase 6 de Histona/antagonistas & inibidores , Desacetilase 6 de Histona/metabolismo , Humanos , Mieloma Múltiplo/metabolismo
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