Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 3.637
Filtrar
1.
Org Lett ; 26(23): 5021-5026, 2024 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-38842216

RESUMO

We describe a simple and robust oxidation strategy for preparing N-terminal thiazolidine-containing peptide thioesters from peptide hydrazides. We find for the first time that l-thioproline can be used as a protective agent to prevent the nitrosation of N-terminal thiazolidine during peptide hydrazide oxidation. The thioproline-based oxidation strategy has been successfully applied to the chemical synthesis of CC chemokine ligand-2 (69aa) and omniligase-C (113aa), thereby demonstrating its utility in hydrazide-based native chemical ligation.


Assuntos
Oxirredução , Peptídeos , Tiazolidinas , Tiazolidinas/química , Tiazolidinas/síntese química , Estrutura Molecular , Peptídeos/química , Peptídeos/síntese química , Hidrazinas/química , Prolina/química , Ésteres/química , Compostos de Sulfidrila/química
2.
Sci Rep ; 14(1): 13788, 2024 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-38877117

RESUMO

Root hair (RH) cells are important for the growth and survival of seedlings. They favor plant-microbe interactions and nutrients uptake. When invading the soil, RH cells have to penetrate a dense medium exhibiting a variety of physical properties, such as mechanical resistance, that impact the growth and survival of plants. Here we investigate the effect of the mechanical resistance of the culture medium on RH-physical and phenotypical parameters such as length, time, and speed of growth. We also analyze the impact of the environment on nuclear dynamics. We show that the RH growth rate and the nucleus speed decrease similarly as mechanical resistance increases while the time of growth of RH cells is invariable. Moreover, during RH growth, the nucleus-to-tip distance was found to decrease when the stiffness of the environment was increased. Along this line, using Latrunculin B treatment in liquid growth media, we could internally slow down RH growth to reach speeds similar to those observed in stiff solid media while the nucleus-to-tip distance was only slightly affected, supporting thus the idea of a specific effect of mechanical resistance of the environment on nucleus dynamics.


Assuntos
Núcleo Celular , Raízes de Plantas , Raízes de Plantas/crescimento & desenvolvimento , Núcleo Celular/metabolismo , Arabidopsis/crescimento & desenvolvimento , Arabidopsis/fisiologia , Meios de Cultura , Tiazolidinas/farmacologia , Plântula/crescimento & desenvolvimento , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia
3.
Molecules ; 29(12)2024 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-38930952

RESUMO

Based on the fact that substances with a ß-phenyl-α,ß-unsaturated carbonyl (PUSC) motif confer strong tyrosinase inhibitory activity, benzylidene-3-methyl-2-thioxothiazolidin-4-one (BMTTZD) analogs 1-8 were prepared as potential tyrosinase inhibitors. Four analogs (1-3 and 5) inhibited mushroom tyrosinase strongly. Especially, analog 3 showed an inhibitory effect that was 220 and 22 times more powerful than kojic acid in the presence of l-tyrosine and l-dopa, respectively. A kinetic study utilizing mushroom tyrosinase showed that analogs 1 and 3 competitively inhibited tyrosinase, whereas analogs 2 and 5 inhibited tyrosinase in a mixed manner. A docking simulation study indicated that analogs 2 and 5 could bind to both the tyrosinase active and allosteric sites with high binding affinities. In cell-based experiments using B16F10 cells, analogs 1, 3, and 5 effectively inhibited melanin production; their anti-melanogenic effects were attributed to their ability to inhibit intracellular tyrosinase activity. Moreover, analogs 1, 3, and 5 inhibited in situ B16F10 cellular tyrosinase activity. In three antioxidant experiments, analogs 2 and 3 exhibited strong antioxidant efficacy, similar to that of the positive controls. These results suggest that the BMTTZD analogs are promising tyrosinase inhibitors for the treatment of hyperpigmentation-related disorders.


Assuntos
Agaricales , Antioxidantes , Inibidores Enzimáticos , Melaninas , Simulação de Acoplamento Molecular , Monofenol Mono-Oxigenase , Monofenol Mono-Oxigenase/antagonistas & inibidores , Monofenol Mono-Oxigenase/metabolismo , Agaricales/enzimologia , Animais , Antioxidantes/farmacologia , Antioxidantes/química , Camundongos , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/química , Melaninas/antagonistas & inibidores , Melaninas/biossíntese , Tiazolidinas/química , Tiazolidinas/farmacologia , Linhagem Celular Tumoral , Cinética , Melanoma Experimental/tratamento farmacológico , Melanoma Experimental/patologia , Compostos de Benzilideno/farmacologia , Compostos de Benzilideno/química , Pironas
4.
Cells ; 13(12)2024 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-38920636

RESUMO

Cancer is one of the most important problems of modern societies. Recently, studies have reported the anticancer properties of rosiglitazone related to its ability to bind peroxisome proliferator receptor γ (PPARγ), which has various effects on cancer and can inhibit cell proliferation. In this study, we investigated the effect of new 4-thiazolidinone (4-TZD) hybrids Les-4369 and Les-3467 and their effect on reactive oxygen species (ROS) production, metabolic activity, lactate dehydrogenase (LDH) release, caspase-3 activity, and gene and protein expression in human foreskin fibroblast (BJ) cells and lung adenocarcinoma (A549) cells. The ROS production and caspase-3 activity were mainly increased in the micromolar concentrations of the studied compounds in both cell lines. Les-3467 and Les-4369 increased the mRNA expression of PPARG, P53 (tumor protein P53), and ATM (ATM serine/threonine kinase) in the BJ cells, while the mRNA expression of these genes (except PPARG) was mainly decreased in the A549 cells treated with both of the tested compounds. Our results indicate a decrease in the protein expression of AhR, PPARγ, and PARP-1 in the BJ cells exposed to 1 µM Les-3467 and Les-4369. In the A549 cells, the protein expression of AhR, PPARγ, and PARP-1 increased in the treatment with 1 µM Les-3467 and Les-4369. We have also shown the PPARγ modulatory properties of Les-3467 and Les-4369. However, both compounds prove weak anticancer properties evidenced by their action at high concentrations and non-selective effects against BJ and A549 cells.


Assuntos
PPAR gama , Pirazóis , Espécies Reativas de Oxigênio , Humanos , Células A549 , PPAR gama/metabolismo , PPAR gama/genética , Espécies Reativas de Oxigênio/metabolismo , Pirazóis/farmacologia , Tiazolidinas/farmacologia , Indóis/farmacologia , Caspase 3/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Proteína Supressora de Tumor p53/genética , Proliferação de Células/efeitos dos fármacos , Antineoplásicos/farmacologia , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Apoptose/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo
5.
Molecules ; 29(11)2024 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-38893334

RESUMO

Thiazolin-4-ones and their derivatives represent important heterocyclic scaffolds with various applications in medicinal chemistry. For that reason, the synthesis of two 5-substituted thiazolidin-4-one derivatives was performed. Their structure assignment was conducted by NMR experiments (2D-COSY, 2D-NOESY, 2D-HSQC and 2D-HMBC) and conformational analysis was conducted through Density Functional Theory calculations and 2D-NOESY. Conformational analysis showed that these two molecules adopt exo conformation. Their global minimum structures have two double bonds (C=N, C=C) in Z conformation and the third double (C=N) in E. Our DFT results are in agreement with the 2D-NMR measurements. Furthermore, the reaction isomerization paths were studied via DFT to check the stability of the conformers. Finally, some potential targets were found through the SwissADME platform and docking experiments were performed. Both compounds bind strongly to five macromolecules (triazoloquinazolines, mglur3, Jak3, Danio rerio HDAC6 CD2, acetylcholinesterase) and via SwissADME it was found that these two molecules obey Lipinski's Rule of Five.


Assuntos
Conformação Molecular , Simulação de Acoplamento Molecular , Tiazolidinas , Tiazolidinas/química , Tiazolidinas/síntese química , Isomerismo , Animais , Acetilcolinesterase/química , Acetilcolinesterase/metabolismo , Peixe-Zebra , Espectroscopia de Ressonância Magnética , Janus Quinase 3/antagonistas & inibidores , Janus Quinase 3/metabolismo , Janus Quinase 3/química , Estrutura Molecular
6.
Drug Res (Stuttg) ; 74(5): 227-240, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38830371

RESUMO

PURPOSE: Cancer is the second leading cause of death globally and is responsible for an estimated 9.6 million deaths in 2018. Globally, about 1 in 6 deaths is due to cancer and the chemotherapeutic drugs available have high toxicity and have reported side effects hence, there is a need for the synthesis of novel drugs in the treatment of cancer. METHODS: The current research work dealt with the synthesis of a series of 3-(3-acetyl-2-oxoquinolin-1-(2H)-yl-2-(substitutedphenyl)thiazolidin-4-one (Va-j) derivatives and evaluation of their in-vitro anticancer activity. All the synthesized compounds were satisfactorily characterized by IR and NMR data. Compounds were further evaluated for their in-vitro anticancer activity against A-549 (lung cancer) cell lines. The in-vitro anticancer activity was based upon the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide (MTT) assay method. RESULTS: The synthesized compounds exhibited satisfactory anticancer properties against the A-549 cell line. The compound (VH): showed the highest potency amongst the tested derivatives against the A-549 cell line with IC50 values of 100 µg/ml respectively and was also found to be more potent than Imatinib (150 µg/ml) which was used as a standard drug. Molecular docking studies of the titled compounds (Va-j) were carried out using AutoDock Vina/PyRx software. The synthesized compounds exhibited well-conserved hydrogen bonds with one or more amino acid residues in the active pocket of the EGFRK tyrosine kinase domain (PDB 1m17). CONCLUSION: Among all the synthesized analogues, the binding affinity of the compound (Vh) was found to be higher than other synthesized derivatives and a molecular dynamics simulation study explored the stability of the docked complex system.


Assuntos
Antineoplásicos , Receptores ErbB , Neoplasias Pulmonares , Simulação de Acoplamento Molecular , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/química , Receptores ErbB/antagonistas & inibidores , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Relação Estrutura-Atividade , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/química , Linhagem Celular Tumoral , Células A549 , Tiazolidinas/farmacologia , Tiazolidinas/química , Tiazolidinas/síntese química , Ensaios de Seleção de Medicamentos Antitumorais , Proliferação de Células/efeitos dos fármacos
7.
Lipids Health Dis ; 23(1): 201, 2024 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-38937844

RESUMO

BACKGROUND: Nonalcoholic steatohepatitis (NASH) is a prevalent chronic liver condition. However, the potential therapeutic benefits and underlying mechanism of nicotinate-curcumin (NC) in the treatment of NASH remain uncertain. METHODS: A rat model of NASH induced by a high-fat and high-fructose diet was treated with nicotinate-curcumin (NC, 20, 40 mg·kg- 1), curcumin (Cur, 40 mg·kg- 1) and metformin (Met, 50 mg·kg- 1) for a duration of 4 weeks. The interaction between NASH, Cur and Aldo-Keto reductase family 1 member B10 (AKR1B10) was filter and analyzed using network pharmacology. The interaction of Cur, NC and AKR1B10 was analyzed using molecular docking techniques, and the binding energy of Cur and NC with AKR1B10 was compared. HepG2 cells were induced by Ox-LDL (25 µg·ml- 1, 24 h) in high glucose medium. NC (20µM, 40µM), Cur (40µM) Met (150µM) and epalrestat (Epa, 75µM) were administered individually. The activities of ALT, AST, ALP and the levels of LDL, HDL, TG, TC and FFA in serum were quantified using a chemiluminescence assay. Based on the changes in the above indicators, score according to NAS standards. The activities of Acetyl-CoA and Malonyl-CoA were measured using an ELISA assay. And the expression and cellular localization of AKR1B10 and Acetyl-CoA carboxylase (ACCα) in HepG2 cells were detected by Western blotting and immunofluorescence. RESULTS: The results of the animal experiments demonstrated that NASH rat model induced by a high-fat and high-fructose diet exhibited pronounced dysfunction in liver function and lipid metabolism. Additionally, there was a significant increase in serum levels of FFA and TG, as well as elevated expression of AKR1B10 and ACCα, and heightened activity of Acetyl-CoA and Malonyl-CoA in liver tissue. The administration of NC showed to enhance liver function in rats with NASH, leading to reductions in ALT, AST and ALP levels, and decrease in blood lipid and significant inhibition of FFA and TG synthesis in the liver. Network pharmacological analysis identified AKR1B10 and ACCα as potential targets for NASH treatment. Molecular docking studies revealed that both Cur and NC are capable of binding to AKR1B10, with NC exhibiting a stronger binding energy to AKR1B10. Western blot analysis demonstrated an upregulation in the expression of AKR1B10 and ACCα in the liver tissue of NASH rats, accompanied by elevated Acetyl-CoA and Malonyl-CoA activity, and increased levels of FFA and TG. The results of the HepG2 cell experiments induced by Ox-LDL suggest that NC significantly inhibited the expression and co-localization of AKR1B10 and ACCα, while also reduced levels of TC and LDL-C and increased level of HDL-C. These effects are accompanied by a decrease in the activities of ACCα and Malonyl-CoA, and levels of FFA and TG. Furthermore, the impact of NC appears to be more pronounced compared to Cur. CONCLUSION: NC could effectively treat NASH and improve liver function and lipid metabolism disorder. The mechanism of NC is related to the inhibition of AKR1B10/ACCα pathway and FFA/TG synthesis of liver.


Assuntos
Aldo-Ceto Redutases , Curcumina , Hepatopatia Gordurosa não Alcoólica , Triglicerídeos , Curcumina/farmacologia , Curcumina/análogos & derivados , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/metabolismo , Animais , Humanos , Células Hep G2 , Aldo-Ceto Redutases/metabolismo , Ratos , Masculino , Triglicerídeos/sangue , Triglicerídeos/metabolismo , Acetil-CoA Carboxilase/metabolismo , Aldeído Redutase/metabolismo , Aldeído Redutase/antagonistas & inibidores , Dieta Hiperlipídica/efeitos adversos , Simulação de Acoplamento Molecular , Fígado/efeitos dos fármacos , Fígado/metabolismo , Metformina/farmacologia , Ratos Sprague-Dawley , Modelos Animais de Doenças , Rodanina/análogos & derivados , Tiazolidinas
8.
Methods Enzymol ; 698: 169-194, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38886031

RESUMO

Peptide ligation chemistries have revolutionized the synthesis of proteins with site-specific modifications or proteomimetics through assembly of multiple peptide segments. In order to prepare polypeptide chains consisting of 100-150 amino acid residues or larger generally assembled from three or more peptide segments, iterative purification process that decreases the product yield is usually demanded. Accordingly, methodologies for one-pot peptide ligation that omit the purification steps of intermediate peptide segments have been vigorously developed so far to improve the efficiency of chemical protein synthesis. In this chapter, we first outline the concept and recent advances of one-pot peptide ligation strategies. Then, the practical guideline for the preparation of peptide segments for one-pot peptide ligation is described with an emphasis on diketopiperazine thioester synthesis. Finally, we disclose the explicit protocols for one-pot four segment ligation via repetitive deprotection of N-terminal thiazolidine by a 2-aminobenzamide type aldehyde scavenger.


Assuntos
Peptídeos , Tiazolidinas , Tiazolidinas/química , Peptídeos/química , Dicetopiperazinas/química
9.
J Agric Food Chem ; 72(21): 11968-11979, 2024 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-38759145

RESUMO

With the aim of identifying novel neonicotinoid insecticides with low bee toxicity, a series of compounds bearing thiazolidine moiety, which has been shown to be low bee toxic, were rationally designed through substructure splicing strategy and evaluated insecticidal activities. The optimal compounds A24 and A29 exhibited LC50 values of 30.01 and 17.08 mg/L against Aphis craccivora, respectively. Electrophysiological studies performed on Xenopus oocytes indicated that compound A29 acted on insect nAChR, with EC50 value of 50.11 µM. Docking binding mode analysis demonstrated that A29 bound to Lymnaea stagnalis acetylcholine binding protein through H-bonds with the residues of D_Arg55, D_Leu102, and D_Val114. Quantum mechanics calculation showed that A29 had a higher highest occupied molecular orbit (HOMO) energy and lower vertical ionization potential (IP) value compared to the high bee toxic imidacloprid, showing potentially low bee toxicity. Bee toxicity predictive model also indicated that A29 was nontoxic to honeybees. Our present work identified an innovative insecticidal scaffold and might facilitate the further exploration of low bee toxic neonicotinoid insecticides.


Assuntos
Inseticidas , Neonicotinoides , Tiazolidinas , Animais , Inseticidas/química , Inseticidas/toxicidade , Abelhas/efeitos dos fármacos , Neonicotinoides/química , Neonicotinoides/toxicidade , Tiazolidinas/química , Tiazolidinas/toxicidade , Simulação de Acoplamento Molecular , Proteínas de Insetos/genética , Proteínas de Insetos/química , Proteínas de Insetos/metabolismo , Proteínas de Insetos/toxicidade , Afídeos/efeitos dos fármacos , Afídeos/genética , Relação Estrutura-Atividade , Estrutura Molecular , Receptores Nicotínicos/genética , Receptores Nicotínicos/metabolismo , Receptores Nicotínicos/química
10.
J Pediatr Surg ; 59(7): 1334-1341, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38570263

RESUMO

BACKGROUND: Chemoresistance contributes to relapse in high-risk neuroblastoma. Cancer cells acquire resistance through multiple mechanisms, including drug efflux pumps. In neuroblastoma, multidrug resistance-associated protein-1 (MRP1/ABCC1) efflux pump expression correlates with worse outcomes. These pumps are regulated by PIM kinases, a family of serine-threonine kinases, overexpressed in neuroblastoma. We hypothesized PIM kinase inhibition would sensitize neuroblastoma cells by modulating MRP1. METHODS: Kocak database query evaluated ABCC1, PIM1, PIM2, and PIM3 expression in neuroblastoma patients. SK-N-AS and SK-N-BE(2) cells were treated with doxorubicin or the pan-PIM kinase inhibitor, AZD1208. Flow cytometry assessed intracellular doxorubicin accumulation. AlamarBlue assay measured viability. The lethal dose 50% (LD50) of each drug and combination indices (CI) were calculated and isobolograms constructed to determine synergy. RESULTS: Kocak database query demonstrated positive correlation between PIM genes and ABCC1. PIM kinase inhibition increased intracellular doxorubicin accumulation in both cell lines, suggesting PIM kinase regulation of MRP1. Isobolograms showed synergy between AZD1208 and doxorubicin. CONCLUSIONS: The correlation between PIM and ABCC1 gene expression suggests PIM kinases may contribute to neuroblastoma chemotherapeutic resistance. PIM kinase inhibition increased intracellular doxorubicin accumulation. Combination treatment with AZD1208 and doxorubicin decreased neuroblastoma cell viability in a synergistic fashion. These findings support further investigations of PIM kinase inhibition in neuroblastoma. TYPE OF STUDY: Basic Science Research. LEVEL OF EVIDENCE: NA.


Assuntos
Doxorrubicina , Resistencia a Medicamentos Antineoplásicos , Proteínas Associadas à Resistência a Múltiplos Medicamentos , Neuroblastoma , Proteínas Proto-Oncogênicas c-pim-1 , Humanos , Neuroblastoma/tratamento farmacológico , Neuroblastoma/patologia , Neuroblastoma/genética , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Proteínas Proto-Oncogênicas c-pim-1/antagonistas & inibidores , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Linhagem Celular Tumoral , Antibióticos Antineoplásicos/uso terapêutico , Antibióticos Antineoplásicos/farmacologia , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Sinergismo Farmacológico , Compostos de Bifenilo , Tiazolidinas
11.
Epilepsy Res ; 203: 107365, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38677001

RESUMO

Epilepsy is a chronic neurological disorder characterized by episodic dysfunction of central nervous system. The most basic mechanism of epilepsy falls to the imbalance between excitation and inhibition. In adults, GABAA receptor (GABAAR) is the main inhibitory receptor to prevent neurons from developing hyperexcitability, while its inhibition relies on the low intracellular chloride anion concentration ([Cl-]i). Neuronal-specific electroneutral K+-Cl- cotransporter (KCC2) can mediate chloride efflux to lower [Cl-]i for GABAAR mediated inhibition. Our previous study has revealed that the coordinated downregulation of KCC2 and GABAAR participates in epilepsy. According to a high-throughout screen for compounds that reduce [Cl-]i, CLP290 turns out to be a specific KCC2 functional modulator. In current study, we first confirmed that CLP290 could dose-dependently suppress convulsant-induced seizures in mice in vivo as well as the epileptiform burst activities in cultured hippocampal neurons in vitro. Then, we discovered that CLP290 functioned through preventing the downregulation of the KCC2 phosphorylation at Ser940 and hence the KCC2 membrane expression during convulsant stimulation, and consequently restored the GABA inhibition. In addition, while CLP290 was given in early epileptogenesis period, it also effectively decreased the spontaneous recurrent seizures. Generally, our current results demonstrated that CLP290, as a specific KCC2 modulator by enhancing KCC2 function, not only inhibits the occurrence of the ictal seizures, but also suppresses the epileptogenic process. Therefore, we believe KCC2 may be a suitable target for future anti-epileptic drug development.


Assuntos
Anticonvulsivantes , Hipocampo , Cotransportadores de K e Cl- , Neurônios , Convulsões , Simportadores , Animais , Simportadores/metabolismo , Convulsões/tratamento farmacológico , Convulsões/metabolismo , Camundongos , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , Anticonvulsivantes/farmacologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , Receptores de GABA-A/metabolismo , Relação Dose-Resposta a Droga , Células Cultivadas , Tiazolidinas
12.
Antiviral Res ; 226: 105891, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38649071

RESUMO

Zoonoses such as ZIKV and SARS-CoV-2 pose a severe risk to global health. There is urgent need for broad antiviral strategies based on host-targets filling gaps between pathogen emergence and availability of therapeutic or preventive strategies. Significant reduction of pathogen titers decreases spread of infections and thereby ensures health systems not being overloaded and public life to continue. Based on previously observed interference with FGFR1/2-signaling dependent impact on interferon stimulated gene (ISG)-expression, we identified Pim kinases as promising druggable cellular target. We therefore focused on analyzing the potential of pan-Pim kinase inhibition to trigger a broad antiviral response. The pan-Pim kinase inhibitor AZD1208 exerted an extraordinarily high antiviral effect against various ZIKV isolates, SARS-CoV-2 and HBV. This was reflected by strong reduction in viral RNA, proteins and released infectious particles. Especially in case of SARS-CoV-2, AZD1208 led to a complete removal of viral traces in cells. Kinome-analysis revealed vast changes in kinase landscape upon AZD1208 treatment, especially for inflammation and the PI3K/Akt-pathway. For ZIKV, a clear correlation between antiviral effect and increase in ISG-expression was observed. Based on a cell culture model with impaired ISG-induction, activation of the PI3K-Akt-mTOR axis, leading to major changes in the endolysosomal equilibrium, was identified as second pillar of the antiviral effect triggered by AZD1208-dependent Pim kinase inhibition, also against HBV. We identified Pim-kinases as cellular target for a broad antiviral activity. The antiviral effect exerted by inhibition of Pim kinases is based on at least two pillars: innate immunity and modulation of the endolysosomal system.


Assuntos
Antivirais , Imunidade Inata , Proteínas Proto-Oncogênicas c-akt , Proteínas Proto-Oncogênicas c-pim-1 , SARS-CoV-2 , Transdução de Sinais , Serina-Treonina Quinases TOR , Humanos , Imunidade Inata/efeitos dos fármacos , Antivirais/farmacologia , Serina-Treonina Quinases TOR/metabolismo , Proteínas Proto-Oncogênicas c-pim-1/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-pim-1/metabolismo , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/imunologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Lisossomos/efeitos dos fármacos , Lisossomos/metabolismo , Zika virus/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Animais , Vírus da Hepatite B/efeitos dos fármacos , Endossomos/efeitos dos fármacos , Endossomos/metabolismo , Linhagem Celular , COVID-19/imunologia , COVID-19/virologia , Tratamento Farmacológico da COVID-19 , Replicação Viral/efeitos dos fármacos , Compostos de Bifenilo , Tiazolidinas
13.
Eur J Med Chem ; 271: 116434, 2024 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-38653067

RESUMO

Diabetes mellitus is a chronic metabolic disorder characterized by improper expression/function of a number of key enzymes that can be regarded as targets for anti-diabetic drug design. Herein, we report the design, synthesis, and biological assessment of two series of thiazolidinone-based sulfonamides 4a-l and 5a-c as multitarget directed ligands (MTDLs) with potential anti-diabetic activity through targeting the enzymes: α-glucosidase and human carbonic anhydrase (hCA) II. The synthesized sulfonamides were evaluated for their inhibitory activity against α-glucosidase where most of the compounds showed good to potent activities. Compounds 4d and 4e showed potent inhibitory activities (IC50 = 0.440 and 0.3456 µM), comparable with that of the positive control (acarbose; IC50 = 0.420 µM). All the synthesized derivatives were also tested for their inhibitory activities against hCA I, II, IX, and XII. They exhibited different levels of inhibition against these isoforms. Compound 4d outstood as the most potent one against hCA II with Ki equals to 7.0 nM, more potent than the reference standard (acetazolamide; Ki = 12.0 nM). In silico studies for the most active compounds within the active sites of α-glucosidase and hCA II revealed good binding modes that can explain their biological activities. MM-GBSA refinements and molecular dynamic simulations were performed on the top-ranking docking pose of the most potent compound 4d to confirm the formation of stable complex with both targets. Compound 4d was screened for its in vivo antihyperglycemic efficacy by using the oral glucose tolerance test. Compound 4d decreased blood glucose level to 217 mg/dl, better than the standard acarbose (234 mg/dl). Hence, this revealed its synergistic mode of action on post prandial hyperglycemia and hepatic gluconeogenesis. Thus, these benzenesulfonamide thiazolidinone hybrids could be considered as promising multi-target candidates for the treatment of type II diabetes mellitus.


Assuntos
Benzenossulfonamidas , Anidrase Carbônica II , Inibidores da Anidrase Carbônica , Diabetes Mellitus Tipo 2 , Inibidores de Glicosídeo Hidrolases , Hipoglicemiantes , Sulfonamidas , Tiazolidinas , alfa-Glucosidases , Anidrase Carbônica II/antagonistas & inibidores , Anidrase Carbônica II/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , alfa-Glucosidases/metabolismo , Humanos , Sulfonamidas/química , Sulfonamidas/farmacologia , Sulfonamidas/síntese química , Inibidores de Glicosídeo Hidrolases/farmacologia , Inibidores de Glicosídeo Hidrolases/química , Inibidores de Glicosídeo Hidrolases/síntese química , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Hipoglicemiantes/síntese química , Relação Estrutura-Atividade , Inibidores da Anidrase Carbônica/química , Inibidores da Anidrase Carbônica/farmacologia , Inibidores da Anidrase Carbônica/síntese química , Animais , Ligantes , Tiazolidinas/química , Tiazolidinas/farmacologia , Tiazolidinas/síntese química , Estrutura Molecular , Ratos , Relação Dose-Resposta a Droga , Simulação de Acoplamento Molecular , Diabetes Mellitus Experimental/tratamento farmacológico , Masculino , Ratos Wistar
14.
Sci Total Environ ; 926: 171907, 2024 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-38522548

RESUMO

Traditional risk assessments of chiral pesticides mainly depend on racemic form, which is often incomprehensive. This study conducted systemic investigations on the bioactivity, toxicity, and ecotoxicological effects of hexythiazox (HTZ) at the enantiomer level. The elution order and absolute configuration of HTZ enantiomers were determined. (4R, 5R)-(+)-HTZ exhibited 708 and 1719 times higher bioactivity against Tetranychus cinnabarinus and Tetranychus urticae eggs than (4S, 5S)-(-)-HTZ, respectively. Molecular docking indicated greater interactions between (4R, 5R)-(+)-HTZ and chitin synthase leading to higher bioactivity of (4R, 5R)-(+)-HTZ. However, (4S, 5S)-(-)-HTZ induced greater changes in protein and malondialdehyde content, and antioxidant and detoxification enzyme activities than (4R, 5R)-(+)-HTZ in earthworms. Furthermore, integrated biomarker response results indicated (4S, 5S)-(-)-HTZ exhibited higher toxic effects on earthworms than (4R, 5R)-(+)-HTZ. Finally, significant differentially expressed genes (DEGs) were observed in earthworms after exposure to (4R, 5R)-(+)-HTZ and (4S, 5S)-(-)-HTZ, respectively. These DEGs were mainly enriched in glycolysis/gluconeogenesis and purine metabolism pathways in earthworms. Additionally, six metabolism pathways were also enriched, including pyruvate metabolism, fatty acid biosynthesis, oxidative phosphorylation, citric acid cycle, fatty acid degradation, and ATP-binding cassette transporters. These findings suggest that earthworms exhibited enantiomer-specific responses to (4R, 5R)-(+)-HTZ and (4S, 5S)-(-)-HTZ. This study provides systemic insight into the toxicity mechanism of HTZ at the enantiomer level and the potential to develop (4R, 5R)-(+)-HTZ as a high-efficiency and low-risk pesticide.


Assuntos
Acaricidas , Praguicidas , Tiazolidinas , Acaricidas/toxicidade , Simulação de Acoplamento Molecular , Praguicidas/toxicidade , Comportamento de Redução do Risco , Ácidos Graxos , Estereoisomerismo
15.
PLoS One ; 19(3): e0290672, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38483897

RESUMO

Viral and cellular particles too large to freely diffuse have two different types of mobility in the eukaryotic cell cytoplasm: directed motion mediated by motor proteins moving along cytoskeletal elements with the particle as its load, and motion in random directions mediated by motor proteins interconnecting cytoskeletal elements. The latter motion is referred to as "active diffusion." Mechanisms of directed motion have been extensively studied compared to mechanisms of active diffusion, despite the observation that active diffusion is more common for many viral and cellular particles. Our previous research showed that active diffusion of vesicular stomatitis virus (VSV) ribonucleoproteins (RNPs) in the cytoplasm consists of hopping between traps and that actin filaments and myosin II motors are components of the hop-trap mechanism. This raises the question whether similar mechanisms mediate random motion of larger particles with different physical and biological properties. Live-cell fluorescence imaging and a variational Bayesian analysis used in pattern recognition and machine learning were used to determine the molecular mechanisms of random motion of VSV inclusion bodies and cellular early endosomes. VSV inclusion bodies are membraneless cellular compartments that are the major sites of viral RNA synthesis, and early endosomes are representative of cellular membrane-bound organelles. Like VSV RNPs, inclusion bodies and early endosomes moved from one trapped state to another, but the distance between states was inconsistent with hopping between traps, indicating that the apparent state-to-state movement is mediated by trap movement. Like VSV RNPs, treatment with the actin filament depolymerizing inhibitor latrunculin A increased VSV inclusion body mobility by increasing the size of the traps. In contrast neither treatment with latrunculin A nor depolymerization of microtubules by nocodazole treatment affected the size of traps that confine early endosome mobility, indicating that intermediate filaments are likely major trap components for these cellular organelles.


Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes , Tiazolidinas , Estomatite Vesicular , Humanos , Teorema de Bayes , Endossomos/metabolismo , Corpos de Inclusão , Vesículas Transportadoras , Estomatite Vesicular/metabolismo , Vírus da Estomatite Vesicular Indiana/genética , Vesiculovirus
16.
Mol Reprod Dev ; 91(3): e23737, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38450862

RESUMO

Extracellular vesicles (EVs) play an important role in the development and function of mammalian ovarian follicles. However, the mechanisms by which they are taken up by the follicular granulosa cells remain unclear. In addition, while oocytes play a pivotal role in follicular development, the possible interactions between oocyte-derived paracrine factors (ODPFs) and EV signals are unknown. Therefore, this study aimed to elucidate the mechanism of EV uptake and the effects of ODPFs on EV uptake by follicular somatic mural granulosa cells in mice. Fluorescence-labeled transferrin (TRF) and cholera toxin B (CTB), substrates for clathrin- and caveolae-mediated endocytosis, respectively, were taken up by mural granulosa cells in vitro. Their uptake was inhibited by Pitstop 2 and genistein, inhibitors of clathrin and caveolae pathways, respectively. Mural granulosa cells took up EVs, and this uptake was suppressed by Pitstop 2 and genistein. Moreover, ODPFs promoted the uptake of EVs and CTB, but not TRF, by mural granulosa cells. These results suggest that mural granulosa cells take up EVs through both clathrin- and caveolae-mediated endocytosis and that oocytes may promote caveolae-mediated endocytosis to facilitate the uptake of EVs.


Assuntos
Vesículas Extracelulares , Genisteína , Sulfonamidas , Tiazolidinas , Feminino , Animais , Camundongos , Genisteína/farmacologia , Células da Granulosa , Clatrina , Mamíferos
17.
Biosystems ; 237: 105177, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38458346

RESUMO

The escalating global incidence of cancer poses significant health challenges, underscoring the need for innovative and more efficacious treatments. Cancer immunotherapy, a promising approach leveraging the body's immune system against cancer, emerges as a compelling solution. Consequently, the identification and characterization of tumor T-cell antigens (TTCAs) have become pivotal for exploration. In this manuscript, we introduce TTCA-IF, an integrative machine learning-based framework designed for TTCAs identification. TTCA-IF employs ten feature encoding types in conjunction with five conventional machine learning classifiers. To establish a robust foundation, these classifiers are trained, resulting in the creation of 150 baseline models. The outputs from these baseline models are then fed back into the five classifiers, generating their respective meta-models. Through an ensemble approach, the five meta-models are seamlessly integrated to yield the final predictive model, the TTCA-IF model. Our proposed model, TTCA-IF, surpasses both baseline models and existing predictors in performance. In a comparative analysis involving nine novel peptide sequences, TTCA-IF demonstrated exceptional accuracy by correctly identifying 8 out of 9 peptides as TTCAs. As a tool for screening and pinpointing potential TTCAs, we anticipate TTCA-IF to be invaluable in advancing cancer immunotherapy.


Assuntos
Aprendizado de Máquina , Neoplasias , Humanos , Tiazolidinas , Linfócitos T , Neoplasias/terapia , Neoplasias/diagnóstico
18.
Bioorg Chem ; 146: 107307, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38537337

RESUMO

In this study, two linear and corresponding cyclic heptapeptide versions of mortiamide A-lugdunin hybrids were designed and synthesized by integrating an anti-malarial peptide epitope derived from Mortiamide A, combined with four residues known for their membrane interactions. Using this synthetic strategy, the sequence of mortiamide A was partly re-engineered with an epitope sequence of lugdunin along with an amino acid replacement using all-L and D/L configurations. Importantly, the re-engineered cyclic mortiamides with all-L (3) and D/L (4) configurations exhibited promising anti-malarial activities against the P. falciparum drug-sensitive TM4/8 strain with half-maximal inhibitory concentration (IC50) values of 6.2 ± 0.5 and 4.8 ± 0.1 µM, respectively. Additionally, they exhibited anti-malarial activities against the P. falciparum multidrug-resistant V1/S strain with IC50 values of 5.0 ± 2.6 and 3.7 ± 0.7 µM, respectively. Interestingly, a linear re-engineered mortiamide with D/L configuration (2) exhibited promising anti-malarial activities, surpassing those of the re-engineered cyclic mortiamides (3 and 4), against both the P. falciparum sensitive TM4/8 and multidrug-resistant V1/S strains with IC50 values of 3.6 ± 0.5 and 2.8 ± 0.7 µM (IC50 of Mortiamide A = 7.85 ± 0.97, 5.31 ± 0.24 µM against 3D7 and Dd2 strains) without any cytotoxicity at >100 µM. The presence of D/L forms in a linear structure significantly impacted the anti-malarial activity against both the P. falciparum sensitive TM4/8 strain and the multidrug-resistant V1/S strain.


Assuntos
Antimaláricos , Malária Falciparum , Peptídeos Cíclicos , Plasmodium , Tiazolidinas , Humanos , Antimaláricos/química , Plasmodium falciparum , Malária Falciparum/tratamento farmacológico , Epitopos
19.
Anal Chem ; 96(13): 5125-5133, 2024 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-38502245

RESUMO

Protein modification by lipid-derived electrophiles (LDEs) is associated with various signaling pathways. Among these LDEs, 4-hydroxy-2-nonenal (HNE) is the most toxic, and protein modified with HNE has been linked to various diseases, including Alzheimer's and Parkinson's. However, due to their low abundance, in-depth profiling of HNE modifications still presents challenges. This study introduces a novel strategy utilizing reversible thiazolidine chemistry to selectively capture HNE-modified proteins and a palladium-mediated cleavage reaction to release them. Thousands of HNE-modified sites in different cell lines were identified. Combined with ABPP, we discovered a set of HNE-sensitive sites that offer a new tool for studying LDE modifications in proteomes.


Assuntos
Aldeídos , Processamento de Proteína Pós-Traducional , Tiazolidinas , Aldeídos/metabolismo , Proteoma/metabolismo , Peroxidação de Lipídeos
20.
Ecotoxicol Environ Saf ; 273: 116148, 2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38422791

RESUMO

The chiral pesticide hexythiazox was extensively employed in agricultural activities and has garnered growing concern for its harmful impact on the ecosystem. This study investigates the toxicodynamic earthworm at the enantiomeric level of hexythiazox. Earthworms exhibited notable enantioselectivity during the accumulation stage. Furthermore, the presence of earthworms can impact the rate of degradation and enantioselectivity of hexythiazox in soil. The accumulation of the two hexythiazox enantiomers in the earthworm adhered to the one-compartment model, whereas the elimination phase was governed by the first-order kinetics equation. Furthermore, it was discovered that there was no notable enantioselectivity observed during the elimination phase.


Assuntos
Oligoquetos , Praguicidas , Poluentes do Solo , Tiazolidinas , Animais , Solo , Praguicidas/toxicidade , Praguicidas/metabolismo , Oligoquetos/metabolismo , Poluentes do Solo/análise , Bioacumulação , Ecossistema , Estereoisomerismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...