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1.
Viruses ; 16(3)2024 02 22.
Artigo em Inglês | MEDLINE | ID: mdl-38543704

RESUMO

The continuous emergence of SARS-CoV-2 variants caused the persistence of the COVID-19 epidemic and challenged the effectiveness of the existing vaccines. The viral proteases are the most attractive targets for developing antiviral drugs. In this scenario, our study explores the use of HIV-1 protease inhibitors against SARS-CoV-2. An in silico screening of a library of HIV-1 proteases identified four anti-HIV compounds able to interact with the 3CLpro of SARS-CoV-2. Thus, in vitro studies were designed to evaluate their potential antiviral effectiveness against SARS-CoV-2. We employed pseudovirus technology to simulate, in a highly safe manner, the adsorption of the alpha (α-SARS-CoV-2) and omicron (ο-SARS-CoV-2) variants of SARS-CoV-2 and study the inhibitory mechanism of the selected compounds for cell-virus interaction. The results reported a mild activity against the viral proteases 3CLpro and PLpro, but efficient inhibitory effects on the internalization of both variants mediated by cathepsin B/L. Our findings provide insights into the feasibility of using drugs exhibiting antiviral effects for other viruses against the viral and host SARS-CoV-2 proteases required for entry.


Assuntos
COVID-19 , Cisteína Proteases , Humanos , SARS-CoV-2/genética , Inibidores de Proteases/farmacologia , Antivirais/farmacologia , Antivirais/uso terapêutico , Cisteína Endopeptidases/genética , Proteases Virais , Simulação de Acoplamento Molecular
2.
Int J Mol Sci ; 24(5)2023 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-36901980

RESUMO

Liver cancer is one of the most common causes of cancer death worldwide. In recent years, substantial progress has been made in the development of systemic therapies, but there is still the need for new drugs and technologies that can increase the survival and quality of life of patients. The present investigation reports the development of a liposomal formulation of a carbamate molecule, reported as ANP0903, previously tested as an inhibitor of HIV-1 protease and now evaluated for its ability to induce cytotoxicity in hepatocellular carcinoma cell lines. PEGylated liposomes were prepared and characterized. Small, oligolamellar vesicles were produced, as demonstrated by light scattering results and TEM images. The physical stability of the vesicles in biological fluids was demonstrated in vitro, alongside the stability during storage. An enhanced cellular uptake was verified in HepG2 cells treated with liposomal ANP0903, resulting in a greater cytotoxicity. Several biological assays were performed to elucidate the molecular mechanisms explaining the proapoptotic effect of ANP0903. Our results allow us to hypothesize that the cytotoxic action in tumor cells is probably due to the inhibition of the proteasome, resulting in an increase in the amount of ubiquitinated proteins within the cells, which in turn triggers activation of autophagy and apoptosis processes, resulting in cell death. The proposed liposomal formulation represents a promising approach to deliver a novel antitumor agent to cancer cells and enhance its activity.


Assuntos
Antineoplásicos , Neoplasias , Humanos , Lipossomos/farmacologia , Células Hep G2 , Carbamatos/farmacologia , Qualidade de Vida , Antineoplásicos/farmacologia , Apoptose , Polietilenoglicóis/farmacologia , Linhagem Celular Tumoral
3.
Cells ; 10(11)2021 11 06.
Artigo em Inglês | MEDLINE | ID: mdl-34831275

RESUMO

Background: Several pre-clinical and clinical reports suggest that HIV-1 protease inhibitors, in addition to the antiretroviral properties, possess pleiotropic pharmacological effects including anticancer action. Therefore, we investigated the pro-apoptotic activity in tumor cells of two molecules, RDD-19 and RDD-142, which are hydroxyethylamine derivatives' precursors of darunavir and several HIV-1 protease inhibitors. Methods: Three hepatoma cell lines and one non-pathological cell line were treated with RDD-19 and RDD-142, and cell viability was assessed. The expression levels of several markers for ER stress, autophagy, cellular ubiquitination, and Akt activation were quantified in HepG2 cells treated with RDD-19 and RDD-142 to evaluate apoptotic and non-apoptotic cell death. Results: RDD-19 and RDD-142 showed a greater dose-dependent cytotoxicity towards the hepatic tumor cell line HepG2 compared to the non-pathological hepatic cell line IHH. Both molecules caused two types of cell death, a caspase-dependent apoptosis, which was ascertained by a series of biochemical and morphological assays, and a caspase-independent death that was characterized by the induction of ER stress and autophagy. The strong increase of ubiquitinated proteins inside the cells suggested that the target of these molecules could be the proteasome and in silico molecular docking analysis that was used to support the plausibility of this hypothesis. Furthermore, cells treated with the two compounds displayed decreased levels of p-AKT, which interferes with cell survival and proliferation. Conclusions: These findings demonstrate that two compounds, RDD-19 and RDD-142, have pleiotropic effects and that they may represent promising anticancer candidates.


Assuntos
Carcinoma Hepatocelular/patologia , Darunavir/farmacologia , HIV-1/efeitos dos fármacos , Neoplasias Hepáticas/patologia , Inibidores de Proteases/farmacologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Resposta a Proteínas não Dobradas , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Sítios de Ligação , Forma Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Hep G2 , Humanos , Simulação de Acoplamento Molecular , Inibidores de Proteases/química , Resposta a Proteínas não Dobradas/efeitos dos fármacos
4.
Biomolecules ; 11(11)2021 10 26.
Artigo em Inglês | MEDLINE | ID: mdl-34827582

RESUMO

Here, we report the synthesis, enzyme inhibition and structure-activity relationship studies of a new potent class of HIV-1 protease inhibitors, which contain a pseudo-symmetric hydroxyethylamine core and heteroarylcarboxyamide moieties. The simple synthetic pathway furnished nine compounds in a few steps with high yields. The compounds were designed taking into account our previous results on other series of inhibitors with different substituents at P' and P'' and different ways of linking them to the inhibitor core. Potent inhibitory activity was obtained with nanomolar IC50 values measured with a standard fluorimetric test in 100 mM MES buffer, pH 5.5, containing 400 mM NaCl, 1 mM EDTA, 1 mM DTT and 1 mg/ml BSA. Compounds 9a-c, containing the indole ring in P1, exhibited an HIV-1 protease inhibitory activity more powerful than darunavir in the same assay. To obtain molecular insight into the binding properties of these compounds, docking analysis was performed, and their binding properties were also compared.


Assuntos
HIV-1 , Desenho de Fármacos , Modelos Moleculares , Relação Estrutura-Atividade
5.
Molecules ; 25(18)2020 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-32927879

RESUMO

A library of dihydropyrimidinones was synthesized via a "one-pot" three component Biginelli reaction using different aldehydes in combination with ß-dicarbonyl compounds and urea. Selected 2-thiooxo and 2-imino analogs were also obtained with the Biginelli reaction from thiourea and guanidine hydrochloride, respectively. The products were screened in vitro for their ß-secretase inhibitory activity. The majority of the compounds resulted to be active, with IC50 in the range 100 nM-50 µM.


Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Técnicas de Química Sintética , Pirimidinonas/química , Pirimidinonas/farmacologia , Secretases da Proteína Precursora do Amiloide/química , Ácido Aspártico Endopeptidases/química , Modelos Moleculares , Conformação Molecular , Estrutura Molecular , Pirimidinonas/síntese química , Relação Estrutura-Atividade
6.
Biochem Biophys Res Commun ; 529(4): 1117-1123, 2020 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-32819574

RESUMO

In neurodegenerative diseases, such as Alzheimer's disease, Huntington's disease, Parkinson's disease and multiple sclerosis, neuroinflammation induced by the microglial activation plays a crucial role. In effort to develop effective anti-neuroinflammatory compounds, different new linear polyoxygenated diarylheptanoids were synthesized. In LPS-triggered BV-2 microglial cells their ability to reduce the concentration of IL-6 and TNF-α pro-inflammatory cytokines was evaluated. Moreover, their effect on NF-κB and ATP citrate lyase (ACLY), a recently emerged target of metabolic reprogramming in inflammation, was assessed. Finally, we turned our attention to inflammatory mediators derived from the cleavage of citrate catalyzed by ACLY: prostaglandin E2, nitric oxide and reactive oxygen species. All compounds showed null or minimal cytotoxicity; most of them had a great anti-neuroinflammatory activity. Diarylheptanoids 6b and 6c, bearing a halide atom and benzyl ether protective groups, exhibited the best effect since they blocked the secretion of all inflammatory mediators analyzed and reduced NF-κB and ACLY protein levels.


Assuntos
Encéfalo/patologia , Diarileptanoides/síntese química , Diarileptanoides/farmacologia , Inflamação/patologia , ATP Citrato (pro-S)-Liase/metabolismo , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Diarileptanoides/química , Dinoprostona/metabolismo , Interleucina-6/metabolismo , Lipopolissacarídeos/farmacologia , Camundongos , Microglia/efeitos dos fármacos , Microglia/metabolismo , Microglia/patologia , NF-kappa B/metabolismo , Óxido Nítrico/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
7.
Molecules ; 25(10)2020 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-32429435

RESUMO

This review describes the progress of the last decade on the synthesis of substituted benzofurans, which are useful scaffolds for the synthesis of numerous natural products and pharmaceuticals. In particular, new intramolecular and intermolecular C-C and/or C-O bond-forming processes, with transition-metal catalysis or metal-free are summarized. (1) Introduction. (2) Ring generation via intramolecular cyclization. (2.1) C7a-O bond formation: (route a). (2.2) O-C2 bond formation: (route b). (2.3) C2-C3 bond formation: (route c). (2.4) C3-C3a bond formation: (route d). (3) Ring generation via intermolecular cyclization. (3.1) C7a-O and C3-C3a bond formation (route a + d). (3.2) O-C2 and C2-C3 bond formation: (route b + c). (3.3) O-C2 and C3-C3a bond formation: (route b + d). (4) Benzannulation. (5) Conclusion.


Assuntos
Benzofuranos/síntese química , Produtos Biológicos/síntese química , Técnicas de Química Sintética/métodos , Preparações Farmacêuticas/síntese química , Benzofuranos/química , Produtos Biológicos/química , Catálise , Técnicas de Química Sintética/história , Química Farmacêutica/história , Química Farmacêutica/métodos , Ciclização , História do Século XXI , Humanos , Preparações Farmacêuticas/química
8.
Bioorg Med Chem ; 27(9): 1863-1870, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30922618

RESUMO

New heteroaryl HIV-protease inhibitors bearing a carbamoyl spacer were synthesized in few steps and high yield, from commercially available homochiral epoxides. Different substitution patterns were introduced onto a given isopropanoyl-sulfonamide core that can have either H or benzyl group. The in vitro inhibition activity against recombinant protease showed a general beneficial effect of both carbamoyl moiety and the benzyl group, ranging the IC50 values between 11 and 0.6 nM. In particular, benzofuryl and indolyl derivatives showed IC50 values among the best for such structurally simple inhibitors. Docking analysis allowed to identify the favorable situation of such derivatives in terms of number of interactions in the active site, supporting the experimental results. The inhibition activity was also confirmed in HEK293 mammalian cells and was maintained against protease mutants. Furthermore, the metabolic stability was comparable with that of the commercially available inhibitors.


Assuntos
Carbamatos/química , Inibidores da Protease de HIV/síntese química , Protease de HIV/genética , Sítios de Ligação , Carbamatos/farmacologia , Domínio Catalítico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Células HEK293 , Protease de HIV/metabolismo , Inibidores da Protease de HIV/farmacologia , HIV-1/efeitos dos fármacos , Humanos , Simulação de Acoplamento Molecular , Mutação
9.
ACS Appl Mater Interfaces ; 10(22): 18574-18584, 2018 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-29799715

RESUMO

In medical diagnosis and environmental monitoring, enzymatic biosensors are widely applied because of their high sensitivity, potential selectivity, and their possibility of miniaturization/automation. Enzyme immobilization is a critical process in the development of this type of biosensors with the necessity to avoid the denaturation of the enzymes and ensuring their accessibility toward the analyte. Electrodeposition of macromolecules is increasingly considered to be the most suitable method for the design of biosensors. Being simple and attractive, it finely controls the immobilization of enzymes on electrode surfaces, usually by entrapment or adsorption, using an electrical stimulus. Performed manually, enzyme immobilization by cross-linking prevents enzyme leaching and was never done using an electrochemical stimulus. In this work, we present a mussel-inspired electro-cross-linking process using glucose oxidase (GOX) and a homobifunctionalized catechol ethylene oxide spacer as a cross-linker in the presence of ferrocene methanol (FC) acting as a mediator of the buildup. Performed in one pot, the process takes place in three steps: (i) electro-oxidation of FC, by the application of cyclic voltammetry, creating a gradient of ferrocenium (FC+); (ii) oxidation of bis-catechol into a bis-quinone molecule by reaction with the electrogenerated FC+; and (iii) a chemical reaction of bis-quinone with free amino moieties of GOX through Michael addition and a Schiff's base condensation reaction. Employed for the design of a second-generation glucose biosensor using ferrocene methanol (FC) as a mediator, this new enzyme immobilization process presents several advantages. The cross-linked enzymatic film (i) is obtained in a one-pot process with nonmodified GOX, (ii) is strongly linked to the metallic electrode surface thanks to catechol moieties, and (iii) presents no leakage issues. The developed GOX/bis-catechol film shows a good response to glucose with a quite wide linear range from 1.0 to 12.5 mM as well as a good sensitivity (0.66 µA/mM cm2) and a high selectivity to glucose. These films would distinguish between healthy (3.8 and 6.5 mM) and hyperglycemic subjects (>7 mM). Finally, we show that this electro-cross-linking process allows the development of miniaturized biosensors through the functionalization of a single electrode out of a microelectrode array. Elegant and versatile, this electro-cross-linking process can also be used for the development of enzymatic biofuel cells.


Assuntos
Técnicas Biossensoriais , Eletrodos , Enzimas Imobilizadas , Glucose , Glucose Oxidase
10.
Org Lett ; 14(15): 3928-31, 2012 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-22804107

RESUMO

An effective ligand-free Suzuki coupling protocol to unite methyl (E)-4-bromobut-2-enoate with several arylboronic acids has been accomplished. Thus, a number of variously functionalized methyl 4-arylcrotonates have been achieved in high to excellent yields under mild conditions. This method enables the preparation of diverse aryl-substituted cores of HIV-1 protease inhibitors.


Assuntos
Ácidos Borônicos/química , Crotonatos/síntese química , Inibidores da Protease de HIV/síntese química , Catálise , Técnicas de Química Combinatória , Crotonatos/química , Crotonatos/farmacologia , Inibidores da Protease de HIV/química , Inibidores da Protease de HIV/farmacologia , Humanos , Estrutura Molecular , Paládio/química
11.
Bioorg Med Chem Lett ; 22(8): 2948-50, 2012 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-22414613

RESUMO

Synthesis and biological evaluation of a new series of potential HIV-1 protease inhibitors incorporating different heterocycles are described. The variation of heteroatom in such molecules has displayed totally different biological activities and a benzothiophene containing inhibitor has shown high potency against wild type HIV-1 protease with IC(50)=60 nM, thanks to the lower desolvation penalty to be payed by such hydrophobic moiety.


Assuntos
Antivirais/síntese química , Antivirais/farmacologia , Inibidores da Protease de HIV/síntese química , Inibidores da Protease de HIV/farmacologia , HIV-1/efeitos dos fármacos , Compostos Heterocíclicos/síntese química , Tiofenos/síntese química , Antivirais/química , Inibidores da Protease de HIV/química , Compostos Heterocíclicos/química , Compostos Heterocíclicos/farmacologia , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Tiofenos/química , Tiofenos/farmacologia
12.
Chirality ; 24(4): 345-8, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22344620

RESUMO

A simple high-yield three-steps route to optically active 4-hydroxymethyl-3-(1H-indolyl)oxazolidin-2-ones from (S)-glycidol is described. The key intermediates (R)-oxiran-2-ylmethyl 1H-indol-4/-5-ylcarbamates are obtained in high yields from (S)-glycidol. These are readily transformed to oxazolidin-2-ones, very interesting building blocks in drug synthesis.

13.
Pharmaceuticals (Basel) ; 5(3): 297-316, 2012 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-24281380

RESUMO

This minireview provides a brief outline of the peculiar aspects of the preparation of peptidomimetic and pseudopeptidic structures containing heterocycles. In particular novel tricyclic structures are investigated as potential drugs.

14.
J Med Chem ; 53(4): 1451-7, 2010 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-20108932

RESUMO

A series of new thienyl ring containing analogues of nelfinavir and saquinavir with different substitution patterns were synthesized from suitable enantiopure diols. Their inhibitory activity against wild type recombinant HIV-1 protease was evaluated. In general thienyl groups spaced from the core by a methylene group gave products showing IC(50) in the nanomolar range, irrespective of the type and the substitution pattern of the heterocycle. The range of activity of the two most active compounds is substantially maintained or even increased against two commonly selected mutants, under drug pressure, such as V32I and V82A.


Assuntos
Asparagina/análogos & derivados , Inibidores da Protease de HIV/síntese química , Protease de HIV/química , Nelfinavir/análogos & derivados , Nelfinavir/síntese química , Quinolinas/síntese química , Saquinavir/análogos & derivados , Saquinavir/síntese química , Asparagina/síntese química , Asparagina/química , Protease de HIV/genética , Inibidores da Protease de HIV/química , Mutação , Nelfinavir/química , Quinolinas/química , Proteínas Recombinantes/antagonistas & inibidores , Proteínas Recombinantes/química , Saquinavir/química , Estereoisomerismo , Relação Estrutura-Atividade
15.
J Org Chem ; 73(11): 4233-6, 2008 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-18433172

RESUMO

We report the first asymmetric synthesis of trans optically active (+) C 2 1,3-bisarylepoxide of calix[4]arene in excellent chemical yield and >99% ee, and its enantiospecific conversion to the corresponding bis-dioxolane.

16.
J Org Chem ; 71(19): 7165-79, 2006 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-16958509

RESUMO

The reaction between an iminophosphorane with furan-2-carbaldehyde, thiophene-2-carbaldehyde, furan-3-carbaldehyde, and thiophene-3-carbaldehyde at 60 degrees C gives the corresponding trans imines in 53-84% yields, while the same reaction at 100 degrees C gives a mixture of the corresponding trans and cis imines. Whether the iminophosphorane reacted with 5-nitrofuran-2-carbaldehyde or 5-nitrothiophene-2-carbaldehyde only the trans imines were obtained in 85-89% yields. The irradiation of the imines obtained from thiophene-2-carbaldehyde and thiophene-3-carbaldehyde gave the corresponding photocyclization products. Cis/trans stereochemistry of the imines can be assigned simulating the UV-vis spectra. In the case of the imine from furan-2-carbaldehyde the computed spectra are characterized by an intense absorption at 361 and 357 nm respectively for the trans-1 and trans-2 structures. No other absorptions of comparable intensity have been predicted: the agreement with the experimental spectrum can be considered good. Furthermore, the experimental weak peaks at 280 and 270 nm can be associated to the computed transitions at 278 and 260 nm for the trans-1 isomer. Several minima of the energy surface can be assigned to the cis isomer, and they all present a very similar energy. The structures of the cis-1 and cis-2 isomers present quite coincident computed electronic spectra. In both cases, the computed spectrum shows two principal features. For the cis-1 structure, the first characteristic absorption is located at 414 nm and the second one at 284 nm. For the cis-2 structure, the first feature is located at 412 nm and the second one at 286 nm. The second transition is computed somewhat more intense. The experimental spectrum could be the consequence of similar populations of the planar cis structure (cis-3) and nonplanar cis structures (cis-1, cis-2, and their enantiomers).

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