Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 69
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Exp Parasitol ; 210: 107831, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31926147

RESUMO

Babesia (B.) bovis is one of the main etiological agents of bovine babesiosis, causes serious economic losses to the cattle industry. Control of bovine babesiosis has been hindered by the limited treatment selection for B. bovis, thus, new options are urgently needed. We explored the drug library and unbiasedly screened 640 food and drug administration (FDA) approved drug compounds for their inhibitory activities against B. bovis in vitro. The initial screening identified 13 potentially effective compounds. Four potent compounds, namely mycophenolic acid (MPA), pentamidine (PTD), doxorubicin hydrochloride (DBH) and vorinostat (SAHA) exhibited the lowest IC50 and then selected for further evaluation of their in vitro efficacies using viability, combination inhibitory and cytotoxicity assays. The half-maximal inhibitory concentration (IC50) values of MPA, PTD, DBH, SAHA were 11.38 ± 1.66, 13.12 ± 4.29, 1.79 ± 0.15 and 45.18 ± 7.37 µM, respectively. Of note, DBH exhibited IC50 lower than that calculated for the commonly used antibabesial drug, diminazene aceturate (DA). The viability result revealed the ability of MPA, PTD, DBH, SAHA to prevent the regrowth of treated parasite at 4 × and 2 × of IC50. Antagonistic interactions against B. bovis were observed after treatment with either MPA, PTD, DBH or SAHA in combination with DA. Our findings indicate the richness of FDA approved compounds by novel potent antibabesial candidates and the identified potent compounds especially DBH might be used for the treatment of animal babesiosis caused by B. bovis.


Assuntos
Antiprotozoários/farmacologia , Babesia bovis/efeitos dos fármacos , Animais , Antiprotozoários/toxicidade , Babesia bovis/crescimento & desenvolvimento , Babesiose/tratamento farmacológico , Babesiose/parasitologia , Bovinos , Doenças dos Bovinos/tratamento farmacológico , Doenças dos Bovinos/parasitologia , Cães , Doxorrubicina/farmacologia , Doxorrubicina/toxicidade , Aprovação de Drogas , Combinação de Medicamentos , Avaliação Pré-Clínica de Medicamentos , Ensaios de Triagem em Larga Escala , Concentração Inibidora 50 , Células Madin Darby de Rim Canino/efeitos dos fármacos , Ácido Micofenólico/farmacologia , Ácido Micofenólico/toxicidade , Pentamidina/farmacologia , Pentamidina/toxicidade , Bibliotecas de Moléculas Pequenas , Espectrometria de Fluorescência , Vorinostat/farmacologia , Vorinostat/toxicidade
2.
Curr Top Med Chem ; 20(2): 111-120, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31854280

RESUMO

BACKGROUND: Neuraminidase inhibitors (NAIs) are the only class of antivirals in clinical use against influenza virus approved worldwide. However, approximately 1-3% of circulating strains present resistance mutations to oseltamivir (OST), the most used NAI. Therefore, it is important to catalogue new molecules to inhibit influenza virus, especially OST-resistant strains. Natural products from tropical plants used for human consumption represent a worthy class of substances. Their use could be stimulated in resource-limited setting where the access to expensive antiviral therapies is restricted. METHODS: We evaluated the anti-influenza virus activity of agathisflavone derived from Anacardium occidentale L. RESULTS: The neuraminidase (NA) activity of wild-type and OST-resistant influenza virus was inhibited by agathisflavone, with IC50 values ranging from 20 to 2.0 µM, respectively. Agathisflavone inhibited influenza virus replication with EC50 of 1.3 µM. Sequential passages of the virus in the presence of agathisflavone revealed the emergence of mutation R249S, A250S and R253Q in the NA gene. These changes are outside the OST binding region, meaning that agathisflavone targets this viral enzyme at a region different than conventional NAIs. CONCLUSION: Altogether our data suggest that agathisflavone has a promising chemical structure for the development of anti-influenza drugs.


Assuntos
Anacardium/química , Biflavonoides/farmacologia , Inibidores Enzimáticos/farmacologia , Neuraminidase/antagonistas & inibidores , Orthomyxoviridae/efeitos dos fármacos , Compostos Fitoquímicos/farmacologia , Animais , Biflavonoides/química , Biflavonoides/isolamento & purificação , Sobrevivência Celular/efeitos dos fármacos , Cães , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/química , Inibidores Enzimáticos/isolamento & purificação , Células Madin Darby de Rim Canino/efeitos dos fármacos , Células Madin Darby de Rim Canino/virologia , Testes de Sensibilidade Microbiana , Estrutura Molecular , Neuraminidase/metabolismo , Orthomyxoviridae/enzimologia , Compostos Fitoquímicos/química , Compostos Fitoquímicos/isolamento & purificação , Relação Estrutura-Atividade , Replicação Viral/efeitos dos fármacos
3.
Eur J Med Chem ; 185: 111841, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31708183

RESUMO

Influenza A neuraminidase plays an indispensable role in the process of replication and transmission of influenza, so the neuraminidase inhibition can prevent the reproduction of the viruses therefore achieve the effect of treatment of influenza. However, drug resistance of neuraminidase inhibitors such as oseltamivir highlights the need to develop novel structural neuraminidase inhibitors. Here we explored a series of oseltamivir derivatives bearing pyridyl group. Among them, compound 23b exhibiting potent inhibitory activity against neuraminidase from H5N1 subtype was comparable to oseltamivir carboxylate. Cytopathic effect inhibition assay in MDCK cells indicated that compound 23b exerted powerful inhibitions on influenza viruses. And compound 23b were nontoxic to MDCK cells. Meanwhile, compound 23b showed high stability towards rat liver microsomes, human liver microsomes and human plasma. This research enriched the structural type of neuraminidase inhibitors.


Assuntos
Antivirais/farmacologia , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Virus da Influenza A Subtipo H5N1/efeitos dos fármacos , Neuraminidase/antagonistas & inibidores , Oseltamivir/farmacologia , Animais , Antivirais/síntese química , Antivirais/química , Cães , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Virus da Influenza A Subtipo H5N1/enzimologia , Células Madin Darby de Rim Canino/efeitos dos fármacos , Células Madin Darby de Rim Canino/microbiologia , Testes de Sensibilidade Microbiana , Estrutura Molecular , Neuraminidase/metabolismo , Oseltamivir/síntese química , Oseltamivir/química , Relação Estrutura-Atividade
4.
Eur J Med Chem ; 182: 111655, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31494468

RESUMO

Stereo- and regioisomers of a series of N,N-bis(alkanol)amine aryl ester derivatives have been prepared and studied as multidrug resistance (MDR) modulators. The new compounds contain a 2-(methyl)propyl chain combined with a 3-, 5- or 7-methylenes long chain and carry different aromatic ester portions. Thus, these compounds have a methyl group on the 3-methylenes chain and represent branched homologues of previously studied derivatives. The introduction of the methyl group gives origin to a stereogenic center and consequently to (R) and (S) enantiomers. In the pirarubicin uptake assay on K562/DOX cell line these compounds showed good activity and efficacy and in many cases enantioselectivity was observed. Docking studies confirmed the influence of the stereocenter on the interaction in the P-gp pocket. The P-gp interaction mechanism and selectivity towards MRP1 and BCRP were also evaluated on MDCK transfected cells overexpressing the three transporters. Almost all these compounds inhibited both P-gp and BCRP, but only derivatives with specific structural characteristics showed MRP1 activity. Moreover, two compounds, (S)-3 and (R)-7, showed the ability to induce collateral sensitivity (CS) against MDR cells. Therefore, these two CS-promoting agents could be considered interesting leads for the development of selective cytotoxic agents for drug-resistant cells.


Assuntos
Aminas/farmacologia , Antineoplásicos/farmacologia , Desenho de Fármacos , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Ésteres/farmacologia , Aminas/síntese química , Aminas/química , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Cães , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Ésteres/síntese química , Ésteres/química , Humanos , Células K562 , Células Madin Darby de Rim Canino/efeitos dos fármacos , Simulação de Acoplamento Molecular , Estrutura Molecular , Estereoisomerismo , Relação Estrutura-Atividade
5.
Curr Top Med Chem ; 19(22): 2049-2057, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31364515

RESUMO

BACKGROUND: Scorpion venom causes renal injury and affects vascular ion-channels function. Centruroides margaritatus scorpion is found in Colombia and is frequently the cause of envenomation accidents; however, its renal impact has never been investigated. OBJECTIVE: To evaluate the effects of C. margaritatus venom (CmV) on renal parameters using isolated rat kidney and renal cell culture models. METHODS: Wistar rats (n = 5, weighing 240-300 g) were first perfused with Krebs-Henseleit solution containing 6 g 100 mL-1 bovine serum albumin. After 30 minutes, the kidneys were perfused with CmV to a final concentration of 10 µgmL-1; evaluation was performed by measuring Perfusion Pressure (PP), Renal Vascular Resistance (RVR), Urinary Flow (UF), Glomerular Filtration Rate (GFR), and percentage of electrolyte tubular transport. Moreover, kidney histological analyses and cell cytotoxicity in renal tubule epithelial cells (MDCK) and proximal tubular cells (LLC-MK2) were assessed. RESULTS: CmV increased PP and RVR 60 min after perfusion. On the other hand, UF, GFR, and the percentages of sodium, potassium and chloride tubular transport decreased after experimental envenomation. UF dropped after 120 min, while GFR and percentage of electrolyte tubular transport diminished after 60, 90 and 120 min. CmV was not toxic to MDCK cell line but reduced the viability of LLC-MK2 cells at concentrations ranging from 6.25 to 200 µgmL-1. Histological analyses disclosed hydropic degeneration, edema, and protein deposits. Flow cytometry disclosed that cell death occurred predominantly by necrosis. CONCLUSION: Our results suggest that C. margaritatus venom can trigger renal impairment, mainly in the proximal kidney tubule.


Assuntos
Rim/efeitos dos fármacos , Venenos de Escorpião/farmacologia , Animais , Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Colômbia , Cães , Relação Dose-Resposta a Droga , Rim/patologia , Células Madin Darby de Rim Canino/efeitos dos fármacos , Células Madin Darby de Rim Canino/patologia , Masculino , Ratos , Ratos Wistar , Escorpiões , Relação Estrutura-Atividade
6.
Eur J Med Chem ; 182: 111622, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31425909

RESUMO

The development of entry inhibitors is an emerging approach to the inhibition of influenza virus. In our previous research, oleanolic acid (OA) was discovered as a mild influenza hemagglutinin (HA) inhibitor. Herein, as a further study, we report the preparation of a series of OA-saccharide conjugates via the CuAAC reaction, and the anti-influenza activity of these compounds was evaluated in vitro. Among them, compound 11b, an OA-glucose conjugate, showed a significantly increased anti-influenza activity with an IC50 of 5.47 µM, and no obvious cytotoxic effect on MDCK cells was observed at 100 µM. Hemagglutination inhibition assay and docking experiment indicated that 11b might interfere with influenza virus infection by acting on HA protein. Broad-spectrum anti-influenza experiments showed 11b to be robustly potent against 5 different strains, including influenza A and B viruses, with IC50 values at the low-micromole level. Overall, this finding further extends the utility of OA-saccharide conjugates in anti-influenza virus drug design.


Assuntos
Antivirais/farmacologia , Desenho de Fármacos , Vírus da Influenza A/efeitos dos fármacos , Ácido Oleanólico/farmacologia , Oligossacarídeos/farmacologia , Animais , Antivirais/síntese química , Antivirais/química , Química Click , Cães , Relação Dose-Resposta a Droga , Células Madin Darby de Rim Canino/efeitos dos fármacos , Células Madin Darby de Rim Canino/virologia , Testes de Sensibilidade Microbiana , Estrutura Molecular , Ácido Oleanólico/síntese química , Ácido Oleanólico/química , Oligossacarídeos/síntese química , Oligossacarídeos/química , Relação Estrutura-Atividade
7.
Chem Pharm Bull (Tokyo) ; 67(11): 1201-1207, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31434835

RESUMO

Oleanolic acid (OA) was discovered as a mild influenza hemagglutinin (HA) inhibitor in our earlier studies. In the present work, 20 compounds were prepared by structural modifications of OA, and their antiviral activities against influenza A/WSN/33 (H1N1) virus in Madin-Darby canine kidney (MDCK) cells were evaluated. Based on the biological result, structure-activity relationship (SAR) was discussed. Compound 10 with six-carbon chain and a terminal hydroxyl group showed the strongest anti-influenza activity with an IC50 of 2.98 µM, which is an order of magnitude more potent than OA. Hemagglutination inhibition and Surface plasmon resonance (SPR) assay indicated that compound 10 might interfere with influenza invasion by interacting with HA protein.


Assuntos
Antivirais/farmacologia , Vírus da Influenza A/efeitos dos fármacos , Ácido Oleanólico/farmacologia , Animais , Antivirais/síntese química , Antivirais/química , Cães , Relação Dose-Resposta a Droga , Hemaglutininas/efeitos dos fármacos , Hemaglutininas/metabolismo , Vírus da Influenza A/metabolismo , Células Madin Darby de Rim Canino/efeitos dos fármacos , Células Madin Darby de Rim Canino/virologia , Estrutura Molecular , Ácido Oleanólico/síntese química , Ácido Oleanólico/química , Relação Estrutura-Atividade , Ressonância de Plasmônio de Superfície
8.
Eur J Med Chem ; 178: 623-635, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31226654

RESUMO

Glycyrrhetinic acid (GA) had been the star anticancer lead compound and appealed to many scientists all over the world; however, its antitumor activity was not potent enough. To improve GA's cytoxicity and explore the effect of bonding mode on antitumor activity, 32 compounds including GA-OH series (GO, esters in C-3 position) and GA-NH2 series (GN, with amide linkages in C-3 position) had been designed and synthesized. All the compounds were screened for in vitro cytotoxicity against A549, HepG2, MCF-7, Hela and MDCK cell lines. As a result, all the de-protected (without Boc group) derivatives showed much stronger cytotoxic activity than GA, and surprisingly enough, all the GN series of the compounds were more potent than GO series against various tumor cells. Among them, the compound 26 (amide linkages in C-3 position) exhibited stronger antitumor activity against A549 cell line (IC50 = 2.109 ±â€¯0.11 µM) than the positive drug cisplatin (IC50 = 9.001 ±â€¯0.37 µM). Further studies indicated that compound 26 could induce A549 apoptosis via nuclei fragmentation. The detection of apoptosis and cell cycle analysis indicated that compound 26 could induce the early apoptosis and prevent A549 cells transition from S to G2 phase. Furthermore, the structure-activity relationships were briefly discussed. Among which, current study displayed amide linkages in C-3 position could effectively enhance GA cytotoxicity, providing a new modification strategy for further study.


Assuntos
Antineoplásicos/farmacologia , Ácido Glicirretínico/farmacologia , Células Madin Darby de Rim Canino/efeitos dos fármacos , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Cães , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Ácido Glicirretínico/síntese química , Ácido Glicirretínico/química , Humanos , Estrutura Molecular , Relação Estrutura-Atividade
9.
Georgian Med News ; (288): 158-162, 2019 Mar.
Artigo em Russo | MEDLINE | ID: mdl-31101797

RESUMO

The goal of our study was to establish the anti- proapoptotic activity of the common in Georgia crops on the Jurkat and MDCK cells. Extracts of various varieties of beans (Tirkmela, Batumi meadow, Shulavera, Udelebi, as well as green peas, Lens Culinaris lentils, soy beans) were added to the intact or incubated under oxidative stress conditions Jurkat and MDCK cells. Cell viability (apoptosis intensity) was determined by a cell proliferative activity test (MTT test). Correlation and statistical analysis of ANOVA was performed using the package (SPSS version 11.0). In the presented study the selective effectiveness of extracts with different antioxidant activity on intact and incubated under oxidative stress Jurkat and MDCK cells was revealed, related with different sensitivity of cells to the oxidative stress. In normal MDCK epithelial cells, resistant to redox-active factors (H2O2), inverse relationship between the intensity of apoptosis and the antiradical potential of the extract was found; in leukemia transformated Jurkat cells, characterized by high sensitivity to oxidants (H2O2), a violation of the redox-dependent anti-apoptotic cell protection mechanisms was revealed, which is manifested by the absence of regularity of the cytoprotective / cytotoxic effects of the extracts on intact and incubated cells under oxidative stress conditions. These results can be used in the development of schemes of anti-tumor and anti-inflammatory therapy.


Assuntos
Fabaceae , Extratos Vegetais , Animais , Apoptose , Cães , Fabaceae/química , Humanos , Peróxido de Hidrogênio , Células Jurkat , Células Madin Darby de Rim Canino/efeitos dos fármacos , Estresse Oxidativo , Extratos Vegetais/farmacologia
10.
Colloids Surf B Biointerfaces ; 181: 39-47, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31121380

RESUMO

Understanding the difference in physicochemical properties and biological response between colloidal and powder formulations of identical materials is important before the given materials are used in a medical milieu. In this study we compared a set of biological effects of colloidal and powder formulations of composite nanoparticles comprising superparamagnetic iron oxide cores and silicate/carbon shells. Magnetic dipole interaction between adjacent nanoparticles was more pronounced in their powders than in their colloidal formulations. Nanoparticles delivered as powders were thus more responsive to the magnetic field, but exhibited reduced uptake in bone and brain cancer cells, including K7M2 osteosarcoma line and U87 and E297 glioblastoma lines. Specifically, while the alternate magnetic field elicited a more rapid heat generation in cell culture media supplemented with the magnetic powders, the nanoparticles dispersed in the same media were uptaken by the cancer cells more copiously. The cellular uptake proved to be more crucial in defining the effect on cell survival, given that suspended formulations elicited a greater degree of cancer cell death in the magnetic field compared to the powder-containing formulations. Because of this effect, colloidal formulations were able to target cancer cells more effectively than the powders: they reduced the viability of all three tested cancer cell lines to a significantly greater degree that the viability of the normal, MDCK-MDR1 cell line. It is concluded that better uptake profile can make up for the lower heating rate in the AC field and lead to a more effective magnetic hyperthermia therapy. These results also demonstrate that the direct delivery of ferrofluids is more optimal than the administration of their constitutive particles as powders.


Assuntos
Coloides/farmacologia , Nanopartículas/química , Pós/farmacologia , Animais , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Coloides/síntese química , Coloides/química , Cães , Composição de Medicamentos , Citometria de Fluxo , Células Madin Darby de Rim Canino/efeitos dos fármacos , Tamanho da Partícula , Pós/síntese química , Pós/química , Propriedades de Superfície
11.
Eur J Med Chem ; 161: 526-532, 2019 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-30390440

RESUMO

A novel chemotype topologically similar to known influenza virus PA endonuclease inhibitors has been designed. It was aimed to reproduce the extended topology of the known metal-chelating ligands with a p-phenylidene-linked bis-imidazoline scaffold. It was envisioned that aromatic groups introduced to this scaffolds via metal-catalyzed N-arylation (Buchwald-Hartwig or Chan-Evans-Lam) would contribute to lipophilic binding to the target and one of the imidazoline nitrogen atoms would ensure non-chelating coordination to the prosthetic divalent metal ion. The compounds displayed appreciable anti-influenza activity in vitro and substantial concentration window from the general cytotoxicity range. Docking analysis of low-energy poses of the most active compound (as well as their comparison to the binding of an inactive compound) revealed that these compounds reproduced similar binding components to a known PA endonuclease inhibitor and displayed similar binding pose and desired monodentate metal coordination, as was initially envisioned. These findings warrant further investigation of the mechanism of action of the newly discovered series.


Assuntos
Antivirais/farmacologia , Derivados de Benzeno/farmacologia , Endonucleases/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Imidazolinas/farmacologia , Orthomyxoviridae/efeitos dos fármacos , Animais , Antivirais/síntese química , Antivirais/química , Derivados de Benzeno/química , Cães , Relação Dose-Resposta a Droga , Endonucleases/metabolismo , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Imidazolinas/síntese química , Imidazolinas/química , Células Madin Darby de Rim Canino/efeitos dos fármacos , Células Madin Darby de Rim Canino/microbiologia , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Estrutura Molecular , Orthomyxoviridae/enzimologia , Relação Estrutura-Atividade
12.
Eur J Med Chem ; 161: 433-444, 2019 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-30384046

RESUMO

A series of coniugates bearing a 1,2,3,4-tetrahydroisoquinoline motif linked to substituted 7-hydroxy-2H-chromen-2-ones was synthesized and assayed through calcein-AM test in Madin-Darby Canine Kidney (MDCK) cells overexpressing P-glycoprotein (P-gp) and closely related multidrug resistance associated protein 1 (MRP1) to probe the interference with efflux mechanisms mediated by P-gp and MRP1, respectively. A number of substituents at C3 and C4 of coumarin nucleus along with differently sized and shaped spacers was enrolled to investigate the effects of focused structural modifications over affinity and selectivity. Linker length and flexibility played a key role in enhancing P-gp affinity as proved by the most potent P-gp modulator (3h, IC50 = 70 nM). A phenyl ring within the spacer (3k, 3l, 3o) and bulkier groups (Br in 3r, Ph in 3u) at coumarin C3 led to derivatives showing nanomolar activity (160 nM < IC50 < 280 nM) along with outstanding selectivity over MRP1 (SI > 350). Molecular docking calculations carried out on a human MDR1 homology model structure contributed to gain insights into the ligands' binding modes. Some compounds (3d, 3h, 3l, 3r, 3t, 3u) reversed MDR thereby restoring doxorubicin cytotoxicity when co-administered with the drug into MDCK-MDR1 cells.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Cumarínicos/farmacologia , Células Madin Darby de Rim Canino/efeitos dos fármacos , Tetra-Hidroisoquinolinas/farmacologia , Subfamília B de Transportador de Cassetes de Ligação de ATP/antagonistas & inibidores , Animais , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Cumarínicos/síntese química , Cumarínicos/química , Cães , Relação Dose-Resposta a Droga , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade , Tetra-Hidroisoquinolinas/síntese química , Tetra-Hidroisoquinolinas/química
13.
ChemMedChem ; 14(3): 322-333, 2019 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-30562414

RESUMO

Our laboratories have been investigating synthetic analogues of marine alkaloid rigidins that possess promising anticancer activities. These analogues, based on the 7-deazahypoxanthine skeleton, are available in one- or two-step synthetic sequences and exert cytotoxicity by disrupting microtubule dynamics in cancer cells. In the present work we extended the available structure-activity relationship (SAR) data to N3- and N9-substituted derivatives. Although N3 substitution results in loss of activity, the N9-substituted compounds retain nanomolar antiproliferative activities and the anti-tubulin mode of action of the original unsubstituted compounds. Furthermore, our results also demonstrate that multidrug-resistance (MDR) proteins do not confer resistance to both N9-unsubstituted and -substituted compounds. It was found that sublines overexpressing ABCG2, ABCC1, and ABCB1 proteins are as responsive to the rigidin analogues as their parental cell lines. Thus, the study reported herein provides further impetus to investigate the rigidin-inspired 7-deazahypoxanthines as promising anticancer agents.


Assuntos
Subfamília B de Transportador de Cassetes de Ligação de ATP/antagonistas & inibidores , Alcaloides/farmacologia , Antineoplásicos/farmacologia , Hipoxantina/farmacologia , Microtúbulos/efeitos dos fármacos , Pirimidinas/farmacologia , Pirróis/farmacologia , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Alcaloides/química , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Cães , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células HeLa , Humanos , Hipoxantina/síntese química , Hipoxantina/química , Células MCF-7 , Células Madin Darby de Rim Canino/efeitos dos fármacos , Microtúbulos/metabolismo , Estrutura Molecular , Pirimidinas/química , Pirróis/química , Relação Estrutura-Atividade , Células Tumorais Cultivadas
14.
Eur J Med Chem ; 159: 206-216, 2018 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-30292897

RESUMO

H5N1 virus, one subtype of highly pathogenic influenza A virus in human infection, has recently received attention due to its unpredictable and high mortality. In this study, a series of arylsulfonamide derivatives were identified as improved H5N1 inhibitors for the influenza treatment by systematic structure-activity relationship investigation. Among them, the most potent H5N1 inhibitor 3h exhibited excellent antiviral activity against H5N1 virus with EC50 value of 0.006 µM and selectivity index 33543.3. Moreover, the molecular docking of 3h with M2 proton channel protein provides practical way for understanding the inhibition of H5N1 with this kind of compounds.


Assuntos
Antifúngicos/farmacologia , Antivirais/farmacologia , Virus da Influenza A Subtipo H5N1/efeitos dos fármacos , Sulfonamidas/farmacologia , Animais , Antifúngicos/síntese química , Antifúngicos/química , Antivirais/síntese química , Antivirais/química , Proliferação de Células/efeitos dos fármacos , Cães , Relação Dose-Resposta a Droga , Humanos , Virus da Influenza A Subtipo H5N1/metabolismo , Células Madin Darby de Rim Canino/efeitos dos fármacos , Células Madin Darby de Rim Canino/virologia , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Estrutura Molecular , Saccharomyces cerevisiae/citologia , Saccharomyces cerevisiae/efeitos dos fármacos , Saccharomyces cerevisiae/crescimento & desenvolvimento , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química
15.
Bull Tokyo Dent Coll ; 59(4): 265-275, 2018 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-30333370

RESUMO

Treponema denticola, an anaerobic spirochete found mainly in the oral cavity, is associated with periodontal disease and has a variety of virulence factors. Although in vitro studies have shown that T. denticola is able to penetrate epithelial cell monolayers, its effect on the epithelial barrier junction is not known. Human gingival epithelial cells are closely associated with adjacent membranes, forming barriers in the presence of tight junction proteins, including zonula occludens-1 (ZO-1), claudin-1, and occludin. Tight junction proteins are also expressed by Madin-Darby canine kidney (MDCK) cells in culture. In this study, the MDCK cell profile was investigated following infection with T. denticola (ATCC 35405) wild-type, as well as with its dentilisin-deficient mutant, K1. Basolateral exposure of MDCK cell monolayers to T. denticola at a multiplicity of infection (MOI) of 104 resulted in a decrease in transepithelial electrical resistance (TER). Transepithelial electrical resistance in MDCK cell monolayers also decreased following apical exposure to T. denticola (MOI=104), although this took longer with basolateral exposure. The effect on the TER was time-dependent and required the presence of live bacteria. Meanwhile, MDCK cell viability showed a decrease with either basolateral or apical exposure. Immunofluorescence analysis demonstrated decreases in the amounts of immunoreactive ZO-1 and claudin-1 in association with disruption of cell-cell junctions in MDCK cells exposed apically or basolaterally to T. denticola. Western blot analysis demonstrated degradation of ZO-1 and claudin-1 in culture lysates derived from T. denticola-exposed MDCK cells, suggesting a bacteria-induced protease capable of cleaving these tight junction proteins.


Assuntos
Proteínas de Bactérias/toxicidade , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Células Madin Darby de Rim Canino/efeitos dos fármacos , Ocludina/metabolismo , Peptídeo Hidrolases/toxicidade , Proteínas de Junções Íntimas/metabolismo , Treponema denticola/metabolismo , Proteína da Zônula de Oclusão-1/metabolismo , Animais , Proteínas de Bactérias/genética , Toxinas Bacterianas , Sobrevivência Celular/efeitos dos fármacos , Cães , Impedância Elétrica , Células Epiteliais/microbiologia , Células Epiteliais/patologia , Humanos , Junções Intercelulares/efeitos dos fármacos , Células Madin Darby de Rim Canino/metabolismo , Células Madin Darby de Rim Canino/microbiologia , Peptídeo Hidrolases/genética , Peptídeo Hidrolases/metabolismo , Treponema denticola/genética , Treponema denticola/patogenicidade , Fatores de Virulência
16.
Eur J Med Chem ; 157: 743-758, 2018 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-30142611

RESUMO

The limited treatment options against influenza virus along with the growing public health concerns regarding the continuous emergence of drug-resistant viruses make essential the development of new anti-flu agents with novel mechanisms of action. One of the most attractive targets is the interaction between two subunits of the RNA-dependent RNA polymerase, PA and PB1. Herein we report the rational design of hybrid compounds starting from a 3-cyano-4,6-diphenylpyridine scaffold recently identified as disruptor of PA-PB1 interactions. Guided by the previously reported SAR data, a library of amino acid derivatives was synthesized. The biological evaluation led to the identification of new PA-PB1 inhibitors, that do not show appreciable toxicity. Molecular modeling shed further lights on the inhibition mechanism of these compounds.


Assuntos
Aminoácidos/farmacologia , Antivirais/farmacologia , Orthomyxoviridae/efeitos dos fármacos , Piridinas/farmacologia , RNA Replicase/antagonistas & inibidores , Bibliotecas de Moléculas Pequenas/farmacologia , Aminoácidos/síntese química , Aminoácidos/química , Animais , Antivirais/síntese química , Antivirais/química , Sobrevivência Celular/efeitos dos fármacos , Cães , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Células Madin Darby de Rim Canino/efeitos dos fármacos , Modelos Moleculares , Estrutura Molecular , Orthomyxoviridae/enzimologia , Piridinas/síntese química , Piridinas/química , RNA Replicase/metabolismo , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química , Relação Estrutura-Atividade
17.
Braz J Med Biol Res ; 51(10): e7417, 2018 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-30156610

RESUMO

It is well known that the aminoglycoside antibiotic gentamicin is capable of causing damage to kidney cells. Given the known involvement of Ca2+ in the nephrotoxic action of gentamicin, the purpose of this study was to establish a relationship between the concentration of intracellular Ca2+ ([Ca2+]i) and cellular cytotoxicity using MDCK-C11 cells, a clone that has several properties that resemble those of intercalated cells of the distal nephron. Changes in [Ca2+]i was determined using fluorescence microscopy. Cell viability was evaluated by the neutral red method, and cell cytotoxicity by the MTT method. The [Ca2+]i gradually increased when cells were exposed to 0.1 mM gentamicin for 10, 20, and 30 min. The presence of extracellular Ca2+ was found to be necessary to stimulate the increase in [Ca2+]i induced by gentamicin, since this stimulus disappeared by using 1.8 mM EGTA (a Ca2+ chelator). Morphological changes were observed with scanning electron microscopy in epithelial cells exposed to the antibiotic. Furthermore, with the MTT method, a decrease in metabolic activity induced by gentamicin was observed, which indicates a cytotoxic effect. In conclusion, gentamicin was able to alter [Ca2+]i, change the morphology of MDCK-C11 cells, and promote cytotoxicity.


Assuntos
Antibacterianos/toxicidade , Cálcio/metabolismo , Gentamicinas/toxicidade , Células Madin Darby de Rim Canino/efeitos dos fármacos , Testes de Toxicidade/métodos , Animais , Membrana Celular/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Células Clonais , Cães , Células Madin Darby de Rim Canino/metabolismo , Células Madin Darby de Rim Canino/ultraestrutura , Microscopia Eletrônica de Varredura , Modelos Animais , Néfrons/citologia , Néfrons/efeitos dos fármacos
18.
Bioorg Med Chem Lett ; 28(14): 2408-2412, 2018 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-29934246

RESUMO

We describe a medicinal chemistry approach to the discovery of a novel EP1 antagonist exhibiting high potency and good pharmacokinetics. Our starting point is 1, an EP1 receptor antagonist that exhibits pharmacological efficacy in cystometry models following intravenous administration. Despite its good potency in vitro, the high lipophilicity of 1 is a concern in long-term in vivo studies. Further medicinal chemistry efforts identified 4 as an improved lead compound with good in vitro ADME profile applicable to long term in vivo studies. A rat fracture study was conducted with 4 for 4 weeks to validate its utility in bone fracture healing. The results suggest that this EP1 receptor antagonist stimulates callus formation and thus 4 has potential for enhancing fracture healing.


Assuntos
Descoberta de Drogas , Consolidação da Fratura/efeitos dos fármacos , Fraturas Ósseas/tratamento farmacológico , Receptores de Prostaglandina E Subtipo EP1/antagonistas & inibidores , Tiazóis/farmacologia , Animais , Modelos Animais de Doenças , Cães , Relação Dose-Resposta a Droga , Fraturas Ósseas/metabolismo , Células Madin Darby de Rim Canino/efeitos dos fármacos , Células Madin Darby de Rim Canino/metabolismo , Células Madin Darby de Rim Canino/patologia , Camundongos , Camundongos Knockout , Estrutura Molecular , Receptores de Prostaglandina E Subtipo EP1/deficiência , Receptores de Prostaglandina E Subtipo EP1/metabolismo , Relação Estrutura-Atividade , Tiazóis/química
19.
Bioorg Med Chem Lett ; 28(12): 2195-2200, 2018 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-29764741

RESUMO

New amino-1,4-oxazine derived BACE-1 inhibitors were explored and various synthetic routes developed. The binding mode of the inhibitors was elucidated by co-crystallization of 4 with BACE-1 and X-ray analysis. Subsequent optimization led to inhibitors with low double digit nanomolar activity in a biochemical and single digit nanomolar potency in a cellular assays. To assess the inhibitors for their permeation properties and potential to cross the blood-brain-barrier a MDR1-MDCK cell model was successfully applied. Compound 8a confirmed the in vitro results by dose-dependently reducing Aß levels in mice in an acute treatment regimen.


Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Descoberta de Drogas , Inibidores Enzimáticos/farmacologia , Oxazinas/farmacologia , Secretases da Proteína Precursora do Amiloide/metabolismo , Animais , Ácido Aspártico Endopeptidases/metabolismo , Cães , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Células Madin Darby de Rim Canino/efeitos dos fármacos , Camundongos , Modelos Moleculares , Conformação Molecular , Oxazinas/síntese química , Oxazinas/química , Relação Estrutura-Atividade
20.
BMC Vet Res ; 14(1): 74, 2018 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-29514628

RESUMO

BACKGROUND: Crepis lacera is a plant from the Asteraceae family that is common in the Mediterranean region. Farmers believe that this plant may be deadly to small ruminants in areas of southern Italy. However, scientific evidence is lacking, and no proof exists that C. lacera is toxic to ruminants. Necropsies conducted on four sheep revealed lesions in their livers and kidneys. RESULTS: In the current study, we described sheep poisoning and isolated secondary metabolites from Crepis lacera to assess the metabolites' biological activity both in vitro and in vivo. Phytochemical study of the aerial portions of Crepis lacera led to the isolation of five sesquiterpene lactones and two phenolic compounds. Cellular viability was evaluated in cell cultures of the bovine kidney cell line Madin Darby Bovine Kidney (MDBK) after incubation with phytochemicals. Our results showed that three sesquiterpene lactones, 8-epidesacylcynaropicrin-3-O-ß-glucopyranoside (2), 8-epigrosheimin (3), and 8-ß-hydroxydehydrozaluzanin C (4), were cytotoxic after 48 h of incubation. In addition, in the in vivo study, animals that received 1 mg/kg body weight (bw) of Crepis lacera extract and were then sacrificed after 48 h showed significant lesions in their liver, lungs and kidneys. These lesions were also found in rats that received 2 mg/kg bw of the same extract and sacrificed after 24 and 48 h. CONCLUSIONS: These results validate the hypothesis that C. lacera is potentially dangerous when ingested in large quantities by grazing small domestic ruminants. Further studies are necessary to clarify the molecular mechanisms of Crepis spp. toxicity in animals.


Assuntos
Crepis/toxicidade , Intoxicação por Plantas/veterinária , Doenças dos Ovinos/etiologia , Ração Animal/toxicidade , Animais , Cães , Rim/efeitos dos fármacos , Rim/patologia , Fígado/efeitos dos fármacos , Fígado/patologia , Células Madin Darby de Rim Canino/efeitos dos fármacos , Masculino , Extratos Vegetais/toxicidade , Intoxicação por Plantas/etiologia , Ratos , Ratos Sprague-Dawley , Ovinos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA