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1.
Molecules ; 26(5)2021 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-33668340

RESUMO

Sigma-1 (σ-1) receptor agonists are considered as potential treatment for stroke. TS-157 is an alkoxyisoxazole-based σ-1 receptor agonist previously discovered in our group. The present study describes TS-157 profile in a battery of tests for cerebral ischemia. Initial evaluation demonstrated the compound's safety profile and blood-brain barrier permeability, as well as its ability to induce neurite outgrowth in vitro. The neurite outgrowth was shown to be mediated via σ-1 receptor agonism and involves upregulation of ERK phosphorylation (pERK). In particular, TS-157 also significantly accelerated the recovery of motor function in rats with transient middle cerebral artery occlusion (tMCAO). Overall, the results herein support the notion that σ-1 receptor agonists are potential therapeutics for stroke and further animal efficacy studies are warranted.


Assuntos
MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Infarto da Artéria Cerebral Média/tratamento farmacológico , Atividade Motora/efeitos dos fármacos , Crescimento Neuronal/efeitos dos fármacos , Oxazóis/farmacologia , Receptores sigma/agonistas , Recuperação de Função Fisiológica/efeitos dos fármacos , Animais , Infarto da Artéria Cerebral Média/metabolismo , Masculino , Estrutura Molecular , Oxazóis/síntese química , Oxazóis/química , Fosforilação/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley
2.
Int J Mol Sci ; 22(2)2021 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-33467196

RESUMO

In ß-thalassemia, ineffective erythropoiesis leads to anemia and systemic iron overload. The management of iron overload by chelation therapy is a standard of care. However, iron chelation does not improve the ineffective erythropoiesis. We recently showed that the oral ferroportin inhibitor VIT-2763 ameliorates anemia and erythropoiesis in the Hbbth3/+ mouse model of ß-thalassemia. In this study, we investigated whether concurrent use of the iron chelator deferasirox (DFX) and the ferroportin inhibitor VIT-2763 causes any pharmacodynamic interactions in the Hbbth3/+ mouse model of ß-thalassemia. Mice were treated with VIT-2763 or DFX alone or with the combination of both drugs once daily for three weeks. VIT-2763 alone or in combination with DFX improved anemia and erythropoiesis. VIT-2763 alone decreased serum iron and transferrin saturation (TSAT) but was not able to reduce the liver iron concentration. While DFX alone had no effect on TSAT and erythropoiesis, it significantly reduced the liver iron concentration alone and in the presence of VIT-2763. Our results clearly show that VIT-2763 does not interfere with the iron chelation efficacy of DFX. Furthermore, VIT-2763 retains its beneficial effects on improving ineffective erythropoiesis when combined with DFX in the Hbbth3/+ mouse model. In conclusion, co-administration of the oral ferroportin inhibitor VIT-2763 and the iron chelator DFX is feasible and might offer an opportunity to improve both ineffective erythropoiesis and iron overload in ß-thalassemia.


Assuntos
Benzimidazóis/farmacologia , Eritropoese/efeitos dos fármacos , Oxazóis/farmacologia , Piridinas/farmacologia , Talassemia beta/tratamento farmacológico , Administração Oral , Animais , Benzimidazóis/administração & dosagem , Benzimidazóis/efeitos adversos , Benzimidazóis/uso terapêutico , Proteínas de Transporte de Cátions/antagonistas & inibidores , Células Cultivadas , Deferasirox/administração & dosagem , Deferasirox/farmacologia , Deferasirox/uso terapêutico , Combinação de Medicamentos , Interações Medicamentosas , Feminino , Ferro/sangue , Quelantes de Ferro/administração & dosagem , Quelantes de Ferro/farmacologia , Quelantes de Ferro/uso terapêutico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Oxazóis/administração & dosagem , Oxazóis/efeitos adversos , Oxazóis/uso terapêutico , Piridinas/administração & dosagem , Piridinas/efeitos adversos , Piridinas/uso terapêutico , Transferrina/metabolismo
3.
Int J Mol Sci ; 22(2)2021 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-33440859

RESUMO

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy whose chemoresistance and relapse persist as a problem despite significant advances in its chemotherapeutic treatments. Mitochondrial metabolism has emerged as an interesting therapeutic target given its essential role in maintaining bioenergetic and metabolic homeostasis. T-ALL cells are characterized by high levels of mitochondrial respiration, making them suitable for this type of intervention. Mitochondrial function is sustained by a constitutive transfer of calcium from the endoplasmic reticulum to mitochondria through the inositol 1,4,5-trisphosphate receptor (InsP3R), making T-ALL cells vulnerable to its inhibition. Here, we determine the bioenergetic profile of the T-ALL cell lines CCRF-CEM and Jurkat and evaluate their sensitivity to InsP3R inhibition with the specific inhibitor, Xestospongin B (XeB). Our results show that T-ALL cell lines exhibit higher mitochondrial respiration than non-malignant cells, which is blunted by the inhibition of the InsP3R. Prolonged treatment with XeB causes T-ALL cell death without affecting the normal counterpart. Moreover, the combination of XeB and glucocorticoids significantly enhanced cell death in the CCRF-CEM cells. The inhibition of InsP3R with XeB rises as a potential therapeutic alternative for the treatment of T-ALL.


Assuntos
Respiração Celular/efeitos dos fármacos , Receptores de Inositol 1,4,5-Trifosfato/antagonistas & inibidores , Compostos Macrocíclicos/farmacologia , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Oxazóis/farmacologia , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Biomarcadores , Morte Celular , Linhagem Celular Tumoral , Humanos , Leucócitos Mononucleares/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/etiologia
4.
J Mater Chem B ; 9(3): 857-863, 2021 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-33367439

RESUMO

A near-infrared fluorescent probe (AH+) has been prepared by incorporating an oxazolidine switch into a near-infrared hemicyanine dye. The probe shows fast and sensitive responses to pH from an oxazolidine switch to the hemicyanine dye upon pH decreases from 10.0 to 5.0. The probe shows good photostability, low cytotoxicity, and reversible fluorescence responses to pH changes with a pKa value of 7.6. It has been successfully used to determine pH changes in mitochondria.


Assuntos
Carbocianinas/química , Corantes Fluorescentes/química , Oxazóis/química , Carbocianinas/síntese química , Carbocianinas/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Teoria da Densidade Funcional , Relação Dose-Resposta a Droga , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/farmacologia , Células HeLa , Humanos , Concentração de Íons de Hidrogênio , Mitocôndrias/efeitos dos fármacos , Estrutura Molecular , Oxazóis/farmacologia , Tamanho da Partícula , Espectrometria de Fluorescência , Propriedades de Superfície
5.
J Med Chem ; 64(1): 677-694, 2021 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-33370104

RESUMO

A search for structurally diversified Tyk2 JH2 ligands from 6 (BMS-986165), a pyridazine carboxamide-derived Tyk2 JH2 ligand as a clinical Tyk2 inhibitor currently in late development for the treatment of psoriasis, began with a survey of six-membered heteroaryl groups in place of the N-methyl triazolyl moiety in 6. The X-ray co-crystal structure of an early lead (12) revealed a potential new binding pocket. Exploration of the new pocket resulted in two frontrunners for a clinical candidate. The potential hydrogen bonding interaction with Thr599 in the pocket was achieved with a tertiary amide moiety, confirmed by the X-ray co-crystal structure of 29. When the diversity search was extended to nicotinamides, a single fluorine atom addition was found to significantly enhance the permeability, which directly led to the discovery of 7 (BMS-986202) as a clinical Tyk2 inhibitor that binds to Tyk2 JH2. The preclinical studies of 7, including efficacy studies in mouse models of IL-23-driven acanthosis, anti-CD40-induced colitis, and spontaneous lupus, will also be presented.


Assuntos
Ciclopropanos/farmacologia , Descoberta de Drogas , Oxazóis/farmacologia , Inibidores de Proteínas Quinases/farmacologia , TYK2 Quinase/antagonistas & inibidores , Animais , Catálise , Cristalografia por Raios X , Ciclopropanos/química , Humanos , Camundongos , Oxazóis/química , Ligação Proteica , Inibidores de Proteínas Quinases/química , Psoríase/tratamento farmacológico , Relação Estrutura-Atividade , TYK2 Quinase/metabolismo
6.
Int J Mol Sci ; 21(24)2020 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-33339154

RESUMO

Neuroinflammation is a key process of many neurodegenerative diseases and other brain disturbances, and astrocytes play an essential role in neuroinflammation. Therefore, the regulation of astrocyte responses for inflammatory stimuli, using small molecules, is a potential therapeutic strategy. We investigated the potency of peroxisome proliferator-activated receptor (PPAR) ligands to modulate the stimulating effect of lipopolysaccharide (LPS) in the primary rat astrocytes on (1) polyunsaturated fatty acid (PUFAs) derivative (oxylipins) synthesis; (2) cytokines TNFα and interleukin-10 (IL-10) release; (3) p38, JNK, ERK mitogen-activated protein kinase (MAPKs) phosphorylation. Astrocytes were exposed to LPS alone or in combination with the PPAR ligands: PPARα (fenofibrate, GW6471); PPARß (GW501516, GSK0660); PPARγ (rosiglitazone, GW9662). We detected 28 oxylipins with mass spectrometry (UPLC-MS/MS), classified according to their metabolic pathways: cyclooxygenase (COX), cytochrome P450 monooxygenases (CYP), lipoxygenase (LOX) and PUFAs: arachidonic (AA), docosahexaenoic (DHA), eicosapentaenoic (EPA). All tested PPAR ligands decrease COX-derived oxylipins; both PPARß ligands possessed the strongest effect. The PPARß agonist, GW501516 is a strong inducer of pro-resolution substances, derivatives of DHA: 4-HDoHE, 11-HDoHE, 17-HDoHE. All tested PPAR ligands decreased the release of the proinflammatory cytokine, TNFα. The PPARß agonist GW501516 and the PPARγ agonist, rosiglitazone induced the IL-10 release of the anti-inflammatory cytokine, IL-10; the cytokine index, (IL-10/TNFα) was more for GW501516. The PPARß ligands, GW501516 and GSK0660, are also the strongest inhibitors of LPS-induced phosphorylation of p38, JNK, ERK MAPKs. Overall, our data revealed that the PPARß ligands are a potential pro-resolution and anti-inflammatory drug for targeting glia-mediated neuroinflammation.


Assuntos
Anti-Inflamatórios/farmacologia , Astrócitos/metabolismo , Interleucina-10/metabolismo , Oxilipinas/metabolismo , PPAR gama/agonistas , PPAR beta/agonistas , Fator de Necrose Tumoral alfa/metabolismo , Anilidas/farmacologia , Animais , Astrócitos/efeitos dos fármacos , Células Cultivadas , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Fenofibrato/farmacologia , Lipopolissacarídeos/toxicidade , MAP Quinase Quinase 4/metabolismo , Oxazóis/farmacologia , PPAR gama/antagonistas & inibidores , PPAR beta/antagonistas & inibidores , Ratos , Ratos Wistar , Rosiglitazona/farmacologia , Tiazóis/farmacologia , Tirosina/análogos & derivados , Tirosina/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
7.
Respir Med ; 167: 105956, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32421540

RESUMO

PURPOSE: The Korea Centers for Disease Control & Prevention has implemented a review process for the approval of new drugs used to treat patients with multidrug-resistant tuberculosis (MDR-TB) since September 2016. Therefore, this study aimed to evaluate the efficacy and safety of these new drugs bedaquiline (Bdq) and delamanid (Dlm). METHODS: A total of 318 patients with MDR-TB were reviewed by the committee from September 2016 to February 2018; 282 (88.7%) of them were treated with the new drugs (Bdq, 107 patients; Dlm, 108 patients; and both concurrently or sequentially, 67 patients) and retrospectively evaluated. Culture conversion rates, interim treatment outcomes at 12 months, and predictors of unfavorable outcomes were analyzed. Treatment efficacy was also compared between Bdq and Dlm. RESULTS: The mean age of the patients was 49.3 years, and 197 (69.9%) were male. Three patients were HIV seropositive and 151 (53.5%) were quinolone resistant. The culture conversion rates at 2 and 6 months were 57.4% (81/141) and 89.4% (126/141), respectively. A favorable outcome at 12 months was achieved in 84.8% of patients (239/282). Differences in the culture conversion rate or interim treatment outcomes were not statistically significant among the drug susceptibility test patterns or new drugs used. Multivariable analysis showed that age >60 years and body mass index of <18.5 kg/m2 were significant risk factors for unfavorable outcomes at 12 months. CONCLUSIONS: The use of new drugs resulted in satisfactory interim treatment results, without significant differences between them.


Assuntos
Diarilquinolinas/uso terapêutico , Nitroimidazóis/uso terapêutico , Oxazóis/uso terapêutico , Tuberculose Pulmonar/tratamento farmacológico , Fatores Etários , Idoso , Índice de Massa Corporal , Diarilquinolinas/farmacologia , Farmacorresistência Bacteriana , Resistência a Múltiplos Medicamentos , Quimioterapia Combinada , Humanos , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Nitroimidazóis/farmacologia , Oxazóis/farmacologia , República da Coreia , Estudos Retrospectivos , Fatores de Risco , Segurança , Fatores de Tempo , Resultado do Tratamento , Tuberculose Pulmonar/microbiologia
8.
Eur J Cancer ; 134: 29-40, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32460179

RESUMO

PURPOSE: We conducted preclinical experiments and phase I clinical trial to investigate the safety, pharmacokinetics (PK) and antitumour effects of GT0918 in castration-resistant prostate cancer (CRPC). EXPERIMENTAL DESIGN: An androgen receptor (AR) competitive binding assay was performed, followed by evaluation of GT0918 on AR protein expression. The efficacy of GT0918 was investigated in a castration-resistant xenograft model. A phase I dose-escalation study of GT0918 in CRPC was also carried out to evaluate its safety, PK and antitumour efficacy. RESULTS: GT0918 was demonstrated to inhibit the binding of androgen to AR more potently than MDV3100, and to effectively reduce the AR protein level. GT0918 inhibited the transcriptional activity of wild-type AR and AR with clinically relevant ligand-binding domain mutations. Furthermore, GT0918 significantly inhibited the growth of prostate cancer. A total of 16 patients was treated with GT0918 at five dose levels. Among these 16 patients, 10 and 2 patients, respectively, completed a three-cycle and six-cycle treatment, in which MTD was not reached. All the treatment-related adverse events were grade I, including hypercholesterolemia, hypertriglyceridemia, fatigue and anaemia. PK parameters showed that drug exposure increased with dose proportionally from 50 to 300 mg and a saturation was observed between 300 and 400 mg. PSA declines of ≥30% and ≥50% were, respectively, observed in six and two cases. All the 12 patients with metastatic soft tissue lesions confirmed stable disease. CONCLUSIONS: GT0918, a full AR antagonist without agonist effect, has high binding affinity to AR with AR protein down-regulation activity. GT0918 is demonstrated to be well tolerated with a favourable PK profile and exhibits promising antitumour activity in CRPC. CLINICALTRIALS: gov identifier CTR20150501.


Assuntos
Oxazóis/farmacologia , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Tioidantoínas/farmacologia , Idoso , Animais , Apoptose , Proliferação de Células , Seguimentos , Humanos , Masculino , Dose Máxima Tolerável , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Oxazóis/farmacocinética , Prognóstico , Neoplasias de Próstata Resistentes à Castração/patologia , Tioidantoínas/farmacocinética , Distribuição Tecidual , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Gen Physiol Biophys ; 39(2): 169-177, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32329444

RESUMO

The present study aimed to investigate the effects of histone deacetylase 6 (HDAC6) inhibitor Cay10603 (Cay) on high glucose (HG)-stimulated human retinal pigment epithelium (RPE) cells and its underlying mechanisms. ARPE-19 cells were cultured under normal glucose (NG) or high glucose (HG) conditions. The results revealed that HDAC6 was upregulated in HG-stimulated ARPE-19 cells. Cay treatment caused a decrease in intracellular reactive oxygen species (ROS). The levels of malondialdehyde (MDA) and myeloperoxidase (MPO) were reduced accompanied by increase in the activities of superoxide dismutase (SOD) and catalase (CAT) after treatment with Cay. Besides, Cay decreased the levels of tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), IL-6 and monocyte chemoattractant protein-1 (MCP-1) in supernatant. Meanwhile, the apoptotic rate in Cay-treated ARPE-19 cells notably reduced, coupled with an upregulation in Bcl-2 expression and a downregulation in cleaved caspase-3 and cleaved caspase-9 expression. Cay decreased the expression of phospho (p)-NF-κB p65, p-IκB-α, NLRP3, cleaved caspase-1 and ASC while increased the expression of NF-κB p65 (cytoplasm). Taken together, these findings demonstrated that Cay suppressed HG-induced oxidative stress, inflammation and apoptosis via regulating NF-κB and NLRP3 inflammasome pathway in HG-induced ARPE-19 cells, suggesting that Cay might be a therapeutic agent for the treatment of diabetic retinopathy.


Assuntos
Apoptose , Carbamatos/farmacologia , Células Epiteliais/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Inflamassomos/metabolismo , NF-kappa B/metabolismo , Oxazóis/farmacologia , Estresse Oxidativo , Células Epiteliais/citologia , Glucose , Humanos , Inflamação , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Retina/citologia
10.
J Pathol ; 251(3): 297-309, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32333795

RESUMO

Oestrogen receptor ß (ERß) has been suggested to have anti-proliferative and anti-tumour effects in breast and prostate cancer cells, but other studies have indicated its tumour-promoting effects. Understanding the complex effects of this receptor in different contexts requires further study. We reported that high ERß expression is independently associated with improved prognosis in female colorectal cancer (CRC) patients. Herein, we investigated the possible anti-tumour effect of ERß and its selective agonist. CRC patients with high ERß expression had significantly higher levels of membrane-associated ß-catenin, cysteinyl leukotriene receptor 2 (CysLT2 R), and 15-hydroxyprostaglandin dehydrogenase (15-PGDH), which have anti-tumour effects, but lower levels of nuclear ß-catenin, cysteinyl leukotriene receptor 1 (CysLT1 R), and cyclooxygenase-2 (COX-2), which have tumour-promoting effects. These interesting findings were further supported by two different publicly available CRC mRNA datasets that showed a significant positive correlation between ERß expression and 15-PGDH and CysLT2 R expression and a negative correlation between ERß expression and ß-catenin, CysLT1 R, and COX-2 expression. We next evaluated ERß expression in three different colon cancer mouse models; ERß expression was negatively correlated with tumourigenesis. Furthermore, treatment with the ERß-agonist ERB-041 reduced CysLT1 R, active ß-catenin, and COX-2 levels but increased phospho-ß-catenin, CysLT2 R, and 15-PGDH levels in HCT-116, Caco-2, and SW-480 colon cancer cells compared to vehicle-treated cells. Interestingly, ERB-041-treated cells showed significantly decreased migration, survival, and colonosphere formation and increased apoptotic activity, as indicated by increased CASPASE-3 and apoptotic blebs. Finally, patients with low ERß expression had significantly more distant metastasis at the time of diagnosis than patients with high ERß expression. Therefore, we studied the effects of ERB-041-treated colon cancer cells in a zebrafish xenograft model. We found significantly less distant metastasis of ERB-041-treated cells compared to vehicle-treated cells. These results further support ERß's anti-tumour role in CRC and the possible use of its agonist in CRC patients. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.


Assuntos
Movimento Celular , Proliferação de Células , Neoplasias Colorretais/metabolismo , Receptor beta de Estrogênio/metabolismo , Animais , Antineoplásicos/farmacologia , Apoptose , Células CACO-2 , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Receptor beta de Estrogênio/agonistas , Receptor beta de Estrogênio/genética , Feminino , Genes APC , Células HCT116 , Células HT29 , Humanos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Metástase Neoplásica , Oxazóis/farmacologia , Receptores de Leucotrienos/genética , Receptores de Leucotrienos/metabolismo , Transdução de Sinais , Ensaios Antitumorais Modelo de Xenoenxerto , Peixe-Zebra
11.
Eur J Med Chem ; 191: 112146, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32088496

RESUMO

In continuation of our pharmacomodulation work on the nitroimidazooxazole series, we report the synthesis of new 5-substituted 6-nitroimidazooxazole derivatives. Our aim was to evaluate how functionalization of the 5-position of the 6-nitroimidazooxazole scaffold affects antileishmanial and antitrypanosomal in vitro activities. Twenty-one original compounds were synthesized and evaluated for their in vitro antileishmanial (L. donovani) and antitrypanosomal (T. cruzi) properties. Pallado-catalyzed cross-coupling reactions were used to introduce an aryl or ethynyl aryl substituent in 5-position from a 5-brominated-6-nitroimidazooxazole starting product. Unfortunately, the first series of compounds bearing an aryl group in 5-position presented limited in vitro activities against L. donovani and T. cruzi, with IC50 > 10 µM (vs 0.18 µM and 2.31 µM for the reference drugs amphotericin B and benznidazole respectively). Interestingly, the second series of compounds bearing an ethynyl aryl substituent in 5-position showed more promising, particularly against T. cruzi. Compounds 6a, 6b, 6c, 6g and 6h had better activity than the reference drug benznidazole (0.92 µM ≤ IC50 ≤ 2.18 µM vs IC50 = 2.31 µM), whereas the non-functionalized 2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b]oxazole 2 was not active against T. cruzi (IC50 > 10 µM).


Assuntos
Antiprotozoários/farmacologia , Leishmania donovani/efeitos dos fármacos , Nitroimidazóis/farmacologia , Oxazóis/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Antiprotozoários/síntese química , Antiprotozoários/química , Relação Dose-Resposta a Droga , Estrutura Molecular , Nitroimidazóis/síntese química , Nitroimidazóis/química , Oxazóis/síntese química , Oxazóis/química , Testes de Sensibilidade Parasitária , Relação Estrutura-Atividade
12.
PLoS Pathog ; 16(2): e1008287, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32032366

RESUMO

Our inability to predict which mutations could result in antibiotic resistance has made it difficult to rapidly identify the emergence of resistance, identify pre-existing resistant populations, and manage our use of antibiotics to effectively treat patients and prevent or slow the spread of resistance. Here we investigated the potential for resistance against the new antitubercular nitroimidazole prodrugs pretomanid and delamanid to emerge in Mycobacterium tuberculosis, the causative agent of tuberculosis (TB). Deazaflavin-dependent nitroreductase (Ddn) is the only identified enzyme within M. tuberculosis that activates these prodrugs, via an F420H2-dependent reaction. We show that the native menaquinone-reductase activity of Ddn is essential for emergence from hypoxia, which suggests that for resistance to spread and pose a threat to human health, the native activity of Ddn must be at least partially retained. We tested 75 unique mutations, including all known sequence polymorphisms identified among ~15,000 sequenced M. tuberculosis genomes. Several mutations abolished pretomanid and delamanid activation in vitro, without causing complete loss of the native activity. We confirmed that a transmissible M. tuberculosis isolate from the hypervirulent Beijing family already possesses one such mutation and is resistant to pretomanid, before being exposed to the drug. Notably, delamanid was still effective against this strain, which is consistent with structural analysis that indicates delamanid and pretomanid bind to Ddn differently. We suggest that the mutations identified in this work be monitored for informed use of delamanid and pretomanid treatment and to slow the emergence of resistance.


Assuntos
Antituberculosos/farmacologia , Proteínas de Bactérias , Farmacorresistência Bacteriana , Mutação , Mycobacterium tuberculosis , Nitroimidazóis/farmacologia , Nitrorredutases , Oxazóis/farmacologia , Engenharia de Proteínas , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Farmacorresistência Bacteriana/efeitos dos fármacos , Farmacorresistência Bacteriana/genética , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/metabolismo , Nitrorredutases/genética , Nitrorredutases/metabolismo , Polimorfismo Genético
13.
Eur J Med Chem ; 189: 112064, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31972393

RESUMO

Although a relatively wide range of therapeutic options is currently available for the treatment of HIV/AIDS, it is still among the most serious and virulent diseases and is associated with a high mortality rate. Integrase strand transfer inhibitors (INSTIs), e.g., FDA-approved dolutegravir (DTG), bictegravir (BIC) and cabotegravir (CAB), have recently been included in standard highly active antiretroviral therapy (HAART) schemes as one of the five major components responsible for the most beneficial clinical outcome. In this paper, we describe a combinatorial amide synthesis, biological evaluation and in silico modeling of new INSTIs containing heteroaromatic bioisosteric substitution instead of the well-studied halogen-substituted benzyl fragment. With the focus on the mentioned diversity point, a medium-sized library of compounds was selected for synthesis. A biological study revealed that many molecules were highly active INSTIs (EC50 < 10 nM). Two compounds 1{4} and 1{26} demonstrated picomolar antiviral activity that was comparable with CAB and were more active than DTG and BIC. Molecular docking study was performed to evaluate the binding mode of compounds in the active site of HIV-1 IN. In rats, lead compound 1{26} showed two-fold greater bioavailability than CAB and had a similar half-life. Compound 1{26} and its sodium salt were considerably more soluble in water than the parent drugs. Both molecules were very stable in human liver microsomes and plasma, demonstrated high affinity towards plasma proteins and did not show cytochrome (CYP) inhibition. This benefit profile indicates the great potential of these molecules as attractive candidates for subsequent evaluation as oral long-acting drugs and long-acting nanosuspension formulations for intramuscular injection.


Assuntos
Simulação por Computador , Infecções por HIV/tratamento farmacológico , Inibidores de Integrase de HIV/síntese química , Inibidores de Integrase de HIV/farmacologia , Integrase de HIV/química , HIV-1/efeitos dos fármacos , Modelos Moleculares , Oxazóis/síntese química , Oxazóis/farmacologia , Animais , Infecções por HIV/virologia , Humanos , Masculino , Simulação de Acoplamento Molecular , Mutação , Ratos , Ratos Sprague-Dawley , Replicação Viral
14.
Int J Mol Sci ; 21(2)2020 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-31963392

RESUMO

The Warburg effect is an emerging hallmark of cancer, which has the tumor suppressor p53 as its major regulator. Herein, we unveiled that p53 activation by (S)-tryptophanol-derived oxazoloisoindolinone (SLMP53-1) mediated the reprograming of glucose metabolism in cancer cells and xenograft human tumor tissue, interfering with angiogenesis and migration. Particularly, we showed that SLMP53-1 regulated glycolysis by downregulating glucose transporter 1 (GLUT1), hexokinase-2 (HK2), and phosphofructokinase-2 isoform 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase-3 (PFKFB3) (key glycolytic enzymes), while upregulating the mitochondrial markers synthesis of cytochrome c oxidase 2 (SCO2), cytochrome c oxidase subunit 4 (COX4), and OXPHOS mitochondrial complexes. SLMP53-1 also downregulated the monocarboxylate transporter 4 (MCT4), causing the subsequent reduction of lactate export by cancer cells. Besides the acidification of the extracellular environment, SLMP53-1 further increased E-cadherin and reduced metalloproteinase-9 (MMP-9) expression levels in both cancer cells and xenograft human tumor tissue, which suggested the interference of SLMP53-1 in extracellular matrix remodeling and epithelial-to-mesenchymal transition. Consistently, SLMP53-1 depleted angiogenesis, decreasing endothelial cell tube formation and vascular endothelial growth factor (VEGF) expression levels. SLMP53-1 also exhibited synergistic growth inhibitory activity in combination with the metabolic modulator dichloroacetic acid. These data reinforce the promising application of the p53-activating agent SLMP53-1 in cancer therapy, by targeting p53-mediated pathways of growth and dissemination.


Assuntos
Inibidores da Angiogênese/farmacologia , Metabolismo dos Carboidratos/efeitos dos fármacos , Neoplasias do Colo/tratamento farmacológico , Glucose/metabolismo , Isoindóis/farmacologia , Neovascularização Patológica/tratamento farmacológico , Oxazóis/farmacologia , Proteína Supressora de Tumor p53/metabolismo , Animais , Apoptose , Ciclo Celular , Proliferação de Células , Neoplasias do Colo/irrigação sanguínea , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Glicólise , Humanos , Camundongos , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Células Tumorais Cultivadas , Proteína Supressora de Tumor p53/genética , Ensaios Antitumorais Modelo de Xenoenxerto
15.
PLoS One ; 15(1): e0228212, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31990961

RESUMO

Acetyl-CoA carboxylase (ACC) catalyzes the rate-limiting step in de novo lipogenesis, which is increased in the livers of patients with nonalcoholic steatohepatitis. GS-0976 (firsocostat), an inhibitor of isoforms ACC1 and ACC2, reduced hepatic steatosis and serum fibrosis biomarkers such as tissue inhibitor of metalloproteinase 1 in patients with nonalcoholic steatohepatitis in a randomized controlled trial, although the impact of this improvement on fibrosis has not fully been evaluated in preclinical models. Here, we used Western diet-fed melanocortin 4 receptor-deficient mice that have similar phenotypes to nonalcoholic steatohepatitis patients including progressively developed hepatic steatosis as well as fibrosis. We evaluated the effects of ACC1/2 inhibition on hepatic fibrosis. After the confirmation of significant hepatic fibrosis with a 13-week pre-feeding, GS-0976 (4 and 16 mg/kg/day) treatment for 9 weeks lowered malonyl-CoA and triglyceride content in the liver and improved steatosis, histologically. Furthermore, GS-0976 reduced the histological area of hepatic fibrosis, hydroxyproline content, mRNA expression level of type I collagen in the liver, and plasma tissue metalloproteinase inhibitor 1, suggesting an improvement of hepatic fibrosis. The treatment with GS-0976 was also accompanied by reductions of plasma ALT and AST levels. These data demonstrate that improvement of hepatic lipid metabolism by ACC1/2 inhibition could be a new option to suppress fibrosis progression as well as to improve hepatic steatosis in nonalcoholic steatohepatitis.


Assuntos
Acetil-CoA Carboxilase/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Técnicas de Inativação de Genes , Cirrose Hepática/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Receptor Tipo 4 de Melanocortina/deficiência , Receptor Tipo 4 de Melanocortina/genética , Animais , Modelos Animais de Doenças , Inibidores Enzimáticos/uso terapêutico , Isobutiratos/farmacologia , Isobutiratos/uso terapêutico , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Camundongos , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Tamanho do Órgão/efeitos dos fármacos , Oxazóis/farmacologia , Oxazóis/uso terapêutico , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Triglicerídeos/metabolismo
16.
Cell Mol Neurobiol ; 40(2): 215-228, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31734895

RESUMO

Trace amine-associated receptor 1 (TAAR1) is a widely recognized new perspective target for the neuropsychiatric pharmacological treatment. Despite a growing number of studies investigating TAAR1 role in the animal models of different pathologies, information of TAAR1 agonists impact on executive cognitive functions is limited. The goal of the present study was to evaluate the activity of highly selective partial TAAR1 agonist RO5263397 on various executive cognitive functions. The results of the present study demonstrated that the pretreatment with RO5263397 was able to increase attention and decrease cognitive flexibility in rats. The analysis of the RO5263397 action on impulsivity demonstrated that the TAAR1 activation failed to affect premature responding but was able to slightly modify impulsive choice. Problem solving was resistant to the pharmacological intervention.


Assuntos
Função Executiva/efeitos dos fármacos , Função Executiva/fisiologia , Oxazóis/farmacologia , Receptores Acoplados a Proteínas-G/agonistas , Receptores Acoplados a Proteínas-G/fisiologia , Animais , Condicionamento Operante/efeitos dos fármacos , Condicionamento Operante/fisiologia , Relação Dose-Resposta a Droga , Masculino , Ratos , Ratos Wistar
17.
Am J Hematol ; 95(1): 68-77, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31674058

RESUMO

Restriction of iron availability by ferroportin inhibition is a novel approach to treating non-transfusion-dependent thalassemia (ß-thalassemia intermedia). This first-in-human, Phase I study (https://www.clinicaltrialsregister.eu; EudraCT no. 2017-003395-31) assessed the safety, tolerability, pharmacokinetics and pharmacodynamics of single- and multiple-ascending doses (SAD and MAD) of the oral ferroportin inhibitor, VIT-2763, in healthy volunteers. Participants received VIT-2763 5/15/60/120/240 mg or placebo in the SAD phase and VIT-2763 60/120 mg once daily, VIT-2763 60/120 mg twice daily, or placebo for 7 days in the MAD phase. Seventy-two participants completed treatment. VIT-2763 was well tolerated and demonstrated a similar safety profile to the placebo. There were no serious or severe adverse events, or discontinuations due to adverse events. VIT-2763 absorption was relatively fast, with detectable levels 15 to 30 minutes post-dose. Following multiple dosing there was no apparent change in absorption and accumulation was minimal. Mean elimination half-life was 1.9 to 5.3 hours following single dosing, and 2.1 to 3.8 hours on Day 1 and 2.6 to 5.3 hours on Day 7, following repeated dosing. There was a temporary decrease in mean serum iron levels with VIT-2763 single doses ≥60 mg and all multiple doses; mean calculated transferrin saturation (only assessed following multiple dosing) also temporarily decreased. A shift in mean serum hepcidin peaks followed administration of all iron-lowering doses of VIT-2763. This effect was less pronounced after 7 days of multiple dosing (aside from with 120 mg once daily). These results support the initiation of clinical studies in patients with non-transfusion-dependent thalassemia and documented iron overload due to ineffective erythropoiesis.


Assuntos
Benzimidazóis/uso terapêutico , Proteínas de Transporte de Cátions/antagonistas & inibidores , Oxazóis/uso terapêutico , Piridinas/uso terapêutico , Talassemia/tratamento farmacológico , Administração Oral , Benzimidazóis/farmacologia , Relação Dose-Resposta a Droga , Esquema de Medicação , Voluntários Saudáveis , Hepcidinas/sangue , Humanos , Ferro/sangue , Sobrecarga de Ferro/tratamento farmacológico , Oxazóis/farmacologia , Piridinas/farmacologia
18.
J Pharmacol Exp Ther ; 372(1): 83-94, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31694876

RESUMO

The imidizodiazepine, 5-(8-ethynyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,5-a][1,4]diazepin-3-yl)oxazole (KRM-II-81), is selective for α2/3-containing GABAA receptors. KRM-II-81 dampens seizure activity in rodent models with enhanced efficacy and reduced motor-impairment compared with diazepam. In the present study, KRM-II-81 was studied in assays designed to detect antiepileptics with improved chances of impacting pharmaco-resistant epilepsies. The potential for reducing neural hyperactivity weeks after traumatic brain injury was also studied. KRM-II-81 suppressed convulsions in corneal-kindled mice. Mice with kainate-induced mesial temporal lobe seizures exhibited spontaneous recurrent hippocampal paroxysmal discharges that were significantly reduced by KRM-II-81 (15 mg/kg, orally). KRM-II-81 also decreased convulsions in rats undergoing amygdala kindling in the presence of lamotrigine (lamotrigine-insensitive model) (ED50 = 19 mg/kg, i.p.). KRM-II-81 reduced focal and generalized seizures in a kainate-induced chronic epilepsy model in rats (20 mg/kg, i.p., three times per day). In mice with damage to the left cerebral cortex by controlled-cortical impact, enduring neuronal hyperactivity was dampened by KRM-II-81 (10 mg/kg, i.p.) as observed through in vivo two-photon imaging of layer II/III pyramidal neurons in GCaMP6-expressing transgenic mice. No notable side effects emerged up to doses of 300 mg/kg KRM-II-81. Molecular modeling studies were conducted: docking in the binding site of the α1ß3γ2L GABAA receptor showed that replacing the C8 chlorine atom of alprazolam with the acetylene of KRM-II-81 led to loss of the key interaction with α1His102, providing a structural rationale for its low affinity for α1-containing GABAA receptors compared with benzodiazepines such as alprazolam. Overall, these findings predict that KRM-II-81 has improved therapeutic potential for epilepsy and post-traumatic epilepsy. SIGNIFICANCE STATEMENT: We describe the effects of a relatively new orally bioavailable small molecule in rodent models of pharmaco-resistant epilepsy and traumatic brain injury. KRM-II-81 is more potent and generally more efficacious than standard-of-care antiepileptics. In silico docking experiments begin to describe the structural basis for the relative lack of motor impairment induced by KRM-II-81. KRM-II-81 has unique structural and anticonvulsant effects, predicting its potential as an improved antiepileptic drug and novel therapy for post-traumatic epilepsy.


Assuntos
Anticonvulsivantes/uso terapêutico , Lesões Encefálicas Traumáticas/complicações , Epilepsia Resistente a Medicamentos/tratamento farmacológico , GABAérgicos/uso terapêutico , Oxazóis/uso terapêutico , Receptores de GABA-A/metabolismo , Regulação Alostérica , Tonsila do Cerebelo/efeitos dos fármacos , Tonsila do Cerebelo/fisiopatologia , Animais , Anticonvulsivantes/administração & dosagem , Anticonvulsivantes/farmacologia , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/fisiopatologia , Epilepsia Resistente a Medicamentos/etiologia , GABAérgicos/efeitos adversos , GABAérgicos/farmacologia , Excitação Neurológica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Oxazóis/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores de GABA-A/química
19.
Expert Opin Investig Drugs ; 29(2): 135-141, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31519114

RESUMO

Introduction: De novo lipogenesis (DNL) plays a major role in fatty acid metabolism and contributes significantly to triglyceride accumulation within the hepatocytes in patients with nonalcoholic steatohepatitis (NASH). Acetyl-CoA carboxylase (ACC) converts acetyl-CoA to malonyl CoA and is a rate-controlling step in DNL. Furthermore, malonyl-CoA is an important regulator of hepatic mitochondrial fat oxidation through its ability to inhibit carnitine palmitoyltransferase I. Therefore, inhibiting ACC pharmacologically represents an attractive approach to treating NASH.Areas covered: This article summarizes preclinical and clinical data on the efficacy and safety of the liver-targeted ACC inhibitor GS-0976 (Firsocostat) for the treatment of NASH. In a phase 2 trial that included 126 patients with NASH and fibrosis, GS-0976 20 mg daily for 12 weeks showed significant relative reduction in liver fat by 29%; however, treatment was associated with an increase in plasma triglycerides with 16 patients having levels >500 mg/dL.Expert opinion: Preclinical and preliminary clinical data support the development of GS-0976 as treatment for NASH. ACC-induced hypertriglyceridemia can be mitigated by fish oil or fibrates, but the long-term cardiovascular effects require further investigations.


Assuntos
Inibidores Enzimáticos/uso terapêutico , Isobutiratos/uso terapêutico , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Oxazóis/uso terapêutico , Pirimidinas/uso terapêutico , Acetil-CoA Carboxilase/antagonistas & inibidores , Animais , Drogas em Investigação/efeitos adversos , Drogas em Investigação/farmacologia , Drogas em Investigação/uso terapêutico , Inibidores Enzimáticos/efeitos adversos , Inibidores Enzimáticos/farmacologia , Ácidos Graxos/metabolismo , Humanos , Isobutiratos/efeitos adversos , Isobutiratos/farmacologia , Lipogênese/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/fisiopatologia , Oxazóis/efeitos adversos , Oxazóis/farmacologia , Pirimidinas/efeitos adversos , Pirimidinas/farmacologia , Triglicerídeos/sangue
20.
Biochim Biophys Acta Gen Subj ; 1864(1): 129440, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31536751

RESUMO

BACKGROUND: Half of human cancers harbour TP53 mutations that render p53 inactive as a tumor suppressor. As such, reactivation of mutant (mut)p53 through restoration of wild-type (wt)-like function represents one of the most promising therapeutic strategies in cancer treatment. Recently, we have reported the (S)-tryptophanol-derived oxazoloisoindolinone SLMP53-1 as a new reactivator of wt and mutp53 R280K with in vitro and in vivo p53-dependent antitumor activity. The present work aimed a mechanistic elucidation of mutp53 reactivation by SLMP53-1. METHODS AND RESULTS: By cellular thermal shift assay (CETSA), it is shown that SLMP53-1 induces wt and mutp53 R280K thermal stabilization, which is indicative of intermolecular interactions with these proteins. Accordingly, in silico studies of wt and mutp53 R280K DNA-binding domain with SLMP53-1 unveiled that the compound binds at the interface of the p53 homodimer with the DNA minor groove. Additionally, using yeast and p53-null tumor cells ectopically expressing distinct highly prevalent mutp53, the ability of SLMP53-1 to reactivate multiple mutp53 is evidenced. CONCLUSIONS: SLMP53-1 is a p53-activating agent with the ability to directly target wt and a set of hotspot mutp53. GENERAL SIGNIFICANCE: This work reinforces the encouraging application of SLMP53-1 in the personalized treatment of cancer patients harboring distinct p53 status.


Assuntos
Proteínas de Ligação a DNA/genética , Isoindóis/farmacologia , Neoplasias/tratamento farmacológico , Oxazóis/farmacologia , Proteína Supressora de Tumor p53/genética , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proteínas de Ligação a DNA/antagonistas & inibidores , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Isoindóis/química , Mutação/efeitos dos fármacos , Neoplasias/genética , Neoplasias/patologia , Oxazóis/química , Domínios Proteicos/efeitos dos fármacos , Proteína Supressora de Tumor p53/antagonistas & inibidores
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