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1.
Molecules ; 27(1)2021 Dec 28.
Artigo em Inglês | MEDLINE | ID: mdl-35011390

RESUMO

The conditions for determining the antioxidant properties of cyclitols (d-pinitol, l-quebrachitol, myo-, l-chiro-, and d-chiro-inositol), selected flavanones (hesperetin, naringenin, eriodictyol, and liquiritigenin) and glutathione by spectrophotometric methods-CUPRAC and with DPPH radical, and by a chromatographic method DPPH-UHPLC-UV, have been identified. Interactions of the tested compounds and their impact on the ox-red properties were investigated. The RSA (%) of the compounds tested was determined. Very low antioxidative properties of cyclitols, compared with flavanones and glutathione alone, were revealed. However, a significant increase in the determined antioxidative properties of glutathione by methyl-ether derivatives of cyclitols (d-pinitol and l-quebrachitol) was demonstrated for the first time. Thus, cyclitols seem to be a good candidate for creating drugs for the treatment of many diseases associated with reactive oxygen species (ROS) generation.


Assuntos
Antioxidantes/química , Antioxidantes/farmacologia , Ciclitóis/química , Ciclitóis/farmacologia , Relação Dose-Resposta a Droga , Flavanonas/química , Flavanonas/farmacologia , Sequestradores de Radicais Livres , Cromatografia Gasosa-Espectrometria de Massas , Glutationa/química , Glutationa/farmacologia , Estrutura Molecular , Análise Espectral , Relação Estrutura-Atividade
2.
Int J Mol Sci ; 21(23)2020 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-33256104

RESUMO

Cancer is now the second leading cause of death worldwide. It is estimated that every year, approximately 9.6 million people die of oncologic diseases. The most common origins of malignancy are the lungs, breasts, and colorectum. Even though in recent years, many new drugs and therapeutic options have been introduced, there are still no safe, effective chemopreventive agents. Cyclitols seem poised to improve this situation. There is a body of evidence that suggests that their supplementation can decrease the incidence of colorectal cancer, lower the risk of metastasis occurrence, lower the proliferation index, induce apoptosis in malignant cells, enhance natural killer (NK) cell activity, protect cells from free radical damage, and induce positive molecular changes, as well as reduce the side effects of anticancer treatments such as chemotherapy or surgery. Cyclitol supplementation appears to be both safe and well-tolerated. This review focuses on presenting, in a comprehensive way, the currently available knowledge regarding the use of cyclitols in the treatment of different malignancies, particularly in lung, breast, colorectal, and prostate cancers.


Assuntos
Produtos Biológicos/uso terapêutico , Ciclitóis/uso terapêutico , Dieta , Neoplasias/tratamento farmacológico , Neoplasias/prevenção & controle , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Produtos Biológicos/química , Produtos Biológicos/farmacologia , Ciclitóis/química , Ciclitóis/farmacologia , Humanos
3.
Carbohydr Res ; 493: 108027, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32445981

RESUMO

A short synthetic route to a small library of aminocyclitols 14·HCl-19·HCl has been elaborated from the common shikimic acid-derived scaffolds 20 and 21. The developed strategy features three oxidative processes ‒ ozonolysis, dihydroxylation and epoxidation ‒ as the key transformations. The stereochemistry of the newly created stereocentres was confirmed either via crystallographic analysis or by means of NOESY experiments conducted on advanced intermediates. Glycosidase inhibition study revealed no glucosidase inhibition and only weak inhibitory activity against recombinant Drosophila melanogaster Golgi mannosidase (GMIIb).


Assuntos
Ciclitóis/farmacologia , Inibidores Enzimáticos/farmacologia , Manosidases/antagonistas & inibidores , Ácido Chiquímico/química , Bibliotecas de Moléculas Pequenas/farmacologia , Configuração de Carboidratos , Ciclitóis/síntese química , Ciclitóis/química , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Manosidases/metabolismo , Ácido Chiquímico/análogos & derivados , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química
4.
Biol Pharm Bull ; 42(12): 2076-2082, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31787722

RESUMO

The cyclitol bornesitol is the main constituent of the leaves from the antihypertensive medicinal plant Hancornia speciosa. This study aimed to investigate the ability of bornesitol to reduce blood pressure and its mechanism of action. Normotensive Wistar rats were divided into control group and bornesitol groups treated intravenously with bornesitol (0.1, 1.0 and 3.0 mg/kg). Systolic blood pressure (SBP) and diastolic blood pressure (DBP) were recorded in non-anesthetized awake animals. Nitric oxide (NO) and angiotensin-converting enzyme (ACE) were measured in plasma by using colorimetric methods. Vascular reactivity study was performed in rat aorta rings and the involvement of nitric oxide synthase (NOS), calcium-calmodulin complex and phosphatidylinositol-3-kinase (PI3K)/Akt pathway in the vasodilator effect was investigated. Administration of bornesitol significantly reduced the SBP, increased the plasmatic level of nitrite, and decreased ACE activity in normotensive rats. In the rat aorta, bornesitol induced endothelium-dependent vasodilatation, which was abolished by NOS blockade. While calcium-calmodulin complex inhibition decreased the vasodilator effect of bornesitol, the inhibition of PI3K/Akt pathway did not alter it. Bornesitol reduced the blood pressure by a mechanism involving an increased production or bioavailability of NO, inhibition of ACE, and by an endothelium- and NO-dependent vasodilator effect. The present results support the use of bornesitol as an active marker for the cardiovascular activity of Hancornia speciosa.


Assuntos
Anti-Hipertensivos/farmacologia , Apocynaceae , Ciclitóis/farmacologia , Vasodilatadores/farmacologia , Animais , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/fisiologia , Pressão Sanguínea/efeitos dos fármacos , Brasil , Masculino , Óxido Nítrico/sangue , Nitritos/sangue , Peptidil Dipeptidase A/sangue , Folhas de Planta , Plantas Medicinais , Ratos Wistar
5.
Nutrients ; 10(12)2018 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-30513929

RESUMO

INTRODUCTION: Myo-inositol and its derivatives cyclitols play an important role in the processes of cell regulation, signal transduction, osmoregulation, and ion channel physiology, and are a component of the cell membrane. Free cyclitols present in food or released during the degradation of galactosyl cyclitols by bacteria (in digestive tract) show some physiological benefits. AIM: The aim of this paper is to present and analyze the documented data about curative and healing properties of cyclitols. RESULTS AND DISCUSSION: Cyclitols are well known compounds in the treatment of an accompanied diabetes insulin resistance, and also obesity and polycystic ovarian syndrome. d-chiro-Inositol deficiency exacerbates insulin resistance in the liver, muscles, and fat, while depletion of myo-inositol results in the development of diabetic complications. Cyclitols are successfully applied in treatment of polycystic ovarian syndrome, simultaneous are observed effective reducing of BMI, improving the hormonal profile, and increasing fertility. Moreover, cyclitols have anti-atherogenic, anti-oxidative, anti-inflammatory, and anti-cancer properties. CONCLUSION: The properties of cyclitols may be a good therapeutic option in the reduction of metabolically induced inflammation. Due to well drugs tolerance and low toxicity of these compounds, cyclitols are recommend for pregnant women and also for children. Another advantage is their widespread presence and easy availability, which encourages their use in medicine.


Assuntos
Ciclitóis/farmacologia , Doenças Metabólicas/tratamento farmacológico , Configuração de Carboidratos , Ciclitóis/química , Humanos , Doenças Metabólicas/metabolismo
6.
J Chromatogr B Analyt Technol Biomed Life Sci ; 1093-1094: 31-38, 2018 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-29980101

RESUMO

The antihypertensive activity of the medicinal plant Hancornia speciosa has been previously demonstrated by us, being the activity ascribed to polyphenols and cyclitols like l-(+)-bornesitol. We herein evaluated the stability of the bioactive marker bornesitol submitted to forced degradation conditions. Bornesitol employed in the study was isolated from H. speciosa leaves. An UHPLC-ESI-MS/MS method was developed to investigate bornesitol stability based on MRM (Multiple Reaction Monitoring) acquisition mode and negative ionization mode, employing both specific (m/z 193 → 161 Da) and confirmatory (m/z 193 → 175 Da) transitions. A gradient elution of 0.1% formic acid in water and acetonitrile was performed on a HILIC column. The method was validated and showed adequate linearity (r2 > 0.99), selectivity, specificity, accuracy, and precision (RSD < 2.9%). The method was robust for deliberate variations on dessolvation temperature, but not for changes in the flow rate and dessolvation gas. The results from the stability studies allowed us to classify bornesitol as labile for acidic and alkaline hydrolysis, but as very stable for oxidative and neutral hydrolysis exposure. Bornesitol was categorized as practically stable under photolysis degradation, whereas a considerable reduction on its contents was induced by metal ions and thermolysis exposure. Degraded samples from neutral hydrolysis and thermolysis were assayed in vitro for ACE inhibition and showed a substantial decrease in biological activity as compared to intact bornesitol. myo-Inositol was identified as the major degradation products in both matrices. This is the first report on bornesitol stability under different stress conditions and the obtained data are relevant for the development and quality control of standardized products from H. speciosa leaves.


Assuntos
Apocynaceae/química , Cromatografia Líquida de Alta Pressão/métodos , Ciclitóis , Espectrometria de Massas/métodos , Peptidil Dipeptidase A/efeitos dos fármacos , Inibidores da Enzima Conversora de Angiotensina/análise , Inibidores da Enzima Conversora de Angiotensina/química , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Biomarcadores/análise , Biomarcadores/química , Ciclitóis/análise , Ciclitóis/química , Ciclitóis/farmacologia , Estabilidade de Medicamentos , Limite de Detecção , Modelos Lineares , Peptidil Dipeptidase A/metabolismo , Extratos Vegetais/química , Reprodutibilidade dos Testes
7.
Phytother Res ; 29(12): 1887-93, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26344935

RESUMO

The leaves of Hancornia speciosa Gomes (Apocynaceae), a medicinal species found in the Brazilian cerrado biome, are traditionally used to treat wounds and inflammatory disorders. The goal of the present study was to investigate the in vitro wound healing properties of ethanolic extract of H. speciosa leaves and its isolated compounds, using the scratch assay, and to evaluate their effects on the release of the pro-inflammatory cytokine tumor necrosis factor (TNF-α) by lipopolysaccharide (LPS)-stimulated human acute monocytic (THP-1) cells. H. speciosa ethanolic extract significantly increased (42.8% ± 5.4 at 25 µg/mL) cell migration and proliferation of fibroblasts compared with control cells, as well as the isolated compounds bornesitol (80.8% ± 5.1) and quinic acid (69.1% ± 6.2), both assayed at 50 µM. TNF-α release by LPS-stimulated THP-1 cells was significantly reduced by the ethanolic extract (62.9% ± 8.2, i.e. 1791.1 ± 394.7 pg/mL) at 10 µg/mL, bornesitol (48.9% ± 0.9, i.e. 2461.6 ± 43.1 pg/mL) at 50 µM, and quinic acid (90.2% ± 3.4, i.e. 473.5 ± 164.4 pg/mL) and rutin (82.4% ± 5.6, i.e. 847.0 ± 271.8 pg/mL) at 10 µM. These results provided evidences to support the traditional use of H. speciosa leaves to treat wounds and inflammatory disorders.


Assuntos
Apocynaceae/química , Fibroblastos/efeitos dos fármacos , Extratos Vegetais/farmacologia , Cicatrização/efeitos dos fármacos , Brasil , Linhagem Celular , Ciclitóis/isolamento & purificação , Ciclitóis/farmacologia , Humanos , Lipopolissacarídeos , Folhas de Planta/química , Ácido Quínico/isolamento & purificação , Ácido Quínico/farmacologia , Rutina/isolamento & purificação , Rutina/farmacologia , Fator de Necrose Tumoral alfa/metabolismo
8.
J Plant Physiol ; 171(10): 807-16, 2014 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-24877672

RESUMO

Cyclitols were prepared from corresponding allylic hydroperoxides, synthesized by photooxygenation of the appropriate cyclic alkenes. These hydroperoxides were then separately treated with a catalytic amount of OsO4. Synthesized dl-cyclopentane-1,2,3-triol 9 (A), dl-cyclohexane-1,2,3-triol 12 (B), and dl-cycloheptane-1,2,3-triol 15 (C) were used in the investigation of plant stress. Antioxidants, lipid peroxidation, and water status of chickpea species exposed to synthetic cyclitols under water deficit were examined. Cyclitol derivatives significantly decreased leaf water potential, lipid peroxidation and H2O2 levels of wild and cultivated species under water deficit. Cyclitol treatments affected antioxidant enzyme activities differently in both species under water deficit. The highest SOD activity was found in A10-treated Cicer arietinum (cultivar) and C10-treated Cicer reticulatum (wild type) under water deficit. CAT activity increased in C. arietinum exposed to A cyclitols, while it increased slightly and then decreased in cyclitol-treated C. reticulatum under stress conditions. AP and GR activities were significantly increased in C. arietinum under water deficit. AP activity increased in C derivatives-treated C. arietinum, while it remained unchanged in C. reticulatum on day 1 of water deficit. GR activity was increased in A derivaties-treated C. arietinum and C derivatives-treated C. reticulatum on day 1 of water deficit and decreased with severity of stress (except for B10-treated C. arietinum). The level of AsA in C treatments and GSH in A treatments increased in C. arietinum on day 1 of water deficit, while in C. reticulatum, AsA and GSH levels decreased under stress conditions. We conclude that exogenous synthetic cyclitol derivatives are biologically active and noncytotoxic, resulting in higher antioxidant activities and lower water potential, thus increasing the water deficit tolerance of chickpea under water deficit, especially of cultivated chickpea. We also propose that synthetic cyclitol derivatives can reduce reactive oxygen species and membrane damage and are beneficial for stress adaptation.


Assuntos
Cicer/efeitos dos fármacos , Ciclitóis/farmacologia , Regulação Enzimológica da Expressão Gênica , Água/fisiologia , Antioxidantes/metabolismo , Ascorbato Peroxidases/metabolismo , Ácido Ascórbico/metabolismo , Catalase/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Cicer/enzimologia , Cicer/fisiologia , Ciclitóis/síntese química , Ciclitóis/química , Desidratação , Regulação da Expressão Gênica de Plantas , Glutationa/metabolismo , Glutationa Redutase/metabolismo , Peróxido de Hidrogênio/metabolismo , Peroxidação de Lipídeos , Estresse Oxidativo , Reguladores de Crescimento de Plantas/metabolismo , Folhas de Planta/efeitos dos fármacos , Folhas de Planta/fisiologia , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase/metabolismo
9.
Org Lett ; 16(5): 1422-5, 2014 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-24552164

RESUMO

A straightforward chemo-enzymatic synthesis of new polyhydroxylated benzopyrrolizidines and cyclohexapyrrolizidines is developed. The two-step strategy consists of l-fuculose-1-phosphate aldolase variant F131A-catalyzed aldol addition of dihydroxyacetone phosphate to rac-N-benzyloxycarbonylindoline-2-carbaldehyde as well as (2S*,3aS*,7aS*)- and (2S*,3aR*,7aR*)-N-benzyloxycarbonyloctahydroindole-2-carbaldehydes and a subsequent one-step catalytic deprotection-reductive amination.


Assuntos
Ciclitóis/síntese química , Frutose-Bifosfato Aldolase/metabolismo , Compostos Heterocíclicos com 3 Anéis/síntese química , Aldeído Liases/metabolismo , Aldeídos/química , Aminação , Catálise , Ciclitóis/química , Ciclitóis/farmacologia , Fosfato de Di-Hidroxiacetona/química , Glicosídeo Hidrolases/metabolismo , Compostos Heterocíclicos com 3 Anéis/química , Compostos Heterocíclicos com 3 Anéis/farmacologia , Modelos Moleculares , Estrutura Molecular , Estereoisomerismo
10.
Bioorg Med Chem ; 21(14): 4225-32, 2013 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-23721916

RESUMO

A small library of compounds was prepared by a combination of toluene dioxygenase (TDO)-catalyzed enzymatic dihydroxylation and copper(I)-catalyzed Hüisgen cycloaddition. Some compounds were obtained by coupling an alkyne and a conduritol derivative, while more complex structures were obtained by a double Hüisgen reaction of a dialkyne and two molecules of the cyclitol. The compounds were fully characterized and subjected to preliminary biological screening.


Assuntos
Ciclitóis/síntese química , Ciclitóis/farmacologia , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/farmacologia , Animais , Antifúngicos/síntese química , Antifúngicos/química , Antifúngicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Ciclitóis/química , Reação de Cicloadição , Imunossupressores/síntese química , Imunossupressores/química , Imunossupressores/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estrutura Molecular , Bibliotecas de Moléculas Pequenas/química , Triazóis/síntese química , Triazóis/química , Triazóis/farmacologia
11.
Future Med Chem ; 5(5): 573-90, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23573974

RESUMO

Gaucher disease is a progressive lysosomal storage disorder caused by a deficiency in the activity of ß-glucocerebrosidase and is characterized by the accumulation of the glycosphingolipid glucosylceramide in the lysosomes of macrophages that leads to dysfunction in multiple organ system. An emerging strategy for the treatment of Gaucher disease is pharmacological chaperone therapy, based on the use of ß-glucocerebrosidase inhibitors that are capable of enhancing residual hydrolytic activity at subinhibitory concentrations. In this article, the most common lysosomal storage disorder, Gaucher disease, is introduced and the current therapeutic strategies based on the use of enzyme inhibitors to ameliorate this disease are discussed, with a focus on the efforts being made toward finding and optimizing novel molecules as pharmacological chaperones for Gaucher disease that offer the promise to remedy this malady.


Assuntos
Inibidores Enzimáticos/química , Inibidores Enzimáticos/uso terapêutico , Doença de Gaucher/tratamento farmacológico , Doença de Gaucher/enzimologia , Glucosilceramidase/antagonistas & inibidores , Animais , Ciclitóis/química , Ciclitóis/farmacologia , Ciclitóis/uso terapêutico , Inibidores Enzimáticos/farmacologia , Glucosilceramidase/metabolismo , Humanos , Imino Açúcares/química , Imino Açúcares/farmacologia , Imino Açúcares/uso terapêutico , Modelos Moleculares
12.
Bioorg Med Chem ; 21(7): 1911-7, 2013 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-23419323

RESUMO

The design and synthesis of a small library of pyrrolidine iminocyclitol inhibitors with a structural similarity to 1,4-dideoxy-1,4-imino-D-arabitol (DAB-1) is reported. This library was specifically designed to gain a better insight into the mechanism of inhibition of glycosidases by polyhydroxylated pyrrolidines or iminocyclitols. Pyrrolidine-3,4-diol 15a and pyrrolidine-3,4-diol diacetate 15b had emerged as the most potent α-glucosidase inhibitors in the series. Docking studies performed with an homology model of α-glucosidase disclosed binding poses for compounds 15a, 15b, 16a, and 16a' occupying the same region as the NH group of the terminal ring of acarbose and suggest a closer and stronger binding of compound 15a and 15b with the enzyme active site residues. Our studies indicate that 2 or 5-hydroxyl substituents appear to be vital for high inhibitory activity.


Assuntos
Ciclitóis/química , Ciclitóis/farmacologia , Inibidores de Glicosídeo Hidrolases , Pirrolidinas/química , Pirrolidinas/farmacologia , Saccharomyces cerevisiae/enzimologia , Ciclitóis/síntese química , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Simulação de Acoplamento Molecular , Ligação Proteica , Pirrolidinas/síntese química , Saccharomyces cerevisiae/química , Saccharomyces cerevisiae/efeitos dos fármacos , alfa-Glucosidases/química , alfa-Glucosidases/metabolismo
13.
J Med Chem ; 55(9): 4479-88, 2012 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-22512696

RESUMO

Amino-myo-inositol derivatives have been found to be potent inhibitors of glucocerebrosidase (GCase), the ß-glucosidase enzyme deficient in Gaucher disease (GD). When tested using lymphoblasts derived from patients with GD homozygous for N370S or L444P mutations, the compounds enhanced GCase activity at very low concentrations. The most potent inhibitor, (1R,2S,3R,4S,5S,6R)-5-(nonylamino)-6-(nonyloxy)cyclohexane-1,2,3,4-tetraol had a K(i) of 1 nM using isolated enzyme and an IC(50) of 4.3 nM when assayed in human fibroblast cell culture. This aminocyclitol produced maximum increases of GCase activities of 90% in N370S lymphoblasts at 1 nM and 40% in L444P at 0.01 nM following a three-day incubation. In addition to inhibitory potency, this compound has the permeability, subcellular distribution, and cell metabolism characteristics that are important for use as a pharmacological chaperone. It is a remarkable finding that picomolar concentrations of aminocyclitols are sufficient to enhance activity in the L444P variant, which produces a severe neuronopathic form of GD without clinical treatment.


Assuntos
Ciclitóis/síntese química , Ciclitóis/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Doença de Gaucher/tratamento farmacológico , Glucosilceramidase/antagonistas & inibidores , Animais , Ciclitóis/química , Ciclitóis/farmacocinética , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Fibroblastos/efeitos dos fármacos , Doença de Gaucher/sangue , Doença de Gaucher/enzimologia , Glucosilceramidase/metabolismo , Humanos , Concentração Inibidora 50 , Linfócitos/enzimologia , Espectroscopia de Ressonância Magnética , Camundongos , Modelos Moleculares , Espectrometria de Massas por Ionização por Electrospray , Espectroscopia de Infravermelho com Transformada de Fourier , Estereoisomerismo , Relação Estrutura-Atividade
14.
J Immunol ; 188(5): 2254-65, 2012 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-22301545

RESUMO

Activation of type I NKT (iNKT) cells by CD1d-presented agonists is a potent immunotherapeutic tool. α-Galactosylceramide (α-GalCer) is the prototypic agonist, but its excessive potency with simultaneous production of both pro- and anti-inflammatory cytokines hampers its potential therapeutic use. In search for novel agonists, we have analyzed the structure and function of HS44, a synthetic aminocyclitolic ceramide analog designed to avoid unrestrained iNKT cell activation. HS44 is a weaker agonist compared with α-GalCer in vitro, although in vivo it induces robust IFN-γ production, and highly reduced but still functional Th2 response. The characteristic cytokine storm produced upon α-GalCer activation was not induced. Consequently, HS44 induced a very efficient iNKT cell-dependent antitumoral response in B16 animal model. In addition, intranasal administration showed the capacity to induce lung inflammation and airway hyperreactivity, a cardinal asthma feature. Thus, HS44 is able to elicit functional Th1 or Th2 responses. Structural studies show that HS44 binds to CD1d with the same conformation as α-GalCer. The TCR binds to HS44 similarly as α-GalCer, but forms less contacts, thus explaining its weaker TCR affinity and, consequently, its weaker recognition by iNKT cells. The ability of this compound to activate an efficient, but not massive, tailored functional immune response makes it an attractive reagent for immune manipulation.


Assuntos
Ciclitóis/química , Galactosilceramidas/química , Galactosilceramidas/farmacologia , Fatores Imunológicos/química , Fatores Imunológicos/farmacologia , Células T Matadoras Naturais/efeitos dos fármacos , Células T Matadoras Naturais/imunologia , Relação Quantitativa Estrutura-Atividade , Animais , Hiper-Reatividade Brônquica/tratamento farmacológico , Hiper-Reatividade Brônquica/imunologia , Hiper-Reatividade Brônquica/patologia , Células Cultivadas , Cristalografia por Raios X , Ciclitóis/agonistas , Ciclitóis/farmacologia , Modelos Animais de Doenças , Feminino , Galactosilceramidas/agonistas , Fatores Imunológicos/classificação , Ativação Linfocitária/efeitos dos fármacos , Melanoma Experimental/tratamento farmacológico , Melanoma Experimental/imunologia , Melanoma Experimental/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Células T Matadoras Naturais/patologia
15.
J Am Chem Soc ; 133(31): 12079-84, 2011 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-21728320

RESUMO

A new class of α-galactosylceramide (αGC) nonglycosidic analogues bearing galacto-configured aminocyclitols as sugar surrogates have been obtained. The aminocyclohexane having a hydroxyl substitution pattern similar to an α-galactoside is efficiently obtained by a sequence involving Evans aldol reaction and ring-closing metathesis with a Grubbs catalyst to give a key intermediate cyclohexene, which has been converted in galacto-aminocyclohexanes that are linked through a secondary amine to a phytoceramide lipid having a cerotyl N-acyl group. Natural Killer T (NKT) cellular assays have resulted in the identification of an active compound, HS161, which has been found to promote NKT cell expansion in vitro in a similar fashion but more weakly than αGC. This compound stimulates the release of Interferon-γ (IFNγ) and Interleukin-4 (IL-4) in iNKT cell culture but with lower potency than αGC. The activation of Invariant Natural Killer T (iNKT) cells by this compound has been confirmed in flow cytometry experiments. Remarkably, when tested in mice, HS161 selectively induces a very strong production of IFN-γ indicative of a potent Th1 cytokine profile. Overall, these data confirm the agonist activity of αGC lipid analogues having charged amino-substituted polar heads and their capacity to modulate the response arising from iNKT cell activation in vivo.


Assuntos
Ciclitóis/farmacologia , Galactosilceramidas/farmacologia , Células T Matadoras Naturais/efeitos dos fármacos , Animais , Proliferação de Células/efeitos dos fármacos , Ciclitóis/síntese química , Ciclitóis/química , Relação Dose-Resposta a Droga , Galactosilceramidas/síntese química , Galactosilceramidas/química , Camundongos , Conformação Molecular , Estereoisomerismo , Relação Estrutura-Atividade
16.
J Med Chem ; 54(7): 2069-79, 2011 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-21370884

RESUMO

A library of aminocyclitols derived from CuAAC reaction between N-propargylaminocyclitol 4 and a series of azides [1-25] is described and tested against GCase. Azides have been chosen from a large collection of potential candidates that has been filtered according to physical and reactivity constraints. A synthetic methodology has been optimized in order to avoid the use of protecting groups on the aminocyclitol scaffold. Because the reaction can be carried out in an aqueous system, the resulting library members can be screened in situ with minimal manipulation. From the preliminary GCase inhibition data, the most potent library members have been individually resynthesized for further biological screening and complete characterization. Some of the library members have shown biochemical data (IC(50), K(i), and stabilization ratio) similar or superior to those reported for NNDNJ. Docking studies have been used to postulate ligand-enzyme interactions to account for the experimental results.


Assuntos
Química Click , Ciclitóis/química , Ciclitóis/farmacologia , Avaliação Pré-Clínica de Medicamentos/métodos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Glucosilceramidase/antagonistas & inibidores , Ciclitóis/síntese química , Inibidores Enzimáticos/síntese química , Glucosilceramidase/química , Humanos , Concentração Inibidora 50 , Modelos Moleculares , Conformação Proteica , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia
17.
J Med Chem ; 53(14): 5248-55, 2010 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-20557054

RESUMO

New N-alkylaminocyclitols bearing a 1,2,3-triazole system at different positions of the alkyl chain have been prepared as potential GCase pharmacological chaperones using click chemistry approaches. Among them, compounds 1d and 1e, with the shorter spacer (n = 1) between the alkyltriazolyl system and the aminocyclitol core, were the most active ones as GCase inhibitors, revealing a determinant effect of the location of the triazole ring on the activity. Furthermore, SAR data and computational docking models indicate a correlation between lipophilicity and enzyme inhibition and suggest "extended" and "bent" potential binding modes for the compounds. In the "bent" mode, the most active compounds could establish a hydrogen-bond interaction between the triazole moiety and enzyme residue Q284. Such an interaction would be precluded in compounds with a longer spacer between the triazole and the aminocyclitol core.


Assuntos
Ciclitóis/síntese química , Glucosilceramidase/antagonistas & inibidores , Triazóis/síntese química , Ciclitóis/química , Ciclitóis/farmacologia , Doença de Gaucher/tratamento farmacológico , Doença de Gaucher/enzimologia , Humanos , Ligação de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Modelos Moleculares , Relação Estrutura-Atividade , Triazóis/química , Triazóis/farmacologia
18.
Curr Med Chem ; 17(22): 2393-418, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-20491637

RESUMO

Aminocyclitols comprise an important group of compounds with remarkable biological activities. From a structural standpoint, aminocyclitols are amino polyhydroxy cycloalkanes that can be found in nature in several families of natural products. Among them, the aminoglycoside antibiotics, since the discovery of streptomycin, have become particularly relevant at the forefront of the antibacterial treatment. Another group of aminocyclitols, generally referred to as aminocarbasugars, have been found as key structural components of some families of alkaloids that have evolved as suitable leads for the development of potent glycosidase inhibitors with a vast array of applications in medicinal chemistry, both as therapeutically useful agents as well as valuable pharmacological tools. On the other hand, the aminocyclitol moiety has been used by medicinal chemists as a versatile scaffold in drug design. Thus, in the antiviral arena, it is found as the key component of several families of carbocyclic nucleoside analogues, designed as metabolically stable surrogates of the natural nucleosides. Finally, in a still relatively unexplored area, some aminocyclitol derivatives are being used as key components of artificial receptors for which promising applications in drug research can be envisaged. In all cases, the development of the modern regio- and stereoselective synthetic methodologies enables a large variety of stereochemically defined aminocyclitol analogues in order to study in depth the influence of this moiety on the structure-activity relationships from a given lead.


Assuntos
Aminas/química , Aminas/farmacologia , Ciclitóis/química , Ciclitóis/farmacologia , Aminas/síntese química , Química Farmacêutica , Ciclitóis/síntese química , Desenho de Fármacos , Humanos , Relação Estrutura-Atividade
19.
Org Biomol Chem ; 8(7): 1527-30, 2010 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-20237662

RESUMO

A new and short synthesis of hitherto unreported stereo analogue of amino-modified five-membered iminocyclitols from readily available tri-O-benzyl-D-glucal is described. Significantly, glycosidase inhibition studies of alkylamino substituted iminocyclitols display a high degree of selectivity towards alpha-galactosidase.


Assuntos
Ciclitóis/química , Ciclitóis/farmacologia , Iminas/química , Iminas/farmacologia , alfa-Galactosidase/antagonistas & inibidores , Coffea/enzimologia , Ciclitóis/síntese química , Escherichia coli/enzimologia , Iminas/síntese química , Prunus/enzimologia , Saccharomyces cerevisiae/enzimologia , alfa-Galactosidase/metabolismo
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