RESUMO
The failure to undergo remyelination is a critical impediment to recovery in multiple sclerosis. Chondroitin sulfate proteoglycans (CSPGs) accumulate at demyelinating lesions creating a nonpermissive environment that impairs axon regeneration and remyelination. Here, we reveal a new role for 2-arachidonoylglycerol (2-AG), the major CNS endocannabinoid, in the modulation of CSPGs deposition in a progressive model of multiple sclerosis, the Theiler's murine encephalomyelitis virus-induced demyelinating disease. Treatment with a potent reversible inhibitor of the enzyme monoacylglycerol lipase, which accounts for 85% of the 2-AG degradation in the mouse CNS, modulates neuroinflammation and reduces CSPGs accumulation and astrogliosis around demyelinated lesions in the spinal cord of Theiler's murine encephalomyelitis virus-infected mice. Inhibition of 2-AG hydrolysis augments the number of mature oligodendrocytes and increases MBP, leading to remyelination and functional recovery of mice. Our findings establish a mechanism for 2-AG promotion of remyelination with implications in axonal repair in CNS demyelinating pathologies.SIGNIFICANCE STATEMENT The deposition of chondroitin sulfate proteoglycans contributes to the failure in remyelination associated with multiple sclerosis. Here we unveil a new role for 2-arachidonoylglycerol, the major CNS endocannabinoid, in the modulation of chondroitin sulfate proteoglycan accumulation in Theiler's murine encephalomyelitis virus-induced demyelinating disease. The treatment during the chronic phase with a potent reversible inhibitor of the enzyme monoacylglycerol lipase, which accounts for 85% of the 2-arachidonoylglycerol degradation in the mouse CNS, modulates neuroinflammation and reduces chondroitin sulfate proteoglycan deposition around demyelinated lesions in the spinal cord of Theiler's murine encephalomyelitis virus-infected mice. The increased 2-arachidonoylglycerol tone promotes remyelination in a model of progressive multiple sclerosis ameliorating motor dysfunction.
Assuntos
Ácidos Araquidônicos/farmacologia , Ácidos Araquidônicos/uso terapêutico , Endocanabinoides/farmacologia , Endocanabinoides/uso terapêutico , Glicerídeos/farmacologia , Glicerídeos/uso terapêutico , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/fisiopatologia , Fibras Nervosas Mielinizadas/efeitos dos fármacos , Fibras Nervosas Mielinizadas/patologia , Proteoglicanas/metabolismo , Animais , Agonistas de Receptores de Canabinoides/farmacologia , Agonistas de Receptores de Canabinoides/uso terapêutico , Relação Dose-Resposta a Droga , Regulação para Baixo/efeitos dos fármacos , Feminino , Camundongos , Esclerose Múltipla/patologia , Neurogênese/efeitos dos fármacosRESUMO
The innate immune response is mediated by primary immune modulators such as cytokines and chemokines that together with immune cells and resident glia orchestrate CNS immunity and inflammation. Growing evidence supports that the endocannabinoid 2-arachidonoylglycerol (2-AG) exerts protective actions in CNS injury models. Here, we used the acute phase of Theiler's virus induced demyelination disease (TMEV-IDD) as a model of acute neuroinflammation to investigate whether 2-AG modifies the brain innate immune responses to TMEV and CNS leukocyte trafficking. 2-AG or the inhibition of its hydrolysis diminished the reactivity and number of microglia at the TMEV injection site reducing their morphological complexity and modulating them towards an anti-inflammatory state via CB2 receptors. Indeed, 2-AG dampened the infiltration of immune cells into the CNS and inhibited their egress from the spleen, resulting in long-term beneficial effects at the chronic phase of the disease. Intriguingly, it is not a generalized action over leukocytes since 2-AG increased the presence and suppressive potency of myeloid derived suppressor cells (MDSCs) in the brain resulting in higher apoptotic CD4+ T cells at the injection site. Together, these data suggest a robust modulatory effect in the peripheral and central immunity by 2-AG and highlight the interest of modulating endogenous cannabinoids to regulate CNS inflammatory conditions.
Assuntos
Ácidos Araquidônicos/metabolismo , Infecções por Cardiovirus/imunologia , Endocanabinoides/metabolismo , Glicerídeos/metabolismo , Inflamação/imunologia , Microglia/imunologia , Theilovirus , Animais , Ácidos Araquidônicos/administração & dosagem , Encéfalo/imunologia , Encéfalo/patologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/patologia , Infecções por Cardiovirus/patologia , Modelos Animais de Doenças , Endocanabinoides/administração & dosagem , Feminino , Glicerídeos/administração & dosagem , Imunidade Inata/imunologia , Inflamação/patologia , Camundongos , Microglia/patologia , Monoacilglicerol Lipases/antagonistas & inibidores , Monoacilglicerol Lipases/metabolismo , Receptor CB2 de Canabinoide/antagonistas & inibidores , Receptor CB2 de Canabinoide/metabolismoRESUMO
Serotonin (5-HT) modulates key aspects of the immune system. However, its precise function and the receptors involved in the observed effects have remained elusive. Among the different serotonin receptors, 5-HT1A plays an important role in the immune system given its presence in cells involved in both the innate and adaptive immune responses, but its actual levels of expression under different conditions have not been comprehensively studied due to the lack of suitable tools. To further clarify the role of 5-HT1A receptor in the immune system, we have developed a fluorescent small molecule probe that enables the direct study of the receptor levels in native cells. This probe allows direct profiling of the receptor expression in immune cells using flow cytometry. Our results show that important subsets of immune cells including human monocytes and dendritic cells express functional 5-HT1A and that its activation is associated with anti-inflammatory signaling. Furthermore, application of the probe to the experimental autoimmune encephalomyelitis model of multiple sclerosis demonstrates its potential to detect the specific overexpression of the 5-HT1A receptor in CD4+ T cells. Accordingly, the probe reported herein represents a useful tool whose use can be extended to study the levels of 5-HT1A receptor in ex vivo samples of different immune system conditions.
Assuntos
Compostos de Boro/química , Citometria de Fluxo/métodos , Corantes Fluorescentes/química , Receptor 5-HT1A de Serotonina/análise , Animais , Compostos de Boro/síntese química , Técnicas de Química Sintética , Células Dendríticas/química , Corantes Fluorescentes/síntese química , Humanos , Leucócitos Mononucleares/patologia , Camundongos , Monócitos/química , Esclerose Múltipla/patologia , Linfócitos T/químicaRESUMO
Monoacylglycerol lipase (MAGL) is the enzyme responsible for the inactivation of the endocannabinoid 2-arachidonoylglycerol (2-AG). MAGL inhibitors show analgesic and tissue-protecting effects in several disease models. However, the few efficient and selective MAGL inhibitors described to date block the enzyme irreversibly, and this can lead to pharmacological tolerance. Hence, additional classes of MAGL inhibitors are needed to validate this enzyme as a therapeutic target. Here we report a potent, selective, and reversible MAGL inhibitor (IC50=0.18â µM) which is active in vivo and ameliorates the clinical progression of a multiple sclerosis (MS) mouse model without inducing undesirable CB1 -mediated side effects. These results support the interest in MAGL as a target for the treatment of MS.
Assuntos
Monoacilglicerol Lipases/antagonistas & inibidores , Esclerose Múltipla/tratamento farmacológico , Animais , Modelos Animais de Doenças , Inibidores Enzimáticos/uso terapêutico , CamundongosRESUMO
Selective inhibition of the RGD (Arg-Gly-Asp) integrin αvß1 has been recently identified as an attractive therapeutic approach for the treatment of liver fibrosis given its function, target expression, and safety profile. Our identification of a non-RGD small molecule lead followed by focused, systematic changes to the core structure utilizing a crystal structure, in silico modeling, and a tractable synthetic approach resulted in the identification of a potent small molecule exhibiting a remarkable affinity for αvß1 relative to several other integrin isoforms measured. Azabenzimidazolone 25 demonstrated antifibrotic efficacy in an in vivo rat liver fibrosis model and represents a tool compound capable of further exploring the biological consequences of selective αvß1 inhibition.
Assuntos
Desenho de Fármacos , Receptores de Vitronectina , Animais , Ratos , Humanos , Receptores de Vitronectina/antagonistas & inibidores , Receptores de Vitronectina/metabolismo , Relação Estrutura-Atividade , Cirrose Hepática/tratamento farmacológico , Modelos Moleculares , Descoberta de Drogas , Ratos Sprague-Dawley , Masculino , Cristalografia por Raios X , Benzimidazóis/farmacologia , Benzimidazóis/química , Benzimidazóis/síntese químicaRESUMO
Given the significance of carbohydrates in life, medicine, and industry, the development of simple and efficient de novo methods to synthesize carbohydrates are highly desirable. Organocatalytic asymmetric assembly reactions are powerful tools to rapidly construct molecules with stereochemical complexity from simple precursors. Here, we present a simple and robust methodology for the asymmetric synthesis of pyranose derivatives with talo- and manno- configurations from simple achiral precursors through organocatalytic asymmetric intermolecular Michael-Henry reaction sequences. In this process, (tert-butyldimethylsilyloxy)acetaldehyde 1 was successfully utilized in two ways: as a donor in a highly selective anti-Michael reaction and as an acceptor in a consecutive Henry reaction. Varied nitroolefins served as Michael acceptors and varied aldehydes substituted for 1 as Henry acceptors providing for the construction of a wide range of carbohydrates with up to 5 stereocenters. In these reactions, a catalyst-controlled Michael reaction followed by a substrate-controlled Henry reaction provided 3,4-dideoxytalose derivatives 6 in a highly stereoselective manner. The Henry reaction was affected by addition of a simple base such as triethylamine: A complex chiral base was not necessary. 3,4-Dideoxymannose derivatives 7 were produced by simply changing the base from triethylamine to 1,8-diazabicyclo[5.4.0]undec-7-ene. Extension of this methodology to a syn-Michael initiated sequence was also successful. A mechanistic discussion is provided to explain the unusual substrate-induced stereoselectivity of the Henry reaction.
Assuntos
Carboidratos/química , Carboidratos/síntese química , Modelos Químicos , Catálise , Cristalografia por Raios X , Lactonas/química , Manose/químicaRESUMO
Carbazolespirooxindole derivatives were synthesized in a high-yielding, atypically rapid, stereocontrolled Diels-Alder reaction catalyzed by a C(2)-symmetric bisthiourea organocatalyst. Simple precursors and mild conditions were used to construct carbazolespirooxindole derivatives with high enantiopurity and structural diversity under H-bonding catalysis. The practical approach recycles the organocatalyst and solvent. This simple and efficient operational procedure will allow diversity-oriented syntheses of this intriguing class of compounds.
Assuntos
Indóis/química , Catálise , Ligação de Hidrogênio , Indóis/síntese química , Estereoisomerismo , Tioureia/químicaRESUMO
Good to excellent stereoselectivities were achieved in the reductive cyclization (with Et(3)SiH/trimethylsilyl trifluoromethanesulfonate (TMSOTf)) of enantiopure hydroxy sulfinyl ketones en route to 2,5-cis-disubstituted tetrahydrofuran skeletons. Electrostatic effects of the exocyclic sulfoxide, which stabilized the reactive intermediate oxocarbenium conformations, were responsible for the observed stereocontrol. A model is proposed to explain the results. The use of this reaction and the asymmetric ß-ketosulfoxide reduction as key steps facilitated the total enantioselective synthesis of the natural ß-C-aryl glycoside (+)-goniothalesdiol.
Assuntos
Produtos Biológicos/química , Furanos/química , Metano/análogos & derivados , Sulfóxidos/química , Ciclização , Furanos/síntese química , Espectroscopia de Ressonância Magnética , Metano/química , Conformação Molecular , Estrutura Molecular , EstereoisomerismoRESUMO
Neuropathic pain (NP) is a complex chronic pain state with a prevalence of almost 10% in the general population. Pharmacological options for NP are limited and weakly effective, so there is a need to develop more efficacious NP attenuating drugs. Activation of the type 1 lysophosphatidic acid (LPA1) receptor is a crucial factor in the initiation of NP. Hence, it is conceivable that a functional antagonism strategy could lead to NP mitigation. Here we describe a new series of LPA1 agonists among which derivative (S)-17 (UCM-05194) stands out as the most potent and selective LPA1 receptor agonist described so far (Emax = 118%, EC50 = 0.24 µM, KD = 19.6 nM; inactive at autotaxin and LPA2-6 receptors). This compound induces characteristic LPA1-mediated cellular effects and prompts the internalization of the receptor leading to its functional inactivation in primary sensory neurons and to an efficacious attenuation of the pain perception in an in vivo model of NP.
Assuntos
Analgésicos/química , Analgésicos/uso terapêutico , Neuralgia/tratamento farmacológico , Receptores de Ácidos Lisofosfatídicos/agonistas , Animais , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Células Cultivadas , Descoberta de Drogas , Feminino , Humanos , Hidrocarbonetos Aromáticos/química , Hidrocarbonetos Aromáticos/uso terapêutico , Camundongos Endogâmicos C57BL , Modelos Moleculares , Neuralgia/metabolismo , Percepção da Dor/efeitos dos fármacos , Ratos Wistar , Receptores de Ácidos Lisofosfatídicos/metabolismo , Células Receptoras Sensoriais/efeitos dos fármacos , Células Receptoras Sensoriais/metabolismoRESUMO
Background: The diabetic neuropathy is the most common microvascular complication of diabetes mellitus. The reported prevalence ranges from 10-90%. Electrophysiological alterations can be demonstrated in nearly 100% of diabetics. Objective: To know the current profile of the patient with diabetic polyneuropathy. Methods: Retrospective and descriptive study from 2015 to 2016. Reports of electroneuromyography with diabetic polyneuropathy result were analyzed, evaluating neuroconduction parameters of motor and sensory nerves, late F responses and myography. Descriptive statistics, Student's t-test and Pearson's correlation coefficient were used. Results: The sample included 72 men (65.5%) and 38 women (34.5%), mean age 61.2 years, mean duration of diabetes of 9.9 years. The most affected nerve was superficial peroneus, absent in 70% of the population.A positive correlation was found (p < 0.001) for the affection of all the nerves symmetrically and predominantly in neuroconduction velocities of the lower and upper limbs. Conclusion: The most frequent electrophysiological finding in diabetic polyneuropathy was sensory affection, being more severe in lower limbs. A finding in patients with recent diagnosis is the prolongation of proximal latencies in the lower extremities.
Introducción: la neuropatía diabética es la complicación microvascular más frecuente de la diabetes mellitus. Las prevalencias reportadas oscilan del 10 al 90%. Se pueden demostrar alteraciones electrofisiológicas en casi el 100% de los diabéticos. Objetivo: conocer el perfil actual del paciente con polineuropatía diabética. Métodos: estudio retrospectivo y descriptivo del año 2015 a 2016. Se analizaron reportes de electroneuromiografía con resultado de polineuropatía diabética, evaluando parámetros de neuroconducción de nervios motores y sensoriales, respuestas tardías F y miografía. Se utilizó estadística descriptiva, la prueba de t de Student y el coeficiente de correlación de Pearson. Resultados: la muestra incluyó a 72 hombres (65.5%) y 38 mujeres (34.5%), con edad media de 61.2 años, todos con diagnóstico de diabetes mellitus tipo 2, con duración media de la diabetes de 9.9 años. El nervio más afectado fue el peroneo superficial, ausente en el 70% de la población. Se encontró una correlación positiva(p < 0.001) para la afección de todos los nervios de forma simétrica y de predominio en velocidades de neuroconducción de miembros inferiores y superiores. Conclusión: el hallazgo electrofisiológico más frecuente en polineuropatía diabética fue la afección sensorial, siendo más severa en miembros inferiores. Un hallazgo en pacientes con reciente diagnóstico es la prolongación de latencias proximales en extremidades inferiores.
RESUMO
An efficient approach to (Rp) planar-chiral tri- and tetracyclic ortho-condensed aromatic ferrocenes was developed through the enantioselective cationic Au(i)-catalyzed cycloisomerization, in the presence of bidentate phosphine ligand (R)-DTBM-Segphos, from readily available ortho-alkynylaryl ferrocenes under very mild conditions (11 examples, up to 92% yield and 93% ee).
RESUMO
[reaction: see text] The stereoselective synthesis of (+)-goniothalesdiol (1) was accomplished in nine steps starting from commercially available (-)-(2S,3S)-dimethyl D-tartrate (3). The key features were a completely diastereoselective reduction of a beta-ketosulfoxide to generate the stereogenic center at C-5 in 7 and formation of the 2,5-cis-substituted tetrahydrofuran ring in 10 from a stereoselective Et(3)SiH/TMSOTf-promoted reductive cyclization/deoxygenation.
Assuntos
Furanos/síntese química , Catálise , Furanos/química , Estrutura Molecular , Estereoisomerismo , Tartaratos/químicaRESUMO
Cochinchinenone has been synthesized in only five steps and four pots and in 58% overall yield from commercially available 2,3-dimethoxy-4-hydroxy-benzaldehyde and OPMB-protected p-hydroxy acetophenone, the key step being the oxone-mediated oxidative dearomatization of the corresponding ketone-containing p-substituted phenol.
Assuntos
Antibacterianos/síntese química , Produtos Biológicos/síntese química , Chalconas/síntese química , Antibacterianos/química , Antibacterianos/isolamento & purificação , Antibacterianos/farmacologia , Produtos Biológicos/química , Produtos Biológicos/isolamento & purificação , Produtos Biológicos/farmacologia , Catálise , Chalconas/química , Chalconas/isolamento & purificação , Chalconas/farmacologia , Helicobacter pylori/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Ressonância Magnética Nuclear BiomolecularRESUMO
Organocatalytic stereospecific dibromination of a wide variety of functionalized alkenes was achieved using a stable, inexpensive halogen source, 1,3-dibromo 5,5-dimethylhydantoin, and a simple thiourea catalyst at room temperature. The presence of a tertiary amine enhanced the rate of the dibromination reaction, and yields were good in various solvents, including aqueous solvents. The procedure was extended to alkynes and aromatic rings and to dichlorination reactions by using the 1,3-dichloro hydantoin derivative.
Assuntos
Alcenos/química , Hidantoínas/química , Hidrocarbonetos Bromados/síntese química , Catálise , Hidrocarbonetos Bromados/química , Estrutura Molecular , EstereoisomerismoRESUMO
An enantioselective α-amination of aryl oxindoles catalyzed by a dimeric quinidine has been developed. The reaction is general, broad in substrate scope, and affords the desired products in good yields with good to excellent enantioselectivities. This study provides the first examples of a general organocatalytic method for the creation of nitrogen-containing, tetrasubstituted chiral centers at C(3) of various aryl oxindoles. Furthermore, new catalysts and insights into structural elements of the catalysts that significantly influence enantioselectivities are disclosed.
Assuntos
Alcaloides/química , Indóis/química , Aminação , Catálise , Dimerização , Estrutura Molecular , Oxindóis , EstereoisomerismoRESUMO
The asymmetric synthesis of the natural gamma-tocopherol metabolite (S)-gamma-CEHC (1) is described in 10 steps and 18.4% overall yield starting from 2,3-dimethylhydroquinone. The key step is a stereoselective TiCl(4)-mediated homochiral sulfoxide-directed allylation of ketal (SS)-3 to efficiently generate the challenging C-2 stereogenic carbon of chroman (SS,S)-2 with the correct absolute configuration.
Assuntos
Cromanos/síntese química , Propionatos/síntese química , gama-Tocoferol/metabolismo , Animais , Catálise , Cromanos/química , Estrutura Molecular , Propionatos/química , Ratos , EstereoisomerismoRESUMO
(2R,4'RS,8'RS)-alpha-tocopherol (1) was prepared using, as the two key steps, a novel diastereoselective TiCl(4)-promoted (S)-sulfoxide-directed allylation of ketal 2 with allyl trimethyl silane 3 to efficiently generate the challenging (2R) stereocenter of the chroman moiety and a cross-metathesis reaction with olefin 4 to efficiently join the lipophilic alkyl chain present in the final target.
Assuntos
Cromanos/química , alfa-Tocoferol/síntese química , Alcenos/química , Catálise , Estrutura Molecular , Estereoisomerismo , alfa-Tocoferol/químicaRESUMO
Sulfoxides are nowadays recognised as powerful chiral auxiliaries that may participate in a wide range of asymmetric reactions. Their high configurational stability, the existence of several efficient methods allowing the access to both configurations as well as their synthetic versatility are characteristic features offering a tremendous potential to develop new applications. Significant recent advances leading to high asymmetric inductions in carbon-carbon and carbon-oxygen bond forming reactions, and applications of homochiral sulfoxides to atroposelective synthesis and asymmetric catalysis are discussed. New uses of sulfoxides in the design of chiroptical switches are also shown.