RESUMO
The exponential growth of the aged population worldwide is followed by an increase in the prevalence of age-related disorders. Oxidative stress plays central role in damage accumulation during ageing and cell senescence. Thus, a major target of today's anti-ageing research has been focused on antioxidants counteracting senescence. In the current work, six novel 5,7,8-trimethyl-1,4-benzoxazine/catechol or resorcinol hybrids were synthesized connected through a methoxymethyl-1,2,3-triazolyl or a 1,2,3-triazoly linker. The compounds were evaluated for their antioxidant capacity in a cell-free system and for their ability to reduce intracellular ROS levels in human skin fibroblasts, both young (early-passage) and senescent. The most efficient compounds were further tested in these cells for their ability to induce the expression of the gene heme oxygenase-1 (ho-1), known to regulate redox homeostasis, and cellular glutathione (GSH) levels. Overall, the two catechol derivatives were found to be more potent than the resorcinol analogues. Furthermore, these two derivatives were shown to act coordinately as radical scavengers, ROS inhibitors, ho-1 gene expression inducers, and GSH enhancers. Interestingly, one of the two catechol derivatives was also found to enhance human skin fibroblast viability. The properties of the synthesized compounds support their potential use in cosmetic applications, especially in products targeting skin ageing.
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A role for vitamin D in immune modulation and in cancer has been suggested. In this work, we report that mice with increased availability of vitamin D display greater immune-dependent resistance to transplantable cancers and augmented responses to checkpoint blockade immunotherapies. Similarly, in humans, vitamin D-induced genes correlate with improved responses to immune checkpoint inhibitor treatment as well as with immunity to cancer and increased overall survival. In mice, resistance is attributable to the activity of vitamin D on intestinal epithelial cells, which alters microbiome composition in favor of Bacteroides fragilis, which positively regulates cancer immunity. Our findings indicate a previously unappreciated connection between vitamin D, microbial commensal communities, and immune responses to cancer. Collectively, they highlight vitamin D levels as a potential determinant of cancer immunity and immunotherapy success.
Assuntos
Bacteroides fragilis , Microbioma Gastrointestinal , Inibidores de Checkpoint Imunológico , Neoplasias , Vitamina D , Animais , Feminino , Humanos , Masculino , Camundongos , Bacteroides fragilis/metabolismo , Microbioma Gastrointestinal/efeitos dos fármacos , Inibidores de Checkpoint Imunológico/uso terapêutico , Inibidores de Checkpoint Imunológico/farmacologia , Imunoterapia , Mucosa Intestinal/imunologia , Mucosa Intestinal/microbiologia , Mucosa Intestinal/metabolismo , Camundongos Endogâmicos C57BL , Neoplasias/imunologia , Neoplasias/microbiologia , Neoplasias/terapia , Vitamina D/administração & dosagem , Vitamina D/metabolismo , Dieta , Linhagem Celular Tumoral , Calcifediol/administração & dosagem , Calcifediol/metabolismo , Proteína de Ligação a Vitamina D/genética , Proteína de Ligação a Vitamina D/metabolismoRESUMO
Purine analogues bearing a nitrate ester motif were previously discovered as cardioprotective and anti-inflammatory agents, but the anti-inflammatory mechanism remains to be established. We therefore investigated the anti-inflammatory effect of two purine analogues, MK118 bearing a nitrate ester moiety and the methyl-substituted analogue MK196 in Aortic Smooth Muscle Cells (AoSMCs), with emphasis on IL-1ß release. The AoSMCs were stimulated with LPS with or without purine analogue, followed by ELISA, Olink proteomics, Western blot and real time PCR of NLRP3 inflammasome components. Both purine analogues inhibited the release of proteins involved in inflammation, such as TRAIL, CCL4, CSF1 and IL-1ß in AoSMCs, as well as intracellular gene and protein expression of IL-1ß and NLRP3 inflammasome components. MK196, but not MK118, also inhibited the LPS-induced release of IL-7, CXCL10, PD-L1, FLT3L and CCL20. We also showed that MK118 and possibly MK196 act via inhibition of JAKs. In silico studies showed that the purine moiety is a competent hinge binding motif and that the purine-piperazine scaffold is well accommodated in the lipophilic groove of JAK1-3. Both compounds establish interactions with catalytic amino acids in the active site of JAK1-3 and the terminal nitrate ester of MK118 was revealed as a promising pharmacophore. Our data suggest that MK118 and MK196 inhibit the release of proinflammatory proteins in AoSMCs, and targets JAK1-3 activation. Purine analogues also inhibit the expression of NLRP3 inflammasome genes and proteins and may in the future be evaluated for anti-inflammatory aspects on inflammatory diseases.
Assuntos
Inflamassomos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Caspase 1/metabolismo , Ésteres , Humanos , Inflamassomos/metabolismo , Interleucina-1beta/metabolismo , Lipopolissacarídeos/farmacologia , Miócitos de Músculo Liso/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Nitratos , PurinasRESUMO
Cytotoxic therapies, besides directly inducing cancer cell death, can stimulate immune-dependent tumor growth control or paradoxically accelerate tumor progression. The underlying mechanisms dictating these opposing outcomes are poorly defined. Here, we show that cytotoxic therapy acutely upregulates cyclooxygenase (COX)-2 expression and prostaglandin E2 (PGE2) production in cancer cells with pre-existing COX-2 activity. Screening a compound library of 1280 approved drugs, we find that all classes of chemotherapy drugs enhance COX-2 transcription whilst arresting cancer cell proliferation. Genetic manipulation of COX-2 expression or its gene promoter region uncover how augmented COX-2/PGE2 activity post-treatment profoundly alters the inflammatory properties of chemotherapy-treated cancer cells in vivo. Pharmacological COX-2 inhibition boosts the efficacy of the combination of chemotherapy and PD-1 blockade. Crucially, in a poorly immunogenic breast cancer model, only the triple therapy unleashes tumor growth control and significantly reduces relapse and spontaneous metastatic spread in an adjuvant setting. Our findings suggest COX-2/PGE2 upregulation by dying cancer cells acts as a major barrier to cytotoxic therapy-driven tumor immunity and uncover a strategy to improve the outcomes of immunotherapy and chemotherapy combinations.
Assuntos
Antineoplásicos , Neoplasias , Antineoplásicos/farmacologia , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Dinoprostona/metabolismo , Imunoterapia , Regulação para CimaRESUMO
Beyond the conventional perception of solid tumours as mere masses of cancer cells, advanced cancer research focuses on the complex contributions of tumour-associated host cells that are known as "tumour microenvironment" (TME). It has been long appreciated that the tumour stroma, composed mainly of blood vessels, cancer-associated fibroblasts and immune cells, together with the extracellular matrix (ECM), define the tumour architecture and influence cancer cell properties. Besides soluble cues, that mediate the crosstalk between tumour and stroma cells, cell adhesion to ECM arises as a crucial determinant in cancer progression. In this review, we discuss how adhesome, the intracellular protein network formed at cell adhesions, regulate the TME and control malignancy. The role of adhesome extends beyond the physical attachment of cells to ECM and the regulation of cytoskeletal remodelling and acts as a signalling and mechanosensing hub, orchestrating cellular responses that shape the tumour milieu.
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The P2X7 receptor is a promising target for the treatment of various diseases due to its significant role in inflammation and immune cell signaling. This work describes the design, synthesis, and inâ vitro evaluation of a series of novel derivatives bearing diverse scaffolds as potent P2X7 antagonists. Our approach was based on structural modifications of reported (adamantan-1-yl)methylbenzamides able to inhibit the receptor activation. The adamantane moieties and the amide bond were replaced, and the replacements were evaluated by a ligand-based pharmacophore model. The antagonistic potency of the synthesized analogues was assessed by two-electrode voltage clamp experiments, using Xenopus laevis oocytes that express the human P2X7 receptor. SAR studies suggested that the replacement of the adamantane ring by an aryl-cyclohexyl moiety afforded the most potent antagonists against the activation of the P2X7 cation channel, with analogue 2-chloro-N-[1-(3-(nitrooxymethyl)phenyl)cyclohexyl)methyl]benzamide (56) exhibiting the best potency with an IC50 value of 0.39â µM.
Assuntos
Benzamidas/farmacologia , Antagonistas do Receptor Purinérgico P2X/farmacologia , Receptores Purinérgicos P2X7/metabolismo , Adamantano/análogos & derivados , Adamantano/farmacologia , Animais , Benzamidas/síntese química , Cicloexanos/síntese química , Cicloexanos/farmacologia , Desenho de Fármacos , Humanos , Estrutura Molecular , Antagonistas do Receptor Purinérgico P2X/síntese química , Relação Estrutura-Atividade , Xenopus laevisRESUMO
Natural purines like ATP, ADP and adenosine have crucial roles in platelet physiology. This knowledge has been significant in drug development and today ADP receptor antagonists are widely used for prevention of thrombotic events following myocardial infarction and ischaemic stroke. Recent studies have shown that a purine analogue bearing nitrate ester group (denoted MK128) has anti-inflammatory effects probably due to its ability to donate nitric oxide (NO). However, other pharmacological mechanisms may contribute to the observed effect. The aim of the present study was to establish the anti-platelet activity and elucidate the underlying molecular mechanism(s) of the purine analogue MK128. We found that MK128 reduced aggregation and secretion induced by the thrombin receptor agonist SFLLRN and nearly abolished aggregation and secretion induced by thromboxane A2 (TxA2) and collagen receptor agonists. The inhibition took place despite blockage of the NO/cGMP signalling system. Furthermore, interaction between MK128 and platelet purinergic receptors did not explain the observed inhibition. Instead, we found that MK128 concentration-dependently inhibited Rho-associated kinase (ROCK), which led to decreased ROCK-dependent myosin phosphatase target subunit (MYPT)-1 phosphorylation and suppression of platelet functional responses.
Assuntos
Ésteres/química , Nitratos/química , Ativação Plaquetária/efeitos dos fármacos , Purinas/química , Purinas/farmacologia , Quinases Associadas a rho/antagonistas & inibidores , GMP Cíclico/metabolismo , Humanos , Óxido Nítrico/metabolismo , Agregação Plaquetária/efeitos dos fármacos , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Receptores Purinérgicos P1/metabolismo , Receptores Purinérgicos P2/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
Four heteroaromatic compounds bearing nitrate esters were selected using a virtual-screening procedure as putative sterol 14α-demethylase (CYP51) Candida albicans inhibitors. Compounds were examined for their inhibition on C.â albicans growth and biofilm formation as well as for their toxicity. NMR spectroscopy studies, inâ silico docking, and molecular dynamics simulations were used to investigate further the selectivity of these compounds to fungal CYP51. All compounds exhibited good antimicrobial properties, indicated with low minimal inhibitory concentrations and ability to inhibit formation of fungal biofilm. Moreover, all of the compounds had the ability to inhibit growth of C.â albicans cells. N-(2-Nitrooxyethyl)-1Η-indole-2-carboxamide was the only compound with selectivity on C.â albicans CYP51 that did not exhibit cytotoxic effect on cells isolated from liver and should be further investigated for selective application in new leads for the treatment of candidiasis.
Assuntos
Inibidores de 14-alfa Desmetilase/síntese química , Amidas/síntese química , Antifúngicos/síntese química , Candida albicans/enzimologia , Ésteres/química , Indóis/síntese química , Inibidores de 14-alfa Desmetilase/farmacologia , Inibidores de 14-alfa Desmetilase/toxicidade , Amidas/farmacologia , Amidas/toxicidade , Animais , Antifúngicos/farmacologia , Antifúngicos/toxicidade , Biofilmes/efeitos dos fármacos , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Desenho de Fármacos , Ésteres/farmacologia , Humanos , Indóis/farmacologia , Indóis/toxicidade , Fígado/citologia , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Ligação Proteica , Esterol 14-Desmetilase/metabolismo , Relação Estrutura-Atividade , SuínosRESUMO
Natural ß-thujaplicin displays a remarkable array of biological activities for the prevention or treatment of various disorders while its tropolone scaffold inspired the synthesis of new analogs. The main goal of the current study was to evaluate the influence of 4-substituted piperazine moieties at position 7 of the ß-thujaplicin scaffold, on the antimicrobial activity. In order to determine the biological activity of the ß-thujaplicin derivatives, a microdilution method was used against a wide variety of bacteria and fungi. Pseudomonas aeruginosa PAO 1 was used for testing antiquorum and antibiofilm effects. Four human tumor cell lines (MCF-7, NCI-H460, HeLa, and HepG2) and a porcine liver derived cell line (PLP2) were used for testing antitumor and cytotoxic activity. The compounds present better antibacterial and antifungal activity in comparison with approved antimicrobials used as control agents. ß-Thujaplicin showed strong antibacterial and antifungal activities against all tested species. Further studies of their antibacterial activity revealed that all compounds presented good antibiofilm and antiquorum effects. Fungi were more susceptible than bacteria to the tested compounds, with the exception of MK150, which possessed the best antibacterial effect. None of the tested compounds, at the GI50 values obtained for the tumor cell lines, have shown toxicity for non-tumor liver cells (PLP2). The prediction of physicochemical properties of the compounds was performed to further explain the structure-activity relationship. Finally, in order to explore a possible mechanism of action of the synthesized compounds, molecular docking studies were performed on CYP51 (14-a lanosterol demethylase), an important component of the fungal cell membrane.
Assuntos
Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Biofilmes/efeitos dos fármacos , Monoterpenos/química , Monoterpenos/farmacologia , Tropolona/análogos & derivados , Animais , Linhagem Celular , Linhagem Celular Tumoral , Humanos , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Percepção de Quorum/efeitos dos fármacos , Relação Estrutura-Atividade , Suínos , Tropolona/química , Tropolona/farmacologiaRESUMO
INTRODUCTION: The vitamin E family consists of four tocopherols and four tocotrienols. α-Tocopherol is the most studied member of this family for its antioxidant and non-antioxidant properties, while tocotrienols have attracted recent research interest. The structural motifs of the vitamin E family and specifically the chroman moiety, are amenable to various modifications in order to improve their bioactivities towards numerous therapeutic targets. AREAS COVERED: This review includes the patent literature from 2010 - 2015 related to vitamin E derivatives and it is focused on 2-, 5- or 6-substituted chroman analogues. The patent search was performed using Reaxys® and esp@cenet. EXPERT OPINION: The chroman moiety of vitamin E is a privileged structure and an essential pharmacophore which inspired organic chemists to synthesize new analogues with improved bioactivities. Modifications at the 2- and 5- positions of the chroman ring resulted in very interesting active compounds in cellular and animal models of diseases related to oxidative stress. More recent publications and patents reported 6-substituted chromans as anticancer agents in vitro and in vivo. Additionally, an emerging interest is observed towards the use of vitamin E analogues incorporated in drug delivery systems and for medical imaging as contrast agents or fluorescent probes.
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Desenho de Fármacos , Tocoferóis/administração & dosagem , Tocotrienóis/administração & dosagem , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Antineoplásicos/farmacologia , Antioxidantes/administração & dosagem , Antioxidantes/química , Antioxidantes/farmacologia , Sistemas de Liberação de Medicamentos , Humanos , Estresse Oxidativo/efeitos dos fármacos , Patentes como Assunto , Tocoferóis/química , Tocoferóis/farmacologia , Tocotrienóis/química , Tocotrienóis/farmacologiaRESUMO
INTRODUCTION: Lipoic acid (LA), a naturally occurring 1,2-dithiolane analog that plays an essential role in mitochondrial bioenergetic reactions, has gained unprecedented attention as nutritional supplement and as therapeutic agent. Moreover, LA conjugates with other pharmacophores represent a promising approach toward the development of multifunctional drugs. AREAS COVERED: The reviewed patent applications from January 2011 to April 2014 include combinations of LA with other bioactive compounds as well as LA conjugates for the treatment of a wide range of clinical conditions. Additionally, some patents disclose methods to overcome the stability problems of LA. EXPERT OPINION: LA is currently in clinical use for the treatment of diabetic neuropathy, while small clinical trials using combinations of LA with known bioactive agents have been undertaken. The use of the LA is hampered by its instability and its rapid metabolism. Thus, formulations containing LA, in a form ensuring its stability and improving its bioavailability, can have important applications as medicines, nutritional supplements or cosmeceuticals. LA hybrids with other pharmacophores endowed with various activities, possess an enormous potential to promote human health and have been the subject of numerous publications and patent applications. Nevertheless, reliable in vivo data and clinical trials are necessary to prove these beneficial effects.
Assuntos
Suplementos Nutricionais , Desenho de Fármacos , Ácido Tióctico/uso terapêutico , Animais , Disponibilidade Biológica , Química Farmacêutica , Neuropatias Diabéticas/tratamento farmacológico , Estabilidade de Medicamentos , Humanos , Patentes como Assunto , Ácido Tióctico/química , Ácido Tióctico/farmacocinéticaRESUMO
One-pot uncatalysed microwave-assisted 1,3-dipolar cycloaddition reactions between in situ generated nitrile oxides and alkynes bearing protected antioxidant substituents, were regioselectively afforded 3,5-disubstituted isoxazoles. The yields were moderate, based on the starting aldehydes, while the reaction times were in general shorter than those reported in the literature. The cytoprotective and anti-ageing effect of the final deprotected compounds was evaluated in vitro, on cellular survival following oxidative challenge and in vivo, on organismal longevity using the nematode Caenorhabditis elegans. The activity of the isoxazole analogues depends on the nature and the number of the antioxidant substituents. Analogue 17 bearing a phenolic group and a 6-OH-chroman group is a promising anti-ageing agent, since it increased survival of human primary fibroblasts following treatment with H2O2 and extended C. elegans lifespan.
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Envelhecimento/efeitos dos fármacos , Isoxazóis/síntese química , Isoxazóis/farmacologia , Micro-Ondas , Alcinos/química , Animais , Caenorhabditis elegans/efeitos dos fármacos , Caenorhabditis elegans/fisiologia , Linhagem Celular , Técnicas de Química Sintética , Humanos , Isoxazóis/química , Longevidade/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Óxidos/química , Estereoisomerismo , Especificidade por SubstratoRESUMO
Six purine analogues bearing a nitrate ester group (potential NO donor) were tested on human THP-1 macrophages to investigate their effects on the inflammatory response. Only three analogues increased the basal level of IL-1ß. Two analogues exacerbated the inflammatory response induced by ATP but not that induced by H2O2. Only 6-[4-(6-nitroxyacetyl)piperazin-1-yl]-9H-purine (compound MK128) abolished ATP or H2O2-induced IL-1ß production in the culture medium. Similar results were reproduced on macrophages differentiated from buffy coats and stimulated with LPS. MK128 was the only analogue to release NO and leading to nitrite formation in the culture medium. The EC50 for inhibition of induced IL-1ß production by the cells was estimated to be 10-12µg/ml (about 36µM) and corresponded to the production of around 30µM nitrites in the culture medium. This anti-inflammatory effect of MK128 was mimicked by trinitrin used in 10 fold higher concentrations. Preincubation of cells with NO trapper cPTIO partially abolished the beneficial effect of MK128 while MK137, a ONO2 deprived analogue of MK128, was not able to inhibit induced IL-1ß production and proved to be inflammatory. Moreover, purinergic channel inhibitors (oATP and U73122) inhibited the MK137 inflammatory effect. Finally, MK128 reduced the quantity of p20 caspase-1 produced in the culture medium. We suggest that MK128 inhibits IL-1ß production via NO production and subsequent inflammasome component nitrosylation. On the opposite MK137, deprived from ONO2 group, could act as agonist of purinergic receptors and could thus activate inflammasome.
Assuntos
Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Nitratos/química , Purinas/química , Purinas/farmacologia , Anti-Inflamatórios/efeitos adversos , Anti-Inflamatórios/metabolismo , Caspase 1/metabolismo , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Ésteres , Humanos , Inflamação/tratamento farmacológico , Interleucina-1beta/biossíntese , Óxido Nítrico/biossíntese , Purinas/efeitos adversos , Purinas/metabolismo , Receptores Purinérgicos P2/metabolismoRESUMO
Herein is reported a one-pot three-step process for the regioselective synthesis of 3,5-disubstituted isoxazoles based on copper(I)-catalyzed cycloaddition reaction between in situ generated nitrile oxides (from the corresponding aldehydes) and alkynes, using ultrasound irradiation, avoiding toxic reagents and solvents and isolation/purification of intermediates. The combined use of 40 kHz ultrasonic bath and 20 kHz probe in the presence of copper turnings reduced reaction time to 1h and resulted in only one final purification step with increased yields, clearly indicating that there is a dual-frequency synergistic effect. In addition, under metal free conditions, the 1,3-dipolar cycloaddition was regioselective giving low to modest yields.
Assuntos
Isoxazóis/química , Isoxazóis/síntese química , Ultrassom , Aldeídos/química , Alcinos/química , Técnicas de Química SintéticaRESUMO
Novel purine analogues bearing nitrate esters were designed and synthesized in an effort to develop compounds triggering endogenous cardioprotective mechanisms such as ischemic preconditioning (IPC) or postconditioning (PostC). The majority of the compounds reduced infarct size compared to the control group in anesthetized rabbits, whereas administration of the most active analogue 16 at a dose of 3.8 µmol/kg resulted on a significant reduction of infarct size, compared to PostC group (13.4 ± 1.9% vs 26.4 ± 2.3%). These findings introduce a novel class of promising pharmacological compounds that could be used as mimics or enhancers of PostC.
Assuntos
Cardiotônicos/química , Cardiotônicos/uso terapêutico , Pós-Condicionamento Isquêmico/métodos , Infarto do Miocárdio/tratamento farmacológico , Purinas/química , Purinas/uso terapêutico , Animais , Coração/efeitos dos fármacos , Hemodinâmica/efeitos dos fármacos , Infarto do Miocárdio/patologia , Miocárdio/patologia , Nitratos/química , Nitratos/uso terapêutico , CoelhosRESUMO
We have previously reported that catechol-bearing regioisomers of 5-isoxazolyl-6-hydroxy-chroman display higher in vitro neuroprotective activity, compared to hybrids with other nitrogen heterocycles, but their activity is hampered by cytotoxicity at higher concentrations. In an effort to discover non-cytotoxic isoxazole substituted chromans of high neuroprotective activity, 20 new 3- and 5-substituted (chroman-5-yl)-isoxazoles and (chroman-2-yl)-isoxazoles were synthesized using the copper(I)-catalysed cycloaddition reaction between in situ generated nitrile oxides and terminal acetylenes. An additional aim was to further explore the effect of the isoxazole ring substituents on the neuroprotective activity. The activity of these compounds against oxidative stress-induced death (oxytosis) of neuronal HT22 cells was evaluated and interesting SARs for this group of analogues were derived. The vast majority of new chroman analogues displayed high in vitro neuroprotective activity displaying EC(50) values below 1 µM and lacked cytotoxicity. The position of substituents on the isoxazole ring influences the activity of the regioisomers, with the 3-aryl-5-(chroman-5-yl)-isoxazoles, 17 and 18 and bis-chroman 20 displaying higher neuroprotective activity (EC(50)â¼0.3 µM) compared to other (chroman-5-yl) and (chroman-2-yl)-isoxazoles.
Assuntos
Cromanos/síntese química , Isoxazóis/síntese química , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/síntese química , Estresse Oxidativo/efeitos dos fármacos , Animais , Catecóis/síntese química , Catecóis/química , Catecóis/farmacologia , Morte Celular/efeitos dos fármacos , Cromanos/química , Cromanos/farmacologia , Avaliação Pré-Clínica de Medicamentos , Hipocampo/citologia , Hipocampo/efeitos dos fármacos , Humanos , Isoxazóis/química , Isoxazóis/farmacologia , Camundongos , Neurônios/fisiologia , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacologiaRESUMO
A new generation of chroman/catechol hybrids bearing heterocyclic five-membered rings, such as 1,2,4-oxadiazole 1,3,4-oxadiazole, 1,2,3-triazole, tetrazole and isoxazole, were designed and synthesized. The activity of the new derivatives against oxidative stress induced neuronal damage, was evaluated using glutamate-challenged hippocampal HT22 cells. Compound 3 in which a 3,4-dimethoxyphenyl moiety, is directly attached to the 1,2,4-oxadiazole ring was the most active among the 2-substituted chroman analogues, with EC(50)=254+/-65nM. Concerning the 5-subtituted chroman analogues, isoxazole derivative 29 exhibited the strongest activity (EC(50)=245+/-38nM). However, 29 was cytotoxic at concentrations higher than 1microM, while the triazole analogue 24 (EC(50)=801+/-229nM), was non-toxic at all concentrations tested.
Assuntos
Catecóis/síntese química , Cromanos/síntese química , Neurônios/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Animais , Azóis/química , Catecóis/farmacologia , Morte Celular/efeitos dos fármacos , Linhagem Celular , Cromanos/farmacologia , Relação Dose-Resposta a Droga , Hipocampo/citologia , Camundongos , Relação Estrutura-AtividadeRESUMO
The design and synthesis of hybrid molecules encompassing two pharmacophores in one molecular scaffold is a well-established approach to the synthesis of more potent drugs with dual activity. In this chapter, we will present the most important synthetic methodologies we have applied for the preparation of hybrid compounds containing the "universal antioxidant" alpha-lipoic acid. Experimental details for the synthesis and purification techniques of specific examples of molecules will be given. The synthesized molecules combine antioxidant activity with a variety of other biological activities such as protection against reperfusion arrhythmias, neuroprotective, and anti-inflammatory activity.
Assuntos
Antioxidantes/química , Antioxidantes/síntese química , Ácido Tióctico/química , Ácido Tióctico/síntese química , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
beta-Thujaplicin (hinokitiol or 2-hydroxy-4-isopropyl-2,4,6-cycloheptatrien-1-one), a natural tropolone, shows numerous activities while its synthetic analogues were found to exhibit anticancer and anti-ischemic activity. However, the ability of tropolone derivatives to protect neuronal cells from oxidative stress-induced cell damage has not been studied so far. As an ongoing effort toward highly effective antioxidants with potential neuroprotective activity, we have synthesized 7-substituted derivatives of beta-thujaplicin and its methoxy analogue. The substituents were heterocycles (piperazine, morpholine) or heteroaromatics (triazoles, pyridine). Only the piperazine derivatives of beta-thujaplicin were able to protect HT22 hippocampal neurons from oxidative stress-induced cell death.
Assuntos
Hipocampo/efeitos dos fármacos , Monoterpenos/síntese química , Monoterpenos/farmacologia , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores , Tropolona/análogos & derivados , Tropolona/síntese química , Tropolona/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Antioxidantes/síntese química , Antioxidantes/química , Antioxidantes/farmacologia , Morte Celular , Linhagem Celular , Hipocampo/citologia , Estrutura Molecular , Monoterpenos/química , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/farmacologia , Tropolona/químicaRESUMO
Novel 1,2-dithiolane/chroman hybrids bearing heterocyclic rings such as 1,2,4- and 1,3,4-oxadiazole, 1,2,3-triazole and tetrazole were designed and synthesized. The neuroprotective activity of the new analogues was tested against oxidative stress-induced cell death of glutamate-challenged HT22 hippocampal neurons. Our results show that bioisosteric replacement of amide group in 2-position of the chroman moiety, by 1,3,4-oxadiazole did not affect activity. However, analogue 5 bearing the 1,2,4-oxadiazole moiety showed improved neuroprotective activity. The presence of nitrogen heterocycles strongly influences the neuroprotective activity of 5-substituted chroman derivatives, depending on the nature of heterocycle. Replacement of the amide group of the first generation analogues by 1,2,4-oxadiazole or 1,2,3-triazole resulted in significant improvement of the activity against glutamate induced oxidative stress.