RESUMO
The discovery and optimisation of a novel series of potent and selective p38α inhibitors is described. Evaluating the structure-activity relationship of an aminoalkyl substituent at the 3 position of the 2(1H)-pyrazinone core, p38α potency was increased 20000-fold. The most advanced compound (25) demonstrated excellent in vivo properties suitable for an inhaled route of administration.
Assuntos
Anti-Inflamatórios/síntese química , Inflamação/tratamento farmacológico , Proteína Quinase 14 Ativada por Mitógeno/antagonistas & inibidores , Inibidores de Proteínas Quinases/síntese química , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Pirazinas/síntese química , Administração por Inalação , Alcanos/química , Aminas/química , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/efeitos adversos , Anti-Inflamatórios/farmacocinética , Benzamidas/farmacologia , Cães , Avaliação Pré-Clínica de Medicamentos , Humanos , Modelos Moleculares , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacocinética , Pirazinas/farmacologia , Quinazolinas/farmacologia , Ratos , Relação Estrutura-AtividadeRESUMO
While bronchodilators and inhaled corticosteroids are the mainstay of asthma treatment, up to 50% of asthmatics remain uncontrolled. Many studies show that the cysteinyl leukotriene cascade remains highly activated in some asthmatics, even those on high-dose inhaled or oral corticosteroids. Hence, inhibition of the leukotriene C4 synthase (LTC4S) enzyme could provide a new and differentiated core treatment for patients with a highly activated cysteinyl leukotriene cascade. Starting from a screening hit (3), a program to discover oral inhibitors of LTC4S led to (1S,2S)-2-({5-[(5-chloro-2,4-difluorophenyl)(2-fluoro-2-methylpropyl)amino]-3-methoxypyrazin-2-yl}carbonyl)cyclopropanecarboxylic acid (AZD9898) (36), a picomolar LTC4S inhibitor (IC50 = 0.28 nM) with high lipophilic ligand efficiency (LLE = 8.5), which displays nanomolar potency in cells (peripheral blood mononuclear cell, IC50,free = 6.2 nM) and good in vivo pharmacodynamics in a calcium ionophore-stimulated rat model after oral dosing (in vivo, IC50,free = 34 nM). Compound 36 mitigates the GABA binding, hepatic toxicity signal, and in vivo toxicology findings of an early lead compound 7 with a human dose predicted to be 30 mg once daily.
Assuntos
Antiasmáticos/farmacologia , Asma/tratamento farmacológico , Descoberta de Drogas , Inibidores Enzimáticos/farmacologia , Glutationa Transferase/antagonistas & inibidores , Pirazinas/farmacologia , Administração Oral , Animais , Antiasmáticos/administração & dosagem , Antiasmáticos/química , Asma/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/química , Glutationa Transferase/metabolismo , Humanos , Estrutura Molecular , Pirazinas/síntese química , Pirazinas/química , Ratos , Relação Estrutura-AtividadeRESUMO
Ru(II) compounds are potential candidates for photodynamic therapy (PDT) and auxiliary ligands may have an impact on the property of the resulting coordination compounds. In the present study, two Ru(II) compounds based on 5-(2-pyrazinyl)tetrazole (Hpztz) and two classic auxiliary ligands, 2,2'-bipyridine (bipy) or 1,10-phenanthroline (phen) have been prepared and characterized, namely [Ru(pztz)(bipy)2][PF6] (1) and [Ru(pztz)(phen)2][PF6] (2). The nanoparticles (NPs) of the two compounds have been prepared by self-assembly in aqueous solution. In vitro MTT assay on HeLa cells show that [Ru(pztz)(phen)2][PF6] with a lower IC50 (half-maximal inhibitory concentration) of only 7.4⯵g/mL is superior to that of [Ru(pztz)(bipy)2][PF6] (17.8⯵g/mL) under irradiation. Meanwhile, negligible dark toxicity have been also observed for the two compounds. In addition, in vivo fluorescence imaging suggests that [Ru(pztz)(phen)2][PF6] NPs are able to target to the tumor by enhanced permeability and retention effect (EPR). Furthermore, in vivo phototherapy on nude mice demonstrate that such NPs can effectively inhibit the growth of the tumor. After treatment for 10 cycles, an obvious decrease in the tumor volume can be observed while the normal tissues, including heart, liver, spleen, lung and kidney, suffer from no damage, indicating the high phototoxicity, low dark toxicity and excellent biocompatibility of [Ru(pztz)(phen)2][PF6] NPs.
Assuntos
Antineoplásicos/uso terapêutico , Complexos de Coordenação/uso terapêutico , Fármacos Fotossensibilizantes/uso terapêutico , Pirazinas/uso terapêutico , Tetrazóis/uso terapêutico , Neoplasias do Colo do Útero/tratamento farmacológico , Animais , Antineoplásicos/síntese química , Antineoplásicos/efeitos da radiação , Complexos de Coordenação/síntese química , Complexos de Coordenação/efeitos da radiação , Feminino , Células HeLa , Humanos , Ligantes , Luz , Camundongos Nus , Fotoquimioterapia , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/efeitos da radiação , Pirazinas/síntese química , Pirazinas/efeitos da radiação , Rutênio/química , Tetrazóis/síntese química , Tetrazóis/efeitos da radiação , Neoplasias do Colo do Útero/patologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
An expeditious catalyst-free heteroannulation reaction for imidazo[1,2- a]pyridines/pyrimidines/pyrazines was developed in green solvent under microwave irradiation. Using H2O-IPA as the reaction medium, various substituted 2-aminopyridines/pyrazines/pyrimidines underwent annulation reaction with α-bromoketones under microwave irradiation to provide the corresponding imidazo[1,2- a]pyridines/pyrimidines/pyrazines in excellent yields. The synthetic methodology appears to be very simple and superior to the already reported procedures with the high abundance of commercial reagents and great ability in expanding the molecular diversity. The present synthetic sequence is visualized as an environmentally benign process which allows the introduction of three points of structural diversity to expand chemical space with excellent purity and yields. The anti-inflammatory and antimicrobial activities of the derivatives were evaluated. Screening results uncovered three derivatives with strong inhibition of albumin denaturation and two derivatives were active on Proteus and Klebsiella bacteria. These positive bioassay results implied that the library of potential anti-inflammatory agents could be rapidly prepared in an ecofriendly manner, and provided new insights into drug discovery for medicinal chemists.
Assuntos
Imidazóis/síntese química , Pirazinas/síntese química , Piridinas/síntese química , Pirimidinas/síntese química , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Catálise , Técnicas de Química Combinatória/métodos , Avaliação Pré-Clínica de Medicamentos/métodos , Química Verde/métodos , Humanos , Micro-Ondas , Estrutura Molecular , Desnaturação Proteica , Bibliotecas de Moléculas Pequenas/síntese química , Solventes , Relação Estrutura-AtividadeRESUMO
BACKGROUND: Isoxazoles, pyridazines, and pyrimidopyrazines have recently attracted attention due to their potent pharmacological activities. They exhibited anticancer, neuroprotective, analgesic and anti-inflammatory effects. OBJECTIVE: The study aimed to synthesize novel isoxazoles, pyridazines, and pyrimidopyrazines through efficient high yield protocol for evaluating their analgesics and anti-inflammatory activities. METHOD: A series of novel isoxazole-, pyridazine-, pyrimidopyrazine derivatives was prepared from 5,8-alkyl-1,3-dimethyl-5,6-dihydropyrimido[5,6-e]pyrazine-2,4,7-trione (1a,b) as the starting material. RESULTS: The prepared derivatives were synthesized in moderate to good yields (60-75%) in a stepwise efficient protocol under mild condition. These new compounds have been proven by several spectroscopic techniques as IR, 1D and 2D NMR techniques and mass analysis. The in vivo anti-inflammatory was assessed for the synthesized compounds using carrageenan-induced rat hind paw edema model. Also, the in vivo analgesic activity for these products was examined utilizing hot-plate and acetic acid-induced writhing response assays. CONCLUSION: The isoxazole derivatives (3a-f) showed the most forceful anti-inflammatory and analgesic activities. Pyrimidopyrazines (4a-f) demonstrated weaker but comparable antiinflammatory and analgesic activities to the positive controls.
Assuntos
Analgésicos/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , Isoxazóis/farmacologia , Pirazinas/farmacologia , Piridazinas/farmacologia , Pirimidinas/farmacologia , Analgésicos/síntese química , Analgésicos/química , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Avaliação Pré-Clínica de Medicamentos , Feminino , Isoxazóis/síntese química , Isoxazóis/química , Masculino , Camundongos , Estrutura Molecular , Pirazinas/síntese química , Pirazinas/química , Piridazinas/síntese química , Piridazinas/química , Pirimidinas/síntese química , Pirimidinas/química , Ratos Sprague-DawleyRESUMO
Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) has become a frequently deadly infection due to increasing antimicrobial resistance. This serious issue has driven efforts worldwide to discover new drugs effective against Mtb. One research area is the synthesis and evaluation of pyrazinamide derivatives as potential anti-TB drugs. In this paper we report the synthesis and biological evaluations of a series of ureidopyrazines. Compounds were synthesized by reacting alkyl/aryl isocyanates with aminopyrazine or with propyl 5-aminopyrazine-2-carboxylate. Reactions were performed in pressurized vials using a CEM Discover microwave reactor with a focused field. Purity and chemical structures of products were assessed, and the final compounds were tested in vitro for their antimycobacterial, antibacterial, and antifungal activities. Propyl 5-(3-phenylureido)pyrazine-2-carboxylate (compound 4, MICMtb = 1.56 µg/mL, 5.19 µM) and propyl 5-(3-(4-methoxyphenyl)ureido)pyrazine-2-carboxylate (compound 6, MICMtb = 6.25 µg/mL, 18.91 µM) had high antimycobacterial activity against Mtb H37Rv with no in vitro cytotoxicity on HepG2 cell line. Therefore 4 and 6 are suitable for further structural modifications that might improve their biological activity and physicochemical properties. Based on the structural similarity to 1-(2-chloropyridin-4-yl)-3-phenylurea, a known plant growth regulator, two selected compounds were evaluated for similar activity as abiotic elicitors.
Assuntos
Antituberculosos/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Pirazinas/farmacologia , Antituberculosos/síntese química , Antituberculosos/química , Proliferação de Células/efeitos dos fármacos , Fagopyrum/química , Células Hep G2 , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Reguladores de Crescimento de Plantas/síntese química , Reguladores de Crescimento de Plantas/química , Reguladores de Crescimento de Plantas/farmacologia , Pirazinamida/química , Pirazinamida/farmacologia , Pirazinas/síntese química , Pirazinas/química , Estresse Fisiológico/efeitos dos fármacosRESUMO
Six novel ligustrazine chalcone aromatic oxygen alkyl acids compounds and two pyridine chalcone aromatic oxygen alkyl acids ester compounds were synthesized according to the traditional Chinese medicine theory removing blood stasis. The structures of target compounds were identified by IR, NMR and ESI-MS. The inhibitory activities of platelet aggregation induced by adenosine diphosphate (ADP) and arachidonic acid(AA) were measured by the liver microsomal incubation method in vitro. Hypolipidemic activities of compounds were tested in vivo for better inhibitory activities of platelet aggregation. Preliminary pharmacological results showed that compounds 7c, 8a and 11 a had potent inhibitory activity against platelet aggregation induced by AA, compounds 7c, 7d, 8a and 11 b showed significant inhibitory activity against platelet aggregation induced by ADP. Compounds 7c and 8a exhibited good hypolipidemic activities in high-fat-diet(HFD) induced hyperlipidemia C57/BL6 mice and worthy for further investigation.
Assuntos
Chalconas/farmacologia , Inibidores da Agregação Plaquetária/farmacologia , Pirazinas/farmacologia , Difosfato de Adenosina , Animais , Ácido Araquidônico , Chalconas/síntese química , Hiperlipidemias/tratamento farmacológico , Hipolipemiantes/síntese química , Hipolipemiantes/farmacologia , Camundongos Endogâmicos C57BL , Oxigênio , Agregação Plaquetária , Inibidores da Agregação Plaquetária/síntese química , Pirazinas/síntese químicaRESUMO
A series of novel stereochemically pure derivatives of the investigative broad-spectrum anticonvulsant ADD408003 was designed and synthesized. Five-center four-component (U-5C-4CR) and four-center three-component (U-4C-3CR) variants of Ugi reaction were used in the key step of the synthetic pathways. The compounds obtained were evaluated for the anticonvulsant activitiy in the maximal electroshock seizure (MES), subcutaneous Metrazole (scMET) and minimal clonic seizure (6 Hz) animal models of epilepsy. The efficacies of most derivatives in the 6 Hz model of pharmacoresistant partial seizures were markedly higher than in the 'classical' MES and scMET models. The most active compounds, (4R,8aR)-3a, and (4S,8aS)-6 displayed median effective doses (ED50) of 47.90 and 126.19 mg/kg, respectively, for the 6 Hz test.
Assuntos
Anticonvulsivantes/síntese química , Anticonvulsivantes/farmacologia , Epilepsia/tratamento farmacológico , Pirazinas/síntese química , Pirazinas/farmacologia , Animais , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Masculino , Camundongos , Estrutura MolecularRESUMO
Ligustrazine, one of the major effective components of the Chinese traditional medicinal herb Ligusticum Chuanxiong Hort, has been reported plenty of biological activities, such as protect cardiovascular and cerebrovascular, neuroprotection and anti-tumor, et al. Because of its remarkable effects, studies on structural modification of ligustrazine have attracted much attention. Ligustrazine synthetic derivatives reported in recent decades are mainly derived from four primary intermediates (TMP-COOH, TMP-OH, TMP-NH2, HO-TMP-OH). To explore the neuroprotection activitiy of ligustrazine intermediates, six ligustrazine intermediates (2, 5, 8, 11, 12, 13) were synthesized and their protective effects against CoCl2-induced neurotoxicity in differentiated PC12 cells were studied. The target compounds were prepared via different chemical methods, including oxidation, substitution, esterification and amidation without changing the structure nucleus of ligustrazine. Compared with TMP (EC50 = 56.03 micromol x L(-1)), four compounds (2, 5, 12 and 13) exhibited higher activity (EC50 < 50 micromol x L(-1)) respectively, of which, compound 2 displayed the highest protective effect against the damaged PC12 cells (EC50 = 32.86 micromol x L(-1)), but target compounds 8 and 11 appeared lower activity (EC50 > 70 micromol x L(-1)). By structure-activity relationships analysis, the introduction of carboxyl, amino to the side chain of ligustrazine and appropriately increase the proportion of ligustrazine may contribute to enhance its neuroprotective activity, which provides a reference for the design, synthesis and activity screening of relevant series of ligustrazine derivatives in the future.
Assuntos
Diferenciação Celular/efeitos dos fármacos , Cobalto/toxicidade , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/farmacologia , Neurotoxinas/toxicidade , Pirazinas/síntese química , Pirazinas/farmacologia , Animais , Técnicas de Química Sintética , Medicamentos de Ervas Chinesas/química , Fármacos Neuroprotetores/química , Células PC12 , Pirazinas/química , RatosRESUMO
The results of a high-throughput screening assay using the dengue virus-2 replicon showed that the imidazole 4,5-dicarboxamide (I45DC) derivative (15a) has a high dengue virus inhibitory activity. Based on 15a as a lead compound, a novel class of both disubstituted I45DCs and the resembling pyrazine 2,3-dicarboxamides (P23DCs) were synthesized. Here, we report on their in vitro inhibitory activity against dengue virus (DENV) and yellow fever virus (YFV). Some of these first generation compounds have shown activity against both viruses in the micromolar range. Within this series, compound 15b was observed to display the highest antiviral potency against YFV with an EC50 = 1.85 µM. In addition, compounds 20a and 20b both potently inhibited replication of DENV (EC50 = 0.93 µM) in Vero cells.
Assuntos
Vírus da Dengue/efeitos dos fármacos , Imidazóis/síntese química , Imidazóis/farmacologia , Pirazinas/síntese química , Vírus da Febre Amarela/efeitos dos fármacos , Amidas/química , Avaliação Pré-Clínica de Medicamentos , Imidazóis/química , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Testes de Sensibilidade Microbiana , Pirazinas/química , Pirazinas/farmacologiaAssuntos
Pirazinas/química , Piridazinas/química , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Animais , Linhagem Celular , Modelos Animais de Doenças , Cães , Avaliação Pré-Clínica de Medicamentos , Canal de Potássio ERG1 , Canais de Potássio Éter-A-Go-Go/metabolismo , Meia-Vida , Humanos , Camundongos , Pirazinas/síntese química , Pirazinas/farmacocinética , Piridazinas/síntese química , Piridazinas/farmacocinética , Ratos , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Receptor Smoothened , Solubilidade , Relação Estrutura-AtividadeRESUMO
We report the discovery and structure-activity relationship of 2,6-disubstituted pyrazines, which are potent and selective CK2 inhibitors. Lead compound 1 was identified, and derivatives were prepared to develop potent inhibitory activity. As a result, we obtained compound 7, which was the smallest unit that retained potency. Then, introducing an aminoalkyl group at the 6-position of the indazole ring resulted in improved efficacy in both enzymatic and cell-based CK2 inhibition assays. Moreover, compound 13 showed selectivity against other kinases and in vivo efficacy in a rat nephritis model. These results show that 2,6-disubstituted pyrazines have potential as therapeutic agents for nephritis.
Assuntos
Caseína Quinase II/antagonistas & inibidores , Indazóis/química , Inibidores de Proteínas Quinases/química , Pirazinas/química , Animais , Sítios de Ligação , Caseína Quinase II/metabolismo , Simulação por Computador , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Humanos , Indazóis/síntese química , Indazóis/uso terapêutico , Injeções Intraperitoneais , Nefrite/tratamento farmacológico , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/uso terapêutico , Estrutura Terciária de Proteína , Pirazinas/síntese química , Pirazinas/uso terapêutico , Ratos , Relação Estrutura-AtividadeRESUMO
To discover new anti-cancer agents with multi-effect and low toxicity, a series of ligustrazine derivatives were synthesized using several effective anti-tumor ingredients of Shiquandabu Wan as starting materials. Our idea was enlightened by the "combination principle" in drug discovery. The ligustrazine derivatives' anti-tumor activities were evaluated on the HCT-8, Bel-7402, BGC-823, A-549 and A2780 human cancer cell lines. In addition the angiogenesis activities were valued by the chick chorioallantoic membrane (CAM) assay. 1,7-bis(4-(3,5,6-Trimethylpyrazin-2-yl)-3-methoxyphenyl)-1,6-heptadiene-3,5-dione (4) and 3 α,12 α-dihydroxy-5ß-dholanic acid-3,5,6-trimethylpyrazin-2-methyl ester (5) not only displayed antiproliferative activities on these cancer cells, but also dramatically suppressed normal angiogenesis in CAM. The LD50 value of the compound 5 exceeded 3.0 g/kg by oral administration in mice.
Assuntos
Inibidores da Angiogênese/síntese química , Antineoplásicos Fitogênicos/síntese química , Membrana Corioalantoide/irrigação sanguínea , Medicamentos de Ervas Chinesas/química , Pirazinas/síntese química , Inibidores da Angiogênese/farmacologia , Animais , Antineoplásicos Fitogênicos/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Embrião de Galinha , Membrana Corioalantoide/efeitos dos fármacos , Descoberta de Drogas , Feminino , Humanos , Dose Letal Mediana , Espectroscopia de Ressonância Magnética , Camundongos , Neovascularização Fisiológica/efeitos dos fármacos , Pirazinas/farmacologiaRESUMO
Our continued effort toward the development of the imidazo[1,2-a]pyrazine scaffold as Aurora kinase inhibitors is described. Bioisosteric approach was applied to optimize the 8-position of the core. Several new potent Aurora A/B dual inhibitors, such as 25k and 25l, were identified.
Assuntos
Imidazóis/química , Inibidores de Proteínas Quinases/química , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Pirazinas/química , Animais , Aurora Quinase A , Aurora Quinases , Avaliação Pré-Clínica de Medicamentos , Imidazóis/síntese química , Imidazóis/farmacocinética , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacocinética , Proteínas Serina-Treonina Quinases/metabolismo , Pirazinas/síntese química , Pirazinas/farmacocinética , RatosRESUMO
A series of novel imidazopyrazinone derivatives were synthesized and evaluated with regard to their ability to inhibit dipeptidyl peptidase IV (DPP-IV) in vitro. Of these compounds (2R)-4-oxo-4-[2-(3-carbamoylbenzyl)-hexahydro-3-oxoimidazo [1,5-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine fumaric acid (17h, IC(50)=78 nM) was shown to effectively inhibit the activity of the dipeptidyl peptidase IV enzyme. Molecular docking studies were also performed to illustrate the binding mode of compounds 15c and 17h. Favorable interactions were identified from the binding of inhibitor 15c with DPP-IV. By analogy to the binding mode of compound 15c, it seems that the introduction of a substituted benzyl moiety onto the imidazopyrazinone could remarkably improve the inhibitory activity of compound 17h.
Assuntos
Inibidores da Dipeptidil Peptidase IV/síntese química , Inibidores da Dipeptidil Peptidase IV/farmacologia , Pirazinas/síntese química , Pirazinas/farmacologia , Inibidores da Dipeptidil Peptidase IV/química , Avaliação Pré-Clínica de Medicamentos , Humanos , Técnicas In Vitro , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Pirazinas/químicaRESUMO
A tetramethylpyrazine analogue, CXC195, was synthesized by the Boekelheide reaction, in which the second methyl group of tetramethylpyrazine (TMP) was replaced with (4,4'-fluorine) diphenyl-methyl-1-piperazidine, the active group of flunarizine. We have observed protective effects of CXC195 on vascular endothelial cell survival under oxidative stress in previous study. The aim of the present study was to investigate the effects of CXC195 against apoptosis induced by hydrogen peroxide in human umbilical vein endothelial cells (HUVECs). Accordingly, a biochemical approach to elucidate the apoptotic signal pathways was attempted. HUVECs were exposed to 150 muM H(2)O(2) for 12 h, resulting in an increase of apoptotic cells assessed by the nuclear staining assay and flow cytometry. Mitochondrial membrane potential was detected by retention of rhodamine123. The concentration of free intracellular calcium was determined by fura-2/AM fluorometry. Co-incubation with CXC195 reduced the percentage of apoptotic cells and inhibited the loss of mitochondrial membrane potential and intracellular calcium overload induced by H(2)O(2). Induction of p53, the activation of caspase-3 by H(2)O(2) which accompanying downregulation of bcl-2, was blocked by CXC195. In addition, CXC195 clearly improved phosphorylation levels of the antiapoptotic extracellular signal-regulated kinase-1/2 (ERK1/2) in cells undergoing oxidative damage. Moreover, CXC195 showed stronger effects on inhibition of apoptotic cells and loss of mitochondrial membrane potential and activation of phosphorylated ERK1/2 than TMP. These results suggest that CXC195 prevents reactive oxygen species-induced apoptosis through inhibition of the mitochondria-dependent caspase-3 pathway and ERK pathway to show a better beneficial effect in protecting endothelial cells than TMP.
Assuntos
Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Cálcio/metabolismo , Medicamentos de Ervas Chinesas/farmacologia , Células Endoteliais/efeitos dos fármacos , Ligusticum/química , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Piperazinas/farmacologia , Pirazinas/farmacologia , Antioxidantes/síntese química , Caspase 3/metabolismo , Linhagem Celular , Regulação para Baixo , Células Endoteliais/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Citometria de Fluxo , Humanos , Peróxido de Hidrogênio/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Fosforilação , Fitoterapia , Piperazinas/síntese química , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Pirazinas/síntese química , Proteína Supressora de Tumor p53/metabolismo , Veias UmbilicaisRESUMO
High-throughput screening highlighted 9-oxo-9H-indeno[1,2-b]pyrazine-2,3-dicarbonitrile (1) as an active inhibitor of ubiquitin-specific proteases (USPs), a family of hydrolytic enzymes involved in the removal of ubiquitin from protein substrates. The chemical behavior of compound 1 was examined. Moreover, the synthesis and in vitro evaluation of new compounds, analogues of 1, led to the identification of potent and selective inhibitors of the deubiquitinating enzyme USP8.
Assuntos
Complexos Endossomais de Distribuição Requeridos para Transporte/antagonistas & inibidores , Inibidores Enzimáticos/síntese química , Indenos/química , Pirazinas/química , Ubiquitina Tiolesterase/antagonistas & inibidores , Cristalografia por Raios X , Avaliação Pré-Clínica de Medicamentos , Endopeptidases/metabolismo , Complexos Endossomais de Distribuição Requeridos para Transporte/metabolismo , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Ensaios de Triagem em Larga Escala , Humanos , Indenos/farmacologia , Conformação Molecular , Pirazinas/síntese química , Pirazinas/farmacologia , Ubiquitina Tiolesterase/metabolismo , Peptidase 7 Específica de UbiquitinaRESUMO
Successive regio- and chemoselective metalations of chloropyrazines using TMPMgCl x LiCl and TMPZnCl x LiCl furnish, after trapping with electrophiles, highly functionalized pyrazines in high yields. Application to a synthesis of coelenterazine, a bioluminescent natural product in jellyfish Aequorea victoria, in nine steps (9% overall yield) is reported.
Assuntos
Imidazóis/síntese química , Compostos Organometálicos/química , Pirazinas/química , Aldeído Pirúvico/síntese química , Animais , Imidazóis/química , Pirazinas/síntese química , Aldeído Pirúvico/química , Cifozoários/químicaRESUMO
A versatile combinatorial approach was developed for the rapid synthesis of 2,5-dihydro-1H-pyrroles, 1,3-dioxo-2,3,5,7a-tetrahydro-1H-pyrrolo[1,2-c]imidazoles, and 1,4-dioxo-1,2,3,4,6,8a-hexahydropyrrolo[1,2-a]pyrazines libraries. The synthetic strategy includes electrophilic addition, dehydrohalogenation, 1,3-dipolar cycloaddition, N-acylation, amino carbonylation-cyclization, N-alkylation, lactamization, and oxidation-elimination.
Assuntos
Técnicas de Química Combinatória/métodos , Imidazóis/síntese química , Pirazinas/síntese química , Pirróis/síntese química , Selênio/química , Acilação , Alquilação , Ciclização , Halogenação , Imidazóis/química , Pirazinas/química , Pirróis/químicaRESUMO
N-Acylsulfonamide and N-acylsulfonylurea derivatives of the carboxylic acid prostacyclin receptor agonist 1 were synthesized and their potential as prodrug forms of the carboxylic acid was evaluated in vitro and in vivo. These compounds were converted to the active compound 1 by hepatic microsomes from rats, dogs, monkeys, and humans, and some of the compounds were shown to yield sustained plasma concentrations of 1 when they were orally administered to monkeys. These types of analogues, including NS-304 (2a), are potentially useful prodrugs of 1.