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1.
J Enzyme Inhib Med Chem ; 36(1): 1952-1967, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34455887

RESUMO

A series of 6-amidinobenzothiazoles, linked via phenoxymethylene or directly to the 1,2,3-triazole ring with a p-substituted phenyl or benzyl moiety, were synthesised and evaluated in vitro against four human tumour cell lines and the protozoan parasite Trypanosoma brucei. The influence of the type of amidino substituent and phenoxymethylene linker on antiproliferative and antitrypanosomal activities was observed, showing that the imidazoline moiety had a major impact on both activities. Benzothiazole imidazoline 14a, which was directly connected to N-1-phenyl-1,2,3-triazole, had the most potent growth-inhibitory effect (IC50 = 0.25 µM) on colorectal adenocarcinoma (SW620), while benzothiazole imidazoline 11b, containing a phenoxymethylene linker, exhibited the best antitrypanosomal potency (IC90 = 0.12 µM). DNA binding assays showed a non-covalent interaction of 6-amidinobenzothiazole ligands, indicating both minor groove binding and intercalation modes of DNA interaction. Our findings encourage further development of novel structurally related 6-amidino-2-arylbenzothiazoles to obtain more selective anticancer and anti-HAT agents.


Assuntos
Antiprotozoários/síntese química , Benzotiazóis/síntese química , Substâncias Intercalantes/síntese química , Trypanosoma brucei brucei/efeitos dos fármacos , Amidinas/química , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Antiprotozoários/farmacologia , Benzotiazóis/farmacologia , Proliferação de Células/efeitos dos fármacos , Neoplasias Colorretais/tratamento farmacológico , DNA/química , Avaliação Pré-Clínica de Medicamentos , Humanos , Imidazolinas/química , Substâncias Intercalantes/farmacologia , Conformação de Ácido Nucleico , Relação Estrutura-Atividade , Triazóis/química
2.
Cell Death Dis ; 12(7): 663, 2021 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-34230456

RESUMO

A majority of mesothelioma specimens were defective of p14 and p16 expression due to deletion of the INK4A/ARF region, and the p53 pathway was consequently inactivated by elevated MDM2 functions which facilitated p53 degradaton. We investigated a role of p53 elevation by MDM2 inhibitors, nutlin-3a and RG7112, in cytotoxicity of replication-competent adenoviruses (Ad) lacking the p53-binding E1B55kDa gene (Ad-delE1B). We found that a growth inhibition by p53-activating Ad-delE1B was irrelevant to p53 expression in the infected cells, but combination of Ad-delE1B and the MDM2 inhibitor produced synergistic inhibitory effects on mesothelioma with the wild-type but not mutated p53 genotype. The combination augmented p53 phosphorylation, activated apoptotic but not autophagic pathway, and enhanced DNA damage signals through ATM-Chk2 phosphorylation. The MDM2 inhibitors facilitated production of the Ad progenies through augmented expression of nuclear factor I (NFI), one of the transcriptional factors involved in Ad replications. Knocking down of p53 with siRNA did not increase the progeny production or the NFI expression. We also demonstrated anti-tumor effects by the combination of Ad-delE1B and the MDM2 inhibitors in an orthotopic animal model. These data collectively indicated that upregulation of wild-type p53 expression contributed to cytotoxicity by E1B55kDa-defective replicative Ad through NFI induction and suggested that replication-competent Ad together with augmented p53 levels was a therapeutic strategy for p53 wild-type mesothelioma.


Assuntos
Adenoviridae/genética , Proteínas E1 de Adenovirus/genética , Antineoplásicos/farmacologia , Imidazóis/farmacologia , Imidazolinas/farmacologia , Mesotelioma/terapia , Neurofibromina 1/metabolismo , Terapia Viral Oncolítica , Vírus Oncolíticos/genética , Piperazinas/farmacologia , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Proteína Supressora de Tumor p53/metabolismo , Adenoviridae/crescimento & desenvolvimento , Animais , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Linhagem Celular Tumoral , Quimioterapia Adjuvante , Regulação Neoplásica da Expressão Gênica , Mesotelioma/genética , Mesotelioma/metabolismo , Mesotelioma/virologia , Camundongos Endogâmicos BALB C , Camundongos Nus , Neurofibromina 1/genética , Vírus Oncolíticos/crescimento & desenvolvimento , Proteínas Proto-Oncogênicas c-mdm2/genética , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Carga Tumoral/efeitos dos fármacos , Proteína Supressora de Tumor p53/genética , Replicação Viral , Ensaios Antitumorais Modelo de Xenoenxerto
3.
FASEB J ; 35(7): e21645, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34105824

RESUMO

Peripheral arterial disease (PAD) is one of the major complications of diabetes due to an impairment in angiogenesis. Since there is currently no drug with satisfactory efficacy to enhance blood vessel formation, discovering therapies to improve angiogenesis is critical. An imidazolinone metabolite of the metformin-methylglyoxal scavenging reaction, (E)-1,1-dimethyl-2-(5-methyl-4-oxo-4,5-dihydro-1H-imidazol-2-yl) guanidine (IMZ), was recently characterized and identified in the urine of type-2 diabetic patients. Here, we report the pro-angiogenesis effect of IMZ (increased aortic sprouting, cell migration, network formation, and upregulated multiple pro-angiogenic factors) in human umbilical vein endothelial cells. Using genetic and pharmacological approaches, we showed that IMZ augmented angiogenesis by activating the endothelial nitric oxide synthase (eNOS)/hypoxia-inducible factor-1 alpha (HIF-1α) pathway. Furthermore, IMZ significantly promoted capillary density in the in vivo Matrigel plug angiogenesis model. Finally, the role of IMZ in post-ischemic angiogenesis was examined in a chronic hyperglycemia mouse model subjected to hind limb ischemia. We observed improved blood perfusion, increased capillary density, and reduced tissue necrosis in mice receiving IMZ compared to control mice. Our data demonstrate the pro-angiogenic effects of IMZ, its underlying mechanism, and provides a structural basis for the development of potential pro-angiogenic agents for the treatment of PAD.


Assuntos
Membro Posterior/fisiopatologia , Hiperglicemia/complicações , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Isquemia/complicações , Metformina/metabolismo , Neovascularização Patológica/patologia , Óxido Nítrico Sintase Tipo III/metabolismo , Animais , Hipoglicemiantes/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Imidazolinas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neovascularização Patológica/genética , Neovascularização Patológica/metabolismo , Óxido Nítrico Sintase Tipo III/genética , Aldeído Pirúvico/metabolismo
4.
Methods Mol Biol ; 2323: 121-140, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34086278

RESUMO

The development of fluorescent biosensors is motivated by the desire to monitor cellular metabolite levels in real time. Most genetically encodable fluorescent biosensors are based on receptor proteins fused to fluorescent protein domains. More recently, small molecule-binding riboswitches have been adapted for use as fluorescent biosensors through fusion to the in vitro selected Spinach aptamer, which binds a profluorescent, cell-permeable small molecule mimic of the GFP chromophore, DFHBI. Here we describe methods to prepare and analyze riboswitch-Spinach tRNA fusions for ligand-dependent activation of fluorescence in vivo. Example procedures describe the use of the Vc2-Spinach tRNA biosensor to monitor perturbations in cellular levels of cyclic di-GMP using either fluorescence microscopy or flow cytometry. In this updated chapter, we have added procedures on using biosensors in flow cytometry to detect exogenously added compounds. The relative ease of cloning and imaging of these biosensors, as well as their modular nature, should make this method appealing to other researchers interested in utilizing riboswitch-based biosensors for metabolite sensing.


Assuntos
Aptâmeros de Nucleotídeos/genética , Técnicas Biossensoriais/métodos , Citometria de Fluxo/métodos , Corantes Fluorescentes/análise , Microscopia Intravital/métodos , Microscopia de Fluorescência/métodos , RNA de Transferência/genética , RNA/genética , Riboswitch/genética , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Compostos de Benzil , Clonagem Molecular/métodos , GMP Cíclico/análogos & derivados , GMP Cíclico/metabolismo , Proteínas de Escherichia coli/genética , Proteínas de Escherichia coli/metabolismo , Imidazolinas , Isopropiltiogalactosídeo/farmacologia , Conformação de Ácido Nucleico , Fósforo-Oxigênio Liases/genética , Fósforo-Oxigênio Liases/metabolismo , Plasmídeos
5.
Methods Mol Biol ; 2323: 141-152, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34086279

RESUMO

Fluorescence-based tools are invaluable in studying cellular functions. Traditional small molecule or protein-based fluorescent sensors have been widely used for the cellular imaging, but the choice of targets is still limited. Recently, fluorogenic RNA-based sensors gained lots of attention. This novel sensor system can function as a general platform for various cellular targets. Here, we describe the steps to rationally design, optimize, and apply fluorogenic RNA-based sensors, using the intracellular imaging of tetracycline in living E. coli cells as an example.


Assuntos
Aptâmeros de Nucleotídeos/química , Técnicas Biossensoriais/métodos , Corantes Fluorescentes/química , Microscopia Intravital/métodos , Tetraciclina/análise , Regulação Alostérica , Compostos de Benzil/análise , Clonagem Molecular/métodos , Simulação por Computador , Desenho de Fármacos , Escherichia coli/química , Escherichia coli/ultraestrutura , Imidazolinas/análise , Estrutura Molecular , Conformação de Ácido Nucleico
6.
Molecules ; 26(11)2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-34071640

RESUMO

A facile solid-phase synthetic method for incorporating the imidazoline ring motif, a surrogate for a trans peptide bond, into bioactive peptides is reported. The example described is the synthesis of an imidazoline peptidomimetic analog of an insect pyrokinin neuropeptide via a cyclization reaction of an iminium salt generated from the preceding amino acid and 2,4-diaminopropanoic acid (Dap).


Assuntos
Imidazolinas/química , Neuropeptídeos/química , Peptídeos/química , beta-Alanina/análogos & derivados , Animais , Química Orgânica/métodos , Éteres/química , Hormônios de Inseto/química , Insetos , Espectroscopia de Ressonância Magnética , Polímeros/química , Propionatos/química , Técnicas de Síntese em Fase Sólida , Solventes/química , Espectrometria de Massas por Ionização por Electrospray , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , beta-Alanina/química
7.
J Pharm Biomed Anal ; 202: 114135, 2021 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-34022667

RESUMO

2-Imidazoline drugs are used in a variety of applications, such as the treatment of hypertension and opioid withdrawal. It is known these drugs bind to serum proteins and have significant variations within this class of compounds in the overall level of this binding. However, little specific information is available on the interactions of these compounds with the two major transport proteins for many drugs, human serum albumin (HSA) and alpha1-acid glycoprotein (AGP). This study examined binding by 2-imidazolines to these proteins by using 25 mm × 2.1 mm i.d. high-performance affinity microcolumns that contained HSA or AGP. The drugs that were examined were antazoline, clonidine, dexmedetomidine, lofexidine, moxonidine, phentolamine, and tizanidine, which represented a wide range of structures and pharmaceutical applications. The major metabolite of lofexidine, N-(2-aminoethyl)-2-(2,6-dichlorophenoxy) propenamide (LADP), was also examined. All these 2-imidazolines were found to have weak-to-moderate binding to HSA, with global affinities that ranged from 1.62 × 102 to 1.07 × 104 M-1 at pH 7.4 and 37 °C. These compounds had stronger binding with AGP, with global affinities constants ranging from 3.80 × 102 to 1.85 × 104 M-1. No stereoselectivity was observed by HSA for the enantiomers of dexmedetomidine, lofexidine, or LADP. However, AGP did show some stereoselectivity for lofexidine and LADP but not for dexmedetomidine. These results provide a better understanding of interactions of 2-imidazoline with HSA vs AGP in the circulation and of how this binding can change between drugs within this class of compounds.


Assuntos
Imidazolinas , Orosomucoide , Cromatografia de Afinidade , Humanos , Imidazóis , Orosomucoide/metabolismo , Ligação Proteica , Albumina Sérica Humana/metabolismo
8.
Sci Rep ; 11(1): 7356, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33795733

RESUMO

The discovery of the GFP-type dye DFHBI that becomes fluorescent upon binding to an RNA aptamer, termed Spinach, led to the development of a variety of fluorogenic RNA systems that enable genetic encoding of living cells. In view of increasing interest in small RNA aptamers and the scarcity of their photophysical characterisation, this paper is a model study on Baby Spinach, a truncated Spinach aptamer with half its sequence. Fluorescence and fluorescence excitation spectra of DFHBI complexes of Spinach and Baby Spinach are known to be similar. Surprisingly, a significant divergence between absorption and fluorescence excitation spectra of the DFHBI/RNA complex was observed on conditions of saturation at large excess of RNA over DFHBI. Since absorption spectra were not reported for any Spinach-type aptamer, this effect is new. Quantitative modelling of the absorption spectrum based on competing dark and fluorescent binding sites could explain it. However, following reasoning of fluorescence lifetimes of bound DFHBI, femtosecond-fluorescence lifetime profiles would be more supportive of the notion that the abnormal absorption spectrum is largely caused by trans-isomers formed  within the cis-bound DFHBI/RNA complex. Independent of the origin, the unexpected discrepancy between absorption and fluorescence excitation spectra allows for easily accessed screening and insight into the efficiency of a fluorogenic dye/RNA system.


Assuntos
Aptâmeros de Nucleotídeos/química , Compostos de Benzil/química , Corantes Fluorescentes/química , Imidazolinas/química , Spinacia oleracea/química , Sítios de Ligação , Fluorescência , Processamento de Imagem Assistida por Computador , Cinética , Teoria Quântica , RNA de Plantas/genética , Reprodutibilidade dos Testes , Software , Spinacia oleracea/efeitos dos fármacos , Termodinâmica
9.
Int J Mol Sci ; 22(3)2021 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-33498150

RESUMO

The introduction of Clearfield technology allows the use of imidazolinone (IMI) herbicides to control weedy rice. Imidazolinone herbicides stop the acetolactate synthase (ALS) enzyme from synthesizing branched-chain amino acids, resulting in the death of the plant. Since the launch of Clearfield technology in Malaysia in 2010, many farmers have replaced traditional cultivars with Clearfield (CL) rice lines (MR220-CL1 and MR220-CL2). This technology was initially effective; however, in recent years, local farmers have reported the reduced efficacy of IMI herbicides in controlling the spread of weedy rice. Under IMI herbicide treatment, in previous weedy rice studies, the target-site resistance (TSR) mechanism of the ALS gene has been suggested as a key factor conferring herbicide resistance. In our study, a combination of ALS gene sequencing, enzyme colorimetric assay, and a genome-wide association study (GWAS) highlighted that a non-target-site resistance (NTSR) can be an alternative molecular mechanism in IMI-resistant weedy rice. This is supported by a series of evidence, including a weak correlation between single nucleotide polymorphisms (SNPs) within the ALS exonic region and ALS enzyme activity. Our findings suggest that the adaptability of weedy rice in Clearfield rice fields can be more complicated than previously found in other rice strains.


Assuntos
Resistência a Medicamentos , Herbicidas/toxicidade , Imidazolinas/toxicidade , Oryza/genética , Acetolactato Sintase/genética , Oryza/efeitos dos fármacos , Proteínas de Plantas/genética , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas
10.
Ecotoxicol Environ Saf ; 208: 111629, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33396149

RESUMO

As an alternative to volatile organic solvents, ionic liquids (ILs) are known as "green solvents", and widely used in industrial applications. However, due to their high solubility and stability, ILs have tendency to persist in the water environment, thus having potential negative impacts on the aquatic ecosystem. For assessing the environmental risks of ILs, a fundamental understanding of the toxic effects and mechanisms of ILs is needed. Here we evaluated the cytotoxicity of 1-methyl-3-decylimidazolium chloride ([C10mim]Cl) and elucidated the main toxic mechanism of [C10mim]Cl in human cervical carcinoma (Hela) cells. Microstructural analysis revealed that [C10mim]Cl exposure caused the cell membrane breakage, swollen and vacuolated mitochondria, and spherical cytoskeletal structure. Cytotoxicity assays found that [C10mim]Cl exposure increased ROS production, decreased mitochondrial membrane potential, induced cell apoptosis and cell cycle arrest. These results indicated that [C10mim]Cl could induce damage to cellular membrane structure, affect the integrity of cell ultrastructure, cause the oxidative damage and ultimately lead to the inhibition of cell proliferation. Moreover, alterations of biochemical information including the increased ratios of unsaturated fatty acid and carbonyl groups to lipid, and lipid to protein, and the decreased ratios of Amide I to Amide II, and α-helix to ß-sheet were observed in [C10mim]Cl treated cells, suggesting that [C10mim]Cl could affect the structure of membrane lipid alkyl chain and cell membrane fluidity, promote the lipid peroxidation and alter the protein secondary structure. The findings from this work demonstrated that membrane structure is the key target, and membrane damage is involved in [C10mim]Cl induced cytotoxicity.


Assuntos
Substâncias Perigosas/toxicidade , Líquidos Iônicos/toxicidade , Membrana Celular/efeitos dos fármacos , Ecossistema , Células HeLa , Humanos , Imidazolinas/toxicidade , Mitocôndrias , Estrutura Secundária de Proteína , Solventes
11.
Angew Chem Int Ed Engl ; 60(3): 1605-1609, 2021 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-33015909

RESUMO

A nickel-catalyzed asymmetric reductive hydroarylation of vinyl amides to produce enantioenriched α-arylbenzamides is reported. The use of a chiral bisimidazoline (BIm) ligand, in combination with diethoxymethylsilane and aryl halides, enables the regioselective introduction of aryl groups to the internal position of the olefin, forging a new stereogenic center α to the N atom. The use of neutral reagents and mild reaction conditions provides simple access to pharmacologically relevant motifs present in anticancer, SARS-CoV PLpro inhibitors, and KCNQ channel openers.


Assuntos
Benzamidas/síntese química , Níquel/química , Alcenos/química , Catálise , Imidazolinas/química , Conformação Molecular , Compostos de Organossilício/química , Estereoisomerismo , Termodinâmica
12.
Br J Pharmacol ; 178(3): 654-671, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33140839

RESUMO

BACKGROUND AND PURPOSE: Activation of type 2 imidazoline receptors has been shown to exhibit neuroprotective properties including anti-apoptotic and anti-inflammatory effects, suggesting a potential therapeutic value in Alzheimer's disease (AD). Here, we explored the effects of the imidazoline-2 ligand BU224 in a model of amyloidosis. EXPERIMENTAL APPROACH: Six-month-old female transgenic 5XFAD and wild-type (WT) mice were treated intraperitoneally with 5-mg·kg-1 BU224 or vehicle twice a day for 10 days. Behavioural tests were performed for cognitive functions and neuropathological changes were investigated by immunohistochemistry, Western blot, elisa and qPCR. Effects of BU224 on amyloid precursor protein (APP) processing, spine density and calcium imaging were analysed in brain organotypic cultures and N2a cells. KEY RESULTS: BU224 treatment attenuated spatial and perirhinal cortex-dependent recognition memory deficits in 5XFAD mice. Fear-conditioning testing revealed that BU224 also improved both associative learning and hippocampal- and amygdala-dependent memory in transgenic but not in WT mice. In the brain, BU224 reduced levels of the microglial marker Iba1 and pro-inflammatory cytokines IL-1ß and TNF-α and increased the expression of astrocytic marker GFAP in 5XFAD mice. These beneficial effects were not associated with changes in amyloid pathology, neuronal apoptosis, mitochondrial density, oxidative stress or autophagy markers. Interestingly, ex vivo and in vitro studies suggested that BU224 treatment increased the size of dendritic spines and induced a threefold reduction in amyloid-ß (Aß)-induced functional changes in NMDA receptors. CONCLUSION AND IMPLICATIONS: Sub-chronic treatment with BU224 restores memory and reduces inflammation in transgenic AD mice, at stages when animals display severe pathology.


Assuntos
Doença de Alzheimer , Imidazolinas , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides , Precursor de Proteína beta-Amiloide/genética , Animais , Cognição , Modelos Animais de Doenças , Feminino , Imidazóis , Ligantes , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos
13.
Eur J Med Chem ; 209: 112947, 2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-33139112

RESUMO

Compounds with excellent receptor engagement displaying α2-AR antagonist activity are useful not only for therapeutic purposes (e.g. antidepressants), but also to help in the crystallization of this particular GPCR. Therefore, based on our broad experience in the topic, we have prepared eighteen di-aryl (phenyl and/or pyridin-2-yl) mono- or di-substituted guanidines and 2-aminoimidazolines. The in vitro α2-AR binding affinity experiments in human brain tissue showed the advantage of a 2-aminoimidazolinium cation, a di-arylmethylene core, a conformationally locked pyridin-2-yl-guanidine and a di-substituted guanidinium to achieve good α2-AR engagement. After different in vitro [35S]GTPγS binding experiments in human prefrontal cortex tissue, it was possible to identify that compounds 7a, 7b and 7c were α2-AR partial agonist, whereas 8h was a potent α2-AR antagonist. Docking and MD studies with a model of α2A-AR and two crystal structures suggest that antagonism is achieved by compounds carrying a di-substituted guanidine which substituent occupy a pocket adjacent to TM5 without engaging S2005.42 or S2045.46, and a mono-substituted cationic group, which favorably interacts with E942.65.


Assuntos
Antagonistas de Receptores Adrenérgicos alfa 2/síntese química , Antidepressivos/síntese química , Guanidina/síntese química , Antagonistas de Receptores Adrenérgicos alfa 2/farmacologia , Animais , Antidepressivos/farmacologia , Encéfalo , Desenho de Fármacos , Guanidina/farmacologia , Guanidinas/química , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Humanos , Imidazolinas/química , Modelos Moleculares , Ligação Proteica , Relação Estrutura-Atividade
14.
J Am Chem Soc ; 142(51): 21368-21381, 2020 12 23.
Artigo em Inglês | MEDLINE | ID: mdl-33305945

RESUMO

Exchange processes which include conformational change, protonation/deprotonation, and binding equilibria are routinely studied by 2D exchange NMR techniques, where information about the exchange of nuclei between environments with different NMR shifts is obtained from the development of cross-peaks. Whereas 2D NMR enables the real time study of millisecond and slower exchange processes, 2D ESR in the form of 2D-ELDOR (two-dimensional electron-electron double resonance) has the potential for such studies over the nanosecond to microsecond real time scales. Cross-peak development due to chemical exchange has been seen previously for semiquinones in ESR, but this is not possible for most common ESR probes, such as nitroxides, studied at typical ESR frequencies because, unlike NMR, the exchanging states yield ESR signals that are not resolved from each other within their respective line widths. But at 95 GHz, it becomes possible to resolve them in many cases because of the increased g-factor resolution. The 95 GHz instrumental developments occurring at ACERT now enable such studies. We demonstrate these new capabilities in two studies: (A) the protonation/deprotonation process for a pH-sensitive imidazoline spin label in aqueous solution where the exchange rate and the population ratio of the exchanging states are controlled by the concentration and pH of the buffer solution, respectively, and (B) a nitroxide radical partitioning between polar (aqueous) and nonpolar (phospholipid) environments in multilamellar lipid vesicles, where the cross-peak development arises from the exchange of the nitroxide between the two phases. This work represents the first example of the observation and analysis of cross-peaks arising from chemical exchange processes involving nitroxide spin labels.


Assuntos
Espectroscopia de Ressonância de Spin Eletrônica , Tampões (Química) , Concentração de Íons de Hidrogênio , Imidazolinas/química , Cinética , Espectroscopia de Ressonância Magnética , Fosfolipídeos/química , Prótons , Marcadores de Spin , Água/química
15.
Bioorg Med Chem Lett ; 30(23): 127595, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-33031924

RESUMO

A series of substituted imidazoline derivatives were synthesized and characterized. Compounds were tested in-vivo for their antihypertensive, analgesic, antiaggressive, depressant, antidepressant, and ALD50 activities. The compounds 3a, 3c, 4c, 5a, and 6c showed cardiovascular as well as central nervous system activities and are potential candidate as drug among all fifteen compounds tested. All these compounds have shown better activity for antihypertensive, analgesic, antiaggressive, and depressant-antidepressant, properties than reference compounds clonidine, morphine, diazepam, and imipramine respectively. Most of the compounds have shown ALD50 > 500 mg/kg with maximum in 4a and 5a (>1000 mg/kg).


Assuntos
Anti-Hipertensivos/uso terapêutico , Fármacos do Sistema Nervoso Central/uso terapêutico , Depressão/tratamento farmacológico , Hipertensão/tratamento farmacológico , Imidazolinas/uso terapêutico , Dor/tratamento farmacológico , Animais , Anti-Hipertensivos/síntese química , Fármacos do Sistema Nervoso Central/síntese química , Feminino , Imidazolinas/síntese química , Masculino , Ratos
16.
ChemSusChem ; 13(22): 6016-6027, 2020 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-33021034

RESUMO

Hydrothermal liquefaction (HTL) of microalgae for biofuel production is suffering from low bio-oil yield and high heteroatomic compositions owing to their low efficiency and selectivity to hydrolysis of cellular compounds. Hereby we report Keggin-type (Mo-V-P) heteropolyacids (HPAs)-catalyzed HTL of microalgae for efficient low-nitrogen biocrude production. The increases of reaction temperature, reaction time, and vanadium substitution degrees of HPAs are favorable to biocrude yield initially, whereas a significant decrease of biocrude yield is observed owing to the enhanced oxidation of carbohydrates above the optimum reaction conditions. The maximum biocrude yield of HPAs-catalyzed HTL of microalgae is 29.95 % at reaction temperature of 300 °C, reaction time of 2 h, and 5 wt% of HPA-4, which is about 19.66 % higher than that of control with 71.17 % less N-containing compounds, including 1,3-propanediamine, 1-pentanamine, and 2, 2'-heptamethylene-di-2-imidazoline than that of control. This work reveals that HPAs with Brønsted acidity and reversible redox properties are capable of both enhancing biocrude production via catalyzing the hydrolysis of cellular compounds and reducing their nitrogen content through avoiding the Maillard reactions between the intermediates of hydrolysis of carbohydrates and proteins. HPAs-catalyzed HTL is an efficient strategy to produce low N-containing biofuels, possibly paving the way of their direct use in modern motors.


Assuntos
Clorófitas/metabolismo , Molibdênio/química , Molibdênio/metabolismo , Nitrogênio/metabolismo , Ácidos Fosfóricos/química , Ácidos Fosfóricos/metabolismo , Biocombustíveis , Catálise , Diaminas/química , Imidazolinas/química , Oxirredução , Temperatura , Fatores de Tempo
17.
Org Lett ; 22(21): 8475-8479, 2020 11 06.
Artigo em Inglês | MEDLINE | ID: mdl-33104369

RESUMO

N-Aminoimidazolidin-2-one (Aid)-containing peptides with a constrained backbone present a novel class of peptidomimetics for drug discovery. The introduction of Aid residues into peptide sequences has been achieved by intramolecular Mitsunobu cyclization of a serine side chain onto the α-NH of an aza-glycine residue. The effectiveness of this new strategy was demonstrated by synthesizing six Aid-containing analogues of angiotensin-(1-7) on solid support. The Aid analogues of angiotensin-(1-7) exhibited increased peptidase stability against human ACE and DPP3 and improved anti-inflammation and antiproliferation activity.


Assuntos
Angiotensina I/química , Imidazolinas/química , Fragmentos de Peptídeos/química , Peptidomiméticos/síntese química , Peptidomiméticos/farmacologia , Técnicas de Química Sintética , Dipeptidil Peptidases e Tripeptidil Peptidases/antagonistas & inibidores , Humanos , Peptidomiméticos/química , Peptidil Dipeptidase A/metabolismo
18.
Acta Crystallogr B Struct Sci Cryst Eng Mater ; 76(Pt 5): 850-864, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-33017318

RESUMO

The synthetically modified green fluorescent protein chromophore analogue 3,4,5-trimethoxybenzylidene imidazolinone (1) yielded five polymorphs (I, II, III, IV, V) concomitantly irrespective of the solvent used for crystallization. The pentamorphic modification of 1 is solely due to the interplay of iso-energetic weak intermolecular interactions in molecular associations as well as the conformational flexibility offered by a C-C single bond, which connects the electron-deficient moiety imidazolinone with the electron-rich trimethoxybenzylidene group. A common structural feature observed in all the polymorphs is the formation of a `zero-dimensional' centrosymmetric dimeric unit through a short and linear C-H...O hydrogen bond engaging phenyl C-H and imidazolinone carbonyl oxygen. However, the networking of these dimeric units showed a subtle difference in all the polymorphs. The 2D isostructurality was observed between polymorphs I, II and III, while the other two polymorphs IV and V revealed only `zero-dimensional' isostructurality. The different fluorescence emissions of Form I (blue) and Forms II to V (yellow) were attributed to the differences in π-stacking interactions. It shows that one can modulate the photophysical properties of these smart materials by slightly altering their crystal structure. Such an approach will aid in developing new multi-colour organic fluorescent materials of varying crystal structures for live-cell imaging and fluorescent sensing applications.


Assuntos
Compostos de Benzilideno/química , Proteínas de Fluorescência Verde/química , Imidazolinas/química , Substâncias Luminescentes/química , Cristalização , Cristalografia por Raios X , Ligação de Hidrogênio , Modelos Moleculares
19.
Org Lett ; 22(21): 8496-8499, 2020 11 06.
Artigo em Inglês | MEDLINE | ID: mdl-33054232

RESUMO

The first enantio- and diastereoselective synthesis of Tepe's human proteasome modulator is described. Routes to this and other highly substituted chiral imidazolines generally produce racemic material. Key to the route disclosed here is a gram-scale anti-selective aza-Henry reaction of an α-alkyl α-nitro ester nucleophile, catalyzed by a Bis(Amidine) [BAM] chiral proton complex, delivering the key intermediate in high yield as a single stereoisomer. The adduct is reduced to the amino ester and converted to an imidazoline.


Assuntos
Imidazolinas/síntese química , Imidazolinas/farmacologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Técnicas de Química Sintética , Humanos , Imidazolinas/química , Estereoisomerismo
20.
Eur J Med Chem ; 207: 112802, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-32927230

RESUMO

Novel imidazoline benzimidazole derivatives containing diversely substituted phenoxy moieties were synthesized with the aim of evaluating their antitrypanosomal activity, DNA/RNA binding affinity and in vitro ADME properties. The presence of the diethylaminoethyl subunit in 18a-18c led to enhanced antitrypanosomal potency, particularly for 18a and 18c, which contain unsubstituted and methoxy-substituted phenoxy moieties. They were found to be > 2-fold more potent against African trypanosomes than nifurtimox. Fluorescence and CD spectroscopy, thermal denaturation assays and computational analysis indicated a preference of 18a-18c toward AT-rich DNA and their minor groove binding mode. Replacement of the amidine group with less basic and ionisable nitrogen-containing moieties failed to improve membrane permeability of the investigated compounds. Due to structural diversification, the compounds displayed a range of physico-chemical features resulting in variable in vitro ADME properties, leaving space for further optimization of the biological profiles.


Assuntos
Benzimidazóis/síntese química , Benzimidazóis/farmacologia , DNA/metabolismo , Desenho de Fármacos , Imidazolinas/química , RNA/metabolismo , Trypanosoma/efeitos dos fármacos , Antiprotozoários/síntese química , Antiprotozoários/química , Antiprotozoários/metabolismo , Antiprotozoários/farmacologia , Benzimidazóis/química , Benzimidazóis/metabolismo , Técnicas de Química Sintética
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