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1.
Bioorg Med Chem ; 26(21): 5664-5671, 2018 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-30366786

RESUMO

CD4 mimics such as YIR-821 and its derivatives are small molecules which inhibit the interaction between the Phe43 cavity of HIV-1 gp120 with host CD4, an interaction that is involved in the entry of HIV to cells. Known CD4 mimics generally possess three structural features, an aromatic ring, an oxalamide linker and a piperidine moiety. We have shown previously that introduction of a cyclohexyl group and a guanidine group into the piperidine moiety and a fluorine atom at the meta-position of the aromatic ring leads to a significant increase in the anti-HIV activity. In the current study, the effects of conformational flexibility were investigated by introduction of an indole-type group in the junction between the oxalamide linker and the aromatic moiety or by replacement of the oxalamide linker with a glycine linker. This led to the development of compounds with high anti-HIV activity, showing the importance of the junction region for the expression of high anti-HIV activity. The present data are expected to be useful in the future design of novel CD4 mimic molecules.


Assuntos
Materiais Biomiméticos/farmacologia , Glicina/análogos & derivados , Glicina/farmacologia , Inibidores da Fusão de HIV/farmacologia , Indóis/farmacologia , Sítios de Ligação , Materiais Biomiméticos/síntese química , Materiais Biomiméticos/química , Materiais Biomiméticos/toxicidade , Antígenos CD4/química , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Glicina/síntese química , Glicina/toxicidade , Proteína gp120 do Envelope de HIV/química , Inibidores da Fusão de HIV/síntese química , Inibidores da Fusão de HIV/química , Inibidores da Fusão de HIV/toxicidade , HIV-1/química , Humanos , Indóis/síntese química , Indóis/química , Indóis/toxicidade , Simulação de Acoplamento Molecular , Maleabilidade
2.
J Enzyme Inhib Med Chem ; 33(1): 1405-1414, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30191734

RESUMO

Adenylosuccinate synthetase (AdSS) is an enzyme at regulatory point of purine metabolism. In pathogenic organisms which utilise only the purine salvage pathway, AdSS asserts itself as a promising drug target. One of these organisms is Helicobacter pylori, a wide-spread human pathogen involved in the development of many diseases. The rate of H. pylori antibiotic resistance is on the increase, making the quest for new drugs against this pathogen more important than ever. In this context, we describe here the properties of H. pylori AdSS. This enzyme exists in a dimeric active form independently of the presence of its ligands. Its narrow stability range and pH-neutral optimal working conditions reflect the bacterium's high level of adaptation to its living environment. Efficient inhibition of H. pylori AdSS with hadacidin and adenylosuccinate gives hope of finding novel drugs that aim at eradicating this dangerous pathogen.


Assuntos
Monofosfato de Adenosina/análogos & derivados , Adenilossuccinato Sintase/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Glicina/análogos & derivados , Helicobacter pylori/efeitos dos fármacos , Helicobacter pylori/enzimologia , Monofosfato de Adenosina/síntese química , Monofosfato de Adenosina/química , Monofosfato de Adenosina/farmacologia , Adenilossuccinato Sintase/metabolismo , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Glicina/síntese química , Glicina/química , Glicina/farmacologia , Estrutura Molecular , Relação Estrutura-Atividade
3.
Amino Acids ; 50(10): 1307-1328, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30099594

RESUMO

The ethynylglycine synthon {(R)-2,2-dimethyl-3-(tert-butoxycarbonyl)-4-ethynyl-oxazolidine} is a chiral compound with valuable synthetic interest. An update (covering literature from 2005 to 2017) on the different synthetic utilities is reviewed and discussed.


Assuntos
Compostos de Bifenilo/química , Glicina/síntese química , Catálise , Glicina/química , Oxazóis/química , Estereoisomerismo
4.
Bioorg Med Chem ; 26(14): 4153-4167, 2018 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-30001846

RESUMO

In accordance with the structural characteristics of thiazolidinedione drugs and highly bioactive tyrosine derivatives, we tentatively designed the l-phenylglycine derivatives TM1 and TM2 based on basic principles of drug design and then synthesized them. The in vitro screening of peroxisome proliferator-activated receptor gamma (PPARγ) activated activity, α-glucosidase inhibitory and dipeptidyl peptidase-4 inhibitory activities showed that the novel molecule M5 had efficient PPAR response element (PPRE) activated activity (PPRE relative activity 105.04% at 10 µg·mL-1 compared with the positive control pioglitazone, with 100% activity). Therefore, M5 was selected as the hit compound from which the TM3 and TM4 series of compounds were further designed and synthesized. Based on the PPRE relative activities of TM3 and TM4, we discovered another new molecule, TM4h, which had the strongest PPRE relative activity (120.42% at 10 µg·mL-1). In addition, the concentration-dependent activity of the highly active compounds was determined by assaying their half-maximal effective concentration (EC50) values. The molecular physical parameter calculation and the molecular toxicity prediction were used to theoretically evaluate the lead-likeness and safety of the active compounds. In conclusion, we identified a potential PPARγ lead molecule and developed a tangible strategy for antidiabetic drug development.


Assuntos
Desenho de Drogas , Glicina/análogos & derivados , Inibidores de Glicosídeo Hidrolases/farmacologia , Hipoglicemiantes/farmacologia , PPAR gama/antagonistas & inibidores , alfa-Glucosidases/metabolismo , Relação Dose-Resposta a Droga , Glicina/síntese química , Glicina/química , Glicina/farmacologia , Inibidores de Glicosídeo Hidrolases/síntese química , Inibidores de Glicosídeo Hidrolases/química , Células Hep G2 , Humanos , Hipoglicemiantes/síntese química , Hipoglicemiantes/química , Estrutura Molecular , PPAR gama/metabolismo , Relação Estrutura-Atividade
5.
Comput Biol Chem ; 74: 212-217, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29653432

RESUMO

Amide derivatives of N-phthaloylglycine were synthesized under Schotten Baumann reaction condition. The structures of synthesized compounds (4a-d) were characterized by using FTIR, 1HNMR and EI-MS. The compounds were evaluated for their in-vitro Butyrylcholinesterase inhibition and all of them exhibited good activity against this enzyme. Compound 4a (IC50 = 6.5 ±â€¯0.1) was found to be most potent compared with the reference compound Galantamine (IC50 = 6.6 ±â€¯0.00038) and the other compounds (4b,4c,4d) were also possess that activity and hence can be employed for the discovery of lead compounds against Alzheimer's disease. The depth analysis of the binding mechanism of these newly synthesized compounds inside the binding gorge of BChE, an in silico technique, molecular docking was performed. All the compounds were found to be well accommodated within the binding pocket of BChE. Compounds 4a, 4b and 4c showed hydrogen bonding interaction with binding site residue TYR332. Moreover, hydrophobic and π-π interaction assisted the compounds to attain their enzyme inhibitory activity. These theoretical studies showed significant correlation with experimental results.


Assuntos
Amidas/farmacologia , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Desenho de Drogas , Glicina/análogos & derivados , Simulação de Acoplamento Molecular , Amidas/síntese química , Amidas/química , Animais , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Relação Dose-Resposta a Droga , Electrophorus , Glicina/síntese química , Glicina/química , Glicina/farmacologia , Estrutura Molecular , Relação Estrutura-Atividade
6.
Biosci Biotechnol Biochem ; 82(7): 1252-1259, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29558858

RESUMO

Ultraviolet-absorbing chemicals are useful in cosmetics and skin care to prevent UV-induced skin damage. We demonstrate here that heterologous production of shinorine, which shows broad absorption maxima in the UV-A and UV-B region. A shinorine producing Corynebacterium glutamicum strain was constructed by expressing four genes from Actinosynnema mirum DSM 43827, which are responsible for the biosynthesis of shinorine from sedoheptulose-7-phosphate in the pentose phosphate pathway. Deletion of transaldolase encoding gene improved shinorine production by 5.2-fold. Among the other genes in pentose phosphate pathway, overexpression of 6-phosphogluconate dehydrogenase encoding gene further increased shinorine production by 60% (19.1 mg/L). The genetic engineering of the pentose phosphate pathway in C. glutamicum improved shinorine production by 8.3-fold in total, and could be applied to produce the other chemicals derived from sedoheptulose-7-phosphate.


Assuntos
Corynebacterium glutamicum/metabolismo , Cicloexilaminas/síntese química , Glicina/análogos & derivados , Engenharia Metabólica , Protetores Solares/síntese química , Actinobacteria/genética , Corynebacterium glutamicum/genética , Genes Bacterianos , Glicina/síntese química , Espectrometria de Massas , Via de Pentose Fosfato , Fosfogluconato Desidrogenase/metabolismo , Recombinação Genética , Fosfatos Açúcares/química , Transaldolase/genética , Raios Ultravioleta
7.
Molecules ; 23(4)2018 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-29570637

RESUMO

N-(2-trifluoromethyl-4-chlorophenyl)-2-oxocyclohexyl sulfonamide (chesulfamide) is in the limelight as a novel fungicide, and has fungicidal activity against Botrytis cinerea. For exploring more novel structures, 33 new compounds were synthesized by N-alkylation and acid-amine coupling reactions with chesulfamide as the core moiety, and their structures were characterized and established by ¹H-NMR, 13C-NMR, MS, and elemental analysis. The structure of (1R,2S)-2-(2-(N-(4-chloro-2-trifluoromethylphenyl)sulfamoyl)-cyclohexylamino)-N-(2-trifluoromethylphenyl) acetamide (II-19) was defined by X-ray single crystal diffraction. The in vivo and in vitro fungicidal activities against B. cinerea were evaluated. The bioassay results of mycelial growth demonstrated that most compounds exhibited excellent inhibitory activity against B. cinerea at 50 µg mL-1, and 7 compounds showed lower EC50 values than boscalid (EC50 = 4.46 µg mL-1) against B. cinerea (CY-09). In cucumber pot experiment, the inhibitory rates of four compounds (II-4, II-5, II-12, and II-13) against B. cinerea were 90.48, 93.45, 92.86, and 91.07, which were better than cyprodinil (88.69%), the best performing of all controls. In tomato pot experiment, the control efficacy of two analogs (II-8 and II-15) were 87.98 and 87.97% at 200 µg mL-1, which were significantly higher than boscalid (78.10%). Most compounds have an excellent fungicidal effect on B. cinerea, with potential as a lead compound for developing new pesticides.


Assuntos
Botrytis/efeitos dos fármacos , Fungicidas Industriais/síntese química , Fungicidas Industriais/farmacologia , Glicina/análogos & derivados , Sulfonamidas/síntese química , Sulfonamidas/farmacologia , Fungicidas Industriais/química , Glicina/síntese química , Glicina/química , Glicina/farmacologia , Relação Estrutura-Atividade , Sulfonamidas/química
8.
Chem Commun (Camb) ; 54(17): 2146-2149, 2018 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-29423498

RESUMO

Non-ribosomal peptides contain an array of amino acid building blocks that can present challenges for the synthesis of important intermediates. Here, we report the synthesis of glycopeptide antibiotic (GPA) thioester peptides that retains the crucial stereochemical purity of the terminal phenylglycine residue, which we show is essential for the enzymatic GPA cyclisation cascade.


Assuntos
Antibacterianos/síntese química , Glicina/análogos & derivados , Glicopeptídeos/síntese química , Antibacterianos/química , Antibacterianos/metabolismo , Vias Biossintéticas , Técnicas de Química Sintética/métodos , Ciclização , Esterificação , Glicina/síntese química , Glicina/metabolismo , Glicopeptídeos/química , Glicopeptídeos/metabolismo , Estereoisomerismo , Compostos de Sulfidrila/síntese química , Compostos de Sulfidrila/química , Compostos de Sulfidrila/metabolismo
9.
Nucleosides Nucleotides Nucleic Acids ; 37(2): 79-88, 2018 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-29376768

RESUMO

An efficient five-step synthetic route for multigram-scale preparation of formylglycinamide ribonucleotide (FGAR) from peracetylated ß-d-ribofuranosyl azide has been developed.


Assuntos
Glicina/análogos & derivados , Ribonucleotídeos/síntese química , Azidas/química , Glicina/síntese química
10.
J Biomol Struct Dyn ; 36(4): 893-905, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-28335682

RESUMO

Investigation of side effects and solubility of anticancer drugs is a major challenge in chemotherapy science. Thus, design and synthesis of cisplatin analogs with higher lipophilicity as novel water-soluble anticancer drugs is valuable. In this work, two new Pt(II) complexes were synthesized with formula cis-[Pt(NH3)2(amylgly)]NO3 and cis-[Pt(amylamine)2(amylgly)]NO3, where gly is penthyl glycine as an amino acid. The new compounds were synthesized and extensively characterized using analytical techniques; spectroscopic methods, and conductivity measurement. The anticancer activity of synthesized complexes was investigated against colon cancer cell line HCT116 using MTT assay and results showed excellent anticancer activity with Cc50 values of 36 and 270 M after 24-h incubation time for cis-[Pt(NH3)2(amylgly)]NO3 and cis-[Pt(NH2-amyl)2(amylgly)]NO3, respectively; which is lower than that for cisplatin. These complexes were also interacted with highly polymerized calf thymus DNA and the binding mode of the complexes to CT-DNA was evaluated by fluorescence, circular dichroism, and UV spectroscopy. The calculation of binding and thermodynamic of Pt(II) complexes with CT-DNA can provide deeper insight into mechanism of the action of these types of complexes with nucleic acids. So, thermodynamic parameters were also determined according to isothermal titration. In comparison with cis-[Pt(NH3)2(amylgly)]NO3 in DNA interaction, the result show that cis-[Pt(NH2-amyl)2(amylgly)]NO3 has higher affinity with binding constant Kf = 8.72 mM to CT-DNA. The results indicate that cis-[Pt(amylamine)2(amylgly)]NO3 with large and bulky aliphatic group bind to CT-DNA by different modes and covalent and groove bindings were preferred mode of interaction with DNA.


Assuntos
Aminas/química , Antineoplásicos/química , Cisplatino/química , Glicina/química , Aminas/síntese química , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Dicroísmo Circular , Cisplatino/análogos & derivados , Cisplatino/síntese química , Cisplatino/farmacologia , DNA/efeitos dos fármacos , Glicina/síntese química , Células HCT116 , Humanos , Ligantes , Neoplasias/tratamento farmacológico , Termodinâmica
11.
Int J Biol Macromol ; 107(Pt B): 1491-1500, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28993295

RESUMO

Metalloproteases are a class of proteases having metal ion(s) at their catalytic sites. Bacterial collagenases are involved in human gas gangrene, periodontal diseases, food etc. The Clostridium collagenase occurs in two isoforms COL_G and Col_H. The present work is based on the protein structure-based approach for the development of collagenase inhibitors. The sequence analysis and structural alignment of both isoforms showed significant similarity in active site except aspartate switch present in Col_H. The homology model was developed and validated for Col_H peptidase domain with open aspartate switch followed by the docking of designed ligands. Compound 8b showed better interaction due to the presence of the nitro group. The N-benzyl-arylsulfonyl-phenylglycine derivatives were synthesized and characterized by FT-IR, 1H NMR, 13C NMR and mass spectral analysis. The compounds were evaluated for C. histolyticum collagenase inhibitory activity using gelatin-ninhydrin based assay. Compounds 5b, 3b, 11b, 6b and 8b with IC50 of 24.34µM, 29.61µM, 28.39µM, 31.4 and 32.11µM respectively were found to be more active. Further, The Ki of most active compound 5b was found to be 22.02µM showing the competitive mode of inhibition of the enzyme. The activity of the derivatives showed correlation with the docking results.


Assuntos
Colagenases/metabolismo , Desenho de Drogas , Glicina/análogos & derivados , Inibidores de Metaloproteinases de Matriz/síntese química , Inibidores de Metaloproteinases de Matriz/farmacologia , Glicina/síntese química , Glicina/farmacologia , Concentração Inibidora 50 , Simulação de Acoplamento Molecular , Análise de Sequência de Proteína , Homologia Estrutural de Proteína
12.
J Med Chem ; 60(19): 7984-7999, 2017 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-28892629

RESUMO

Inhibition of lysine specific demethylase 1 (LSD1) has been shown to induce the differentiation of leukemia stem cells in acute myeloid leukemia (AML). Irreversible inhibitors developed from the nonspecific inhibitor tranylcypromine have entered clinical trials; however, the development of effective reversible inhibitors has proved more challenging. Herein, we describe our efforts to identify reversible inhibitors of LSD1 from a high throughput screen and subsequent in silico modeling approaches. From a single hit (12) validated by biochemical and biophysical assays, we describe our efforts to develop acyclic scaffold-hops from GSK-690 (1). A further scaffold modification to a (4-cyanophenyl)glycinamide (e.g., 29a) led to the development of compound 32, with a Kd value of 32 nM and an EC50 value of 0.67 µM in a surrogate cellular biomarker assay. Moreover, this derivative does not display the same level of hERG liability as observed with 1 and represents a promising lead for further development.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Glicina/análogos & derivados , Histona Desmetilases/antagonistas & inibidores , Leucemia/tratamento farmacológico , Compostos de Espiro/farmacologia , Biomarcadores , Linhagem Celular Tumoral , Simulação por Computador , Desenho de Drogas , Descoberta de Drogas , Canais de Potássio Éter-A-Go-Go/efeitos dos fármacos , Glicina/síntese química , Glicina/farmacologia , Ensaios de Triagem em Larga Escala , Humanos , Modelos Moleculares , Simulação de Acoplamento Molecular , Compostos de Espiro/síntese química , Relação Estrutura-Atividade , Tranilcipromina/análogos & derivados , Tranilcipromina/química , Tranilcipromina/farmacologia
13.
ChemMedChem ; 12(20): 1723-1736, 2017 10 20.
Artigo em Inglês | MEDLINE | ID: mdl-28837260

RESUMO

Cancer cells express high levels of CK2, and its inhibition leads to apoptosis. CK2 has therefore emerged as a new drug target for cancer therapy. A biligand inhibitor ARC-772 was constructed by conjugating 4-(2-amino-1,3-thiazol-5-yl)benzoic acid and a carboxylate-rich peptoid. ARC-772 was found to bind CK2 with a Kd value of 0.3 nm and showed remarkable CK2 inhibitory selectivity in a panel of 140 protein kinases (Gini coefficient: 0.75 at c=100 nm). ARC-775, the acetoxymethyl ester prodrug of ARC-772, was efficiently taken up by cells. Once internalized, the inhibitor is activated by cellular esterase activity. In HeLa cancer cells ARC-775 was found to activate caspase-3 (an apoptosis marker) at sub-micromolar concentrations (EC50 =0.3 µm), a 20-fold lower extracellular concentration than CX-4945, the only CK2 inhibitor under clinical trials. At micromolar concentrations, ARC-775 was also found to inhibit ADP-induced aggregation of human platelets. The overall results of this study demonstrate that oligo-anionic biligand inhibitors have good potential for drug development.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Caseína Quinase II/antagonistas & inibidores , Caspase 3/metabolismo , Glicina/análogos & derivados , Agregação Plaquetária/efeitos dos fármacos , Tiazóis/síntese química , Tiazóis/farmacologia , Caseína Quinase II/metabolismo , Caspase 3/genética , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Chaperoninas/genética , Chaperoninas/metabolismo , Ativação Enzimática/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glicina/síntese química , Glicina/farmacologia , Células HeLa , Humanos , Estrutura Molecular , Fosforilação
14.
Amino Acids ; 49(9): 1487-1520, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28674862

RESUMO

This review article critically discusses examples of asymmetric synthesis of tailor-made α-amino acids via homologation of Ni(II) complexes of glycine and alanine Schiff bases, reported in the literature from 2013 through the end of 2016. Where it is possible, reaction mechanism and origin of the stereochemical outcome is discussed in detail. Special attention is given to various aspects of practicality and scalability of the reported methods. Among the most noticeable developments in this area are novel designs of axially chiral ligands, application of electro- and mechano-chemical (ball-milling) conditions, and development of dynamic kinetic resolution procedures.


Assuntos
Alanina/síntese química , Complexos de Coordenação/síntese química , Desenho de Drogas , Glicina/síntese química , Níquel/química , Peptidomiméticos/síntese química , Alanina/análogos & derivados , Técnicas de Química Sintética , Química Farmacêutica , Glicina/análogos & derivados , Humanos , Cinética , Bases de Schiff/química , Estereoisomerismo
15.
J Org Chem ; 82(16): 8514-8526, 2017 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-28737944

RESUMO

An acetyl chloride-mediated cascade transformation involving a primary carbamate, ethyl glyoxylate, and various types of nucleophiles is reported for the synthesis of orthogonally protected α-amino esters. These reactions proceeded rapidly to afford the pivotal α-chloroglycine intermediate in excellent yields, which can be directly functionalized in situ with various types of nucleophiles. A mild and unique AcOH(cat.)/AcCl system was found to promote an autocatalytic-like condensation and facilitate the multicomponent assembly of non-proteinogenic α-amino esters. To better understand this one-pot transformation and the orchestration of the components' condensations, the investigation of a broader scope of nucleophiles and some kinetic studies are presented. Our findings suggest that the halogenation step toward the formation of α-chloroglycine is the rate-determining step likely proceeding through the formation of N-carbamoyl iminium. Also, the initial kinetic profiling for the nucleophilic substitution supports an SN1-like (SN2C+) mechanism in which nucleophiles add to the iminium-chloride tight ionic pair. These results lead ultimately to the design of a new protocol in which an achiral hydrogen bond donor thiourea catalyst was utilized to enhance the reaction scope and enable silylated nucleophiles to be efficiently exploited to synthesize novel non-proteinogenic α-amino esters.


Assuntos
Aminoácidos/síntese química , Cloraminas/síntese química , Ésteres/síntese química , Glicina/síntese química , Aminoácidos/química , Cloraminas/química , Ésteres/química , Glicina/química , Estrutura Molecular
16.
ACS Chem Neurosci ; 8(9): 1949-1959, 2017 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-28574249

RESUMO

It has been demonstrated previously that the endogenous compound N-arachidonyl-glycine inhibits the glycine transporter GlyT2, stimulates glycinergic neurotransmission, and provides analgesia in animal models of neuropathic and inflammatory pain. However, it is a relatively weak inhibitor with an IC50 of 9 µM and is subject to oxidation via cyclooxygenase, limiting its therapeutic value. In this paper we describe the synthesis and testing of a novel series of monounsaturated C18 and C16 acyl-glycine molecules as inhibitors of the glycine transporter GlyT2. We demonstrate that they are up to 28 fold more potent that N-arachidonyl-glycine with no activity at the closely related GlyT1 transporter at concentrations up to 30 µM. This novel class of compounds show considerable promise as a first generation of GlyT2 transport inhibitors.


Assuntos
Proteínas da Membrana Plasmática de Transporte de Glicina/antagonistas & inibidores , Glicina/síntese química , Glicina/farmacologia , Moduladores de Transporte de Membrana/síntese química , Moduladores de Transporte de Membrana/farmacologia , Analgésicos/síntese química , Analgésicos/farmacologia , Animais , Ácidos Araquidônicos/farmacologia , Glicina/análogos & derivados , Proteínas da Membrana Plasmática de Transporte de Glicina/genética , Proteínas da Membrana Plasmática de Transporte de Glicina/metabolismo , Potenciais da Membrana/efeitos dos fármacos , Potenciais da Membrana/fisiologia , Micelas , Estrutura Molecular , Oócitos , RNA Mensageiro/metabolismo , Trítio , Xenopus laevis
17.
Bioorg Med Chem ; 25(15): 4110-4122, 2017 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-28601507

RESUMO

Vascular adhesion protein-1 (VAP-1) is a promising therapeutic target for the treatment of diabetic nephropathy. Here, we conducted optimization studies of our lead compound 1, which we previously reported as a novel VAP-1 inhibitor, to enhance the inhibition of human VAP-1 and to reduce CYP3A4 and CYP2C19 inhibition. As a result, we identified 3-chloro-4-{4-[5-(3-{[glycyl(methyl)amino]methyl}phenyl)pyrimidin-2-yl]piperazin-1-yl}benzoic acid (17h) as a novel orally active VAP-1 inhibitor, with 14-fold increased human VAP-1 inhibitory activity compared to 1, without CYP3A4 and CYP2C19 inhibition. Oral administration of 17h significantly inhibited the progression of proteinuria in streptozotocin (STZ) induced diabetic rats at 0.3 and 1mg/kg, suggesting that this compound has potential to be a therapeutic agent for the treatment of diabetic nephropathy.


Assuntos
Amina Oxidase (contendo Cobre)/antagonistas & inibidores , Moléculas de Adesão Celular/antagonistas & inibidores , Inibidores do Citocromo P-450 CYP2C19/farmacologia , Inibidores do Citocromo P-450 CYP3A/farmacologia , Glicina/análogos & derivados , Animais , Nefropatias Diabéticas/tratamento farmacológico , Glicina/síntese química , Glicina/química , Glicina/farmacologia , Glicina/uso terapêutico , Humanos , Simulação de Acoplamento Molecular , Espectroscopia de Prótons por Ressonância Magnética , Ratos , Espectrometria de Massas por Ionização por Electrospray
18.
Org Biomol Chem ; 15(26): 5468-5471, 2017 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-28639651

RESUMO

A ruthenium pincer catalyst has been shown to be highly efficient for the hydrogenation of a wide range of α-ketimino esters derived from α-keto esters and chiral 2-methylpropyl-2-sulfinamide, affording chiral aryl glycine derivatives with high yields and diasteroselectivities (20 examples, dr values up to 99 : 1).


Assuntos
Glicina/síntese química , Rutênio/química , Compostos de Sulfônio/química , Catálise , Glicina/análogos & derivados , Glicina/química , Hidrogenação , Conformação Molecular , Estereoisomerismo
19.
Bioorg Med Chem ; 25(2): 805-812, 2017 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-27956039

RESUMO

The orphan receptor GPR88 is an attractive therapeutic target because of its implications in a number of basal ganglia-associated disorders. To date, pharmacological characterization of GPR88 has been limited due to the lack of potent and selective agonists and antagonists appropriate for CNS investigations. We have previously reported that GPR88 couples to Gαi proteins and modulates cAMP levels upon treatment with a small molecule agonist 2-PCCA. Recently, another chemotype of GPR88 agonist, represented by 2-AMPP [(2S)-N-((1R)-2-amino-1-(4-(2-methylpentyloxy)-phenyl)ethyl)-2-phenylpropanamide], has also been discovered. In this report, a new series of 2-AMPP structurally related 4-hydroxyphenylglycine and 4-hydroxyphenylglycinol derivatives have been designed and evaluated for agonist activity at GPR88. The structure-activity relationship (SAR) studies suggest that the amine group in 2-AMPP can be replaced by hydroxyl, ester and amide groups, resulting in analogues with good to moderate potency, whereas the phenyl group on the amide cap is essential for activity and has limited size, shape and electronic tolerance.


Assuntos
Desenho de Drogas , Etilenoglicóis/farmacologia , Glicina/análogos & derivados , Fenóis/farmacologia , Receptores Acoplados a Proteínas-G/agonistas , Animais , Células CHO , Cricetulus , Relação Dose-Resposta a Droga , Etilenoglicóis/síntese química , Etilenoglicóis/química , Glicina/síntese química , Glicina/química , Glicina/farmacologia , Humanos , Estrutura Molecular , Fenóis/síntese química , Fenóis/química , Relação Estrutura-Atividade
20.
Orig Life Evol Biosph ; 47(4): 413-425, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27663450

RESUMO

Submarine hydrothermal vents are generally considered as the likely habitats for the origin and evolution of early life on Earth. In recent years, a novel hydrothermal system in Archean subseafloor has been proposed. In this model, highly alkaline and high temperature hydrothermal fluids were generated in basalt-hosted hydrothermal vents, where H2 and CO2 could be abundantly provided. These extreme conditions could have played an irreplaceable role in the early evolution of life. Nevertheless, sufficient information has not yet been obtained for the abiotic synthesis of amino acids, which are indispensable components of life, at high temperature and alkaline condition. This study aims to propose a new method for the synthesis of glycine in simulated Archean submarine alkaline vent systems. We investigated the formation of glycine from ethanolamine under conditions of high temperature (80-160 °C) and highly alkaline solutions (pH = 9.70). Experiments were performed in an anaerobic environment under mild pressure (0.1-8.0 MPa) at the same time. The results suggested that the formation of glycine from ethanolamine occurred rapidly and efficiently in the presence of metal powders, and was favored by high temperatures and high pressures. The experiment provides a new pathway for prebiotic glycine formation and points out the phenomenal influence of high-temperature alkaline hydrothermal vents in origin of life in the early ocean.


Assuntos
Etanolamina/síntese química , Glicina/síntese química , Origem da Vida , Água do Mar/química , Concentração de Íons de Hidrogênio , Fontes Hidrotermais
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