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1.
Chem Pharm Bull (Tokyo) ; 67(8): 824-838, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31366832

RESUMO

We synthesized and evaluated novel 5-[2-(thiophen-2-yl)propan-2-yl]-4H-1,2,4-triazole derivatives as 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) inhibitors. Optimization of the thiophene ring and the substituents on the 1,2,4-triazole ring produced 3,4-dicyclopropyl-5-{2-[3-fluoro-5-(trifluoromethyl)thiophen-2-yl]propan-2-yl}-4H-1,2,4-triazole monohydrochloride (9a), which showed potent and selective inhibitory activity against human 11ß-HSD1. Compound 9a was also metabolically stable against human and mouse liver microsomes. Oral administration of 9a to diabetic ob/ob mice lowered corticosterone levels in adipose tissue, and thereby reduced plasma glucose and insulin levels in a dose-dependent manner.


Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , Diabetes Mellitus Tipo 2/tratamento farmacológico , Descoberta de Drogas , Inibidores Enzimáticos/farmacologia , Hipoglicemiantes/farmacologia , Triazóis/farmacologia , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/metabolismo , Administração Oral , Animais , Diabetes Mellitus Tipo 2/metabolismo , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/química , Células HEK293 , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/química , Masculino , Camundongos , Camundongos Obesos , Estrutura Molecular , Relação Estrutura-Atividade , Triazóis/administração & dosagem , Triazóis/química
2.
Chem Commun (Camb) ; 55(69): 10214-10217, 2019 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-31380528

RESUMO

The l,d-transpeptidases (Ldts) are promising antibiotic targets for treating tuberculosis. We report screening of cysteine-reactive inhibitors against LdtMt2 from Mycobacterium tuberculosis. Structural studies on LdtMt2 with potent inhibitor ebselen reveal opening of the benzisoselenazolone ring by a nucleophilic cysteine, forming a complex involving extensive hydrophobic interactions with a substrate-binding loop.


Assuntos
Azóis/química , Azóis/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Mycobacterium tuberculosis/enzimologia , Compostos Organosselênicos/química , Compostos Organosselênicos/farmacologia , Peptidil Transferases/antagonistas & inibidores , Antituberculosos/química , Antituberculosos/farmacologia , Derivados de Benzeno/química , Derivados de Benzeno/farmacologia , Cisteína/metabolismo , Humanos , Simulação de Acoplamento Molecular , Mycobacterium tuberculosis/efeitos dos fármacos , Peptidil Transferases/metabolismo , Tuberculose/tratamento farmacológico , Tuberculose/microbiologia
4.
J Enzyme Inhib Med Chem ; 34(1): 1426-1438, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31401883

RESUMO

Anaplastic lymphoma kinase (ALK) has been recognised as a promising molecular target of targeted therapy for NSCLC. We performed SAR study of pyrazolo[3,4-b]pyridines to override crizotinib resistance caused by ALK-L1196M mutation and identified a novel and potent L1196M inhibitor, 10g. 10g displayed exceptional enzymatic activities (<0.5 nM of IC50) against ALK-L1196M as well as against ALK-wt. In addition, 10g is an extremely potent inhibitor of ROS1 (<0.5 nM of IC50) and displays excellent selectivity over c-Met. Moreover, 10g strongly suppresses proliferation of ALK-L1196M-Ba/F3 and H2228 cells harbouring EML4-ALK via apoptosis and the ALK signalling blockade. The results of molecular docking studies reveal that, in contrast to crizotinib, 10g engages in a favourable interaction with M1196 in the kinase domain of ALK-L1196M and hydrogen bonding with K1150 and E1210. This SAR study has provided a useful insight into the design of novel and potent inhibitors against ALK gatekeeper mutant.


Assuntos
Quinase do Linfoma Anaplásico/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Pirazóis/farmacologia , Piridinas/farmacologia , Quinase do Linfoma Anaplásico/metabolismo , Apoptose/efeitos dos fármacos , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Linhagem Celular Transformada , Proliferação de Células/efeitos dos fármacos , Cromatografia Líquida , Cristalografia por Raios X , Inibidores Enzimáticos/química , Humanos , Concentração Inibidora 50 , Simulação de Acoplamento Molecular , Espectroscopia de Prótons por Ressonância Magnética , Pirazóis/química , Piridinas/química , Transdução de Sinais/efeitos dos fármacos , Espectrometria de Massas por Ionização por Electrospray , Relação Estrutura-Atividade
6.
J Enzyme Inhib Med Chem ; 34(1): 1481-1488, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31423846

RESUMO

Indoleamine 2,3-dioxygenase 1 (IDO1), a tryptophan catabolising enzyme, is known as a tumour cell survival factor that causes immune escape in several types of cancer. Flavonoids of Sophora flavescens have a variety of biological benefits for humans; however, cancer immunotherapy effect has not been fully investigated. The flavonoids (1-6) isolated from S. flavescens showed IDO1 inhibitory activities (IC50 4.3-31.4 µM). The representative flavonoids (4-6) of S. flavescens were determined to be non-competitive inhibitors of IDO1 by kinetic analyses. Their binding affinity to IDO1 was confirmed using thermal stability and surface plasmon resonance (SPR) assays. The molecular docking analysis and mutagenesis assay revealed the structural details of the interactions between the flavonoids (1-6) and IDO1. These results suggest that the flavonoids (1-6) of S. flavescens, especially kushenol E (6), as IDO1 inhibitors might be useful in the development of immunotherapeutic agents against cancers.


Assuntos
Antineoplásicos/farmacologia , Inibidores Enzimáticos/farmacologia , Flavonoides/farmacologia , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Sophora/química , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/química , Inibidores Enzimáticos/isolamento & purificação , Flavonoides/química , Flavonoides/isolamento & purificação , Células HeLa , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/genética , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Modelos Moleculares , Estrutura Molecular , Mutagênese Sítio-Dirigida , Relação Estrutura-Atividade , Células Tumorais Cultivadas
7.
Inorg Chem ; 58(17): 11649-11655, 2019 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-31436093

RESUMO

A new mixed-valent dicopper complex [5] was generated from ligand exchange by dissolving a bis(CH3CN) precursor [3] in acetone. Introduction of a water molecule in place of an acetonitrile ligand was evidenced by base titration and the presence of a remaining coordinated CH3CN by IR, 19F NMR, and theoretical methods. The proposed structure (CH3CN-Cu-(SR)-Cu-OH2) was successfully DFT-optimized and the calculated parameters are in agreement with the experimental data. [5] has a unique temperature-dependence EPR behavior, with a localized valence from 10 to 120 K that undergoes delocalized at room temperature. The electrochemical signatures are in the line of the other aquo parent [2] and sensibly different from the rest of the series. Similar to the case of [2], [5] was finally capable of single turnover N2O reduction at room temperature. N2 was detected by GC-MS, and the redox character was confirmed by EPR and ESI-MS. Kinetic data indicate a reaction rate order close to 1 and a rate 10 times faster compared to [2]. [5] is thus the second example of that kind and highlights not only the main role of the Cu-OH2 motif, but also that the adjacent Cu-X partner (X = OTf- in [2] and CH3CN in [5]) is a new actor in the casting to establish structure/activity correlations.


Assuntos
Cobre/farmacologia , Inibidores Enzimáticos/farmacologia , Compostos Organometálicos/farmacologia , Oxirredutases/antagonistas & inibidores , Peptídeos/farmacologia , Cobre/química , Teoria da Densidade Funcional , Técnicas Eletroquímicas , Inibidores Enzimáticos/química , Estrutura Molecular , Compostos Organometálicos/química , Oxirredutases/metabolismo , Peptídeos/química
8.
J Enzyme Inhib Med Chem ; 34(1): 1271-1286, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31307240

RESUMO

17ß-Hydroxysteroid dehydrogenase type 1 (17ß-HSD1) is a key enzyme in the biosynthesis of 17ß-estradiol. Novel estrone-based compounds bearing various 15ß-oxa-linked substituents and hydroxy, methoxy, benzyloxy, and sulfamate groups in position C3 as potential 17ß-HSD1 inhibitors have been synthesized. In addition, in vitro inhibitory potentials measured in the presence of excess amount of NADPH or NADH were investigated. We observed substantial inhibitory potentials for several derivatives (IC50 < 1 µM) and increased binding affinities compared to unsubstituted core molecules. Binding and inhibition were found to be cofactor-dependent for some of the compounds and we propose structural explanations for this phenomenon. Our results may contribute to the development of new 17ß-HSD1 inhibitors, potential drug candidates for antiestrogen therapy of hormone-dependent gynecological cancers.


Assuntos
17-Hidroxiesteroide Desidrogenases/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Estrona/farmacologia , 17-Hidroxiesteroide Desidrogenases/metabolismo , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Estrona/síntese química , Estrona/química , Humanos , Conformação Molecular , Relação Estrutura-Atividade
9.
J Agric Food Chem ; 67(33): 9254-9264, 2019 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-31356740

RESUMO

In continuation of our search for potent protoporphyrinogen IX oxidase (PPO, EC 1.3.3.4) inhibitors, we designed and synthesized a series of novel herbicidal cycloalka[d]quinazoline-2,4-dione-benzoxazinones. The bioassay results of these synthesized compounds indicated that most of the compounds exhibited very strong Nicotiana tabacum PPO (NtPPO) inhibition activity. More than half of the 37 synthesized compounds displayed over 80% control of all three tested broadleaf weeds at 37.5-150 g ai/ha by postemergent application, and a majority of them showed no phytotoxicity toward at least one kind of crop at 150 g ai/ha. Promisingly, 17i (Ki = 6.7 nM) was 6 and 4 times more potent than flumioxazin (Ki = 46 nM) and trifludimoxazin (Ki = 31 nM), respectively. Moreover, 17i displayed excellent, broad-spectrum herbicidal activity, even at levels as low as 37.5 g ai/ha, and it was determined to be safe for wheat at 150 g ai/ha in postemergent application, indicating the great potential for 17i development as a herbicide for weed control in wheat fields.


Assuntos
Benzoxazinas/química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Herbicidas/química , Herbicidas/farmacologia , Proteínas de Plantas/antagonistas & inibidores , Protoporfirinogênio Oxidase/antagonistas & inibidores , Quinazolinas/química , Benzoxazinas/farmacologia , Desenho de Drogas , Cinética , Proteínas de Plantas/química , Plantas Daninhas/efeitos dos fármacos , Plantas Daninhas/enzimologia , Protoporfirinogênio Oxidase/química , Relação Quantitativa Estrutura-Atividade , Quinazolinas/farmacologia , Tabaco/efeitos dos fármacos , Tabaco/enzimologia , Controle de Plantas Daninhas
10.
J Agric Food Chem ; 67(32): 8977-8985, 2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31334649

RESUMO

The high-temperature treatment of caffeic acid by a model reaction for the processing of foods by roasting enhanced its xanthine oxidase (XO) inhibitory activity. The thermal reaction products included various oligomeric compounds, whose structures were determined as being produced via the intermediate 4-vinylcatechol. Measurements of their XO inhibitory activities were also carried out. Among the identified oligomers, the coupling products of caffeic acid and vinylcatechol, which were mainly produced at 140-170 °C, presented stronger XO inhibitory activities than the other types of oligomers produced. Further reacted compounds, which were mainly formed at 200 °C by the addition or elimination of catechol unit in the oligomers, displayed weaker activities. These results indicated that thermal enhancement of the XO inhibitory activity of caffeic acid can be explained by the differences in the XO inhibitory activities of the various constituents of the thermal reaction products. Caffeic acid and its derivatives are polyphenols found widely distributed in foods. Moreover, XO inhibition is closely related to the prevention of the life-style-related disease gout. The results suggest that a simple roasting process (170 °C) can lend useful human-health-related functionalities to caffeic acid containing foods such as coffee.


Assuntos
Ácidos Cafeicos/química , Inibidores Enzimáticos/química , Xantina Oxidase/química , Temperatura Alta , Cinética , Oxirredução
11.
J Agric Food Chem ; 67(32): 9060-9069, 2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31339696

RESUMO

Glutathione S-transferases (GSTs) play an active role in the development of drug resistance by numerous cancer cells, including melanoma cells, which is a major cause of chemotherapy failure. As part of our continuous effort to explore why dietary polyphenols bearing the catechol moiety (dietary catechols) show usually anticancer activity, catechol-type diphenylbutadiene (3,4-DHB) was selected as a model of dietary catechols to probe whether they work as pro-oxidative chemosensitizers via GST inhibition in melanoma cells. It was found that, in human melanoma A375 cells, 3,4-DHB is easily converted to its ortho-quinone via copper-containing tyrosinase-mediated two-electron oxidation along with generation of reactive oxygen species (ROS) derived from the oxidation; the resulting ortho-quinone and ROS are responsible for its ability to sensitize the cisplatin-resistant cells by inhibiting GST, followed by induction of apoptosis in an ASK1-JNK/p38 signaling cascade and mitochondria-dependent pathway. This work provides further evidence to support that dietary catechols exhibit antimelanoma activity by virtue of their tyrosinase-dependent pro-oxidative role and gives useful information for designing polyphenol-inspired GST inhibitors and sensitizers in chemotherapy against melanoma.


Assuntos
Antineoplásicos/farmacologia , Butadienos/farmacologia , Catecóis/farmacologia , Inibidores Enzimáticos/farmacologia , Glutationa Transferase/antagonistas & inibidores , Melanoma/enzimologia , Monofenol Mono-Oxigenase/química , Antineoplásicos/química , Antineoplásicos/metabolismo , Apoptose , Butadienos/química , Butadienos/metabolismo , Catecóis/química , Catecóis/metabolismo , Linhagem Celular Tumoral , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Glutationa Transferase/metabolismo , Humanos , Melanoma/metabolismo , Melanoma/fisiopatologia , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Modelos Químicos , Monofenol Mono-Oxigenase/metabolismo , Oxirredução , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo
12.
Chem Commun (Camb) ; 55(63): 9241-9250, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31328738

RESUMO

The field of chemical biology has introduced several approaches, typically using chemical probes, to measure the direct binding interaction of a small molecule with its biological target in cells. The use of these direct target engagement assays in pharmaceutical development can support mechanism of action hypothesis testing, rank ordering of compounds, and iterative improvements of chemical matter. This Feature Article highlights a newer application of these approaches: the quantification of target engagement in animal models to support late stage preclinical development and the nomination of a drug candidate to clinical trials. Broadly speaking, these efforts can be divided between compounds that covalently and reversibly interact with protein targets; recent examples for both categories are discussed for a range of targets, along with their limitations. New, promising technologies are also highlighted, in addition to the application of target engagement determination to new therapeutic modalities.


Assuntos
Modelos Animais , Preparações Farmacêuticas/metabolismo , Animais , Interações de Medicamentos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Preparações Farmacêuticas/química , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacocinética
13.
J Agric Food Chem ; 67(31): 8617-8625, 2019 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-31293160

RESUMO

Inhibiting starch digestion can effectively control postprandial blood sugar level. In this study, the in vitro digestion differences among the mixtures of five polyphenols (i.e., procyanidins [PAs], catechin [CA], tannic acid [TA], rutin [RU], and quercetin [QU]) and starch were analyzed through an in vitro simulation test of starch digestion. The interaction characteristics of these five polyphenols with α-amylase and α-glucosidase were investigated in terms of the inhibition effect, dynamics, fluorescence quenching, and circular dichroism (CD). The results revealed that the rapidly digestible starch (RDS) contents decreased, while the resistant starch (RS) contents increased. All five polyphenols inhibited the α-amylase activity through the noncompetitive approach but inhibited the α-glucosidase activity through the competitive approach. Five polyphenols combined with α-amylase spontaneously by using the hydrophobic effect. The interaction of PAs and QU with α-glucosidase were recognized as van der Waals forces and H bonding, whereas CA and TA interacted with α-glucosidase through the hydrophobic effect. All five polyphenols can cause conformational changes in enzymes.


Assuntos
Extratos Vegetais/química , Polifenóis/química , Amido/química , Animais , Digestão , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Proteínas Fúngicas/química , Proteínas Fúngicas/metabolismo , Cinética , Modelos Biológicos , Extratos Vegetais/metabolismo , Polifenóis/metabolismo , Amido/metabolismo , Suínos , Leveduras/enzimologia , alfa-Amilases/química , alfa-Amilases/metabolismo , alfa-Glucosidases/química , alfa-Glucosidases/metabolismo
14.
J Enzyme Inhib Med Chem ; 34(1): 1368-1372, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31347930

RESUMO

To develop multifunctional aldose reductase (AKR1B1) inhibitors for anti-diabetic complications, a novel series of 2-phenoxypyrido[3,2-b]pyrazin-3(4H)-one derivatives were designed and synthesised. Most of the derivatives were found to be potent and selective against AKR1B1, and 2-(7-chloro-2-(3,5-dihydroxyphenoxy)-3-oxopyrido[3,2-b]pyrazin-4(3H)-yl) acetic acid (4k) was the most active with an IC50 value of 0.023 µM. Moreover, it was encouraging to find that some derivatives showed strong antioxidant activity, and among them, the phenolic 3,5-dihydroxyl compound 4l with 7-bromo in the core structure was proved to be the most potent, even comparable to that of the well-known antioxidant Trolox. Thus the results suggested success in the construction of potent and selective AKR1B1 inhibitors with antioxidant activity.


Assuntos
Aldeído Redutase/antagonistas & inibidores , Antioxidantes/farmacologia , Desenho de Drogas , Inibidores Enzimáticos/farmacologia , Hipoglicemiantes/farmacologia , Pirazinas/farmacologia , Antioxidantes/química , Compostos de Bifenilo/química , Inibidores Enzimáticos/química , Hipoglicemiantes/química , Simulação de Acoplamento Molecular , Estrutura Molecular , Picratos/química , Pirazinas/química , Relação Estrutura-Atividade
15.
Nat Commun ; 10(1): 2917, 2019 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-31266949

RESUMO

Novel antibacterial agents are needed to address the emergence of global antibiotic resistance. MraY is a promising candidate for antibiotic development because it is the target of five classes of naturally occurring nucleoside inhibitors with potent antibacterial activity. Although these natural products share a common uridine moiety, their core structures vary substantially and they exhibit different activity profiles. An incomplete understanding of the structural and mechanistic basis of MraY inhibition has hindered the translation of these compounds to the clinic. Here we present crystal structures of MraY in complex with representative members of the liposidomycin/caprazamycin, capuramycin, and mureidomycin classes of nucleoside inhibitors. Our structures reveal cryptic druggable hot spots in the shallow inhibitor binding site of MraY that were not previously appreciated. Structural analyses of nucleoside inhibitor binding provide insights into the chemical logic of MraY inhibition, which can guide novel approaches to MraY-targeted antibiotic design.


Assuntos
Antibacterianos/química , Bactérias/enzimologia , Proteínas de Bactérias/química , Produtos Biológicos/química , Inibidores Enzimáticos/química , Nucleosídeos/antagonistas & inibidores , Transferases/química , Aminoglicosídeos/química , Arginina/análogos & derivados , Arginina/química , Bactérias/química , Bactérias/genética , Proteínas de Bactérias/antagonistas & inibidores , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Sítios de Ligação , Cristalografia por Raios X , Transferases/antagonistas & inibidores , Transferases/genética , Transferases/metabolismo
16.
Chem Pharm Bull (Tokyo) ; 67(9): 985-991, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31270295

RESUMO

Chemically stable ester derivatives of taxifolin have become a focus of interest for their role in the satisfactory effects on human health. Accordingly, the aim of this study was to evaluate the physical and chemical stability of different formulations containing 0.02% taxifolin tetra-octanoate, which was proved to possess higher inhibitory effect on tyrosinase activity compared with taxifolin in a cell-free system. In the studies of physical stability, a Brookfield viscometer was used to determine rheological behavior of formulations containing taxifolin tetra-octanoate, and a portable pH meter was used to determine pH change. Moreover, chemical stability was determined by HPLC with UV detection. Formulations were evaluated for 12 weeks stored at 25 and 40°C. Results showed that storage time had no significant influence on viscosity of the formulations containing taxifolin tetra-octanoate, and pH value was relatively stable, which was within the limits of normal skin pH range. In the chemical stability studies, taxifolin tetra-octanoate in the essence formulation was most unstable at 40°C with about 81% degradation in 12 weeks of storage, however, the percentage of remaining taxifolin tetra-octanoate in cream formulation stored for 12 weeks at 25°C was the highest, about 93%. The results in this study may contribute to the development of more stable formulations containing taxifolin tetra-octanoate.


Assuntos
Caprilatos/farmacologia , Inibidores Enzimáticos/farmacologia , Monofenol Mono-Oxigenase/antagonistas & inibidores , Quercetina/análogos & derivados , Caprilatos/síntese química , Caprilatos/química , Cromatografia Líquida de Alta Pressão , Composição de Medicamentos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Concentração de Íons de Hidrogênio , Estrutura Molecular , Monofenol Mono-Oxigenase/metabolismo , Quercetina/síntese química , Quercetina/química , Quercetina/farmacologia , Relação Estrutura-Atividade , Viscosidade
17.
Phytochemistry ; 166: 112054, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31284174

RESUMO

Eremophila bignoniiflora is a shrub distributed throughout inland northern and eastern Australia, and it has been used in several medicinal applications by some Australian Aboriginal people. In our continued search for anti-diabetic constituents from natural resources, the crude ethyl acetate extract of E. bignoniiflora was found to have protein-tyrosine phosphatase 1B (PTP1B) inhibitory activity with an IC50 value of 23.9 ±â€¯1.9 µg/mL. High-resolution PTP1B inhibition profiling combined with HRMS and NMR were subsequently used to investigate the individual compounds responsible for the observed bioactivity of the crude extract. This led to identification of five undescribed 2(5H)-furanone sesquiterpenes, together with 13 flavonoids and phenolic compounds. Dose-response curves of the isolated compounds revealed that two 2(5H)-furanone sesquiterpene cinnamates and three flavonoids exhibited moderate PTP1B inhibitory activity with IC50 values from 41.4 ±â€¯1.4 to 154.5 ±â€¯8.9 µM.


Assuntos
Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Furanos/química , Proteína Tirosina Fosfatase não Receptora Tipo 1/antagonistas & inibidores , Scrophulariaceae/química , Sesquiterpenos/química , Sesquiterpenos/farmacologia
18.
Phytochemistry ; 166: 112060, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31302343

RESUMO

Continued interest in bioactive alkaloids led to the isolation of four undescribed alkaloids along with 74 known ones from the aerial parts of Tabernaemontana bufalina Lour. The structures of the yet undescribed alkaloids were elucidated based on NMR, IR, UV, MS and CD spectroscopic data and X-ray crystal diffraction and, according to the plant source, named as taberhaines A-D (1-4). The known compounds comprised of 66 monoterpenoid indole, three carboline and five isoquinoline alkaloids. Among them, the known apparicine inhibited significantly the activity of xanthine oxidase, which plays an important role for gout, with an IC50 value of 0.65 µM, compared to the standard drug allopurinol (IC50 = 0.60 µM).


Assuntos
Alcaloides/química , Alcaloides/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Tabernaemontana/química , Xantina Oxidase/antagonistas & inibidores , Alcaloides/isolamento & purificação , Domínio Catalítico , Inibidores Enzimáticos/isolamento & purificação , Concentração Inibidora 50 , Modelos Moleculares , Xantina Oxidase/química
19.
Eur J Med Chem ; 177: 316-337, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31158747

RESUMO

Residues in the histone substrate binding sites that differ between the KDM4 and KDM5 subfamilies were identified. Subsequently, a C8-substituted pyrido[3,4-d]pyrimidin-4(3H)-one series was designed to rationally exploit these residue differences between the histone substrate binding sites in order to improve affinity for the KDM4-subfamily over KDM5-subfamily enzymes. In particular, residues E169 and V313 (KDM4A numbering) were targeted. Additionally, conformational restriction of the flexible pyridopyrimidinone C8-substituent was investigated. These approaches yielded potent and cell-penetrant dual KDM4/5-subfamily inhibitors including 19a (KDM4A and KDM5B Ki = 0.004 and 0.007 µM, respectively). Compound cellular profiling in two orthogonal target engagement assays revealed a significant reduction from biochemical to cell-based activity across multiple analogues; this decrease was shown to be consistent with 2OG competition, and suggests that sub-nanomolar biochemical potency will be required with C8-substituted pyrido[3,4-d]pyrimidin-4(3H)-one compounds to achieve sub-micromolar target inhibition in cells.


Assuntos
Inibidores Enzimáticos/farmacologia , Histona Desmetilases com o Domínio Jumonji/antagonistas & inibidores , Piridinas/farmacologia , Pirimidinonas/farmacologia , Linhagem Celular Tumoral , Cristalografia por Raios X , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Humanos , Interações Hidrofóbicas e Hidrofílicas , Histona Desmetilases com o Domínio Jumonji/química , Histona Desmetilases com o Domínio Jumonji/metabolismo , Estrutura Molecular , Ligação Proteica , Piridinas/síntese química , Piridinas/química , Piridinas/metabolismo , Pirimidinonas/síntese química , Pirimidinonas/química , Pirimidinonas/metabolismo , Relação Estrutura-Atividade
20.
Chem Biodivers ; 16(8): e1900243, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31207061

RESUMO

The new complex compounds [RuLCl(p-cymene)] ⋅ 3H2 O and [NiL2 (H2 O)2 ] ⋅ 3H2 O (L: 1-{4-[(2-hydroxy-3-methoxybenzylidene)amino]phenyl}ethanone) were prepared and characterized using FT-IR, 1 H- and 13 C-NMR, mass spectroscopy, TGA, elemental analysis, X-ray powder diffraction and magnetic moment techniques. Octahedral geometry for new Ni(II) and Ru(II) complexes was proposed. Thermal decomposition confirmed the existence of lattice and coordinated water molecule in the complexes. To determine the antioxidant properties of Schiff base ligand and its Ni(II), Ru(II) metal complexes, FRAP, CUPRAC, ABTS and DPPH methods of antioxidant assays were used. Moreover, enzyme inhibition of complexes was evaluated against carbonic anhydrase I and II isoenzymes (CA I and CA II) and acetylcholinesterase (AChE). For CA I and CA II, the best inhibition enzymes, was the Ni(II) complex with 62.98±18.41, 86.17±23.62 Ki values, whereas this inhibition effect showed ligand with 24.53±2.66 Ki value for the AChE enzyme.


Assuntos
Antioxidantes/química , Complexos de Coordenação/química , Inibidores Enzimáticos/química , Níquel/química , Rutênio/química , Bases de Schiff/química , Acetilcolinesterase/química , Acetilcolinesterase/metabolismo , Anidrase Carbônica I/antagonistas & inibidores , Anidrase Carbônica I/metabolismo , Anidrase Carbônica II/antagonistas & inibidores , Anidrase Carbônica II/metabolismo , Complexos de Coordenação/farmacologia , Inibidores Enzimáticos/metabolismo , Concentração Inibidora 50 , Espectrofotometria Infravermelho
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