Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 8.174
Filtrar
1.
J Agric Food Chem ; 67(39): 10844-10852, 2019 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-31525997

RESUMO

The discovery of 4-hydroxyphenylpyruvate dioxygenase (HPPD, EC 1.13.11.27) inhibitors has been an active area of research due to their great potential as herbicides for weed control. Starting from the binding mode of known inhibitors of HPPD, a series of HPPD inhibitors with new molecular scaffolds were designed and synthesized by hybridizing 2-benzoylethen-1-ol and isoindoline-1,3-dione fragments. The results of the in vitro tests indicated that the newly synthesized compounds showed good HPPD inhibitory activity with IC50 values against the recombinant Arabidopsis thaliana HPPD (AtHPPD) ranging from 0.0039 µM to over 1 µM. Most promisingly, compound 4ae, 2-benzyl-5-(5-hydroxy-1,3-dimethyl-1H-pyrazole-4- carbonyl)isoindoline-1,3-dione, showed the highest AtHPPD inhibitory activity with a Ki value of 3.92 nM, making it approximately 10 times more potent than pyrasulfotole (Ki = 44 nM) and slightly more potent than mesotrione (Ki = 4.56 nM). In addition, the cocrystal structure of the AtHPPD-4ae complex was successfully resolved at a resolution of 1.8 Å. The X-ray diffraction analysis indicated that the two carbonyl groups of 2-benzoylethen-1-ol formed a bidentate chelating interaction with the metal ion, while the isoindoline-1,3-dione moiety formed pronounced π-π stacking interactions with Phe381 and Phe424. Moreover, water-mediated hydrogen bonding interactions were observed between Asn282 and the nitrogen atoms of the pyrazole ring of 4ae. The above results showed that the pyrazole-isoindoline-1,3-dione hybrid is a promising scaffold for developing HPPD inhibitors.


Assuntos
4-Hidroxifenilpiruvato Dioxigenase/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Herbicidas/farmacologia , Isoindóis/farmacologia , Proteínas de Plantas/antagonistas & inibidores , Pirazóis/farmacologia , 4-Hidroxifenilpiruvato Dioxigenase/química , 4-Hidroxifenilpiruvato Dioxigenase/metabolismo , Arabidopsis/efeitos dos fármacos , Arabidopsis/crescimento & desenvolvimento , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Herbicidas/síntese química , Herbicidas/química , Isoindóis/química , Cinética , Estrutura Molecular , Proteínas de Plantas/química , Proteínas de Plantas/metabolismo , Plantas Daninhas/efeitos dos fármacos , Plantas Daninhas/crescimento & desenvolvimento , Pirazóis/química , Relação Estrutura-Atividade
2.
Chemistry ; 25(49): 11416-11421, 2019 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-31407832

RESUMO

Trypanothione reductase (TR) plays a key role in the unique redox metabolism of trypanosomatids, the causative agents of human African trypanosomiasis (HAT), Chagas' disease, and leishmaniases. Introduction of a new, lean propargylic vector to a known class of TR inhibitors resulted in the strongest reported competitive inhibitor of Trypanosoma (T.) brucei TR, with an inhibition constant Ki of 73 nm, which is fully selective against human glutathione reductase (hGR). The best ligands exhibited in vitro IC50 values (half-maximal inhibitory concentration) against the HAT pathogen, T. brucei rhodesiense, in the mid-nanomolar range, reaching down to 50 nm. X-Ray co-crystal structures confirmed the binding mode of the ligands and revealed the presence of a HEPES buffer molecule in the large active site. Extension of the propargylic vector, guided by structure-based design, to replace the HEPES buffer molecule should give inhibitors with low nanomolar Ki and IC50 values for in vivo studies.


Assuntos
Desenho de Drogas , Inibidores Enzimáticos/química , NADH NADPH Oxirredutases/antagonistas & inibidores , Proteínas de Protozoários/antagonistas & inibidores , Trypanosoma brucei brucei/enzimologia , Sítios de Ligação , Domínio Catalítico , Cristalografia por Raios X , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/metabolismo , Concentração Inibidora 50 , Ligantes , Simulação de Dinâmica Molecular , NADH NADPH Oxirredutases/metabolismo , Proteínas de Protozoários/metabolismo , Relação Estrutura-Atividade
3.
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
4.
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
5.
Eur J Med Chem ; 178: 380-389, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31202126

RESUMO

The development of Tyrosinase inhibitors (TYRIs) could represent an efficacious strategy for pharmacological intervention on skin pathologies related to aberrant production of melanin. Based on in silico studies we designed and tested a library of twenty-four compounds bearing the 4-(4-fluorobenzyl)piperazin-1-yl]-fragment. As result, we identified several compounds with excellent inhibit effects at low micromolar concentration against TYR from Agaricus bisporus (TyM). Among them, compound 25 (IC50 = 0.96 µM) proved to be ∼20-fold more potent than the reference compound kojic acid (IC50 = 17.76 µM) having wide applications in the cosmetics and pharmaceutical industries. The mode of interaction of active inhibitor 25 was deciphered by means of crystallography as well as molecular docking and these results were consistent with kinetic experiments. Moreover, the identified compound 25 exhibited no considerable cytotoxicity and showed anti-melanogenic effects on B16F10 melanoma cells. Therefore, a combination of computational and biochemical approaches could represent a rational guidelines for further structural modification of this class of compounds as future anti-melanogenic agents.


Assuntos
Antineoplásicos/farmacologia , Desenho de Drogas , Inibidores Enzimáticos/farmacologia , Monofenol Mono-Oxigenase/antagonistas & inibidores , Agaricus/química , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Modelos Moleculares , Estrutura Molecular , Monofenol Mono-Oxigenase/metabolismo , Relação Estrutura-Atividade
6.
Eur J Med Chem ; 178: 259-286, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31195169

RESUMO

Acetylation, a key component in post-translational modification regulated by HATs and HDACs, is relevant to many crucial cellular contexts in organisms. Based on crucial pharmacophore patterns and the structure of targeted proteins, HAT inhibitors are designed and modified for higher affinity and better bioactivity. However, there are still some challenges, such as cell permeability, selectivity, toxicity and synthetic availability, which limit the improvement of HAT inhibitors. So far, only few HAT inhibitors have been approved for commercialization, indicating the urgent need for more successful and effective structure-based drug design and synthetic strategies. Here, we summarized three classes of HAT inhibitors based on their sources and structural scaffolds, emphasizing on their synthetic methods and structure-activity relationships and molecular mechanisms, hoping to facilitate the development and further application of HAT inhibitors.


Assuntos
Inibidores Enzimáticos/farmacologia , Histona Acetiltransferases/antagonistas & inibidores , Acetilação/efeitos dos fármacos , Animais , Domínio Catalítico , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Histona Acetiltransferases/química , Humanos , Camundongos , Estrutura Molecular , Relação Estrutura-Atividade
7.
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
8.
Chem Pharm Bull (Tokyo) ; 67(6): 556-565, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31155561

RESUMO

Aldose reductase (AR) is associated with the onset of diabetic complications. Botryllazine A and its analogues were synthesized and evaluated for human AR inhibitory activity. Analogues possessing aromatic bicyclic systems at the C5 position of the central pyrazine ring exhibited superior AR inhibiting activity relative to the parent botryllazine A. In addition, the benzoyl groups at positions C2 and C3 of the pyrazine ring were dispensable for this improved inhibitory activity. Conversely, a benzoyl group-containing phenolic hydroxyl groups-at either position C2 or C3 of the pyrazine ring was essential for attainment of high inhibitory activity approaching that of sorbinil (a highly effective AR inhibitor).


Assuntos
Aldeído Redutase/metabolismo , Inibidores Enzimáticos/síntese química , Pirazinas/química , Aldeído Redutase/antagonistas & inibidores , Sítios de Ligação , Domínio Catalítico , Cristalografia por Raios X , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Humanos , Ligações de Hidrogênio , Concentração Inibidora 50 , Conformação Molecular , Simulação de Acoplamento Molecular , Pirazinas/síntese química , Pirazinas/metabolismo
9.
Mini Rev Med Chem ; 19(10): 796-808, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31244414

RESUMO

Cutaneous pigmentation plays critical role in determining the color of skin along with photo protection of skin from dreadful effects of ultraviolet radiations. Conversely, abnormal accumulation of melanin is responsible for hyper pigmentary disorders such as melasma, senile lentigines and freckles. Because of the visible nature of dermatologic diseases, they have a considerable psychosomatic effect on affected patients. Tyrosinase inhibitors are molecules that interrelate in some way with the enzyme to prevent it from working in the normal manner. Past many decades witnessed the quest for the development of natural tyrosinase inhibitors due to imperative role played by tyrosinase in the process of melanogenesis and fungi or fruit enzymatic browning. Mechanism of pigmentation is characterized by the intact process of the synthesis of specialized black pigment within melanosomes. Melanin is synthesized by a cascade of enzymatic and chemical reactions. For this reason, melanin production is mainly controlled by the expression and activation of tyrosinase. In the current article, we discussed tyrosinase inhibitors from the natural sources, which can be an essential constituent of cosmetics products and depigmenting agents for the treatment of hyperpigmentory disorders.


Assuntos
Produtos Biológicos/farmacologia , Inibidores Enzimáticos/farmacologia , Hiperpigmentação/tratamento farmacológico , Melaninas/biossíntese , Monofenol Mono-Oxigenase/antagonistas & inibidores , Fitoterapia , Preparações Clareadoras de Pele/farmacologia , Pigmentação da Pele/efeitos dos fármacos , Animais , Produtos Biológicos/síntese química , Produtos Biológicos/química , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Estrutura Molecular , Monofenol Mono-Oxigenase/metabolismo , Preparações Clareadoras de Pele/síntese química , Preparações Clareadoras de Pele/química
10.
Eur J Med Chem ; 178: 64-80, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31176096

RESUMO

Encouraged by our earlier discovery of neuraminidase inhibitors targeting 150-cavity or 430-cavity, herein, to yield more potent inhibitors, we designed, synthesized, and biologically evaluated a series of novel oseltamivir derivatives via modification of C-1 and C5-NH2 of oseltamivir by exploiting 150-cavity and/or 430-cavity. Among the synthesized compounds, compound 15e, the most potent N1-selective inhibitor targeting 150-cavity, showed 1.5 and 1.8 times greater activity than oseltamivir carboxylate (OSC) against N1 (H5N1) and N1 (H5N1-H274Y). In cellular assays, 15e also exhibited greater potency than OSC against H5N1 with EC50 of 0.66 µM. In addition, 15e demonstrated low cytotoxicity in vitro and low acute toxicity in mice. Molecular docking studies provided insights into the high potency of 15e against N1 and N1-H274Y mutant NA. Overall, we envisioned that the significant breakthrough in the discovery of potent group-1-specific neuraminidase inhibitors may lead to further investigation of more potent anti-influenza agents.


Assuntos
Antivirais/farmacologia , Inibidores Enzimáticos/farmacologia , Neuraminidase/antagonistas & inibidores , Oseltamivir/análogos & derivados , Oseltamivir/farmacologia , Proteínas Virais/antagonistas & inibidores , Animais , Antivirais/síntese química , Antivirais/química , Antivirais/toxicidade , Domínio Catalítico , Linhagem Celular , Galinhas , Desenho de Drogas , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/toxicidade , Feminino , Influenzavirus A/enzimologia , Influenzavirus B/enzimologia , Masculino , Camundongos , Simulação de Acoplamento Molecular , Neuraminidase/química , Oseltamivir/síntese química , Oseltamivir/toxicidade , Proteínas Virais/química
11.
Eur J Med Chem ; 178: 93-107, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31176098

RESUMO

Estrogens are the major female sex steroid hormones, estradiol (E2) being the most potent form in humans. Disturbing the balance between E2 and its weakly active oxidized form estrone (E1) leads to diverse types of estrogen-dependent diseases such as endometriosis or osteoporosis. 17ß-Hydroxysteroid dehydrogenase type 1 (17ß-HSD1) catalyzes the biosynthesis of E2 by reduction of E1 while the type 2 enzyme catalyzes the reverse reaction. Thus, 17ß-HSD1 and 17ß-HSD2 are attractive targets for treatment of estrogen-dependent diseases. Recently, we reported the first proof-of-principle study of a 17ß-HSD2 inhibitor in a bone fracture mouse model, using subcutaneous administration. In the present study, our aim was to improve the in vitro ADME profile of the most potent 17ß-HSD1 and 17ß-HSD2 inhibitors described so far. The optimized compounds show strong and selective inhibition of both the human enzymes and their murine orthologs. In addition, they display good metabolic stability in human liver microsomes (S9 fraction), low in vitro cytotoxicity as well as better aqueous solubility and physicochemical properties compared to the lead compounds. These achievements make the compounds eligible for testing in preclinical in vivo animal model studies on the effects of inhibition of 17ß-HSD1 and 17ß-HSD2.


Assuntos
17-Hidroxiesteroide Desidrogenases/antagonistas & inibidores , Inibidores Enzimáticos/farmacocinética , Estradiol Desidrogenases/antagonistas & inibidores , Fenóis/farmacocinética , Tiofenos/farmacocinética , Animais , Sítios de Ligação , Desenho de Drogas , Estabilidade de Medicamentos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Estradiol Desidrogenases/química , Estradiol Desidrogenases/metabolismo , Células HEK293 , Humanos , Camundongos , Microssomos Hepáticos/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Fenóis/síntese química , Fenóis/química , Fenóis/metabolismo , Ligação Proteica , Solubilidade , Relação Estrutura-Atividade , Tiofenos/síntese química , Tiofenos/química , Tiofenos/metabolismo
12.
J Enzyme Inhib Med Chem ; 34(1): 1140-1151, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31159606

RESUMO

Increasing knowledge of the relationship between cancer and dysregulated polyamine catabolism suggests interfering with aberrant polyamine metabolism for anticancer therapy that will have considerable clinical promise. SMO (spermine oxidase) plays an essential role in regulating the polyamines homeostasis. Therefore, development of SMO inhibitors has increasingly attracted much attention. Previously, we successfully purified and characterised SMO. Here, we presented an in silico drug discovery pipeline by combining pharmacophore modelling and molecular docking for the virtual screening of SMO inhibitors. In vitro evaluation showed that N-(3-{[3-(dimethylamino)propyl]amino}propyl)-8-quinolinecarboxamide (SI-4650) inhibited SMO enzyme activity, increased substrate spermine content and reduced product spermidine content, indicating that SI-4650 can interfere with polyamine metabolism. Furthermore, SI-4650 treatment suppressed cell proliferation and migration. Mechanistically, SI-4650 caused cell cycle arrest, induced cell apoptosis, and promoted autophagy. These results demonstrated the properties of interfering with polyamine metabolism of SI-4650 as a SMO inhibitor and the potential for cancer treatment.


Assuntos
Antineoplásicos/farmacologia , Descoberta de Drogas , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/farmacologia , Oxirredutases atuantes sobre Doadores de Grupo CH-NH/antagonistas & inibidores , Células A549 , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Modelos Moleculares , Oxirredutases atuantes sobre Doadores de Grupo CH-NH/metabolismo , Relação Estrutura-Atividade
13.
J Enzyme Inhib Med Chem ; 34(1): 1131-1139, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31169043

RESUMO

The antitumor agent 6-((7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)thio)hexan-1-ol (1) is a potent inhibitor of GSTP1-1, a glutathione S-transferase capable of inhibiting apoptosis by binding to JNK1 and TRAF2. We recently demonstrated that, unlike its parent compound, the benzoyl ester of 1 (compound 3) exhibits negligible reactivity towards GSH, and has a different mode of interaction with GSTP1-1. Unfortunately, 3 is susceptible to rapid metabolic hydrolysis. In an effort to improve the metabolic stability of 3, its ester group has been replaced by an amide, leading to N-(6-((7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)thio)hexyl)benzamide (4). Unlike 3, compound 4 was stable to human liver microsomal carboxylesterases, but retained the ability to disrupt the interaction between GSTP1-1 and TRAF2 regardless of GSH levels. Moreover, 4 exhibited both a higher stability in the presence of GSH and a greater cytotoxicity towards cultured A375 melanoma cells, in comparison with 1 and its analog 2. These findings suggest that 4 deserves further preclinical testing.


Assuntos
4-Cloro-7-nitrobenzofurazano/farmacologia , Antineoplásicos/farmacologia , Benzamidas/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Glutationa S-Transferase pi/antagonistas & inibidores , 4-Cloro-7-nitrobenzofurazano/síntese química , 4-Cloro-7-nitrobenzofurazano/química , Antineoplásicos/síntese química , Antineoplásicos/química , Benzamidas/química , Linhagem Celular Tumoral , 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 , Glutationa S-Transferase pi/metabolismo , Humanos , Hidrólise , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade
14.
J Enzyme Inhib Med Chem ; 34(1): 1158-1163, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31179772

RESUMO

Even though phenazines have been extensively reported as anticancer molecules, the molecular target of these compounds is severely lagging behind. Our study consequently focuses on the anticancer target of a phenazine analogue (CPUL1) for its potently antitumor activities in initial stage. Along with redox status courses of Hep G2 cells, thioredoxin reductase I (TrxR1) was speculated as anticancer target of CPUL1. By virtue of zymologic, immunological and molecular biological experiments, we demonstrated that TrxR1 could be the anticancer target of CPUL1. The knowledge on phenazine targeting to TrxR1 have not been reported previously. Thus, it can provide valuable information for further development of the TrxR1 inhibitors.


Assuntos
Antineoplásicos/farmacologia , Inibidores Enzimáticos/farmacologia , Fenazinas/química , Fenazinas/farmacologia , Tiorredoxina Redutase 1/antagonistas & inibidores , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Células Hep G2 , Humanos , Modelos Moleculares , Estrutura Molecular , Fenazinas/síntese química , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-Atividade , Tiorredoxina Redutase 1/metabolismo
15.
Chem Commun (Camb) ; 55(49): 7109-7112, 2019 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-31157339

RESUMO

E3 ligases play a critical role in ubiquitin (Ub) conjugation cascades, and any aberration in their activity is associated with a number of diseases. Advancement in our knowledge of understanding the roles of HECT E3s requires biochemical tools such as activity-based probes (ABPs). In this study we developed a novel dehydroalanine (Dha)-based E2-Ub ABP using a strategy that is a combination of practical hydrazide-based native chemical ligation and sequential Dha formation. The probe could be used for labeling HECT E3s not only in vitro but also in endogenous cellular contexts. Our easy-to-implement method is expected to be useful for the preparation of Dha based Ub family E2 conjugate ABPs.


Assuntos
Alanina/análogos & derivados , Inibidores Enzimáticos/farmacologia , Ubiquitina-Proteína Ligases/antagonistas & inibidores , Alanina/síntese química , Alanina/química , Alanina/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade , Ubiquitina-Proteína Ligases/metabolismo
16.
17.
Eur J Med Chem ; 177: 386-400, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31158752

RESUMO

We explored the approach of using an analog of E-64, a well-known and hydrophilic cysteine cathepsin (CC) inhibitor, as a potent cysteine cathepsin-trapping agent (CCTA) to improve the tumor retention of low-molecular-weight, receptor-targeted radiopharmaceuticals. The synthesized hydrophilic CCTA-incorporated, NTSR1-targeted agents demonstrated a substantial increase in cellular retention upon uptake into the NTRS1-positive HT-29 human colon cancer cell line. Similarly, biodistribution studies using HT-29 xenograft mice revealed a significant and substantial increase in tumor retention for the CCTA-incorporated, NTSR1-targeted agent. The intracellular trapping mechanism of the CCTA-incorporated agents by macromolecular adduct formation was confirmed using multiple in vitro and in vivo techniques. Furthermore, utilization of the more hydrophilic CCTA greatly increased the hydrophilicity of the resulting NTSR1-targeted constructs leading to substantial decreases in most non-target tissues in contrast to our previously reported dipeptidyl acyloxymethyl ketone (AOMK) constructs. This work further confirms that the CCTA trapping approach can make significant improvements in the clinical potential of NTSR1-and other receptor-targeted radiopharmaceuticals.


Assuntos
Catepsinas/antagonistas & inibidores , Inibidores Enzimáticos/metabolismo , Peptídeos/metabolismo , Compostos Radiofarmacêuticos/metabolismo , Receptores de Neurotensina/metabolismo , Animais , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Feminino , Células HT29 , Humanos , Interações Hidrofóbicas e Hidrofílicas , Lutécio/química , Camundongos SCID , Neoplasias/diagnóstico , Peptídeos/síntese química , Peptídeos/química , Radioisótopos/química , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/química , Distribuição Tecidual
18.
Eur J Med Chem ; 175: 357-372, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31096156

RESUMO

Lysine-specific demethylase 1 (LSD1), demethylase against mono- and di - methylated histone3 lysine 4, has emerged as a promising target in oncology. More specifically, it has been demonstrated as a key promoter in acute myeloid leukemia (AML), and several LSD1 inhibitors have already entered into clinical trials for the treatment of AML. In this paper, a series of new indole derivatives were designed and synthesized based on a lead compound obtained by a high-throughput screening with our in-house compound library. Among the synthetic compounds, 9e was characterized as a potent LSD1 inhibitor with an IC50 of 1.230 µM and can inhibit the proliferation of THP-1 cells effectively. And most importantly, this is the first irreversible LSD1 inhibitor that is not derived from monoamine oxidase inhibitors. Hence, the discovery of 9e may serve as a proof of concept work for AML treatment.


Assuntos
Descoberta de Drogas , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Histona Desmetilases/antagonistas & inibidores , Indóis/síntese química , Indóis/farmacologia , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Furanos/química , Ensaios de Triagem em Larga Escala , Histona Desmetilases/metabolismo , Humanos , Indóis/química , Indóis/metabolismo , Concentração Inibidora 50 , Leucemia Mieloide Aguda/patologia , Proteínas Recombinantes/efeitos dos fármacos , Proteínas Recombinantes/metabolismo , Relação Estrutura-Atividade
19.
J Microbiol Biotechnol ; 29(6): 856-862, 2019 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-31091864

RESUMO

A series of thienopyrimidine compounds (6Aa-g and 6Ba-d) were synthesized and characterized by NMR spectroscopy and mass spectrometry. These compounds (6Aa-g and 6Ba-d) potently inhibited STAT3 expression induced by IL-6 in a dose-dependent manner with IC50 values of 5.73-0.32 µM. Among the prepared thienopyrimidine derivatives, 6Aa, 6Ab, 6Ba and 6Bc significantly suppressed the phosphorylation of STAT3 and ERK1/2 stimulated by IL-6 in Hep3B cells. Furthermore, the synthesized compounds might be useful remedies for the treatment of inflammatory diseases by inhibiting the action of IL-6.


Assuntos
Anti-Inflamatórios/síntese química , Anti-Inflamatórios/farmacologia , Pirimidinas/síntese química , Pirimidinas/farmacologia , Fator de Transcrição STAT3/antagonistas & inibidores , Anti-Inflamatórios/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Humanos , Interleucina-6/antagonistas & inibidores , Interleucina-6/farmacologia , Estrutura Molecular , Fosforilação/efeitos dos fármacos , Regiões Promotoras Genéticas , Pirimidinas/química , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo
20.
Carbohydr Res ; 478: 10-17, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-31039450

RESUMO

A series of novel tricyclic quinazolinone-iminosugars 1 (a-c) were synthesized from the benzyl protected sugars through three steps. Firstly, the benzyl protected sugar (aldehyde) 5 reacted with o-aminobenzamide by the iodine-induced oxidative condensation to afford the corresponding aldo-quizanolinone 6. Secondly, through the intramolecular cyclization of the unprotected OH and the amide NH in 6, the tricyclic compounds 7 and 8 were constructed by the key Mitsunobu reaction. Finally, removal of the benzyl group gave the target tricyclic quinazolinone-iminosugars 1. The protocol was effective for the preparation of the tricyclic iminosugars in satisfactory yield. Interestingly, an unusual C-2 epimerization was observed with d-mannose and d-ribose compounds under the conditions of the Mitsunobu reaction that generated the products having the trans configuration at the C-2 and C-3 positions. Unfortunately, such tricyclic quinazolinone-iminosugars showed no inhibitory effects on the tested five glycosidases.


Assuntos
Inibidores Enzimáticos/farmacologia , Glicosídeo Hidrolases/antagonistas & inibidores , Imino Açúcares/farmacologia , Quinazolinonas/farmacologia , Aspergillus niger/enzimologia , Canavalia/enzimologia , Configuração de Carboidratos , Café/enzimologia , Ciclização , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Escherichia coli/enzimologia , Glicosídeo Hidrolases/metabolismo , Imino Açúcares/síntese química , Imino Açúcares/química , Prunus dulcis/enzimologia , Quinazolinonas/síntese química , Quinazolinonas/química
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA