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1.
J Immunother Cancer ; 12(4)2024 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-38580335

RESUMO

BACKGROUND: Ovarian cancer is the most lethal gynecological malignancy, with limited treatment options after failure of standard therapies. Despite the potential of poly(ADP-ribose) polymerase inhibitors in treating DNA damage response (DDR)-deficient ovarian cancer, the development of resistance and immunosuppression limit their efficacy, necessitating alternative therapeutic strategies. Inhibitors of poly(ADP-ribose) glycohydrolase (PARG) represent a novel class of inhibitors that are currently being assessed in preclinical and clinical studies for cancer treatment. METHODS: By using a PARG small-molecule inhibitor, COH34, and a cell-penetrating antibody targeting the PARG's catalytic domain, we investigated the effects of PARG inhibition on signal transducer and activator of transcription 3 (STAT3) in OVCAR8, PEO1, and Brca1-null ID8 ovarian cancer cell lines, as well as in immune cells. We examined PARG inhibition-induced effects on STAT3 phosphorylation, nuclear localization, target gene expression, and antitumor immune responses in vitro, in patient-derived tumor organoids, and in an immunocompetent Brca1-null ID8 ovarian mouse tumor model that mirrors DDR-deficient human high-grade serous ovarian cancer. We also tested the effects of overexpressing a constitutively activated STAT3 mutant on COH34-induced tumor cell growth inhibition. RESULTS: Our findings show that PARG inhibition downregulates STAT3 activity through dephosphorylation in ovarian cancer cells. Importantly, overexpression of a constitutively activated STAT3 mutant in tumor cells attenuates PARG inhibitor-induced growth inhibition. Additionally, PARG inhibition reduces STAT3 phosphorylation in immune cells, leading to the activation of antitumor immune responses, shown in immune cells cocultured with ovarian cancer patient tumor-derived organoids and in immune-competent mice-bearing mouse ovarian tumors. CONCLUSIONS: We have identified a novel antitumor mechanism underlying PARG inhibition beyond its primary antitumor effects through blocking DDR in ovarian cancer. Furthermore, targeting PARG activates antitumor immune responses, thereby potentially increasing response rates to immunotherapy in patients with ovarian cancer.


Assuntos
Glicosídeo Hidrolases , Neoplasias Ovarianas , Fator de Transcrição STAT3 , Animais , Feminino , Humanos , Camundongos , Linhagem Celular , Imunidade , Neoplasias Ovarianas/tratamento farmacológico , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Fator de Transcrição STAT3/efeitos dos fármacos , Fator de Transcrição STAT3/metabolismo , Glicosídeo Hidrolases/antagonistas & inibidores , Glicosídeo Hidrolases/metabolismo
2.
Bioorg Chem ; 147: 107366, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38636435

RESUMO

α-Glycosidase inhibition is one of the main approaches to treat Diabetes mellitus. Polyphenolic moieties are known to be responsible for yielding exhibit potent α-glycosidase inhibitory effects. In addition, compounds containing benzothiazole and Schiff base functionalities were previously reported to show α-glycosidase inhibition. In this paper, the synthesis of seven new phloroglucinol-containing benzothiazole Schiff base derivatives through the reaction of 6-substituted-2-aminobenzothiazole compounds with 2,4,6-trihydroxybenzaldehyde using acetic acid as a catalyst was reported. The synthesized compounds were characterized using spectroscopic methods such as FT-IR, 1H NMR, 13C NMR, and elemental analysis. The synthesized compounds were evaluated for their inhibitory effects on α-glycosidase, compounds 3f and 3g were found to show significant inhibitory properties when compared to the positive control. The IC50 values of 3f and 3g were calculated as 24.05 ± 2.28 and 18.51 ± 1.19 µM, respectively. Kinetic studies revealed that compounds 3f and 3g exhibited uncompetitive mode of inhibition against α-glycosidase. Molecular modeling predicted druglikeness for the title compounds and underpinned the importance of phloroglucinol hydroxyls for interacting with the key residues of α-glycosidase.


Assuntos
Benzotiazóis , Inibidores Enzimáticos , Polifenóis , Benzotiazóis/química , Benzotiazóis/farmacologia , Benzotiazóis/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/síntese química , Polifenóis/química , Polifenóis/farmacologia , Polifenóis/síntese química , Relação Estrutura-Atividade , Estrutura Molecular , Glicosídeo Hidrolases/antagonistas & inibidores , Glicosídeo Hidrolases/metabolismo , Inibidores de Glicosídeo Hidrolases/química , Inibidores de Glicosídeo Hidrolases/farmacologia , Inibidores de Glicosídeo Hidrolases/síntese química , Simulação de Acoplamento Molecular , Humanos , Relação Dose-Resposta a Droga , alfa-Glucosidases/metabolismo , Cinética
3.
Curr Med Chem ; 29(7): 1271-1292, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34951354

RESUMO

Glycosidases, the enzymes responsible for the breakdown of glycoconjugates, including di-, oligo- and polysaccharides, are present across all kingdoms of life. The extreme chemical stability of the glycosidic bond combined with the catalytic rates achieved by glycosidases makes them among the most proficient of all enzymes. Given their multitude of roles in vivo, inhibition of these enzymes is highly attractive with potential in the treatment of a vast array of pathologies ranging from lysosomal storage and diabetes to viral infections. Therefore great efforts have been invested in the last three decades to design and synthesize inhibitors of glycosidases leading to a number of drugs currently on the market. Amongst the vast array of structures that have been disclosed, sugars incorporating an amidine moiety have been the focus of many research groups around the world because of their glycosidase transition state-like structure. In this review, we report and discuss the structure, the inhibition profile, and the use of these molecules, including related structural congeners as transition state analogs.


Assuntos
Amidinas , Glicosídeo Hidrolases , Amidinas/química , Amidinas/farmacologia , Carboidratos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Glicosídeo Hidrolases/antagonistas & inibidores , Humanos , Açúcares/química
4.
Bioorg Chem ; 116: 105245, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34482168

RESUMO

The GH-51 α-l-arabinofuranosidase from Thermobacillus xylanilyticus (TxAbf) possesses versatile catalytic properties, displaying not only the ability to hydrolyze glycosidic linkages but also to synthesize furanobiosides in α-l-Araf and ß-d-Galf series. Herein, mutants are investigated to evaluate their ability to perform self-condensation, assessing both yield improvements and changes in regioselectivity. Overall yields of oligo-α-l-arabino- and oligo-ß-d-galactofuranosides were increased up to 4.8-fold compared to the wild-type enzyme. In depth characterization revealed that the mutants exhibit increased transfer rates and thus a hydrolysis/self-condensation ratio in favor of synthesis. The consequence of the substitution N216W is the creation of an additional binding subsite that provides the basis for an alternative acceptor substrate binding mode. As a result, mutants bearing N216W synthesize not only (1,2)-linked furanobiosides, but also (1,3)- and even (1,5)-linked furanobiosides. Since the self-condensation is under kinetic control, the yield of homo-disaccharides was maximized using higher substrate concentrations. In this way, the mutant R69H-N216W produced oligo-ß-d-galactofuranosides in > 70% yield. Overall, this study further demonstrates the potential usefulness of TxAbf mutants for glycosynthesis and shows how these might be used to synthesize biologically-relevant glycoconjugates.


Assuntos
Bacillales/enzimologia , Inibidores Enzimáticos/farmacologia , Furanos/farmacologia , Glicosídeo Hidrolases/antagonistas & inibidores , Configuração de Carboidratos , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Furanos/síntese química , Furanos/química , Glicosídeo Hidrolases/genética , Glicosídeo Hidrolases/metabolismo , Modelos Moleculares , Relação Estrutura-Atividade
5.
Nutrients ; 13(8)2021 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-34444856

RESUMO

With a yearly production of about 39 million tons, brewer's spent grain (BSG) is the most abundant brewing industry byproduct. Because it is rich in fiber and protein, it is commonly used as cattle feed but could also be used within the human diet. Additionally, it contains many bioactive substances such as hydroxycinnamic acids that are known to be antioxidants and potent inhibitors of enzymes of glucose metabolism. Therefore, our study aim was to prepare different extracts-A1-A7 (solid-liquid extraction with 60% acetone); HE1-HE6 (alkaline hydrolysis followed by ethyl acetate extraction) and HA1-HA3 (60% acetone extraction of alkaline residue)-from various BSGs which were characterized for their total phenolic (TPC) and total flavonoid (TFC) contents, before conducting in vitro studies on their effects on the glucose metabolism enzymes α-amylase, α-glucosidase, dipeptidyl peptidase IV (DPP IV), and glycogen phosphorylase α (GPα). Depending on the extraction procedures, TPCs ranged from 20-350 µg gallic acid equivalents/mg extract and TFCs were as high as 94 µg catechin equivalents/mg extract. Strong inhibition of glucose metabolism enzymes was also observed: the IC50 values for α-glucosidase inhibition ranged from 67.4 ± 8.1 µg/mL to 268.1 ± 29.4 µg/mL, for DPP IV inhibition they ranged from 290.6 ± 97.4 to 778.4 ± 95.5 µg/mL and for GPα enzyme inhibition from 12.6 ± 1.1 to 261 ± 6 µg/mL. However, the extracts did not strongly inhibit α-amylase. In general, the A extracts from solid-liquid extraction with 60% acetone showed stronger inhibitory potential towards a-glucosidase and GPα than other extracts whereby no correlation with TPC or TFC were observed. Additionally, DPP IV was mainly inhibited by HE extracts but the effect was not of biological relevance. Our results show that BSG is a potent source of α-glucosidase and GPα inhibitors, but further research is needed to identify these bioactive compounds within BSG extracts focusing on extracts from solid-liquid extraction with 60% acetone.


Assuntos
Grão Comestível/química , Inibidores Enzimáticos/farmacologia , Glucose/metabolismo , Glicosídeo Hidrolases/efeitos dos fármacos , Extratos Vegetais/farmacologia , Antioxidantes/farmacologia , Flavonoides/farmacologia , Glicosídeo Hidrolases/antagonistas & inibidores , Humanos , Fenóis/farmacologia
6.
Food Chem ; 361: 130047, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34029903

RESUMO

Inhibition of maltase, sucrase, isomaltase and glucoamylase activity by acarbose, epigallocatechin gallate, epicatechin gallate and four polyphenol-rich tea extract from white, green, oolong, black tea, were investigated by using rat intestinal enzymes and human Caco-2 cells. Regarding rat intestinal enzyme mixture, all four tea extracts were very effective in inhibiting maltase and glucoamylase activity, but only white tea extract inhibited sucrase and isomaltase activity and the inhibition was limited. Mixed-type inhibition on rat maltase activity was observed. Tea extracts in combination with acarbose, produced a synergistic inhibitory effect on rat maltase activity. Caco-2 cells experiments were conducted in Transwells. Green tea extract and epigallocatechin gallate show dose-dependent inhibition on human sucrase activity, but no inhibition on rat sucrase activity. The opposite was observed on maltase activity. The results highlighted the different response in the two investigated model systems and show that tea polyphenols are good inhibitors for α-glucosidase activity.


Assuntos
Glicosídeo Hidrolases/antagonistas & inibidores , Intestinos/enzimologia , Extratos Vegetais/química , Polifenóis/farmacologia , Chá/química , Acarbose/farmacologia , Animais , Células CACO-2 , Catequina/análogos & derivados , Catequina/farmacologia , Glucana 1,4-alfa-Glucosidase/antagonistas & inibidores , Inibidores de Glicosídeo Hidrolases/farmacologia , Humanos , Cinética , Oligo-1,6-Glucosidase/antagonistas & inibidores , Ratos , Sacarase/antagonistas & inibidores , alfa-Glucosidases/efeitos dos fármacos
7.
J Med Chem ; 64(9): 5863-5873, 2021 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-33886333

RESUMO

Although multivalent glycosidase inhibitors have shown enhanced glycosidase inhibition activities, further applications and research directions need to be developed in the future. In this paper, two positional isomeric perylene bisimide derivatives (PBI-4DNJ-1 and PBI-4DNJ-2) with 1-deoxynojirimycin conjugated were synthesized. Furthermore, PBI-4DNJ-1 and PBI-4DNJ-2 showed positional isomeric effects on the optical properties, self-assembly behaviors, glycosidase inhibition activities, and hypoglycemic effects. Importantly, PBI-4DNJ-1 exhibited potent hypoglycemic effects in mice with 41.33 ± 2.84 and 37.45 ± 3.94% decreases in blood glucose at 15 and 30 min, respectively. The molecular docking results showed that the active fragment of PBI-4DNJ-1 has the highest binding energy (9.649 kcal/mol) and the highest total hydrogen bond energy (62.83 kJ/mol), which were related to the positional isomeric effect on the hypoglycemic effect in mice. This work introduced a new means to develop antihyperglycemic agents in the field of multivalent glycomimetics.


Assuntos
Glucosamina/análogos & derivados , Glicosídeo Hidrolases/metabolismo , Hipoglicemiantes/química , Imidas/química , Perileno/análogos & derivados , Administração Oral , Animais , Sítios de Ligação , Glicemia/análise , Glucosamina/química , Glicosídeo Hidrolases/antagonistas & inibidores , Ligação de Hidrogênio , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/metabolismo , Isomerismo , Cinética , Camundongos , Conformação Molecular , Simulação de Acoplamento Molecular , Perileno/química , Ligação Proteica , Termodinâmica
8.
Protein Sci ; 30(6): 1144-1156, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33837990

RESUMO

Protein-protein interactions are crucial in biology and play roles in for example, the immune system, signaling pathways, and enzyme regulation. Ultra-high affinity interactions (Kd <0.1 nM) occur in these systems, however, structures and energetics behind stability of ultra-high affinity protein-protein complexes are not well understood. Regulation of the starch debranching barley limit dextrinase (LD) and its endogenous cereal type inhibitor (LDI) exemplifies an ultra-high affinity complex (Kd of 42 pM). In this study the LD-LDI complex is investigated to unveil how robust the ultra-high affinity is to LDI sequence variation at the protein-protein interface and whether alternative sequences can retain the ultra-high binding affinity. The interface of LD-LDI was engineered using computational protein redesign aiming at identifying LDI variants predicted to retain ultra-high binding affinity. These variants present a very diverse set of mutations going beyond conservative and alanine substitutions typically used to probe interfaces. Surface plasmon resonance analysis of the LDI variants revealed that high affinity of LD-LDI requires interactions of several residues at the rim of the protein interface, unlike the classical hotspot arrangement where key residues are found at the center of the interface. Notably, substitution of interface residues in LDI, including amino acids with functional groups different from the wild-type, could occur without loss of affinity. This demonstrates that ultra-high binding affinity can be conferred without hotspot residues, thus making complexes more robust to mutational drift in evolution. The present mutational analysis also demonstrates how energetic coupling can emerge between residues at large distances at the interface.


Assuntos
Inibidores Enzimáticos/química , Glicosídeo Hidrolases/antagonistas & inibidores , Glicosídeo Hidrolases/química , Hordeum/química , Modelos Moleculares , Proteínas de Plantas/química
9.
Bioorg Chem ; 110: 104720, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33662896

RESUMO

Naturally occurring anti-diabetic compound curcumin can prevent diabetes complications due to antioxidant and anti-inflammatory properties as well as the attenuation of postprandial hyperglycemia. In this line, we have synthesized thirteen curcumin based derivatives (L1-L13) by multi-component reaction, characterized by IR, 1HNMR, 13C NMR, MS, elemental analysis and evaluated for possible antioxidant properties and α-glucosidase (α-Glu) and α-amylase (α-Amy) inhibitory potential. The curcumin-based pyrano[2,3-d]pyrimidine derivatives could inhibit α-Glu and α-Amy enzyme activity which showed desirable antioxidant activity. Furthermore, among the series, L5, L12, L9, L10, L8 and L11 were identified as more potent inhibitors of α-Glu enzyme than curcumin and the compounds of L12, L4, L9, L5, L10, L8, L13, and L11 were the stronger inhibitors of the α-Amy enzyme in vitro. Besides, among them, L12 had the lowest IC50 for the inhibition of both enzymes. Since strong inhibitors for pancreatic α-Amy result in the progression of severe gastrointestinal side effects, the inhibitors that show the lower α-Amy/α-Glu inhibitory ratio have attracted much attention in medicinal chemistry. Besides, considering antioxidant characteristics of synthesized compounds, the L7 derivative with the highest antioxidant activity and the lowest "α-Amy/α-Glu inhibitory" ratio could be an appropriate candidate for further study through the rational drug design to the exploration of a new class of powerful anti-diabetic drugs.


Assuntos
Antioxidantes/síntese química , Antioxidantes/farmacologia , Curcumina/química , Diabetes Mellitus/tratamento farmacológico , Glicosídeo Hidrolases/antagonistas & inibidores , Hipoglicemiantes/farmacologia , Animais , Desenho de Fármacos , Hipoglicemiantes/síntese química , Hipoglicemiantes/química , Intestinos/enzimologia , Modelos Moleculares , Simulação de Acoplamento Molecular , Estrutura Molecular , Pâncreas/enzimologia , Ligação Proteica , Conformação Proteica , Ratos , Relação Estrutura-Atividade , alfa-Amilases/genética , alfa-Amilases/metabolismo , alfa-Glucosidases/genética , alfa-Glucosidases/metabolismo
10.
Prog Biophys Mol Biol ; 163: 171-186, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33636189

RESUMO

Arrival of the novel SARS-CoV-2 has launched a worldwide effort to identify both pre-approved and novel therapeutics targeting the viral proteome, highlighting the urgent need for efficient drug discovery strategies. Even with effective vaccines, infection is possible, and at-risk populations would benefit from effective drug compounds that reduce the lethality and lasting damage of COVID-19 infection. The CoV-2 MacroD-like macrodomain (Mac1) is implicated in viral pathogenicity by disrupting host innate immunity through its mono (ADP-ribosyl) hydrolase activity, making it a prime target for antiviral therapy. We therefore solved the structure of CoV-2 Mac1 from non-structural protein 3 (Nsp3) and applied structural and sequence-based genetic tracing, including newly determined A. pompejana MacroD2 and GDAP2 amino acid sequences, to compare and contrast CoV-2 Mac1 with the functionally related human DNA-damage signaling factor poly (ADP-ribose) glycohydrolase (PARG). Previously, identified targetable features of the PARG active site allowed us to develop a pharmacologically useful PARG inhibitor (PARGi). Here, we developed a focused chemical library and determined 6 novel PARGi X-ray crystal structures for comparative analysis. We applied this knowledge to discovery of CoV-2 Mac1 inhibitors by combining computation and structural analysis to identify PARGi fragments with potential to bind the distal-ribose and adenosyl pockets of the CoV-2 Mac1 active site. Scaffold development of these PARGi fragments has yielded two novel compounds, PARG-345 and PARG-329, that crystallize within the Mac1 active site, providing critical structure-activity data and a pathway for inhibitor optimization. The reported structural findings demonstrate ways to harness our PARGi synthesis and characterization pipeline to develop CoV-2 Mac1 inhibitors targeting the ADP-ribose active site. Together, these structural and computational analyses reveal a path for accelerating development of antiviral therapeutics from pre-existing drug optimization pipelines.


Assuntos
Antivirais/química , Proteases Semelhantes à Papaína de Coronavírus/metabolismo , Inibidores Enzimáticos/química , Glicosídeo Hidrolases/antagonistas & inibidores , Bibliotecas de Moléculas Pequenas/química , Xantinas/química , Sequência de Aminoácidos , Antivirais/farmacologia , Domínio Catalítico , Cristalografia por Raios X , Descoberta de Drogas , Inibidores Enzimáticos/farmacologia , Humanos , Modelos Moleculares , Domínios Proteicos , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/metabolismo , Bibliotecas de Moléculas Pequenas/farmacologia , Relação Estrutura-Atividade , Xantinas/farmacologia , Tratamento Farmacológico da COVID-19
11.
Angew Chem Int Ed Engl ; 60(11): 5754-5758, 2021 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-33528085

RESUMO

The recent discovery of zinc-dependent retaining glycoside hydrolases (GHs), with active sites built around a Zn(Cys)3 (Glu) coordination complex, has presented unresolved mechanistic questions. In particular, the proposed mechanism, depending on a Zn-coordinated cysteine nucleophile and passing through a thioglycosyl enzyme intermediate, remains controversial. This is primarily due to the expected stability of the intermediate C-S bond. To facilitate the study of this atypical mechanism, we report the synthesis of a cyclophellitol-derived ß-l-arabinofuranosidase inhibitor, hypothesised to react with the catalytic nucleophile to form a non-hydrolysable adduct analogous to the mechanistic covalent intermediate. This ß-l-arabinofuranosidase inhibitor reacts exclusively with the proposed cysteine thiol catalytic nucleophiles of representatives of GH families 127 and 146. X-ray crystal structures determined for the resulting adducts enable MD and QM/MM simulations, which provide insight into the mechanism of thioglycosyl enzyme intermediate breakdown. Leveraging the unique chemistry of cyclophellitol derivatives, the structures and simulations presented here support the assignment of a zinc-coordinated cysteine as the catalytic nucleophile and illuminate the finely tuned energetics of this remarkable metalloenzyme clan.


Assuntos
Cicloexanóis/metabolismo , Cisteína/metabolismo , Inibidores Enzimáticos/metabolismo , Glicosídeo Hidrolases/metabolismo , Biocatálise , Cristalografia por Raios X , Cicloexanóis/química , Cicloexanóis/farmacologia , Cisteína/química , Teoria da Densidade Funcional , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Glicosídeo Hidrolases/antagonistas & inibidores , Glicosídeo Hidrolases/química , Simulação de Dinâmica Molecular , Estrutura Molecular
12.
Org Biomol Chem ; 19(5): 1083-1099, 2021 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-33427829

RESUMO

A highly enantioselective synthesis of (R,S) or (S,S)-2,6-disubstituted dehydropiperidines has been previously achieved through Sn/Li transmetalation of the corresponding stannylated dehydropiperidines or of their precursors. Herein, we successively consider their Upjohn's syn dihydroxylation and their anti-dihydroxylation via an epoxidation reaction followed by epoxide opening reaction. The stereochemical course of these reactions was first reported including the use of appropriate protecting groups before considering the conversion of the obtained compounds into NH or NMe iminosugar hydrochlorides. A primary evaluation of the designed iminosugar C-glycosides as glycosidase inhibitors suggests candidates for the selective inhibition of α-galactosidase, amyloglycosidase and naringinase. Beyond the reported results, the method constitutes a highly modulable route for the synthesis of well stereodefined iminosugar C-glycosides, an advantage which might be used for the design of iminosugars to enhance their biological properties.


Assuntos
Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Glicosídeo Hidrolases/antagonistas & inibidores , Glicosídeos/síntese química , Glicosídeos/farmacologia , Imino Açúcares/química , Configuração de Carboidratos , Técnicas de Química Sintética , Inibidores Enzimáticos/química , Glicosídeos/química , Modelos Moleculares , Estereoisomerismo
13.
Bioorg Chem ; 107: 104600, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33453645

RESUMO

Two new hybrid sorbicillinoids (1 and 5), three new bisorbicillinoids (2-4), and three monomeric sorbicillinoids (6-8), along with eighteen known sorbicillinoids (9-26) were isolated from cultures of the deep-sea sediment derived fungus Penicillium sp. SCSIO06871. Their structures and absolute configurations were elucidated based upon the extensive spectroscopic analysis, X-ray crystallography analysis and the comparison of the experimental and calculated ECD data. Bisorbicillpyrone A (4) is the first example of bisorbicillinoid containing an α-pyrone derivative unit. All of the isolated compounds were evaluated for their antibacterial, antifungal and enzyme inhibitory activities against α-glycosidase and acetylcholinesterase (AChE) in vitro. Compound 6 displayed more potent inhibitory activity against α-glycosidase than acarbose with IC50 value of 36.0 µM and compounds 4, 12, 18, 22, 23 exhibited moderate inhibitory activity with IC50 values ranging from 115.8 to 208.5 µM. Compounds 10 and 22 showed weak enzyme inhibitory activities against AChE with 55.1% and 51.1% inhibitions at concentration of 50 µg/mL, respectively. Besides, compounds 11 and 12 exhibited significant antibacterial activities against Staphylococcus aureus with MIC values of 10.0 and 5.0 µg/mL, respectively. The hypothetical biosynthetic pathway of the isolated sorbicillinoids with three different structural types was discussed.


Assuntos
Antibacterianos/farmacologia , Inibidores da Anidrase Carbônica/farmacologia , Inibidores da Colinesterase/farmacologia , Cicloexanonas/farmacologia , Penicillium/química , Staphylococcus aureus/efeitos dos fármacos , Acetilcolinesterase/metabolismo , Antibacterianos/química , Antibacterianos/isolamento & purificação , Inibidores da Anidrase Carbônica/química , Inibidores da Anidrase Carbônica/isolamento & purificação , Inibidores da Colinesterase/química , Inibidores da Colinesterase/isolamento & purificação , Cicloexanonas/química , Cicloexanonas/isolamento & purificação , Relação Dose-Resposta a Droga , Glicosídeo Hidrolases/antagonistas & inibidores , Glicosídeo Hidrolases/metabolismo , Testes de Sensibilidade Microbiana , Estrutura Molecular , Staphylococcus aureus/enzimologia , Relação Estrutura-Atividade
14.
Molecules ; 26(2)2021 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-33451060

RESUMO

Cyclopropanated iminosugars have a locked conformation that may enhance the inhibitory activity and selectivity against different glycosidases. We show the synthesis of new cyclopropane-containing piperidines bearing five stereogenic centers from natural amino acids l-serine and l-alanine. Those prepared from the latter amino acid may mimic l-fucose, a natural-occurring monosaccharide involved in many molecular recognition events. Final compounds prepared from l-serine bear S configurations on the C5 position. The synthesis involved a stereoselective cyclopropanation reaction of an α,ß-unsaturated piperidone, which was prepared through a ring-closing metathesis. The final compounds were tested as possible inhibitors of different glycosidases. The results, although, in general, with low inhibition activity, showed selectivity, depending on the compound and enzyme, and in some cases, an unexpected activity enhancement was observed.


Assuntos
Aminoácidos/química , Produtos Biológicos/química , Inibidores Enzimáticos/farmacologia , Imino Açúcares/farmacologia , Animais , Café/enzimologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Geobacillus stearothermophilus/enzimologia , Glicosídeo Hidrolases/antagonistas & inibidores , Glicosídeo Hidrolases/metabolismo , Caracois Helix/enzimologia , Imino Açúcares/síntese química , Imino Açúcares/química , Estrutura Molecular , Phaseolus/enzimologia
15.
J Sep Sci ; 44(7): 1404-1420, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33464708

RESUMO

Ribes meyeri leaves are used as traditional Kazakh medicine in China. However, no study on the characterization of the phenolic compounds in R. meyeri leaves has been reported, resulting in the lack of quality control measures and poor standardization. This study was conducted to identify the phenolic compounds in R. meyeri leaves and evaluate their antioxidant and antidiabetic activities. A total of 77 phenolics were tentatively identified by liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry. Ultra-high performance liquid chromatography coupled with triple quadrupole mass spectrometry was applied to simultaneously quantify 12 phenolics in R. meyeri leaves. Rutin, epigallocatechin, isoquercitrin, epicatechin, protocatechuic acid, and kaempferol-3-O-rutinoside were abundant in the R. meyeri leaves. The methanol extract and four different extracts enhanced the glucose uptake in 3T3-L1 adipocytes. The ethyl acetate extracts showed a total phenolic content of 966.89 ± 3.59 mg gallic acid equivalents/g, a total flavonoid content of 263.58 ± 17.09 mg catechin equivalents/g, and good protein-tyrosine phosphatase-1B inhibitory activities (IC50 : 0.60 ± 0.03 µg/mL). To our knowledge, this work is the first to identify and quantify the major phenolics in R. meyeri leaves.


Assuntos
Antioxidantes/farmacologia , Inibidores Enzimáticos/farmacologia , Fenóis/farmacologia , Ribes/química , Células 3T3-L1 , Animais , Antioxidantes/análise , Benzotiazóis/antagonistas & inibidores , Compostos de Bifenilo/antagonistas & inibidores , Cromatografia Líquida de Alta Pressão , Inibidores Enzimáticos/análise , Glicosídeo Hidrolases/antagonistas & inibidores , Glicosídeo Hidrolases/metabolismo , Humanos , Camundongos , Fenóis/análise , Picratos/antagonistas & inibidores , Proteína Tirosina Fosfatase não Receptora Tipo 1/antagonistas & inibidores , Proteína Tirosina Fosfatase não Receptora Tipo 1/metabolismo , Ácidos Sulfônicos/antagonistas & inibidores , Espectrometria de Massas em Tandem
16.
Med Chem ; 17(7): 677-698, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-32370719

RESUMO

BACKGROUND: Curcumin, as the substantial constituent of the turmeric plant (Curcuma longa), plays a significant role in the prevention of various diseases, including diabetes. It possesses ideal structure features as an enzyme inhibitor, including a flexible backbone, hydrophobic nature, and several available hydrogen bond (H-bond) donors and acceptors. OBJECTIVE: The present study aimed at synthesizing several novel curcumin derivatives and further evaluation of these compounds for possible antioxidant and anti-diabetic properties along with inhibitory effect against two carbohydrate-hydrolyzing enzymes, α-amylase and α-glucosidase, as these enzymes are therapeutic targets for attenuation of postprandial hyperglycemia. METHODS: Therefore, curcumin-based pyrido[2,3-d]pyrimidine derivatives were synthesized and identified using an instrumental technique like NMR spectroscopy and then screened for antioxidant and enzyme inhibitory potential. Total antioxidant activity, reducing power assay and 1,1-diphenyl-2- picrylhydrazyl (DPPH•) radical scavenging activity were done to appraise the antioxidant potential of these compounds in vitro. RESULTS: Compounds L6-L9 showed higher antioxidant activity while L4, L9, L12 and especially L8 exhibited the best selectivity index (lowest α-amylase/α-glucosidase inhibition ratio). CONCLUSION: These antioxidant inhibitors may be potential anti-diabetic drugs, not only to reduce glycemic index but also to limit the activity of the major reactive oxygen species (ROS) producing pathways.


Assuntos
Curcumina/síntese química , Curcumina/farmacologia , Glicosídeo Hidrolases/antagonistas & inibidores , Antioxidantes/síntese química , Antioxidantes/química , Antioxidantes/farmacologia , Técnicas de Química Sintética , Curcumina/química , Inibidores de Glicosídeo Hidrolases/síntese química , Inibidores de Glicosídeo Hidrolases/química , Inibidores de Glicosídeo Hidrolases/farmacologia , Hipoglicemiantes/síntese química , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia
17.
Arch Pharm (Weinheim) ; 354(4): e2000334, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33300644

RESUMO

A new class of cyanopyridine derivatives (10a-e and 11a-e) containing the phenylurea unit was synthesized and tested against some metabolic enzymes including acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and α-glycosidase (α-Gly). The new cyanopyridine derivatives showed Ki values in the range of 40.73 ± 6.54 to 87.05 ± 16.98 µM against AChE, 29.17 ± 4.88 to 124.03 ± 22.43 µM against BChE, and 3.66 ± 0.93 to 26.33 ± 5.05 µM against α-Gly. These inhibition effects were compared with standard enzyme inhibitors like tacrine (for AChE and BChE) and acarbose (for α-Gly). Also, these cyanopyridine derivatives with the best inhibition score were docked into the active site of the indicated metabolic enzymes. Finally, molecular docking calculations were made to compare the biological activities of the compounds against AChE (-8.81 kcal/mol for molecule 11d), BChE (-3.52 kcal/mol for molecule 11d), and α-Gly (-2.98 kcal/mol for molecule 11a). After molecular docking calculations, the ADME/T analysis was performed to examine the future drug use properties of the new cyanopyridine derivatives containing phenylurea.


Assuntos
Inibidores da Colinesterase/farmacologia , Inibidores de Glicosídeo Hidrolases/farmacologia , Simulação de Acoplamento Molecular , Compostos de Fenilureia/farmacologia , Piridinas/farmacologia , Acetilcolinesterase/metabolismo , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Relação Dose-Resposta a Droga , Inibidores de Glicosídeo Hidrolases/síntese química , Inibidores de Glicosídeo Hidrolases/química , Glicosídeo Hidrolases/antagonistas & inibidores , Humanos , Estrutura Molecular , Compostos de Fenilureia/química , Piridinas/síntese química , Piridinas/química , Relação Estrutura-Atividade
18.
Bioorg Chem ; 107: 104554, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33383322

RESUMO

With the fading of 'one drug-one target' approach, Multi-Target-Directed Ligands (MTDL) has become a central idea in modern Medicinal Chemistry. The present study aimed to design, develop and characterize a novel series of 4-(Diethylamino)-salicylaldehyde based thiosemicarbazones (3a-p) and evaluates their biological activity against cholinesterase, carbonic anhydrases and α-glycosidase enzymes. The hCA I isoform was inhibited by these novel 4-(diethylamino)-salicylaldehyde-based thiosemicarbazones (3a-p) in low nanomolar levels, the Ki of which differed between 407.73 ± 43.71 and 1104.11 ± 80.66 nM. Against the physiologically dominant isoform hCA II, the novel compounds demonstrated Kis varying from 323.04 ± 56.88 to 991.62 ± 77.26 nM. Also, these novel 4-(diethylamino)-salicylaldehyde based thiosemicarbazones (3a-p) effectively inhibited AChE, with Ki values in the range of 121.74 ± 23.52 to 548.63 ± 73.74 nM. For BChE, Ki values were obtained with in the range of 132.85 ± 12.53 to 618.53 ± 74.23 nM. For α-glycosidase, the most effective Ki values of 3b, 3k, and 3g were with Ki values of 77.85 ± 10.64, 96.15 ± 9.64, and 124.95 ± 11.44 nM, respectively. We have identified inhibition mechanism of 3b, 3g, 3k, and 3n on α-glycosidase AChE, hCA I, hCA II, and BChE enzyme activities. Hydrazine-1-carbothioamide and hydroxybenzylidene moieties of compounds play an important role in the inhibition of AChE, hCA I, and hCA II enzymes. Hydroxybenzylidene moieties are critical for inhibition of both BChE and α-glycosidase enzymes. The findings of in vitro and in silico evaluations indicate 4-(diethylamino)-salicylaldehyde-based thiosemicarbazone scaffold to be a promising hit for drug development for multifactorial diseases like Alzheimer's disease.


Assuntos
Acetilcolinesterase/química , Butirilcolinesterase/química , Anidrases Carbônicas/química , Glicosídeo Hidrolases/antagonistas & inibidores , Tiossemicarbazonas/química , Acetilcolinesterase/metabolismo , Aldeídos/química , Sítios de Ligação , Butirilcolinesterase/metabolismo , Inibidores da Anidrase Carbônica/química , Inibidores da Anidrase Carbônica/metabolismo , Anidrases Carbônicas/metabolismo , Domínio Catalítico , Glicosídeo Hidrolases/metabolismo , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Cinética , Ligantes , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade , Tiossemicarbazonas/metabolismo
19.
Biochemistry ; 59(51): 4845-4855, 2020 12 29.
Artigo em Inglês | MEDLINE | ID: mdl-33326210

RESUMO

The P22 tailspike endorhamnosidase confers the high specificity of bacteriophage P22 for some serogroups of Salmonella differing only slightly in their O-antigen polysaccharide. We used several biophysical methods to study the binding and hydrolysis of O-antigen fragments of different lengths by P22 tailspike protein. O-Antigen saccharides of defined length labeled with fluorophors could be purified with higher resolution than previously possible. Small amounts of naturally occurring variations of O-antigen fragments missing the nonreducing terminal galactose could be used to determine the contribution of this part to the free energy of binding to be ∼7 kJ/mol. We were able to show via several independent lines of evidence that an unproductive binding mode is highly favored in binding over all other possible binding modes leading to hydrolysis. This is true even under circumstances under which the O-antigen fragment is long enough to be cleaved efficiently by the enzyme. The high-affinity unproductive binding mode results in a strong self-competitive inhibition in addition to product inhibition observed for this system. Self-competitive inhibition is observed for all substrates that have a free reducing end rhamnose. Naturally occurring O-antigen, while still attached to the bacterial outer membrane, does not have a free reducing end and therefore does not perform self-competitive inhibition.


Assuntos
Bacteriófago P22/enzimologia , Glicosídeo Hidrolases/metabolismo , Antígenos O/metabolismo , Oligossacarídeos/metabolismo , Proteínas da Cauda Viral/metabolismo , Domínio Catalítico , Corantes Fluorescentes/química , Glicosídeo Hidrolases/antagonistas & inibidores , Glicosídeo Hidrolases/química , Hidrólise , Antígenos O/química , Oligossacarídeos/química , Ligação Proteica , Salmonella enterica/química , Proteínas da Cauda Viral/antagonistas & inibidores , Proteínas da Cauda Viral/química
20.
Int J Mol Sci ; 21(19)2020 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-33022933

RESUMO

γ-conglutin (γC) is a major protein of Lupinus albus seeds, but its function is still unknown. It shares high structural similarity with xyloglucan-specific endo-glucanase inhibitor proteins (XEGIPs) and, to a lesser extent, with Triticum aestivum endoxylanase inhibitors (TAXI-I), active against fungal glycoside hydrolases GH12 and GH11, respectively. However, γC lacks both these inhibitory activities. Since ß-galactomannans are major components of the cell walls of endosperm in several legume plants, we tested the inhibitory activity of γC against a GH2 ß-mannosidase (EC 3.2.1.25). γC was actually able to inhibit the enzyme, and this effect was enhanced by the presence of zinc ions. The stoichiometry of the γC/enzyme interaction was 1:1, and the calculated Ki was 1.55 µM. To obtain further insights into the interaction between γC and ß-mannosidase, an in silico structural bioinformatic approach was followed, including some docking analyses. By and large, this work describes experimental findings that highlight new scenarios for understanding the natural role of γC. Although structural predictions can leave space for speculative interpretations, the full complexity of the data reported in this work allows one to hypothesize mechanisms of action for the basis of inhibition. At least two mechanisms seem plausible, both involving lupin-γC-peculiar structures.


Assuntos
Glucanos/química , Glicosídeo Hidrolases/genética , Lupinus/química , Proteínas de Plantas/genética , Xilanos/química , Sequência de Aminoácidos/genética , Glucanos/genética , Glicosídeo Hidrolases/antagonistas & inibidores , Proteínas de Plantas/ultraestrutura , Proteínas de Armazenamento de Sementes/genética , Proteínas de Armazenamento de Sementes/ultraestrutura , Sementes/química , Sementes/crescimento & desenvolvimento , Triticum/química , Xilanos/genética
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