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1.
Molecules ; 28(7)2023 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-37049820

RESUMO

While platinum-based compounds such as cisplatin form the backbone of chemotherapy, the use of these compounds is limited by resistance and toxicity, driving the development of novel complexes with cytostatic properties. In this study, we synthesized a set of half-sandwich complexes of platinum-group metal ions (Ru(II), Os(II), Ir(III) and Rh(III)) with an N,N-bidentate ligand comprising a C-glucosaminyl group and a heterocycle, such as pyridine, pyridazine, pyrimidine, pyrazine or quinoline. The sugar-containing ligands themselves are unknown compounds and were obtained by nucleophilic additions of lithiated heterocycles to O-perbenzylated 2-nitro-glucal. Reduction of the adducts and, where necessary, subsequent protecting group manipulations furnished the above C-glucosaminyl heterocycles in their O-perbenzylated, O-perbenzoylated and O-unprotected forms. The derived complexes were tested on A2780 ovarian cancer cells. Pyridine, pyrazine and pyridazine-containing complexes proved to be cytostatic and cytotoxic on A2780 cells, while pyrimidine and quinoline derivatives were inactive. The best complexes contained pyridine as the heterocycle. The metal ion with polyhapto arene/arenyl moiety also impacted on the biological activity of the complexes. Ruthenium complexes with p-cymene and iridium complexes with Cp* had the best performance in ovarian cancer cells, followed by osmium complexes with p-cymene and rhodium complexes with Cp*. Finally, the chemical nature of the protective groups on the hydroxyl groups of the carbohydrate moiety were also key determinants of bioactivity; in particular, O-benzyl groups were superior to O-benzoyl groups. The IC50 values of the complexes were in the low micromolar range, and, importantly, the complexes were less active against primary, untransformed human dermal fibroblasts; however, the anticipated therapeutic window is narrow. The bioactive complexes exerted cytostasis on a set of carcinomas such as cell models of glioblastoma, as well as breast and pancreatic cancers. Furthermore, the same complexes exhibited bacteriostatic properties against multiresistant Gram-positive Staphylococcus aureus and Enterococcus clinical isolates in the low micromolar range.


Assuntos
Anti-Infecciosos , Antineoplásicos , Complexos de Coordenação , Citostáticos , Neoplasias Ovarianas , Quinolinas , Rutênio , Humanos , Feminino , Complexos de Coordenação/química , Citostáticos/uso terapêutico , Linhagem Celular Tumoral , Neoplasias Ovarianas/tratamento farmacológico , Antineoplásicos/química , Metais , Compostos Azo/uso terapêutico , Quinolinas/uso terapêutico , Piridinas/farmacologia , Piridinas/uso terapêutico , Anti-Infecciosos/farmacologia , Anti-Infecciosos/uso terapêutico , Rutênio/química
2.
Front Chem ; 11: 1086267, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36793764

RESUMO

The toxicity of and resistance to platinum complexes as cisplatin, oxaliplatin or carboplatin calls for the replacement of these therapeutic agents in clinical settings. We have previously identified a set of half sandwich-type osmium, ruthenium and iridium complexes with bidentate glycosyl heterocyclic ligands exerting specific cytostatic activity on cancer cells but not on non-transformed primary cells. The apolar nature of the complexes, conferred by large, apolar benzoyl protective groups on the hydroxyl groups of the carbohydrate moiety, was the main molecular feature to induce cytostasis. We exchanged the benzoyl protective groups to straight chain alkanoyl groups with varying length (3 to 7 carbon units) that increased the IC50 value as compared to the benzoyl-protected complexes and rendered the complexes toxic. These results suggest a need for aromatic groups in the molecule. The pyridine moiety of the bidentate ligand was exchanged for a quinoline group to enlarge the apolar surface of the molecule. This modification decreased the IC50 value of the complexes. The complexes containing [(η6-p-cymene)Ru(II)], [(η6-p-cymene)Os(II)] or [(η5-Cp*)Ir(III)] were biologically active unlike the complex containing [(η5-Cp*)Rh(III)]. The complexes with cytostatic activity were active on ovarian cancer (A2780, ID8), pancreatic adenocarcinoma (Capan2), sarcoma (Saos) and lymphoma cell lines (L428), but not on primary dermal fibroblasts and their activity was dependent on reactive oxygen species production. Importantly, these complexes were cytostatic on cisplatin-resistant A2780 ovarian cancer cells with similar IC50 values as on cisplatin-sensitive A2780 cells. In addition, the quinoline-containing Ru and Os complexes and the short chain alkanoyl-modified complexes (C3 and C4) proved to be bacteriostatic in multiresistant Gram-positive Enterococcus and Staphylococcus aureus isolates. Hereby, we identified a set of complexes with submicromolar to low micromolar inhibitory constants against a wide range of cancer cells, including platinum resistant cells and against multiresistant Gram-positive bacteria.

3.
Molecules ; 27(22)2022 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-36431902

RESUMO

C-glycopyranosyl derivatives of six-membered heterocycles are scarcely represented in the chemical literature and the title 3-glycopyranosyl-1,2,4-triazines are completely unknown. In this paper, the first synthesis of this compound class is accomplished by the cyclocondensation of C-glycosyl formamidrazones and 1,2-dicarbonyl derivatives. In addition, the synthesis of C-glycopyranosyl 1,2,4-triazin-5(4H)-ones was also carried out by the transformation of the above formamidrazones with α-keto-carboxylic esters. Inverse electron demand Diels-Alder reactions of 3-glycopyranosyl-1,2,4-triazines with a bicyclononyne derivative yielded the corresponding annulated 2-glycopyranosyl pyridines.


Assuntos
Elétrons , Triazinas , Reação de Cicloadição , Triazinas/química , Ciclização , Piridinas/química
4.
Front Chem ; 10: 868234, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35494644

RESUMO

Bacterial resistance to antibiotics is an ever-growing problem in heathcare. We have previously identified a set of osmium(II), ruthenium(II), iridium(III) and rhodium(III) half-sandwich type complexes with bidentate monosaccharide ligands possessing cytostatic properties against carcinoma, lymphoma and sarcoma cells with low micromolar or submicromolar IC50 values. Importantly, these complexes were not active on primary, non-transformed cells. These complexes have now been assessed as to their antimicrobial properties and found to be potent inhibitors of the growth of reference strains of Staphylococcus aureus and Enterococcus faecalis (Gram-positive species), though the compounds proved inactive on reference strains of Pseudomonas aerugonisa, Escherichia coli, Candida albicans, Candida auris and Acinetobacter baumannii (Gram-negative species and fungi). Furthermore, clinical isolates of Staphylococcus aureus and Enterococcus sp. (both multiresistant and susceptible strains) were also susceptible to the organometallic complexes in this study with similar MIC values as the reference strains. Taken together, we identified a set of osmium(II), ruthenium(II), iridium(III) and rhodium(III) half-sandwich type antineoplastic organometallic complexes which also have antimicrobial activity among Gram-positive bacteria. These compounds represent a novel class of antimicrobial agents that are not detoxified by multiresistant bacteria suggesting a potential to be used to combat multiresistant infections.

5.
Int J Mol Sci ; 23(2)2022 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-35054999

RESUMO

Platinum complexes are used in chemotherapy, primarily as antineoplastic agents. In this study, we assessed the cytotoxic and cytostatic properties of a set of osmium(II), ruthenium(II), iridium(III) and rhodium(III) half-sandwich-type complexes with bidentate monosaccharide ligands. We identified 5 compounds with moderate to negligible acute cytotoxicity but with potent long-term cytostatic activity. These structure-activity relationship studies revealed that: (1) osmium(II) p-cymene complexes were active in all models, while rhodium(III) and iridium(III) Cp* complexes proved largely inactive; (2) the biological effect was influenced by the nature of the central azole ring of the ligands-1,2,3-triazole was the most effective, followed by 1,3,4-oxadiazole, while the isomeric 1,2,4-oxadiazole abolished the cytostatic activity; (3) we found a correlation between the hydrophobic character of the complexes and their cytostatic activity: compounds with O-benzoyl protective groups on the carbohydrate moiety were active, compared to O-deprotected ones. The best compound, an osmium(II) complex, had an IC50 value of 0.70 µM. Furthermore, the steepness of the inhibitory curve of the active complexes suggested cooperative binding; cooperative molecules were better inhibitors than non-cooperative ones. The cytostatic activity of the active complexes was abolished by a lipid-soluble antioxidant, vitamin E, suggesting that oxidative stress plays a major role in the biological activity of the complexes. The complexes were active on ovarian cancer, pancreatic adenocarcinoma, osteosarcoma and Hodgkin's lymphoma cells, but were inactive on primary, non-transformed human fibroblasts, indicating their applicability as potential anticancer agents.


Assuntos
Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Metais Pesados/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Técnicas de Química Sintética , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Relação Dose-Resposta a Droga , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Humanos , Irídio , Ligantes , Metais Pesados/química , Modelos Moleculares , Estrutura Molecular , Osmio , Ródio , Rutênio , Relação Estrutura-Atividade
6.
Int J Mol Sci ; 22(19)2021 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-34638791

RESUMO

Ruthenium complexes are developed as substitutes for platinum complexes to be used in the chemotherapy of hematological and gynecological malignancies, such as ovarian cancer. We synthesized and screened 14 ruthenium half-sandwich complexes with bidentate monosaccharide ligands in ovarian cancer cell models. Four complexes were cytostatic, but not cytotoxic on A2780 and ID8 cells. The IC50 values were in the low micromolar range (the best being 0.87 µM) and were similar to or lower than those of the clinically available platinum complexes. The active complexes were cytostatic in cell models of glioblastoma, breast cancer, and pancreatic adenocarcinoma, while they were not cytostatic on non-transformed human skin fibroblasts. The bioactive ruthenium complexes showed cooperative binding to yet unidentified cellular target(s), and their activity was dependent on reactive oxygen species production. Large hydrophobic protective groups on the hydroxyl groups of the sugar moiety were needed for biological activity. The cytostatic activity of the ruthenium complexes was dependent on reactive species production. Rucaparib, a PARP inhibitor, potentiated the effects of ruthenium complexes.


Assuntos
Neoplasias/tratamento farmacológico , Compostos de Rutênio/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Complexos de Coordenação , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Indóis/farmacologia , Indóis/uso terapêutico , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Pancreáticas/tratamento farmacológico , Espécies Reativas de Oxigênio , Compostos de Rutênio/síntese química , Compostos de Rutênio/química , Compostos de Rutênio/uso terapêutico
7.
Environ Geochem Health ; 43(6): 2317-2330, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33866466

RESUMO

Toxic metal phytoextraction potential of some higher plants, the white mustard (Sinapis alba L.), perennial rye grass (Lolium perenne L.) and also two cultivated plants, as green pea (Pisum sativum L. var. Rajnai törpe), radish (Raphanus sativus L. var. Szentesi óriás vaj), was studied in a field experiment, along the river Danube in close vicinity of an industrial town, Dunaújváros, Hungary. Soil/sediment and the various plant organs (leaves, stems and roots) were assessed for the contamination with some potentially toxic elements (PTE), such as the cadmium (Cd), nickel (Ni), copper (Cu), and zinc (Zn). It was found that Cd and Ni concentration was below, while the Cu and Zn elements were above the Hungarian permissible limits in each of the studied soil/sediment samples. Bioconcentration factor (BAF) was less than 1 in the shoot biomass of test plant samples and followed the order of Cu > Zn > Cd and Ni. Phytoremediation potential of selected test plants was found to be rather limited. The translocation factor (TF) was more than 1 for Cu and Zn elements, at each test plants. Cadmium was translocated into the leaves in case of the radish, only. Considering of the potential human daily intake of metals (DIM), it was less than 1 both for the adults and for the children. Health risk index (HRI) values of children, however, were higher than 1 for the Cd in case of radish, and for Zn and Cu in case of the pea. Results suggest that consumption of these plants grown in gardens of contaminated sediments can result in some risks for citizens in the industrial town of Dunaújváros. Further studies are required to identify appropriate plants with greater toxic metal phytoextraction potential.


Assuntos
Biodegradação Ambiental , Metais Pesados/isolamento & purificação , Pisum sativum , Raphanus , Poluentes do Solo/isolamento & purificação , Biomassa , Exposição Dietética/efeitos adversos , Contaminação de Alimentos , Sedimentos Geológicos , Hungria , Lolium/química , Lolium/efeitos dos fármacos , Metais Pesados/análise , Metais Pesados/toxicidade , Pisum sativum/química , Pisum sativum/efeitos dos fármacos , Folhas de Planta/química , Folhas de Planta/efeitos dos fármacos , Raízes de Plantas/química , Raízes de Plantas/efeitos dos fármacos , Brotos de Planta/química , Brotos de Planta/efeitos dos fármacos , Raphanus/química , Raphanus/efeitos dos fármacos , Rios , Poluentes do Solo/análise , Poluentes do Solo/toxicidade , Poluentes Químicos da Água/análise
8.
Pharmaceuticals (Basel) ; 14(4)2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33920838

RESUMO

A current trend in the quest for new therapies for complex, multifactorial diseases, such as diabetes mellitus (DM), is to find dual or even multi-target inhibitors. In DM, the sodium dependent glucose cotransporter 2 (SGLT2) in the kidneys and the glycogen phosphorylase (GP) in the liver are validated targets. Several (ß-D-glucopyranosylaryl)methyl (het)arene type compounds, called gliflozins, are marketed drugs that target SGLT2. For GP, low nanomolar glucose analogue inhibitors exist. The purpose of this study was to identify dual acting compounds which inhibit both SGLTs and GP. To this end, we have extended the structure-activity relationships of SGLT2 and GP inhibitors to scarcely known (C-ß-D-glucopyranosylhetaryl)methyl arene type compounds and studied several (C-ß-D-glucopyranosylhetaryl)arene type GP inhibitors against SGLT. New compounds, such as 5-arylmethyl-3-(ß-D-glucopyranosyl)-1,2,4-oxadiazoles, 5-arylmethyl-2-(ß-D-glucopyranosyl)-1,3,4-oxadiazoles, 4-arylmethyl-2-(ß-D-glucopyranosyl)pyrimidines and 4(5)-benzyl-2-(ß-D-glucopyranosyl)imidazole were prepared by adapting our previous synthetic methods. None of the studied compounds exhibited cytotoxicity and all of them were assayed for their SGLT1 and 2 inhibitory potentials in a SGLT-overexpressing TSA201 cell system. GP inhibition was also determined by known methods. Several newly synthesized (C-ß-D-glucopyranosylhetaryl)methyl arene derivatives had low micromolar SGLT2 inhibitory activity; however, none of these compounds inhibited GP. On the other hand, several (C-ß-D-glucopyranosylhetaryl)arene type GP inhibitor compounds with low micromolar efficacy against SGLT2 were identified. The best dual inhibitor, 2-(ß-D-glucopyranosyl)-4(5)-(2-naphthyl)-imidazole, had a Ki of 31 nM for GP and IC50 of 3.5 µM for SGLT2. This first example of an SGLT-GP dual inhibitor can prospectively be developed into even more efficient dual-target compounds with potential applications in future antidiabetic therapy.

9.
Molecules ; 25(3)2020 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-32041285

RESUMO

Despite the substantial interest in C-glycosyl heterocycles as mimetics of biologically active native glycans, the appearance of C-glycopyranosyl derivatives of six-membered heterocycles, both in synthetic and biological contexts, is rather scarce. As part of our ongoing research program aimed at preparing hitherto barely known 2-C-glycopyranosyl pyrimidines, the goal of the present study was to synthesize new 5-mono- and multiply substituted derivatives of this compound class. Thus, 2-C-(ß-D-glucopyranosyl)-5,6-disubstituted-pyrimidin-4(3H)-ones and 4-amino-2-C-(ß-D-glucopyranosyl)-5,6-disubstituted-pyrimidines were prepared by base-mediated cyclocondensations of O-perbenzylated and O-unprotected C-(ß-D-glucopyranosyl) formamidine hydrochlorides with methylenemalonic acid derivatives. The 2-C-(ß-D-glucopyranosyl)-5-substituted-pyrimidines were obtained from the same amidine precursors upon treatment with vinamidinium salts. The deprotected derivatives of these pyrimidines were tested as inhibitors of some glycoenzymes. None of them showed inhibitory activity towards glycogen phosphorylase and α- and ß-glucosidase enzymes, but some members of the sets exhibited moderate inhibition against bovine liver ß-galactosidase.


Assuntos
Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Glicogênio Fosforilase/antagonistas & inibidores , Pirimidinas/síntese química , Pirimidinas/farmacologia , Animais , Bovinos , alfa-Glucosidases/metabolismo , beta-Galactosidase/metabolismo
10.
Bioorg Med Chem ; 28(1): 115196, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31767404

RESUMO

C-Glucopyranosyl imidazoles, thiazoles, and an N-glucopyranosyl tetrazole were assessed in vitro and ex vivo for their inhibitory efficiency against isoforms of glycogen phosphorylase (GP; a validated pharmacological target for the development of anti-hyperglycaemic agents). Imidazoles proved to be more potent inhibitors than the corresponding thiazoles or the tetrazole. The most potent derivative has a 2-naphthyl substituent, a Ki value of 3.2 µM for hepatic glycogen phosphorylase, displaying also 60% inhibition of GP activity in HepG2 cells, compared to control vehicle treated cells, at 100 µM. X-Ray crystallography studies of the protein - inhibitor complexes revealed the importance of the architecture of inhibitor associated hydrogen bonds or sulfur σ-hole bond interactions to Asn284 OD1, offering new insights to structure-based design efforts. Moreover, while the 2-glucopyranosyl-tetrazole seems to bind differently from the corresponding 1,2,3-triazole compound, the two inhibitors are equipotent.


Assuntos
Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Glicogênio Fosforilase Hepática/antagonistas & inibidores , Imidazóis/farmacologia , Tetrazóis/farmacologia , Tiazóis/farmacologia , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Glicogênio Fosforilase Hepática/metabolismo , Células Hep G2 , Humanos , Hidrogênio/química , Imidazóis/síntese química , Imidazóis/química , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade , Enxofre/química , Tetrazóis/síntese química , Tetrazóis/química , Tiazóis/síntese química , Tiazóis/química
11.
ACS Chem Biol ; 14(7): 1460-1470, 2019 07 19.
Artigo em Inglês | MEDLINE | ID: mdl-31243960

RESUMO

Several C-ß-d-glucopyranosyl azoles have recently been uncovered as among the most potent glycogen phosphorylase (GP) catalytic site inhibitors discovered to date. Toward further exploring their translational potential, ex vivo experiments have been performed for their effectiveness in reduction of glycogenolysis in hepatocytes. New compounds for these experiments were predicted in silico where, for the first time, effective ranking of GP catalytic site inhibitor potencies using the molecular mechanics-generalized Born surface area (MM-GBSA) method has been demonstrated. For a congeneric training set of 27 ligands, excellent statistics in terms of Pearson (RP) and Spearman (RS) correlations (both 0.98), predictive index (PI = 0.99), and area under the receiver operating characteristic curve (AU-ROC = 0.99) for predicted versus experimental binding affinities were obtained, with ligand tautomeric/ionization states additionally considered using density functional theory (DFT). Seven 2-aryl-4(5)-(ß-d-glucopyranosyl)-imidazoles and 2-aryl-4-(ß-d-glucopyranosyl)-thiazoles were subsequently synthesized, and kinetics experiments against rabbit muscle GPb revealed new potent inhibitors with best Ki values in the low micromolar range (5c = 1.97 µM; 13b = 4.58 µM). Ten C-ß-d-glucopyranosyl azoles were then tested ex vivo in mouse primary hepatocytes. Four of these (5a-c and 9d) demonstrated significant reduction of glucagon stimulated glycogenolysis (IC50 = 30-60 µM). Structural and predicted physicochemical properties associated with their effectiveness were analyzed with permeability related parameters identified as crucial factors. The most effective ligand series 5 contained an imidazole ring, and the calculated pKa (Epik: 6.2; Jaguar 5.5) for protonated imidazole suggests that cellular permeation through the neutral state is favored, while within the cell, there is predicted more favorable binding to GP in the protonated form.


Assuntos
Azóis/farmacologia , Inibidores Enzimáticos/farmacologia , Glicogênio Fosforilase/antagonistas & inibidores , Glicogenólise/efeitos dos fármacos , Hepatócitos/efeitos dos fármacos , Animais , Azóis/química , Células CACO-2 , Desenho de Fármacos , Inibidores Enzimáticos/química , Glicogênio Fosforilase/metabolismo , Hepatócitos/metabolismo , Humanos , Modelos Moleculares , Coelhos , Relação Estrutura-Atividade
12.
Carbohydr Res ; 472: 33-41, 2019 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-30453096

RESUMO

Annulated C-ß-d-glucopyranosyl heterocycles were synthesized and tested as inhibitors of glycogen phosphorylase. 2-(ß-d-Glucopyranosyl)-1H-imidazo[4,5-b]pyridine was formed by ring-closure of O-perbenzoylated C-ß-d-glucopyranosyl formic acid with 2,3-diaminopyridine in the presence of triphenylphosphite. Cyclisations of bromomethyl 2,3,4,6-tetra-O-benzoyl-ß-d-glucopyranosyl ketone with a set of 2-aminoheterocycles resulted in constitutionally reversed C-ß-d-glucopyranosyl imidazoles fused by pyridine, pyrimidine, thiazole, 1,3,4-thiadiazole, benzothiazole and benzimidazole. O-Debenzoylation of the above compounds was effected by standard transesterification to get the test compounds. The 1H-imidazo[4,5-b]pyridine proved to be a low micromolar inhibitor (Ki = 21.1 µM) of rabbit muscle glycogen phosphorylase b, while the other heterocycles displayed weak or no inhibition against the same enzyme.


Assuntos
Inibidores Enzimáticos/síntese química , Glicogênio Fosforilase Muscular/antagonistas & inibidores , Imidazóis/síntese química , Piridinas/síntese química , Animais , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Esterificação , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/química , Compostos Heterocíclicos/farmacologia , Imidazóis/química , Imidazóis/farmacologia , Estrutura Molecular , Pirazóis/química , Piridinas/química , Piridinas/farmacologia , Coelhos , Relação Estrutura-Atividade
13.
Molecules ; 23(3)2018 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-29543771

RESUMO

The aim of the present study was to broaden the structure-activity relationships of C- and N-ß-d-glucopyranosyl azole type inhibitors of glycogen phosphorylase. 1-Aryl-4-ß-d-gluco-pyranosyl-1,2,3-triazoles were prepared by copper catalyzed azide-alkyne cycloadditions between O-perbenzylated or O-peracetylated ß-d-glucopyranosyl ethynes and aryl azides. 1-ß-d-Gluco-pyranosyl-4-phenyl imidazole was obtained in a glycosylation of 4(5)-phenylimidazole with O-peracetylated α-d-glucopyranosyl bromide. C-ß-d-Glucopyranosyl-N-substituted-tetrazoles were synthesized by alkylation/arylation of O-perbenzoylated 5-ß-d-glucopyranosyl-tetrazole or from a 2,6-anhydroheptose tosylhydrazone and arenediazonium salts. 5-Substituted tetrazoles were glycosylated by O-peracetylated α-d-glucopyranosyl bromide to give N-ß-d-glucopyranosyl-C-substituted-tetrazoles. Standard deprotections gave test compounds which were assayed against rabbit muscle glycogen phosphorylase b. Most of the compounds proved inactive, the best inhibitor was 2-ß-d-glucopyranosyl-5-phenyltetrazole (IC50 600 µM). These studies extended the structure-activity relationships of ß-d-glucopyranosyl azole type inhibitors and revealed the extreme sensitivity of such type of inhibitors towards the structure of the azole moiety.


Assuntos
Inibidores Enzimáticos/síntese química , Glicogênio Fosforilase Muscular/antagonistas & inibidores , Triazóis/síntese química , Animais , Reação de Cicloadição , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Estrutura Molecular , Coelhos , Relação Estrutura-Atividade , Triazóis/química , Triazóis/farmacologia
14.
Eur J Med Chem ; 147: 266-278, 2018 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-29453094

RESUMO

3-(ß-d-Glucopyranosyl)-5-substituted-1,2,4-triazoles have been revealed as an effective scaffold for the development of potent glycogen phosphorylase (GP) inhibitors but with the potency very sensitive to the nature of the alkyl/aryl 5-substituent (Kun et al., Eur. J. Med. Chem. 2014, 76, 567). For a training set of these ligands, quantum mechanics-polarized ligand docking (QM-PLD) demonstrated good potential to identify larger differences in potencies (predictive index PI = 0.82) and potent inhibitors with Ki's < 10 µM (AU-ROC = 0.86). Accordingly, in silico screening of 2335 new analogues exploiting the ZINC docking database was performed and nine predicted candidates selected for synthesis. The compounds were prepared in O-perbenzoylated forms by either ring transformation of 5-ß-d-glucopyranosyl tetrazole by N-benzyl-arenecarboximidoyl chlorides, ring closure of C-(ß-d-glucopyranosyl)formamidrazone with aroyl chlorides, or that of N-(ß-d-glucopyranosylcarbonyl)arenethiocarboxamides by hydrazine, followed by deprotections. Kinetics experiments against rabbit muscle GPb (rmGPb) and human liver GPa (hlGPa) revealed five compounds as potent low µM inhibitors with three of these on the submicromolar range for rmGPa. X-ray crystallographic analysis sourced the potency to a combination of favorable interactions from the 1,2,4-triazole and suitable aryl substituents in the GP catalytic site. The compounds also revealed promising calculated pharmacokinetic profiles.


Assuntos
Inibidores Enzimáticos/farmacologia , Glicogênio Fosforilase/antagonistas & inibidores , Teoria Quântica , Triazóis/farmacologia , Células CACO-2 , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Glicogênio Fosforilase/metabolismo , Humanos , Cinética , Ligantes , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade , Triazóis/síntese química , Triazóis/química
15.
Bioorg Chem ; 77: 485-493, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29454281

RESUMO

Human liver glycogen phosphorylase (hlGP), a key enzyme in glycogen metabolism, is a valid pharmaceutical target for the development of new anti-hyperglycaemic agents for type 2 diabetes. Inhibitor discovery studies have focused on the active site and in particular on glucopyranose based compounds with a ß-1 substituent long enough to exploit interactions with a cavity adjacent to the active site, termed the ß-pocket. Recently, C-ß-d-glucopyranosyl imidazoles and 1, 2, 4-triazoles proved to be the best known glucose derived inhibitors of hlGP. Here we probe the ß-pocket by studying the inhibitory effect of six different groups at the para position of 3-(ß-d-glucopyranosyl phenyl)-5-phenyl-, 1, 2, 4-triazoles in hlGP by kinetics and X-ray crystallography. The most bioactive compound was the one with an amine substituent to show a Ki value of 0.43 µM. Structural studies have revealed the physicochemical diversity of the ß-pocket providing information for future rational inhibitor design studies.


Assuntos
Inibidores Enzimáticos/farmacologia , Glicogênio Fosforilase/antagonistas & inibidores , Fígado/enzimologia , Triazóis/farmacologia , Animais , Domínio Catalítico/efeitos dos fármacos , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Glicogênio Fosforilase/isolamento & purificação , Glicogênio Fosforilase/metabolismo , Humanos , Cinética , Modelos Moleculares , Estrutura Molecular , Coelhos , Relação Estrutura-Atividade , Triazóis/síntese química , Triazóis/química
16.
Br J Pharmacol ; 175(2): 301-319, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28409826

RESUMO

BACKGROUND AND PURPOSE: Glycogen phosphorylase (GP) is the key enzyme for glycogen degradation. GP inhibitors (GPi-s) are glucose lowering agents that cause the accumulation of glucose in the liver as glycogen. Glycogen metabolism has implications in beta cell function. Glycogen degradation can maintain cellular glucose levels, which feeds into catabolism to maintain insulin secretion, and elevated glycogen degradation levels contribute to glucotoxicity. The purpose of this study was to assess whether influencing glycogen metabolism in beta cells by GPi-s affects the function of these cells. EXPERIMENTAL APPROACH: The effects of structurally different GPi-s were investigated on MIN6 insulinoma cells and in a mouse model of diabetes. KEY RESULTS: GPi treatment increased glycogen content and, consequently, the surface area of glycogen in MIN6 cells. Furthermore, GPi treatment induced insulin receptor ß (InsRß), Akt and p70S6K phosphorylation, as well as pancreatic and duodenal homeobox 1(PDX1) and insulin expression. In line with these findings, GPi-s enhanced non-stimulated and glucose-stimulated insulin secretion in MIN6 cells. The InsRß was shown to co-localize with glycogen particles as confirmed by in silico screening, where components of InsR signalling were identified as glycogen-bound proteins. GPi-s also activated the pathway of insulin secretion, indicated by enhanced glycolysis, mitochondrial oxidation and calcium signalling. Finally, GPi-s increased the size of islets of Langerhans and improved glucose-induced insulin release in mice. CONCLUSION AND IMPLICATIONS: These data suggest that GPi-s also target beta cells and can be repurposed as agents to preserve beta cell function or even ameliorate beta cell dysfunction in different forms of diabetes. LINKED ARTICLES: This article is part of a themed section on Inventing New Therapies Without Reinventing the Wheel: The Power of Drug Repurposing. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.2/issuetoc.


Assuntos
Glicogênio Fosforilase/antagonistas & inibidores , Células Secretoras de Insulina/efeitos dos fármacos , Animais , Sinalização do Cálcio/efeitos dos fármacos , Células Cultivadas , Glicogênio/metabolismo , Glicólise/efeitos dos fármacos , Insulina/metabolismo , Ilhotas Pancreáticas/efeitos dos fármacos , Masculino , Camundongos , Mitocôndrias/metabolismo , Receptor de Insulina/metabolismo
17.
J Med Chem ; 60(22): 9251-9262, 2017 11 22.
Artigo em Inglês | MEDLINE | ID: mdl-28925695

RESUMO

Aryl substituted 1-(ß-d-glucosaminyl)-1,2,3-triazoles as well as C-ß-d-glucosaminyl 1,2,4-triazoles and imidazoles were synthesized and tested as inhibitors against muscle and liver isoforms of glycogen phosphorylase (GP). While the N-ß-d-glucosaminyl 1,2,3-triazoles showed weak or no inhibition, the C-ß-d-glucosaminyl derivatives had potent activity, and the best inhibitor was the 2-(ß-d-glucosaminyl)-4(5)-(2-naphthyl)-imidazole with a Ki value of 143 nM against human liver GPa. An X-ray crystallography study of the rabbit muscle GPb inhibitor complexes revealed structural features of the strong binding and offered an explanation for the differences in inhibitory potency between glucosyl and glucosaminyl derivatives and also for the differences between imidazole and 1,2,4-triazole analogues.


Assuntos
Glucosamina/análogos & derivados , Glicogênio Fosforilase/antagonistas & inibidores , Imidazóis/farmacologia , Triazóis/farmacologia , Animais , Cristalografia por Raios X , Glucosamina/síntese química , Glucosamina/farmacologia , Humanos , Ligação de Hidrogênio , Imidazóis/síntese química , Cinética , Fígado/enzimologia , Músculo Esquelético/enzimologia , Domínios Proteicos , Coelhos , Relação Estrutura-Atividade , Triazóis/síntese química
18.
J Struct Biol ; 199(1): 57-67, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28483603

RESUMO

3-(C-Glucopyranosyl)-5aryl-1,2,4-triazoles with an aryl moiety larger than phenyl have been shown to have strong inhibitory potency (Ki values in the range of upper nM) for human liver glycogen phosphorylase (hlGP), a pharmacologically relevant target for diabetes type 2. In this study we investigate in a comparative manner the inhibitory effect of the above triazoles and their respective imidazoles on hlGPa. Kinetic studies show that the imidazole derivatives are 6-8 times more potent than their corresponding triazoles. We also seek to answer how the type of the aryl moiety affects the potency in hlGPa, and by determination of the crystal structure of rmGPb in complex with the triazole derivatives the structural basis of their inhibitory efficacy is also elucidated. Our studies revealed that the van der Waals interactions between the aryl moiety and residues in a hydrophobic pocket within the active site are mainly responsible for the variations in the potency of these inhibitors.


Assuntos
Glicogênio Fosforilase/antagonistas & inibidores , Triazóis/farmacologia , Sítios de Ligação , Domínio Catalítico , Cristalografia por Raios X , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores Enzimáticos/farmacologia , Humanos , Interações Hidrofóbicas e Hidrofílicas , Imidazóis/farmacologia , Cinética , Fígado/enzimologia
19.
Chem Rev ; 117(3): 1687-1764, 2017 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-28121130

RESUMO

This Review summarizes close to 500 primary publications and surveys published since 2000 about the syntheses and diverse bioactivities of C-glycopyranosyl (het)arenes. A classification of the preparative routes to these synthetic targets according to methodologies and compound categories is provided. Several of these compounds, regardless of their natural or synthetic origin, display antidiabetic properties due to enzyme inhibition (glycogen phosphorylase, protein tyrosine phosphatase 1B) or by inhibiting renal sodium-dependent glucose cotransporter 2 (SGLT2). The latter class of synthetic inhibitors, very recently approved as antihyperglycemic drugs, opens new perspectives in the pharmacological treatment of type 2 diabetes. Various compounds with the C-glycopyranosyl (het)arene motif were subjected to biological studies displaying among others antioxidant, antiviral, antibiotic, antiadhesive, cytotoxic, and glycoenzyme inhibitory effects.


Assuntos
Hidrocarbonetos/química , Hipoglicemiantes/farmacologia , Glicosilação
20.
Eur J Med Chem ; 123: 737-745, 2016 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-27522507

RESUMO

C-ß-d-Glucopyranosyl pyrrole derivatives were prepared in the reactions of pyrrole, 2-, and 3-aryl-pyrroles with O-peracetylated ß-d-glucopyranosyl trichloroacetimidate, while 2-(ß-d-glucopyranosyl) indole was obtained by a cross coupling of O-perbenzylated ß-d-glucopyranosyl acetylene with N-tosyl-2-iodoaniline followed by spontaneous ring closure. An improved synthesis of O-perbenzoylated 2-(ß-d-glucopyranosyl) imidazoles was achieved by reacting C-glucopyranosyl formimidates with α-aminoketones. The deprotected compounds were assayed with isoforms of glycogen phosphorylase (GP) to show no activity of the pyrroles against rabbit muscle GPb. The imidazoles proved to be the best known glucose derived inhibitors of not only the muscle enzymes (both a and b) but also of the pharmacologically relevant human liver GPa (Ki = 156 and 26 nM for the 4(5)-phenyl and -(2-naphthyl) derivatives, respectively). An X-ray crystallographic study of the rmGPb-imidazole complexes revealed structural features of the strong binding, and also allowed to explain the absence of inhibition for the pyrrole derivatives.


Assuntos
Glicogênio Fosforilase/antagonistas & inibidores , Glicogênio Fosforilase/química , Imidazóis/química , Imidazóis/farmacologia , Fígado/enzimologia , Pirróis/química , Pirróis/farmacologia , Animais , Técnicas de Química Sintética , Cristalografia por Raios X , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Glicogênio Fosforilase/metabolismo , Humanos , Cinética , Modelos Moleculares , Conformação Proteica , Coelhos , Relação Estrutura-Atividade
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