RESUMO
Glycyrrhizinic acid (GA) is one of the active substances in licorice root. It exhibits antiviral activity against various enveloped viruses, for example, SARS-CoV-2. GA derivatives are promising biologically active compounds from perspective of developing broad-spectrum antiviral agents. Given that GA nicotinate derivatives (Glycyvir) demonstrate activity against various DNA- and RNA-viruses, a search for a possible mechanism of action of these compounds is required. In the present paper, the interaction of Glycyvir with the transmembrane domain of the SARS-CoV-2 E-protein (ETM) in a model lipid membrane was investigated by NMR spectroscopy and molecular dynamics simulation. The lipid-mediated influence on localization of the SARS-CoV-2 E-protein by Glycyvir was observed. The presence of Glycyvir leads to deeper immersion of the ETM in lipid bilayer. Taking into account that E-protein plays a significant role in virus production and takes part in virion assembly and budding, the data on the effect of potential antiviral agents on ETM localization and structure in the lipid environment may provide a basis for further studies of potential coronavirus E-protein inhibitors.
Assuntos
Antivirais , Ácido Glicirrízico , Bicamadas Lipídicas , Simulação de Dinâmica Molecular , SARS-CoV-2 , Bicamadas Lipídicas/metabolismo , Bicamadas Lipídicas/química , Ácido Glicirrízico/farmacologia , Ácido Glicirrízico/química , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/metabolismo , Antivirais/farmacologia , Antivirais/química , Proteínas do Envelope de Coronavírus/metabolismo , Proteínas do Envelope de Coronavírus/química , Humanos , Domínios Proteicos , Tratamento Farmacológico da COVID-19RESUMO
Chiral oxygen-containing heterocyclic compounds are of great interest for the development of pharmaceuticals. Monoterpenes and their derivatives are naturally abundant precursors of novel synthetic chiral oxygen-containing heterocyclic compounds. In this study, acid catalyzed reactions of salicylic aldehydes with (-)-8-acetoxy-6-hydroxymethyllimonene, readily accessible from α-pinene, leads to the formation of chiral polycyclic products of various structural types. Three of the six isolated chiral heterocyclic products obtained from salicylic aldehyde contain previously unknown polycyclic ring types. Having carried out the reaction in the presence of Brønsted or Lewis acids (Amberlyst 15, trifluoromethanesulfonic acid, trifluoroacetic acid and boron trifluoride etherate) or aluminosilicates (montmorillonite K10, halloysite nanotubes), we found that the nature of products depends on the catalyst as well as the reaction conditions (reaction time, reactant ratio, presence or absence of solvent). Detailed mechanistic insight on the complex cascade reactions for product formation is provided with extensive experimental and quantum mechanical computational studies.
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At the Institute of Cytology and Genetics (Novosibirsk, Russia) for over 85 generations, gray rats have been selected for high aggression toward humans (aggressive rats) or its complete absence (tame rats). Aggressive rats are an interesting model for studying fear-induced aggression. Benzopentathiepin TC-2153 exerts an antiaggressive effect on aggressive rats and affects the serotonergic system: an important regulator of aggression. The aim of this study was to investigate effects of TC-2153 on key serotonergic-system enzymes - tryptophan hydroxylase 2 (TPH2) and monoamine oxidase A (MAOA) - in the brain of aggressive and tame rats. Either TC-2153 (10 or 20 mg/kg) or vehicle was administered once intraperitoneally to aggressive and tame male rats. TPH2 and MAOA enzymatic activities and mRNA and protein levels were assessed. The selection for high aggression resulted in upregulation of Tph2 mRNA in the midbrain, of the TPH2 protein in the hippocampus, and of proteins TPH2 and MAOA in the hypothalamus, as compared to tame rats. MAO enzymatic activity was higher in the midbrain and hippocampus of aggressive rats while TPH2 activity did not differ between the strains. The single TC-2153 administration decreased TPH2 and MAO activity in the hypothalamus and midbrain, respectively. The drug affected MAOA protein levels in the hypothalamus: upregulated them in aggressive rats and downregulated them in tame ones. Thus, this study shows profound differences in the expression and activity of key serotonergic system enzymes in the brain of rats selectively bred for either highly aggressive behavior toward humans or its absence, and the effects of benzopentathiepin TC-2153 on these enzymes may point to mechanisms of its antiaggressive action.
Assuntos
Agressão , Encéfalo , Monoaminoxidase , Triptofano Hidroxilase , Animais , Triptofano Hidroxilase/metabolismo , Triptofano Hidroxilase/genética , Monoaminoxidase/metabolismo , Monoaminoxidase/genética , Ratos , Masculino , Encéfalo/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/enzimologia , Agressão/efeitos dos fármacos , Humanos , Serotonina/metabolismoRESUMO
A new series of heterocyclic derivatives with a 1,7,7-trimethylbicyclo[2.2.1]heptane fragment was designed, synthesised and biologically evaluated. Synthesis of the target compounds was performed using the Cu(I) catalysed cycloaddition reaction. The key starting substances in the click reaction were an alkyne containing a 1,7,7-trimethylbicyclo[2.2.1]heptane fragment and a series of azides with saturated nitrogen-containing heterocycles. Some of the derivatives were found to exhibit strong antiviral activity against Marburg and Ebola pseudotype viruses. Lysosomal trapping assays revealed the derivatives to possess lysosomotropic properties. The molecular modelling study demonstrated the binding affinity between the compounds investigated and the possible active site to be mainly due to hydrophobic interactions. Thus, combining a natural hydrophobic structural fragment and a lysosome-targetable heterocycle may be an effective strategy for designing antiviral agents.
Assuntos
Heptanos , Triazóis , Relação Estrutura-Atividade , Catálise , Triazóis/farmacologia , Antivirais/farmacologiaRESUMO
Tyrosyl-DNA phosphodiesterase 1 (Tdp1) is an important DNA repair enzyme and one of the causes of tumor resistance to topoisomerase 1 inhibitors such as topotecan. Inhibitors of this Tdp1 in combination with topotecan may improve the effectiveness of therapy. In this work, we synthesized usnic acid derivatives, which are hybrids of its known derivatives: tumor sensitizers to topotecan. New compounds inhibit Tdp1 in the micromolar and submicromolar concentration range; some of them enhance the effect of topotecan on the metabolic activity of cells of various lines according to the MTT test. One of the new compounds (compound 7) not only sensitizes Krebs-2 and Lewis carcinomas of mice to the action of topotecan, but also normalizes the state of the peripheral blood of mice, which is disturbed in the presence of a tumor. Thus, the synthesized substances may be the prototype of a new class of additional therapy for cancer.
Assuntos
Benzofuranos , Carcinoma , Topotecan , Animais , Camundongos , Topotecan/farmacologia , Topotecan/uso terapêutico , Inibidores de Fosfodiesterase/farmacologia , Diester Fosfórico Hidrolases/metabolismo , EsterasesRESUMO
Deoxycholic acid derivatives containing various heterocyclic functional groups at C-3 on the steroid scaffold were designed and synthesized as promising dual tyrosyl-DNA phosphodiesterase 1 and 2 (TDP1 and TDP2) inhibitors, which are potential targets to potentiate topoisomerase poison antitumor therapy. The methyl esters of DCA derivatives with benzothiazole or benzimidazole moieties at C-3 demonstrated promising inhibitory activity in vitro against TDP1 with IC50 values in the submicromolar range. Furthermore, methyl esters 4d-e, as well as their acid counterparts 3d-e, inhibited the phosphodiesterase activity of both TDP1 and TDP2. The combinations of compounds 3d-e and 4d-e with low-toxic concentrations of antitumor drugs topotecan and etoposide showed significantly greater cytotoxicity than the compounds alone. The docking of the derivatives into the binding sites of TDP1 and TDP2 predicted plausible binding modes of the DCA derivatives.
Assuntos
Inibidores de Fosfodiesterase , Diester Fosfórico Hidrolases , Inibidores de Fosfodiesterase/química , Diester Fosfórico Hidrolases/metabolismo , Modelos Moleculares , Ácido Desoxicólico/farmacologia , Relação Estrutura-AtividadeRESUMO
Metabolic syndrome is a complex of abnormalities involving impaired glucose and lipid metabolism, which needs effective pharmacotherapy. One way to reduce lipid and glucose levels associated with this pathology is the simultaneous activation of nuclear PPAR-alpha and gamma. For this purpose, we synthesized a number of potential agonists based on the pharmacophore fragment of glitazars with the inclusion of mono- or diterpenic moiety in the molecular structure. The study of their pharmacological activity in mice with obesity and type 2 diabetes mellitus (C57Bl/6Ay) revealed one substance that was capable of reducing the triglyceride levels in the liver and adipose tissue of mice by enhancing their catabolism and expressing a hypoglycemic effect connected with the sensitization of mice tissue to insulin. It has also been shown to have no toxic effects on the liver.
RESUMO
The Bdnf (brain-derived neurotrophic factor) gene contains eight regulatory exons (I-VIII) alternatively spliced to the protein-coding exon IX. Only exons I, II, IV, and VI are relatively well studied. The BDNF system and brain serotonergic system are tightly interconnected and associated with aggression. The benzopentathiepine TC-2153 affects both systems and exerts antiaggressive action. Our aim was to evaluate the effects of TC-2153 on the Bdnf exons I-IX's expressions and serotonin receptors' mRNA levels in the brain of rats featuring high aggression toward humans (aggressive) or its absence (tame). Aggressive and tame adult male rats were treated once with vehicle or 10 or 20 mg/kg of TC-2153. mRNA was quantified in the cortex, hippocampus, hypothalamus, and midbrain with real-time PCR. Selective breeding for high aggression or its absence affected the serotonin receptors' and Bdnf exons' transcripts differentially, depending on the genotype (strain) and brain region. TC-2153 had comprehensive effects on the Bdnf exons' expressions. The main trend was downregulation in the hypothalamus and midbrain. TC-2153 increased 5-HT1B receptor hypothalamusc mRNA expression. For the first time, an influence of TC-2153 on the expressions of Bdnf regulatory exons and the 5-HT1B receptor was shown, as was an association between Bdnf regulatory exons and fear-induced aggression involving genetic predisposition.
Assuntos
Fator Neurotrófico Derivado do Encéfalo , Receptor 5-HT1B de Serotonina , Humanos , Ratos , Animais , Masculino , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Receptor 5-HT1B de Serotonina/genética , Receptor 5-HT1B de Serotonina/metabolismo , Encéfalo/metabolismo , Medo/fisiologia , RNA Mensageiro/análise , Hipocampo/metabolismo , Agressão/fisiologiaRESUMO
Tyrosyl-DNA phosphodiesterase 1 (TDP1) is an important repair enzyme that removes various covalent adducts from the 3' end of DNA. Particularly, covalent complexes of topoisomerase 1 (TOP1) with DNA stabilized by DNA damage or by various chemical agents are an examples of such adducts. Anticancer drugs such as the TOP1 poisons topotecan and irinotecan are responsible for the stabilization of these complexes. TDP1 neutralizes the effect of these anticancer drugs, eliminating the DNA adducts. Therefore, the inhibition of TDP1 can sensitize tumor cells to the action of TOP1 poisons. This review contains information about methods for determining the TDP1 activity, as well as describing the inhibitors of these enzyme derivatives of natural biologically active substances, such as aminoglycosides, nucleosides, polyphenolic compounds, and terpenoids. Data on the efficiency of combined inhibition of TOP1 and TDP1 in vitro and in vivo are presented.
Assuntos
Antineoplásicos , Produtos Biológicos , Produtos Biológicos/farmacologia , Diester Fosfórico Hidrolases/metabolismo , Enzimas Reparadoras do DNA/genética , Antineoplásicos/farmacologia , Antineoplásicos/química , DNA Topoisomerases Tipo I/metabolismo , Reparo do DNA , DNARESUMO
Tyrosyl-DNA-phosphodiesterase 1 (TDP1) is a promising target for antitumor therapy; the use of TDP1 inhibitors with a topoisomerase 1 poison such as topotecan is a potential combination therapy. In this work, a novel series of 3,5-disubstituted thiazolidine-2,4-diones was synthesized and tested against TDP1. The screening revealed some active compounds with IC50 values less than 5 µM. Interestingly, compounds 20d and 21d were the most active, with IC50 values in the submicromolar concentration range. None of the compounds showed cytotoxicity against HCT-116 (colon carcinoma) and MRC-5 (human lung fibroblasts) cell lines in the 1-100 µM concentration range. Finally, this class of compounds did not sensitize cancer cells to the cytotoxic effect of topotecan.
Assuntos
Inibidores de Fosfodiesterase , Diester Fosfórico Hidrolases , Tiazolidinedionas , Humanos , Modelos Moleculares , Monoterpenos/farmacologia , Inibidores de Fosfodiesterase/farmacologia , Diester Fosfórico Hidrolases/metabolismo , Topotecan/farmacologia , Tiazolidinedionas/farmacologiaRESUMO
Free fatty acid receptor-1 (FFAR1) agonists are promising candidates for therapy of type 2 diabetes because of their ability to normalize blood sugar levels during hyperglycemia without the risk of hypoglycemia. Previously, we synthesized compound QS-528, a FFA1 receptor agonist with a hypoglycemic effect in C57BL/6NCrl mice. In the present work, structural analogs of QS-528 based on (hydroxyphenyl)propanoic acid bearing a bornyl fragment in its structure were synthesized. The seven novel compounds synthesized were structural isomers of compound QS-528, varying the positions of the substituents in the aromatic fragments as well as the configuration of the asymmetric center in the bornyl moiety. The studied compounds were shown to have the ability to activate FFAR1 at a concentration of 10 µM. The cytotoxicity of the compounds as well as their effect on glucose uptake in HepG2 cells were studied. The synthesized compounds were found to increase glucose uptake by cells and have no cytotoxic effect. Two compounds, based on the meta-substituted phenylpropanoic acid, 3-(3-(4-(((1R,2R,4R)-1,7,7-trimethylbicyclo-[2.2.1]heptan-2-ylamino)methyl)benzyloxy)phenyl)propanoic acid and 3-(3-(3-(((1R,2R,4R)-1,7,7-trimethylbicyclo [2.2.1]heptan-2-ylamino)methyl)benzyloxy)phenyl)propanoic acid, were shown to have a pronounced hypoglycemic effect in the oral glucose tolerance test with CD-1 mice.
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Diabetes Mellitus Tipo 2 , Hipoglicemiantes , Camundongos , Animais , Hipoglicemiantes/química , Diabetes Mellitus Tipo 2/tratamento farmacológico , Propionatos/farmacologia , Propionatos/química , Camundongos Endogâmicos C57BL , Receptores Acoplados a Proteínas G/agonistas , Glucose , Relação Estrutura-AtividadeRESUMO
Respiratory syncytial virus (RSV) is known to cause annual epidemics of respiratory infections; however, the lack of specific treatment options for this disease poses a challenge. In light of this, there has been a concerted effort to identify small molecules that can effectively combat RSV. This article focuses on the mechanism of action of compound K142, which was identified as a primary screening leader in the earlier stages of the project. The research conducted demonstrates that K142 significantly reduces the intensity of virus penetration into the cells, as well as the formation of syncytia from infected cells. These findings show that the compound's interaction with the surface proteins of RSV is a key factor in its antiviral activity. Furthermore, pharmacological modeling supports that K142 effectively interacts with the F-protein. However, in vivo studies have shown only weak antiviral activity against RSV infection, with a slight decrease in viral load observed in lung tissues. As a result, there is a need to enhance the bioavailability or antiviral properties of this compound. Based on these findings, we hypothesize that further modifications of the compound under study could potentially increase its antiviral activity.
Assuntos
Infecções por Vírus Respiratório Sincicial , Vírus Sincicial Respiratório Humano , Infecções Respiratórias , Humanos , Infecções por Vírus Respiratório Sincicial/tratamento farmacológico , Antivirais/farmacologia , Disponibilidade BiológicaRESUMO
Tyrosyl-DNA-phosphodiesterase 1 (TDP1) is an important enzyme in the DNA repair system. The ability of the enzyme to repair DNA damage induced by a topoisomerase 1 poison such as the anticancer drug topotecan makes TDP1 a promising target for complex antitumor therapy. In this work, a set of new 5-hydroxycoumarin derivatives containing monoterpene moieties was synthesized. It was shown that most of the conjugates synthesized demonstrated high inhibitory properties against TDP1 with an IC50 in low micromolar or nanomolar ranges. Geraniol derivative 33a was the most potent inhibitor with IC50 130 nM. Docking the ligands to TDP1 predicted a good fit with the catalytic pocket blocking access to it. The conjugates used in non-toxic concentration increased cytotoxicity of topotecan against HeLa cancer cell line but not against conditionally normal HEK 293A cells. Thus, a new structural series of TDP1 inhibitors, which are able to sensitize cancer cells to the topotecan cytotoxic effect has been discovered.
Assuntos
Antineoplásicos , Topotecan , Humanos , Topotecan/farmacologia , Inibidores de Fosfodiesterase/farmacologia , Inibidores de Fosfodiesterase/química , Relação Estrutura-Atividade , Diester Fosfórico Hidrolases/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/química , Linhagem Celular TumoralRESUMO
Topoisomerase 1 (TOP1) is an enzyme that regulates DNA topology and is essential for replication, recombination, and other processes. The normal TOP1 catalytic cycle involves the formation of a short-lived covalent complex with the 3' end of DNA (TOP1 cleavage complex, TOP1cc), which can be stabilized, resulting in cell death. This fact substantiates the effectiveness of anticancer drugs-TOP1 poisons, such as topotecan, that block the relegation of DNA and fix TOP1cc. Tyrosyl-DNA phosphodiesterase 1 (TDP1) is able to eliminate TOP1cc. Thus, TDP1 interferes with the action of topotecan. Poly(ADP-ribose) polymerase 1 (PARP1) is a key regulator of many processes in the cell, such as maintaining the integrity of the genome, regulation of the cell cycle, cell death, and others. PARP1 also controls the repair of TOP1cc. We performed a transcriptomic analysis of wild type and PARP1 knockout HEK293A cells treated with topotecan and TDP1 inhibitor OL9-119 alone and in combination. The largest number of differentially expressed genes (DEGs, about 4000 both up- and down-regulated genes) was found in knockout cells. Topotecan and OL9-119 treatment elicited significantly fewer DEGs in WT cells and negligible DEGs in PARP1-KO cells. A significant part of the changes caused by PARP1-KO affected the synthesis and processing of proteins. Differences under the action of treatment with TOP1 or TDP1 inhibitors alone were found in the signaling pathways for the development of cancer, DNA repair, and the proteasome. The drug combination resulted in DEGs in the ribosome, proteasome, spliceosome, and oxidative phosphorylation pathways.
Assuntos
Diester Fosfórico Hidrolases , Topotecan , Sistemas CRISPR-Cas , DNA , Reparo do DNA , DNA Topoisomerases Tipo I/genética , DNA Topoisomerases Tipo I/metabolismo , Esterases/metabolismo , Diester Fosfórico Hidrolases/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Topotecan/farmacologia , Transcriptoma , Poli(ADP-Ribose) Polimerase-1/metabolismoRESUMO
Two approaches to the synthesis of para-menthene epoxide ((1S,5S,6R)-4) are developed. The first approach includes a reaction between chlorohydrin 7 and NaH in THF. The second involves the formation of epoxide in the reaction of corresponding diacetate 6 with sodium tert-butoxide. One possible mechanism of this reaction is proposed to explain unexpected outcomes in the regio- and stereospecificity of epoxide (1S,5S,6R)-4 formation. The epoxide ring in (1S,5S,6R)-4 is then opened by various S- and O-nucleophiles. This series of reactions allows for the stereoselective synthesis of diverse derivatives of the monoterpenoid Prottremine 1, a compound known for its antiparkinsonian activity, including promising antiparkinsonian properties.
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Respiratory syncytial virus (RSV) causes annual epidemics of respiratory infection. Usually harmless to adults, the RSV infection can be dangerous to children under 3 years of age and elderly people over 65 years of age, often causing serious problems, even death. At present, there are no vaccines and specific chemotherapeutic agents for the treatment of this disease, so the search for low-molecular weight compounds to combat RSV is a challenge. In this work, we have shown, for the first time, that monoterpene-substituted arylcoumarins are efficient RSV replication inhibitors at low micromolar concentrations. The most active compound has a selectivity index of about 200 and acts most effectively at the early stages of infection. The F protein of RSV is a potential target for these compounds, which is also confirmed by molecular docking and molecular dynamics simulation data.
Assuntos
Infecções por Vírus Respiratório Sincicial , Vírus Sincicial Respiratório Humano , Criança , Humanos , Pré-Escolar , Idoso , Simulação de Acoplamento Molecular , Anticorpos Antivirais , Proteínas Virais de Fusão , Infecções por Vírus Respiratório Sincicial/tratamento farmacológico , Replicação ViralRESUMO
This article describes the synthesis and antiviral activity evaluation of new substituted 1,2,4-oxadiazoles containing a bicyclic substituent at position 5 of the heterocycle and O-acylated amidoximes as precursors for their synthesis. New compounds were obtained from the (+)-camphor derivative (+)-ketopinic acid. The chemical library was tested in vitro for cytotoxicity against the MDCK cell line and for antiviral activity against influenza viruses of H1N1 and H7N9 subtypes. The synthesised compounds exhibited high virus-inhibiting activity against the H1N1 influenza virus. Some synthesised compounds were also active against the influenza virus of a different antigenic subtype: H7N9. The mechanism of the virus-inhibiting activity of these compounds is based on their interference with the fusion activity of viral hemagglutinin (HA). No interference with the receptor-binding activity of HA has been demonstrated. According to molecular docking results, the selective antiviral activity of O-acylated amidoximes and 1,2,4-oxadiazoles is associated with their structural features. O-Acylated amidoximes are likely more complementary to the binding site located at the site of the fusion peptide, and 1,2,4-oxadiazoles are more complimentary to the site located at the site of proteolysis. Significant differences in the amino acid residues of the binding sites of HA's of different types allow us to explain the selective antiviral activity of the compounds under study.
Assuntos
Antivirais/farmacologia , Hidrocarbonetos Aromáticos com Pontes/farmacologia , Vírus da Influenza A Subtipo H1N1/efeitos dos fármacos , Subtipo H7N9 do Vírus da Influenza A/efeitos dos fármacos , Cetonas/farmacologia , Oxidiazóis/farmacologia , Oximas/farmacologia , Acilação , Antivirais/síntese química , Antivirais/química , Hidrocarbonetos Aromáticos com Pontes/química , Relação Dose-Resposta a Droga , Cetonas/química , Testes de Sensibilidade Microbiana , Estrutura Molecular , Oxidiazóis/síntese química , Oxidiazóis/química , Oximas/síntese química , Oximas/química , Relação Estrutura-AtividadeRESUMO
Tyrosyl-DNA phosphodiesterase 1(TDP1) is a promising target for a new therapy in oncological disease as an adjunct to topoisomerase 1 (TOP1) drugs. In this paper, novel thiazolidin-4-one derivatives with a benzyl and monoterpene substituents were synthesized. Compounds with a monoterpene fragment attached via a phenyloxy linker were active against TDP1 with IC50 values in the 1 ÷ 3 µM range, while direct attachment of monoterpene moiety to the thiazolidin-4-one fragment had no activity. Molecular modelling predicted two plausible binding modes of the active compounds both effectively blocking access to the catalytic site of TDP. At non-toxic concentrations the active ligands potentiated the efficacy of the TOP1 poison topotecan in human cervical cancer HeLa cells, but not in non-cancerous HEK293A cells.
Assuntos
Inibidores de Fosfodiesterase , Diester Fosfórico Hidrolases , Esterases/metabolismo , Células HeLa , Humanos , Monoterpenos/farmacologia , Inibidores de Fosfodiesterase/farmacologia , Diester Fosfórico Hidrolases/metabolismo , Relação Estrutura-AtividadeRESUMO
Novel 9-N-alkyltetrahydroberberine derivatives were synthesized, among which, based on the results of OGTT, one compound containing the longest aliphatic substituent was selected for study in mice C57BL/6Ay, which demonstrate obesity, impaired glucose tolerance, and concomitant liver non-alcoholic fatty disease. Administration of this substance at a dose of 15 mg/kg for four weeks improved the insulin sensitivity of mice, which resulted in a decrease in fasting glucose levels and improved the tolerance of mice to OGTT glucose loading. A decrease in the level of lactate in the blood and a decrease in the amount of glucokinase in the liver were also found. The introduction of compound 3c did not have a toxic effect on animals based on biochemical data, histological analysis, and measurements of general parameters such as body weight and feed intake. Thus, the 9-N-heptyltetrahydroberberine derivative showed prominent hypoglycemic effects, which makes it promising to obtain and study other derivatives with longer substituents.
Assuntos
Hipoglicemiantes , Insulina , Camundongos , Animais , Hipoglicemiantes/farmacologia , Camundongos Endogâmicos C57BL , Teste de Tolerância a Glucose , GlucoseRESUMO
It is known that epoxide-bearing compounds display pronounced pharmacological activities, and the epoxidation of natural metabolites can be a promising strategy to improve their bioactivity. Here, we report the design, synthesis and evaluation of biological properties of αO-SM and ßO-SM, novel epoxides of soloxolone methyl (SM), a cyanoenone-bearing derivative of 18ßH-glycyrrhetinic acid. We demonstrated that the replacement of a double-bound within the cyanoenone pharmacophore group of SM with α- and ß-epoxide moieties did not abrogate the high antitumor and anti-inflammatory potentials of the triterpenoid. It was found that novel SM epoxides induced the death of tumor cells at low micromolar concentrations (IC50(24h) = 0.7-4.1 µM) via the induction of mitochondrial-mediated apoptosis, reinforced intracellular accumulation of doxorubicin in B16 melanoma cells, probably by direct interaction with key drug efflux pumps (P-glycoprotein, MRP1, MXR1), and the suppressed pro-metastatic phenotype of B16 cells, effectively inhibiting their metastasis in a murine model. Moreover, αO-SM and ßO-SM hampered macrophage functionality in vitro (motility, NO production) and significantly suppressed carrageenan-induced peritonitis in vivo. Furthermore, the effect of the stereoisomerism of SM epoxides on the mentioned bioactivities and toxic profiles of these compounds in vivo were evaluated. Considering the comparable antitumor and anti-inflammatory effects of SM epoxides with SM and reference drugs (dacarbazine, dexamethasone), αO-SM and ßO-SM can be considered novel promising antitumor and anti-inflammatory drug candidates.