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Current treatments for type 2 diabetes (T2D) mainly rely on exercise, dietary control, and anti-diabetic drugs to enhance insulin secretion and improve insulin sensitivity. However, there is a need for more therapeutic options. A potential target that has attracted attention is the protein tyrosine phosphatase 1B (PTP1B), which negatively regulates the insulin signaling pathway. In this work, a comprehensive computational screening was carried out using cheminformatics and molecular docking on PTP1B, employing a rigorous repurposing approach. The screening involved approved drugs and compounds under research as anti-diabetics that bind to targets such as peroxisome proliferator-activated receptor gamma (PPAR-gamma) and alpha-glucosidase. Some computational hits were then meticulously tested in vitro against PTP1B; particularly the 13-cis-retinoic acid ( 3a) showed an IC 50 of 0.044 mM and competitive inhibition. Molecular dynamics studies agrees that 3a can bind to the catalytic binding site of PTP1B. It is worth mentioning that 3a has been reported by the first time as an inhibitor of PTP1B in this work, making it a potentially valuable candidate for further studies in D2T treatment.
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Ilama leaves are an important source of secondary metabolites with promising anticancer properties. Cancer is a disease that affects a great number of people worldwide. This work aimed to investigate the in vivo, in vitro and in silico anticancer properties of three acyclic terpenoids (geranylgeraniol, phytol and farnesyl acetate) isolated from petroleum ether extract of ilama leaves. Their cytotoxic activity against U-937 cells was assessed using flow cytometry to determine the type of cell death and production of reactive oxygen species (ROS). Also, a morphological analysis of the lymph nodes and a molecular docking study using three proteins related with cancer as targets, namely, Bcl-2, Mcl-1 and VEGFR-2, were performed. The flow cytometry and histomorphological analysis revealed that geranylgeraniol, phytol and farnesyl acetate induced the death of U-937 cells by late apoptosis and necrosis. Geranylgeraniol and phytol induced a significant increase in ROS production. The molecular docking studies showed that geranylgeraniol had more affinity for Bcl-2 and VEGFR-2. In the case of farnesyl acetate, it showed the best affinity for Mcl-1. This study provides information that supports the anticancer potential of geranylgeraniol, phytol and farnesyl acetate as compounds for the treatment of cancer, particularly with the potential to treat non-Hodgkin's lymphoma.
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Simulação de Acoplamento Molecular , Extratos Vegetais , Folhas de Planta , Plantas Medicinais , Espécies Reativas de Oxigênio , Humanos , Folhas de Planta/química , Plantas Medicinais/química , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/química , México , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Animais , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Simulação por Computador , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Células U937RESUMO
Valproic acid (VPA) is a drug that has various therapeutic applications; however, it has been associated with liver damage. Furthermore, it is interesting to propose new compounds derived from VPA as N-(2-hydroxyphenyl)-2-propylpentanamide (HO-AAVPA). The HO-AAVPA has better antiproliferative activity than the VPA in different cancer cell lines. The purpose of this study was to evaluate the liver injury of HO-AAVPA by acute treatment (once administration) and repeated doses for 7 days under intraperitoneal administration. The median lethal dose value (LD50) was determined in rats and mice (females and males) using OECD Guideline 425. In the study, male rats were randomly divided into 4 groups (n = 7), G1: control (without treatment), G2: vehicle, G3: VPA (500 mg/kg), and G4: HO-AAVPA (708 mg/kg, in equimolar ratio to VPA). Some biomarkers related to hepatotoxicity were evaluated. In addition, macroscopic and histological studies were performed. The LD50 value of HO-AAVPA was greater than 2000 mg/kg. Regarding macroscopy and biochemistry, the HO-AAVPA does not induce liver injury according to the measures of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, glutathione peroxidase, glutathione reductase, and catalase activities. Comparing the treatment with HO-AAVPA and VPA did not show a significant difference with the control group, while malondialdehyde and glutathione-reduced levels in the group treated with HO-AAVPA were close to those of the control (p ≤ 0.05). The histological study shows that liver lesions caused by HO-AAVPA were less severe compared with VPA. Therefore, it is suggested that HO-AAVPA does not induce hepatotoxicity at therapeutic doses, considering that in the future it could be proposed as an antineoplastic drug.
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Doença Hepática Induzida por Substâncias e Drogas , Neoplasias , Masculino , Feminino , Animais , Camundongos , Ratos , Ácido Valproico/efeitos adversos , Glutationa , Doença Hepática Induzida por Substâncias e Drogas/etiologiaRESUMO
Annona macroprophyllata Donn (A. macroprophyllata) is used in traditional Mexican medicine for the treatment of cancer, diabetes, inflammation, and pain. In this work, we evaluated the antitumor activity of three acyclic terpenoids obtained from A. macroprophyllata to assess their potential as antilymphoma agents. We identified the terpenoids farnesyl acetate (FA), phytol (PT) and geranylgeraniol (Gg) using gas chromatography-mass spectroscopy (GC-MS) and spectroscopic (1H, and 13C NMR) methods applied to petroleum ether extract of leaves from A. macroprophyllata (PEAm). We investigated antitumor potential in Balb/c mice inoculated with U-937 cells by assessing brine shrimp lethality (BSL), and cytotoxic activity in these cells. In addition, to assess the potential toxicity of PEAm, FA, PT and Gg in humans, we tested their acute oral toxicity in mice. Our results showed that the three terpenoids exhibited considerable antilymphoma and cytotoxic activity. In terms of lethality, we determined a median lethal dose (LD50) for thirteen isolated products of PEAm. Gg, PT and AF all exhibited a higher lethality with values of 1.41 ± 0.42, 3.03 ± 0.33 and 5.82 ± 0.58 µg mL-1, respectively. To assess cytotoxic activity against U-937 cells, we calculated the mean cytotoxic concentration (CC50) and found that FA and PT were closer in respect to the control drug methotrexate (MTX, 0.243 ± 0.007 µM). In terms of antilymphoma activity, we found that FA, PT and Gg considerably inhibited lymph node growth, with median effective doses (ED50) of 5.89 ± 0.39, 6.71 ± 0.31 and 7.22 ± 0.51 mg kg-1 in females and 5.09 ± 0.66, 5.83 ± 0.50 and 6.98 ± 0.57mg kg -1 in males, respectively. Regarding acute oral toxicity, we classified all three terpenoids as category IV, indicating a high safety margin for human administration. Finally, in a molecular docking study of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, we found binding of terpenoids to some amino acids of the catalytic site, suggesting an effect upon activity with a resulting decrease in the synthesis of intermediates involved in the prenylation of proteins involved in cancer progression. Our findings suggest that the acyclic terpenoids FA, PT, and Gg may serve as scaffolds for the development of new treatments for non-Hodgkin's lymphoma.
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Annona , Antineoplásicos , Masculino , Feminino , Camundongos , Humanos , Animais , Annona/química , Terpenos/farmacologia , Simulação de Acoplamento Molecular , Metotrexato , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Antineoplásicos/farmacologia , Fitol , AminoácidosRESUMO
Breast cancer (BC) is the most frequently diagnosed cancer and is the second-most common cause of death in women worldwide. Because of this, the search for new drugs and targeted therapy to treat BC is an urgent and global need. Histone deacetylase 6 (HDAC6) is a promising anti-BC drug target associated with its development and progression. In the present work, the design and synthesis of a new family of dihydropyrazole-carbohydrazide derivatives (DPCH) derivatives focused on HDAC6 inhibitory activity is presented. Computational chemistry approaches were employed to rationalize the design and evaluate their physicochemical and toxic-biological properties. The new family of nine DPCH was synthesized and characterized. Compounds exhibited optimal physicochemical and toxicobiological properties for potential application as drugs to be used in humans. The in silico studies showed that compounds with -Br, -Cl, and -OH substituents had good affinity with the catalytic domain 2 of HDAC6 like the reference compounds. Nine DPCH derivatives were assayed on MCF-7 and MDA-MB-231 BC cell lines, showing antiproliferative activity with IC50 at µM range. Compound 2b showed, in vitro, an IC50 value of 12 ± 3 µM on human HDAC6. The antioxidant activity of DPCH derivatives showed that all the compounds exhibit antioxidant activity similar to that of ascorbic acid. In conclusion, the DPCH derivatives are promising drugs with therapeutic potential for the epigenetic treatment of BC, with low cytotoxicity towards healthy cells and important antioxidant activity.
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Compound 5-{[(2E)-3-bromo-3-carboxyprop-2-enoyl]amino}-2-hydroxybenzoic acid (C1), a new 5-aminosalicylic acid (5-ASA) derivative, has proven to be an antioxidant in vitro and an anti-inflammatory agent in mice. The in vivo inhibition of myeloperoxidase was comparable to that of indomethacin. The aim of this study was to take another step in the preclinical evaluation of C1 by examining acute toxicity with the up-and-down OECD method and pharmacokinetic profiles by administration of the compound to Wistar rats through intravenous (i.v.), oral (p.o.), and intraperitoneal (i.p.) routes. According to the Globally Harmonized System, C1 belongs to categories 4 and 5 for the i.p. and p.o. routes, respectively. An RP-HPLC method for C1 quantification in plasma was successfully validated. Regarding the pharmacokinetic profile, the elimination half-life was approximately 0.9 h with a clearance of 24 mL/min after i.v. administration of C1 (50 mg/kg). After p.o. administration (50 mg/kg), the maximum plasma concentration was reached at 33 min, the oral bioavailability was about 77%, and the compound was amply distributed to all tissues evaluated. Therefore, C1 administered p.o. in rats is suitable for reaching the colon where it can exert its effect, suggesting an important advantage over 5-ASA and indomethacin in treating ulcerative colitis and Crohn's disease.
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Ácidos Aminossalicílicos/farmacocinética , Ácidos Aminossalicílicos/toxicidade , Anti-Inflamatórios não Esteroides/farmacocinética , Anti-Inflamatórios não Esteroides/toxicidade , Ácidos Aminossalicílicos/química , Animais , Anti-Inflamatórios não Esteroides/química , Disponibilidade Biológica , Colite Ulcerativa/tratamento farmacológico , Doença de Crohn/tratamento farmacológico , Avaliação Pré-Clínica de Medicamentos , Feminino , Hidroxibenzoatos/química , Hidroxibenzoatos/farmacocinética , Hidroxibenzoatos/toxicidade , Dose Letal Mediana , Masculino , Ratos , Ratos Wistar , Distribuição TecidualRESUMO
Myeloperoxidase (MPO) is an enzyme present in human neutrophils, whose main role is to provide defenses against invading pathogens. However, highly reactive oxygen species (ROS), such as HOCl, are generated from MPO activity, leading to chronic diseases. Herein, we report the microwave-assisted synthesis of a new series of stable (E)-(2-hydroxy)-α-aminocinnamic acids, in good yields, which are structurally analogous to the natural products (Z)-2-hydroxycinnamic acids. The radical scavenging activity (RSA), MPO inhibitory activity and cytotoxicity of the reported compounds were evaluated. The hydroxy derivatives showed the most potent RSA, reducing the presence of DPPH and ABTS radicals by 77% at 0.32 mM and 100% at 0.04 mM, respectively. Their mechanism of action was modeled with BDEOH, IP and ΔEH-L theoretical calculations at the B3LYP/6 - 31 + G(d,p) level. Compounds showed in vitro inhibitory activity of MPO with IC50 values comparable to indomethacin and 5-ASA, but cytotoxicities below 15% at 100-200 µM. Docking calculations revealed that they reach the amino acid residues present in the distal cavity of the MPO active site, where both the amino and carboxylic acid groups of the α-aminopropenoic acid arm are structural requirements for anchoring. (E)-2-hydroxy-α-aminocinnamic acids have been synthesized for the first time with a reliable method and their antioxidant properties demonstrated.
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Thiazolidinediones (TZDs), used to treat type 2 diabetes mellitus, act as full agonists of the peroxisome proliferator-activated receptor gamma. Unfortunately, they produce adverse effects, including weight gain, hepatic toxicity, and heart failure. Our group previously reported the design, synthesis, in silico evaluation, and acute oral toxicity test of two TZD derivatives, compounds 40 (C40) and 81 (C81), characterized as category 5 and 4, respectively, under the Globally Harmonized System. The aim of this study was to determine whether C40, C81, and a new compound, C4, act as euglycemic and antioxidant agents in male Wistar rats with streptozotocin-induced diabetes. The animals were randomly divided into six groups (n = 7): the control, those with diabetes and untreated, and those with diabetes and treated with pioglitazone, C40, C81, or C4 (daily for 21 days). At the end of the experiment, tissue samples were collected to quantify the level of glucose, insulin, triglycerides, total cholesterol, and liver enzymes, as well as enzymatic and nonenzymatic antioxidant activity. C4, without a hypoglycemic effect, displayed the best antioxidant activity. Whereas C81 could only attenuate the elevated level of blood glucose, C40 generated euglycemia by the end of the treatment. All compounds produced a significant decrease in triglycerides.
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N-(2'-hydroxyphenyl)-2-propylpentanamide (HO-AAVPA) is a VPA derivative designed to be a histone deacetylase (HDAC) inhibitor. HO-AAVPA has better antiproliferative effect than VPA in cancer cell lines. Therefore, in this work, the inhibitory effect of HO-AAVPA on HDAC1, HDAC6, and HDAC8 was determined by in silico and in vitro enzymatic assay. Furthermore, its antiproliferative effect on the cervical cancer cell line (SiHa) and the translocation of HMGB1 and ROS production were evaluated. The results showed that HO-AAVPA inhibits HDAC1, which could be related with HMGB1 translocation from the nucleus to the cytoplasm due to HDAC1 being involved in the deacetylation of HMGB1. Furthermore, an increase in ROS production was observed after the treatment with HO-AAVPA, which also could contribute to HMGB1 translocation. Therefore, the results suggest that one of the possible antiproliferative mechanisms of HO-AAVPA is by HDAC1 inhibition which entails HMGB1 translocation and ROS increased levels that could trigger the cell apoptosis.
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Amidas/farmacologia , Antineoplásicos/farmacologia , Proteína HMGB1/metabolismo , Histona Desacetilase 1/metabolismo , Inibidores de Histona Desacetilases/farmacologia , Pentanos/farmacologia , Neoplasias do Colo do Útero/metabolismo , Transporte Ativo do Núcleo Celular/efeitos dos fármacos , Amidas/química , Antineoplásicos/química , Sítios de Ligação , Linhagem Celular Tumoral , Núcleo Celular/metabolismo , Proliferação de Células/efeitos dos fármacos , Feminino , Histona Desacetilase 1/antagonistas & inibidores , Histona Desacetilase 1/química , Inibidores de Histona Desacetilases/química , Humanos , Simulação de Acoplamento Molecular , Pentanos/química , Ligação ProteicaRESUMO
Annona diversifolia Safford and two acyclic terpenoids were evaluated to determine their antihyperglycemic activity as potential α-glucosidase and selective SGLT-1 inhibitiors. Ethanolic extract (EEAd), chloroformic (CHCl3Fr), ethyl acetate (EtOAcFr), aqueous residual (AcRFr), secondary 5 (Fr5) fractions, farnesal (1), and farnesol (2) were evaluated on normoglycemic and streptozocin-induced diabetic mice. EEAd, CHCl3Fr, Fr5, (1) and (2) showed antihyperglycemic activity. The potential as α-glucosidase inhibitors of products was evaluated with oral sucrose and lactose tolerance (OSTT and OLTT, respectively) and intestinal sucrose hydrolysis (ISH) tests; the potential as SGLT-1 inhibitors was evaluated using oral glucose tolerance (OGTT), intestinal glucose absorption (IGA), and urinary glucose excretion (UGE) tests. In OSTT and OLTT, all treatments showed significant activity at two and four hours. In ISH, half maximal effective concentrations (CE50) of 565, 662 and 590 µg/mL, 682 and 802 µM were calculated, respectively. In OGTT, all treatments showed significant activity at two hours. In IGA, CE50 values of 1059, 783 and 539 µg/mL, 1211 and 327 µM were calculated, respectively. In UGE Fr5, (1) and (2) showed significant reduction of the glucose excreted compared with canagliflozin. These results suggest that the antihyperglycemic activity is mediated by α-glucosidase and selective SGLT-1 inhibition.