RESUMO
The search for new drugs for the treatment of leishmaniasis is an important strategy for improving the current therapeutic arsenal for the disease. There are several limitations to the available drugs including high toxicity, low efficacy, prolonged parenteral administration, and high costs. Steroids are a diverse group of compounds with various applications in pharmacology. However, the antileishmanial activity of this class of molecules has not yet been explored. Therefore, in the present study, we investigated the antileishmanial activity and cytotoxicity of novel steroids against murine macrophages with a focus on the derivatives of cholesterol (CD), cholic acid (CA), and deoxycholic acid (DA). Furthermore, the mechanism of action of the best compound was assessed, and in silico studies to evaluate the physicochemical and pharmacokinetic properties were also conducted. Among the sixteen derivatives, schiffbase2, CD2 and deoxycholic acid derivatives (DOCADs) were effective against promastigotes of Leishmania species. Despite their low toxicity to macrophages, the majority of DOCADs were active against intracellular amastigotes of L. amazonensis, and DOCAD5 exhibited the best biological effect against these parasitic stages (IC50 = 15.34 µM). Neither the CA derivatives (CAD) nor DA alone inhibited the intracellular parasites. Thus, the absence of hydroxyl in the C-7 position of the steroid nucleus, as well as the modification of the acid group in DOCADs were considered important for antileishmanial activity. The treatment of L. amazonensis promastigote forms with DOCAD5 induced biochemical changes such as depolarization of the mitochondrial membrane potential, increased ROS production and cell cycle arrest. No alterations in parasite plasma membrane integrity were observed. In silico physicochemical and pharmacokinetic studies suggest that DOCAD5 could be a good candidate for an oral drug. The data demonstrate the potential antileishmanial effect of certain steroid derivatives and encourage new in vivo studies.
Assuntos
Colesterol/farmacologia , Ácido Desoxicólico/farmacologia , Descoberta de Drogas/métodos , Leishmania/efeitos dos fármacos , Leishmaniose/tratamento farmacológico , Macrófagos Peritoneais/efeitos dos fármacos , Tripanossomicidas/farmacologia , Administração Oral , Animais , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Colesterol/análogos & derivados , Colesterol/síntese química , Colesterol/farmacocinética , Ácido Cólico/síntese química , Ácido Cólico/farmacocinética , Ácido Cólico/farmacologia , Ácido Desoxicólico/análogos & derivados , Ácido Desoxicólico/síntese química , Ácido Desoxicólico/farmacocinética , Relação Dose-Resposta a Droga , Leishmania/crescimento & desenvolvimento , Leishmania/metabolismo , Leishmaniose/parasitologia , Macrófagos Peritoneais/parasitologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Modelos Biológicos , Estrutura Molecular , Estresse Oxidativo/efeitos dos fármacos , Testes de Sensibilidade Parasitária , Relação Estrutura-Atividade , Tripanossomicidas/síntese química , Tripanossomicidas/farmacocinéticaRESUMO
An improved synthesis route for obtaining known brassinosteroid analogues, i.e., methyl 2α,3α-dihydroxy-6-oxo-5α-cholan-24-oate (11), methyl 3α-hydroxy-6-oxo-7-oxa-5α-cholan-24-oate (15) and methyl 3α-hydroxy-6-oxa-7-oxo-5α-cholan-24-oate (16), from hyodeoxycholic acid (4) maintaining the native side chain is described. In the alternative procedure, the di-oxidized product 6, obtained in the oxidation of methyl hyodeoxycholate 5, was converted almost quantitatively into the target monoketone 7 by stereoselective reduction with NaBH4, increasing the overall yield of this synthetic route to 96.8%. The complete ¹H- and (13)C-NMR assignments for all compounds synthesized in this work have been made by 1D and 2D heteronuclear correlation gs-HSQC and gs-HMBC techniques. Thus, it was possible to update the spectroscopic information of ¹H-NMR and to accomplish a complete assignment of all (13)C-NMR signals for analogues 5-16, which were previously reported only in partial form.
Assuntos
Ácido Desoxicólico , Fitosteróis/química , Fitosteróis/síntese química , Ácido Desoxicólico/análogos & derivados , Ácido Desoxicólico/química , Espectroscopia de Ressonância MagnéticaRESUMO
The hydrophilic bile acid ursodeoxycholic acid (UDCA) has recently been shown to improve indexes of liver function in adult patients with various liver diseases. The clinical and biochemical responses to UDCA administration (10 to 15 mg/kg body weight per day) were therefore investigated in nine patients with cystic fibrosis and evidence of liver disease. All patients were receiving pancreatic enzymes and taurine supplementation. Liver function tests were done and serum bile acid concentrations and biliary bile acid composition were determined before and during UDCA therapy; fat balance studies and fecal bile acid excretion were carried out before and 6 months after UDCA treatment. After 2 months of bile acid therapy, biliary bile acid composition was enriched in UDCA from approximately 5% before treatment to 25%, at the expense of cholic and chenodeoxycholic acids, thus making the pool more hydrophilic. This enrichment is lower than that reported for adults with chronic liver diseases. Serum concentrations of UDCA increased significantly but variably. UDCA became the predominant fecal bile acid excreted (12% to 67%), indicating a variable absorption of the administered bile acid. Liver function improved in all patients after 2 to 6 months of therapy, although the degree of improvement (aspartate aminotransferase, -34%; alanine aminotransferase, -41%; gamma-glutamyltranspeptidase, -41% alkaline phosphatase, -19%) was lower than that observed in adults with chronic liver diseases. Mean coefficient of fat absorption and growth rate were, on average, unaffected by UDCA therapy, although an improvement was noted for three patients with greater severity of steatorrhea. The study indicates that UDCA can be used safely in this patient population but that higher doses of UDCA may be of greater benefit in the treatment of the liver disease associated with cystic fibrosis.
Assuntos
Fibrose Cística/complicações , Ácido Desoxicólico/análogos & derivados , Hepatopatias/complicações , Ácido Ursodesoxicólico/uso terapêutico , Adolescente , Ácidos e Sais Biliares/metabolismo , Criança , Feminino , Humanos , Hepatopatias/tratamento farmacológico , Hepatopatias/enzimologia , Testes de Função Hepática , Masculino , Taurina/uso terapêutico , Ácido Ursodesoxicólico/sangueRESUMO
The modification in the composition of bile acids in hamster by the administration of high dose of ursodeoxycholic acid (UDCA) was investigated. Male Golden Syrian hamsters were divided into five groups: a control group, two groups that received 0.5 g of UDCA per 100 g of standard diet during 30 and 60 days and another two groups that received 1 g of UDCA per 100 g of standard diet during 30 and 60 days. After ether anaesthesia the gallbladder was removed and bile was immediately aspirated. Bile acids were determined by high performance liquid chromatography (HPLC). Taurolithocholic (TLCA) and glycolithocholic acids (GLCA) increased significantly in all treated groups. The glyco/tauro ratio of 0.69 in controls became more than 1 in treated animals except in the case of lithocholic acid (LCA) conjugates which remained less than 1. UDCA derivatives increased proportionally to the administered dose and the cholic/cheno ratio diminished significantly. A moderate increase of 3- and 7-keto derivatives of chenodeoxycholic acid (CDCA) was observed in all treated groups but the above mentioned increment was especially evident in 3-keto derivatives. A high percentage of UDCA administered in the hamster was likely transformed to CDCA and the glyco conjugates of the bile acids were the predominant species except for the LCA derivatives.
Assuntos
Ácidos e Sais Biliares/análise , Bile/análise , Ácido Desoxicólico/análogos & derivados , Ácido Ursodesoxicólico/farmacologia , Animais , Ácido Quenodesoxicólico/análise , Ácidos Cólicos/análise , Cromatografia Líquida de Alta Pressão , Cricetinae , Ácido Desoxicólico/análise , Relação Dose-Resposta a Droga , Esquema de Medicação , Masculino , Mesocricetus , Ácido Ursodesoxicólico/administração & dosagemAssuntos
Ácido Quenodesoxicólico/uso terapêutico , Colecistectomia , Colelitíase/terapia , Ácido Desoxicólico/análogos & derivados , Ácido Ursodesoxicólico/uso terapêutico , Animais , Colecistectomia/efeitos adversos , Colesterol/metabolismo , Neoplasias do Colo/etiologia , Feminino , Humanos , Masculino , RiscoRESUMO
22 patients with radiolucid stones and functioning gallbladder were grouped to establish ursodeoxycholic acid efficacy (i.e. gallstones dissolution) and innocuousness for gallbladder lithiasis. Methodological aspects were detailed, the dose determined (8 and 10 mg/k/d.) and the patients evaluated after a six months' treatment. 11 patients received "day-time" doses and the other 11 "overnight" dose. Only 7 subjects turned out to be evaluated for the study of biliary lipids, to the other 15 the development of their gallstones was followed up. Successful gallstone dissolution was achieved in 8 patients (53,3%), 2 reduced size and number. 5 out of these 8 patients received "day-time" doses and the other 3 "overnight" doses. From an attendance point of view, we do not consider biliary lipids study (bile cholesterol saturation rate) to be necessary.
Assuntos
Colelitíase/tratamento farmacológico , Ácido Desoxicólico/análogos & derivados , Ácido Ursodesoxicólico/uso terapêutico , Colesterol/metabolismo , Esquema de Medicação , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Ácido Ursodesoxicólico/administração & dosagemRESUMO
To investigate ursodeoxycholic acid (Urso) action on liver histology, 30 male hamsters were allocated to 2 groups of 15 animals each; one group was treated with Urso, and the other one acted as control. Thirty days later, a light and electron microscopy study of the liver of all the animals was performed. All the group receiving Urso acid revealed minimal changes consisting in hepatocytic nuclear vacuolization around the centrelobulilla area; the vacuoles were homogeneous and contained a pale basofilic material. Neither inflammatory lesions nor hepatic cell necrosis was observed. Electron microscopy showed folding of the nuclear membrane corresponding to vacuoles observed under light microscopy. Further studies must be carried out to make clear the meaning of our findings and to confirm or otherwise rectify Urso inocuity on the liver of hamsters.