Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 20
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Steroids ; 157: 108594, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32068077

RESUMO

Five cholic acid derivatives (including allo-ω-muricholic acid and CDCA) were synthesized from hyodeoxycholic acid via selective oxidation of C3- or C6-hydroxyl groups by IBX and NBS oxidants and stereocontrolled conversion. The hydroxyl group could be introduced through hydrolyzing α-Br keto with K2CO3 aqueous solution or through oxidizing the double bond by monoperoxyphthalic acid. The reduction of C6-O6 carbonyl to methylene could undergo with PTSH, NaBH3CN and ZnCl2 only at 5ß configuration. A feasible synthetic route of CDCA from HDCA has been established to avoid the epimerization with the yield of 45% (8 steps). These strategies provided good yields, stereoselectivity and reproducibility for the preparation of cholic acid derivates and CDCA.


Assuntos
Ácido Cólico/síntese química , Ácido Desoxicólico/química , Ácido Cólico/química , Conformação Molecular , Estereoisomerismo
2.
Org Lett ; 21(11): 3994-3997, 2019 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-31140819

RESUMO

Cholic acid has been elaborated into a carbamate-based tripodal architecture, which is able to promote an asymmetric organic transformation inside its chiral cavity. The nature of this steroidal catalyst has been disclosed by quantum-chemical calculations. It comprises the preorganization and confinement of the reagents within the cavity of the steroid to form a supramolecular complex held together by means of cooperative H-bond contacts. This operational mode resembles that of some enzymes.


Assuntos
Carbamatos/química , Ácido Cólico/química , Catálise , Ácido Cólico/síntese química , Humanos , Modelos Moleculares , Conformação Molecular , Teoria Quântica , Estereoisomerismo
3.
Bioorg Med Chem Lett ; 29(11): 1330-1335, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30952591

RESUMO

A study of the structural requirements of cholic acid derivatives as liver X receptor (LXR) ligands was performed. A model of cholenamide derivative 1 complexed with LXR showed that the C24 carbonyl oxygen forms a hydrogen bond with His435 located close to Trp457. The N,N-dimethyl group is located in a hydrophobic pocket. Based on these data, we designed compounds with high affinity for LXRs. Cholenamide derivatives 1-11 were synthesized from 3ß-acetyl-Δ5-cholenic acid 20, and lactams 12-19 were synthesized from alcohol 25. Tertiary amides 3 and 4 showed higher activity in reporter assays, and compounds with hydrophobic residues exhibited the highest activity of all derivatives. The stereochemistry at C23 was found to be an important determinant of EC50 and gene transactivation, as each isomer exhibited different activity.


Assuntos
Amidas/farmacologia , Ácido Cólico/farmacologia , Receptores X do Fígado/metabolismo , Amidas/síntese química , Amidas/química , Animais , Ácido Cólico/síntese química , Ácido Cólico/química , Relação Dose-Resposta a Droga , Humanos , Ligantes , Camundongos , Estrutura Molecular , Relação Estrutura-Atividade
4.
Biomed Pharmacother ; 106: 1082-1090, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30119174

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/farmacocinética
5.
Bioorg Chem ; 80: 396-407, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29986186

RESUMO

Bile acids, initially discovered as endogenous ligands of farnesoid X receptor (FXR), play a central role in the regulation of triglyceride and cholesterol metabolism and have recently emerged as a privileged structure for interacting with nuclear receptors relevant to a large array of metabolic processes. In this paper, phenoxy containing cholic acid derivatives with excellent drug-likeness have been designed, synthesized, and assayed as agents against cholesterol accumulation in Raw264.7 macrophages. The most active compound 14b reduced total cholesterol accumulation in Raw264.7 cells up to 30.5% at non-toxic 10 µM and dosage-dependently attenuated oxLDL-induced foam cell formation. Western blotting and qPCR results demonstrate that 14b reduced both cholesterol and lipid in Raw264.7 cells through (1) increasing the expression of cholesterol transporters ABCA1 and ABCG1, (2) accelerating ApoA1-mediated cholesterol efflux. Through a cell-based luciferase reporter assay and molecular docking analysis, LXR was identified as the potential target for 14b. Interestingly, unlike conventional LXR agonist, 14b did not increase lipogenesis gene SREBP-1c expression. Overall, these diverse properties disclosed herein highlight the potential of 14b as a promising lead for further development of multifunctional agents in the therapy of cardiovascular disease.


Assuntos
Colesterol/metabolismo , Ácido Cólico/química , Ácido Cólico/farmacologia , Desenho de Fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Animais , Anticolesterolemiantes/síntese química , Anticolesterolemiantes/química , Anticolesterolemiantes/farmacologia , Ácido Cólico/síntese química , Descoberta de Drogas , Receptores X do Fígado/metabolismo , Macrófagos/metabolismo , Camundongos , Simulação de Acoplamento Molecular , Células RAW 264.7 , Transdução de Sinais/efeitos dos fármacos
6.
Nucl Med Biol ; 43(10): 642-9, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27513813

RESUMO

INTRODUCTION: Hepatobiliary transport mechanisms are crucial for the excretion of substrate toxic compounds. Drugs can inhibit these transporters, which can lead to drug-drug interactions causing toxicity. Therefore, it is important to assess this early during the development of new drug candidates. The aim of the current study is the (radio)synthesis, in vitro and in vivo evaluation of a technetium labeled chenodeoxycholic and cholic acid analogue: [(99m)Tc]-DTPA-CDCA and [(99m)]Tc-DTPA-CA, respectively, as biomarker for disturbed transporter functionality. METHODS: [99mTc]-DTPA-CDCA([(99m)Tc]-3a) and [99mTc]-DTPA-CA ([(99m)Tc]-3b) were synthesized and evaluated in vitro and in vivo. Uptake of both tracers was investigated in NTCP, OCT1, OATP1B1, OATP1B3 transfected cell lines. Km and Vmax values were determined and compared to [(99m)Tc]-mebrofenin ([(99m)Tc]-MEB). Efflux was investigated by means of CTRL, MRP2 and BSEP transfected inside-out vesicles. Metabolite analysis was performed using pooled human liver S9. Wild type (n=3) and rifampicin treated (n=3) mice were intravenously injected with 37MBq of tracer. After dynamic small-animal SPECT and short CT acquisitions, time-activity curves of heart, liver, gallbladder and intestines were obtained. RESULTS: We demonstrated that OATP1B1 and OATP1B3 are the involved uptake transporters of both compounds. Both tracers show a higher affinity compared to [(99m)Tc]-MEB, but are in a similar range as endogenous bile acids for OATP1B1 and OATP1B3. [(99m)Tc]-3a shows higher affinities compared to [(99m)Tc]-3b. Vmax values were lower compared to [(99m)Tc]-MEB, but in the same range as endogenous bile acids. MRP2 was identified as efflux transporter. Less than 7% of both radiotracers was metabolized in the liver. In vitro results were confirmed by in vivo results. Uptake in the liver and efflux to gallbladder + intestines and urinary bladder of both tracers was observed. Transport was inhibited by rifampicin. CONCLUSION: The involved transporters were identified; both tracers are taken up in the hepatocytes by OATP1B1 andOATP1B3 with Km and Vmax values in the same range as endogenous bile acids and are secreted into bile canaliculi via MRP2. Dynamic small-animal SPECT imaging can be a useful noninvasive method of visualizing and quantifying hepatobiliary transporter functionality and disturbances thereof in vivo, which could predict drug pharmacokinetics.


Assuntos
Ácido Quenodesoxicólico/química , Ácido Cólico/química , Transportador 1 de Ânion Orgânico Específico do Fígado/metabolismo , Transportadores de Ânions Orgânicos Sódio-Independentes/metabolismo , Tecnécio/química , Tomografia Computadorizada de Emissão de Fóton Único/métodos , Animais , Transporte Biológico , Linhagem Celular , Técnicas de Química Sintética , Ácido Quenodesoxicólico/síntese química , Ácido Quenodesoxicólico/metabolismo , Ácido Cólico/síntese química , Ácido Cólico/metabolismo , Feminino , Humanos , Marcação por Isótopo , Camundongos , Radioquímica , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto
7.
Steroids ; 76(7): 690-4, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21440565

RESUMO

Using cholic acid and deoxycholic acid as starting materials, a series of 3-aza-A-homo-4-one bile acid and 7-deoxycholic acid derivatives were synthesized by the esterification, oxidation, reduction, oximation and Beckman rearrangement etc. The cytotoxicity of the synthesized compounds against MGC 7901 (human ventriculi carcinoma cell line), hela (human cervical carcinoma cell line), SMMC 7404 (human liver carcinoma cell line) were investigated. The results showed that bile acid and 7-deoxycholic-acid derivatives with 3-aza-A-homo-4-one configuration bearing a 6-hydroximino or 12-hydroximino group displayed a distinct cytotoxicity to Hela tumor cell line. In particular, the IC(50) values of the compounds 6 and 13 were 14.3 and 24.3 µmol/L against Hela human tumor cell line respectively. The information obtained from the studies may be useful for the design of novel chemotherapeutic drugs.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Ácido Cólico/química , Ácido Cólico/farmacologia , Ácido Desoxicólico/química , Ácido Desoxicólico/farmacologia , Lactamas/química , Antineoplásicos/síntese química , Linhagem Celular Tumoral , Ácido Cólico/síntese química , Ácido Desoxicólico/síntese química , Humanos
8.
J Colloid Interface Sci ; 353(2): 420-5, 2011 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-20965512

RESUMO

Alkyne-derivatized poly(ethylene glycol) (M.W. 5000) was coupled to several azide-terminated oligocholates by the click reaction to form amphiphilic block copolymers. A copolymer with a cholate hexamer as the hydrophobic block formed polymeric micelles that shrank by ~50% over a period of 10 h at 25°C. Shrinkage was faster and more dramatic at 35°C. Shortening the oligocholate by two units or inserting a 4-aminobutyroyl spacer in the hexacholate eliminated or diminished the shrinkage. Metastable aggregates were proposed to form when the block copolymers began to aggregate in water. The large hydrophobic surface, awkward shape, rigidity, and facial amphiphilicity of the cholate repeat unit and the long chain made it difficult for the oligocholates to adjust within the micellar core. As the oligocholates rearranged to maximize hydrophobic interactions and hydrogen-bonding while minimizing conformational strain, the polymeric micelles became more compact over time.


Assuntos
Ácido Cólico/química , Micelas , Polietilenoglicóis/química , Ácido Cólico/síntese química , Fluorescência , Interações Hidrofóbicas e Hidrofílicas , Microscopia Eletrônica de Transmissão , Polietilenoglicóis/síntese química , Fatores de Tempo
9.
Steroids ; 75(6): 424-31, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20171237

RESUMO

The objective of this work was to study the effect of structure of bile acids on their membranolytic potential and extent of overlapping of the information about the membranolytic potential of bile acids and their physico-chemical parameters, namely: retention index R(M0) (as a measure of bile acid hydrophobicity, reversed-phase thin-layer chromatography (RPTLC)), lecithin solubilisation (measure of the interaction of bile acids with phospholipids) and critical micellar concentration (CMC). It was found that bile acid concentrations at 100% lysis of erythrocyte membranes is described best by their CMC values, whereas at 50% lysis the parameter used is lecithin solubilisation. This indicates that different mixed micelles are formed in the membrane lysis at lower and higher concentrations of bile acids. Replacement of the hydroxyl (OH) group in the bile acid molecule with an oxo group yields derivatives with lowered hydrophobicity, power of lecithin solubilisation, tendency for self-aggregation as well as the membranolytic activity.


Assuntos
Ácido Quenodesoxicólico , Ácido Cólico , Ácido Desoxicólico , Hemólise/efeitos dos fármacos , Animais , Ácido Quenodesoxicólico/síntese química , Ácido Quenodesoxicólico/química , Ácido Quenodesoxicólico/farmacologia , Colagogos e Coleréticos/síntese química , Colagogos e Coleréticos/química , Colagogos e Coleréticos/farmacologia , Ácido Cólico/síntese química , Ácido Cólico/química , Ácido Cólico/farmacologia , Ácido Desoxicólico/síntese química , Ácido Desoxicólico/química , Ácido Desoxicólico/farmacologia , Eritrócitos/citologia , Eritrócitos/efeitos dos fármacos , Fármacos Gastrointestinais/síntese química , Fármacos Gastrointestinais/química , Fármacos Gastrointestinais/farmacologia , Interações Hidrofóbicas e Hidrofílicas , Lecitinas/química , Modelos Moleculares , Estrutura Molecular , Coelhos
10.
Steroids ; 74(9): 766-72, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19394355

RESUMO

In Niemann-Pick disease, type C1, increased amounts of 3beta,7beta-dihydroxy-5-cholenoic acid are reported to be present in urinary bile acids. The compound occurs as a tri-conjugate, sulfated at C-3, N-acetylglucosamidated at C-7, and N-acylamidated with taurine or glycine at C-24. For sensitive LC-MS/MS analysis of this bile acid, a suitable internal standard is needed. We report here the synthesis of a satisfactory internal standard, 3beta-sulfooxy-7beta-hydroxy-24-nor-5-cholenoic acid (as the disodium salt). The key reactions involved were (1) the so-called "second order" Beckmann rearrangement (one-carbon degradation at C-24) of hyodeoxycholic acid (HDCA) 3,6-diformate with sodium nitrite in a mixture of trifluoroacetic anhydride and trifluoroacetic acid, (2) simultaneous inversion at C-3 and elimination at C-6 of the ditosylate derivatives of the resulting 3alpha,6alpha-dihydroxy-24-nor-5beta-cholanoic acid with potassium acetate in aqueous N,N-dimethylformamide, and (3) regioselective sulfation at C-3 of an intermediary 3beta,7beta-dihydroxy-24-nor-Delta(5) derivative using sulfur trioxide-trimethylamine complex. Overall yield of the desired compound was 1.8% in 12 steps from HDCA.


Assuntos
Ácidos e Sais Biliares/química , Ácidos e Sais Biliares/urina , Ácido Cólico/síntese química , Espectrometria de Massas/normas , Doenças de Niemann-Pick/urina , Noresteroides/síntese química , Ésteres do Ácido Sulfúrico/síntese química , Ácido Cólico/química , Ácido Cólico/urina , Cromatografia Líquida de Alta Pressão , Cromatografia Líquida , Humanos , Noresteroides/química , Noresteroides/urina , Padrões de Referência , Sensibilidade e Especificidade , Ésteres do Ácido Sulfúrico/química , Ésteres do Ácido Sulfúrico/urina
11.
ChemMedChem ; 4(3): 466-72, 2009 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19173214

RESUMO

One of the most common mechanisms of hepatotoxicity is drug-induced cholestasis. Hence, new approaches for screening the cholestatic potential of drug candidates are desirable. In this context, we describe herein the use of synthetic 4-nitrobenzo-2-oxa-1,3-diazole (NBD) fluorescent conjugates of cholic acid (ChA) at positions 3alpha, 3beta, 7alpha, and 7beta for in vitro assessment of bile acid uptake. All the conjugates show a strong absorption band between 400 and 550 nm and have a fluorescence quantum yield of approximately 0.45, with an emission maximum centered at approximately 530 nm. After their photophysical characterization, 3alpha-, 3beta-, 7alpha-, and 7beta-NBD-ChA were used to monitor uptake in freshly isolated rat hepatocytes by means of a previously optimized flow cytometry technique. Transport of the cholic acid derivatives inside the cell was detected and quantified by measuring the increase of NBD green fluorescence within cells over time. The effect of troglitazone, a well-known inhibitor of bile acid uptake by the sodium taurocholate co-transporting polypeptide, supports the specificity of fluorescent NBD-ChA transport. According to the final intracellular fluorescence level attained and the uptake rate, 3alpha-NBD-ChA was found to be the most efficient derivative. Furthermore, sodium valproate, cyclosporin A, and chlorpromazine decreased the uptake of 3alpha-NBD-ChA, in agreement with their relative in vivo potency as cholestatic compounds; in contrast, sodium citrate (the negative control) had no effect. These results support the suitability of the in vitro flow cytometric assay with NBD-ChA to detect compounds that affect bile acid uptake.


Assuntos
Benzoxazóis/metabolismo , Ácidos e Sais Biliares/metabolismo , Ácido Cólico/metabolismo , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/metabolismo , Animais , Benzoxazóis/síntese química , Benzoxazóis/química , Permeabilidade da Membrana Celular/efeitos dos fármacos , Ácido Cólico/síntese química , Ácido Cólico/química , Cromanos/farmacologia , Citometria de Fluxo , Corantes Fluorescentes/química , Hepatócitos/citologia , Masculino , Fotoquímica , Ratos , Ratos Sprague-Dawley , Tiazolidinedionas/farmacologia , Troglitazona
12.
Org Biomol Chem ; 6(20): 3823-30, 2008 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-18843413

RESUMO

We report herein the synthesis and biological evaluation of bile acid dimers linked through 1,2,3-triazole and bis-beta-lactam. The dimers were synthesized using 1,3-dipolar cycloaddition reaction of diazido bis-beta-lactams , and terminal alkynes derived from cholic acid/deoxycholic acid in the presence of Cu(i) catalyst (click chemistry). These novel molecules were evaluated in vitro for their antifungal and antibacterial activity. Most of the compounds exhibited significant antifungal as well as antibacterial activity against all the tested fungal and bacterial strains. Moreover, their in vitro cytotoxicities towards HEK-293 and MCF-7 cells were also established.


Assuntos
Ácido Cólico/síntese química , Ácido Cólico/farmacologia , Ácido Desoxicólico/síntese química , Ácido Desoxicólico/farmacologia , Triazóis/química , beta-Lactamas/química , Antibacterianos/síntese química , Antibacterianos/química , Antibacterianos/farmacologia , Antibacterianos/toxicidade , Antifúngicos/síntese química , Antifúngicos/química , Antifúngicos/farmacologia , Antifúngicos/toxicidade , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Ácido Cólico/química , Ácido Cólico/toxicidade , Ácido Desoxicólico/química , Ácido Desoxicólico/toxicidade , Dimerização , Humanos , Testes de Sensibilidade Microbiana
13.
Org Biomol Chem ; 6(1): 162-8, 2008 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-18075662

RESUMO

A novel ditopic cholic acid-based fluorescent chemosensor for ATP, 1a, was designed and synthesized. Its interactions with phosphates, AMP, ADP, ATP, CTP, GTP, and TTP have been investigated. When ATP was added to a 1:1 aqueous CH3CN solution of the sensor at pH 7.4, a significant decrease in fluorescence of 1a was observed, whereas other guest molecules showed a much smaller effect. The complex between 1a and ATP was confirmed through combined UV, 1H, 13C and 31P NMR spectroscopic methods. The uniqueness of the new sensor is that it binds with ATP 33-124 times more selectively than other nucleotides, as evidenced from the respective binding constants. 1a is a highly sensitive sensing probe; as little as 30 nM ATP can cause 15% fluorescence quenching of the sensor.


Assuntos
Trifosfato de Adenosina/análise , Ácido Cólico/química , Ácido Cólico/síntese química , Corantes Fluorescentes/química , Corantes Fluorescentes/síntese química , Adenina/química , Trifosfato de Adenosina/química , Ânions/química , Fluorescência , Espectroscopia de Ressonância Magnética , Nucleotídeos/química , Fosfatos/química
14.
Acta Pharmacol Sin ; 28(10): 1591-6, 2007 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-17883945

RESUMO

AIM: To seek a novel and potent antitussive drug based on Shedan-Chuanbei powder, a complex of traditional Chinese medicine preparation for cough therapy. METHODS: Verticinone-cholic acid (Ver-CA) salt, a novel, salifying derivative of verticinone and cholic acid, both of which are the major bioactive components in Shedan-Chuanbei powder, was synthesized. We then evaluated the antitussive activity and the acute toxicity of the salt. RESULTS: The new compound, with good solubility in water, has much more potent antitussive activity in comparison with the same dose of single verticinone and single cholic acid. The administration 3 mg/kg of Ver-CA could result in over 50% reduction of a citric acid-induced cough. Pretreatment with naloxone (0.8 mg/kg, ip) can only partially antagonize its antitussive effect. On the other hand, glybenclamide (3 mg/kg, ip), an ATP-sensitive K+ channel blocker, can also significantly reduce the antitussive effect of Ver-CA. A further acute toxicity study showed that the LD(50) values of Ver-CA were 3 times that of verticinone. CONCLUSION: Based on the studies of pharmacology and acute toxicity, the salt has a synergic and attenuated toxicity compared with single verticinone and cholic acid. Moreover, the present study also suggests that Ver-CA, a potential novel antitussive agent, may exert its antitussive effect via both the peripheral (modulated by ATP-sensitive K+ channels) and central mechanisms (modulated by the opioid receptor).


Assuntos
Antitussígenos/farmacologia , Cevanas/farmacologia , Ácido Cólico/farmacologia , Tosse/tratamento farmacológico , Animais , Antitussígenos/síntese química , Antitussígenos/química , Cevanas/síntese química , Cevanas/química , Ácido Cólico/síntese química , Ácido Cólico/química , Relação Dose-Resposta a Droga , Composição de Medicamentos , Feminino , Glibureto/farmacologia , Cobaias , Canais KATP/antagonistas & inibidores , Masculino , Camundongos , Estrutura Molecular , Naloxona/farmacologia , Antagonistas de Entorpecentes , Distribuição Aleatória
15.
J Med Chem ; 49(8): 2652-5, 2006 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-16610808

RESUMO

Synthesis of C-11 azido/amino functionalized cholic acid derivatives has been achieved in excellent yields. Contrary to the previous prediction of analogous compounds to be HIV-1 protease inhibitors, in the present study these novel cholic acid derivatives induced host cell fusion during the progress of HIV-1 infection and produced multinucleated giant cells. This is the first report of syncytia induction and enhancement of viral replication in HIV-1 infected T cells by cholic acid derivatives.


Assuntos
Linfócitos T CD4-Positivos/virologia , Ácido Cólico/farmacologia , Células Gigantes/efeitos dos fármacos , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linhagem Celular , Células Cultivadas , Ácido Cólico/síntese química , Ácido Cólico/química , Células Gigantes/virologia , HIV-1/fisiologia , Humanos , Estrutura Molecular , Estereoisomerismo , Relação Estrutura-Atividade , Replicação Viral/fisiologia
16.
Steroids ; 70(8): 531-7, 2005 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-15894037

RESUMO

Bile acids in the family of steroid compounds can be chemically modified for biochemical and other applications. Derivatives of cholic acid with multiple methacrylate groups can be prepared by the use of methacrylic acid, methacryloyl chloride and methacryloyl anhydride as the acylating agents. The hydroxyl groups of cholic acid methyl ester and cholic acid ethylene glycol ester have been selectively acylated by changing the acylating agents and the number of substitutions have been varied by changing the amount of the acylating agents used. In the acylation reactions with methacryloyl chloride, the reactivity of secondary hydroxyl groups on the steroid skeleton of cholic acid derivatives follows the order of C3>C12>C7.


Assuntos
Ácido Cólico/síntese química , Acilação , Ácido Cólico/química , Ácido Cólico/isolamento & purificação , Esterificação , Hidrogênio , Radical Hidroxila/química , Cinética , Espectroscopia de Ressonância Magnética , Metacrilatos/síntese química , Metacrilatos/química , Estrutura Molecular , Espectroscopia de Infravermelho com Transformada de Fourier
17.
Bioorg Med Chem Lett ; 14(3): 773-7, 2004 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-14741287

RESUMO

Cholic and deoxycholic acid amides 10-17 have been synthesised from (1R,2R)-1-phenyl-2-amino-1,3-propanediol 2, (1S,2S)-1-phenyl-2-amino-1,3-propanediol 4, (1R,2R)-1-para-nitrophenyl-2-amino-1,3-propanediol 3, (1S,2S)-1-para-nitrophenyl-2-amino-1,3-propanediol 5. Amide 12 derived from N-succinimidyl ester 9 of deoxycholic acid and (1R,2R)-1-phenyl-2-amino-1,3-propanediol 2, found to be active against Cryptococcus neoformans and the amide 17 obtained from N-succinimidyl ester 9 of deoxycholic acid and (1S,2S)-1-para-nitrophenyl-2-amino-1,3-propanediol 5, is found to be potent against various gram-positive bacteria.


Assuntos
Amidas , Aminoácidos Cíclicos , Antibacterianos/síntese química , Antifúngicos/síntese química , Ácido Cólico , Ácido Desoxicólico , Bactérias Gram-Positivas/efeitos dos fármacos , Amidas/síntese química , Amidas/farmacologia , Aminoácidos Cíclicos/síntese química , Aminoácidos Cíclicos/farmacologia , Antibacterianos/farmacologia , Antifúngicos/farmacologia , Ácido Cólico/síntese química , Ácido Cólico/farmacologia , Cryptococcus neoformans/efeitos dos fármacos , Ácido Desoxicólico/síntese química , Ácido Desoxicólico/farmacologia , Testes de Sensibilidade Microbiana , Estrutura Molecular , Relação Estrutura-Atividade
18.
J Lipid Res ; 45(3): 567-73, 2004 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-14657194

RESUMO

A method for the synthesis of Delta(22)-beta-muricholic acid (Delta(22)-beta-MCA), (22E)-3 alpha,6 beta,7 beta-trihydroxy-5 beta-chol-22-en-24-oic acid, and its taurine and glycine conjugates (Delta(22)-beta-muricholyltaurine and Delta(22)-beta-muricholylglycine) is described. The key intermediate, 3 alpha,6 beta,7 beta-triformyloxy-23,24-dinor-5 beta-cholan-22-al, was prepared from beta-muricholic acid (beta-MCA) via the 24-nor-22-ene and 24-nor-22,23-diol derivatives. Wittig reaction of the aldehyde with (carbomethoxymethylene) triphenylphosphorane and subsequent hydrolysis gave (unconjugated) Delta(22)-beta-MCA. Condensation reaction of the unconjugated acid with taurine or glycine methyl ester using diethylphosphorocyanide yielded the naturally occurring taurine or glycine conjugate (N-acylamidate) of Delta(22)-beta-MCA. These synthetic reference compounds are now available for investigation of the metabolism of beta-MCA by bacterial and hepatic enzymes in the rat and should also be useful as substrates for reductive deuteration or tritiation to give the 22,23-(2)H or (3)H-beta-MCA.


Assuntos
Ácidos e Sais Biliares/síntese química , Ácido Cólico/síntese química , Ácidos Cólicos , Glicina/química , Taurina/química , Animais , Ácidos e Sais Biliares/química , Ácido Cólico/química , Estrutura Molecular , Ratos , Espectrometria de Massas por Ionização por Electrospray
19.
Biotechnol Bioeng ; 81(4): 391-6, 2003 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-12491524

RESUMO

A 39-member library of bile acid derivatives was prepared starting from 3alpha,7alpha,12alpha-trihydroxy-5beta-cholan-24-oic acid methyl ester using a combinatorial biocatalytic approach. A regioselective oxidation step, catalyzed by hydroxysteroid dehydrogenases, followed by an acylation step with a series of different acyl donors catalyzed by Candida antarctica lipase B, led to the modification of the bile acid scaffold. Each member of the library was obtained in high purity and good yield.


Assuntos
Ácido Cólico/síntese química , Técnicas de Química Combinatória/métodos , Hidroxiesteroide Desidrogenases/química , Lipase/química , Acilação , Ácidos e Sais Biliares/síntese química , Ácidos e Sais Biliares/química , Catálise , Ácido Cólico/química , Ácido Cólico/isolamento & purificação , Esterificação , Proteínas Fúngicas , Isomerismo , Complexos Multienzimáticos/química , Oxirredução , Projetos Piloto , Especificidade por Substrato
20.
J Antimicrob Chemother ; 47(5): 671-4, 2001 May.
Artigo em Inglês | MEDLINE | ID: mdl-11328782

RESUMO

Cationic cholic acid derivatives displayed potent and broad-spectrum activity against multidrug-resistant Gram-negative and -positive bacteria. Specific examples were effective permeabilizers of the outer membranes of many strains of multidrug-resistant Gram-negative bacteria and sensitized these to hydrophobic antibiotics. We also prepared a new cholic acid derivative with improved apparent selectivity for prokaryote membranes.


Assuntos
Antibacterianos/farmacologia , Ácido Cólico/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Antibacterianos/síntese química , Antibacterianos/química , Ácido Cólico/síntese química , Ácido Cólico/química , Resistência a Múltiplos Medicamentos , Escherichia coli/efeitos dos fármacos , Humanos , Testes de Sensibilidade Microbiana , Salmonella typhimurium/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacos , Streptococcus pneumoniae/efeitos dos fármacos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...