RESUMO
A safe, functional-group-tolerant and high-throughput version of the trimethylaluminium mediated amide bond formation reaction has been developed in a microreactor system; rimonabant and efaproxiral were prepared to illustrate the utility of the method.
Assuntos
Alcanos/química , Alumínio/química , Amidas/síntese química , Compostos de Anilina/síntese química , Piperidinas/síntese química , Propionatos/síntese química , Pirazóis/síntese química , Amidas/química , Amidas/efeitos da radiação , Compostos de Anilina/química , Compostos de Anilina/efeitos da radiação , Desenho de Equipamento , Micro-Ondas , Miniaturização , Estrutura Molecular , Piperidinas/química , Piperidinas/efeitos da radiação , Propionatos/química , Propionatos/efeitos da radiação , Pirazóis/química , Pirazóis/efeitos da radiação , Rimonabanto , EstereoisomerismoRESUMO
The pungent compounds piperine and isomers thereof, secondary metabolites present in black and white pepper fruit, undergo light-induced isomerizations. To facilitate studies in this area, an HPLC method has been developed for analysis and isolation of the following four possible piperine-derived photoinduced isomers: piperine, isopiperine, chavicine, and isochavicine. The limits of detection (LOD) estimated from calibration plots were approximately 15-30 ng for each isomer. Reproducibilities of the analyses were excellent, and recoveries of spiked samples were as follows (average +/- SD; n = 3): chavicine, 98.4 +/- 2.1%; isopiperine, 96.2 +/- 3.2%; piperine, 104 +/- 3.8%; isochavicine, 98.9 +/- 3.0%. To determine the kinetics of these isomerizations, fluorescent light, sunlight, and UV radiation at 254 nm was used to induce cis-trans geometric isomerization as a function of light intensities and time of exposure determined with the aid of high-performance liquid chromatography (HPLC) and liquid chromatography with diode array UV detection-mass spectrometry (LC-DAD/MS). HPLC was also used to determine the distribution of the isomers in four commercial ground black pepper products used as spices in culinary practice. Isomerization increased with light intensities and time of exposure and leveled off at the so-called photostationary phases. The piperine levels of the four products were quite similar, ranging (in wt %) from 10.17 to 11.68. The amounts of the other three isomers ranged from 0.01 to 0.07 of the total for chavicine; from 0.15 to 0.23 for isopiperine; and from 0.37 to 0.42 for isochavicine. The results establish the utility of the HPLC method for simultaneous analysis of the four isomers both in pure form and in black pepper extracts. The dietary significance of the results is discussed.
Assuntos
Alcaloides/análise , Alcaloides/química , Benzodioxóis/análise , Benzodioxóis/química , Luz , Piper nigrum/química , Piperidinas/análise , Piperidinas/química , Alcamidas Poli-Insaturadas/análise , Alcamidas Poli-Insaturadas/química , Alcaloides/efeitos da radiação , Benzodioxóis/efeitos da radiação , Cromatografia Líquida de Alta Pressão , Isomerismo , Cinética , Espectrometria de Massas , Piperidinas/efeitos da radiação , Alcamidas Poli-Insaturadas/efeitos da radiaçãoRESUMO
Piperine, the major alkaloid of black pepper (Piper nigrum L.; Piperaceae), stimulates melanocyte proliferation and dendrite formation in vitro. This property renders it a potential treatment for the skin depigmentation disorder vitiligo. However, piperine does not stimulate melanin synthesis in vitro, and treatments based on this compound may therefore be more effective with concomitant exposure of the skin to ultraviolet (UV) radiation or sunlight. The present study investigated the effect of UVA and simulated solar radiation (SSR) on the chemical stability of piperine, its melanocyte stimulatory effects and its ability to bind protein and DNA. Chromatographic and spectroscopic analysis confirmed the anticipated photoisomerization of irradiated piperine and showed the absence of any hydrolysis to piperinic acid. Isomerization resulted in the loss of ability to stimulate proliferation of a mouse melanocyte cell line, and to bind to human serum albumin. There was no evidence of DNA binding by piperine either before or after irradiation, showing the absence of photoadduct formation by either piperine or its geometric isomers. This is unlike the situation with psoralens, which form DNA adducts when administered with UVA in treating skin diseases. The present study suggests that exposure to bright sunlight should be avoided both during active application of piperine to the skin and in the storage of piperine products. If UVA radiation is used with piperine in the treatment of vitiligo, application of the compound and irradiation should be staggered to minimize photoisomerization. This approach is shown to effectively induce pigmentation in a sparsely pigmented mouse strain.
Assuntos
Alcaloides/farmacologia , Alcaloides/efeitos da radiação , Benzodioxóis/farmacologia , Benzodioxóis/efeitos da radiação , Melanócitos/fisiologia , Melanócitos/efeitos da radiação , Piperidinas/farmacologia , Piperidinas/efeitos da radiação , Alcamidas Poli-Insaturadas/farmacologia , Alcamidas Poli-Insaturadas/efeitos da radiação , Alcaloides/química , Animais , Benzodioxóis/química , Divisão Celular/efeitos da radiação , Linhagem Celular , Inibidores das Enzimas do Citocromo P-450 , Humanos , Camundongos , Modelos Moleculares , Piper nigrum , Piperidinas/química , Alcamidas Poli-Insaturadas/química , Ligação Proteica , Albumina Sérica/metabolismo , Espectrofotometria Ultravioleta , Luz Solar , Raios UltravioletaRESUMO
The CXCR3 receptor, a class A G protein-coupled receptor (GPCR), is involved in the regulation and trafficking of various immune cells. CXCR3 antagonists have been proposed to be beneficial for the treatment of a wide range of disorders including but not limited to inflammatory and autoimmune diseases. The structure-based design of CXCR3 ligands remains, however, hampered by a lack of structural information describing in detail the interactions between an allosteric ligand and the receptor. We designed and synthesized photoactivatable probes for the structural and functional characterization, using photoaffinity labeling followed by mass spectrometry, of the CXCR3 allosteric binding pocket of AMG 487 and RAMX3, two potent and selective CXCR3 negative allosteric modulators. Photoaffinity labeling is a common approach to elucidate binding modes of small-molecule ligands of GPCRs through the aid of photoactivatable probes that convert to extremely reactive intermediates upon photolysis. The photolabile probe N-[({1-[3-(4-ethoxyphenyl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl]ethyl}-2-[4-fluoro-3-(trifluoromethyl)phenyl]-N-{1-[4-(3-(trifluoromethyl)-3H-diazirin-3-yl]benzyl}piperidin-4-yl)methyl]acetamide (10) showed significant labeling of the CXCR3 receptor (80%) in a [(3) H]RAMX3 radioligand displacement assay. Compound 10 will serve as an important tool compound for the detailed investigation of the binding pocket of CXCR3 by mass spectrometry.
Assuntos
Acetamidas/farmacologia , Acetamidas/efeitos da radiação , Marcadores de Fotoafinidade/farmacologia , Piperidinas/farmacologia , Piperidinas/efeitos da radiação , Receptores CXCR3/antagonistas & inibidores , Acetamidas/síntese química , Quimiocina CXCL11/metabolismo , AMP Cíclico/química , Células HEK293 , Humanos , Espectrometria de Massas , Marcadores de Fotoafinidade/síntese química , Marcadores de Fotoafinidade/efeitos da radiação , Fotólise , Piperidinas/síntese química , Pirimidinonas/farmacologia , Receptores CXCR3/química , TrítioRESUMO
Electron spin resonance spectroscopy has been used to demonstrate that the phototoxic antimalarial drug, 6,8-dichloro-2-phenyl-a-2-piperidnylquinolinemethanol (WR 7930), when irradiated with long-wave ultraviolet (UV) light (lambda greater than 320 nm) while held in a glassy matrix at 73 degrees K, enters a triplet state and releases hydrogen atoms in its environment. The steady-state concentration of triplet WR 7930 molecules and of hydrogen atoms is reduced 2 to 3 times when mercaptoethylamine (MEA) is also present in the UV-irradiated glass. Organosulfur radicals form on MEA while hydrogen atoms and triplet-state molecules are reduced in number. Hydrogen atoms and triplet WR 7930 molecules are considered as mediators of the phototoxicity of the antimalarial drug. Thus, hydrogen atom scavanging and chemical quenching of the triplet state are possible mechanisms by which protection against phototoxic effects could be gained. Protection is demonstrated in mice receiving 20 mg per kg WR 7930 intraperitoneally and exposed to long-wave UV for 20 hr when the radioprotective aminothiol-forming compound, 2-(3-aminopropylamino) ethyl dihydrogen phosphorothioate (WR 2721), is administered at 400 mg per kg immediately before irradiation. When no protective drug is administered concurrently, WR 7930 administration results in intense erythema, edema, and eventual necrosis of ear tissues.
Assuntos
Antimaláricos/toxicidade , Mercaptoetilaminas/farmacologia , Transtornos de Fotossensibilidade/induzido quimicamente , Quinolinas/toxicidade , Protetores contra Radiação/farmacologia , Raios Ultravioleta , Animais , Antimaláricos/efeitos da radiação , Fenômenos Químicos , Química , Diaminas/farmacologia , Relação Dose-Resposta a Droga , Espectroscopia de Ressonância de Spin Eletrônica , Eritema/induzido quimicamente , Feminino , Radicais Livres , Hidrogênio/farmacologia , Camundongos , Camundongos Endogâmicos , Necrose , Compostos Organotiofosforados/farmacologia , Piperidinas/efeitos da radiação , Piperidinas/toxicidade , Quinolinas/efeitos da radiação , Efeitos da RadiaçãoRESUMO
Column chromatography, thin-layer chromatography, high-performance liquid chromatography, nuclear magnetic resonance spectrometry, and high-resolution mass spectrometry were employed to separate and identify the photodegradation products of pirmenol hydrochloride [(+/-)-cis-alpha-[3-(2,6-dimethyl-1-piperidinyl)propyl]-alpha-phenyl-2- pyridinemethanol monohydrochloride monohydrate], a new antiarrhythmic drug. A methanol solution of pirmenol was irradiated using a low-pressure mercury lamp. The solution afforded four major degradation products, three of which were identified as 3-(cis-2,6-dimethylpiperidinyl)propyl 2-(2-pyridyl)phenyl ketone, 2-(2-pyridyl)benzoic acid, and methyl 2-(2-pyridyl)-benzoate. The degradation followed apparent-first-order reaction kinetics. In addition, the possible photodegradation pathways are discussed with reference to reaction mechanisms.
Assuntos
Antiarrítmicos/química , Piperidinas/química , Antiarrítmicos/efeitos da radiação , Cromatografia em Camada Fina , Cinética , Luz , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Fotoquímica , Piperidinas/efeitos da radiação , Espectrofotometria Infravermelho , Espectrofotometria UltravioletaRESUMO
Photoexcitation of complexes between cyclophane 1 and 1- or 2-chloronaphthalene in aqueous solution leads to rapid dechlorination of the guest, a reaction driven by electron transfer from host to excited guest. The main photoproducts contain a naphthyl group covalently attached to the host framework. The results may lead to new approaches for remediating water contaminated with chlorinated aromatic compounds.
Assuntos
Cloro/química , Éteres Cíclicos/efeitos da radiação , Naftalenos/efeitos da radiação , Fotólise/efeitos da radiação , Piperidinas/efeitos da radiação , Éteres Cíclicos/química , Espectrometria de Massas , Conformação Molecular/efeitos da radiação , Naftalenos/química , Fotoquímica/métodos , Piperidinas/química , Água/químicaRESUMO
Exposure of aqueous solutions of the antitumor drug vandetanib to UV-A light results in the photochemical degradation. Two main photodegradation products were identified by HPLC-MS analysis and their structures were elucidated, after their isolation by HPLC, on the basis of LC-MS and NMR spectra. The photoproducts derived from a simple debromination (N-(2-fluorophenyl)-6-methoxy-7-((1-methylpiperidin-4 yl)methoxy)quinazolin-4-amine, FP3) or from the loss of the bromide atom followed by the solvent addition (N-(4-hydroxy-2-fluorophenyl)-6-methoxy-7-((1-methylpiperidin-4 yl)methoxy)quinazolin-4-amine, FP2). At our knowledge this is the first report about the photodegradation of vandetanib.
Assuntos
Piperidinas/química , Piperidinas/efeitos da radiação , Quinazolinas/química , Quinazolinas/efeitos da radiação , Antineoplásicos/química , Antineoplásicos/efeitos da radiação , Cromatografia Líquida de Alta Pressão/métodos , Cinética , Espectroscopia de Ressonância Magnética/métodos , Espectrometria de Massas/métodos , Fotoquímica/métodos , Fotólise , Soluções/química , Solventes/química , Raios UltravioletaRESUMO
The ultrasound-promoted synthesis of novel bipodal and tripodalpiperidin-4-ones was carried out by the reaction of 4-piperidone hydrochloride monohydrate with different alkylating and acylating agents. It was preferably reduced to respective piperidin-4-ols by ultrasonic irradiation using silica chloride, which maintains higher yields by acting as an effective supporting polymer. The sterically hindered phthaloyl derivative of piperidin-4-one was synthesized by ultrasonic irradiation which was difficult by conventional methods.
Assuntos
Alquilantes/química , Cloretos/química , Piperidinas/síntese química , Dióxido de Silício/química , Sonicação/métodos , Alquilantes/efeitos da radiação , Cloretos/efeitos da radiação , Ondas de Choque de Alta Energia , Piperidinas/efeitos da radiação , Doses de Radiação , Dióxido de Silício/efeitos da radiaçãoRESUMO
Ester-imine derivatives of beta-amino acids were methylenated with dimethyltitanocene under microwave irradiation and the resulting enol ethers cyclized with Brönsted acid or triisopropylaluminium to give 2,6-syn-disubstituted piperidinones in good yield and diastereoselectivity. The method is analogous to the Petasis-Ferrier rearrangement of 1,3-dioxan-4-ones to give tetrahydropyranones.
Assuntos
Ácidos/química , Aminoácidos/química , Piperidinas/síntese química , Alumínio/química , Aminoácidos/efeitos da radiação , Ciclização , Metilação , Micro-Ondas , Estrutura Molecular , Compostos Organometálicos/química , Piperidinas/química , Piperidinas/efeitos da radiação , EstereoisomerismoRESUMO
STATEMENT OF PROBLEM: External prostheses composed of silicone elastomers exhibit an unwanted color change over time. PURPOSE: This study evaluated color stability when an ultraviolet light absorber and hindered amine light stabilizer were mixed in the maxillofacial elastomer containing either organic or inorganic pigments. MATERIAL AND METHODS: The materials used were an RTV silicone elastomer, 1 natural inorganic dry-earth pigment (burnt sienna) and 2 synthesized organic pigments (hansa yellow and alizarin red), ultraviolet light absorber (UVA) and hindered amine light stabilizer (HALS). Specimens (n=160) were fabricated in a custom mold and randomly assigned and exposed to weathering sites in Miami and Phoenix for approximately 3 months. Eight test groups (2 of each 4 material types with or without additives) of 10 specimens each were assigned to each site. L*, a*, b* readings were obtained before and after weathering from a spectrocolorimeter. Nonpigmented elastomers served as the control. Three-factor ANOVA was conducted to examine interaction effects between weathering sites, specimen type, and the presence of additive (alpha=.05). Overall color change (Delta E) and change in color coordinates (Delta L*, Delta a*, Delta b*) of specimen groups with and without additive were analyzed with independent sample t tests. RESULTS: In specimen groups with the additives (UVA and HALS), color change decreased significantly (P<.05) in burnt sienna and hansa yellow in Phoenix and in the control and hansa yellow in Miami. Additives did not affect color change in the alizarin red group. CONCLUSION: UVA and HALS were shown to be effective in retarding color change in some circumstances.