RESUMO
To overcome the problem of poor aqueous solubility and bioavailability of indirubin-3-oximes, the compounds were modified by attaching a quaternary ammonium group at the oxime moiety. Exploring the prodrug concept, an oxime ester with acetyl-l-carnitine was prepared, and the rate of its hydrolysis was investigated to assess its suitability for clinical administration. In addition, the cytotoxic potency of new stable oxime ethers with a choline moiety and their influence on the cell cycle were tested in human cancer cell lines.
Assuntos
Antineoplásicos/química , Indóis/química , Água/química , Acetilcarnitina/síntese química , Acetilcarnitina/química , Antineoplásicos/síntese química , Antineoplásicos/toxicidade , Cátions/química , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Hidrólise , Índigo Carmim , Indóis/síntese química , Indóis/toxicidade , Oximas/química , SolubilidadeRESUMO
The syntheses of L-carnitine, O-acetyl CoA, and O-acetyl-L-carnitine labelled with 11C at the 1- or 2-position of the acetyl group or the N-methyl position of carnitine, using the enzymes acetyl CoA synthetase and carnitine acetyltransferase, are described. With a total synthesis time of 45 min, O-[1-11C]acetyl CoA and O-[2[11C]acetyl CoA was obtained in 60-70% decay-corrected radiochemical yield, and O-[1-11C]acetyl-L-carnitine and O-[2-11C] acetyl-L-carnitine in 70-80% yield, based on [1-11C]acetate or [2-11C]acetate, respectively. By an N-methylation reaction with [11C]methyl iodide, L-[methyl-11C]carnitine was obtained within 30 min, and O-acetyl-L-[methyl-11C]carnitine within 40 min, giving a decay-corrected radiochemical yield of 60% and 40-50%, respectively, based on [11C]methyl iodide. Initial data of the kinetics of the different 11C-labelled L-carnitine and acetyl-L-carnitines in renal cortex of anaesthetized monkey (Macaca mulatta) are presented.
Assuntos
Acetilcoenzima A/farmacocinética , Acetilcarnitina/farmacocinética , Radioisótopos de Carbono , Carnitina/farmacocinética , Marcação por Isótopo , Acetilcoenzima A/síntese química , Acetilcarnitina/síntese química , Animais , Carnitina/síntese química , Córtex Renal/metabolismo , Macaca mulatta , Tomografia Computadorizada de EmissãoRESUMO
[1-14C]Acetylcarnitine was prepared from [1-14C]acetate and L-carnitine using acetyl-CoA synthetase and carnitine acetyltransferase. The product was purified by ion-exchange and thin-layer chromatography. Conversion of [1-14C]acetate to [1-14C]acetylcarnitine was better than 90% and overall recovery of the pure product was greater that 80%.
Assuntos
Acetilcarnitina/síntese química , Proteínas Repressoras , Proteínas de Saccharomyces cerevisiae , Acetatos/química , Acetilcarnitina/isolamento & purificação , Radioisótopos de Carbono , Carnitina/química , Carnitina O-Acetiltransferase/metabolismo , Cromatografia por Troca Iônica/métodos , Cromatografia em Camada Fina/métodos , Coenzima A Ligases/metabolismo , Marcação por Isótopo/métodos , Fatores de TempoRESUMO
Several inherited metabolic disorders, particularly the organic acidurias and acidemias, are often characterised by excretion of acylcarnitines, especially octanoylcarnitine, in the urine. Clinical investigation of such serious disorders ideally requires a rapid, simple and selective method for determining acylcarnitines in urine. Initial results are given here of a method that may approach this ideal. The procedure involves chemical derivatisation, in which the zwitterionic acylcarnitines are cyclised to volatile lactones, and analysis by gas chromatography and gas chromatography--mass spectrometry. Preparation of urine samples by ion-exchange purification and an illustrative application of the proposed method to a clinical sample are also outlined.
