RESUMO
Compounds that bind to sickle hemoglobin (Hb S) producing an allosteric shift to the high-affinity Hb S that does not polymerize are being developed to treat sickle cell anemia (SCA). In this study, three series of pyridyl derivatives of substituted benzaldehydes (Classes I-III) that combine structural features of two previously determined potent antisickling agents, vanillin and pyridoxal, were synthesized. When analyzed with normal human whole blood, the compounds form Schiff-base adducts with Hb and left shift the oxygen equilibrium curve (OEC) to the more soluble high-affinity Hb, more than vanillin or pyridoxal. Generally, Class-I compounds with an aromatic aldehyde located ortho to the pyridyl substituent are the most potent, followed by the Class-II compounds with the aldehyde at the meta-position. Class-III compounds with the aldehyde at the para position show the weakest activity. The structure-activity studies of these pyridyl derivatives of substituted benzaldehydes demonstrate significant allosteric potency that may be useful for treating SCA.
Assuntos
Antidrepanocíticos/síntese química , Antidrepanocíticos/farmacologia , Benzaldeídos/síntese química , Benzaldeídos/farmacologia , Piridinas/química , Antidrepanocíticos/química , Antidrepanocíticos/classificação , Benzaldeídos/química , Benzaldeídos/classificação , Células Sanguíneas/efeitos dos fármacos , Células Sanguíneas/metabolismo , Humanos , Estrutura Molecular , Oxigênio/metabolismo , Relação Estrutura-AtividadeRESUMO
The application of single-drop microextraction (SDME) followed by gas chromatography/chemical ionization mass spectrometry (GC/CI-MS) was investigated for the determination of anisaldehyde isomers in human urine and blood serum. The effects of extraction solvent, sample agitation rate, salt addition, sampling time and temperature on the extraction efficiency were examined and optimized. Analytical parameters such as linearity, reproducibility, detection limit and relative recovery were evaluated under the optimized experimental conditions. Good reproducibilities of replicate extractions (n = 5) were obtained, with relative standard deviation (RSD) values below 6%. The limits of detection (LOD) using an extraction time of 5 min were found to be in the range 2-5 ng/mL under the selected ion monitoring (SIM) mode of GC/MS. Recoveries of 82-98% were achieved after 5 min extraction.
