RESUMO
A series of N-hydroxy-3-phenyl-2-propenamides were prepared as novel inhibitors of human histone deacetylase (HDAC). These compounds were potent enzyme inhibitors, having IC(50)s < 400 nM in a partially purified enzyme assay. However, potency in cell growth inhibition assays ranged over 2 orders of magnitude in two human carcinoma cell lines. Selected compounds having cellular IC(50) < 750 nM were tested for maximum tolerated dose (MTD) and for efficacy in the HCT116 human colon tumor xenograft assay. Four compounds having an MTD > or = 100 mg/kg were selected for dose-response studies in the HCT116 xenograft model. One compound, 9 (NVP-LAQ824), had significant dose-related activity in the HCT116 colon and A549 lung tumor models, high MTD, and low gross toxicity. On the basis, in part, of these properties, 9 has entered human clinical trials in 2002.
Assuntos
Acetiltransferases/antagonistas & inibidores , Acrilamidas/síntese química , Acrilamidas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Ácidos Hidroxâmicos/síntese química , Ácidos Hidroxâmicos/farmacologia , Proteínas de Saccharomyces cerevisiae/antagonistas & inibidores , Animais , Peso Corporal/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Histona Acetiltransferases , Humanos , Indicadores e Reagentes , Camundongos , Camundongos Nus , Conformação Molecular , Transplante de NeoplasiasRESUMO
We evaluated the normal Raman (NR) and the surface-enhanced Raman scattering (SERS) of three sympathomimetic amines: phenethylamine, ephedrine, and 3,4-methylenedioxymethamphetamine (MDMA). In addition, quantum mechanical calculations-geometry optimization and calculations of the harmonic vibrational frequencies-were performed using the density functional theory (DFT) approach. Vibrational assignments were made by comparing the experimental and calculated spectra. The study found that both NR and SERS provided excellent spectra for the drugs tested. Certain conditions, such as response to various laser wavelengths and background fluorescence of the analyte, could be easily managed using SERS techniques. The DFT-calculated spectra could be correlated with the experimental spectra without the aid of a scaling factor. We also present a set of discriminant bands, useful for distinguishing the three compounds, despite their structural similarities.