RESUMO
Kidney-type glutaminase [KGA/isoenzyme glutaminase C (GAC)] is becoming an important tumor metabolism target in cancer chemotherapy. Its allosteric inhibitor, CB839, showed early promise in cancer therapeutics but limited efficacy in in vivo cancer models. To improve the in vivo activity, we explored a bioisostere replacement of the sulfur atom in bis-2-(5-phenylacetamido-1,2,4-thiadiazol)ethyl sulfide and CB839 analogues with selenium using a novel synthesis of the selenadiazole moiety from carboxylic acids or nitriles. The resulting selenadiazole compounds showed enhanced KGA inhibition, more potent induction of reactive oxygen species, improved inhibition of cancer cells, and higher cellular and tumor accumulation than the corresponding sulfur-containing molecules. However, both CB839 and its selenium analogues show incomplete inhibition of the tested cancer cells, and a partial reduction in tumor size was observed in both the glutamine-dependent HCT116 and aggressive H22 liver cancer xenograft models. Despite this, tumor tissue damage and prolonged survival were observed in animals treated with the selenium analogue of CB839.
Assuntos
Antineoplásicos/química , Azóis/química , Inibidores Enzimáticos/química , Glutaminase/antagonistas & inibidores , Regulação Alostérica , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Azóis/farmacologia , Azóis/uso terapêutico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Glutaminase/metabolismo , Humanos , Rim/enzimologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Camundongos , Camundongos Endogâmicos ICR , Camundongos Nus , Espécies Reativas de Oxigênio/metabolismo , Selênio/química , Relação Estrutura-Atividade , Tiadiazóis/química , Tiadiazóis/farmacologia , Tiadiazóis/uso terapêutico , Transplante HeterólogoRESUMO
A simple method for the extraction and determination of ginsenoside Rb(1), astragaloside IV and dulcitol in sugar-free "Fufangfufangteng Heji" was developed using an ultrasonic-assisted liquid-liquid extraction (UALLE) coupled with Hydrophilic Interaction Liquid Interface Chromatography and Evaporative Light Scattering Detector (HILIC-ELSD) analysis. Good chromatographic separation was achieved using a Phenomenex Luna HILIC column (250mm×4.6mm i.d., 5µm), and a mobile phase consisting of acetonitrile-water at a flow rate of 1.0ml/min with a gradient elution within 25min was also used. Compared to the conventional analysis method, the proposed method had the advantages of a longer column life, shorter analysis time, lower baseline noise, short sample pretreatment time and low consumption of organic solvent. The linear ranges for ginsenoside Rb(1), astragaloside IV and dulcitol were 0.0256-0.179, 0.110-0.770, 0.105-0.630mg/ml, respectively. The recoveries of ginsenoside Rb(1), astragaloside IV and dulcitol during the pharmaceutical preparation were within the range of 97.2-100.3%, and their relative standard deviations were 1.2-3.1%.