...
  • 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Biochemical Pharmacology >Phosphono analogs of glutathione: inhibition of glutathione transferases, metabolic stability, and uptake by cancer cells.
【24h】

Phosphono analogs of glutathione: inhibition of glutathione transferases, metabolic stability, and uptake by cancer cells.

机译：谷胱甘肽的膦酸酯类似物：谷胱甘肽转移酶的抑制，代谢稳定性和癌细胞的摄取。

获取原文
获取原文并翻译 | 示例
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

Glutathione transferases (GSTs) have been shown to play an important role in multiple drug resistance in cancer chemotherapy. The inactivation of GST isoforms could lead to an enhanced activity of cytotoxic drugs. Thus, we have developed glutathione phosphono analogs [(S)-gamma-glutamyl-(2RS)-(+/-)-2-amino-(dialkoxyphosphinyl)-ac etylgl ycines], which were previously shown to be inhibitors of GSTP1-1. In the present study, the inhibition characteristics of these analogs, including isoenzyme specificities, type of inhibition, and determination of K(i) values, were determined. The inhibition of class alpha GSTs was competitive towards GSH. A mixed-type, non-competitive inhibition of class mu and pi GSTs was observed. The K(i) values varied between 880 +/- 210 and 0.45 +/- 0.1 microM. The inhibitors were most effective towards class mu GSTs. In order to investigate the potential use of these GST inhibitors in intact cellular systems, two additional approaches were examined. Firstly, the metabolic stability was tested with purified gamma-glutamyl transpeptidase and cell homogenates as well as during incubation of cell lines. No appreciable degradation was observed in any of the tested systems. Secondly, to facilitate cellular uptake, three derivatives were synthesized in which the glycine carboxylic group was esterified. Uptake and a possible intracellular cleavage to the corresponding free acids were monitored by HPLC analysis. The esters were effectively transported into HT29 (colon cancer) and EPG85-257P (gastric cancer) cells, respectively, and readily converted into the more active free acids. In conclusion, the tested inhibitors may be regarded as model compounds for the development of modulating agents in cancer chemotherapy.
机译：谷胱甘肽转移酶（GSTs）已被证明在癌症化学疗法的多重耐药性中起重要作用。 GST同工型的失活可以导致细胞毒性药物活性增强。因此，我们开发了谷胱甘肽膦酰基类似物[（S）-γ-谷氨酰基-（2RS）-（+/-）-2-氨基-（二烷氧基膦基）-ac乙炔基]，以前已证明是GSTP1-的抑制剂。 1。在本研究中，确定了这些类似物的抑制特性，包括同工酶特异性，抑制类型和K（i）值的确定。抑制α类GST对GSH具有竞争性。观察到对mu和pi类GST的混合型，非竞争性抑制。 K（i）值在880 +/- 210和0.45 +/- 0.1 microM之间变化。抑制剂对μ类GST最有效。为了研究这些GST抑制剂在完整细胞系统中的潜在用途，研究了两种其他方法。首先，用纯化的γ-谷氨酰转肽酶和细胞匀浆以及在细胞系孵育期间测试代谢稳定性。在任何测试系统中均未观察到明显的降解。其次，为了促进细胞摄取，合成了其中甘氨酸羧基被酯化的三种衍生物。通过HPLC分析监测摄取和可能的细胞内裂解为相应的游离酸。这些酯分别有效地转运到HT29（结肠癌）和EPG85-257P（胃癌）细胞中，并易于转化为活性更高的游离酸。总之，被测试的抑制剂可以被认为是癌症化学治疗中调节剂开发的模型化合物。

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号