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Overcoming multi-drug resistance using GST-activated anticancer agents.

机译：使用GST激活的抗癌药克服多药耐药性。

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摘要

Multi-drug resistance (MDR) is an important challenge in medicinal enzymology. Since the pi isozyme of human Glutathione S-transferase (hGSTP1-1) is often over-expressed in MDR tumor cells, one strategy to overcome MDR is to make substrates that will become more toxic in the presence of hGSTP1-1. A class of 2-crotonyloxymethylcycloalkenone compounds (COMCs), derivatives of a cytotoxic metabolite isolated from Streptomyces griseosporeus , was investigated as substrates for hGSTP1-1. Catalysis was found to involve the formation of a cytotoxic exocyclic enone that accounts for the anti-tumor activities of these compounds.;Other workers have found that nitric oxide induces apoptosis in tumor cells when delivered by nitric oxide donors -- diazeniumdiolates.;A diazeniumdiolate derivative of COMC, O2-(2-methyl-cyclohexen-1-one) [1-(N, N-diethylamino)diazen-1-ium-1,2-diolate] (COMC-NO) was synthesized. The kinetic parameters from the reaction between COMC-NO and glutathione were obtained: non-enzymatic second order rate constant = 0.109 mM-1min -1 and kcat/KM = 0.56 x 103 mM-1 min-1. These rate constants suggest possible MDR selectivities.;The synthesis of lactam derivative of COMC was attempted unsuccessfully.
机译：多药耐药性（MDR）是药物酶学中的重要挑战。由于人谷胱甘肽S-转移酶（hGSTP1-1）的pi同工酶通常在MDR肿瘤细胞中过表达，因此克服MDR的一种策略是使底物在hGSTP1-1存在下变得更具毒性。研究了一类2-巴豆酰氧基甲基环烯酮化合物（COMCs），它是从灰链霉菌中分离出的细胞毒性代谢产物的衍生物，作为hGSTP1-1的底物。发现催化作用涉及细胞毒性的环外烯酮的形成，这解释了这些化合物的抗肿瘤活性;其他工作人员发现一氧化氮在由一氧化氮供体-二醇二氮烯delivered传递时诱导肿瘤细胞凋亡。合成了COMC的衍生物O2-（2-甲基-环己烯-1-酮）[1-（N，N-二乙氨基）重氮-1-1,2-二醇酸酯]（COMC-NO）。从COMC-NO和谷胱甘肽之间的反应获得动力学参数：非酶促二阶速率常数＝ 0.109mM-1min -1和kcat / KM ＝ 0.56×103mM-1min-1。这些速率常数表明可能存在MDR选择性。;未成功尝试合成COMC的内酰胺衍生物。

著录项

  • 作者

    See, Bee Koon.;

  • 作者单位

    University of Maryland, Baltimore County.;

  • 授予单位 University of Maryland, Baltimore County.;
  • 学科 Chemistry Biochemistry.
  • 学位 M.S.
  • 年度 2008
  • 页码 115 p.
  • 总页数 115
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 生物化学;
  • 关键词

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