Disulfide Reductases of Parasites and Cancer Cells as Targets of Medicinal Chemistry

寄生虫和癌细胞的二硫键还原酶作为药物化学的靶标

• 批准号: 5383507
• 负责人: Professorin Dr. Katja Becker
• 金额: --
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2002
• 资助国家: 德国
• 起止时间: 2001-12-31 至 2004-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/5383507?language=en
• 关键词: Disulfide; Reductases; Parasites; Cancer; Cells

New drugs against parasitic and cancer diseases are urgentlyand continuously needed. The aim of this interdisciplinaryproject is to substantiate disulfide reductase inhibitors asantiparasitic and cytostatic agents. Such compounds are activeper se but, in addition, they can reverse thiol-basedresistance against other drugs in parasites and tumour cells.Our strategy is based on the synthesis of inhibitors andsubversive substrates of the selected targets, namely theglutathione reductases (GR) of the malarial parasite Plasmodiumfalciparum and man, the thioredoxin reductases (TrxR) of P.falciparum and man, and - as a biological standard -trypanothione reductase (TR) from Trypanosoma cruzi. Inparticular, the preparation of focused chemical libraries willbe developed by the French team (RT 1) in order to introducestructural diversity and to optimize the most potent inhibitorsof the respective enzymes, using both classical medicinalchemistry and parallel synthesis. With the expectation ofsynergistic effect, novel double-headed prodrugs will beprepared. Such compounds consist of a disulfide reductaseinhibitor linked bioreversibly to a drug that is known to bedirected to a specific subcellular compartment. Research teams2 (glutathione-dependent redox networks) and 3(thioredoxin-dependent redox proteins) will examine themodifications of enzyme structure and function exerted by thenovel lead compounds. Furthermore their effects on malarialparasites and on human cancer cell lines will be studied, withspecial emphasis on strains and cell lines that are resistanttowards the most commonly used drugs in chemotherapy, i.e. theantimalarial chloroquine (CQ) and the anticancer agentcis-dichlorodiamminoplatinum. New compounds will be selected aspotential antiparasitic or cytostatic drug candidates by thefollowing criteria: high antiparasitic or antineoplasticactivity, low toxicity against normal human cells, decrease ofintracellular glutathione, thioredoxin or trypanothione levels,reversal of drug resistance, and tolerance by blood cells ofpersons with G6PD deficiency. The lead compounds will beproduced by chemical bulk procedures and serve as candidatesfor in vivo experiments using mouse models. Validation of theselected targets will be achieved by correlating the molecularmode of action and the in vivo activities of the drugcandidates. The synergy of the three research teams has stoodthe test of practice.

针对寄生虫病和癌症的新药是迫切和持续需要的。这一交叉学科项目的目的是证实二硫化物还原酶抑制剂作为抗寄生虫剂和细胞抑制剂。这些化合物本身是活性物质，但除此之外，它们还可以逆转寄生虫和肿瘤细胞中基于硫醇的抗药性。我们的策略是基于选定靶标的抑制剂和颠覆性底物的合成，即疟疾寄生虫和人的谷胱甘肽还原酶(GR)，恶性疟原虫和人的硫氧还蛋白还原酶(TrxR)，以及-作为生物标准-来自克氏锥虫的锥虫还原酶(TRR)。特别是，法国团队将开发重点化学库的准备工作(RT 1)，以引入结构多样性，并利用经典药物化学和平行合成优化相应酶的最有效抑制剂。在期待协同效应的情况下，将会有新的双头前药被开发出来。这类化合物包括一种二硫化物还原酶抑制剂，它以生物可逆的方式连接到一种已知指向特定亚细胞室的药物上。研究小组2(谷胱甘肽依赖的氧化还原网络)和3(依赖硫氧还蛋白的氧化还原蛋白)将研究新型先导化合物对酶结构和功能的修饰。此外，还将研究它们对疟疾寄生虫和人类癌细胞株的影响，特别是对化疗中最常用的药物，即抗疟药氯喹(CQ)和抗癌剂顺式二氯二氨铂耐药的菌株和细胞系。新化合物将根据以下标准被选为潜在的抗寄生虫或抑制细胞药物候选：抗寄生虫或抗肿瘤活性高，对正常细胞毒性低，降低细胞内谷胱甘肽、硫氧还蛋白或色氨酸水平，逆转耐药性，以及G6PD缺乏者的血细胞耐受性。先导化合物将通过化学批量程序生产，并作为使用小鼠模型进行体内实验的候选者。通过将候选药物的分子作用模式和体内活性联系起来，将实现对选定目标的验证。三个研究团队的协同工作更是经受住了实践的考验。