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

对寄生虫病和癌症的新药的需求是迫切和持续的。这个跨学科项目的目的是证实二硫还原酶抑制剂作为抗寄生虫和细胞生长抑制剂。这些化合物本身是有活性的，但除此之外，它们还可以逆转寄生虫和肿瘤细胞对其他药物的基于巯基的耐药性。我们的策略是基于所选靶点的抑制剂和破坏性底物的合成，所选靶点即恶性疟原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），以及作为生物标准品的来自克氏锥虫的锥虫硫酮还原酶（TR）。特别是，法国团队（RT 1）将开发重点化学库的制备，以引入结构多样性并优化各自酶的最有效的底物，使用经典的药物化学和平行合成。在此基础上，有望制备出新型的双头前药。这种化合物由一个二硫键还原酶抑制剂与一种药物生物可逆地连接而成，这种药物已知是定向于一个特定的亚细胞区室。研究小组2（谷胱甘肽依赖的氧化还原网络）和3（硫氧还蛋白依赖的氧化还原蛋白）将研究新型先导化合物对酶结构和功能的改变。此外，还将研究它们对疟疾寄生虫和人类癌细胞系的影响，特别强调对化疗中最常用药物（即抗疟氯喹（CQ）和抗癌剂顺式二氯二氨铂）具有耐药性的菌株和细胞系。新化合物将根据以下标准被选择作为潜在的抗寄生虫或细胞生长抑制药物候选物：高抗寄生虫或抗寄生虫可塑性活性，对正常人细胞的低毒性，细胞内谷胱甘肽、硫氧还蛋白或锥虫硫酮水平的降低，耐药性的逆转，以及G6PD缺乏症患者血细胞的耐受性。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的体内实验的候选物。这些选定的靶点的验证将通过关联作用的分子模式和候选药物的体内活性来实现。三个研究团队的协同作用经受住了实践的考验。

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.