Evaluation of (S)‐ and (R)‐Misonidazole as GPX Inhibitors: Synthesis, Characterization Including Circular Dichroism and In Vitro Testing on Bovine GPx‐1
Evaluation of (S)‐ and (R)‐Misonidazole as GPX Inhibitors: Synthesis, Characterization Including Circular Dichroism and In Vitro Testing on Bovine GPx‐1
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DOI：
10.1002/ardp.201300285
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发表时间：
2014-03
影响因子：
5.1
通讯作者：
F. Wilde;C. Chamseddin;Heidi L. Lemmerhirt;P. Bednarski;T. Jira;A. Link
中科院分区：
文献类型：
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作者：
F. Wilde;C. Chamseddin;Heidi L. Lemmerhirt;P. Bednarski;T. Jira;A. Link
外消旋米索硝唑是一种放射增敏剂，曾被报道对小鼠谷胱甘肽过氧化物酶（GPX）有较强的抑制作用。这似乎使米索硝唑有资格作为开发新型GPX抑制剂的先导结构，以在化疗耐药肿瘤中引起氧化应激。米索硝唑作为GPX抑制剂的独特特征是不存在硫醇官能团。因此，预期其选择性靶向抑制，而不与阳离子和巯基发生混杂相互作用。我们合成了米索硝唑的异构体，并分析了手性高效液相色谱（HPLC）鉴别特定对映体的能力。由于手性池合成，可以验证正确构型的归属。最后，我们评估了两种异构体对牛红细胞GPx-1的抑制活性，该酶与人类酶具有87%的同源性。尽管之前报道了外消旋米索硝唑对同源性较低的小鼠GPx-1的抑制作用，但我们没有发现任何异构体对牛酶的显著抑制活性。虽然米索硝唑似乎不太可能是人类GPx-1活性的抑制剂，但我们仍然认为米索硝唑通常是一种有前途的片段样先导结构。
Racemic misonidazole, a radiosensitizer formally used in radiation therapy of cancer and to date still applied, was once reported to exhibit strong inhibitory effects on mouse glutathione peroxidases (GPX). This appeared to qualify misonidazole as a lead structure for the development of novel GPX inhibitors to cause oxidative stress in chemotherapy‐resistant tumors. A unique feature of misonidazole as an inhibitor of GPX is the absence of a thiol functionality. Therefore, it was expected to selectively target inhibition devoid of promiscuous interactions with cations and sulfhydryl groups. We synthesized the isomers of misonidazole and analyzed the ability of chiroptical high‐performance liquid chromatography (HPLC) to identify the particular enantiomers. Due to the chiral pool synthesis, the assignment of the correct configuration could be verified. Finally, we evaluated both isomers for their inhibitory activities on bovine erythrocyte GPx‐1, which is 87% homologous to the human enzyme. Despite the previously reported inhibition of racemic misonidazole on the less homologous mouse GPx‐1, we did not find any significant inhibitory activity on the bovine enzyme for either isomer. Though misonidazole appears unlikely to be an inhibitor of human GPx‐1 activity, we still spotlight misonidazole as a promising fragment‐like lead structure in general.