The antioxidant 2,6-di-tert-butylphenol moiety attenuates the pro-oxidant properties of the auranofin analogue†,Metallomics

当前位置： X-MOL 学术 › Metallomics › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

The antioxidant 2,6-di-tert-butylphenol moiety attenuates the pro-oxidant properties of the auranofin analogue†
Metallomics ( IF 2.9 ) Pub Date : 2018-01-17 00:00:00 , DOI: 10.1039/c7mt00286f
D. B. Shpakovsky _{1,

2,

3,

4} , A. A. Shtil _{1,

2,

3,

4,

5} , E. V. Kharitonashvili _{1,

2,

3,

4} , V. Yu. Tyurin _{1,

2,

3,

4} , T. A. Antonenko _{1,

2,

3,

4} , A. A. Nazarov _{1,

2,

3,

4} , V. P. Osipova _{4,

6,

7} , N. T. Berberova _{4,

6,

7} , L. S. Foteeva _{3,

4,

8} , C. Schmidt _{9,

10,

11,

12} , I. Ott _{9,

10,

11,

12} , E. R. Milaeva _{1,

2,

3,

4}

Affiliation

Metal-based drugs are gaining momentum as a rapidly developing area of medicinal inorganic chemistry. Among gold pharmaceuticals, auranofin is a well known antirheumatic drug. The efficacy of gold–organic complexes largely depends on their pro-oxidant properties since auranofin targets the redox enzyme thioredoxin reductase (TrxR). However, an uncontrollable oxygen burst may be harmful for healthy cells; therefore, the search for chemical modifications to attenuate oxidation-related general toxicity of gold containing anti-inflammatory drugs is justified. In this study, we demonstrate that the incorporation of a specific antioxidant phenol fragment can counterbalance the pro-oxidative potential of the Au containing complex molecule. The electrochemical studies of AuPPh₃SR (1, R= 3,5-di-tert-butyl-4-hydroxyphenyl) and its precursors AuPPh₃Cl (2) and RSH (3) showed that complex 1 and phenol 3 efficiently scavenged the radicals (as detected by cyclic voltammetry) whereas 2 had no effect. Compound 1 inhibited TrxR in vitro with IC₅₀ 0.57 ± 0.15 μM, a value one order of magnitude bigger than the potency reported for auranofin. Compound 1 (5 mg kg⁻¹ daily gavage for 14 days) caused a decrease in ex vivo spontaneous and ascorbate-induced lipid peroxidation in the homogenates of rat lung, heart muscle, spleen, liver, kidneys, testicles and brain as assessed by the thiobarbituric acid reactive substances. Importantly, in animals fed with 1, no discernible general toxicity was registered suggesting that this compound is well tolerated. Our results provide evidence for an efficient synthetic route to obtain gold containing anti-inflammatory drug candidates with balanced pro/anti-oxidative properties.

中文翻译：

抗氧化剂2,6-二叔丁基苯酚部分减弱了金诺芬类似物的促氧化性能†

作为药物无机化学的快速发展领域，金属基药物正获得发展势头。在金药物中，金诺芬是众所周知的抗风湿药。金-有机配合物的功效在很大程度上取决于其促氧化剂特性，因为金诺芬可靶向氧化还原酶硫氧还蛋白还原酶（TrxR）。但是，无法控制的氧气爆发可能对健康的细胞有害。因此，寻求化学修饰以减弱含金的消炎药与氧化有关的一般毒性的理由是合理的。在这项研究中，我们证明了特定抗氧化剂酚片段的掺入可以抵消含金复合分子的促氧化潜力。AuPPh ₃ SR（1，R = 3,5-二叔丁基-4-羟苯基）及其前体AuPPh ₃ Cl（2）和RSH（3）表明，配合物1和酚3有效清除了自由基（通过循环伏安法检测），而2没有效果。化合物1体外抑制TrxR的IC _50为0.57±0.15μM，该值比报道的金诺芬的效价大一个数量级。化合物1（5 mg kg ^-1的每天灌食14天）导致离体量减少通过硫代巴比妥酸反应性物质评估，大鼠肺，心肌，脾脏，肝脏，肾脏，睾丸和脑的匀浆中自发和抗坏血酸诱导的脂质过氧化作用。重要的是，在饲喂1的动物中，没有发现可识别的一般毒性，表明该化合物具有良好的耐受性。我们的结果为获得具有平衡的前/后抗氧化特性的含金消炎药候选物的有效合成途径提供了证据。

更新日期：2018-01-17

点击分享查看原文

点击收藏

阅读更多本刊最新论文本刊介绍/投稿指南11