Structural Modification of Aminophenylarsenoxides Generates Candidates for Leukemia Treatment via Thioredoxin Reductase Inhibition,Journal of Medicinal Chemistry

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Structural Modification of Aminophenylarsenoxides Generates Candidates for Leukemia Treatment via Thioredoxin Reductase Inhibition
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2021-10-27 , DOI: 10.1021/acs.jmedchem.1c01441
Zi-Long Song _{1,

2} , Junmin Zhang _{1,

3} , Qianhe Xu ₁ , Danfeng Shi ₁ , Xiaojun Yao _{1,

3} , Jianguo Fang ₁

Affiliation

Upregulation of the selenoprotein thioredoxin reductase (TrxR) is of pathological significance in maintaining tumor phenotypes. Thus, TrxR inhibitors are promising cancer therapeutic agents. We prepared different amino-substituted phenylarsine oxides and evaluated their cytotoxicity and inhibition of TrxR. Compared with our reported p-substituted molecule (8), the o-substituted molecule (10) shows improved efficacy (nearly a fourfold increase) to kill leukemia HL-60 cells. Although the compounds 8 and 10 display similar potency to inhibit the purified TrxR, the o-substitution 10 exhibits higher potency than the p-substitution 8 to inhibit the cellular TrxR activity. Molecular docking results demonstrate the favorable weak interactions of the o-amino group with the TrxR C-terminal active site. Efficient inhibition of TrxR consequently induces the oxidative stress-mediated apoptosis of cancer cells. Silence of the TrxR expression sensitizes the cells to the arsenic compound treatment, further supporting the critical involvement of TrxR in the cellular actions of compound 10.

中文翻译：

氨基苯砷氧化物的结构修饰通过抑制硫氧还蛋白还原酶产生用于白血病治疗的候选药物

硒蛋白硫氧还蛋白还原酶（TrxR）的上调在维持肿瘤表型方面具有病理学意义。因此，TrxR 抑制剂是有前途的癌症治疗剂。我们制备了不同的氨基取代的苯胂氧化物，并评估了它们的细胞毒性和对 TrxR 的抑制作用。与我们报道的p取代分子 ( 8 ) 相比，o取代分子 ( 10 ) 显示出提高的杀死白血病 HL-60 细胞的功效（几乎增加了四倍）。尽管化合物8和10显示出相似的抑制纯化 TrxR 的效力，但o-取代10显示出比p更高的效力-取代8以抑制细胞TrxR活性。分子对接结果表明邻氨基与 TrxR C 末端活性位点之间存在有利的弱相互作用。因此，有效抑制 TrxR 会诱导氧化应激介导的癌细胞凋亡。TrxR 表达的沉默使细胞对砷化合物处理敏感，进一步支持了 TrxR 在化合物10的细胞作用中的关键参与。

更新日期：2021-11-11

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