Characterization of potent and selective iodonium-class inhibitors of NADPH oxidases.
Characterization of potent and selective iodonium-class inhibitors of NADPH oxidases.
复制标题
NADPH 氧化酶的有效选择性碘鎓类抑制剂的表征。
DOI：
10.1016/j.bcp.2017.07.007
复制
发表时间：
2017-11-01
影响因子：
5.8
通讯作者：
Doroshow JH
中科院分区：
文献类型：
--
作者：
Lu J;Risbood P;Kane CT Jr;Hossain MT;Anderson L;Hill K;Monks A;Wu Y;Antony S;Juhasz A;Liu H;Jiang G;Harris E;Roy K;Meitzler JL;Konaté M;Doroshow JH
NADPH氧化酶（NOXs）在炎症相关疾病和癌症的发生和发展中发挥着公认的作用。迄今为止，通过高通量筛选或有针对性地破坏NOX相互作用伙伴，已经开发了几种NOX抑制剂，尽管只有少数进入临床试验。为了提高碘类氮氧化物抑制剂二苯碘（diphenylene iodonium， DPI）的有效性和生物利用度，我们合成了36种DPI类似物，重点研究了其溶解度和功能化性能。通过对依赖NOX增殖潜能的结肠癌细胞系（HT-29）的细胞活力和克隆性研究，研究了类似物的抑制活性。在相关的碘类似物浓度下，细胞呼吸也没有改变。此外，在表达特定NOX异构体的细胞模型中，通过超氧化物发光试验或Amplex Red®H2O2生成试验来评估ROS生成的抑制作用。DPI和四种类似物（NSCs 740104、751140、734428、737392）以浓度依赖性的方式强烈抑制HT-29细胞的生长和ROS的产生。NSC 737392和734428在元位上都有硝基官能团，它们对双氧化酶2 （DUOX2）过表达的细胞产生ROS的活性比其他化合物高10倍（IC50≈200-400 nM）。在此基础上，合成了具有最佳抗DUOX2效价的NSC 780521并进行了实验。具有抗癌活性的碘类似物，包括第一代针对DUOX2特异性提高的靶向药物，可能为nox驱动的肿瘤提供一种新的治疗方法。
The NADPH oxidases (NOXs) play a recognized role in the development and progression of inflammation-associated disorders, as well as cancer. To date, several NOX inhibitors have been developed, through either high throughput screening or targeted disruption of NOX interaction partners, although only a few have reached clinical trials. To improve the efficacy and bioavailability of the iodonium class NOX inhibitor diphenylene iodonium (DPI), we synthesized 36 analogs of DPI, focusing on improved solubility and functionalization. The inhibitory activity of the analogs was interrogated through cell viability and clonogenic studies with a colon cancer cell line (HT-29) that depends on NOX for its proliferative potential. Lack of altered cellular respiration at relevant iodonium analog concentrations was also demonstrated. Additionally, inhibition of ROS generation was evaluated with a luminescence assay for superoxide, or by Amplex Red® assay for H2O2 production, in cell models expressing specific NOX isoforms. DPI and four analogs (NSCs 740104, 751140, 734428, 737392) strongly inhibited HT-29 cell growth and ROS production with nanomolar potency in a concentration-dependent manner. NSC 737392 and 734428, which both feature nitro functional groups at the meta position, had >10-fold higher activity against ROS production by cells that overexpress dual oxidase 2 (DUOX2) than the other compounds examined (IC50 ≈ 200–400 nM). Based on these results, we synthesized and tested NSC 780521 with optimized potency against DUOX2. Iodonium analogs with anticancer activity, including the first generation of targeted agents with improved specificity against DUOX2, may provide a novel therapeutic approach to NOX-driven tumors.
登录
查看更多内容
影响因子：
4
作者：
Gianni, Davide;Taulet, Nicolas;Zhang, Hui;DerMardirossian, Celine;Kister, Jeremy;Martinez, Luis;Roush, William R.;Brown, Steven J.;Bokoch, Gary M.;Rosen, Hugh
通讯作者：
Rosen, Hugh
影响因子：
7.4
作者：
Antony, Smitha;Wu, Yongzhong;Hewitt, Stephen M.;Anver, Miriam R.;Butcher, Donna;Jiang, Guojian;Meitzler, Jennifer L.;Liu, Han;Juhasz, Agnes;Lu, Jiamo;Roy, Krishnendu K.;Doroshow, James H.
通讯作者：
Doroshow, James H.
基于NCI-60人类肿瘤细胞板的分子谱，黄素脱氢酶抑制剂二苯基二苯和DI-2-噻二乙烯二元的作用机理。
影响因子：
5.8
作者：
Doroshow, James H.;Juhasz, Agnes;Ge, Yun;Holbeck, Susan;Lu, Jiamo;Antony, Smitha;Wu, Yongzhong;Jiang, Guojian;Roy, Krishnendu
通讯作者：
Roy, Krishnendu
碘苯立级黄素脱氢酶抑制剂对生长，活性氧的产生，细胞周期进展，NADPH氧化酶1水平以及人类结肠癌细胞和异种移植物中的基因表达的影响。
影响因子：
7.4
作者：
Doroshow, James H.;Gaur, Shikha;Markel, Susan;Lu, Jiamo;van Balgooy, Josephus;Synold, Timothy W.;Xi, Bixin;Wu, Xiwei;Juhasz, Agnes
通讯作者：
Juhasz, Agnes
影响因子：
8
作者：
Altenhofer, Sebastian;Kleikers, Pamela W. M.;Radermacher, Kim A.;Scheurer, Peter;Hermans, J. J. Rob;Schiffers, Paul;Ho, Heidi;Wingler, Kirstin;Schmidt, Harald H. H. W.
通讯作者：
Schmidt, Harald H. H. W.