Fragment-growing guided design of Keap1-Nrf2 protein-protein interaction inhibitors for targeting myocarditis was written by Meng, Ning;Tang, Hua;Zhang, Hao;Jiang, Chengshi;Su, Li;Min, Xiao;Zhang, Wannian;Zhang, Hua;Miao, Zhenyuan;Zhang, Wen;Zhuang, Chunlin. And the article was included in Free Radical Biology & Medicine in 2018.Electric Literature of C7H4ClF3O2S This article mentions the following:
Small-mol. inhibitors that block the Keap1-Nrf2 protein-protein interactions are being intensely pursued as a new therapeutic strategy for oxidative stress-related diseases, such as cancer, diabetes, Alzheimer’s disease, arteriosclerosis, inflammation and myocarditis. However, there are not enough studies on antioxidant treatments using small mols. in myocarditis. The authors herein provided a series of novel hydronaphthoquinones as the Keap1-Nrf2 interaction inhibitors targeting LPS-induced myocarditis both in vitro and in vivo. These compounds were designed through an in-silico fragment growing approach based on the previous reported compound The new compounds were predicted to form addnl. hydrogen bonds with the S363 residue, leading to higher inhibitory activity. Among these new derivatives, compounds I and II emerged as inhibitors with significant biochem. potency, as determined by fluorescent anisotropy assay and confirmed by surface plasmon resonance (SPR) and differential scanning fluorometry (DSF) assays. These inhibitors can dose-dependently protect the H9c2 cardiac cells against LPS-induced injury (100% at 2 μM and 4 μM) and effectively prolong survival or save the life of LPS-injured mice. Mechanistic studies showed that these inhibitors could release Nrf2 in H9c2 cells and LPS-inflammatory mouse models and translocate into the nucleus in a dose-response manner, which significantly increased the downstream genes (HO-1, NQO-1) and the pro-inflammatory cytokines (TNF-α, IL-1β, IL-6), while ROS production dramatically decreased. Their protective effects and the mechanism of action were further confirmed by siNrf2 transfected experiment Collectively, the novel hydronaphthoquinones can be used as promising lead compounds for the study of Keap1-Nrf2 protein-protein interactions and further antimyocarditis drug development. In the experiment, the researchers used many compounds, for example, 3-(Trifluoromethyl)benzene-1-sulfonyl chloride (cas: 777-44-6Electric Literature of C7H4ClF3O2S).
3-(Trifluoromethyl)benzene-1-sulfonyl chloride (cas: 777-44-6) belongs to organic chlorides. Organochlorines are organic compounds having multiple chlorine atoms. They were the first synthetic pesticides that were used in agriculture. They are resistant to most microbial and chemical degradations. Alkyl chlorides are versatile building blocks in organic chemistry. While alkyl bromides and iodides are more reactive, alkyl chlorides tend to be less expensive and more readily available.Electric Literature of C7H4ClF3O2S
Referemce:
Chloride – Wikipedia,
Chlorides – an overview | ScienceDirect Topics