Discovery of benzo[d]isothiazole derivatives as novel scaffold inhibitors targeting the programmed cell death-1/programmed cell death-ligand 1 (PD-1/PD-L1) interaction through “ring fusion” strategy was written by Gao, Yinli;Wang, Hanxun;Shen, Lanlan;Xu, Hanqing;Deng, Minghui;Cheng, Maosheng;Wang, Jian. And the article was included in Bioorganic Chemistry in 2022.COA of Formula: C3H9NO The following contents are mentioned in the article:
The inhibition of programmed cell death-1/programmed cell death-ligand 1 (PD-1/PD-L1) interaction by monoclonal antibodies (mAbs) has achieved promising outcomes in cancer immunotherapy. Due to the inherent deficiencies of mAbs drugs, such as high cost of treatment, immunogenicity, poor pharmacokinetics and penetration of solid tumors, researchers are encouraged to develop small mol. inhibitors, to overcome mAbs drugs deficiencies and change the situation where small mol. drugs are not available on the market. Herein, we reported a series of benzo[d]isothiazole derivatives targeting the PD-1/PD-L1 interaction through “ring fusion” strategy using BMS-202 as a starting point. Among them, compound (3-bromo-4-((7-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)benzo[d] isothiazol-3-yl)amino)benzyl)-L-serine exhibited the best inhibitory activity with an IC50 value of 5.7 nM by homogeneous time-resolved fluorescence (HTRF) binding assay. In immunotoxicity anal., (3-bromo-4-((7-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)benzo[d] isothiazol-3-yl)amino)benzyl)-L-serine showed low cytotoxicity to Jurkat T cells in CCK-8 assay compared to BMS-202. The binding mode between (3-bromo-4-((7-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)benzo[d] isothiazol-3-yl)amino)benzyl)-L-serine and PD-L1 protein was explored by mol. docking and mol. dynamics (MD) simulations, which revealed crucial chem. groups, such as biphenyl group interacting with Ile54A, Tyr56A, Met115A, Ala121A, Ile54B, Met115B, Ala121B and Tyr123B by hydrophobic interactions, bromobenzene moiety forming π-π stacking interaction with Tyr56B, as well as L-serine moiety forming hydrogen bond (H-bond) and salt bridge interactions with Asp122A and Lys124A. Furthermore, mol. modeling studies showed that (3-bromo-4-((7-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)benzo[d] isothiazol-3-yl)amino)benzyl)-L-serine is likely to bind to the FA8 (fatty acid 8) binding site of human serum albumin (HSA). Taken together, (3-bromo-4-((7-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)benzo[d] isothiazol-3-yl)amino)benzyl)-L-serine significantly inhibits the PD-1/PD-L1 interaction with low cytotoxicity, indicating that (3-bromo-4-((7-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)benzo[d] isothiazol-3-yl)amino)benzyl)-L-serine is a promising starting point for further drug development in cancer immunotherapy. This study involved multiple reactions and reactants, such as 2-Methoxyethylamine (cas: 109-85-3COA of Formula: C3H9NO).
2-Methoxyethylamine (cas: 109-85-3) belongs to ethers. Esters are widespread in nature and are widely used in industry. In nature, fats are in general triesters derived from glycerol and fatty acids. Esters are responsible for the aroma of many fruits. Esterification is the general name for a chemical reaction in which two reactants (typically an alcohol and an acid) form an ester as the reaction product. Esters are common in organic chemistry and biological materials.COA of Formula: C3H9NO
Referemce:
Ether – Wikipedia,
Ether | (C2H5)2O – PubChem