Synthesis Of Selective Protein Tyrosine Phosphatases 1B(PTP1B) Inhibitor Candidates Using Sulfur(Ⅵ)-fluoride Exchange Chemistry

Nowadays,more and more people suffer from diabetes and obesity with the continuous change in the food habits and lifestyle.Diabetes has been identified as a major disease after cancer and cardiovascular disease.It is a metabolic disease caused by endocrine disorders.Diabetes is subdivided into Type 1 diabetes and Type 2 diabetes.Type 1 diabetes is an insulin-deficient disease,while Type 2 diabetes is characterized by insulin resistance.It reported that there is a relationship between obesity and diabetes which in turn related to insulin resistance.Based on the negative regulation of protein tyrosine phosphatase 1B(PTP1B)in insulin signaling,PTP1 B inhibitors can be designed to achieve hypoglycemic effects,which are critical for the treatment of diabetes or other diseases.Fragment-based drug discovery(FBDD)is an early stage drug discovery approach which uses weak binding fragments(molecular weight <300 Da)as starting points for lead development.Among the different FBDD approaches,the in situ screening approach that mainly uses click chemistry pioneered by Sharpless remains versatile to assemble enzyme inhibitors.This method neither requires sophisticated instrument nor mutation of target proteins.So far,more than 30 compounds have obtained through fragment-based drug discovery at different stages of clinical trials,and two compounds have been approved by FDA as Zelboraf and Venetoclax.Fragment-based drug discovery is now widely used in industry and academia.Protein tyrosine phosphatases(PTPs)are signaling enzymes that dephosphorylate phosphorylated tyrosine residues.Together with protein tyrosine kinases,PTPs regulate the level and extent of protein tyrosine phosphorylation and play vital roles in regulating many and diverse cellular processes.These include cell growth,proliferation and differentiation,metabolism,immune responses and cell-cell adhesion.Protein tyrosine phosphatase 1B(PTP1B)is a prototype of all PTPs.PTP1 B is believed to be the negative regulator of insulin and leptin signaling pathways.Mice lacking functional PTP1B(gene knock-out experiments)exhibit the phenotypes of increased insulin sensitivity,improved glucose tolerance,and resistance to diet-induced obesity.PTP1 B is a validated drug target and inhibitors of PTP1 B are potential therapeutics for the treatment of type 2 diabetes and obesity.However,the active site of most PTPs is highly conserved making it challenging to develop selective inhibitors against a particular PTP(including PTP1B).There is a secondary binding site adjacent to the active site of PTP1 B is known which can accommodate suitably functionalized aromatic fragments.By targeting both the active and the secondary binding sites,one could develop more specific inhibitors against PTP1 B.We have developed a new version of sulfur(Ⅵ)-fluoride exchange(Su FEx)chemistry based on vinyl silyl ethers and have developed it as a platform to assemble enzyme inhibitor candidates.Su FEx is a chemoselective reaction between a silyl ether and either a sulfonyl fluoride or a fluorosulfate in the presence of a suitable base(catalytic amount)to yield stable sulfonate or sulfate linkage.For the first time we have successfully developed this chemistry on vinyl aryl silyl ether systems.Isoxazole carboxylic acids are known cell-permeable inhibitors of PTP1 B.A variety of functionalized isoxazoles were synthesized and linked to vinyl silyl ethers.An array of aromatic compounds was designed and functionalized with either sulfonyl fluoride or fluorosulfate functionality.Right Su FEx reaction conditions to click these two types of fragments were investigated and identified,and used to construct a library of 60 candidates.Thus demonstrating Su FEx chemistry as a platform to assemble fragments.