Design And Synthesis Of Potential Monosaccharide-based Inhibitors Against PTP1B/SHP-2/Cdc25B Via CuAAC

CuAAC(Cu(I)-catalyzed azide and alkyne cycloaddition), better known as "Click Chemistry", plays a pivotal role in chemical biology and drug discovery. As members of PTPs(protein tyrosin phosphatases), PTP1B is a potent target for treating type 2 diabetes, obesis and even some cancers; SHP-2 is expected to be useful in the therapy for a lot of leukemia and solid tumors; Cdc25B is linked to oncogenic transformation and human cancers. Monosaccharides have always been considered as desired scaffolds for their chiral properties and unique bioactivities.Based upon the above mentioned, a series of glucose-based salicylic bidentates were designed, synthesized via CuAAC and assayed against PTP1B to gauge their potential inhibitory activities, and the results show that some compounds are modest PTP1B inhitors, among which compound 23 is the best (IC50=7.7μM) with a 7-fold selectivity over TCPTP. A library of glucose-based serine derivatives were designed to inhibit PTP1B, SHP-2 and Cdc25B selectively, and the required azides as well as alkyne were synthesized and are expected to react with each other via CuAAC to afford the trizole products, which are to be screened for inhibitory efficacy. Also a series of glucose- and galactose-based aryl diketo acids were designed as potential PTP1B inhitors, which were not obtained due to the unexpected cleavage of C-C bond, and among the 8 obtained sugar-based aryl ketones 2 compounds exhibit poor inhibition activities with IC5068.1μM and 33.3μM respectively.