N-Acylamino Saccharin as an Emerging Cysteine-Directed Covalent Warhead and Its Application in the Identification of Novel FBPase Inhibitors toward Glucose Reduction

Abstract

With a resurgence of covalent drugs, there is an urgent need for the identification of new moieties capable of cysteine bond formation. Herein, we report on the N-acylamino saccharin moieties capable of novel covalent reactions with cysteine. Their utility as alternative electrophilic warheads was demonstrated through the covalent modification of fructose-1,6bisphosphatase (FBPase), a promising target associated with cancer and type 2 diabetes. The cocrystal structure of title compound W8 bound with FBPase unexpectedly revealed that the N-acylamino saccharin moiety worked as an electrophile warhead that covalently modified the noncatalytic C128 site in FBPase while releasing saccharin, suggesting a previously undiscovered covalent reaction mechanism of saccharin derivatives with cysteine. Treatment of title compound W8 displayed potent inhibition of glucose production in vitro and in vivo. This newly discovered reactive warhead supplements the current repertoire of cysteine covalent modifiers while avoiding some of the limitations generally associated with established moieties.

Robust links in photoactive covalent organic frameworks enable effective photocatalytic reactions under harsh conditions

“…To demonstrate this deduction, the core fragments of both quinoline-linked COFs with their related imine-linked COFs were then constructed to determine the orbital distribution of electrons in the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO) by DFT calculations (Fig. 5j–m ) with the basis set of b3lyp/6-311 g + (d, p) 68 , 69 . According to the calculated results, TFPA-TAPT-COF-Q showed a more dispersed electron distribution in LUMO as compared to TFPA-TAPT-COF (Fig.…”