Sulfonyl Group-Containing Compounds in the Design of Potential Drugs for the Treatment of Diabetes and Its Complications

Abstract

Sulfonyl group-containing compounds constitute an important class of therapeutical agents in medicinal chemistry presumably because of the tense chemical structure and functionality of the sulfonyl, which could not only form hydrogen bonding interactions with active site residues of biological targets but also, as incorporated into core ring structure, constrain the side chains and allowed their specific conformations that fit the active sites. This review focuses on sulfonamides and sulfones, which cover more than 40 series and are associated with at least 10 potential pharmaceutical targets in pathways of glucose metabolism and insulin signaling. A large number of such compounds have been reported as pharmaceuticals every year in the last decade. In particular, increasing studies suggest that sulfonamides and sulfones play a key role in the design of pharmaceutical agents with potential application for the treatment of diabetes and its complications. First, they are inhibitors of a variety of enzymes including 11β-hydroxysteroid dehydrogenase type 1, α- glucosidase, carnitine palmitoyltransferase and cytosolic phosphoenolpyruvate carboxykinase, and in turn involved in the regulation of the metabolism of glucose. In addition, they are active as activators of glucokinase and as antagonists of ghrelin receptors. These enzyme and receptors are tightly associated with the regulation of glucose metabolism and the improvement of insulin resistance. Secondly, sulfonamides and sulfones act in the insulin secretion. As agonists, they activate insulin receptor tyrosine kinase and thus increase insulin sensitivity. Moreover, they as inhibitors suppress protein tyrosine phosphatase 1B and dipeptidyl peptidase IV, and thus normalize the insulin signaling pathway. Finally, a number of sulfonamides and sulfones are inhibitors of aldose reductase, which have been linked to diabetic complications.

RASS‐Enabled S/P−C and S−N Bond Formation for DEL Synthesis

“…Previously this process has been used to construct high value C(sp 2 )−C(sp 3 ), and C(sp 2 )−N bonds through a low valent nickel mediator that was shown to be water sensitive . These results inspired the pursuit of a suite of reactions for the robust incorporation of medicinally relevant C−S and S−N bonds on‐DNA …”

A map describing the association between effective components of traditional Chinese medicine and signaling pathways in cancer cells in vitro and in vivo

“…In recent years, a few reports suggested that certain kinds of chemical structures may relate to some corresponding cellular signaling pathways (5). Thus, we summarized the last five years' studies on TCM components functions on cancer cell signaling pathways and aimed at looking for association between chemical structure of TCM constituents and cancer cell signaling pathways.…”

A Novel Sulfonyl-Based Small Molecule Exhibiting Anti-cancer Properties

“…In the same context, we believe that the sulfonyl group might impart the bioactivity of InhiTinib. In fact, sulfonyls are present in several established drugs known to antagonize multiple enzymes and receptors partaking in cellular processes such as metabolic regulation, angiogenesis, and tumor progression (Casini et al, 2002;Chen et al, 2012). Accordingly, InhiTinib may target: (i) the unfolded protein response by binding to heat shock factor 1 protein, (ii) the epigenome of cancer cells via histone methyltransferases modulation, and/or (iii) reduce antioxidant defenses by inhibiting thioredoxin reductase activity.…”

“…Using this HTS assay, we discovered a small compound, we named InhiTinib, exhibiting both immunomodulatory and anti-cancer properties. Although the involved molecular targets are still under investigation, InhiTinib's dual activity might originate from its sulfonyl group, which is a known bioactive entity affecting metabolic signaling pathways and present in several FDA-approved drugs (Chen et al, 2012;Piton et al, 2018). Indeed, InhiTinib's properties were herein elucidated in a series of in vitro and in vivo experiments which further test its safety and efficacy while highlighting its therapeutic potential.…”