Recent Advances on SGLT 2 Inhibitors: Synthetic Approaches, Therapeutic Benefits, and Adverse Events

Glucosylpolyphenols as Inhibitors of Aβ-Induced Fyn Kinase Activation and Tau Phosphorylation: Synthesis, Membrane Permeability, and Exploratory Target Assessment within the Scope of Type 2 Diabetes and Alzheimer’s Disease

“…16,[18][19][20][21] Importantly, C-glycosyl polyphenols are not liable to chemical and enzymatic hydrolysis, as sugar is linked to the polyphenol by a C-C bond, and have been described to show higher antidiabetic effects with improved target selectivity; for instance, the glucosyldihydrochalcone analogue of the glucoside phlorizin is selective towards SGLT-2 vs. SGLT-1 transporters, while phlorizin is not. [22][23][24] For all the above mentioned reasons, we were interested in exploring the potential multitarget bioactivity of glucosylpolyphenols based on the structure of 8-β-D-glucosylgenistein (1, Figure 1), a natural glucosylisoflavone previously reported by our group as a new and potent antidiabetic compound with potential against Aβ 1−42 -induced neurotoxicity. 25 This compound was found to inhibit IAPP aggregation and to interact with Aβ(1-42) polypeptide through the same binding mode, involving the sugar moiety, H-6 of ring A, and the aromatic protons of ring B.…”

“…For this purpose, we turned to nature for inspiration. Polyphenols have been widely reported in the literature for their vast therapeutic potential, with described antidiabetic, anti-inflammatory, and neuroprotective effects. ,− Polyphenol glucosides ( O -glucosyl polyphenols) and glucosylpolyphenols ( C -glucosyl polyphenols, frequently named as polyphenol C -glucosides), however, have improved palatability, oral bioavailability due to increased solubility, and enhanced biological activity when compared to the corresponding aglycones, including improved amyloid-remodeling effects. ,− Importantly, C- glucosyl polyphenols are not liable to chemical and enzymatic hydrolysis, as sugar is linked to the polyphenol by a C–C bond, and have been described to show higher antidiabetic effects with improved target selectivity; for instance, the glucosyldihydrochalcone analogue of the glucoside phlorizin is selective toward SGLT-2 vs SGLT-1 transporters, while phlorizin is not. − …”

The (Poly)phenol-Carbohydrate Combination for Diabetes: Where Do We Stand?

“…Notwithstanding, for natural (poly)phenols that do pass that stage, there are strong hints that C -glucosylation should be considered when it comes to the pursuit of non-reactive lipophilic (poly)phenols with antidiabetic properties: (1) C -glucosides extracted from natural plant sources are increasingly recognized as functional ingredients for their potent antihyperglycaemic, anti-aggregation, and antioxidant bioactivities, both alone or in combination with other antidiabetic compounds [ 17 , 22 , 23 , 24 , 25 , 26 ]; (2) sugar-linked compounds may exhibit improved toxicity, solubility, and membrane permeability profiles versus their aglycones, which may enhance their bioavailability [ 27 , 28 , 29 ]; (3) when compared to O -glycosides, their (poly)phenol C -glucosyl analogs may also lead to improved selectivity and metabolic stability [ 17 , 30 ]; (4) as mentioned above, they seem to prevent membrane-disrupting effects of lipophilic (poly)phenol PAINS/IMPs [ 14 ]. Let us consider the successful case of gliflozins, a class of C -glucosyl aromatic compounds originally developed and approved as SGLT2 inhibitors for the treatment of type 2 diabetes [ 31 ]. The primary ancestor of gliflozins is the natural membrane dipole potential reducer phloretin, found in apples, pears, and other fruits [ 32 ].…”

“…This and several other steps of structural optimization culminated in the approval of dapagliflozin in 2014, a life-changer for millions of diabetic patients around the world. Many more gliflozins have been developed for the treatment of type 2 diabetes since, and additional indications focused on typical comorbidities of diabetes, such as heart and kidney disease, have been approved in recent years [ 31 ]. This further highlights the intrinsic value of these C -glucosyl aromatic molecules as multitarget antidiabetic agents.…”