Abstract: Type 2 diabetes mellitus (T2DM) is the most common type of diabetes. Unfortunately, current therapeutic agents are not so effective that only less than 36% of the patients have been treated satisfactorily. Thus, we set out to investigate novel small-molecule carbohydrate mimics as potential antidiabetic agents to supplement the existing medication. Selective inhibition of the transporter protein sodium-glucose cotransporter 2 (SGLT2) has emerged as a promising way to control blood glucose level in T2DM patients. We have pioneered the design and synthesis of some novel carbasugars (pseudosugars), readily available from inexpensive ᴅ-gluconolactone, which contains a metabolically stable “pseudo-glycosidic” C-O bond. Their aza-analogues (with a C-N bond) and carbon-analogues (with a C-C bond) have been prepared to provide important insights into the structure-activity relationship (SAR) of these inhibitors, thereby aiding the development of carbasugar SGLT2 inhibitors as potential antidiabetic agents. Our synthetic targets are the carbocyclic analogues of sergliflozin and dapagliflozin, which are readily accessible via various transition metal-catalyzed cross-coupling reactions. We herein describe our novel synthetic approaches towards carbasugar SGLT2 inhibitors, and discuss their SAR.
J. Syn. Org. Chem. Jpn., 2018, 76, 1215-1222.
Full text (open access): https://www.jstage.jst.go.jp/article/yukigoseikyokaishi/76/11/76_1215/_pdf/-char/en