Synthesis of Benzyl C‐Analogues of Dapagliflozin as Potential SGLT2 Inhibitors

Abstract

Sodium‐glucose co‐transporter (SGLT) inhibitors are a novel class of therapeutic agents for the treatment of type 2 diabetes based on blocking of renal reabsorption of glucose. Dapagliflozin, a C‐aryl glucoside, has emerged as a successful drug in the market based on this concept. We have synthesized hitherto unreported C‐benzyl glucoside analogues of Dapagliflozin carrying the same aglycon present in the drug. The synthetic strategy involves in situ generation of functionalized arylmagnesium bromide with Weinreb‐amide (WA) functionality for the first time, and addition on to the 1‐β‐formyl‐2,3,4,6‐tetra‐O‐benzyl‐D‐glucopyranoside for the synthesis of a C‐benzyl glucoside building block 16. The WA functionality therein enabled variation in the nature of the distal ring of biarylmethane aglycon for convenient access to other analogues. All the new compounds were screened for their sodium‐glucose co‐transporters (SGLT1 and SGLT2) inhibition activity using cell‐based nonradioactive fluorescence glucose uptake assay. Among them, 14 with IC50: 0.64 nm emerged as the most potent SGLT2 inhibitor with the best selectivity for inhibition of SGLT2 (IC50:0.64 nm) over SGLT1 (IC50: 500 nm) as compare to Dapagliflozin. On the other hand, compound 15a exhibited moderate selectivity for inhibition of SGLT2 (IC50: 4.94 nm) over SGLT1 (IC50: 68.46 nm). These results presented herein amply demonstrate the promise of C‐benzyl analogues of Dapagliflozin as novel SGLT2 inhibitors for future investigations.

Novel Sars-CoV-2 Variants & Therapeutic Effects

“…Moreover, the activity of Orf9b and its association with TOM70 was regulated by phosphorylation. We propose that more effective innate immune suppression, through enhanced expression of specific viral antagonist proteins, increases the likelihood of successful Alpha transmission, and may increase in vivo replication and duration of infection 4 . The importance of mutations outside Spike in adaptation of SARS-CoV-2 to humans is underscored by the observation that similar mutations exist in the Delta and Omicron N/Orf9b regulatory regions.…”

“…The importance of mutations outside Spike in adaptation of SARS-CoV-2 to humans is underscored by the observation that similar mutations exist in the Delta and Omicron N/Orf9b regulatory regions. Humans have infected a wide range of animals with SARS-CoV-2 viruses [1][2][3][4][5] , but the establishment of a new natural animal reservoir has not been observed. Here, we document that free-ranging white-tailed deer (Odocoileus virginianus) are highly susceptible to infection with SARS-CoV-2 virus, are exposed to a range of viral diversity from humans, and are capable of sustaining transmission in nature.…”

A Review Article on Transdermal Drug Delivery System Based On- Microneedles

“…APPLICATION OF MICRONEEDLES [31][32][33][34][35] The microneedle delivery method has seen widespread usage in cancer therapy, diabetes detection and treatment, and anti-inflammatory and analgesic treatment, among other areas, and has seen rapid development in recent years.…”

Natural Products & Bioactivity Inspired Synthetic Pursuits Interfacing with Carbohydrates: Ongoing Journey with C‐Glycosides

“…Subsequent deoxygenation using Barton ‐ McCombie deoxygenation method afforded the desired building block 130 . The Weinreb‐amide (WA) functionality in the building block allowed the formation of the diaryl ketones 146 a – f which on hydrogenation under pressure furnished the desired C ‐benzyl analogue 105 a of the drug dapagliflozin, among other analogues 105 b – f [97a] . The SGLT2 inhibition studies were performed in collaboration [97b]…”