Synthesis and biological evaluation of novel C-aryl d-glucofuranosides as sodium-dependent glucose co-transporter 2 inhibitors

Lin, Tzung-Sheng; Liw, Ya-Wen; Song, Jen‐Shin; Hsieh, Tsung-Chih; Yeh, Hsien‐Wei; Hsu, Lih‐Ching; Lin, Chun-Jung; Wu, Szu-Huei; Liang, Pi‐Hui

doi:10.1016/j.bmc.2013.08.067

Cited by 13 publications

(3 citation statements)

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“…The synthetic methods of saponins have been well reviewed, providing complete information on the organic synthesis to perform SAR optimization [6,7]. Based on the research experiences on carbohydrate [8,9] and medicinal [10][11][12][13][14][15][16][17][18][19][20][21][22] chemistry in our lab, we summarize the biological effects and preliminary SAR results of synthetic saponins over the last five years to serve as a bridge between chemistry and biology, providing an insight for further structure optimization and mechanism studies, finally facilitating the development of saponin-based bioactive compounds.…”

Section: Introductionmentioning

confidence: 99%

Biological and Pharmacological Effects of Synthetic Saponins

Juang

Liang

2020

Molecules

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Saponins are amphiphilic molecules consisting of carbohydrate and either triterpenoid or steroid aglycone moieties and are noted for their multiple biological activities—Fungicidal, antimicrobial, antiviral, anti-inflammatory, anticancer, antioxidant and immunomodulatory effects have all been observed. Saponins from natural sources have long been used in herbal and traditional medicines; however, the isolation of complexed saponins from nature is difficult and laborious, due to the scarce amount and structure heterogeneity. Chemical synthesis is considered a powerful tool to expand the structural diversity of saponin, leading to the discovery of promising compounds. This review focuses on recent developments in the structure optimization and biological evaluation of synthetic triterpenoid and steroid saponin derivatives. By summarizing the structure–activity relationship (SAR) results, we hope to provide the direction for future development of saponin-based bioactive compounds.

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Section: Introductionmentioning

confidence: 99%

Biological and Pharmacological Effects of Synthetic Saponins

Juang

Liang

2020

Molecules

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“…117 Furthermore, dapagliflozin-derived D-glucofuranosides were synthesized to assess the effect exerted on SGLT-2 inhibition by the furanosic form of the glucose moiety. 118 While the furanoside analogue of dapagliflozin was shown to be inactive (26a, IC 50 > 50 μM) compared to the parent drug, the replacement of the ethoxy group on the distal phenyl ring with an ethyl and the simultaneous introduction of a methoxy in the position 6 of the proximal phenyl ring led to the most effective SGLT-2 inhibitor of this series (compound 26b, Figure 12) with an IC 50 value of 0.62 μM toward hSGLT-2 and 47-fold selectivity over hSGLT-1. 118 However, all tested glucofuranosides turned out to be markedly less potent SGLT-2 inhibitors than glucopyranosides, revealing that the pyranose ring is required to effectively inhibit SGLT symporters through an optimal adaptation to their glucose binding site.…”

Section: Sglt-1 and Sglt-2 Inhibitors: From Discovery To Development ...mentioning

confidence: 99%

Sodium-Glucose Cotransporter Inhibitors as Antidiabetic Drugs: Current Development and Future Perspectives

Maccari

Ottanà

2022

J. Med. Chem.

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Sodium-glucose cotransporter 2 (SGLT-2) inhibitors (gliflozins) represent the most recently approved class of oral antidiabetic drugs. SGLT-2 overexpression in diabetic patients contributes significantly to hyperglycemia and related complications. Therefore, SGLT-2 became a highly interesting therapeutic target, culminating in the approval for clinical use of dapagliflozin and analogues in the past decade. Gliflozins improve glycemic control through a novel insulin-independent mechanism of action and, moreover, exhibit significant cardiorenal protective effects in both diabetic and nondiabetic subjects. Therefore, gliflozins have received increasing attention, prompting extensive structure− activity relationship studies and optimization approaches. The discovery that intestinal SGLT-1 inhibition can provide a novel opportunity to control hyperglycemia, through a multifactorial mechanism, recently encouraged the design of low adsorbable inhibitors selectively directed to the intestinal SGLT-1 subtype as well as of dual SGLT-1/SGLT-2 inhibitors, representing a compelling strategy to identify new antidiabetic drug candidates.

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“…In the past decade, several other modified C -arylglucosides were synthesized in pursuit of achieving better efficacy. In addition to this, a myriad of novel synthetic routes were also explored to obtain cost-effective processes to address the needs of diabetic patients . Several of these C -arylglucosides, namely, Dapagliflozin, Empagliflozin, Tofogliflozin, Sotagliflozin, Ipragliflozin, Luseogliflozin, PF-04971729, and YM543 (Figure ), are currently under different stages of clinical trials, and a few of them have been approved.…”

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confidence: 99%