Design, Synthesis, and Biological Evaluation of Thioglucoside Analogues of Gliflozin as Potent New Gliflozin Drugs,Journal of Medicinal Chemistry

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Design, Synthesis, and Biological Evaluation of Thioglucoside Analogues of Gliflozin as Potent New Gliflozin Drugs
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2023-08-22 , DOI: 10.1021/acs.jmedchem.3c01138
Guang-Jing Feng _{1,

2} , Yang-Fan Guo ₁ , Yuming Tang ₁ , Min Li ₁ , Yufei Jia ₁ , Zhimeng Li ₁ , Shuangshuang Wang ₁ , Hongmei Liu ₁ , Yuzhou Wu ₁ , Hai Dong ₁

Affiliation

In this study, we have investigated the potential of two classes of thioglucoside analogues of gliflozins as antidiabetic drugs, one with substitutions of S-atoms in meta-positions (similar to C-glucoside SGLT2 inhibitors, TAGs A, B, and C) and the other with substitutions of S-atoms in ortho-positions (similar to O-glucoside SGLT2 inhibitors, TAGs D, E, F, and G). These TAGs were confirmed to show good stability against β-glucosidase and to have no acute toxicity to cultured cells. Most importantly, TAGs D, E, F, and G all showed high inhibitory activity against SGLT2 (IC₅₀: 2.0–5.9 nM) and thus have great potential to be developed as new gliflozin drugs. Compared with the synthesis of C-glucoside gliflozins, the synthesis of TAGs is simple, efficient, and associated with low costs, high yields, and very mild reaction conditions.

中文翻译：

格列净硫代葡萄糖苷类似物作为有效新格列净药物的设计、合成和生物学评价

在这项研究中，我们研究了两类格列净硫代葡萄糖苷类似物作为抗糖尿病药物的潜力，一类在间位取代了 S 原子（类似于 C-葡萄糖苷 SGLT2 抑制剂，TAG A 、 B和C ），另一个在邻位取代了 S 原子（类似于O-葡萄糖苷 SGLT2 抑制剂，TAG D、E、F和G）。这些TAG被证实对β-葡萄糖苷酶表现出良好的稳定性，并且对培养细胞没有急性毒性。最重要的是，TAGs D、E、F和G均表现出对 SGLT2 的高抑制活性（IC ₅₀：2.0–5.9 nM），因此具有开发为新格列净药物的巨大潜力。与C-葡萄糖苷格列净的合成相比，TAG的合成简单、高效、成本低、收率高、反应条件非常温和。

更新日期：2023-08-22

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