Xanthones with multiple roles against diabetes: their synthesis, structure-activity relationship, and mechanism studies

IF 3.5 4区医学 Q2 CHEMISTRY, MEDICINAL

Drug Development Research Pub Date : 2024-03-13 DOI:10.1002/ddr.22170

Youhong Ke, Qinfang Xu, Jianling Hu, Jianrun Zhang, Shijian Chen, Zhijun Liu, Shuling Peng, Chao Zhang, Zhenqiang Chen, Heru Chen

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引用次数: 0

Abstract

A four-step synthetic process has been developed to prepare 1,3,5,8-tetrahydroxyxanthone (2a) and its isomer 1,3,7,8-tetrahydroxyxanthone (2b). 25 more xanthones were also synthesized by a modified scheme. Xanthone 2a was identified as the most active inhibitor against both α-glucosidase and aldose reductase (ALR2), with IC₅₀ values of 7.8 ± 0.5 μM and 63.2 ± 0.6 nM, respectively, which was far active than acarbose (35.0 ± 0.1 μM), and a little more active than epalrestat (67.0 ± 3.0 nM). 2a was also confirmed as the most active antioxidant in vitro with EC₅₀ value of 8.9 ± 0.1 μM. Any structural modification including methylation, deletion, and position change of hydroxyl group in 2a will cause an activity loss in inhibitory and antioxidation. By applying a H₂O₂-induced oxidative stress nematode model, it was confirmed that xanthone 2a can be absorbed by Caenorhabditis elegans and is bioavailable to attenuate in vivo oxidative stress, including the effects on lifespan, superoxide dismutase, Catalase, and malondialdehyde. 2a was verified with in vivo hypoglycemic effect and mitigation of embryo malformations in high glucose. All our data support that xanthone 2a behaves triple roles and is a potential agent to treat diabetic mellitus, gestational diabetes mellitus, and diabetic complications.

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具有多种抗糖尿病作用的氧杂蒽酮：其合成、结构-活性关系和机理研究。

我们开发了一种四步合成工艺来制备 1,3,5,8-四羟基氧杂蒽酮（2a）及其异构体 1,3,7,8-四羟基氧杂蒽酮（2b）。通过修改方案，还合成了另外 25 种anthone。经鉴定，氧杂蒽酮 2a 是对α-葡萄糖苷酶和醛糖还原酶（ALR2）最有效的抑制剂，其 IC50 值分别为 7.8 ± 0.5 μM 和 63.2 ± 0.6 nM，远高于阿卡波糖（35.0 ± 0.1 μM），略高于依帕司他（67.0 ± 3.0 nM）。2a 也被证实是体外活性最高的抗氧化剂，其 EC50 值为 8.9 ± 0.1 μM。任何结构修饰，包括甲基化、缺失和羟基位置的改变，都会导致 2a 的抑制和抗氧化活性降低。通过应用 H2 O2 诱导的氧化应激线虫模型，证实氧杂蒽酮 2a 可被秀丽隐杆线虫吸收，并具有生物可利用性，可减轻体内氧化应激，包括对寿命、超氧化物歧化酶、过氧化氢酶和丙二醛的影响。2a 的体内降血糖作用和在高糖条件下减轻胚胎畸形的作用得到了验证。我们的所有数据都支持黄酮 2a 具有三重作用，是治疗糖尿病、妊娠糖尿病和糖尿病并发症的潜在药物。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Drug Development Research 医学-药学

CiteScore

6.40

自引率

2.60%

发文量

104

审稿时长

6-12 weeks

期刊介绍： Drug Development Research focuses on research topics related to the discovery and development of new therapeutic entities. The journal publishes original research articles on medicinal chemistry, pharmacology, biotechnology and biopharmaceuticals, toxicology, and drug delivery, formulation, and pharmacokinetics. The journal welcomes manuscripts on new compounds and technologies in all areas focused on human therapeutics, as well as global management, health care policy, and regulatory issues involving the drug discovery and development process. In addition to full-length articles, Drug Development Research publishes Brief Reports on important and timely new research findings, as well as in-depth review articles. The journal also features periodic special thematic issues devoted to specific compound classes, new technologies, and broad aspects of drug discovery and development.