8,8-Dimethyldihydroberberine with improved bioavailability and oral efficacy on obese and diabetic mouse models

被引：92

作者：

Cheng, Zhe ^{[2
]}

Chen, An-Feng ^{[1
]}

Wu, Fang ^{[2
]}

Sheng, Li ^{[2
]}

Zhang, Han-Kun ^{[1
]}

Gu, Min ^{[2
]}

Li, Yuan-Yuan ^{[2
]}

Zhang, Li-Na ^{[2
]}

Hu, Li-Hong ^{[1
]}

Li, Jing-Ya ^{[2
]}

Li, Jia ^{[2
]}

机构：

[1] Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai Inst Biol Sci, Shanghai Res Ctr Modernizat Tradit Chinese Med, Shanghai 201203, Peoples R China

[2] Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai Inst Biol Sci, Natl Ctr Drug Screening, Shanghai 201203, Peoples R China

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2010年 / 18卷 / 16期

基金：

中国国家自然科学基金;

关键词：

Berberine; Dihydroberberine; Di-Me; AMPK; Diet-induced obese mice; db/db mice; ACTIVATED PROTEIN-KINASE; BERBERINE DERIVATIVES; GLUCOSE-METABOLISM; INSULIN-RESISTANCE; MECHANISM DISTINCT; RATS; DIET; DYSLIPIDEMIA; MITOCHONDRIA; INHIBITION;

D O I：

10.1016/j.bmc.2010.06.085

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

The clinical use of the natural alkaloid berberine (BBR) as an antidiabetic reagent is limited by its poor bioavailability. Our previous work demonstrated that dihydroberberine (dhBBR) has enhanced bioavailability and in vivo efficacy compared with berberine. Here we synthesized the 8,8-dimethyldihydroberberine (Di-Me) with improved stability, and bioavailability over dhBBR. Similar to BBR and dhBBR, Di-Me inhibited mitochondria respiration, increased AMP:ATP ratio, activated AMPK and stimulated glucose uptake in L6 myotubes. In diet-induced obese (DIO) mice, Di-Me counteracted the increased adiposity, tissue triglyceride accumulation and insulin resistance, and improved glucose tolerance at a dosage of 15 mg/kg. Administered to db/db mice with a dosage of 50 mg/kg, Di-Me effectively reduced random fed and fasting blood glucose, improved glucose tolerance, alleviated insulin resistance and reduced plasma triglycerides, with better efficacy than dhBBR at the same dosage. Our work highlights the importance of dihydroberberine analogs as potential therapeutic reagents for type 2 diabetes treatment. (C) 2010 Elsevier Ltd. All rights reserved.

引用

页码：5915 / 5924

页数：10

共 44 条

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Inhibition of mouse liver respiration by Chelidonium majus isoquinoline alkaloids [J].