Synthesis of novel curcumin analogues for inhibition of 11β-hydroxysteroid dehydrogenase type 1 with anti-diabetic properties

Xiaohuan Yuan; Hongzhi Li; He Bai; Zhijian Su; Qi Xiang; Chaonan Wang; Binghai Zhao; Yufei Zhang; Qihao Zhang; Yanhui Chu; Yadong Huang

doi:10.1016/j.ejmech.2014.03.012

Synthesis of novel curcumin analogues for inhibition of 11β-hydroxysteroid dehydrogenase type 1 with anti-diabetic properties

Eur J Med Chem. 2014 Apr 22:77:223-30. doi: 10.1016/j.ejmech.2014.03.012. Epub 2014 Mar 6.

Authors

Xiaohuan Yuan¹, Hongzhi Li², He Bai², Zhijian Su³, Qi Xiang³, Chaonan Wang², Binghai Zhao², Yufei Zhang², Qihao Zhang³, Yanhui Chu⁴, Yadong Huang⁵

Affiliations

¹ Institute of Biomedicine, College of Life Science and Technology, Jinan University, Guangzhou 510632, PR China; Heilongjiang Key Laboratory of Tissue Damage and Repair, Mudanjiang Medical University, Heilongjiang 157011, PR China.
² Heilongjiang Key Laboratory of Tissue Damage and Repair, Mudanjiang Medical University, Heilongjiang 157011, PR China.
³ Institute of Biomedicine, College of Life Science and Technology, Jinan University, Guangzhou 510632, PR China.
⁴ Heilongjiang Key Laboratory of Tissue Damage and Repair, Mudanjiang Medical University, Heilongjiang 157011, PR China. Electronic address: yanhui_chu@sina.com.
⁵ Institute of Biomedicine, College of Life Science and Technology, Jinan University, Guangzhou 510632, PR China. Electronic address: tydhuang@jnu.edu.cn.

PMID: 24642565
DOI: 10.1016/j.ejmech.2014.03.012

Abstract

In the present study, a series of mono-carbonyl analogues of curcumin were designed and synthesized by deleting the reactive beta-diketone moiety, which is responsible for the pharmacokinetic limitation of curcumin. We demonstrated that 4 of 9 curcumin analogues were selective inhibitors of human and rodent 11β-HSD1. The level of this inhibitor was 4-20 times more than that of curcumin. Curcumin analogues weakly inhibited 11β-HSD2, and further analyses revealed that these compounds were highly selective, favoring 11β-HSD1. These 4 curcumin analogues are potential therapeutic agents for type-2 diabetes by targeting 11β-HSD1. The compound 8 displays anti-diabetic properties in diabetic mice induced by streptozocin and high-fat-diet (STZHFD).

Keywords: Anti-diabetic activity; Curcumin analogues; Pharmacokinetic; Stability.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

11-beta-Hydroxysteroid Dehydrogenase Type 1 / antagonists & inhibitors*
11-beta-Hydroxysteroid Dehydrogenase Type 1 / metabolism
Animals
Curcumin / chemical synthesis
Curcumin / chemistry
Curcumin / pharmacology*
Diabetes Mellitus, Experimental / chemically induced
Diabetes Mellitus, Experimental / drug therapy*
Diabetes Mellitus, Type 2 / chemically induced
Diabetes Mellitus, Type 2 / drug therapy*
Diet, High-Fat
Dose-Response Relationship, Drug
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Humans
Hypoglycemic Agents / chemical synthesis
Hypoglycemic Agents / chemistry
Hypoglycemic Agents / pharmacology*
Male
Mice
Mice, Inbred C57BL
Mice, Obese
Molecular Structure
Streptozocin / administration & dosage
Structure-Activity Relationship

Substances

Enzyme Inhibitors
Hypoglycemic Agents
Streptozocin
11-beta-Hydroxysteroid Dehydrogenase Type 1
Curcumin