Total synthesis of 8-(6″-umbelliferyl)-apigenin and its analogs as anti-diabetic reagents

Guojun Pan; Lianbo Zhao; Na Xiao; Ke Yang; Yantao Ma; Xia Zhao; Zhenchuan Fan; Yongmin Zhang; Qingwei Yao; Kui Lu; Peng Yu

doi:10.1016/j.ejmech.2016.07.015

Total synthesis of 8-(6″-umbelliferyl)-apigenin and its analogs as anti-diabetic reagents

Eur J Med Chem. 2016 Oct 21:122:674-683. doi: 10.1016/j.ejmech.2016.07.015. Epub 2016 Jul 11.

Authors

Guojun Pan¹, Lianbo Zhao¹, Na Xiao², Ke Yang¹, Yantao Ma¹, Xia Zhao³, Zhenchuan Fan⁴, Yongmin Zhang¹, Qingwei Yao⁵, Kui Lu⁶, Peng Yu⁷

Affiliations

¹ China International Science and Technology Cooperation Base of Food Nutrition/Safety and Medicinal Chemistry, Key Lab of Industrial Fermentation Microbiology, Tianjin Key Lab of Industrial Microbiology, Sino-French Joint Lab of Food Nutrition/Safety and Medicinal Chemistry, College of Biotechnology, Tianjin University of Science and Technology, Tianjin, 300457, PR China.
² State Key Laboratory of Natural Medicines, Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, Nanjing, 211198, PR China.
³ College of Chemistry, Tianjin Key Laboratory of Structure and Performance for Functional Molecules, Tianjin Normal University, Tianjin, 300387, PR China.
⁴ College of Food Engineering and Biotechnology, Tianjin University of Science and Technology, Tianjin, 300457, PR China.
⁵ 382 Longvalley Lane, DeKalb, IL 80115, USA.
⁶ China International Science and Technology Cooperation Base of Food Nutrition/Safety and Medicinal Chemistry, Key Lab of Industrial Fermentation Microbiology, Tianjin Key Lab of Industrial Microbiology, Sino-French Joint Lab of Food Nutrition/Safety and Medicinal Chemistry, College of Biotechnology, Tianjin University of Science and Technology, Tianjin, 300457, PR China. Electronic address: [email protected].
⁷ China International Science and Technology Cooperation Base of Food Nutrition/Safety and Medicinal Chemistry, Key Lab of Industrial Fermentation Microbiology, Tianjin Key Lab of Industrial Microbiology, Sino-French Joint Lab of Food Nutrition/Safety and Medicinal Chemistry, College of Biotechnology, Tianjin University of Science and Technology, Tianjin, 300457, PR China. Electronic address: [email protected].

PMID: 27448923
DOI: 10.1016/j.ejmech.2016.07.015

Abstract

The naturally occurring flavone 8-(6″-umbelliferyl)apigenin, a hybrid structure of apigenin and coumarin, as well as seven of its analogues were synthesized for the first time by using iodination and Suzuki coupling reactions as key steps. The synthesis of 8-(6″-umbelliferyl)-apigenin was achieved in seven linear steps from the commercially available 1-(2,4,6-trihydroxyphenyl)ethan-1-one and 7-hydroxyl coumarine with 31% overall yield. Effects of these compounds on glucose disposal were investigated in adipocytes. All of the flavonoid and coumarin hydrids were found to have better bioactivities than their corresponding flavonoid cores. The most potent compound 15 (10 μΜ) could promote glucose consumption by 57% which exhibited similar effect as the positive control metformin at 1 mM. Moreover, fluorescence microscopy showed that four 8-(6″-umbelliferyl)apigenin analogues 2, 15, 30 and 31 could promote the 2-NBDG uptake into 3T3-L1 cells, which consist with those observed in the regulation of glucose.

Keywords: 8-(6′′-umbelliferyl)-apigenin; Anti-diabetic; Coumarins; Flavonoid; Suzuki coupling reaction.

MeSH terms

3T3-L1 Cells
Adipocytes / drug effects
Adipocytes / metabolism
Alkylation
Animals
Apigenin / chemical synthesis*
Apigenin / chemistry
Apigenin / pharmacology*
Chemistry Techniques, Synthetic
Drug Design*
Glucose / metabolism
Hypoglycemic Agents / chemical synthesis*
Hypoglycemic Agents / chemistry
Hypoglycemic Agents / pharmacology*
Mice

Substances

Hypoglycemic Agents
Apigenin
Glucose