European Journal of Medicinal Chemistry p. 736 - 753 (2018)
Update date:2022-08-18
Topics:
S?ther, Thomas
Paulsen, Steinar M.
Tungen, J?rn E.
Vik, Anders
Aursnes, Marius
Holen, Torgeir
Hansen, Trond Vidar
Nebb, Hilde I.
Obesity and associated disorders such as metabolic syndrome and type 2 diabetes (T2D) have reached epidemic proportions. Several natural products have been reported as Peroxisome Proliferator-Activated Receptor (PPAR) agonists, functioning as lead compounds towards developing new anti-diabetic drugs due to adverse side effects of existing PPAR drugs. We recently isolated and identified (7E)-9-oxohexadec-7-enoic acid (1) and (10E)-9-oxohexadec-10-enoic acid (2) from the marine algae Chaetoceros karianus. Herein we report the total synthesis, pharmacological characterization, and biological evaluations of these naturally occurring oxo-fatty acids (oFAs). The syntheses of 1 and 2 afforded sufficient material for extensive biological evaluations. Both oFAs show an appreciable dose-dependent activation of PPARα and -γ with EC50 values in the micromolar range, and an ability to regulate important PPAR target genes in hepatocytes and adipocytes. Moreover, both 1 and 2 are able to drive adipogenesis when evaluated in the Simpson-Golabi-Behmel syndrome (SGBS) pre-adipocyte cell model, but with lowered expression of adipocyte markers and reduced lipid accumulation compared to the drug rosiglitazone. This seems to be caused by a transient upregulation of PPARγ and C/EBPα expression. Importantly, whole transcriptome analysis shows that both compounds induce anti-diabetic gene programs in adipocytes by upregulating insulin-sensitizing adipokines and repressing pro-inflammatory cytokines.
View MoreContact:86-25-84683399
Address:605, Phoenix Herui Plaza, No.389, South Taiping Road, Nanjing, China 210002
Suzhou CarbonWell Pharma-Tech Co., Ltd
Contact:Tel: + 86 (0)512-8898-1216; + 86-18606258602
Address:2358 Changan Road, Wujiang Scientific Innovation Park, Wujiang, Jiangsu Province, P. R. China 215200
Contact:86-10-87645213
Address:Sifangjing Garden Fengtai District Beijing
Nanjing Xi Ze Biological Technology Co., Ltd
Contact:86-025-66023220
Address:Address: Nanjin Qixia District Maigaoqiao R & D base in Pioneer Park Chun Yin Road 18-A928
Contact:+8613400661290
Address:No 908,Kangwan Rd, Liuyang Economic
Doi:10.1021/ja00064a028
(1993)Doi:10.1021/op800066m
(2008)Doi:10.1134/S0036023610020038
(2010)Doi:10.1002/aoc.5805
(2020)Doi:10.1039/b104268h
(2001)Doi:10.1039/c39940001795
(1994)