Design, synthesis and biological evaluation of novel bouchardatine analogs as potential inhibitors of adipogenesis/lipogenesis in 3T3-L1 adipocytes

Gao, L, Xu, Z, Rao, Y, Lu, Y, Hu, Y, Yu, H, Xu, Y, Song, Q, Ye, J and Huang, Z 2018, 'Design, synthesis and biological evaluation of novel bouchardatine analogs as potential inhibitors of adipogenesis/lipogenesis in 3T3-L1 adipocytes', European Journal of Medicinal Chemistry, vol. 147, pp. 90-101.


Document type: Journal Article
Collection: Journal Articles

Title Design, synthesis and biological evaluation of novel bouchardatine analogs as potential inhibitors of adipogenesis/lipogenesis in 3T3-L1 adipocytes
Author(s) Gao, L
Xu, Z
Rao, Y
Lu, Y
Hu, Y
Yu, H
Xu, Y
Song, Q
Ye, J
Huang, Z
Year 2018
Journal name European Journal of Medicinal Chemistry
Volume number 147
Start page 90
End page 101
Total pages 12
Publisher Elsevier Masson
Abstract Inhibition of the differentiation of adipocytes and reduced lipid synthesis are efficacious approaches for treating obesity-related metabolic disorders. Bouchardatine (Bou) is a natural alkaloid that has been reported to moderately inhibit the differentiation of 3T3-L1 cells without inducing toxicity. To explore the importance of aldehyde group at 8a-position of Bou and optimize the activity, we synthesized 35 (31 novel) compounds by discarding or replacing aldehyde group with halogen and introducing different amine chains at 5-position of Bou. The lipid-lowering activity was evaluated using a cell-based screening system. The substitution of the group at the 8a-position of compounds was important for its lipid lowering activity, and the SAR was discussed. The selective compound 6e showed a 93-fold increase in its lipid-lowering effect (EC50 = 0.24 mu M) compared with Bou (EC50 approximate to 25 mu M). Further mechanistic studies revealed that compound 6e activated AMP-activated protein kinase (AMPK) pathway and inhibited MCE activity to block cell proliferation and induce cell cycle arrest at the early stage of differentiation, thus decreasing the expression of adipogenic factors and fatty acid synthesis-related proteins.
Subject Pharmacology and Pharmaceutical Sciences not elsewhere classified
Medicinal and Biomolecular Chemistry not elsewhere classified
Organic Chemistry not elsewhere classified
Keyword(s) 3T3-L1 adipocytes
Adipogenesis/lipogenesis
Bouchardatine derivatives
Lipid-lowering
Mitosis clonal expansion
DOI - identifier 10.1016/j.ejmech.2018.01.089
Copyright notice © 2018 Elsevier Masson SAS. All rights reserved.
ISSN 0223-5234
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