1639899-90-3Relevant academic research and scientific papers
Structure-based design, synthesis, PPAR-γ activation, and molecular docking of N-substituted phthalimides
Xiao, Bin,Wang, Shumin,She, Zhanfei,Cao, Qingfeng,Zhao, Na,Tian, Xiangrong,Su, Yixin
, p. 1628 - 1634 (2017)
N-substituted phthalimides showed peroxisome proliferator-activated receptors-γ activation in rat liver epithelial Ac2F cells in our previous study. In order to explore better peroxisome proliferator-activated receptors-γ agonists, new N-substituted phthalimide derivatives were designed and synthesized based on a pharmacophore study of natural peroxisome proliferator-activated receptors-γ agonist paecilocin A and synthetic leads. Peroxisome proliferator-activated receptors-γ activation by the new derivatives was evaluated using rat liver epithelial Ac2F cells at a concentration of 10 μM (same as previous study). All the new derivatives showed comparable or better activities than that of rosiglitazone, in which 3-hydroxy-N-(p-methoxy-phenethyl) phthalimide (compound 6) appeared as the best. Molecular docking suggested that the free hydroxyl group on the phthalimide head, a proper hydrophobic tail including a phenyl linker, were beneficial for peroxisome proliferator-activated receptors-γ activation. These N-substituted phthalimide derivatives are valuable as scaffolds for new peroxisome proliferator-activated receptors-γ agonists.
Synthesis of phthalimide derivatives as potential PPAR-γ ligands
Eom, So Hyeon,Liu, Sen,Su, Mingzhi,Noh, Tae Hwan,Hong, Jongki,Kim, Nam Deuk,Chung, Hae Young,Yang, Min Hye,Jung, Jee H.
, (2016/07/06)
Paecilocin A, a phthalide derivative isolated from the jellyfish-derived fungus Paecilomyces variotii, activates PPAR-γ (Peroxisome proliferator-activated receptor gamma) in rat liver Ac2F cells. Based on a SAR (Structure-activity relationships) study and in silico analysis of paecilocin A-mimetic derivatives, additional N-substituted phthalimide derivatives were synthesized and evaluated for PPAR-γagonistic activity in both murine liver Ac2F cells and in human liver HepG2 cells by luciferase assay, and for adipogenic activity in 3T3-L1 cells. Docking simulation indicated PD6 was likely to bind most strongly to the ligand binding domain of PPAR-γ by establishing crucial H-bonds with key amino acid residues. However, in in vitro assays, PD1 and PD2 consistently displayed significant PPAR-activation in Ac2F and HepG2 cells, and adipogenic activity in 3T3-L1 preadipocytes.
Synthesis of PPAR-γ activators inspired by the marine natural product, paecilocin A
Xiao, Bin,Su, Mingzhi,Kim, Eun La,Hong, Jongki,Chung, Hae Young,Kim, Hyung Sik,Yin, Jun,Jung, Jee H.
, p. 926 - 939 (2014/03/21)
A series of N-substituted phthalimide derivatives were synthesized based on a pharmacophore study of paecilocin A (a natural PPAR-γ agonist) and synthetic leads. The introduction of hydrophilic and hydrophobic groups to the phthalimide skeleton yielded compounds 3-14. Compound 7 showed significant PPAR-γ activation in a luciferase assay using rat liver Ac2F cells. Docking simulations showed that a free hydroxyl group on the phthalimide head and a suitable hydrophilic tail, including a phenyl linker, were beneficial for PPAR-γ activation. Compound 7 and rosiglitazone concentration-dependently activated PPAR-γ with EC50 values of 0.67 μM and 0.028 μM, respectively. These phthalimide derivatives could be further investigated as a new class of PPAR-γ ligands.
