Abstract: 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.
Keywords: PPAR-γ; diabetes; phthalimide; luciferase assay; docking simulation; cell proliferation
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Xiao, B.; Su, M.; Kim, E.L.; Hong, J.; Chung, H.Y.; Kim, H.S.; Yin, J.; Jung, J.H. Synthesis of PPAR-γ Activators Inspired by the Marine Natural Product, Paecilocin A. Mar. Drugs 2014, 12, 926-939.
Xiao B, Su M, Kim EL, Hong J, Chung HY, Kim HS, Yin J, Jung JH. Synthesis of PPAR-γ Activators Inspired by the Marine Natural Product, Paecilocin A. Marine Drugs. 2014; 12(2):926-939.
Xiao, Bin; Su, Mingzhi; Kim, Eun L.; Hong, Jongki; Chung, Hae Y.; Kim, Hyung S.; Yin, Jun; Jung, Jee H. 2014. "Synthesis of PPAR-γ Activators Inspired by the Marine Natural Product, Paecilocin A." Mar. Drugs 12, no. 2: 926-939.