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Mar. Drugs 2014, 12(2), 926-939; doi:10.3390/md12020926
Article

Synthesis of PPAR-γ Activators Inspired by the Marine Natural Product, Paecilocin A

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1 College of Pharmacy, Pusan National University, Busan 609-735, Korea 2 College of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, China 3 College of Pharmacy, Kyung Hee University, Seoul 130-701, Korea 4 College of Pharmacy, Sungkyunkwan University, Suwon 440-746, Korea
* Author to whom correspondence should be addressed.
Received: 24 December 2013 / Revised: 10 January 2014 / Accepted: 22 January 2014 / Published: 13 February 2014
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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 314. 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 PPAR-γ; diabetes; phthalimide; luciferase assay; docking simulation; cell proliferation
This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).
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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.

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