title: Synthesis of PPAR-γ activators inspired by the marine natural product, paecilocin A.
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.
authors: College of Pharmacy, Pusan National University, Busan 609-735, Korea. Yinjun2002@yahoo.com.
authors: Bin
authors: B
authors: Xiao
authors: College of Pharmacy, Pusan National University, Busan 609-735, Korea. sumingzhi0310@gmail.com.
authors: Mingzhi
authors: M
authors: Su
authors: College of Pharmacy, Pusan National University, Busan 609-735, Korea. eunlakim@gmail.com.
authors: Eun La
authors: EL
authors: Kim
authors: College of Pharmacy, Kyung Hee University, Seoul 130-701, Korea. jhong@khu.ac.kr.
authors: Jongki
authors: J
authors: Hong
authors: College of Pharmacy, Pusan National University, Busan 609-735, Korea. hyjung@pusan.ac.kr.
authors: Hae Young
authors: HY
authors: Chung
authors: College of Pharmacy, Sungkyunkwan University, Suwon 440-746, Korea. hkims@skky.edu.
authors: Hyung Sik
authors: HS
authors: Kim
authors: College of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, China. Yinjun2002@yahoo.com.
authors: Jun
authors: J
authors: Yin
authors: College of Pharmacy, Pusan National University, Busan 609-735, Korea. jhjung@pusan.ac.kr.
authors: Jee H
authors: JH
authors: Jung
mesh_terms: D000818:Animals; D001572:Benzofurans / Q000737:chemistry / Q000494:pharmacology*; D001688:Biological Products / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D057927:Hydrophobic and Hydrophilic Interactions; D007783:Lactones / Q000737:chemistry / Q000494:pharmacology*; D008024:Ligands; D008099:Liver / Q000166:cytology / Q000187:drug effects; D062105:Molecular Docking Simulation; D047495:PPAR gamma / Q000187:drug effects* / Q000378:metabolism; D010797:Phthalimides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D001572:Benzofurans; D001688:Biological Products; D007783:Lactones; D008024:Ligands; D047495:PPAR gamma; D010797:Phthalimides; D045162:Thiazolidinediones; C000591702:paecilocin A; D000077154:Rosiglitazone