title: Synthesis of docosahexaenoic acid derivatives designed as novel PPARgamma agonists and antidiabetic agents.
abstract: To discover novel peroxisome proliferator-activated receptor gamma (PPARgamma) agonists that could be used as antidiabetic agents, we designed docosahexaenoic acid (DHA) derivatives (2 and 3), which have a hydrophilic substituent at the C4-position, based on the crystal structure of the ligand-binding pocket of PPARgamma. These compounds were synthesized via iodolactone as a key intermediate. We found that both DHA derivatives (2 and 3) showed PPARgamma transactivation higher than, or comparable to, that of pioglitazone, which is a TZD derivative used as an antidiabetic agent. DHA derivatives related to these potent compounds 2 and 3 were also synthesized to study structure-activity relationships. Furthermore, 4-OH DHA 2, which shows strong PPARgamma transcriptional activity, was separated as an optically pure form.
authors.affiliation: Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062, Japan.
authors.forename: Toshimasa
authors.initials: T
authors.lastname: Itoh
authors.forename: Itsuki
authors.initials: I
authors.lastname: Murota
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Yoshikai
authors.forename: Sachiko
authors.initials: S
authors.lastname: Yamada
authors.forename: Keiko
authors.initials: K
authors.lastname: Yamamoto
mesh_terms: D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D018360:Crystallography, X-Ray; D004281:Docosahexaenoic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015195:Drug Design; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D047495:PPAR gamma / Q000819:agonists*; D013056:Spectrophotometry, Ultraviolet
chemical_list: D007004:Hypoglycemic Agents; D047495:PPAR gamma; D004281:Docosahexaenoic Acids