Synthesis of docosahexaenoic acid derivatives designed as novel PPARgamma agonists and antidiabetic agents.
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.
Itoh
Toshimasa
T
Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062, Japan.
Murota
Itsuki
I
Yoshikai
Kazuyoshi
K
Yamada
Sachiko
S
Yamamoto
Keiko
K
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
D007004:Hypoglycemic Agents; D047495:PPAR gamma; D004281:Docosahexaenoic Acids