Synthesis of docosahexaenoic acid derivatives designed as novel PPARγ agonists and antidiabetic agents

To discover novel peroxisome proliferator-activated receptor γ (PPARγ) agonists that could be used as antidiabetic agents, we designed docosahexaenoic acid (DHA) derivatives (2 and 3), which have a hydrophilic substituent at the C(4)-position, based on the crystal structure of the ligand-binding pocket of PPARγ. These compounds were synthesized via iodolactone as a key intermediate. We found that both DHA derivatives (2 and 3) showed PPARγ 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 PPARγ transcriptional activity, was separated as an optically pure form.

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