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

Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062, Japan.
Bioorganic & Medicinal Chemistry (Impact Factor: 2.9). 02/2006; 14(1):98-108. DOI: 10.1016/j.bmc.2005.07.074
Source: PubMed

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.

  • [Show abstract] [Hide abstract]
    ABSTRACT: INTRODUCTION: During the early 1970s, Danish physicians Jorn Dyerberg and colleagues observed that Greenland Eskimos consuming fatty fishes exhibited low incidences of heart disease. Fish oil is now one of the most commonly consumed dietary supplements. In 2004, concentrated fish oil was approved as a drug by the FDA for the treatment of hyperlipidemia. Fish oil contains two major omega-3 fatty acids: eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). With advancements in lipid concentration and purification techniques, EPA- or DHA-enriched products are now commercially available, and the availability of these components in isolation allows their individual effects to be examined. Newly synthesized derivatives and endogenously discovered metabolites of DHA exhibit therapeutic utility for obesity, metabolic syndrome and cardiovascular disease. AREAS COVERED: This review summarizes our current knowledge on the distinct effects of EPA and DHA to prevent metabolic syndrome and reduce cardiotoxicity risk. Since EPA is an integral component of fish oil, we will briefly review EPA effects, but our main theme will be to summarize effects of the DHA derivatives that are available today. We focus on using nutrition-based drug discovery to explore the potential of DHA derivatives for the treatment of obesity, metabolic syndrome and cardiovascular diseases. EXPERT OPINION: The safety and efficacy evaluation of DHA derivatives will provide novel biomolecules for the drug discovery arsenal. Novel nutritional-based drug discoveries of DHA derivatives or metabolites may provide realistic and alternative strategies for the treatment of metabolic and cardiovascular disease.
    Expert Opinion on Drug Discovery 06/2012; 7(8):711-21. · 2.30 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The synthesis of the marine natural product 1,6Z,9Z,12Z,15Z-octadecapentaen-3-one (1) has been achieved by two different routes starting from the ethyl esters of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), respectively. Using EPA ethyl ester as starting material the polyunsaturated vinyl ketone lipid 1 was obtained in 17% overall yield.
    Molecules 01/2014; 19(3):3804-12. · 2.43 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Ozonolysis of Z,Z,Z-cylonona-1,4,7-triene leads to a 1,9-difunctionalised Z,Z-3,6-nonadiene which is readily converted into a range of polyunsaturated pheromones and fatty acids.
    Chemistry and Physics of Lipids 05/2014; · 2.59 Impact Factor