Synthesis of main metabolites of several aromatase inhibitors and antiestrogens as reference compounds for doping analytics

  • Conversion, Unified Project Model (Principal Investigator)

    Project: Research project

    Project Details

    Description (abstract)

    Inhibitors of aromatase (estrogen synthetase) and antiestrogens have been developed mainly as treatment for menopausal breast cancer. The purpose of these drugs is the same, to reduce effects of estrogen. Aromatase inhibitors (letrozole, anastrozole, ex-emestane) inhibit the production of estrogen, whereas antiestrogens (tamoxifen, tore-mifene, clomiphene) block the estrogen receptors and thus prevent the interaction of estrogen with the receptors. Abuse of these drugs in sports stems from the fact that they can be used to counteract the adverse effects of an extensive use of anabolic androgenic steroids (gynaecomastia), and to increase testosterone concentration by stimulation of testosterone biosynthesis.
    All of the previously mentioned drugs are included in the World Anti-Doping Agency’s list of substances and methods that are prohibited in sports. In doping analysis, the analytical data obtained from the sample are compared to the data obtained from a negative and positive reference. According to the WADA’s international laboratory standard and ISO 17025 standard, well characterized reference materials are recom-mended to be used as references in the analysis.
    Presently, the metabolites of aromatase inhibitors (letrozole, anastrozole, exemestane) and antiestrogens (clomiphene, toremifene) are not commercially available as refer-ence substances. Therefore, we propose to develop a high-yielding and selective syn-thesis method for the preparation of these metabolites or synthesize some of the me-tabolites according to the published methods. Although tamoxifen metabolite is com-mercially available, it will be synthesized for comparison purposes. The synthesized metabolites would then be available as reference substances to the world’s antidoping community. Fully characterized reference substances would enable the reliable and legally defensible confirmation analysis of the drugs. The synthesized substances could also be used in quality assurance and in development of new analytical methods.
    Effective start/end date01/01/200831/12/2010