The development of new synthetic methods for the enantio- and regiospecific construction of molecules of medicinal interest for the treatment of Acquired Immunodeficiency Syndrome (AIDS) is important to the overall mission of the NIH.
The specific aims of this project encompass the development of new synthetic methods for the preparation of the HIV-inhibitor, conocurvone. Conocurvone is a naturally occurring trimeric quinone that was isolated from an Australian shrub by researchers at the National Cancer Institute. The key structural feature of the molecule is a quinone central core to which is attached to hydroxyquinone subunits called teretifolione B. Conocurvone has been shown to possess potent anti- HIV-1 activity in the in vitro HIV-1/CEM-SS assay model. An important feature of the biological activity of conocurvone is its wide therapeutic index of approximately 2500! The high potency and low toxicity of conocurvone makes it an ideal candidate for further drug development.The first phase of the project involves the development of regiospecific routes to conocurvone and related trimeric quinones. An underlying theme of the proposed chemistry is the use of palladium metal to facilitate the formation of the carbon-carbon bonds that link the hydroxyquinone subunits to the quinone central core. The second phase of the project will involve synthesis and biological testing of conocurvone analogs.
| Emadi, Ashkan; Le, Anne; Harwood, Cynthia J et al. (2011) Metabolic and electrochemical mechanisms of dimeric naphthoquinones cytotoxicity in breast cancer cells. Bioorg Med Chem 19:7057-62 |
