This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The primary goal of this research is to develop novel anti-cancer agents based on fusarochromanone (FC101a), a natural mycotoxin and a fungal metabolite produced by Fusarium equiseti. FC101a has been identified as an attractive lead drug candidate because of its diverse biological properties, including potent anti-angiogenic and direct anti-tumor activity. Like most other bioactive natural compounds, the potency of FC101a is compromised in-vivo, and the project's goal involves the establishment of structure-function relationships among some of FC101a's more potent analogs. We have made progress towards both the chemical and biological synthesis of FC101a. We have employed a new pathway for synthesizing the unique multifunctional four-carbon side chain in the parent compound. We have also been successful in utilizing the Suzuki reaction to couple both triflate intermediates (6-OTf-chromanone and 5-amino-6-OTf-chromanone) to a model side chain based on styrene. 13C and 1H-NMR analyses have confirmed the correct structure for both coupling products. Additionally, we have synthesized two novel acetal analogs of FC101a and will present the rational for choosing these structural analogs for devising structure activity relationships for this series of compounds. For the biological synthesis, we have obtained a highly fluorescent metabolite from the rice culture of two Fusarium strains (F4482 and F8505) that resembles FC101a, based on TLC analyses. We have also developed an efficient HPLC purification protocol to obtain samples of this compound with high purity. We are currently working to scale up this separation and confirm the structure of this compound through 1H, 13C-NMR as well as high-resolution mass spectrometry analyses. We have extended our preliminary studies of the biological function of FC101a, including investigation of the expression levels and phosphorylation states of key proteins involved in cell proliferation signaling pathways, cell sorting profiles, and FACS analyses. In addition, we have initiated several experiments to assess the anti-angiogenic properties of the parent FC101a. Finally, we have utilized the INBRE funding to purchase or upgrade several key pieces of instrumentation needed to conduct this research and have completed the installation and development of appropriate student training protocols for the use of the instrumentation.
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