Abstract 1363: Development of novel anticancer agents based on fusarochromanone

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL The primary goal of this research is to develop novel anti-cancer agents based on fusarochromanone (FC101a), a natural mycotoxin with potent anti-angiogenic and direct anti-tumor activity. This research may lead to new cancer chemotherapeutic agents that are more potent and less toxic than conventional chemotherapy. Like most other bioactive natural compounds, the potency of FC101a is compromised in-vivo, suggesting unfavorable bioavailability, distribution, and/or metabolism. Development of FC101a as a chemotherapeutic drug requires the completion of its total synthesis, as well as the synthesis of a series of structural analogs with greater in-vivo potency than the lead compound. Progress towards both the chemical and biological synthesis of FC101a will be presented. 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 synthesizing the 6-iodo-4-chromanone, a key intermediate that is needed for the coupling reaction with the side-chain. 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 (#4482 and #8508) 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 will report our preliminary results on the inhibition effects of FC101a on the growth of human aggressive skin cancer carcinoma (SCC) both in-vitro and in-vivo. We have also investigated the mechanism of the biological function of FC101a. We will report our results on the expression levels and phosphorylation states of key proteins involved in cell proliferation signaling pathways, cell sorting profiles, and FACS analyses. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1363. doi:10.1158/1538-7445.AM2011-1363