ORGN 681 |
| Cycloproparadicicol, a congener of natural product radicicol, is one of the most promising preclinical anticancer agents targeting Hsp90. The heat shock protein 90 (Hsp90) is an important molecular chaperone required to stabilize and refold client proteins such as Raf1 and Her2. Recently, Hsp90 has been regarded as a novel and attractive target for cancer therapies. Selective inhibition of Hsp90 could potentially facilitate the degradation of various oncogenic proteins. Cycloproparadicicol, a potent Hsp90 inhibitor (IC50 = 160 nM), showed significant inhibitory activity against MCF-7 breast cancer cells (IC50 = 49 nM) in vitro. In a preliminary in vivo study against mice implanted with human colon carcinoma (HCT-116), cycloproparadicicol (75 mg/kg, QDx7) also suppressed 68% of tumor cell growth. Unfortunately, our current synthesis of cycloproparadicicol suffers from several non-scalable and low-yielding steps that hinder its availability for further clinical studies. Furthermore, the current synthetic route is not optimal for the efficient synthesis of new analogs. Herein, a novel approach for the highly convergent and scalable total synthesis of cycloproparadicicol and novel analogs through diverted total synthesis (DTS) as well as biological evaluations of these molecules will be presented.
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Biologically-Related Molecules and Processes
8:00 AM-12:00 PM, Wednesday, August 22, 2007 BCEC -- 258B, Oral
Division of Organic Chemistry |