Antitumor compounds targeting the spliceosome by molecular concision of FR901464

ORGN 319

Thomas Webb, Thomas.Webb@stjude.org, Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, MS 1000, 332 North Lauderdale St, Memphis, TN 38105
We report the design and highly enantioselective synthesis of new potent analogs of the natural product spliceosome inhibitor FR901464, which eliminates 6 of the 9 chiral centers present in the natural product. We call these compounds ‘concise natural product analogs' since they have all of the requirements for activity but are much more synthetically accessible than the natural product spliceosome inhibitors. The design of these compounds was facilitated by a pharmacophore hypothesis that assumed key interaction types common to FR901464 and an otherwise unrelated natural product (pladienolide). Our synthetic approach allows for the preparation of numerous novel analogs. We will also present new structure-activity data on the in vitro cytotoxicity activity for these compounds against a panel of tumor cell lines. Additionally, we will report results on the in vivo toxicity, metabolism and efficacy of this class of compounds in a cancer xenograft model in mice.
 

Small Molecule Therapeutic Agents
8:30 AM-11:50 AM, Tuesday, August 18, 2009 Walter E. Washington Convention Center -- 207A, Oral

Division of Organic Chemistry

The 238th ACS National Meeting, Washington, DC, August 16-20, 2009