ORGN 291 |
| Aaron R. Minter and Anna K. Mapp. Department of Medicinal Chemistry and Department of Chemistry, University of Michigan, 930 N University, Ann Arbor, MI 48109-1055 |
| Protein•protein interactions are critically involved in a number of biological processes, and thus the ability to control such interactions with small molecules has been the focus of intense effort. Rational approaches toward protein surface recognition would provide a fundamental understanding of how proteins interact and would serve as a possible alternative to current small molecule based therapeutics. Gene regulation at the transcriptional level is mediated via many poorly understood protein•protein interactions. The correlation between a number of human disease states and the mis-regulation of these events has led to a concentrated effort in developing artificial transcriptional activators. Endogenous activators minimally consist of a DNA binding domain (DBD), responsible for localization to a specific sequence of DNA, and an activation domain (AD), the component that directly interacts with the transcriptional machinery. Although there are a number of examples incorporating non-natural DNA binding domains, there remains no report of a small molecule activation domain (SMAD). We describe here the design and synthesis of isoxazolidines that, when functionalized accordingly, serve as a small molecule replacement of the activation domain in gene upregulation. To further investigate the role of the SMAD in transcriptional activation, we have expanded the synthesis to include bisisoxazolidines, accessed from the monoisoxazolidine precursors following a second 1,3-dipolar cycloaddition and subsequent functionalization. With increased functionality available for relevant protein surface recognition, the ability of this new class of small molecule in mediating a variety of protein•protein interactions is currently underway. |
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New Reactions and Methodology
8:00 AM-12:00 PM, Tuesday, August 24, 2004 Pennsylvania Convention Center -- 201A, Oral
Division of Organic Chemistry |