This proposal describes development of artificial receptors for the selective complexation of biologically significant molecules and the design of new biomimetic catalysts based on transition state stabilization. Our approach will exploit combined hydrogen bonding, electrostatic and hydrophobic interactions to maintain strong binding in organic and aqueous solvent. Detailed analysis of the structure as well as thermodynamic and kinetic properties of these systems will lead to increased understanding of intermolecular interactions in a range of solvent environments. In designing receptors that are complementary to postulated transition state structures we hope not only to develop new biomimetic catalysts but also to probe, with a precision not possible in the natural system, details of the reaction mechanism of the catalysts. An important application of the receptors will be in the construction of molecule-selective sensors.
Our specific aims i nclude the design, synthesis and evaluation of artificial receptors for the key second messenger, inositol 1,4,5- trisphosphate. We will use a tris-guanidinium binding site and will investigate the relative importance of solvophobic effects and pi- stacking orientations in binding. A similar approach will be taken to the recognition of other key carbohydrates including sialic acid and inositol. As part of this work we will investigate polyphosphodiesters as a novel class of water soluble, hydrogen bonding receptors. A second major area will be the development of synthetic receptors as catalysts based on the selective recognition and stabilization of key transition state structures. We will focus on several reactions including the rearrangement of chorismate to prephenate. We will prepare a family of chorismate receptors capable of binding to different conformations of the diacid along the reaction pathway. Analysis of the kinetic effects of the hosts will allow us to determine the optimal binding arrangement for stabilizing the transition state. Electrostatic groups will also be incorporated into the receptor potentially to assess their role in the catalytic mechanism. This strategy will also be applied to other reactions including the Claisen and Cope rearrangements and the cis-trans isomerization of amide bonds.
| Tsou, Lun K; Chen, Chin-Ho; Dutschman, Ginger E et al. (2012) Blocking HIV-1 entry by a gp120 surface binding inhibitor. Bioorg Med Chem Lett 22:3358-61 |
| Tsou, Lun K; Dutschman, Ginger E; Gullen, Elizabeth A et al. (2010) Discovery of a synthetic dual inhibitor of HIV and HCV infection based on a tetrabutoxy-calix[4]arene scaffold. Bioorg Med Chem Lett 20:2137-9 |
| Ross, Nathan T; Katt, William P; Hamilton, Andrew D (2010) Synthetic mimetics of protein secondary structure domains. Philos Trans A Math Phys Eng Sci 368:989-1008 |
| Jain, Rishi K; Tsou, Lun K; Hamilton, Andrew D (2009) Combined solid/solution phase synthesis of large surface area scaffolds derived from aminomethyl-benzoates. Tetrahedron Lett 50:2787-2789 |
| Margulies, David; Hamilton, Andrew D (2009) Digital analysis of protein properties by an ensemble of DNA quadruplexes. J Am Chem Soc 131:9142-3 |
| Margulies, David; Opatowsky, Yarden; Fletcher, Steven et al. (2009) Surface binding inhibitors of the SCF-KIT protein-protein interaction. Chembiochem 10:1955-8 |
| Wyrembak, Pauline N; Hamilton, Andrew D (2009) Alkyne-linked 2,2-disubstituted-indolin-3-one oligomers as extended beta-strand mimetics. J Am Chem Soc 131:4566-7 |
| Margulies, David; Hamilton, Andrew D (2009) Protein recognition by an ensemble of fluorescent DNA G-quadruplexes. Angew Chem Int Ed Engl 48:1771-4 |
| Gustafsdottir, Sigrun M; Wennstrom, Stefan; Fredriksson, Simon et al. (2008) Use of proximity ligation to screen for inhibitors of interactions between vascular endothelial growth factor A and its receptors. Clin Chem 54:1218-25 |
| Jayawickramarajah, Janarthanan; Tagore, Debarati M; Tsou, Lun K et al. (2007) Allosteric control of self-assembly: modulating the formation of guanine quadruplexes through orthogonal aromatic interactions. Angew Chem Int Ed Engl 46:7583-6 |
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