Nature relies on structured macromolecules in the form of proteins and catalytic RNA's that fold into specific three-dimensional structures and present reactive functionality in precise constellations in order to carry out the chemical processes of life. The structured nature of these molecules and what we have learned from proteins about structure/function relationships suggests that given the ability to construct macromolecules and control their three-dimensional structures, we could develop macromolecules with biomimetic capabilities and with entirely new chemical functions. Our goal is to develop a novel, basic technology for synthesizing macromolecules with designed three-dimensional shapes and capable of presenting multiple chemically reactive groups in controlled ways to perform new functions. Our approach is to synthesize small, rigid molecular building blocks (bis-amino acids) and couple them through pairs of amide bonds to create ladder oligomers. Each monomer contains multiple stereocenters that are set in the building block synthesis. The bis-amino acids are assembled on solid support, or in solution, in specific sequences to form constitutionally precise macromolecules with specific structures. We propose the following specific goals. 1) We will utilize our prototype monomer to synthesize several scaffolds with interesting structures and determine their structures. 2) We will measure the flexibility of linear and bow-shaped scaffolds. 3) We will develop syntheses of additional monomers. 4) We will synthesize macromolecules that display cavities with dimensions comparable to those of protein active sites and determine their structures. 5) We will discover peptides that selectively bind these cavitand scaffolds and characterize the interaction through structure determination and measurement of binding free energies. 6) We will develop syntheses for bis-amino acids that display an additional functional group akin to the side chain of an amino acid. 7) We will develop a general approach to the design of complex functional group arrays that are capable of biomimetic function and could be used for the development of nanoscale molecular devices. ? ?

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Medicinal Chemistry Study Section (MCHA)
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Lograsso, Philip
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University of Pittsburgh
Schools of Arts and Sciences
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Zhao, Qingquan; Schafmeister, Christian E (2015) Synthesis of Spiroligomer-Containing Macrocycles. J Org Chem 80:8968-78
Parker, Matthew F L; Osuna, Sílvia; Bollot, Guillaume et al. (2014) Acceleration of an aromatic Claisen rearrangement via a designed spiroligozyme catalyst that mimics the ketosteroid isomerase catalytic dyad. J Am Chem Soc 136:3817-27
Kheirabadi, Mahboubeh; Çelebi-Ölçüm, Nihan; Parker, Matthew F L et al. (2012) Spiroligozymes for transesterifications: design and relationship of structure to activity. J Am Chem Soc 134:18345-53
Brown, Zachary Z; Akula, Kavitha; Arzumanyan, Alla et al. (2012) A spiroligomer ?-helix mimic that binds HDM2, penetrates human cells and stabilizes HDM2 in cell culture. PLoS One 7:e45948
Brown, Zachary Z; Schafmeister, Christian E (2010) Synthesis of hexa- and pentasubstituted diketopiperazines from sterically hindered amino acids. Org Lett 12:1436-9
Gupta, Sharad; Schafmeister, Christian E (2009) Synthesis of a carboxylate functionalized bis-amino acid monomer. J Org Chem 74:3652-8
Chakrabarti, Subhasis; Parker, Matthew F L; Morgan, Christopher W et al. (2009) Experimental evidence for water mediated electron transfer through bis-amino acid donor-bridge-acceptor oligomers. J Am Chem Soc 131:2044-5
Bird, Gregory H; Pornsuwan, Soraya; Saxena, Sunil et al. (2008) Distance distributions of end-labeled curved bispeptide oligomers by electron spin resonance. ACS Nano 2:1857-64
Schafmeister, Christian E; Brown, Zachary Z; Gupta, Sharad (2008) Shape-programmable macromolecules. Acc Chem Res 41:1387-98
Brown, Zachary Z; Schafmeister, Christian E (2008) Exploiting an inherent neighboring group effect of alpha-amino acids to synthesize extremely hindered dipeptides. J Am Chem Soc 130:14382-3

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