Dynamic combinatorial libraries of hydrazone based pseudo-peptides : diversity, templating and selection

• Main Author: Cousins, G. R. L.
• Published: University of Cambridge 2000
• Subjects: 547.7
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.598078

Dynamic combinatorial chemistry (DCC) is a rapidly emerging field which offers new protocols for the identification of novel hosts and guests as lead compounds for enzyme mimics and drug molecules. This thesis is concerned with the development of hydrazone exchange as a suitable reversible reaction. This chemistry has been used in several proof of concept experiments including combinatorial diversity, templating in systems under thermodynamic control and selection of lead compounds. Chapter 1 introduces dynamic combinatorial chemistry by consideration of 'static' approaches to enzyme mimics such as rational design, combinatorial chemistry, directed molecular evolution and molecularly imprinted polymers. The later sections develop the concepts of templating and molecular evolution to amplify compounds of particular interest or properties. The chapter concludes with a review of recent successes at the generation of dynamic combinatorial libraries (DCLs) using both covalent and non-covalent chemistry. Chapter 2 is concerned with the construction of building blocks for the formation of libraries of macrocyclic hydrazones. Approaches using cinchona and ephedra alkaloids are described but were not pursued. These studies eventually led to a general synthetic strategy which has been used extensively to afford amino acid based monomers providing diverse combinatorial libraries of hydrazone based pseudo-peptide macrocycles. Molecular diversity has been explored using MS and MS-MS analysis, and thermodynamic exchange in such systems illustrated by MS and HPLC analysis. A proline monomer was shown to undergo proof-reading to afford a thermodynamically preferred cyclic dimer. Chapter 3 presents templating in a DCL to identify and amplify a cyclic pseudo-peptide as a novel receptor for <I>N</I>-methyl ammonium salts, in particular the neurotransmitter Acetylcholine. The receptor, while initially a minor component of the dynamic combinatorial library, is strongly amplified. Template effects coupled with column chromatography have facilitated isolation of the cyclic receptor.