Facile Solid-Phase Parallel Synthesis of Linear and Cyclic Peptoids for Comparative Studies of Biological Activity

Abstract

A series of linear and cyclic peptoids, which were expected to possess better pharmacokinetic properties and biological activities for blocking the interaction between apolipoprotein E and amyloid-beta, were designed and synthesized as possible therapeutic agents. Peptoids were easily synthesized on solid-phase by the submonomer strategy and polar side chain-containing amines were effectively introduced under the modified reaction conditions. For the synthesis of cyclic peptoids, beta-alanine protected with the 2-phenylisopropyl group, which could be selectively removed by 2% TFA, was used as a primary amine to afford a complete peptoid unit. The macrolactamization between the carboxylic acid of beta-alanine moiety and terminal amine of peptoids was successfully performed in the presence of the PyAOP coupling agent on solid-phase in all the cases, providing various sizes of cyclic peptoids. In particular, some cyclic peptoids prepared in this study are the largest in size among cyclic peptoids reported to date. The synthetic strategy which was adopted in this study can also provide a robust platform for solid-phase construction of cyclic peptoid libraries. Currently, synthetic peptoids have been used to test interesting biological activities including the ApoE/A beta interaction inhibition, nontoxicity, the blood-brain barrier permeability, etc.