Incorporation of Heterocycles into the Backbone of Peptoids to Generate Diverse Peptoid-Inspired One Bead One Compound Libraries
ABSTRACT Combinatorial libraries of peptoids (oligo-N-substituted glycines) have proven to be useful sources of protein ligands. Each unit of the peptoid oligomer is derived from 2-haloacetic acid and a primary amine. To increase the chemical diversity available in peptoid libraries, we demonstrate here that heterocyclic halomethyl carboxylic acids can be employed as backbone building blocks in the synthesis of peptoid-based oligomers. Optimized conditions are reported that allow the creation of large, high quality combinatorial libraries containing these units.
- SourceAvailable from: Ute Schepers
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- "However, this often requires large and chemically diverse compound libraries. In recent years, peptoid synthesis has been established on solid phase to allow for the combinatorial synthesis of highly diverse libraries of peptoids [14,16,17,25,26,27,28,29]. The synthesis of diverse peptoid scaffolds is usually performed by the so called submonomer approach through microwave-assisted amide bond formation and subsequent nucleophilic substitution with primary amines or via heterocyclic halomethyl carboxylic building blocks . "
ABSTRACT: Cell penetrating peptoids (CPPos) are potent mimics of the corresponding cell penetrating peptides (CPPs). The synthesis of diverse oligomeric libraries that display a variety of backbone scaffolds and side-chain appendages are a very promising source of novel CPPos, which can be used to either target different cellular organelles or even different tissues and organs. In this study we established the submonomer-based solid phase synthesis of a "proof of principle" peptoid library in IRORI MiniKans to expand the amount for phenotypic high throughput screens of CPPos. The library consisting of tetrameric peptoids [oligo(N-alkylglycines)] was established on Rink amide resin in a split and mix approach with hydrophilic and hydrophobic peptoid side chains. All CPPos of the presented library were labeled with rhodamine B to allow for the monitoring of cellular uptake by fluorescent confocal microscopy. Eventually, all the purified peptoids were subjected to live cell imaging to screen for CPPos with organelle specificity. While highly charged CPPos enter the cells by endocytosis with subsequent endosomal release, critical levels of lipophilicity allow other CPPos to specifically localize to mitochondria once a certain lipophilicity threshold is reached.Pharmaceuticals 12/2012; 5(12):1265-1281. DOI:10.3390/ph5121265
- Combinatorial Chemistry - an Online Journal 05/2009; 11(5):17-19. DOI:10.1016/j.comche.2009.04.001
- Combinatorial Chemistry - an Online Journal 06/2009; 11(6):21-23. DOI:10.1016/j.comche.2009.05.001