A Modular Solid Phase Synthesis Approach for Glycocalix[4]Arene Derivatives and Their Multivalent Presentation on Ultrasmall Gold Nanoparticles.

Abstract

Gold nanoparticles and calix[n]arenes are well-established platforms for creating multivalent carbohydrate ligands that enhance binding avidity and selectivity toward carbohydrate-recognizing receptors, such as bacterial lectins. In this study, we present a modular synthesis protocol for tailor-made and (multi)functional glycocalix[4]arene derivatives using solid-phase polymer synthesis. A calix[4]arene building block with a single carboxyl group on the lower rim and four nitro groups at the upper rim is introduced. This building block is attached to a solid support using standard solid phase peptide coupling conditions, followed by reduction of the upper rim nitro functionalities to yield four amine groups, that are further functionalized through solid-phase polymer synthesis. Using this modular approach, we access a series of glyco-calix[4]arene structures that are then further conjugated onto ultrasmall gold nanoparticles. Conjugation is promoted either via one or via four alkyne groups on the glycocalixarene structure, providing a handle to tune the overall valency of the final glyco[4]calixarene-gold nanoparticle conjugates. Finally, the glycocalix[4]arene derivatives and conjugates are evaluated for their inhibitory potential against bacterial adhesion showing the importance of multivalent carbohydrate presentation to effectively block Escherichia coli (E. coli) adhesion.