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

## TL;DR

This paper introduces a modular method to create glycocalix[4]arene derivatives and attach them to gold nanoparticles to inhibit bacterial adhesion.

## Contribution

A modular solid-phase synthesis approach for glycocalix[4]arene derivatives and their multivalent presentation on gold nanoparticles is developed.

## Key findings

- A calix[4]arene building block with specific functional groups was synthesized for modular solid-phase polymer synthesis.
- Glycocalix[4]arene derivatives were conjugated to ultrasmall gold nanoparticles to tune valency and inhibit bacterial adhesion.
- Multivalent carbohydrate presentation was shown to effectively block Escherichia coli adhesion.

## 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.

In this study, we present a calix[4]arene building block suitable for modular solid‐phase polymer synthesis and the preparation of functional glycocalix[4]arene. This allows us to incorporate carbohydrate ligands and further functionalities, such as alkynes at a specific position at the upper or lower rim of the calix[4]arene as demonstrated for the conjugation onto Au nanoparticles.