Amphiphile-Templated Dynamic Combinatorial Libraries

Abstract

This thesis investigates amphiphile-templated dynamic combinatorial libraries (DCLs) operating through reversible thiol–disulfide exchange, with the aim of elucidating how amphiphilic organization governs molecular selection, amplification, and the emergence of function. By coupling dynamic covalent chemistry with amphiphilic self-assembly, a series of systems was established that exhibit redox-responsive fluorescence regulation, entropy-driven amplification, and persistent supramolecular chirality.

First, a short-chain tetraphenylethene (TPE) amphiphile was designed to act as both a structural template and a fluorescent reporter for oxidation-driven molecular network formation in living cells. Under intracellular oxidative conditions, disulfide bond formation among the building blocks strengthens their supramolecular assembly with the amphiphile and enhances fluorescence, whereas reduction cleaves disulfide bonds, disrupts the assembly, and attenuates the fluorescent response, providing a model for redox-regulated signal transduction in dynamic supramolecular assemblies.

Second, a long-chain TPE amphiphile served as a supramolecular template to preorganize disulfide building blocks in a dynamic combinatorial library, reducing entropic penalties and selectively amplifying octameric macrocycles. Complexation with doxorubicin enabled real-time visualization of drug release via aggregation induced emission, linking dynamic combinatorial chemistry to functional delivery and optical readout.

Third, sodium dodecyl sulfate (SDS) micelles served as transient amphiphilic environments that reshape DCL composition. Distinct SDS concentrations selectively amplified pentameric, hexameric, or trimeric macrocycles, revealing environment-dependent selection. Notably, the pentamer expressed pronounced supramolecular chirality and retained its chiral bias after micelle removal, demonstrating an imprinting and memory effect.

Overall, these results establish amphiphilic templation as an effective strategy for directing adaptive behavior and information storage in dynamic molecular networks.