Synthesis of Polymers Containing Potassium Acyltrifluoroborates (KATs) and Post‐polymerization Ligation and Conjugation

Abstract

We report the synthesis of monomers for atom‐transfer radical polymerization (ATRP) and a reversible addition‐fragmentation chain transfer (RAFT) agent bearing trifluoroborate iminiums (TIMs), which are quantitatively converted into potassium acyltrifluoroborates (KATs) after polymerization. The resulting KAT‐containing polymers are suitable for rapid amide‐forming ligations for both post‐polymerization modification and polymer conjugation. The polymer conjugation occurs rapidly, even under dilute (micromolar) aqueous conditions at ambient temperatures, thereby enabling the synthesis of a variety of linear and star‐shaped block copolymers. In addition, we applied post‐polymerization modification to the covalent linking of a photocaged cyclic antibiotic (gramicidin S) to the side chains of the KAT‐containing copolymer. Cellular assays revealed that the polymer–antibiotic conjugate is biocompatible and provides efficient light‐controlled release of the antibiotic on demand.

Polymer Conjugates of Antimicrobial Peptides (AMPs) with d-Amino Acids (d-aa): State of the Art and Future Opportunities

“…In particular, the AMP was first derivatized on its ornithine amino sidechain with either one of two hydroxylamine linkers, of which one was photocleavable. The orthogonal ligation between hydroxylamines and KAT-modified polymers is highly chemo-selective, and subsequent biological tests indeed confirmed that the AMP activity could be restored through a UV-triggered release from the polymer [147].…”

Mechanism-Based Design of Quinoline Potassium Acyltrifluoroborates for Rapid Amide-Forming Ligations at Physiological pH

“…Potassium acyltrifluoroborates (KATs) are robust, bench stable compounds that undergo amide-forming ligations with O-substituted hydroxylamines under dilute, aqueous conditions. − KAT ligation has already found applications in protein PEGylation, hydrogel formation and modification, and postpolymerization modification. − The reaction is exceptionally fast at lower pH, with rate constants >20 M –1 s –1 at pH 2, but becomes slower as the pH is increased . At pH 7, amide formation can still proceed but at rates that are not suitable for reactions at micromolar concentrations.…”

Dynamic Amide Formation by Reversible Nitrone Exchange of Potassium Acyltrifluoroborates (KATs) and Hydroxylamines in Aqueous Conditions

“…Potassium Acyltrifluoroborates (KATs) are a class of bench stable compounds with versatile reactivity, and have recently found various applications in bioconjugation [35][36][37] and material science [38][39][40][41][42] due to their ability to undergo rapid ligations 43,44 with O-substituted hydroxylamines or N-chloro amines under mild and dilute conditions to form amides. The union of O-unsubstituted hydroxylamines and KATs, however, results in a nitrone, 45 which upon further activation can rearrangement to an amide.…”