Synthesis of Catechol-Containing Cyclic Peptoids Conjugated with Fluorescent Dyes and Antibiotic Drugs

Abstract

Siderophores play a crucial role in the bacterial iron-uptake pathway by shuttling ferric ions through specific receptors. Theses organic iron scavengers possess a high affinity for iron, effectively capturing the metal with their O-ligands. Hijacking the siderophore-mediated pathway provides an opportunity to enhance the potency of existing antibiotics against Gram-negative bacteria. This Trojan Horse strategy enables intracellular delivery through the natural iron-uptake systems. Sideromycin, an antibiotic-conjugated siderophore, has emerged as a promising approach to overcome the permeability and selectivity limitations of conventional antibiotics. In this study, fluorescent dye and antibiotic drug conjugates were developed based on a previously reported siderophore-mimetic peptoid: a cyclic peptoid backbone appended with tris-catechols, showing an octahedral coordination with Fe3+. The design and synthesis of the peptoid scaffolds for conjugation provided attachment points for amide coupling and click chemistry, respectively. The amine submonomers comprising the peptoids were synthesized, employing benzyl groups for catechol protection or an NBoc group for amine protection. The linear peptoids were assembled on resin using three different submonomers, with the catechol alignment varying between alternative or continuous versions. Subsequent head-to-tail cyclization was followed to obtain the cyclic products. HATU-mediated amide coupling was used for dye conjugation to attach a 5(6)-carboxyfluorescein (CF) to the amino-functionalized cyclic peptoid. Click chemistry was utilized to conjugate the azido-functionalized cyclic peptoid and an ampicillin (Amp) modified with an alkynyl moiety. The benzyl-protected catechols of the peptoids were hydrogenated to afford the final products. These conjugates are currently evaluated for biological activities. Imaging studies and antimicrobial activity assays are being conducted employing the CF-conjugates and Amp-conjugates, respectively, to demonstrate the ability of siderophore-mimetic peptoids to internalize bacteria and their effectiveness as sideromycins.