Uropathogenic E. coli (UPEC) initiates urinary tract infections (UTIs) via the interaction of lectin FimH at the tip of E. coli pili binding to oligo-alpha-mannosides on urothelial glycoprotein uroplakin 1a. A strategy for the treatment of UTIs is the anti-adhesin approach, where a soluble ligand acts as an antagonist by competing with the native glycoprotein. The antagonists targeting this interaction are mostly alpha-linked mannose glycosides that have various aglycone moieties. We recently reported on a 1-deoxy-2-O-n-heptlyl septanoside as a flexible analog of n-heptyl alpha-mannoside that bound to the FimH lectin domain. Using thermodynamic and structural information from that study, new septanose ligands were designed, synthesized, and evaluated for binding to FimH. The synthesis leverages a key oxepine intermediate to allow for placement of the C2 hydroxyl group. Varying aryl groups have been added to the C2, allowing for a rapid generation of ligands. This is done using a base-mediated Sn2 alkylation followed by a Suzuki coupling with varying phenylboronic acids. These aryl groups were selected based on mannoside aglycones that have been shown in literature to give strong binding to FimH. Comparing these septanose ligands to their previously tested pyranose counterparts will allow for evaluation of the different rings with binding pocket size and carbohydrate flexibility factors in the difference of binding affinity. Insights gained can be used in expanding outward and applying septanoses as antagonists in other proteins, increasing their therapeutic potential.

Synthesis of 1-deoxy, 2-O-alkyl septanoses as glycomimetics of alpha-mannoside ligands of E. coli FimH

ACS Spring Meeting 2021

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.