Hydrophilic Cyclic Poly(oxa)Norbornene Platforms via Ring‐Expansion Metathesis Polymerization (REMP) for Lectin Binding Inhibition

This study presents the synthesis of cyclic poly(oxanorbornenyl azlactone) ( c‐PONBSAzl ) and poly(norbornenyl azlactone) ( c‐PNBSAzl ) via ring‐expansion metathesis polymerization (REMP). These polymers differ by a single oxygen‐for‐carbon substitution in the backbone, offering a unique platform to investigate how this structural variation influences REMP kinetics, solubility, and lectin‐binding properties. Reactivity studies revealed distinct polymerization behaviors, underscoring the significant impact of the oxanorbornene backbone on REMP efficiency. Subsequent post‐polymerization modification (PPM) by aminolysis with heptyl mannose yielded cyclic glycopolymers with a number‐average degree of polymerization ( DP n ) ≈ 140. In aqueous solution, both cyclic architectures showed excellent solubility, with the oxanorbornene backbones demonstrating higher local mobility and reduced intermolecular association. Binding assays were performed against five therapeutically relevant mannose‐binding lectins (FimH, Bc2L‐A, ConA, DC‐SIGN, and Langerin). Notably, the increased local mobility imparted by the oxanorbornene backbone did not translate into a measurable enhancement in lectin inhibition relative to the norbornene analogue. Instead, both cyclic architectures exhibited strong multivalent interactions and achieved nanomolar‐range inhibition against both lectins. These results reinforce cyclic glycopolymers as potent multivalent lectin binders and broaden their structural and functional scope, establishing them as promising platforms for hydrophilic glycomaterial design.