1,2-Dithiolane vs. Thiol-Functionalized β-Cyclodextrins: Ring Strain Drives Enhanced Crosslinking

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Abstract
Two β-cyclodextrin conjugates differing in their sulfur-bearing substituent, 1,2-dithiolane versus free thiols, were synthesized and evaluated as crosslinkers for polymeric mucin glycoproteins and thiolated polysaccharides, providing a comparison of ring-strain-driven thiol-disulfide exchange and oxidative disulfide formation. Per-thiolated β-cyclodextrin (β-CD-SH) was prepared via complete substitution of hydroxyl groups using phosphorous pentasulfide, while α-lipoic acid modified β-cyclodextrin (β-CD-LA) was obtained via esterification, introducing strained 1,2-dithiolane moieties as exchange-reactive disulfide units. Structural characterization by ¹H NMR and colorimetric assays confirmed successful functionalization of both derivatives. Safety profiles of the modified β‑cyclodextrins were evaluated regarding cytotoxicity, hemolysis, free radical interactions, and biodegradation. Rheological studies revealed stronger crosslinking (5.7-fold) of β-CD-LA with mucus glycoproteins compared to β-CD-SH, resulting in substantial viscosity enhancement and reduced diffusion through model mucus layers. Furthermore, β-CD-LA increased the viscosity of thiolated alginate by 22.1-fold and of thiolated xanthan by 77.3-fold, indicating rapid formation of disulfide-mediated polymer networks. These findings place the two β-cyclodextrin conjugates into distinct mechanistic categories: strain-activated dithiolane versus oxidation-driven thiol systems. This demonstrates that 1,2-dithiolane functionalization represents a superior strategy over free thiols for introducing dynamic covalent crosslinking capability into cyclodextrin-based scaffolds, supporting the use of dithiolane-bearing cyclodextrins as versatile multiarm crosslinkers for polymer network formation.