Abstract
<jats:p>(200 words) Sugammadex (SGX) is a highly effective reversal agent for neuromuscular blockade, yet its associated risk of anaphylaxis has raised clinical concerns. In this article we describe the synthesis of a new family of α-, β-, and γ-cyclodextrin derivatives perfunctionalized at their primary faces with (2-phosphonoethyl)thio appendages. By replacing the carboxylic groups of SGX with phosphonic acid residues (bioisosteres of natural phosphates) we aimed to maintain high binding potency while potentially enhancing biological safety. The interaction of the γ-CD derivative with the anesthetic drugs rocuronium (ROC) and vecuronium (VEC) was investigated using 1H NMR lineshape analysis, 2D ROESY experiments and isothermal titration calorimetry (ITC). Results indicated remarkably high binding constants (107-108 M-1), comparable to those of SGX, though characterized by a 1:2 ROC:CD stoichiometry. Additionally, the β-CD conjugate exhibited a strong affinity for the anticancer drug doxorubicin (K ~9×105 M-1), representing a >400-fold increase over native β-CD. These results suggest that the 2 phosphonated cyclodextrins described here are effective molecular receptors with significant potential for drug delivery and reversal applications.</jats:p>