Rim-differentiation vs. mixture of constitutional isomers: A binding study between pillar[5]arene-based glycoclusters and lectins from pathogenic bacteria

Macrocycle-based glycoclusters, on account of their promising anti-adhesive properties against bacteria, are potential therapeutic alternatives to classic antibiotics through the much less explored anti-adhesive strategy. In this study, a series of constitutionally-pure pentavalent glycoclusters was prepared by con-jugating assorted azido-carbohydrates onto a penta-propargyl rim-differentiated pillar[5]arene (RD-P[5]) scaffold through Cu(I)-catalyzed azide-alkyne cycloaddition "click" reactions. Their binding towards thera-peutically relevant bacterial lectins, such as LecA and LecB from Pseudomonas aeruginosa and concanavalin A (ConA), were evaluated subsequently by isothermal titration calorimetric studies. Most of these isomer -free RD-P[5] pentavalent glycoclusters, except the fucosylated ones, display good affinities to lectins. Nonetheless, the dissociation constants observed are similar to those displayed by an analogous pentava-lent glycocluster consisting of four P[5] constitutional isomers, in which the RD-P[5] component merely accounts for 7% in the mixture. Our results revealed that high constitutional purity is not essential for achieving effective multivalent interactions between P[5]-based glycoclusters and lectins, presumably as a result of the conformationally labile nature of the P[5] scaffold. This information provides valuable design principles for low-cost and facile syntheses of glycosylated P[5]s for biomedical applications.(c) 2022 Published by Elsevier B.V. on behalf of Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.