Symmetry Complementarity-Guided Design of Anthrax Toxin Inhibitors Based on β-Cyclodextrin: Synthesis and Relative Activities of Face-Selective Functionalized Polycationic Clusters

Three new series of potential anthrax toxin inhibitors based on the β-cyclodextrin (βCD) scaffold were developed by exploiting face-selective CuI-catalyzed azide–alkyne 1,3-cycloadditions, amine–isothiocyanate coupling, and allyl group hydroboration–oxidation/hydroxy amine replacement reactions. The molecular design follows the “symmetry–complementarity” concept between homogeneously functionalized polycationic βCD derivatives and protective antigen (PA), a component of anthrax toxin known to form C7-symmetric pores on the cell membrane used by lethal and edema factors to gain access to the cytosol. The synthesis and antitoxin activity of a collection of βCD derivatives differing in the number, arrangement, and face location of the cationic elements are reported herein. These results set the basis for a structure–activity relationship development program of new candidates to combat the anthrax threat.