Symmetry complementarity-guided design of anthrax toxin inhibitors based on β-cyclodextrin: Synthesis and relative...

Three new series of potential anthrax toxin inhibitors based on the β-cyclodextrin (βCD) scaffold were developed by exploiting face-selective Cu(I)-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.