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

• DOI: 10.1002/cmdc.201000419
• Publication Date: 2010-12-07T16:40:12Z
• Authors: Alejandro Díaz‐Mo...; Alejandro Méndez‐...; Fernando Ortega‐C...; Juan M. Benito; Carmen Ortiz Mellet; Jacques Defaye; Tanisha M. Robinson; Adiamseged Yohannes; Vladimir A. Karginov; José M. García Fe...
• Keywords: Models, Molecular; Cyclodextrins; Antigens, Bacterial; Click chemistry; Chemistry, Pharmaceutical; Bacterial Toxins; beta-Cyclodextrins; Polyelectrolytes; 01 natural sciences; Symmetry complementary; Toxin inhibitors; Cell Line; 0104 chemical sciences; 3. Good health; Anthrax; Mice; Structure-Activity Relationship; Bacillus anthracis; Polyamines; Animals; Cluster Analysis; Computer-Aided Design

AbstractThree 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.