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. T...

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Bibliographic Details
Published in:ChemMedChem 2011-01, Vol.6 (1), p.181-192
Main Authors: Díaz-Moscoso, Alejandro, Méndez-Ardoy, Alejandro, Ortega-Caballero, Fernando, Benito, Juan M., Ortiz Mellet, Carmen, Defaye, Jacques, Robinson, Tanisha M., Yohannes, Adiamseged, Karginov, Vladimir A., García Fernández, José M.
Format: Article
Language:English
Subjects:
Animals
anthrax
Anthrax - drug therapy
Anthrax - immunology
Anthrax - metabolism
Antigens, Bacterial - immunology
Antigens, Bacterial - metabolism
Bacillus anthracis - immunology
Bacillus anthracis - metabolism
Bacterial Toxins - antagonists & inhibitors
Bacterial Toxins - immunology
Bacterial Toxins - metabolism
beta-Cyclodextrins - chemical synthesis
beta-Cyclodextrins - metabolism
beta-Cyclodextrins - pharmacology
Cell Line
Chemistry, Pharmaceutical
click chemistry
Cluster Analysis
Computer-Aided Design
cyclodextrins
Mice
Models, Molecular
Polyamines - chemical synthesis
Polyamines - metabolism
Polyamines - pharmacology
Structure-Activity Relationship
symmetry complementarity
toxin inhibitors
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Summary: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. Molecular disarmament: The heptameric pore formed by the anthrax toxin protective antigen (PA) plays a decisive role in infection. Pore blockage was investigated by using size, charge, and C7 symmetry complementary β‐cyclodextrin scaffolds. Toxin inhibitor candidates with potency in the low micromolar range were identified, and intimate structure–activity relationships were inferred.
ISSN:1860-7179
1860-7187
DOI:10.1002/cmdc.201000419