title: Symmetry complementarity-guided design of anthrax toxin inhibitors based on β-cyclodextrin: Synthesis and relative activities of face-selective functionalized polycationic clusters.
abstract: 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.
authors.affiliation: Instituto de Investigaciones Químicas, CSIC - Universidad de Sevilla, Spain.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Díaz-Moscoso
authors.forename: Alejandro
authors.initials: A
authors.lastname: Méndez-Ardoy
authors.forename: Fernando
authors.initials: F
authors.lastname: Ortega-Caballero
authors.forename: Juan M
authors.initials: JM
authors.lastname: Benito
authors.forename: Carmen
authors.initials: C
authors.lastname: Ortiz Mellet
authors.forename: Jacques
authors.initials: J
authors.lastname: Defaye
authors.forename: Tanisha M
authors.initials: TM
authors.lastname: Robinson
authors.forename: Adiamseged
authors.initials: A
authors.lastname: Yohannes
authors.forename: Vladimir A
authors.initials: VA
authors.lastname: Karginov
authors.forename: José M
authors.initials: JM
authors.lastname: García Fernández
mesh_terms: D000818:Animals; D000881:Anthrax / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D000942:Antigens, Bacterial / Q000276:immunology / Q000378:metabolism; D001408:Bacillus anthracis / Q000276:immunology / Q000378:metabolism; D001427:Bacterial Toxins / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D002460:Cell Line; D002626:Chemistry, Pharmaceutical; D016000:Cluster Analysis; D017076:Computer-Aided Design; D051379:Mice; D008958:Models, Molecular; D011073:Polyamines / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D000071228:Polyelectrolytes; D013329:Structure-Activity Relationship; D047392:beta-Cyclodextrins / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology
chemical_list: D000942:Antigens, Bacterial; D001427:Bacterial Toxins; D011073:Polyamines; D000071228:Polyelectrolytes; D047392:beta-Cyclodextrins; C030325:anthrax toxin; C031215:betadex