Examination of α-exosite inhibitors against Botulinum neurotoxin A protease through structure-activity relationship studies of chicoric acid.

Botulinum neurotoxins (BoNT) are among the most toxic known substances and currently there are no effective treatments for intraneuronal BoNT intoxication. Chicoric acid (ChA) was previously reported as a BoNT/A inhibitor that binds to the enzyme's α-exosite. Herein, we report the synthesis and structure-activity relationships (SARs) of a series of ChA derivatives, which revealed essential binding interactions between ChA and BoNT/A.

Toward the discovery of dual inhibitors for botulinum neurotoxin A: concomitant targeting of endocytosis and light chain protease activity.

Dyngo-4a™ has been found to be an endocytic inhibitor of BoNT/A neurotoxicity through dynamin inhibition. Herein, we demonstrate this molecule to have a previously unrecognized dual activity against BoNT/A, dynamin-protease inhibition. To establish the importance of this dual activity, detailed kinetic analysis of Dyngo-4a's inhibition of BoNT/A metalloprotease as well as cellular and animal toxicity studies have been described.

Enantiospecific Synthesis and Biological Investigations of a Nuphar Alkaloid: Proposed Structure of a Castoreum Component.

An enantiospecific synthesis of a Nuphar alkaloid was achieved in 9 steps from -Boc-(L)-proline. The alkaloid is a minor component of castoreum, the dried scent glands of the beaver. During the course of our study, the stereochemistry of three synthetic intermediates was verified by X-ray analysis, which contributes to resolving existing discrepancies among the literature reports regarding the synthesis of this particular compound.

Targeting botulinum A cellular toxicity: a prodrug approach.

The botulinum neurotoxin light chain (LC) protease has become an important therapeutic target for postexposure treatment of botulism. Hydroxamic acid based small molecules have proven to be potent inhibitors of LC/A with nanomolar Ki values, yet they lack cellular activity conceivably due to low membrane permeability. To overcome this potential liability, we investigated two prodrug strategies, 1,4,2-dioxazole and carbamate, based on our 1-adamantylacetohydroxamic acid scaffold.

Three-component synthesis of cyclic enaminones via ketene cyclization.

Cyclic six-membered enaminones were synthesized from three components (bromodiazoacetone, primary amine, and alkyne) in high yields via aza-Michael addition, Wolff rearrangement, and nucleophilic ketene cyclization.

Synthesis of amino acid derived enaminones via Wolff rearrangement using vinylogous amides as carbon nucleophiles.

Cyclic enaminones were synthesized in high yields from amino acids in two steps via Wolff rearrangement. The cyclization represents a rare 6-exo-dig cyclization involving a ketene as an electrophile. No racemization was observed during this reaction.

Ruthenium-catalyzed amino- and alkoxycarbonylations with carbamoyl chlorides and alkyl chloroformates via aromatic C-H bond cleavage.

Ruthenium-catalyzed regioselective direct amino- and alkoxycarbonylations of aromatic rings via C-H bond cleavage using chlorocarbonyl compounds are described. A broad generality of amide and ester groups was achieved taking advantage of the wide availability of carbonylating agents. Alkyl chloroformates, inapplicable to usual Friedel-Crafts methods, can also be used for direct catalytic alkoxycarbonylation.