Alan R. Jacobson

Botulinum Neurotoxin Serotype A Inhibitors: Small-Molecule Mercaptoacetamide Analogs

Botulinum neurotoxin elicits its paralytic activity through a zinc-dependant metalloprotease that cleaves proteins involved in neurotransmitter release. Currently, no drugs are available to reverse the effects of botulinum intoxication. Herein we report the design of a novel series of mercaptoacetamide small-molecule inhibitors active against botulinum neurotoxin serotype A. These analogs show low micromolar inhibitory activity against the isolated enzyme. Structure-activity relationship studies for a series of mercaptoacetamide analogs of 5-amino-3-phenylpyrazole reveal components essential for potent inhibitory activity.

Identification of inhibitors of heparin–growth factor interactions from combinatorial libraries of four-component condensation reactions

Chemical libraries based on four-component condensation (4CC) reactions of isocyanides were constructed to identify compounds capable of blocking heparin binding to vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF). The reaction products in the synthesized libraries contain heparin mimetic functional groups such as carbohydrates, sulfonates, carboxylates, and hydroxy groups. These libraries have been screened for the inhibition of heparin binding to growth factors such as VEGF and bFGF. Single point screening at 5.0 microM of the 18,720 reaction products generated 26 candidates. The IC50S of these 26 compounds were determined using HPLC-purified products and 20 of the 26 showed significant inhibition of heparin binding to VEGF and/or bFGF. Eighteen of the 20 confirmed active compounds have a linear extended structure. Structures identified in this library revealed an initial relationship of structure and activity, thus providing direction for further investigation of this type of heparin mimetic libraries.