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Synthesis and biological evaluation of botulinum neurotoxin a protease inhibitors.

Journal of medicinal chemistry (2010-02-17)
Bing Li, Ramdas Pai, Steven C Cardinale, Michelle M Butler, Norton P Peet, Donald T Moir, Sina Bavari, Terry L Bowlin
ABSTRACT

NSC 240898 was previously identified as a botulinum neurotoxin A light chain (BoNT/A LC) endopeptidase inhibitor by screening the National Cancer Institute Open Repository diversity set. Two types of analogues have been synthesized and shown to inhibit BoNT/A LC in a FRET-based enzyme assay, with confirmation in an HPLC-based assay. These two series of compounds have also been evaluated for inhibition of anthrax lethal factor (LF), an unrelated metalloprotease, to examine enzyme specificity of the BoNT/A LC inhibition. The most potent inhibitor against BoNT/A LC in these two series is compound 12 (IC(50) = 2.5 microM, FRET assay), which is 4.4-fold more potent than the lead structure and 11.2-fold more selective for BoNT/A LC versus the anthrax LF metalloproteinase. Structure-activity relationship studies have revealed structural features important to potency and enzyme specificity.

MATERIALS
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Brand
Product Description

Sigma-Aldrich
4-Methyl-3-nitrobenzonitrile, 97%