Botulinum neurotoxin inhibitor

Scheme 10 DeBoef s route to a botulinum neurotoxin inhibitor employing an oxidative crosscoupling...

DeBoef demonstrated the utility of the C2-selective oxidative cross-coupling of indole and benzene previously reported by his group in the expedient synthesis of a botulinum neurotoxin inhibitor (Scheme 10) [53]. The streamlined synthesis featured an oxidative cross-coupling of methyl-AT-SEM-indole-6-carboxylate with benzene, and after further elaboration, a direct arylation of a thiophene moiety that had been incorporated into the molecule. This formal synthesis highlights the efficiency of transition metal catalyzed reactions at C-H bonds in the planning of synthetic routes. 

Adler, M., Nicholson, J.D., Comille, F., and Hackley, Jr., B E. 1998. Efficacy of a novel metalloprotease inhibitor on botulinum neurotoxin B activity. FEBS Lett. 429 234-238. 

Agarwal, R., Binz, T., and Swaminathan, S. 2005. Structural analysis of botulinum neurotoxin serotype F light chain implications on substrate binding and inhibitor design. Biochemistry 44 11758-11765. 

Boldt, G.E., Eubanks, L.M., and Janda, K.D. 2006a. Identification of a botulinum neurotoxin A protease inhibitor displaying efficacy in a cellular model. Chem. Commun. 29 3063-3065. 

Oost, T., Sukonpan, C., Brewer, M., Goodnough, M., Tepp, W., Johnson, E.A., and Rich, D.H. 2003. Design and synthesis of substrate-based inhibitors of botulinum neurotoxin type B metaUoprotease. Biopolymers 71 602-619. 

Park, J.G., Sill, P.C., Makiyi, E.F., Garcia-Sosa, A.T., Millard, C.B., Schmidt, J.J., and Pang, Y.P. 2006. Serotype-selective, small-molecule inhibitors of the zinc endopeptidase of botulinum neurotoxin serotype A. Bioorg. Med. Chem. 14 395 408. 

Schmidt, J.J. and Stafford, R.G. 2005. Botulinum neurotoxin serotype F identification of substrate recognition requirements and development of inhibitors with low nanomolar affinity. Biochemistry 44 4067 073. 

Schmidt, J.J., Stafford, R.G., and Bostian, K. A., Type A botulinum neurotoxin proteolytic activity Development of competitive inhibitors and implication for substrate specificity at the SR binding site, FEES Lett, 435, 61, 1998. 

To demonstrate the utility of our oxidative coupling reaction, we synthesized one of the best inhibitors of botulinum neurotoxin (Scheme 5). " The overall yield (4.6%) was comparable to the previously published method, which... 

SCHEME 5 Synthesis of an inhibitor of botulinum neurotoxin via oxidative aryiation. 

Potavathri S, Kantak A, DeBoef B (2011) Increasing synthetic efficiency via direct C-H functionalization formal synthesis of an inhibitor of botulinum neurotoxin. Chem Commun. doi 10.1039/clccl0755k... 

Botulinum neurotoxin (BoNT) is the most potent poison known to mankind. Currently no antidote is available to rescue poisoned synapses. An effective medical countermeasure strategy would require developing a drug that could rescue poisoned neuromuscular synapses and include its efficient delivery specifically to poisonedpresynaptic nerve terminals. Here we report a drug delivery strategy that could directly deliver toxin inhibitors into the intoxicated nerve terminal cytosol. 

An effective Botulinum neurotoxin-based drug delivery vehicle can be used to directly deliver toxin inhibitors into the intoxicated nerve terminal cytosol. The concept may possibly be utilized for drug delivery for other neuronal and neuromuscular disorders. Besides a BoNT therapeutic approach, this report also provides new fundamental knowledge of endocytosis and exocytosis as well as of BoNT trafficking in neurons. 

---