Toosendanin: synthesis of the AB-ring and investigations of its anti-botulinum properties (Part II).
Botulinum neurotoxins (BoNTs) are the etiological agents responsible for botulism, a disease characterized by peripheral neuromuscular blockade and a characteristic flaccid paralysis of humans. The natural product toosendanin, a limonoid, is a traditional Chinese medicine that has reported anti-botulinum properties in animal models. Toosendanin effectively inhibits the biological activity of BoNT/A in neuronal cells at concentrations of 200 nM, and partial inhibition can be observed with concentrations as low as 8 nM. Mechanistically, toosendanin's inhibition is due to prevention of transduction of the BoNT LC through the HC channel. Intriguing questions as to the molecular architecture of toosendanin as related to its anti-botulinum properties have focused our attention on a synthesis of toosendanin's unusual AB-ring, containing a unique bridged hemi-acetal. Within the current work, a synthetic strategy allowing access to the AB-fragment of toosendanin was achieved from a trans-decalin system. In addition, this fragment was examined for its modulation of BoNT/A intoxication in a rat spinal cord cellular assay.
Nakai
Yuya
Y
Departments of Chemistry and Immunology and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Pellett
Sabine
S
Tepp
William H
WH
Johnson
Eric A
EA
Janda
Kim D
KD
D000818:Animals; D019274:Botulinum Toxins, Type A / Q000037:antagonists & inhibitors* / Q000302:isolation & purification; D001906:Botulism / Q000188:drug therapy*; D018929:Cell Culture Techniques; D003014:Clostridium botulinum / Q000737:chemistry; D004365:Drugs, Chinese Herbal / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D051381:Rats; D013116:Spinal Cord / Q000166:cytology; D014315:Triterpenes
D019274:Botulinum Toxins, Type A; D004365:Drugs, Chinese Herbal; C036454:toosendanin; D014315:Triterpenes