Function-oriented synthesis applied to the anti-botulinum natural product toosendanin.
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 is a traditional Chinese medicine which has been reported to have anti-botulinum properties in animal models. To establish what chemical functionalities are necessary for the anti-botulinum properties found within toosendanin, a study was initiated with the goal of using function-oriented synthesis (FOS) as a strategy to begin to unravel toosendanin's powerful anti-botulinum properties. From these studies a new synthetic strategy is put forth allowing access to a 4-acetoxy CD fragment analogue (14) of toosendanin, which was achieved from mesityl oxide and acetylacetone in 14 steps. Animal studies on this fragment are also reported.
Nakai
Yuya
Y
Department of Chemistry, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Tepp
William H
WH
Dickerson
Tobin J
TJ
Johnson
Eric A
EA
Janda
Kim D
KD
D000818:Animals; D001905:Botulinum Toxins / Q000037:antagonists & inhibitors*; D001906:Botulism / Q000188:drug therapy; D003014:Clostridium botulinum / Q000187:drug effects; D004365:Drugs, Chinese Herbal / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D036701:Limonins / Q000138:chemical synthesis / Q000737:chemistry; D008516:Medicine, Chinese Traditional; D051379:Mice; D014315:Triterpenes
D001905:Botulinum Toxins; D004365:Drugs, Chinese Herbal; D036701:Limonins; C036454:toosendanin; D014315:Triterpenes