TaClo as a neurotoxic lead: improved synthesis, stereochemical analysis, and inhibition of the mitochondrial respiratory chain.
"TaClo", a highly halogenated tetrahydro-beta-carboline derived from the biogenic amine tryptamine ("Ta") and the synthetic hypnotic chloral ("Clo"), has to be considered as a dopaminergic neurotoxin potentially occurring in vivo. For the preparation of TaClo on a large scale, an improved synthetic pathway was elaborated. The distinct neurotoxic activity of TaClo warrants its intensive study also under stereochemical aspects. For this reason, an analytic device for the separation and stereochemical attribution of its two enantiomers, (R)-TaClo and (S)-TaClo, was developed, based on chromatography on a chiral HPLC phase. Elucidation of the absolute configuration was achieved by CD spectroscopy and confirmed by X-ray crystallography. TaClo exhibits highly selective in vitro inhibition of complex I of the mitochondrial respiratory chain, the required concentrations being much lower than those needed for related halogen-free beta-carbolines or for MPP+ (1-methyl-4-phenyl-pyridinium ion), the active metabolite of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine). Furthermore, TaClo as a novel lead structure stimulated chemical and neuropharmacological investigations also on related highly halogenated beta-carbolines. Thus, some of the tested compounds--both potential TaClo metabolites and unnatural derivatives--showed even an enhanced inhibition of the mitochondrial respiration in vitro.
Bringmann
G
G
Institute of Organic Chemistry, University of Würzburg, Federal Republic of Germany.
God
R
R
Feineis
D
D
Janetzky
B
B
Reichmann
H
H
D000818:Animals; D002243:Carbolines / Q000138:chemical synthesis / Q000737:chemistry / Q000633:toxicity*; D004579:Electron Transport / Q000187:drug effects; D006801:Humans; D008928:Mitochondria / Q000187:drug effects* / Q000201:enzymology; D008958:Models, Molecular; D015394:Molecular Structure; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000037:antagonists & inhibitors*; D009498:Neurotoxins / Q000138:chemical synthesis / Q000737:chemistry / Q000633:toxicity*; D013237:Stereoisomerism
D002243:Carbolines; D009498:Neurotoxins; C067372:1-trichloromethyl-1,2,3,4-tetrahydro-beta-carboline; D016660:NAD(P)H Dehydrogenase (Quinone)