Toxicity and metabolism of the chloral-derived mammalian alkaloid 1-trichloromethyl-1,2,3,4-tetrahydro-beta-carboline (TaClo) in PC12 cells.
Chloral-derived beta-carbolines, which are structurally similar to the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 5), are discussed to contribute to neuronal cell death in idiopathic Parkinson's disease. The cytotoxicity of 1-trichloromethyl-1,2,3,4-tetrahydro-beta-carboline (TaClo, 4) to neuronal-like clonal pheochromocytoma PC12 cells was examined by the determination of lactate dehydrogenase (LDH) release. After incubation for 48 h, 4 showed a strong dose-dependent cytotoxic activity towards PC12 cells with an ED50 value of 230 microM. In PC12 cells reductive dehalogenation of 4 was observed giving rise to the formation of 1-dichloromethyl-1,2,3,4-tetrahydro-beta-carboline (6) as a main TaClo metabolite exhibiting a cytotoxic potential comparable to that of TaClo. An X-ray structure analysis, performed for the trifluoroacetyl derivative of 6, revealed the N-substituent of such a highly chlorinated agent to be dramatically pushed out of the beta-carboline ring 'plane' due to the high steric demand of the huge dichloromethyl group at C(1).
Bringmann
Gerhard
G
Institut für Organische Chemie, Universität Würzburg, Am Hubland, D-97074 Würzburg, Germany. bringman@chemie.uni-wuerzburg.de
Feineis
Doris
D
Münchbach
Miriam
M
God
Ralf
R
Peters
Karl
K
Peters
Eva-Maria
EM
Mössner
Rainald
R
Lesch
Klaus-Peter
KP
D000818:Animals; D002243:Carbolines / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity*; D016923:Cell Death; D002470:Cell Survival / Q000187:drug effects*; D007770:L-Lactate Dehydrogenase / Q000032:analysis; D008958:Models, Molecular; D008968:Molecular Conformation; D016716:PC12 Cells; D010673:Pheochromocytoma; D051381:Rats
D002243:Carbolines; C067372:1-trichloromethyl-1,2,3,4-tetrahydro-beta-carboline; D007770:L-Lactate Dehydrogenase