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1-trichloromethyl-1,2,3,4-tetrahydro-beta-carboline (TaClo); rat phaeochromocytoma (PC12) cells; cytotoxicity; Parkinson's disease
Abstract:
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-p-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 mu M. 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).
