Chemical modification of the mitochondrial complex I inhibitor 1-trichloromethyl-1,2,3,4-tetrahydro-beta-carboline: Synthesis and evaluation of N-alkanoyl derivatives

Several N-alkanoyl derivatives (4-9 and 13-16) of the potent mitochondrial complex I inhibitor TaClo (1-trichloromethyl-1,2,3,4-tetrahydro-beta-carbol ine, 2) have been synthesized in order to elucidate the role of hydrophobic portion in the inhibitory action. Using rat brain homogenates or submitoch ondrial particles, the inhibitory effects of these compounds towards NADH-u biquinone reductase (complex I) activity indeed appeared to correlate quite strongly with their lipophilic character. An X-ray structure analysis, exe mplarily performed for N-acetyl-TaClo (4), revealed the N-substituent of su ch chlorinated agents to be dramatically pushed out of the beta-carboline r ing 'plane' due to the high steric demand of the huge trichloromethyl group at C-1.