Synthesis, characterization and mutagenicity of 2-nitroso-6,7-dimethoxytetrahydroisoquinoline

The compound 6,7-dimethoxytetrahydroisoquinoline (Scheme 2, (ii] reacts with nitrous acid at ambient temperature and pH approximately 3.0 to give, in high yield the expected 2-nitroso-6,7-dimethoxytetrahydroisoquinoline (Scheme 2, (iii)). An unequivocal chemical structure of this nitroso derivative was established by high resolution mass spectrometry and 1H NMR spectrometry. Unlike many N-nitroso compounds, (iii) crystallizes in a single rotational isomer which spontaneously forms, in dimethylsulfoxide (DMSO) solution, an equilibrium mixture of the two E/Z isomeric forms with a t1/2 approximately 53 h. The compound is mutagenic to Salmonella tester strains TA98, TA100, TA1538, TA1535, and TA1537 but only in the presence of induced rat liver microsomes. The highest mutagenic activity of approximately 10 net revertants/nM was obtained with TA100 at a dose of 10 micrograms/plate. The compound (ii) is a close structural analog to the tetrahydroisoquinolines formed by endogenous condensation/cyclization reactions that can occur, between acetaldehyde and dopamine or norepinephrine, when alcohol is consumed.