A series of analogues of the weak
histamine (H2) agonist S-[2-(N,N-
dimethylamine)ethyl] isothiourea (
nordimaprit) was produced to investigate the possibility that bulky substituents on the tertiary
amine of
nordimaprit would enhance potency for depigmentation and killing of
melanoma cells. Cell survival studies showed that neither an increase in lipophilicity nor an increase in size of these groups produced selective toxicity, with only the N,N-diisobutyl derivative being more effective than the N,N-diisopropyl derivative in killing the constitutively pigmented human
melanoma cell line MM418. The most hydrophobic analogue, the N,N-dibenzyl derivative, was also the most toxic to all cell lines tested. The association of toxicity with lipophilicity was confirmed by the
piperidine derivative having greater toxicity than the less hydrophobic
morpholine analogue. The ability to decrease
tyrosinase activity was lost when lipophilicity and size of the N-terminal groups were increased, but these analogues produced marked depigmentation, even greater than that found with either
nordimaprit or the diisopropyl derivative. Surprisingly, an increase in
tyrosinase activity was achieved, the most potent agent being the N-ethyl-N-anilino analogue which caused complete depigmentation (0.6% of control) and elevated
tyrosinase activity (148%) in MM418 cells after 1 month of treatment. This indicates that
nordimaprit and its derivatives possess two different mechanisms of depigmentation, the first being
tyrosinase dependent and the second being
tyrosinase independent. The latter pathway is yet to be elucidated but appears to require a high degree of hydrophobicity.