Inhibition of melanogenesis in human melanoma cells by novel analogues of the partial histamine (H2) agonist nordimaprit.
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.
Fechner
G A
GA
Pharmacy Department, University of Queensland, Australia.
Jacobs
J J
JJ
Parsons
P G
PG
D002460:Cell Line / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D017259:Dimaprit / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D006801:Humans; D008543:Melanins / Q000096:biosynthesis*; D008545:Melanoma / Q000378:metabolism*; D014442:Monophenol Monooxygenase / Q000378:metabolism; D010858:Pigmentation / Q000187:drug effects; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured / Q000187:drug effects
D008543:Melanins; C025838:nordimaprit; D014442:Monophenol Monooxygenase; D017259:Dimaprit