A recent study showed that N-acylserotonin derivatives have strong inhibitory activity against tyrosinase. To clarify the role of the 5-hydroxy group in the indole ring, 2-, 4-, 5-, 6-, and 7-hydroxyindole and 11 related compounds such as 5-hydroxyindan and 6-hydroxyquinoline were tested for their inhibition of catecholase activity of tyrosinase from human HMV-II melanoma cells. 6-Hydroxyindole (5) and 7-hydroxyindole (6) were potent inhibitors, while 5-hydroxyindole (4) was a weaker inhibitor than the above-mentioned compounds (IC50 = 20, 79, 366, and 342 microM for 5, 6, 4, and kojic acid, respectively). 2-Hydroxycarbazole was also active (IC50 = 190 microM), 5-hydroxyindan, 4-aminophenol, and harmalol were slightly active, and other compounds were inactive as an inhibitor. A similar pattern of inhibition was found with these compounds against mouse B16 melanoma tyrosinase, but with some differences from that for HMV-II tyrosinase. Kinetic analysis with HMV-II tyrosinase showed that the inhibition by hydroxyindoles 4, 5, and 6 was competitive with respect to the substrate L-DOPA. Melanin formation in HMV-II cells was suppressed by 14% with 10 microM 5 without cytotoxicity, but 30 or 100 microM 5 decreased the cell viability. The present results suggest that 6-hydroxyindole is a potential and useful pharmacophore of antimelanogenic agents and that the position of a phenolic hydroxy group in a specific heterocyclic ring such as in indole is possibly optimized to yield more active inhibitors for tyrosinase.
