New Thioureas and Related Substances Intended for Melanoma Targeting

Abstract

Thiouracil and a few related drugs are known to be melanoma-seeking agents owing to specific incorporation into nascent melanin. The melanin-affinic properties are apparently due to binding to intermediates, preferably dopaquinone, produced in the melanin synthetic pathway by tyrosinase-catalysed oxidation of tyrosine. In the present paper, in vitro screening methods have been used for the identification of possible melanoma seekers according to the above principle. The binding of test substance to dopaquinone suppressed dopachrome formation by the withdrawal of dopaquinone from the reaction of the mixture, and the decrease in dopachrome concentration was monitored spectrophotometrically at 475 nm. In order to eliminate false results caused by tyrosinase inhibition, which also will decrease the dopachrome concentration, the oxygen consumption was followed potentiometrically. To avoid the effect of tyrosinase inhibition on dopachrome formation, additional experiments with autoxidation of L-dopa in the presence of test substance were performed. Of the 22 substances (mainly thioureylenes and thioamides) studied, 4,5,6-triamino-2(H)- pyrimidinehtionsulfate, trithiocyanuric acid, 2-thiouracil, 6-methyl-2-thiouracil, and 4- amino-2-mercaptopyrimidine most effectively decreased the dopachrome formation with no or little inhibition of tyrosinase activity. They should therefore be regarded as potential melanoma seekers. In a complementary autoradiographic study on the uptake of the potent tyrosinase inhibitor mercaptobenzothiazole (MBT) in B 16 melanoma transplanted to mice, it was found that strong tyrosinase inhibition seems to decrease incorporation into melanin in vitro. MBT was partially accumulated in restricted areas of the tumor which may be explained by the molar dose injected.

Age-related Melanogenesis in the Eye of Mice, Studied by Microautoradiography of3H-methimazole, a Specific Marker of Melanin Synthesis

“…These false precursors, thioureylene derivatives, are superior to the normal melanin precursors in this respect because of their very selective uptake in melanin-synthesizing cells. Methimazole was found to be a potent melanoma seeker (Olander, Larsson and Dencker, 1983), with very high selectivity and low inhibition of tyrosinase activity (Ma/ rs & Larsson 1995), probably due to adduct formation with melanin intermediates late in the melanin synthesis pathway. The purpose of the present study was to investigate the age-related melanogenesis in the eye of DBA-mice using microautoradiography of $H-Methimazole, and to look for the presence of immature melanosomes in electron micrographs from eyes of young and adult mice.…”

S-(−)-10,11-Dihydroxyfarnesoic Acid Methyl Ester Inhibits Melanin Synthesis in Murine Melanocyte Cells

“…Melanin pigment, which contains a combination of melanins, is derived from tyrosine, which is converted to dihydroxyphenylalanine (DOPA), then dopaquinone, and finally dopachrome by tyrosinase and other related enzyme systems [1]. Most of the current research on whitening biomaterial(s) focuses on the inhibition of melanin synthesis by targeting these enzymes [2].…”

Photoelectron spectroscopic study of the negative ions of 4-thiouracil and 2,4-dithiouracil

“…[1][2][3][4][5][6][7][8][9][10][11][12][13][14] The halo-nucleobases may have roles as radiosensitizers in the treatment of cancer. [1][2][3][4][5][6][7][8][9][10][11][12][13][14] The halo-nucleobases may have roles as radiosensitizers in the treatment of cancer.…”