Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Thiopurine Drugs Repositioned as Tyrosinase Inhibitors

Version 1 : Received: 22 October 2017 / Approved: 22 October 2017 / Online: 22 October 2017 (14:03:13 CEST)

A peer-reviewed article of this Preprint also exists.

Choi, J.; Lee, Y.-M.; Jee, J.-G. Thiopurine Drugs Repositioned as Tyrosinase Inhibitors. Int. J. Mol. Sci. 2018, 19, 77. Choi, J.; Lee, Y.-M.; Jee, J.-G. Thiopurine Drugs Repositioned as Tyrosinase Inhibitors. Int. J. Mol. Sci. 2018, 19, 77.


In this study, we repositioned thiopurine drugs used for the treatment of acute leukaemia as new tyrosinase inhibitors. Tyrosinase catalyses two distinct and successive oxidations in melanin biosynthesis: the conversions of tyrosine to dihydroxyphenylalanine (DOPA) and DOPA to dopaquinone. Continuous efforts are underway to discover small molecule inhibitors of tyrosinase for therapeutic, cosmetic, and agricultural purposes. Structure-based virtual screening has predicted inhibitor candidates for mushroom tyrosinase from drugs approved by the US Food and Drug Administration (FDA). Enzyme assays have confirmed the thiopurine leukaemia drug, thioguanine, as a tyrosinase inhibitor. Two other thiopurine drugs, mercaptopurine and azathioprine, were also evaluated for their tyrosinase inhibitory activity; mercaptopurine caused stronger inhibition than thioguanine did, whereas azathioprine was a poor inhibitor. The inhibitory constants of thioguanine and mercaptopurine were calculated as 52 and 16 µM, respectively, and the value of mercaptopurine was comparable to that of the well-known inhibitor kojic acid (13 µM). The cell lysate and melanin content assay in B16F10 melanoma cells confirmed that the compounds inhibited mammalian tyrosinase. In particular, 50 µM thioguanine reduced the melanin content by 57% without cytotoxicity. Furthermore, the thiopurine drugs shared little chemical similarity with the known tyrosinase inhibitors.


cheminformatics; docking simulation; drug repositioning; thiopurine; tyrosinase


Medicine and Pharmacology, Pharmacology and Toxicology

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