Tyrosinase (EC 1.14.18.1) is a copper-containing monooxygenase enzyme widely distributed in nature, which can be found in fungi, and in higher plants and animals.1) It catalyzes the conversion of tyrosine to dopa, dopaquinone, and subsequent autopolymerization to melanin.2) Tyrosinase inhibitor has been used as a whitening agent or antihyperpigment agent because of its ability to suppress dermal-melanin production. Many scientists are working to isolate tyrosinase inhibitors from natural products. Arbutin, 3) kojic acid, 4) and hydroquinones 5) have been reported to have inhibitory activity. They had been widely used in cosmetic industry as whitening composition. However kojic acid and arbutin have been failed to demonstrate the inhibitory activity of pigmentation in intact melanocytes or in clinical trial.6) Hydroquinones are considered to be cytotoxic to melanocytes and potentially mutagenic to mammalian cells. 6) Since the most widely used compounds failed to demonstrate the clinical efficacy, there is a strong need to develop a new tyrosinase inhibitor that is clinically active.Aloe (Liliaceae) is a perennial evergreen, herbaceous plant or tropical woody plant. More than 360 species are known in the world. It has long-been used in folk medicine for the treatment of burns and dermatitis. It is also widely used in the cosmetic industry as a moisturizing agent and skinwhitening composition. Recently aloesin (1) was reported as a tyrosinase-inhibitory principle to this plant, [7][8][9] and it is now used as a whitening composition in cosmetics. Recently one of Korean research group demonstrated clinical efficacy of aloesin.10) Currently, aloesin is purified from aloe, however this purification method involves a complex and time-consuming process. Aloesin is difficult to synthesize due to its C-glycosyl moiety.In this study, we attempted to locate a tyrosinase inhibitory chromone compound which possess more potent tyrosinaseinhibitory activity than aloesin, and which is easier to synthesize. Results and DiscussionAloesin is difficult to synthesize because of the C-glycosyl moiety in the molecule. Since the purpose of this study was to search for a new compound that is easy to synthesize, our first goal centered around whether or not a chromone skeleton without C-glycoside has tyrosinase inhibition activity. Consequently, we synthesized compound 2 that has no C-glycosyl moiety, and then we evaluated its activity. Fortunately, compound 2 exhibited stronger inhibition activity (IC 50 ϭ 0.75 mM) than aloesin (1) itself (IC 50 ϭ0.90 mM).Our next concern was the alkylation of hydroxyl group at the 7-C-position. The protection and deprotection process of hydroxyl group at the 7-C-position in the synthetic pathway of 2, reduced the overall yield. Therefore, alkylation of hydroxyl group at the 7-C-position is beneficial since the deprotection process is unnecessary. We synthesized C 1 -C 4 alkyl ether derivatives (compounds 3-9), and their activity was examined. The longer alkyl group showed weaker inhibition activity. Fo...

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