Kojic acid-derived tyrosinase inhibitors: synthesis and bioactivity

Introduction Melanin is a dark pigment produced by about 10% of skin cells in the innermost layer of the epidermis (1). This compound is a heteropolymer of indole derivatives and is produced inside melanosomes through a series of oxidative reactions involving the amino acid tyrosine in the presence of the enzyme tyrosinase (Fig. 1). The type and amount of produced melanin in the melanosomes generates the actual color of the skin (2). Melanogenesis is a physiological process, which plays an important role in the prevention of sun-induced skin injury. Although the melanin production in human skin is a major defense mechanism against ultraviolet (UV) light, the accumulation of an excess of epidermal pigments can causes various hyperpigmentation disorders, such as melasma, age spots, and sites of actinic damage (3). Tyrosinase (EC 1.14.18.1), also known as polyphenoloxidase (PPO), is a coppercontaining bifunctional enzyme with a molecular weight of approximately 60–70 kDa in mammals and is found exclusively in melanocytes (1,4). It catalyzes two distinct reactions of melanin synthesis (Fig. 1); the hydroxylation of Abstract Tyrosinase is a key enzyme for melanin biosynthesis, catalyzing the oxidation of L-tyrosine to L-dopaquinone. The tyrosinase inhibition is an effective approach to control hyperpigmentation in human skin and enzymatic browning in fruits and vegetables. Kojic acid is a naturally-occurring tyrosinase inhibitor which has been clinically used to treat the hyperpigmentation of skin. However, kojic acid as a hydrophilic small-molecule has insufficient inhibitory activity and stability, with considerable toxicity. To overcome these drawbacks, synthetic derivatives of kojic acid were developed, which exhibited enhanced tyrosinase inhibitory activity and more favorable stability relative to kojic acid. In this context, the synthesis and biological activity of kojic acid derivatives as tyrosinase inhibitors have been highlighted.