In vitro biological evaluation and molecular docking studies of natural and semisynthetic flavones from Gardenia oudiepe (Rubiaceae) as tyrosinase inhibitors

Abstract

Hyperpigmentation disorders are difficult to treat without causing permanent depigmentation or irritation. The most effective hypopigmenting agents are tyrosinase inhibitors, however some of those currently used have shown serious side effects. As several classes of flavonoids have already demonstrated ability to inhibit tyrosinase, a library of natural polymethoxyflavones isolated (1?7) from the bud exudate of Gardenia oudiepe and semi-synthetic derivatives (8,9) were evaluated. IC50 of the most active compounds were in the micromolar range. The strongest inhibitors 1, 2 and 3 all shared a 3′,4′-dimethoxy-5′-hydroxy trisubstituted B ring. These SAR conclusions were confirmed by molecular docking studies. The mode of interaction with the enzyme was elucidated, and important interactions between the most active compounds and catalytic residues of tyrosinase were observed. All of these data provided a library of compounds as potential leaders for the design of new depigmenting agents and formulations.Graphical abstractDownload high-res image (213KB)Download full-size imagePrevious article in issueNext article in issueKeywordsGardenia oudiepePolymethoxylated flavonesTyrosinase inhibitory activityStructure-activity relationshipsMolecular docking1. IntroductionMelanin biosynthesis is one of the most important factors in mammal skin color determination. This pigment protects against UV radiation, preventing mutations in cellular DNA, which could cause abnormal conformations in the expression of DNA [1], [2], [3], [4], [5]. An overproduction of melanin leads to hyperpigmentary disorders, such as lentigo, ephelides, nevus and other skin diseases. These pathologies result in devastating conditions for many patients, strongly impacting the quality of life [6], [7], [8]. Besides, agents currently used to reduce for hyperpigmentation, such as hydroquinone or kojic acid, have undesirable effects such as carcinogenesis, hepatotoxicity, dermatitis [9], [10]. Tyrosinase is responsible for the first two steps on melanin synthesis, and could be thus considered as a key-enzyme in the melanogenic cascade [9], [11], [12]. Flavonoids show a high potential for tyrosinase inhibition [6], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20] and may be an important source of depigmenting agents. We have recently reported the ability of nine polymethoxyflavones (PMF) isolated and semi-synthetized from the bud exudate of Gardenia oudiepe Vieill. (syn. G. cerifera S. Moore) to inhibit xanthine oxidase [21]. The potentiality of these compounds to interact in active sites of enzymes drove us to evaluate their monophenolase mushroom tyrosinase inhibitory activity, in order to establish some structure-activity relationships and to elucidate a plausible binding mode through molecular docking studies.