Abstract
Caffeic acid derivatives represent promising lead compounds in the search for tyrosinase inhibitors to be used in the treatment of skin local hyperpigmentation associated to an overproduction or accumulation of melanin. We recently reported the marked inhibitory activity of a conjugate of caffeic acid with dihydrolipoic acid, 2-S-lipoylcaffeic acid (LCA), on the tyrosine hydroxylase (TH) and dopa oxidase (DO) activities of mushroom tyrosinase. In the present study, we evaluated a more lipophilic derivative, 2-S-lipoyl caffeic acid methyl ester (LCAME), as an inhibitor of tyrosinase from human melanoma cells. Preliminary analysis of the effects of LCAME on mushroom tyrosinase indicated more potent inhibitory effects on either enzyme activities (IC50 = 0.05 ± 0.01 μM for DO and 0.83 ± 0.09 μM for TH) compared with LCA and the reference compound kojic acid. The inhibition of DO of human tyrosinase was effective (Ki = 34.7 ± 1.1 μM) as well, while the action on TH was weaker. Lineweaver–Burk analyses indicated a competitive inhibitor mechanism. LCAME was not substrate of tyrosinase and proved nontoxic at concentrations up to 50 μM. No alteration of basal tyrosinase expression was observed after 24 h treatment of human melanoma cells with the inhibitor, but preliminary evidence suggested LCAME might impair the induction of tyrosinase expression in cells stimulated with α-melanocyte-stimulating hormone. All these data point to this compound as a valuable candidate for further trials toward its use as a skin depigmenting agent. They also highlight the differential effects of tyrosinase inhibitors on the human and mushroom enzymes.
Highlights
Melanin pigmentation is believed to be one of the main determinants of sensitivity to ultraviolet light and susceptibility to sun damage [1]
lipoylcaffeic acid methyl ester (LCAME) was prepared by a procedure previously developed for lipoylcaffeic acid (LCA) [25], involving in situ generation of the o-quinone of caffeic acid ester by the regioselective hydroxylation of p-coumaric acid methyl ester with 2-iodoxybenzoic acid (IBX), followed by addition of Dihydrolipoic acid (DHLA)
The inhibition properties of LCAME were preliminarily investigated on mushroom tyrosinase by spectrophotometric monitoring of dopachrome formation, a method which is routinely used for evaluation of the activity of potential tyrosinase inhibitors [13,21,22]
Summary
Melanin pigmentation is believed to be one of the main determinants of sensitivity to ultraviolet light and susceptibility to sun damage [1]. An overproduction or accumulation of melanin can lead to a local excess of pigmentation (or “hypermelanosis”) associated with disorders such as melasma, lentigo, or postinflammatory hyperpigmentation [2,4,5] whose medical and aesthetical impact has prompted a constant search for new nontoxic depigmenting agents [6,7,8,9,10]. Amidic derivatives of caffeic acid with serine or lysine, in particular N-caffeoyl-O-acetylserine methyl ester, showed strong tyrosinase inhibitory activity [39]. On this basis, in the present study we examined the ability of LCA to inhibit tyrosinase from HBL human melanoma cells. The effects on tyrosinase expression and cell viability were analyzed
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