Conjugation With Dihydrolipoic Acid Imparts Caffeic Acid Ester Potent Inhibitory Effect on Dopa Oxidase Activity of Human Tyrosinase

Int J Mol Sci. 2018 Jul 24;19(8):2156. doi: 10.3390/ijms19082156.

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.

Keywords: caffeic acid; depigmenting agent; dihydrolipoic acid; dopa oxidase; inhibition mechanism; skin lightening; tyrosinase.

MeSH terms

  • Agaricales / enzymology
  • Caffeic Acids / chemistry*
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Inhibitory Concentration 50
  • Melanins / metabolism
  • Melanoma / enzymology
  • Monophenol Monooxygenase / antagonists & inhibitors*
  • Pyrones / pharmacology
  • Skin Lightening Preparations / chemistry
  • Skin Lightening Preparations / pharmacology*
  • Thioctic Acid / analogs & derivatives*
  • Thioctic Acid / chemistry
  • Tyrosine 3-Monooxygenase / antagonists & inhibitors

Substances

  • Caffeic Acids
  • Enzyme Inhibitors
  • Melanins
  • Pyrones
  • Skin Lightening Preparations
  • kojic acid
  • Thioctic Acid
  • dihydrolipoic acid
  • Tyrosine 3-Monooxygenase
  • Monophenol Monooxygenase
  • caffeic acid methyl ester