Characterization of a novel tyrosinase inhibitor, (2RS,4R)-2-(2,4-dihydroxyphenyl)thiazolidine-4-carboxylic acid (MHY384).

Abstract

BACKGROUND:

We synthesized (2RS,4R)-2-(2,4-dihydroxyphenyl)thiazolidine-4-carboxylic acid (MHY384) as a potential tyrosinase inhibitor and investigated its antityrosinase activity.

METHODS:

The structure of MHY384 was established using (1)H and (13)C NMR spectroscopy and mass spectral analyses. To investigate dual mechanisms of action of MHY384 for the inhibition of melanin synthesis, we confirmed the inhibitory effect of tyrosinase catalytic activity of MHY384. Then, we confirmed the inhibitory effect of MHY384 on transcription of tyrosinase mRNA through alpha-MSH-induced cAMP-PKA-MITF signaling. In addition, we supported the inhibitory mechanism of MHY384 against tyrosinase using a kinetic study and docking programs.

RESULTS:

To determine how MHY384 regulates melanogenesis, we measured melanin levels and expression of the genes for microphthalmia-associated transcription factor (MITF) and tyrosinase in α-melanocyte-stimulating hormone (α-MSH)-induced B16F10 melanoma cells. MHY384 potently inhibited tyrosinase activity and melanin production in B16F10 melanoma cells. Through docking models, we were able to construct the tertiary structure of mushroom tyrosinase and simulate its docking with MHY384. The result supports that MHY384 strongly interacts with tyrosinase residues in the active site and it can directly inhibit tyrosinase. To investigate additional mechanisms of action of MHY384, we confirmed that the inhibition of tyrosinase activity was found to be due to the modulation of the expression of tyrosinase and its transcription factor, MITF, through cAMP, which regulates protein kinase A.

CONCLUSIONS:

This study strongly indicates that the depigmenting effect of MHY384 results from the down-regulation of MITF and tyrosinase through direct tyrosinase inhibition.

GENERAL SIGNIFICANCE:

Our findings suggest that MHY384 can be an effective skin-whitening agent.

• Authors: Yu Kyeong Han, Yun Jung Park, Young Mi Ha, Daeui Park, Ji Yeon Lee, Naree Lee, Jeong Hyun Yoon, Hyung Ryong Moon, Hae Young Chung
• Journal: Biochimica et biophysica acta (Biochim Biophys Acta) Vol. 1820 Issue 4 Pg. 542-9 (Apr 2012) ISSN: 0006-3002 [Print] Netherlands
• PMID: 22251576 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier B.V. All rights reserved.

Chemical References

• (2RS,4R)-2-(2,4-dihydroxyphenyl)thiazolidine-4-carboxylic acid
• Melanins
• Microphthalmia-Associated Transcription Factor
• Thiazolidines
• alpha-MSH
• Cyclic AMP
• Monophenol Monooxygenase
• Cyclic AMP-Dependent Protein Kinases

Topics

• Animals
• Catalytic Domain
• Cell Line, Tumor
• Cyclic AMP (metabolism)
• Cyclic AMP-Dependent Protein Kinases (metabolism)
• Melanins (genetics, metabolism)
• Melanoma (metabolism)
• Mice
• Microphthalmia-Associated Transcription Factor (genetics, metabolism)
• Monophenol Monooxygenase (antagonists & inhibitors, chemistry, metabolism)
• Protein Structure, Tertiary
• Signal Transduction (drug effects)
• Thiazolidines (chemical synthesis, chemistry, metabolism, pharmacology)
• alpha-MSH (metabolism)