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

• Published in: Biochimica et biophysica acta Vol. 1820; no. 4; pp. 542 - 549
• Main Authors: Han, Yu Kyeong, Park, Yun Jung, Ha, Young Mi, Park, Daeui, Lee, Ji Yeon, Lee, Naree, Yoon, Jeong Hyun, Moon, Hyung Ryong, Chung, Hae Young
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.04.2012
• Subjects: active sites; alpha-melanocyte-stimulating hormone; alpha-MSH - metabolism; Animals; Antityrosinase activity; carbon; catalytic activity; Catalytic Domain; Cell Line, Tumor; Cyclic adenosine monophosphate; cyclic AMP; Cyclic AMP - metabolism; Cyclic AMP-Dependent Protein Kinases - metabolism; Docking analysis; gene expression; gene expression regulation; mass spectrometry; mechanism of action; melanin; Melanins - genetics; Melanins - metabolism; Melanogenesis; melanoma; Melanoma - metabolism; messenger RNA; Mice; Microphthalmia-associated transcription factor; Microphthalmia-Associated Transcription Factor - genetics; Microphthalmia-Associated Transcription Factor - metabolism; Monophenol Monooxygenase - antagonists & inhibitors; Monophenol Monooxygenase - chemistry; Monophenol Monooxygenase - metabolism; mushrooms; nuclear magnetic resonance spectroscopy; Protein Structure, Tertiary; Signal Transduction - drug effects; Skin-whitening agent; spectral analysis; stable isotopes; Thiazolidines - chemical synthesis; Thiazolidines - chemistry; Thiazolidines - metabolism; Thiazolidines - pharmacology; transcription factors; DMSO; CO2; NaOH; Skin-whitening agent; cAMP; MTT; PDB; Antityrosinase activity; CBP; HCl; DMEM; CREB; ANOVA; FBS; l-DOPA; CDCl3; α-MSH; PBS; Microphthalmia-associated transcription factor; UV; PKA; MITF; Melanogenesis; PVDF; NMR; MC1R; PMSF; NaCl; Docking analysis; Cyclic adenosine monophosphate
• ISSN: 0304-4165; 0006-3002; 1872-8006
• DOI: 10.1016/j.bbagen.2012.01.001

We synthesized (2RS,4R)-2-(2,4-dihydroxyphenyl)thiazolidine-4-carboxylic acid (MHY384) as a potential tyrosinase inhibitor and investigated its antityrosinase activity. The structure of MHY384 was established using 1H and 13C 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. 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. This study strongly indicates that the depigmenting effect of MHY384 results from the down-regulation of MITF and tyrosinase through direct tyrosinase inhibition. Our findings suggest that MHY384 can be an effective skin-whitening agent. [Display omitted] ► We describe the design, synthesis and biological activities of MHY384. ► The depigmentary effect of MHY384 results from down-regulation of MITF. ► MHY384 can suppress the production of melanin. ► MHY384 can be an effective skin-whitening agent.