DOI QR코드

DOI QR Code

Tyrosinase Inhibitory Effect of (E)-2-(substituted benzylidene)-2,3-dihydro-1H-cyclopenta[a]naphthalen-1-one Derivatives

(E)-2-(substituted benzylidene)-2,3-dihydro-1H-cyclopenta[a]naphthalen-1-one 유도체들의 tyrosinase 활성억제 효과

  • Lee, Eun Kyeong (Department of Pharmacy, College of Pharmacy, Pusan National University) ;
  • Kim, Ju Hyun (Department of Pharmacy, College of Pharmacy, Pusan National University) ;
  • Moon, Kyoung Mi (Department of Pharmacy, College of Pharmacy, Pusan National University) ;
  • Ha, Sugyeong (Department of Pharmacy, College of Pharmacy, Pusan National University) ;
  • Noh, Sang-Gyun (Department of Pharmacy, College of Pharmacy, Pusan National University) ;
  • Kim, Dae Hyun (Department of Pharmacy, College of Pharmacy, Pusan National University) ;
  • Lee, Bonggi (Department of Pharmacy, College of Pharmacy, Pusan National University) ;
  • Kim, Do Hyun (Department of Pharmacy, College of Pharmacy, Pusan National University) ;
  • Kim, Su Jeong (Department of Pharmacy, College of Pharmacy, Pusan National University) ;
  • Ullah, Sultan (Department of Pharmacy, College of Pharmacy, Pusan National University) ;
  • Moon, Hyung Ryong (Department of Pharmacy, College of Pharmacy, Pusan National University) ;
  • Chung, Hae Young (Department of Pharmacy, College of Pharmacy, Pusan National University)
  • Received : 2016.11.10
  • Accepted : 2017.01.17
  • Published : 2017.02.28

Abstract

The inhibition of tyrosinase, a key enzyme in mammalian melanin synthesis, plays an important role in preventing skin pigmentation and melanoma. Therefore, tyrosinase inhibitors are very important in the fields of medicine and cosmetics. However, only a few tyrosinase inhibitors are currently available because of their toxic effects on skin or lack of selectivity and stability. Therefore, we synthesized a novel series of (E)-2-(substituted benzylidene)-2,3-dihydro-1H-cyclopenta[a]naphthalen-1-one derivatives and evaluated their inhibitory effects on mushroom tyrosinase, with the aim of discovering a novel tyrosinase inhibitor. Among 19 derivatives, MHY3655 ($IC_{50}=0.1456{\mu}M$) showed the strongest inhibitory effect on tyrosinase activity compared to kojic acid ($IC_{50}=17.2{\mu}M$), a well-known tyrosinase inhibitor. In addition, MHY3655 showed competitive inhibition on Lineweaver-Burk plots. We confirmed that MHY3655 strongly interacts with mushroom tyrosinase residues through the docking simulation. Substitutions with a hydroxy group at both R2 and R4 in the phenyl ring indicated that these groups play a major role in the high binding affinity to tyrosinase. Further, MHY3655 did not show cytotoxicity at the concentrations tested in B16F10 melanoma cells. In conclusion, the novel compound MHY3655 potentially shows tyrosinase inhibitory activity, and it could be used as an ingredient in whitening cosmetics.

본 연구에서는 (E)-2-(substituted benzylidene)-2,3-dihydro-1H-cyclopenta[a]naphthalen-1-one 유도체들을 합성했으며, 합성된 유도체들이 멜라닌 생성과정의 주요 효소인 tyrosinase 활성을 저해할 수 있는지에 대하여 확인하였다. 19종류의 유도체들의 tyrosinase 저해활성을 측정해본 결과, MHY3655 ($IC_{50}=0.1456{\mu}M$)가 가장 큰 저해활성을 나타냈으며 이는 대조군인 코직산($IC_{50}=17.2{\mu}M$) 보다 큰 효능을 보였다. 게다가, Lineweaver-Burk 분석법을 이용하여 MHY3655가 경쟁적 저해 기전으로 tyrosinase 활성을 저해하였고, docking simulation으로 MHY 3655가 tyrosinase에 직접 결합함을 재확인하였다. 마지막으로, B16F10 melanoma 세포에서 MHY3655의 세포독성을 평가한 결과 $1-20{\mu}M$ 사이의 MHY3655는 세포독성을 나타내지 않았다. 이상의 결과에서, 신물질 MHY3655은 우수한 tyrosinase 저해활성을 나타내며, 이는 미백 화장품 소재로서 활용할 가치가 있으리라 사료된다.

Keywords

Acknowledgement

Supported by : 부산대학교

References

  1. Alaluf, S., Heath, A., Carter, N., Atkins, D., Mahalingam, H., Barrett, K., Kolb, R. and Smit, N. 2001. Variation in melanin content and composition in type V and VI photoexposed and photoprotected human skin: The dominant role of DHI. Pigment Cell Res. 14, 337-347. https://doi.org/10.1034/j.1600-0749.2001.140505.x
  2. Battaini, G., Monzani, E., Casella, L., Santagostini, L. and Pagliarin, R. 2000. Inhibition of the catecholase activity of biomimetic dinuclear copper complexes by kojic acid. J. Biol. Inorg. Chem. 5, 262-268. https://doi.org/10.1007/s007750050370
  3. Cheng, S. L., Huang, L. R., Sheu, J. N., Chen, S. T., Sinchaikul, S. and Tsay, G. J. 2006. Toxicogenomics of kojic acid on gene expression profiling of a375 human malignant melanoma cells. Biol. Pharm. Bull. 29, 655-669. https://doi.org/10.1248/bpb.29.655
  4. Draelos, Z. D. 2007. Skin lightening preparations and the hydroquinone controversy. Dermatol. Ther. 20, 308-313. https://doi.org/10.1111/j.1529-8019.2007.00144.x
  5. Garcia-Gavin, J., Gonzalez-Vilas, D., Fernandez-Redondo, V. and Toribio, J. 2010. Pigmented contact dermatitis due to kojic acid. A paradoxical side effect of a skin lightener. Contact Derm. 62, 63-64. https://doi.org/10.1111/j.1600-0536.2009.01673.x
  6. Hamilton, A. J. and Gomez, B. L. 2002. Melanins in fungal pathogens. J. Med. Microbiol. 51, 189-191. https://doi.org/10.1099/0022-1317-51-3-189
  7. Kvam, E. and Tyrrell, R. M. 1999. The role of melanin in the induction of oxidative DNA base damage by ultraviolet a irradiation of DNA or melanoma cells. J. Invest. Dermatol. 113, 209-213. https://doi.org/10.1046/j.1523-1747.1999.00653.x
  8. Lajis, A. F., Hamid, M. and Ariff, A. B. 2012. Depigmenting effect of Kojic acid esters in hyperpigmented B16F1 melanoma cells. J. Biomed. Biotechnol. 2012, 952452.
  9. No, J. K., Soung, D. Y., Kim, Y. J., Shim, K. H., Jun, Y. S., Rhee, S. H., Yokozawa, T. and Chung, H. Y. 1999. Inhibition of tyrosinase by green tea components. Life Sci. 65, PL241-246.
  10. Sturm, R. A., Box, N. F. and Ramsay, M. 1998. Human pigmentation genetics: the difference is only skin deep. Bioessays 20, 712-721. https://doi.org/10.1002/(SICI)1521-1878(199809)20:9<712::AID-BIES4>3.0.CO;2-I
  11. Trott, O. and Olson, A. J. 2010. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J. Comput. Chem. 31, 455-461.
  12. Warwick, L. and Morison, M. D. 1985. What is the function of melanin? Arch. Dermatol. 121, 1160-1163. https://doi.org/10.1001/archderm.1985.01660090074017
  13. Wei, C. I., Huang, T. S., Fernando, S. Y. and Chung, K. T. 1991. Mutagenicity studies of kojic acid. Toxicol. Lett. 59, 213-220. https://doi.org/10.1016/0378-4274(91)90074-G
  14. Wolber, G. and Langer, T. 2005. LigandScout: 3-D pharmacophores derived from protein-bound ligands and their use as virtual screening filters. J. Chem. Inf. Model 45, 160-169. https://doi.org/10.1021/ci049885e