title: Characterization of a small molecule inhibitor of melanogenesis that inhibits tyrosinase activity and scavenges nitric oxide (NO).
abstract: BACKGROUND
  Excessive melanin production and accumulation are characteristics of a large number of skin diseases, including melasma, and post-inflammatory hyperpigmentation. During our on-going search for new agents with an inhibitory effect on tyrosinase, we synthesized a new type of tyrosinase inhibitor, 4-(thiazolidin-2-yl)benzene-1,2-diol (MHY-794), which directly inhibits mushroom tyrosinase.
  
  
  METHODS
  The inhibitory effect of MHY-794 on tyrosinase activity and nitric oxide (NO) scavenging activity was evaluated in cell free system. Additional experiments were performed using B16F10 melanoma cells to demonstrate the effects of MHY-794 in vitro. HRM2 hairless mice were used to evaluate anti-melanogenic effects of MHY-794 in vivo.
  
  
  RESULTS
  MHY-794 effectively inhibited mushroom tyrosinase activity in cell free system. In silico docking simulation also supported the inhibitory effects of MHY-794 on mushroom tyrosinase. MHY-794 also proved to be effective at scavenging nitric oxide (NO), which serves as an important modulator in the melanogenesis signaling pathway. In addition, MHY-794 effectively inhibited SNP (NO donor)-induced melanogenesis by directly inhibiting tyrosinase and diminishing NO-mediated melanogenesis signaling in B16 melanoma cells. The anti-melanogenic effects of MHY-794 were further confirmed in HRM2 hairless mice. Ultraviolet light (UV) significantly up-regulated NO-mediated melanogenesis signaling in HRM2 hairless mice, but MHY-794 effectively inhibited both melanogenesis and diminished UV-induced NO-signaling.
  
  
  CONCLUSIONS
  Our results indicate that MHY-794 is highly effective at inhibiting NO-mediated melanogenesis in vitro and in vivo by direct NO scavenging and directly inhibiting tyrosinase activity, and suggest that MHY-794 be considered a new developmental candidate for the treatment of hyper-pigmentation disorders.
  
  
  CONCLUSIONS
  MHY-794, which showed great efficacy on NO-mediated melanogenesis by direct NO scavenging as well as direct inhibition of tyrosinase catalytic activity, might be utilized for the development of a new candidate for treatment of the hyper-pigmentation disorders.
authors.affiliation: Department of Pharmacy, Pusan National University, Busan, Republic of Korea.
authors.forename: Ki Wung
authors.initials: KW
authors.lastname: Chung
authors.forename: Hyoung Oh
authors.initials: HO
authors.lastname: Jeong
authors.forename: Eun Ji
authors.initials: EJ
authors.lastname: Jang
authors.forename: Yeon Ja
authors.initials: YJ
authors.lastname: Choi
authors.forename: Dae Hyun
authors.initials: DH
authors.lastname: Kim
authors.forename: So Ra
authors.initials: SR
authors.lastname: Kim
authors.forename: Kyung Jin
authors.initials: KJ
authors.lastname: Lee
authors.forename: Hye Jin
authors.initials: HJ
authors.lastname: Lee
authors.forename: Pusoon
authors.initials: P
authors.lastname: Chun
authors.forename: Youngjoo
authors.initials: Y
authors.lastname: Byun
authors.forename: Hyung Ryong
authors.initials: HR
authors.lastname: Moon
authors.forename: Hae Young
authors.initials: HY
authors.lastname: Chung
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D015195:Drug Design; D008543:Melanins / Q000096:biosynthesis*; D008546:Melanoma, Experimental / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D014442:Monophenol Monooxygenase / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism*; D012880:Skin Pigmentation / Q000187:drug effects / Q000528:radiation effects; D054852:Small Molecule Libraries; D053778:Thiazolidines / Q000737:chemistry / Q000494:pharmacology; D014466:Ultraviolet Rays
chemical_list: D008543:Melanins; D054852:Small Molecule Libraries; D053778:Thiazolidines; D009569:Nitric Oxide; D014442:Monophenol Monooxygenase
keywords: HRM2 hairless mouse; Melanogenesis; Nitric oxide (NO); Tyrosinase inhibitor