Identification of quinolines that inhibit melanogenesis by altering tyrosinase family trafficking.
A series of quinolines, including chloroquine and quinine, were identified as potent pigmentation inhibitors through screening a compound library in murine melanocytes. Structure-activity relationship analysis indicated that 4-substituted amino groups with a tertiary amine side chain, such as chloroquine, were associated with robust inhibitory activity. In contrast to many previously identified pigmentation inhibitors, these newly identified inhibitors had no effect on either the level or the enzymatic activity of tyrosinase, the rate-limiting enzyme in melanin production. Rather, our results showed that these quinolines inhibited melanogenesis by disrupting the intracellular trafficking of tyrosinase-related proteins and lysosome-associated membrane protein 1 (Lamp-1). In treated melanocytes, tyrosinase and tyrosinase-related protein 1 accumulated in Lamp-1-positive perinuclear organelles instead of melanosomes, thus preventing melanogenesis. The depigmenting abilities of chloroquine and quinine salicylate were assessed in a human skin equivalent model (MelanoDerm). Both compounds were considerably more effective than arbutin, a widely used lightening agent. Our results indicate that quinolines may be useful agents for "cosmeceutical" skin lightening and treatment of hyperpigmentation disorders.
Ni-Komatsu
Li
L
The Ronald O Perelman Department of Dermatology, New York University School of Medicine, New York, New York 10016, USA. seth.orlow@nyumc.org
Tong
Chunxiang
C
Chen
Guangming
G
Brindzei
Nelya
N
Orlow
Seth J
SJ
D001741:Black or African American; D000818:Animals; D044466:Asian People; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003864:Depression, Chemical; D006801:Humans; D008543:Melanins / Q000378:metabolism; D008544:Melanocytes / Q000166:cytology / Q000187:drug effects*; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D014442:Monophenol Monooxygenase / Q000378:metabolism*; D010088:Oxidoreductases / Q000378:metabolism; D021381:Protein Transport; D011804:Quinolines / Q000737:chemistry / Q000494:pharmacology*; D012880:Skin Pigmentation / Q000187:drug effects*; D013329:Structure-Activity Relationship; D046509:Tissue Culture Techniques
D008543:Melanins; D008562:Membrane Glycoproteins; D011804:Quinolines; D010088:Oxidoreductases; C079621:Tyrp1 protein, mouse; D014442:Monophenol Monooxygenase
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