Evaluation and Optimization of the Anti-Melanogenic Activity of 1-(2-Cyclohexylmethoxy-6-hydroxy-phenyl)-3-(4-hydroxymethyl-phenyl)-propenone Derivatives

• Main Authors: Byung-Hak Kim, Soo-Nam Hong, Sang-Kyu Ye, Jung-Youl Park
• Format: Article
• Language: English
• Published: MDPI AG 2019-04-01
• Series: Molecules
• Subjects: alpha-melanocyte stimulating hormone (α-MSH); chalcone; melanin biosynthesis; (<i>E</i>)-<i>N</i>-(4-(3-(2-(cyclohexylmethoxy)phenyl)-3-oxoprop-1-en-1-yl)phenyl)acetamide (chalcone 21-21); tyrosinase
• Online Access: https://www.mdpi.com/1420-3049/24/7/1372

The chemical modification and optimization of biologically active compounds are essential steps in the identification of promising lead compounds for drug development. We previously reported the anti-melanogenic activity of 1-(2-cyclohexylmethoxy-6-hydroxy-phenyl)-3-(4-hydroxymethyl-phenyl)-propenone (chalcone 21). In this study, we synthesized 21 derivatives of chalcone 21 and evaluated their anti-melanogenic activity in &#945;-MSH-induced B16F10 cells. (<i>E</i>)-<i>N</i>-(4-(3-(2-(Cyclohexylmethoxy)phenyl)-3-oxoprop-1-en-1-yl)phenyl)acetamide (chalcone 21-21) exhibited the strongest inhibition of cellular melanin production, with an IC₅₀ value of 0.54 &#956;M. It was more potent than chalcone 21 and the known anti-melanogenic agents kojic acid and arbutin, whose IC₅₀ values were 4.9, 38.5, and 148.4 &#956;M, respectively. Chalcone 21-21 decreased the expression and activity of tyrosinase. It also decreased the expression of TRP1, TRP2 and MITF, the phosphorylation of CREB and ERK1/2, and the transcriptional activity of MITF and CRE. Our results demonstrate that chalcone-21-21 is an effective lead compound with anti-melanogenic activity.