2-(3, 4-dihydroxybenzylidene)malononitrile as a novel anti-melanogenic compound
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Bonggi Lee1,5,*, Kyoung Mi Moon2,5,*, Jong Seung Lim2, Yeojin Park2, Do Hyun Kim1,2, Sujin Son1,2, Hyoung Oh Jeong2, Dae Hyun Kim1,2, Eun Kyeong Lee2, Ki Wung Chung2, Hye Jin An2, Pusoon Chun3, Arnold Y. Seo4, Ju-Hye Yang5, Bong-Seon Lee5, Jin Yeul Ma5, Won-Kyung Cho5, Hyung Ryong Moon1,2 and Hae Young Chung1,2
1Molecular Inflammation Research Center for Aging Intervention (MRCA), Pusan National University, Busan, Republic of Korea
2College of Pharmacy, Pusan National University, Busan, Republic of Korea
3College of Pharmacy, Inje University, Gimhae, Gyeongnam, Republic of Korea
4Janelia Research Campus, Howard Huge Medical Institute, Ashburn, VA, USA
5Korean Medicine (KM)-Application Center, Korea Institute of Oriental Medicine (KIOM), Dong-gu, Daegu, Korea
*These authors have contributed equally to this work
Hae Young Chung, email: [email protected]
Hyung Ryong Moon, email: [email protected]
Keywords: skin, melanogenesis, tyrosinase inhibitor, pigmentation, photoaging
Received: May 27, 2017 Accepted: July 13, 2017 Published: September 06, 2017
Tyrosinase is a key player in ultraviolet-induced melanogenesis. Because excessive melanin accumulation in the skin can induce hyperpigmentation, the development of tyrosinase inhibitors has attracted attention in cosmetic-related fields. However, side effects including toxicity and low selectivity have limited the use of many tyrosinase inhibitors in cosmetics. We synthesized 12 novel 2-(substituted benzylidene)malononitrile derivatives and investigated their anti-melanogenic activities. Of these 12 compounds, 2-(3, 4-dihydroxy benzylidene)malononitrile (BMN11) exhibited the strongest inhibitory activity against tyrosinase (IC50 = 17.05 μM). In parallel with this, BMN11 treatment notably decreased alpha-melanocyte-stimulating hormone-induced melanin accumulation in B16F10, cells without toxicity and also decreased melanin accumulation in a human skin model. As a mechanism underlying the BMN11-mediated anti-melanogenic effect, docking simulation showed that BMN11 can directly bind to tyrosinase by forming two hydrogen bonds with GLY281 and ASN260 residues, and via three hydrophobic interactions with VAL283, PHE264, and ALA286 residues in the tyrosinase binding pocket, and this likely contributes to its inhibitory effect on tyrosinase. Consistently, Lineweaver-Burk and Cornish-Bowden plots showed that BMN11 is a competitive inhibitor of tyrosinase. We concluded that BMN11 may be a novel tyrosinase inhibitor that could be used in cosmetics.
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