title: Melanogenesis inhibitory activity of a 7-O-9'-linked neolignan from Alpinia galanga fruit.
abstract: An aqueous acetone extract from the fruit of Alpinia galanga (Zingiberaceae) demonstrated inhibitory effects on melanogenesis in theophylline-stimulated murine B16 melanoma 4A5 cells (IC50=7.3μg/mL). Through bioassay-guided separation of the extract, a new 7-O-9'-linked neolignan, named galanganol D diacetate (1), was isolated along with 16 known compounds including 14 phenylpropanoids (2-15). The structure of 1, including its absolute stereochemistry in the C-7 position, was elucidated by means of extensive NMR analysis and total synthesis. Among the isolates, 1 (IC50=2.5μM), 1'S-1'-acetoxychavicol acetate (2, 5.0μM), and 1'S-1'-acetoxyeugenol acetate (3, 5.6μM) exhibited a relatively potent inhibitory effect without notable cytotoxicity at effective concentrations. The following structural requirements were suggested to enhance the inhibitory activity of phenylpropanoids on melanogenesis: (i) compounds with 4-acetoxy group exhibit higher activity than those with 4-hydroxy group; (ii) 3-methoxy group dose not affect the activity; (iii) acetylation of the 1'-hydroxy moiety enhances the activity; and (iv) phenylpropanoid dimers with the 7-O-9'-linked neolignan skeleton exhibited higher activity than those with the corresponding monomer. Their respective enantiomers [1' (IC50=1.9μM) and 2' (4.5μM)] and racemic mixtures [(±)-1 (2.2μM) and (±)-2 (4.4μM)] were found to exhibit melanogenesis inhibitory activities equivalent to those of the naturally occurring optical active compounds (1 and 2). Furthermore, the active compounds 1-3 inhibited tyrosinase, tyrosine-related protein (TRP)-1, and TRP-2 mRNA expressions, which could be the mechanism of melanogenesis inhibitory activity.
authors.affiliation: Pharmaceutical Research and Technology Institute, Kindai University, 3-4-1 Kowakae, Higashi-osaka, Osaka 577-8502, Japan.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Manse
authors.affiliation: Pharmaceutical Research and Technology Institute, Kindai University, 3-4-1 Kowakae, Higashi-osaka, Osaka 577-8502, Japan; Antiaging Center, Kindai University, 3-4-1 Kowakae, Higashi-osaka, Osaka 577-8502, Japan.
authors.forename: Kiyofumi
authors.initials: K
authors.lastname: Ninomiya
authors.affiliation: Pharmaceutical Research and Technology Institute, Kindai University, 3-4-1 Kowakae, Higashi-osaka, Osaka 577-8502, Japan.
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Nishi
authors.affiliation: Pharmaceutical Research and Technology Institute, Kindai University, 3-4-1 Kowakae, Higashi-osaka, Osaka 577-8502, Japan.
authors.forename: Iyori
authors.initials: I
authors.lastname: Kamei
authors.affiliation: Pharmaceutical Research and Technology Institute, Kindai University, 3-4-1 Kowakae, Higashi-osaka, Osaka 577-8502, Japan.
authors.forename: Yushi
authors.initials: Y
authors.lastname: Katsuyama
authors.affiliation: Pharmaceutical Research and Technology Institute, Kindai University, 3-4-1 Kowakae, Higashi-osaka, Osaka 577-8502, Japan.
authors.forename: Takahito
authors.initials: T
authors.lastname: Imagawa
authors.affiliation: Pharmaceutical Research and Technology Institute, Kindai University, 3-4-1 Kowakae, Higashi-osaka, Osaka 577-8502, Japan; Faculty of Agro-Industry, Rajamangala University of Technology Srivijaya, Thungsong, Nakhonsithammarat 80110, Thailand.
authors.forename: Saowanee
authors.initials: S
authors.lastname: Chaipech
authors.affiliation: Pharmaceutical Research and Technology Institute, Kindai University, 3-4-1 Kowakae, Higashi-osaka, Osaka 577-8502, Japan; Antiaging Center, Kindai University, 3-4-1 Kowakae, Higashi-osaka, Osaka 577-8502, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Muraoka
authors.affiliation: Pharmaceutical Research and Technology Institute, Kindai University, 3-4-1 Kowakae, Higashi-osaka, Osaka 577-8502, Japan; Antiaging Center, Kindai University, 3-4-1 Kowakae, Higashi-osaka, Osaka 577-8502, Japan. Electronic address: morikawa@kindai.ac.jp.
authors.forename: Toshio
authors.initials: T
authors.lastname: Morikawa
mesh_terms: D032429:Alpinia / Q000737:chemistry*; D000818:Animals; D045744:Cell Line, Tumor; D005638:Fruit / Q000737:chemistry; D015870:Gene Expression; D019746:Intramolecular Oxidoreductases / Q000235:genetics / Q000378:metabolism; D017705:Lignans / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D008543:Melanins / Q000378:metabolism*; D008544:Melanocytes / Q000187:drug effects* / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D014442:Monophenol Monooxygenase / Q000235:genetics / Q000378:metabolism; D010088:Oxidoreductases / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D013237:Stereoisomerism; D013806:Theophylline / Q000494:pharmacology
chemical_list: D017705:Lignans; D008543:Melanins; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; C000622786:galanganol D diacetate; D013806:Theophylline; D010088:Oxidoreductases; C079621:Tyrp1 protein, mouse; D014442:Monophenol Monooxygenase; D019746:Intramolecular Oxidoreductases; C042501:dopachrome isomerase
keywords: 7-O-9′-Linked neolignan; Alpinia galanga; Galanganol D diacetate; Melanogenesis inhibitor; Phenylpropanoid