Chemical constituents derived from Artocarpus xanthocarpus as inhibitors of melanin biosynthesis
Graphical abstract
Six previously unknown compounds and 18 known compounds from Artocarpus xanthocarpus were isolated and characterized spectroscopically. Their anti-melanogenesis activity were evaluated in B16F10 melanoma cells. The results indicated that some of these constituents may be a candidate for the depigmentation agents.
Introduction
The Artocarpus genus includes monoecious evergreen trees and shrubs capable of producing milky sap and is among the most important genera within the Moraceae family, which are widely distributed in tropical Asia, Polynesia, and the Pacific Islands (Liao, 1996). A number of pharmacologically active constituents have been isolated from Artocarpus species in recent decades, with these having diverse activities including antioxidant, anti-melanogenesis, antimicrobial, anti-arthritic, anti-inflammatory, antiplatelet aggregation, cytotoxic, antityrosinase, and anti-5α-reductase activities (Botta et al., 2005, Hakim et al., 2006, Jagtap and Bapat, 2010, Lan et al., 2013). This success has spurred the continued search for more bioactive constituents of Formosan Artocarpus medicinal plants. Artocarpus xanthocarpus Merr. (Moraceae) is a small tree that grows in the Philippines, Borneo, and Lanyu Island of southeast Taiwan. Lumber from A. xanthocarpus is often used in Lanyu for construction, furniture, or boats (Liao, 1996). To date, the only bioactive compound isolated from A. xanthocarpus is artoxanthochromane, which has antityrosinase and free radical-scavenging activities (Ko et al., 2013). Given the promise of other Artocarpus species, an investigation was carried out to search for additional valuable bioactives from A. xanthocarpus roots.
In humans, solar ultraviolet (UV) radiation, oxidative stress, chronic inflammation, and the excessive release of α-melanocyte-stimulating hormone (α-MSH) can trigger melanin biosynthesis and lead to hyperpigmentation (Jeong et al., 2009, Kim and Yokozawa, 2009, Lee et al., 2010a). Common manifestations of skin hyperpigmentation include freckles, melasma, solar lentigines, age spots, and post-inflammatory hyperpigmentation, all of which can be serious aesthetic concerns. One of the rate-limiting steps of melanin biosynthesis is catalyzed by the enzyme tyrosinase, which is a copper-containing polyphenol oxidase and is widely distributed in plants and in animals (Arung et al., 2007, Donsing et al., 2008). This enzyme catalyzes the conversion of l-tyrosine to L-3,4-dihydroxyphenylalanine (l-DOPA) and O-dopaquinone via hydroxylation and oxidation reactions, respectively (Parvez et al., 2006). The subsequent metabolism of dopaquinone leads to the formation of two types of melanin. Dopaquinone can react with either cysteine or glutathione to form pheomelanin, or it can be converted to eumelanin by tyrosinase-related protein-1 (TRP-1) and tyrosinase related protein-2 (TRP-2) (Cho et al., 2009, Huang et al., 2011). Inhibition of tyrosinase or tyrosinase-like enzymes is, therefore, a potentially valuable strategy for blocking melanin production.
Reactive oxygen species (ROS) generated by UV exposure can induce keratinocytes to produce keratinocyte-derived factors that affect skin pigmentation and can trigger inflammation that contributes to skin cancer (Kim et al., 2008, Yamaguchi and Hearing, 2009). ROS can also stimulate the production of pro-inflammatory factors and activate matrix metalloproteinases, which cause extracellular matrix protein decomposition, collagen and elastin breakdown, and skin aging (Kim et al., 2008, Portugal-Cohen et al., 2011). Numerous cosmetic companies have invested considerable effort into developing whitening or photochemprotective products than could ameliorate hyperpigmentation or photodamage, with much of the recent effort focused on the identification of useful naturally derived products. Accordingly, this investigation of A. xanthocarpus products focused on identifying novel bioactives that could be used for cosmetic or skin-protective applications. In this attempt, twenty-four compounds were identified and tested for inhibition of mushroom tyrosinase and cellular tyrosinase in B16F10 melanoma cells, as well as for free radical scavenging capacity. Here in this article, the structure elucidation of the six new polyphenols and the results of bioassays are reported.
Section snippets
Chemical and structural characterization of compounds isolated from A. xanthocarpus
Compound 1 was obtained as fine yellowish needles, [α]D25 −206 (c 0.01, methanol). The molecular formula C25H26O7Na was deduced from HRESIMS (m/z 461.1573 [M+Na]+). The IR spectrum exhibited absorption peaks attributable to a hydroxy group (3349 cm−1), a conjugated carbonyl group (1646 cm−1), and aromatic rings (1613, 1562, and 1464 cm−1). The UV spectrum showed absorbance maxima at 340 and 270 nm, typical of a flavone skeleton (Musthapa et al., 2009). The 1H NMR spectrum of 1 (Table 1) indicated
Discussion
Tyrosinases are copper-containing enzymes that possess monophenolase and diphenolase activities important to the formation of melanin, which protects skin from the damage caused by UV radiation (Kim and Uyama, 2005). Excessive tyrosinase activity may lead to the overproduction of melanin, known as hyperpigmentation, which is considered an abnormal skin problem. UV radiation also affects melanin production by inducing ROS, which are also harmful to the skin (Yamaguchi and Hearing, 2009).
Conclusion
In conclusion, six new compounds, artoxanthocarpuones A (1) and B (2), hydroxylakoochin A (3), methoxylakoochin A (4), epoxylakoochin A (5) and artoxanthol (6), and 18 known compounds were isolated from A. xanthocarpus roots. The biological activities of the compounds were investigated using anti-oxidant and anti-melanogenic assays both in vitro and in mammalian cells. These results indicate that several of the isolated compounds are effective tyrosinase inhibitors and are capable of
Chemicals and reagents
2,2-Diphenyl-1-picrylhydrazyl (DPPH), xanthine, xanthine oxidase (from buttermilk, 0.07 U/mg), nitrotetrazolium blue chloride (NBT), 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt (ABTS), phenazine methosulfate (PMS), l-tyrosine, mushroom tyrosinase (5370 U/mg), fetal bovine serum (FBS), 2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-terazolium-5-carboxanilide (XTT), l-DOPA, arbutin, and kojic acid were all purchased from Sigma–Aldrich (St. Louis, MO, USA). Dulbecco’s
Acknowledgments
This study was supported by Grants from the National Science Council of Taiwan (NSC-99-2320-B-037-021-MY2), and also supported partially by Kaohsiung Medical University, Taiwan “Aim for the Top Universities Grant, Grant No. KMU-TP103H03” and CMU under the Aim for Top University Plan of the Ministry of Education, Taiwan, and Taiwan Ministry of Health and Welfare Clinical Trial and Research Center of Excellence (MOHW104-TDU-B-212-113002). We thank Miss C. C. Wang and Mr. M. Y. Hung of the
References (51)
- et al.
Isoprenoid-substituted flavonoids from wood of Artocarpus heterophyllus on B16 melanoma cells: cytotoxicity and structural criteria
Fitoterapia
(2010) - et al.
Antioxidant and antityrosinase activity of mulberry (Morus alba L.) twigs and root bark
Food Chem. Toxicol.
(2011) - et al.
A novel stilbene from the wood of Chlorophora excelsa
Phytochemistry
(1988) - et al.
Artocarpus: a review of its traditional uses, phytochemistry and pharmacology
J. Eur.
(2010) - et al.
Further prenylflavonoids from Artocarpus elasticus
Phytochemistry
(1998) - et al.
The anti-melanogenic effect of pycnogenol by its anti-oxidative actions
Food Chem. Toxicol.
(2008) - et al.
Scavenger and antioxidant properties of prenylflavones isolated from Artocarpus heterophyllus
Free Radic. Biol. Med.
(1998) - et al.
Prenylated flavonoids from Artocarpus altilis: antioxidant activities and inhibitory effects on melanin production
Phytochemistry
(2013) - et al.
Studies on formic acid-catalyzed dimerization of isorhapontigenin and of resveratrol to tetralins
Tetrahedron
(2003) - et al.
Oxyresveratrol and resveratrol are potent antioxidants and free radical scavengers: effect on nitrosative and oxidative stress derived from microglial cells
Nitric Oxide
(2003)
Secondary metabolites of Bagassa guianensis Aubl. wood: a study of the chemotaxonomy of the Moraceae family
Phytochemistry
Structure–activity relationship of prenyl-substituted polyphenols from Artocarpus heterophyllus as inhibitors of melanin biosynthesis in cultured melanoma cells
Chem. Biodivers.
Prenylated flavonoids: pharmacology and biotechnology
Curr. Med. Chem.
An updated review of tyrosinase inhibitors
Int. J. Mol. Sci.
Peanut roots as a source of resveratrol
J. Agric. Food Chem.
Inhibitory effect of proanthocyanidin on ultraviolet B irradiation-induced melanogenesis
J. Toxicol. Environ. Health A
Antioxidative characteristics and inhibition of α-melanocyte-stimulating hormone-stimulated melanogenesis of vanillin and vanillic acid from Origanum vulgare
Exp. Dermatol.
The structure and function of estrogens. 10. Synthesis of 5,5-dimethyl-cis-4b,5,6,10b,11,12-hexahydrochrysene-2,8-diol–the estrogenic activity of this and of related c-methylated hydrochrysenediols
Aust. J. Chem.
Evaluation of the effect of Thai breadfruit’s heartwood extract on melanogenesis-inhibitory and antioxidation activities
J. Aesthet. Educ.
Structures of three new flavone derivatives, brosimones G, H, and I, from Brosimopsis oblongifolia
Planta Med.
Artoindonesianins A and B, two new prenylated flavones from the root of Artocarpus champeden
J. Nat. Prod.
Prenylated flavonoids and related compounds of the Indonesian Artocarpus (Moraceae)
J. Nat. Med.
Artonins A and B, two new prenylflavones from the root bark of Artocarpus heterophyllus Lamk
Heterocycles
Cudraflavones C and D, two new prenylflavones from the root bark of Cudrania tricuspidata (Carr.) Bur
Heterocycles
Inhibitory effect of [6]-gingerol on melanogenesis in B16F10 melanoma cells and a possible mechanism of action
Biosci. Biotechnol. Biochem.
Cited by (34)
The bioactivity of prenylated stilbenoids and their structure-activity relationship
2022, Food Research InternationalCitation Excerpt :4-Geranyl oxyresveratrol, also named as chlorophorin, was firstly found in Chlorophora excels (Moraceae) (Padayachee & Odhav, 2001), and later isolated from Artocarpus lakoocha and Artocarpus xanthocarpus as well (Jin et al., 2015; Maneechai et al., 2012). 4-Geranyl oxyresveratrol not only exhibited excellent tyrosinase inhibitory activity against melanin production induced by alpha- melanocyte-stimulating hormone in B16F10 melanoma cells, but also presented low cytotoxicity without affecting the normal cell growth in vitro (Arung et al., 2005, Jin et al., 2015). The extract of Artocarpus lakoocha containing 4-geranyl oxyresveratrol and its analogues reduced melanin formation on the skin of volunteers through in vivo experiments using human volunteers (Arung, Shimizu & Kondo, 2011).
Polyphenols and polyphenol-derived compounds from plants and contact dermatitis
2018, Polyphenols: Prevention and Treatment of Human Disease2-Arylbenzofurans from Artocarpus lakoocha and methyl ether analogs with potent cholinesterase inhibitory activity
2018, European Journal of Medicinal ChemistryPreparation of steppogenin and ascorbic acid, vitamin E, butylated hydroxytoluene oil-in-water microemulsions: Characterization, stability, and antibrowning effects for fresh apple juice
2017, Food ChemistryCitation Excerpt :Moreover, their MEs also exhibited strong antibrowning effects on apple slices or apple juice when combined with VC (Dong et al., 2016; Zheng et al., 2015). Steppogenin (S) is a natural flavanone with strong tyrosinase inhibitory activity and is widely distributed in Moraceae plants, such as Artocarpus heterophyllus, Cudrania tricuspidata, A. xanthocarpus, A. altilis, Morus nigra, M. alba, and M. lhou (Amarasinghe, Jayasinghe, Hara, & Fujimoto, 2008; Jeong et al., 2009; Jin et al., 2015; Lim, Jin, Woo, Lee, & Kim, 2013; Zheng, Cheng, To, Li, & Wang, 2008; Zheng, Tan, Chen, & Wang, 2013; Zheng et al., 2010). However, its poor solubility in aqueous systems greatly limits its application as an anti-browning agent for food products.
Hepatoprotective Activity and Mechanisms of Prenylated Stilbenoids
2024, Journal of Agricultural and Food Chemistry
- 1
These authors contributed equally to this work.