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Effects of hydroxystilbene derivatives on tyrosinase activity
BBRC Biochemical and Biophysical Research Communications 307 (2003) 861–863 www.elsevier.com/locate/ybbrc
Effects of hydroxystilbene derivatives on tyrosinase activity Kenji Ohguchi,a,* Toshiyuki Tanaka,b Tadashi Kido,c Kimiye Baba,c Munekazu Iinuma,d Kenji Matsumoto,a Yukihiro Akao,a and Yoshinori Nozawaa a
Gifu International Institute of Biotechnology, 1-1 Naka-Fudogaoka, Kakamigahara, Gifu 504-0838, Japan Gifu Prefectural Institute of Health and Environmental Sciences, Kakamigahara, Gifu 504-0838, Japan c Osaka University of Pharmaceutical Sciences, Takatsuki, Osaka 569-1094, Japan d Gifu Pharmaceutical University, Mitahora-higashi, Gifu 502-5858, Japan
b
Received 26 June 2003
Abstract Synthesis of melanin starts from the conversion of L -tyrosine to 3,4-dihydroxyphenylalanine (L -dopa) and then the oxidation of yields dopaquinone by tyrosinase. Therefore, tyrosinase inhibitors have been established as important constituents of depigmentation agents. Recently, polyhydroxystilbene compounds, which are trans-resveratrol (3,40 ,5-trihydroxy-trans-stilbene) analogs, have been demonstrated as potent tyrosinase inhibitors. However, their detailed inhibitory mechanisms are not clearly understood. In the present study, a variety of synthesized hydroxystilbene compounds were tested for their inhibitory effects against murine tyrosinase activity. The inhibitory potencies of the hydroxy-trans-stilbene compounds were remarkably elevated by increasing number of phenolic hydroxy substituents. Methylated hydroxy-trans-stilbene lost the inhibitory activity. Furthermore, hydrogenated hydroxystilbene or hydroxy-cis-stilbene exerted little or no inhibitory effect compared with hydroxy-trans-stilbene on tyrosinase activity. The structure–activity relationships demonstrated in the present study suggest that the phenolic hydroxy groups and trans-olefin structure of the parent stilbene skeleton contribute to the inhibitory potency of hydroxystilbene for tyrosinase activity. Ó 2003 Elsevier Inc. All rights reserved. L -dopa
Keywords: Tyrosinase; Hydroxystilbene; Stilbene; Resveratrol; Melanin
Melanin production is principally responsible for skin color and plays an important role in prevention of suninduced skin injury. Melanin is produced by melanocytes in the basal layer of epidermis [1]. Synthesis of melanin starts from the conversion of the amino acid L -tyrosine to 3,4-dihydroxyphenylalanine (L -dopa) and then the oxidation of L -dopa yields dopaquinone by tyrosinase, an enzyme catalyzing the rate-limiting step for the melanin biosynthesis [1]. This tyrosinase process is involved in abnormal accumulation of melanin pigments (hyperpigmentation). Therefore, tyrosinase inhibitors have been established as important constituents of cosmetic materials and depigmenting agents for hyperpigmentation. Stilbene derivatives are known to be abundantly distributed in the plants belonging to Dipterocarpaceae, * Corresponding author. Fax: +81-583-71-4412. E-mail address: [email protected] (K. Ohguchi).
0006-291X/03/$ - see front matter Ó 2003 Elsevier Inc. All rights reserved. doi:10.1016/S0006-291X(03)01284-1
Vitaceae, Gnetaceae, Leguminosae, and Cyperaceae as a variety of trans-resveratrol (3,40 ,5-trihydroxy-trans-stilbene) derivatives [2]. Some of their derivatives have also been reported to possess various biological and pharmacological activities such as anti-carcinogenic [3] and anti-inflammatory [4] effects. Therefore, stilbene derivatives composed of resveratorol are considered to be useful resources for pharmacological agents. Recently, tetrahydroxystilbene compounds, which are resveratrol analogs, have been demonstrated as potent tyrosinase inhibitors [5–7]. Kim et al. [6] have demonstrated that oxyresveratrol (2,30 ,4,50 -tetrahydroxy-trans-stilbene) from Morus alba Linne showed a potent inhibitory effect on tyrosinase activity as a non-competitive inhibitor. We have recently demonstrated that gnetol (2,30 ,50 ,6-tetrahydroxy-trans-stilbene), a naturally occurring compound particularly found in Gnetaceae, exhibited a potent inhibitory effect on tyrosinase activity [7]. The
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K. Ohguchi et al. / Biochemical and Biophysical Research Communications 307 (2003) 861–863
number of phenolic hydroxy groups may play an important role in the inhibitory potency of hydroxystilbene compounds such as oxyresveratrol and gnetol for tyrosinase activity. However, its detailed mechanism(s) has not been clearly understood. To gain further insight into the mechanism underlying the inhibitory effect on tyrosinase activity of hydroxystilbene compounds, we synthesized hydroxystilbene derivatives and analyzed the structure–activity relationships of the compounds in the inhibition of murine tyrosinase activity. Materials and methods Materials. 3,4-Dihydroxyphenylalanine (L -dopa) was from Sigma. Hydroxystilbene derivatives were synthesized as described previously [8]. Gnetol (2,30 ,50 ,6-tetrahydroxy-trans-stilbene) was isolated from the acetone soluble extract of Gnetum gnemon as described previously [9]. Dihydrognetol was obtained by hydrogenation with Pd–C/H2 (atmospheric pressure) in ethanol for 3 h of gnetol. Other reagents were of the highest quality available. Measurement of tyrosinase activity. Tyrosinase source was prepared from murine B16 melanoma cells (Riken Cell Bank, Tsukuba, Japan). The cells were lysed by incubating at 4 °C for 1 h in RIPA buffer (10 mM Tris–HCl, pH7.5, 1% NP-40, 0.1% sodium deoxycholate, 0.1% SDS, 150 mM NaCl, 1 mM EDTA, 0.5 mM AEBSF, and 10 lg/ml leupeptin). The lysates were centrifuged at 10,000g for 30 min to obtain the supernatant as the crude tyrosinase extract for the activity assay as described previously [10]. The reaction mixture contained 50 mM phosphate buffer, pH 6.8, 0.05% L -dopa, and the supernatant (tyrosinase source). After incubation at 37 °C for 20 min, dopachrome formation was monitored by measuring absorbance at wavelength 492 nm in a microplate reader.
Results and discussion To examine the structure–activity relationships of hydroxystilbene compounds on tyrosinase activity, a variety of trans-stilbene compounds with hydroxy groups on phenyl rings of the parent stilbene skeleton were synthesized and the inhibitory activity on tyrosinase was examined. As shown in Fig. 1B, monohydroxytrans-stilbene, the stilbene compounds with one hydroxy group on the phenyl ring of the parent stilbene skeleton, had no inhibitory effects. However, the inhibitory potency was enhanced by introducing another hydroxy group to phenyl-ring of the parent stilbene skeleton. Four dihydroxystilbene compounds with hydroxy group at position 3 were found to exhibit different inhibitory potencies depending on the position of another hydroxy group. 3,5-Dihydroxy-trans-stilbene has a more potent inhibitory activity than 2,3-dihydroxy-trans-stilbene or 3,4-dihydroxy-trans-stilbene and 3,30 -dihydroxy-transstilbene is more inhibitory than 3,5-dihydroxy-transstilbene. Thus, the structural distance of another phenolic hydroxy group from position 3 seems to contribute to the inhibitory potency. Furthermore, addition of one or two phenolic hydroxy groups to 3,30 -dihydroxy-trans-stilbene markedly potentiated the inhibitory
Fig. 1. Effects of hydroxystilbene compounds on murine tyrosinase activity. (A) Chemical structure of the parent stilbene skeleton. Substituent is phenolic hydroxy group (–OH). (B) Measurement of tyrosinase activity was performed as described in Materials and methods. The values of inhibitory effects of the compounds on tyrosinase activity at a concentration of 200 lM represent means SD of two different experiments each carried out in duplicate.
activity (Fig. 1B). 3,30 ,4-Trihydroxy-trans-stilbene and 3,30 ,4,40 -tetrahydroxy-trans-stilbene were more potent in inhibition of tyrosinase activity, as compared with 3,30 -dihydroxy-trans-stilbene. 3,30 ,4,40 -Tetrahydroxy-trans-stilbene showed nearly complete inhibition of tyrosinase activity (Fig. 1B). Thus, the inhibitory potency of the hydroxystilbene compounds was remarkably elevated by increasing number of phenolic hydroxy substituents, suggesting that the number of hydroxy
Fig. 2. Effect of methyoxystilbene compound on murine tyrosinase activity. (A) Chemical structures of 3,5-dihydroxy-trans-stilbene and 3,5-dimethyoxy-trans-stilbene. (B) Measurement of tyrosinase activity was performed as described in Materials and methods. The values of inhibitory effects of the compounds on tyrosinase activity at a concentration of 200 lM are represented as means SD of two different experiments each carried out in duplicate.
K. Ohguchi et al. / Biochemical and Biophysical Research Communications 307 (2003) 861–863
groups on phenyl rings of the hydroxystilbene plays an important role in the inhibitory potency for tyrosinase activity. As shown in Fig. 2, methylation of phenolic hydroxy group was observed to abolish the tyrosinase inhibitory activity. This result also indicated that phenolic hydroxy group is required for inhibition of tyrosinase activity. Recently, we have demonstrated that naturally occurring tetrahydroxystilbene, gnetol, isolated from the acetone soluble extract of Gnetum gnemon, is a potent
Fig. 3. Effect of dihydrognetol on on murine tyrosinase activity. (A) Chemical structures of gnetol and dihydrognetol. Dihydrognetol was obtained by hydrogenation of gnetol. (B) Measurement of tyrosinase activity was performed as described in Materials and methods. The values of inhibitory effects of the compounds on tyrosinase activity at a concentration of 100 lM are represented as means SD of two different experiments each carried out in duplicate.
Fig. 4. Effect of hydroxystilbene compound of cis-olefin structure on murine tyrosinase activity. (A) Chemical structures of 3,30 -dihydroxytrans-stilbene and 3,30 -dimethyoxy-cis-stilbene. (B) Measurement of tyrosinase activity was performed as described in Materials and methods. The values of inhibitory effects of the compounds on tyrosinase activity at a concentration of 200 lM are represented as means SD of two different experiments each carried out in duplicate.
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inhibitor of tyrosinase activity [7]. As shown in Fig. 3B, gnetol exhibited strong inhibition for tyrosinase activity. Interestingly, gnetol was found to be approximately 30fold potent than kojic acid used often as a reference compound (data not shown). In order to investigate the role of the olefin structure, gnetol with a double bond was reduced by hydrogenation. Dihydrognetol thus obtained exerted a greatly lowered inhibitory effect on tyrosinase activity, thus indicating that the double bond in stilbene skeleton is critical for tyrosinase inhibition. To further examine the role of the double bond in stilbene skeleton for the tyrosinase inhibitory activity, the cis-olefin structure of the parent stilbene skeleton was examined for the inhibitory effect on tyrosinase activity. As shown in Fig. 4B, 3,30 -dihydroxy-cis-stilbene abolished the inhibitory effect. Therefore, these findings suggested that the trans-olefin structure of the parent stilbene skeleton is essential for tyrosinase inhibition. In conclusion, the present study showed that the number and position of hydroxy group on phenyl rings in hydroxystilbene are important for the inhibition of tyrosinase activity, and also that the trans-olefin structure of the parent stilbene skeleton is essential for the inhibition. The results obtained here would provide a useful clue for the design and development of new tyrosinase inhibitors.
References [1] V.J. Hearing, M. Jimenez, Analysis of mammalian pigmentation at the molecular level, Pigment. Cell. Res. 2 (1989) 75–85. [2] K.P.L. Bhat, J.W. Kosmeder 2nd, J.M. Pezzuto, Biological effects of resveratrol, Antioxid. Redox Signal. 3 (2001) 1041–1064. [3] T. Ito, Y. Akao, T. Tanaka, M. Iinuma, Y. Nozawa, Vaticanol C, a novel resveratrol tetramer, inhibits cell growth through induction of apoptosis in colon cancer cell lines, Biol. Pharm. Bull. 25 (2002) 147–148. [4] Y. Kimura, H. Okuda, S. Arichi, Effects of stilbenes on arachidonate metabolism in leukocytes, Biochim. Biophys. Acta 834 (1985) 275–278. [5] N.-H. Shin, S.Y. Ryu, E.J. Choi, S.-H. Kang, I.-M. Chang, K.R. Min, R. Kim, Oxyresveratrol as the potent inhibitor on dopa oxidase activity of mushroom tyrosinase, Biochem. Biophys. Res. Commun. 243 (1998) 801–803. [6] Y.M. Kim, J. Yun, C.-K. Lee, H. Lee, K.R. Min, Y. Kim, Oxyresveratrol and hydroxystilbene compounds, J. Biol. Chem. 277 (2002) 16340–16344. [7] K. Ohguchi, T. Tanaka, I. Iliya, T. Ito, M. Iinuma, K. Matsumoto, Y. Akao, Y. Nozawa, Gnetol as a potent tyrosinase inhibitor from genus Gnetum, Biosci. Biotechnol. Biochem. 67 (2003) 663–665. [8] S. Murakami, I. Arai, M. Muramatsu, S. Otomo, K. Baba, T. Kido, M. Kozawa, Effect of stilbene derivatives on gastric Hþ ,Kþ ATPase, Biochem. Pharmacol. 44 (1992) 1947–1951. [9] I. Iliya, T. Tanaka, M. Iinuma, Z. Ali, M. Furusawa, K-I. Nakaya, Dimeric stilbenes from stem lianas of Gnetum africanum, Heterocycles 57 (2002) 1057–1062. [10] H. Takahashi, P.G. Parsons, Rapid and reversible inhibition of tyrosinase activity by glucosidase inhibitors in human melanoma cells, J. Invest. Dermatol. 98 (1992) 481–487.
Effects of hydroxystilbene derivatives on tyrosinase activity Kenji Ohguchi,a,* Toshiyuki Tanaka,b Tadashi Kido,c Kimiye Baba,c Munekazu Iinuma,d Kenji Matsumoto,a Yukihiro Akao,a and Yoshinori Nozawaa a
Gifu International Institute of Biotechnology, 1-1 Naka-Fudogaoka, Kakamigahara, Gifu 504-0838, Japan Gifu Prefectural Institute of Health and Environmental Sciences, Kakamigahara, Gifu 504-0838, Japan c Osaka University of Pharmaceutical Sciences, Takatsuki, Osaka 569-1094, Japan d Gifu Pharmaceutical University, Mitahora-higashi, Gifu 502-5858, Japan
b
Received 26 June 2003
Abstract Synthesis of melanin starts from the conversion of L -tyrosine to 3,4-dihydroxyphenylalanine (L -dopa) and then the oxidation of yields dopaquinone by tyrosinase. Therefore, tyrosinase inhibitors have been established as important constituents of depigmentation agents. Recently, polyhydroxystilbene compounds, which are trans-resveratrol (3,40 ,5-trihydroxy-trans-stilbene) analogs, have been demonstrated as potent tyrosinase inhibitors. However, their detailed inhibitory mechanisms are not clearly understood. In the present study, a variety of synthesized hydroxystilbene compounds were tested for their inhibitory effects against murine tyrosinase activity. The inhibitory potencies of the hydroxy-trans-stilbene compounds were remarkably elevated by increasing number of phenolic hydroxy substituents. Methylated hydroxy-trans-stilbene lost the inhibitory activity. Furthermore, hydrogenated hydroxystilbene or hydroxy-cis-stilbene exerted little or no inhibitory effect compared with hydroxy-trans-stilbene on tyrosinase activity. The structure–activity relationships demonstrated in the present study suggest that the phenolic hydroxy groups and trans-olefin structure of the parent stilbene skeleton contribute to the inhibitory potency of hydroxystilbene for tyrosinase activity. Ó 2003 Elsevier Inc. All rights reserved. L -dopa
Keywords: Tyrosinase; Hydroxystilbene; Stilbene; Resveratrol; Melanin
Melanin production is principally responsible for skin color and plays an important role in prevention of suninduced skin injury. Melanin is produced by melanocytes in the basal layer of epidermis [1]. Synthesis of melanin starts from the conversion of the amino acid L -tyrosine to 3,4-dihydroxyphenylalanine (L -dopa) and then the oxidation of L -dopa yields dopaquinone by tyrosinase, an enzyme catalyzing the rate-limiting step for the melanin biosynthesis [1]. This tyrosinase process is involved in abnormal accumulation of melanin pigments (hyperpigmentation). Therefore, tyrosinase inhibitors have been established as important constituents of cosmetic materials and depigmenting agents for hyperpigmentation. Stilbene derivatives are known to be abundantly distributed in the plants belonging to Dipterocarpaceae, * Corresponding author. Fax: +81-583-71-4412. E-mail address: [email protected] (K. Ohguchi).
0006-291X/03/$ - see front matter Ó 2003 Elsevier Inc. All rights reserved. doi:10.1016/S0006-291X(03)01284-1
Vitaceae, Gnetaceae, Leguminosae, and Cyperaceae as a variety of trans-resveratrol (3,40 ,5-trihydroxy-trans-stilbene) derivatives [2]. Some of their derivatives have also been reported to possess various biological and pharmacological activities such as anti-carcinogenic [3] and anti-inflammatory [4] effects. Therefore, stilbene derivatives composed of resveratorol are considered to be useful resources for pharmacological agents. Recently, tetrahydroxystilbene compounds, which are resveratrol analogs, have been demonstrated as potent tyrosinase inhibitors [5–7]. Kim et al. [6] have demonstrated that oxyresveratrol (2,30 ,4,50 -tetrahydroxy-trans-stilbene) from Morus alba Linne showed a potent inhibitory effect on tyrosinase activity as a non-competitive inhibitor. We have recently demonstrated that gnetol (2,30 ,50 ,6-tetrahydroxy-trans-stilbene), a naturally occurring compound particularly found in Gnetaceae, exhibited a potent inhibitory effect on tyrosinase activity [7]. The
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K. Ohguchi et al. / Biochemical and Biophysical Research Communications 307 (2003) 861–863
number of phenolic hydroxy groups may play an important role in the inhibitory potency of hydroxystilbene compounds such as oxyresveratrol and gnetol for tyrosinase activity. However, its detailed mechanism(s) has not been clearly understood. To gain further insight into the mechanism underlying the inhibitory effect on tyrosinase activity of hydroxystilbene compounds, we synthesized hydroxystilbene derivatives and analyzed the structure–activity relationships of the compounds in the inhibition of murine tyrosinase activity. Materials and methods Materials. 3,4-Dihydroxyphenylalanine (L -dopa) was from Sigma. Hydroxystilbene derivatives were synthesized as described previously [8]. Gnetol (2,30 ,50 ,6-tetrahydroxy-trans-stilbene) was isolated from the acetone soluble extract of Gnetum gnemon as described previously [9]. Dihydrognetol was obtained by hydrogenation with Pd–C/H2 (atmospheric pressure) in ethanol for 3 h of gnetol. Other reagents were of the highest quality available. Measurement of tyrosinase activity. Tyrosinase source was prepared from murine B16 melanoma cells (Riken Cell Bank, Tsukuba, Japan). The cells were lysed by incubating at 4 °C for 1 h in RIPA buffer (10 mM Tris–HCl, pH7.5, 1% NP-40, 0.1% sodium deoxycholate, 0.1% SDS, 150 mM NaCl, 1 mM EDTA, 0.5 mM AEBSF, and 10 lg/ml leupeptin). The lysates were centrifuged at 10,000g for 30 min to obtain the supernatant as the crude tyrosinase extract for the activity assay as described previously [10]. The reaction mixture contained 50 mM phosphate buffer, pH 6.8, 0.05% L -dopa, and the supernatant (tyrosinase source). After incubation at 37 °C for 20 min, dopachrome formation was monitored by measuring absorbance at wavelength 492 nm in a microplate reader.
Results and discussion To examine the structure–activity relationships of hydroxystilbene compounds on tyrosinase activity, a variety of trans-stilbene compounds with hydroxy groups on phenyl rings of the parent stilbene skeleton were synthesized and the inhibitory activity on tyrosinase was examined. As shown in Fig. 1B, monohydroxytrans-stilbene, the stilbene compounds with one hydroxy group on the phenyl ring of the parent stilbene skeleton, had no inhibitory effects. However, the inhibitory potency was enhanced by introducing another hydroxy group to phenyl-ring of the parent stilbene skeleton. Four dihydroxystilbene compounds with hydroxy group at position 3 were found to exhibit different inhibitory potencies depending on the position of another hydroxy group. 3,5-Dihydroxy-trans-stilbene has a more potent inhibitory activity than 2,3-dihydroxy-trans-stilbene or 3,4-dihydroxy-trans-stilbene and 3,30 -dihydroxy-transstilbene is more inhibitory than 3,5-dihydroxy-transstilbene. Thus, the structural distance of another phenolic hydroxy group from position 3 seems to contribute to the inhibitory potency. Furthermore, addition of one or two phenolic hydroxy groups to 3,30 -dihydroxy-trans-stilbene markedly potentiated the inhibitory
Fig. 1. Effects of hydroxystilbene compounds on murine tyrosinase activity. (A) Chemical structure of the parent stilbene skeleton. Substituent is phenolic hydroxy group (–OH). (B) Measurement of tyrosinase activity was performed as described in Materials and methods. The values of inhibitory effects of the compounds on tyrosinase activity at a concentration of 200 lM represent means SD of two different experiments each carried out in duplicate.
activity (Fig. 1B). 3,30 ,4-Trihydroxy-trans-stilbene and 3,30 ,4,40 -tetrahydroxy-trans-stilbene were more potent in inhibition of tyrosinase activity, as compared with 3,30 -dihydroxy-trans-stilbene. 3,30 ,4,40 -Tetrahydroxy-trans-stilbene showed nearly complete inhibition of tyrosinase activity (Fig. 1B). Thus, the inhibitory potency of the hydroxystilbene compounds was remarkably elevated by increasing number of phenolic hydroxy substituents, suggesting that the number of hydroxy
Fig. 2. Effect of methyoxystilbene compound on murine tyrosinase activity. (A) Chemical structures of 3,5-dihydroxy-trans-stilbene and 3,5-dimethyoxy-trans-stilbene. (B) Measurement of tyrosinase activity was performed as described in Materials and methods. The values of inhibitory effects of the compounds on tyrosinase activity at a concentration of 200 lM are represented as means SD of two different experiments each carried out in duplicate.
K. Ohguchi et al. / Biochemical and Biophysical Research Communications 307 (2003) 861–863
groups on phenyl rings of the hydroxystilbene plays an important role in the inhibitory potency for tyrosinase activity. As shown in Fig. 2, methylation of phenolic hydroxy group was observed to abolish the tyrosinase inhibitory activity. This result also indicated that phenolic hydroxy group is required for inhibition of tyrosinase activity. Recently, we have demonstrated that naturally occurring tetrahydroxystilbene, gnetol, isolated from the acetone soluble extract of Gnetum gnemon, is a potent
Fig. 3. Effect of dihydrognetol on on murine tyrosinase activity. (A) Chemical structures of gnetol and dihydrognetol. Dihydrognetol was obtained by hydrogenation of gnetol. (B) Measurement of tyrosinase activity was performed as described in Materials and methods. The values of inhibitory effects of the compounds on tyrosinase activity at a concentration of 100 lM are represented as means SD of two different experiments each carried out in duplicate.
Fig. 4. Effect of hydroxystilbene compound of cis-olefin structure on murine tyrosinase activity. (A) Chemical structures of 3,30 -dihydroxytrans-stilbene and 3,30 -dimethyoxy-cis-stilbene. (B) Measurement of tyrosinase activity was performed as described in Materials and methods. The values of inhibitory effects of the compounds on tyrosinase activity at a concentration of 200 lM are represented as means SD of two different experiments each carried out in duplicate.
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inhibitor of tyrosinase activity [7]. As shown in Fig. 3B, gnetol exhibited strong inhibition for tyrosinase activity. Interestingly, gnetol was found to be approximately 30fold potent than kojic acid used often as a reference compound (data not shown). In order to investigate the role of the olefin structure, gnetol with a double bond was reduced by hydrogenation. Dihydrognetol thus obtained exerted a greatly lowered inhibitory effect on tyrosinase activity, thus indicating that the double bond in stilbene skeleton is critical for tyrosinase inhibition. To further examine the role of the double bond in stilbene skeleton for the tyrosinase inhibitory activity, the cis-olefin structure of the parent stilbene skeleton was examined for the inhibitory effect on tyrosinase activity. As shown in Fig. 4B, 3,30 -dihydroxy-cis-stilbene abolished the inhibitory effect. Therefore, these findings suggested that the trans-olefin structure of the parent stilbene skeleton is essential for tyrosinase inhibition. In conclusion, the present study showed that the number and position of hydroxy group on phenyl rings in hydroxystilbene are important for the inhibition of tyrosinase activity, and also that the trans-olefin structure of the parent stilbene skeleton is essential for the inhibition. The results obtained here would provide a useful clue for the design and development of new tyrosinase inhibitors.
References [1] V.J. Hearing, M. Jimenez, Analysis of mammalian pigmentation at the molecular level, Pigment. Cell. Res. 2 (1989) 75–85. [2] K.P.L. Bhat, J.W. Kosmeder 2nd, J.M. Pezzuto, Biological effects of resveratrol, Antioxid. Redox Signal. 3 (2001) 1041–1064. [3] T. Ito, Y. Akao, T. Tanaka, M. Iinuma, Y. Nozawa, Vaticanol C, a novel resveratrol tetramer, inhibits cell growth through induction of apoptosis in colon cancer cell lines, Biol. Pharm. Bull. 25 (2002) 147–148. [4] Y. Kimura, H. Okuda, S. Arichi, Effects of stilbenes on arachidonate metabolism in leukocytes, Biochim. Biophys. Acta 834 (1985) 275–278. [5] N.-H. Shin, S.Y. Ryu, E.J. Choi, S.-H. Kang, I.-M. Chang, K.R. Min, R. Kim, Oxyresveratrol as the potent inhibitor on dopa oxidase activity of mushroom tyrosinase, Biochem. Biophys. Res. Commun. 243 (1998) 801–803. [6] Y.M. Kim, J. Yun, C.-K. Lee, H. Lee, K.R. Min, Y. Kim, Oxyresveratrol and hydroxystilbene compounds, J. Biol. Chem. 277 (2002) 16340–16344. [7] K. Ohguchi, T. Tanaka, I. Iliya, T. Ito, M. Iinuma, K. Matsumoto, Y. Akao, Y. Nozawa, Gnetol as a potent tyrosinase inhibitor from genus Gnetum, Biosci. Biotechnol. Biochem. 67 (2003) 663–665. [8] S. Murakami, I. Arai, M. Muramatsu, S. Otomo, K. Baba, T. Kido, M. Kozawa, Effect of stilbene derivatives on gastric Hþ ,Kþ ATPase, Biochem. Pharmacol. 44 (1992) 1947–1951. [9] I. Iliya, T. Tanaka, M. Iinuma, Z. Ali, M. Furusawa, K-I. Nakaya, Dimeric stilbenes from stem lianas of Gnetum africanum, Heterocycles 57 (2002) 1057–1062. [10] H. Takahashi, P.G. Parsons, Rapid and reversible inhibition of tyrosinase activity by glucosidase inhibitors in human melanoma cells, J. Invest. Dermatol. 98 (1992) 481–487.