Urolithin and Reduced Urolithin Derivatives as Potent Inhibitors of Tyrosinase and Melanogenesis: Importance of the 4-Substituted Resorcinol Moiety

We previously reported (<i<E</i<)-β-phenyl-α,β-unsaturated carbonyl scaffold ((<i<E</i<)-PUSC) played an important role in showing high tyrosinase inhibitory activity and that derivatives with a 4-substituted resorcinol moiety as the β-phenyl group of the scaffold resulted in...
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Autor*in:	Sanggwon Lee [verfasserIn] Heejeong Choi [verfasserIn] Yujin Park [verfasserIn] Hee Jin Jung [verfasserIn] Sultan Ullah [verfasserIn] Inkyu Choi [verfasserIn] Dongwan Kang [verfasserIn] Chaeun Park [verfasserIn] Il Young Ryu [verfasserIn] Yeongmu Jeong [verfasserIn] YeJi Hwang [verfasserIn] Sojeong Hong [verfasserIn] Pusoon Chun [verfasserIn] Hyung Ryong Moon [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2021

Schlagwörter:	tyrosinase urolithin reduced urolithin 4-substituted resorcinol anti-melanogenesis docking simulation

Übergeordnetes Werk:	In: International Journal of Molecular Sciences - MDPI AG, 2003, 22(2021), 11, p 5616
Übergeordnetes Werk:	volume:22 ; year:2021 ; number:11, p 5616

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc Journal toc

DOI / URN:	10.3390/ijms22115616

Katalog-ID:	DOAJ057657580

Internformat


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245	1	0	\|a Urolithin and Reduced Urolithin Derivatives as Potent Inhibitors of Tyrosinase and Melanogenesis: Importance of the 4-Substituted Resorcinol Moiety
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520			\|a We previously reported (<i<E</i<)-β-phenyl-α,β-unsaturated carbonyl scaffold ((<i<E</i<)-PUSC) played an important role in showing high tyrosinase inhibitory activity and that derivatives with a 4-substituted resorcinol moiety as the β-phenyl group of the scaffold resulted in the greatest tyrosinase inhibitory activity. To examine whether the 4-substituted resorcinol moiety could impart tyrosinase inhibitory activity in the absence of the α,β-unsaturated carbonyl moiety of the (<i<E</i<)-PUSC scaffold, 10 urolithin derivatives were synthesized. To obtain more candidate samples, the lactone ring in synthesized urolithins was reduced to produce nine reduced urolithins. Compounds <b<1c</b< (IC<sub<50</sub< = 18.09 ± 0.25 μM), 1h (IC<sub<50</sub< = 4.14 ± 0.10 μM), and 2a (IC<sub<50</sub< = 15.69 ± 0.40 μM) had greater mushroom tyrosinase-inhibitory activities than kojic acid (KA) (IC<sub<50</sub< = 48.62 ± 3.38 μM). The SAR results suggest that the 4-substituted resorcinol motif makes an important contribution to tyrosinase inhibition. To investigate whether these compounds bind to human tyrosinase, a human tyrosinase homology model was developed. Docking simulations with mushroom and human tyrosinases showed that 1c, 1h, and 2a bind to the active site of both tyrosinases with higher binding affinities than KA. Pharmacophore analyses showed that two hydroxyl groups of the 4-substituted resorcinol entity act as hydrogen bond donors in both mushroom and human tyrosinases. Kinetic analyses indicated that these compounds were all competitive inhibitors. Compound 2a inhibited cellular tyrosinase activity and melanogenesis in α-MSH plus IBMX-stimulated B16F10 melanoma cells more strongly than KA. These results suggest that 2a is a promising candidate for the treatment of skin pigment disorders, and show the 4-substituted resorcinol entity importantly contributes to tyrosinase inhibition.
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700	0		\|a Sultan Ullah \|e verfasserin \|4 aut
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700	0		\|a Hyung Ryong Moon \|e verfasserin \|4 aut
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951			\|a AR
952			\|d 22 \|j 2021 \|e 11, p 5616

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allfields	10.3390/ijms22115616 doi (DE-627)DOAJ057657580 (DE-599)DOAJ4fc225a1cfae4f10bc6fdb83b82f3b4b DE-627 ger DE-627 rakwb eng QH301-705.5 QD1-999 Sanggwon Lee verfasserin aut Urolithin and Reduced Urolithin Derivatives as Potent Inhibitors of Tyrosinase and Melanogenesis: Importance of the 4-Substituted Resorcinol Moiety 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier We previously reported (<i<E</i<)-β-phenyl-α,β-unsaturated carbonyl scaffold ((<i<E</i<)-PUSC) played an important role in showing high tyrosinase inhibitory activity and that derivatives with a 4-substituted resorcinol moiety as the β-phenyl group of the scaffold resulted in the greatest tyrosinase inhibitory activity. To examine whether the 4-substituted resorcinol moiety could impart tyrosinase inhibitory activity in the absence of the α,β-unsaturated carbonyl moiety of the (<i<E</i<)-PUSC scaffold, 10 urolithin derivatives were synthesized. To obtain more candidate samples, the lactone ring in synthesized urolithins was reduced to produce nine reduced urolithins. Compounds <b<1c</b< (IC<sub<50</sub< = 18.09 ± 0.25 μM), 1h (IC<sub<50</sub< = 4.14 ± 0.10 μM), and 2a (IC<sub<50</sub< = 15.69 ± 0.40 μM) had greater mushroom tyrosinase-inhibitory activities than kojic acid (KA) (IC<sub<50</sub< = 48.62 ± 3.38 μM). The SAR results suggest that the 4-substituted resorcinol motif makes an important contribution to tyrosinase inhibition. To investigate whether these compounds bind to human tyrosinase, a human tyrosinase homology model was developed. Docking simulations with mushroom and human tyrosinases showed that 1c, 1h, and 2a bind to the active site of both tyrosinases with higher binding affinities than KA. Pharmacophore analyses showed that two hydroxyl groups of the 4-substituted resorcinol entity act as hydrogen bond donors in both mushroom and human tyrosinases. Kinetic analyses indicated that these compounds were all competitive inhibitors. Compound 2a inhibited cellular tyrosinase activity and melanogenesis in α-MSH plus IBMX-stimulated B16F10 melanoma cells more strongly than KA. These results suggest that 2a is a promising candidate for the treatment of skin pigment disorders, and show the 4-substituted resorcinol entity importantly contributes to tyrosinase inhibition. tyrosinase urolithin reduced urolithin 4-substituted resorcinol anti-melanogenesis docking simulation Biology (General) Chemistry Heejeong Choi verfasserin aut Yujin Park verfasserin aut Hee Jin Jung verfasserin aut Sultan Ullah verfasserin aut Inkyu Choi verfasserin aut Dongwan Kang verfasserin aut Chaeun Park verfasserin aut Il Young Ryu verfasserin aut Yeongmu Jeong verfasserin aut YeJi Hwang verfasserin aut Sojeong Hong verfasserin aut Pusoon Chun verfasserin aut Hyung Ryong Moon verfasserin aut In International Journal of Molecular Sciences MDPI AG, 2003 22(2021), 11, p 5616 (DE-627)316340715 (DE-600)2019364-6 14220067 nnns volume:22 year:2021 number:11, p 5616 https://doi.org/10.3390/ijms22115616 kostenfrei https://doaj.org/article/4fc225a1cfae4f10bc6fdb83b82f3b4b kostenfrei https://www.mdpi.com/1422-0067/22/11/5616 kostenfrei https://doaj.org/toc/1661-6596 Journal toc kostenfrei https://doaj.org/toc/1422-0067 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 22 2021 11, p 5616
spelling	10.3390/ijms22115616 doi (DE-627)DOAJ057657580 (DE-599)DOAJ4fc225a1cfae4f10bc6fdb83b82f3b4b DE-627 ger DE-627 rakwb eng QH301-705.5 QD1-999 Sanggwon Lee verfasserin aut Urolithin and Reduced Urolithin Derivatives as Potent Inhibitors of Tyrosinase and Melanogenesis: Importance of the 4-Substituted Resorcinol Moiety 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier We previously reported (<i<E</i<)-β-phenyl-α,β-unsaturated carbonyl scaffold ((<i<E</i<)-PUSC) played an important role in showing high tyrosinase inhibitory activity and that derivatives with a 4-substituted resorcinol moiety as the β-phenyl group of the scaffold resulted in the greatest tyrosinase inhibitory activity. To examine whether the 4-substituted resorcinol moiety could impart tyrosinase inhibitory activity in the absence of the α,β-unsaturated carbonyl moiety of the (<i<E</i<)-PUSC scaffold, 10 urolithin derivatives were synthesized. To obtain more candidate samples, the lactone ring in synthesized urolithins was reduced to produce nine reduced urolithins. Compounds <b<1c</b< (IC<sub<50</sub< = 18.09 ± 0.25 μM), 1h (IC<sub<50</sub< = 4.14 ± 0.10 μM), and 2a (IC<sub<50</sub< = 15.69 ± 0.40 μM) had greater mushroom tyrosinase-inhibitory activities than kojic acid (KA) (IC<sub<50</sub< = 48.62 ± 3.38 μM). The SAR results suggest that the 4-substituted resorcinol motif makes an important contribution to tyrosinase inhibition. To investigate whether these compounds bind to human tyrosinase, a human tyrosinase homology model was developed. Docking simulations with mushroom and human tyrosinases showed that 1c, 1h, and 2a bind to the active site of both tyrosinases with higher binding affinities than KA. Pharmacophore analyses showed that two hydroxyl groups of the 4-substituted resorcinol entity act as hydrogen bond donors in both mushroom and human tyrosinases. Kinetic analyses indicated that these compounds were all competitive inhibitors. Compound 2a inhibited cellular tyrosinase activity and melanogenesis in α-MSH plus IBMX-stimulated B16F10 melanoma cells more strongly than KA. These results suggest that 2a is a promising candidate for the treatment of skin pigment disorders, and show the 4-substituted resorcinol entity importantly contributes to tyrosinase inhibition. tyrosinase urolithin reduced urolithin 4-substituted resorcinol anti-melanogenesis docking simulation Biology (General) Chemistry Heejeong Choi verfasserin aut Yujin Park verfasserin aut Hee Jin Jung verfasserin aut Sultan Ullah verfasserin aut Inkyu Choi verfasserin aut Dongwan Kang verfasserin aut Chaeun Park verfasserin aut Il Young Ryu verfasserin aut Yeongmu Jeong verfasserin aut YeJi Hwang verfasserin aut Sojeong Hong verfasserin aut Pusoon Chun verfasserin aut Hyung Ryong Moon verfasserin aut In International Journal of Molecular Sciences MDPI AG, 2003 22(2021), 11, p 5616 (DE-627)316340715 (DE-600)2019364-6 14220067 nnns volume:22 year:2021 number:11, p 5616 https://doi.org/10.3390/ijms22115616 kostenfrei https://doaj.org/article/4fc225a1cfae4f10bc6fdb83b82f3b4b kostenfrei https://www.mdpi.com/1422-0067/22/11/5616 kostenfrei https://doaj.org/toc/1661-6596 Journal toc kostenfrei https://doaj.org/toc/1422-0067 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 22 2021 11, p 5616
allfields_unstemmed	10.3390/ijms22115616 doi (DE-627)DOAJ057657580 (DE-599)DOAJ4fc225a1cfae4f10bc6fdb83b82f3b4b DE-627 ger DE-627 rakwb eng QH301-705.5 QD1-999 Sanggwon Lee verfasserin aut Urolithin and Reduced Urolithin Derivatives as Potent Inhibitors of Tyrosinase and Melanogenesis: Importance of the 4-Substituted Resorcinol Moiety 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier We previously reported (<i<E</i<)-β-phenyl-α,β-unsaturated carbonyl scaffold ((<i<E</i<)-PUSC) played an important role in showing high tyrosinase inhibitory activity and that derivatives with a 4-substituted resorcinol moiety as the β-phenyl group of the scaffold resulted in the greatest tyrosinase inhibitory activity. To examine whether the 4-substituted resorcinol moiety could impart tyrosinase inhibitory activity in the absence of the α,β-unsaturated carbonyl moiety of the (<i<E</i<)-PUSC scaffold, 10 urolithin derivatives were synthesized. To obtain more candidate samples, the lactone ring in synthesized urolithins was reduced to produce nine reduced urolithins. Compounds <b<1c</b< (IC<sub<50</sub< = 18.09 ± 0.25 μM), 1h (IC<sub<50</sub< = 4.14 ± 0.10 μM), and 2a (IC<sub<50</sub< = 15.69 ± 0.40 μM) had greater mushroom tyrosinase-inhibitory activities than kojic acid (KA) (IC<sub<50</sub< = 48.62 ± 3.38 μM). The SAR results suggest that the 4-substituted resorcinol motif makes an important contribution to tyrosinase inhibition. To investigate whether these compounds bind to human tyrosinase, a human tyrosinase homology model was developed. Docking simulations with mushroom and human tyrosinases showed that 1c, 1h, and 2a bind to the active site of both tyrosinases with higher binding affinities than KA. Pharmacophore analyses showed that two hydroxyl groups of the 4-substituted resorcinol entity act as hydrogen bond donors in both mushroom and human tyrosinases. Kinetic analyses indicated that these compounds were all competitive inhibitors. Compound 2a inhibited cellular tyrosinase activity and melanogenesis in α-MSH plus IBMX-stimulated B16F10 melanoma cells more strongly than KA. These results suggest that 2a is a promising candidate for the treatment of skin pigment disorders, and show the 4-substituted resorcinol entity importantly contributes to tyrosinase inhibition. tyrosinase urolithin reduced urolithin 4-substituted resorcinol anti-melanogenesis docking simulation Biology (General) Chemistry Heejeong Choi verfasserin aut Yujin Park verfasserin aut Hee Jin Jung verfasserin aut Sultan Ullah verfasserin aut Inkyu Choi verfasserin aut Dongwan Kang verfasserin aut Chaeun Park verfasserin aut Il Young Ryu verfasserin aut Yeongmu Jeong verfasserin aut YeJi Hwang verfasserin aut Sojeong Hong verfasserin aut Pusoon Chun verfasserin aut Hyung Ryong Moon verfasserin aut In International Journal of Molecular Sciences MDPI AG, 2003 22(2021), 11, p 5616 (DE-627)316340715 (DE-600)2019364-6 14220067 nnns volume:22 year:2021 number:11, p 5616 https://doi.org/10.3390/ijms22115616 kostenfrei https://doaj.org/article/4fc225a1cfae4f10bc6fdb83b82f3b4b kostenfrei https://www.mdpi.com/1422-0067/22/11/5616 kostenfrei https://doaj.org/toc/1661-6596 Journal toc kostenfrei https://doaj.org/toc/1422-0067 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 22 2021 11, p 5616
allfieldsGer	10.3390/ijms22115616 doi (DE-627)DOAJ057657580 (DE-599)DOAJ4fc225a1cfae4f10bc6fdb83b82f3b4b DE-627 ger DE-627 rakwb eng QH301-705.5 QD1-999 Sanggwon Lee verfasserin aut Urolithin and Reduced Urolithin Derivatives as Potent Inhibitors of Tyrosinase and Melanogenesis: Importance of the 4-Substituted Resorcinol Moiety 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier We previously reported (<i<E</i<)-β-phenyl-α,β-unsaturated carbonyl scaffold ((<i<E</i<)-PUSC) played an important role in showing high tyrosinase inhibitory activity and that derivatives with a 4-substituted resorcinol moiety as the β-phenyl group of the scaffold resulted in the greatest tyrosinase inhibitory activity. To examine whether the 4-substituted resorcinol moiety could impart tyrosinase inhibitory activity in the absence of the α,β-unsaturated carbonyl moiety of the (<i<E</i<)-PUSC scaffold, 10 urolithin derivatives were synthesized. To obtain more candidate samples, the lactone ring in synthesized urolithins was reduced to produce nine reduced urolithins. Compounds <b<1c</b< (IC<sub<50</sub< = 18.09 ± 0.25 μM), 1h (IC<sub<50</sub< = 4.14 ± 0.10 μM), and 2a (IC<sub<50</sub< = 15.69 ± 0.40 μM) had greater mushroom tyrosinase-inhibitory activities than kojic acid (KA) (IC<sub<50</sub< = 48.62 ± 3.38 μM). The SAR results suggest that the 4-substituted resorcinol motif makes an important contribution to tyrosinase inhibition. To investigate whether these compounds bind to human tyrosinase, a human tyrosinase homology model was developed. Docking simulations with mushroom and human tyrosinases showed that 1c, 1h, and 2a bind to the active site of both tyrosinases with higher binding affinities than KA. Pharmacophore analyses showed that two hydroxyl groups of the 4-substituted resorcinol entity act as hydrogen bond donors in both mushroom and human tyrosinases. Kinetic analyses indicated that these compounds were all competitive inhibitors. Compound 2a inhibited cellular tyrosinase activity and melanogenesis in α-MSH plus IBMX-stimulated B16F10 melanoma cells more strongly than KA. These results suggest that 2a is a promising candidate for the treatment of skin pigment disorders, and show the 4-substituted resorcinol entity importantly contributes to tyrosinase inhibition. tyrosinase urolithin reduced urolithin 4-substituted resorcinol anti-melanogenesis docking simulation Biology (General) Chemistry Heejeong Choi verfasserin aut Yujin Park verfasserin aut Hee Jin Jung verfasserin aut Sultan Ullah verfasserin aut Inkyu Choi verfasserin aut Dongwan Kang verfasserin aut Chaeun Park verfasserin aut Il Young Ryu verfasserin aut Yeongmu Jeong verfasserin aut YeJi Hwang verfasserin aut Sojeong Hong verfasserin aut Pusoon Chun verfasserin aut Hyung Ryong Moon verfasserin aut In International Journal of Molecular Sciences MDPI AG, 2003 22(2021), 11, p 5616 (DE-627)316340715 (DE-600)2019364-6 14220067 nnns volume:22 year:2021 number:11, p 5616 https://doi.org/10.3390/ijms22115616 kostenfrei https://doaj.org/article/4fc225a1cfae4f10bc6fdb83b82f3b4b kostenfrei https://www.mdpi.com/1422-0067/22/11/5616 kostenfrei https://doaj.org/toc/1661-6596 Journal toc kostenfrei https://doaj.org/toc/1422-0067 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 22 2021 11, p 5616
allfieldsSound	10.3390/ijms22115616 doi (DE-627)DOAJ057657580 (DE-599)DOAJ4fc225a1cfae4f10bc6fdb83b82f3b4b DE-627 ger DE-627 rakwb eng QH301-705.5 QD1-999 Sanggwon Lee verfasserin aut Urolithin and Reduced Urolithin Derivatives as Potent Inhibitors of Tyrosinase and Melanogenesis: Importance of the 4-Substituted Resorcinol Moiety 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier We previously reported (<i<E</i<)-β-phenyl-α,β-unsaturated carbonyl scaffold ((<i<E</i<)-PUSC) played an important role in showing high tyrosinase inhibitory activity and that derivatives with a 4-substituted resorcinol moiety as the β-phenyl group of the scaffold resulted in the greatest tyrosinase inhibitory activity. To examine whether the 4-substituted resorcinol moiety could impart tyrosinase inhibitory activity in the absence of the α,β-unsaturated carbonyl moiety of the (<i<E</i<)-PUSC scaffold, 10 urolithin derivatives were synthesized. To obtain more candidate samples, the lactone ring in synthesized urolithins was reduced to produce nine reduced urolithins. Compounds <b<1c</b< (IC<sub<50</sub< = 18.09 ± 0.25 μM), 1h (IC<sub<50</sub< = 4.14 ± 0.10 μM), and 2a (IC<sub<50</sub< = 15.69 ± 0.40 μM) had greater mushroom tyrosinase-inhibitory activities than kojic acid (KA) (IC<sub<50</sub< = 48.62 ± 3.38 μM). The SAR results suggest that the 4-substituted resorcinol motif makes an important contribution to tyrosinase inhibition. To investigate whether these compounds bind to human tyrosinase, a human tyrosinase homology model was developed. Docking simulations with mushroom and human tyrosinases showed that 1c, 1h, and 2a bind to the active site of both tyrosinases with higher binding affinities than KA. Pharmacophore analyses showed that two hydroxyl groups of the 4-substituted resorcinol entity act as hydrogen bond donors in both mushroom and human tyrosinases. Kinetic analyses indicated that these compounds were all competitive inhibitors. Compound 2a inhibited cellular tyrosinase activity and melanogenesis in α-MSH plus IBMX-stimulated B16F10 melanoma cells more strongly than KA. These results suggest that 2a is a promising candidate for the treatment of skin pigment disorders, and show the 4-substituted resorcinol entity importantly contributes to tyrosinase inhibition. tyrosinase urolithin reduced urolithin 4-substituted resorcinol anti-melanogenesis docking simulation Biology (General) Chemistry Heejeong Choi verfasserin aut Yujin Park verfasserin aut Hee Jin Jung verfasserin aut Sultan Ullah verfasserin aut Inkyu Choi verfasserin aut Dongwan Kang verfasserin aut Chaeun Park verfasserin aut Il Young Ryu verfasserin aut Yeongmu Jeong verfasserin aut YeJi Hwang verfasserin aut Sojeong Hong verfasserin aut Pusoon Chun verfasserin aut Hyung Ryong Moon verfasserin aut In International Journal of Molecular Sciences MDPI AG, 2003 22(2021), 11, p 5616 (DE-627)316340715 (DE-600)2019364-6 14220067 nnns volume:22 year:2021 number:11, p 5616 https://doi.org/10.3390/ijms22115616 kostenfrei https://doaj.org/article/4fc225a1cfae4f10bc6fdb83b82f3b4b kostenfrei https://www.mdpi.com/1422-0067/22/11/5616 kostenfrei https://doaj.org/toc/1661-6596 Journal toc kostenfrei https://doaj.org/toc/1422-0067 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 22 2021 11, p 5616
language	English
source	In International Journal of Molecular Sciences 22(2021), 11, p 5616 volume:22 year:2021 number:11, p 5616
sourceStr	In International Journal of Molecular Sciences 22(2021), 11, p 5616 volume:22 year:2021 number:11, p 5616
format_phy_str_mv	Article
institution	findex.gbv.de
topic_facet	tyrosinase urolithin reduced urolithin 4-substituted resorcinol anti-melanogenesis docking simulation Biology (General) Chemistry
isfreeaccess_bool	true
container_title	International Journal of Molecular Sciences
authorswithroles_txt_mv	Sanggwon Lee @@aut@@ Heejeong Choi @@aut@@ Yujin Park @@aut@@ Hee Jin Jung @@aut@@ Sultan Ullah @@aut@@ Inkyu Choi @@aut@@ Dongwan Kang @@aut@@ Chaeun Park @@aut@@ Il Young Ryu @@aut@@ Yeongmu Jeong @@aut@@ YeJi Hwang @@aut@@ Sojeong Hong @@aut@@ Pusoon Chun @@aut@@ Hyung Ryong Moon @@aut@@
publishDateDaySort_date	2021-01-01T00:00:00Z
hierarchy_top_id	316340715
id	DOAJ057657580
language_de	englisch
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callnumber-first	Q - Science
author	Sanggwon Lee
spellingShingle	Sanggwon Lee misc QH301-705.5 misc QD1-999 misc tyrosinase misc urolithin misc reduced urolithin misc 4-substituted resorcinol misc anti-melanogenesis misc docking simulation misc Biology (General) misc Chemistry Urolithin and Reduced Urolithin Derivatives as Potent Inhibitors of Tyrosinase and Melanogenesis: Importance of the 4-Substituted Resorcinol Moiety
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topic_title	QH301-705.5 QD1-999 Urolithin and Reduced Urolithin Derivatives as Potent Inhibitors of Tyrosinase and Melanogenesis: Importance of the 4-Substituted Resorcinol Moiety tyrosinase urolithin reduced urolithin 4-substituted resorcinol anti-melanogenesis docking simulation
topic	misc QH301-705.5 misc QD1-999 misc tyrosinase misc urolithin misc reduced urolithin misc 4-substituted resorcinol misc anti-melanogenesis misc docking simulation misc Biology (General) misc Chemistry
topic_unstemmed	misc QH301-705.5 misc QD1-999 misc tyrosinase misc urolithin misc reduced urolithin misc 4-substituted resorcinol misc anti-melanogenesis misc docking simulation misc Biology (General) misc Chemistry
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title	Urolithin and Reduced Urolithin Derivatives as Potent Inhibitors of Tyrosinase and Melanogenesis: Importance of the 4-Substituted Resorcinol Moiety
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title_full	Urolithin and Reduced Urolithin Derivatives as Potent Inhibitors of Tyrosinase and Melanogenesis: Importance of the 4-Substituted Resorcinol Moiety
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author_browse	Sanggwon Lee Heejeong Choi Yujin Park Hee Jin Jung Sultan Ullah Inkyu Choi Dongwan Kang Chaeun Park Il Young Ryu Yeongmu Jeong YeJi Hwang Sojeong Hong Pusoon Chun Hyung Ryong Moon
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author-letter	Sanggwon Lee
doi_str_mv	10.3390/ijms22115616
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title_sort	urolithin and reduced urolithin derivatives as potent inhibitors of tyrosinase and melanogenesis: importance of the 4-substituted resorcinol moiety
callnumber	QH301-705.5
title_auth	Urolithin and Reduced Urolithin Derivatives as Potent Inhibitors of Tyrosinase and Melanogenesis: Importance of the 4-Substituted Resorcinol Moiety
abstract	We previously reported (<i<E</i<)-β-phenyl-α,β-unsaturated carbonyl scaffold ((<i<E</i<)-PUSC) played an important role in showing high tyrosinase inhibitory activity and that derivatives with a 4-substituted resorcinol moiety as the β-phenyl group of the scaffold resulted in the greatest tyrosinase inhibitory activity. To examine whether the 4-substituted resorcinol moiety could impart tyrosinase inhibitory activity in the absence of the α,β-unsaturated carbonyl moiety of the (<i<E</i<)-PUSC scaffold, 10 urolithin derivatives were synthesized. To obtain more candidate samples, the lactone ring in synthesized urolithins was reduced to produce nine reduced urolithins. Compounds <b<1c</b< (IC<sub<50</sub< = 18.09 ± 0.25 μM), 1h (IC<sub<50</sub< = 4.14 ± 0.10 μM), and 2a (IC<sub<50</sub< = 15.69 ± 0.40 μM) had greater mushroom tyrosinase-inhibitory activities than kojic acid (KA) (IC<sub<50</sub< = 48.62 ± 3.38 μM). The SAR results suggest that the 4-substituted resorcinol motif makes an important contribution to tyrosinase inhibition. To investigate whether these compounds bind to human tyrosinase, a human tyrosinase homology model was developed. Docking simulations with mushroom and human tyrosinases showed that 1c, 1h, and 2a bind to the active site of both tyrosinases with higher binding affinities than KA. Pharmacophore analyses showed that two hydroxyl groups of the 4-substituted resorcinol entity act as hydrogen bond donors in both mushroom and human tyrosinases. Kinetic analyses indicated that these compounds were all competitive inhibitors. Compound 2a inhibited cellular tyrosinase activity and melanogenesis in α-MSH plus IBMX-stimulated B16F10 melanoma cells more strongly than KA. These results suggest that 2a is a promising candidate for the treatment of skin pigment disorders, and show the 4-substituted resorcinol entity importantly contributes to tyrosinase inhibition.
abstractGer	We previously reported (<i<E</i<)-β-phenyl-α,β-unsaturated carbonyl scaffold ((<i<E</i<)-PUSC) played an important role in showing high tyrosinase inhibitory activity and that derivatives with a 4-substituted resorcinol moiety as the β-phenyl group of the scaffold resulted in the greatest tyrosinase inhibitory activity. To examine whether the 4-substituted resorcinol moiety could impart tyrosinase inhibitory activity in the absence of the α,β-unsaturated carbonyl moiety of the (<i<E</i<)-PUSC scaffold, 10 urolithin derivatives were synthesized. To obtain more candidate samples, the lactone ring in synthesized urolithins was reduced to produce nine reduced urolithins. Compounds <b<1c</b< (IC<sub<50</sub< = 18.09 ± 0.25 μM), 1h (IC<sub<50</sub< = 4.14 ± 0.10 μM), and 2a (IC<sub<50</sub< = 15.69 ± 0.40 μM) had greater mushroom tyrosinase-inhibitory activities than kojic acid (KA) (IC<sub<50</sub< = 48.62 ± 3.38 μM). The SAR results suggest that the 4-substituted resorcinol motif makes an important contribution to tyrosinase inhibition. To investigate whether these compounds bind to human tyrosinase, a human tyrosinase homology model was developed. Docking simulations with mushroom and human tyrosinases showed that 1c, 1h, and 2a bind to the active site of both tyrosinases with higher binding affinities than KA. Pharmacophore analyses showed that two hydroxyl groups of the 4-substituted resorcinol entity act as hydrogen bond donors in both mushroom and human tyrosinases. Kinetic analyses indicated that these compounds were all competitive inhibitors. Compound 2a inhibited cellular tyrosinase activity and melanogenesis in α-MSH plus IBMX-stimulated B16F10 melanoma cells more strongly than KA. These results suggest that 2a is a promising candidate for the treatment of skin pigment disorders, and show the 4-substituted resorcinol entity importantly contributes to tyrosinase inhibition.
abstract_unstemmed	We previously reported (<i<E</i<)-β-phenyl-α,β-unsaturated carbonyl scaffold ((<i<E</i<)-PUSC) played an important role in showing high tyrosinase inhibitory activity and that derivatives with a 4-substituted resorcinol moiety as the β-phenyl group of the scaffold resulted in the greatest tyrosinase inhibitory activity. To examine whether the 4-substituted resorcinol moiety could impart tyrosinase inhibitory activity in the absence of the α,β-unsaturated carbonyl moiety of the (<i<E</i<)-PUSC scaffold, 10 urolithin derivatives were synthesized. To obtain more candidate samples, the lactone ring in synthesized urolithins was reduced to produce nine reduced urolithins. Compounds <b<1c</b< (IC<sub<50</sub< = 18.09 ± 0.25 μM), 1h (IC<sub<50</sub< = 4.14 ± 0.10 μM), and 2a (IC<sub<50</sub< = 15.69 ± 0.40 μM) had greater mushroom tyrosinase-inhibitory activities than kojic acid (KA) (IC<sub<50</sub< = 48.62 ± 3.38 μM). The SAR results suggest that the 4-substituted resorcinol motif makes an important contribution to tyrosinase inhibition. To investigate whether these compounds bind to human tyrosinase, a human tyrosinase homology model was developed. Docking simulations with mushroom and human tyrosinases showed that 1c, 1h, and 2a bind to the active site of both tyrosinases with higher binding affinities than KA. Pharmacophore analyses showed that two hydroxyl groups of the 4-substituted resorcinol entity act as hydrogen bond donors in both mushroom and human tyrosinases. Kinetic analyses indicated that these compounds were all competitive inhibitors. Compound 2a inhibited cellular tyrosinase activity and melanogenesis in α-MSH plus IBMX-stimulated B16F10 melanoma cells more strongly than KA. These results suggest that 2a is a promising candidate for the treatment of skin pigment disorders, and show the 4-substituted resorcinol entity importantly contributes to tyrosinase inhibition.
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title_short	Urolithin and Reduced Urolithin Derivatives as Potent Inhibitors of Tyrosinase and Melanogenesis: Importance of the 4-Substituted Resorcinol Moiety
url	https://doi.org/10.3390/ijms22115616 https://doaj.org/article/4fc225a1cfae4f10bc6fdb83b82f3b4b https://www.mdpi.com/1422-0067/22/11/5616 https://doaj.org/toc/1661-6596 https://doaj.org/toc/1422-0067
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To examine whether the 4-substituted resorcinol moiety could impart tyrosinase inhibitory activity in the absence of the α,β-unsaturated carbonyl moiety of the (<i<E</i<)-PUSC scaffold, 10 urolithin derivatives were synthesized. To obtain more candidate samples, the lactone ring in synthesized urolithins was reduced to produce nine reduced urolithins. Compounds <b<1c</b< (IC<sub<50</sub< = 18.09 ± 0.25 μM), 1h (IC<sub<50</sub< = 4.14 ± 0.10 μM), and 2a (IC<sub<50</sub< = 15.69 ± 0.40 μM) had greater mushroom tyrosinase-inhibitory activities than kojic acid (KA) (IC<sub<50</sub< = 48.62 ± 3.38 μM). The SAR results suggest that the 4-substituted resorcinol motif makes an important contribution to tyrosinase inhibition. To investigate whether these compounds bind to human tyrosinase, a human tyrosinase homology model was developed. Docking simulations with mushroom and human tyrosinases showed that 1c, 1h, and 2a bind to the active site of both tyrosinases with higher binding affinities than KA. Pharmacophore analyses showed that two hydroxyl groups of the 4-substituted resorcinol entity act as hydrogen bond donors in both mushroom and human tyrosinases. Kinetic analyses indicated that these compounds were all competitive inhibitors. Compound 2a inhibited cellular tyrosinase activity and melanogenesis in α-MSH plus IBMX-stimulated B16F10 melanoma cells more strongly than KA. 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Urolithin and Reduced Urolithin Derivatives as Potent Inhibitors of Tyrosinase and Melanogenesis: Importance of the 4-Substituted Resorcinol Moiety

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