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Int. J. Mol. Sci. 2018, 19(4), 1144; doi:10.3390/ijms19041144

Structural Requirements of Alkylglyceryl-l-Ascorbic Acid Derivatives for Melanogenesis Inhibitory Activity

1
SEIWA KASEI CO, LTD., 1-2-14, Nunoichicho, Higashi-osaka, Osaka 579-8004, Japan
2
Pharmaceutical Research and Technology Institute, Kindai University, 3-4-1 Kowakae, Higashi-osaka, Osaka 577-8502, Japan
3
Antiaging Center, Kindai University, 3-4-1 Kowakae, Higashi-osaka, Osaka 577-8502, Japan
*
Author to whom correspondence should be addressed.
Received: 23 January 2018 / Revised: 2 April 2018 / Accepted: 6 April 2018 / Published: 10 April 2018
(This article belongs to the Special Issue Melanins and Melanogenesis: From Nature to Applications)
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Abstract

l-Ascorbic acid has multifunctional benefits on skin aesthetics, including inhibition of melanin production, and is widely used in cosmetics. It, however, has low stability and poor skin penetration. We hypothesize that alkylglyceryl-l-ascorbic acid derivatives, highly stable vitamin C–alkylglycerol conjugates, would have similar anti-melanogenic activity with better stability and penetration. We test 28 alkylglyceryl-l-ascorbic acid derivatives (128) on theophylline-stimulated B16 melanoma 4A5 cells to determine if they inhibit melanogenesis and establish any structure–function relationships. Although not the most potent inhibitors, 3-O-(2,3-dihydroxypropyl)-2-O-hexyl-l-ascorbic acid (6, IC50 = 81.4 µM) and 2-O-(2,3-dihydroxypropyl)-3-O-hexyl-l-ascorbic acid (20, IC50 = 117 µM) are deemed the best candidate derivatives based on their inhibitory activities and low toxicities. These derivatives are also found to be more stable than l-ascorbic acid and to have favorable characteristics for skin penetration. The following structural requirements for inhibitory activity of alkylglyceryl-l-ascorbic acid derivatives are also determined: (i) alkylation of glyceryl-l-ascorbic acid is essential for inhibitory activity; (ii) the 3-O-alkyl-derivatives (214) exhibit stronger inhibitory activity than the corresponding 2-O-alkyl-derivatives (1628); and (iii) derivatives with longer alkyl chains have stronger inhibitory activities. Mechanistically, our studies suggest that l-ascorbic acid derivatives exert their effects by suppressing the mRNA expression of tyrosinase and tyrosine-related protein-1. View Full-Text
Keywords: alkylglyceryl-l-ascorbic acid; melanogenesis inhibitor; 3-O-(2,3-dihydroxypropyl)-2-O-hexyl-l-ascorbic acid; 2-O-(2,3-dihydroxypropyl)-3-O-hexyl-l-ascorbic acid; structural requirement; mechanism of action alkylglyceryl-l-ascorbic acid; melanogenesis inhibitor; 3-O-(2,3-dihydroxypropyl)-2-O-hexyl-l-ascorbic acid; 2-O-(2,3-dihydroxypropyl)-3-O-hexyl-l-ascorbic acid; structural requirement; mechanism of action
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Taira, N.; Katsuyama, Y.; Yoshioka, M.; Muraoka, O.; Morikawa, T. Structural Requirements of Alkylglyceryl-l-Ascorbic Acid Derivatives for Melanogenesis Inhibitory Activity. Int. J. Mol. Sci. 2018, 19, 1144.

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