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Novel Hydrogenated Derivatives of Chemically Modified Curcumin CMC2.24 Are Potent Inhibitors of Melanogenesis in an In Vitro Model: Influence of Degree of Hydrogenation

Chemically modified curcumin, CMC2.24, is a promising therapeutic that has shown efficacy in ameliorating excessive pigmentation in our previous studies. However, its inherent disadvantages of color, stability, solubility, and cytotoxicity to melanocytes and keratinocytes at concentrations > 4 µg...

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Autor principal: Goenka, Shilpi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10304319/
https://www.ncbi.nlm.nih.gov/pubmed/37374155
http://dx.doi.org/10.3390/life13061373
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author Goenka, Shilpi
author_facet Goenka, Shilpi
author_sort Goenka, Shilpi
collection PubMed
description Chemically modified curcumin, CMC2.24, is a promising therapeutic that has shown efficacy in ameliorating excessive pigmentation in our previous studies. However, its inherent disadvantages of color, stability, solubility, and cytotoxicity to melanocytes and keratinocytes at concentrations > 4 µg/mL posed challenges in its use in cosmetic formulations. To overcome these limitations, chemical reduction by hydrogenation of CMC2.24 (compound 1) was developed to yield products at different time points of hydrogenation (1 h, 2 h, 4 h, and 24 h) referred to as partially (2, 3, 4) or fully hydrogenated (5) products, and the effects of the degree of hydrogenation on melanogenesis in vitro were explored. Compound 1 and products 2–5 were evaluated using mushroom tyrosinase activity assays with two substrates (L-tyrosine and L-DOPA), then cellular assays using B16F10 mouse melanoma cells, MNT-1 human melanoma cells, and physiological normal human melanocytes (HEMn-DP cells). The cytotoxicity, melanin contents, cellular tyrosinase activities, and cellular oxidative stress were evaluated. Moreover, the recovery of melanin contents in HEMn-DP cells was also studied. Our results provide novel insights into the role of the degree of hydrogenation of compound 1 on the biological effects of melanogenesis, which were dependent on cell type. To the best of our knowledge, this is the first study to show that in HEMn-DP cells, the anti-melanogenic efficacy of the yellow-colored CMC2.24 is retained as early as 1 h after its hydrogenation; this efficacy is enhanced with longer durations of hydrogenation, with a robust efficacy achieved for the 24 h hydrogenated product 5 at the lowest concentration of 4 µg/mL. A similar potency could be achieved for product 4 at higher concentrations, although interestingly, both differ only by a minor amount of dihydro-CMC2.24. Our results indicate promise for using products 4 & 5 as a skin-lightener in cosmetic formulations with the advantages of lack of color combined with a potency much greater than that of the parent compound 1 at lower concentrations and reversibility of the effects on melanocytes. This, along with the easy synthesis and scale-up of the hydrogenation method for CMC2.24 and the documented higher solubility, stability, and bioavailability of tetrahydrocurcumin, provides further impetus to incorporating these derivatives in cosmetic formulations. The results of this study can help to extend the therapeutic window of the lead compound CMC2.24 by providing options for selecting partially or fully hydrogenated derivatives for cosmetic applications where a trade-off between color and efficacy is needed. Thus, the degree of hydrogenation can be tuned for desired biological effects. Further studies are warranted to evaluate the efficacy of products 4 & 5 at suppressing pigmentation in 3D skin-tissue equivalents and in vivo models.
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spelling pubmed-103043192023-06-29 Novel Hydrogenated Derivatives of Chemically Modified Curcumin CMC2.24 Are Potent Inhibitors of Melanogenesis in an In Vitro Model: Influence of Degree of Hydrogenation Goenka, Shilpi Life (Basel) Article Chemically modified curcumin, CMC2.24, is a promising therapeutic that has shown efficacy in ameliorating excessive pigmentation in our previous studies. However, its inherent disadvantages of color, stability, solubility, and cytotoxicity to melanocytes and keratinocytes at concentrations > 4 µg/mL posed challenges in its use in cosmetic formulations. To overcome these limitations, chemical reduction by hydrogenation of CMC2.24 (compound 1) was developed to yield products at different time points of hydrogenation (1 h, 2 h, 4 h, and 24 h) referred to as partially (2, 3, 4) or fully hydrogenated (5) products, and the effects of the degree of hydrogenation on melanogenesis in vitro were explored. Compound 1 and products 2–5 were evaluated using mushroom tyrosinase activity assays with two substrates (L-tyrosine and L-DOPA), then cellular assays using B16F10 mouse melanoma cells, MNT-1 human melanoma cells, and physiological normal human melanocytes (HEMn-DP cells). The cytotoxicity, melanin contents, cellular tyrosinase activities, and cellular oxidative stress were evaluated. Moreover, the recovery of melanin contents in HEMn-DP cells was also studied. Our results provide novel insights into the role of the degree of hydrogenation of compound 1 on the biological effects of melanogenesis, which were dependent on cell type. To the best of our knowledge, this is the first study to show that in HEMn-DP cells, the anti-melanogenic efficacy of the yellow-colored CMC2.24 is retained as early as 1 h after its hydrogenation; this efficacy is enhanced with longer durations of hydrogenation, with a robust efficacy achieved for the 24 h hydrogenated product 5 at the lowest concentration of 4 µg/mL. A similar potency could be achieved for product 4 at higher concentrations, although interestingly, both differ only by a minor amount of dihydro-CMC2.24. Our results indicate promise for using products 4 & 5 as a skin-lightener in cosmetic formulations with the advantages of lack of color combined with a potency much greater than that of the parent compound 1 at lower concentrations and reversibility of the effects on melanocytes. This, along with the easy synthesis and scale-up of the hydrogenation method for CMC2.24 and the documented higher solubility, stability, and bioavailability of tetrahydrocurcumin, provides further impetus to incorporating these derivatives in cosmetic formulations. The results of this study can help to extend the therapeutic window of the lead compound CMC2.24 by providing options for selecting partially or fully hydrogenated derivatives for cosmetic applications where a trade-off between color and efficacy is needed. Thus, the degree of hydrogenation can be tuned for desired biological effects. Further studies are warranted to evaluate the efficacy of products 4 & 5 at suppressing pigmentation in 3D skin-tissue equivalents and in vivo models. MDPI 2023-06-12 /pmc/articles/PMC10304319/ /pubmed/37374155 http://dx.doi.org/10.3390/life13061373 Text en © 2023 by the author. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Goenka, Shilpi
Novel Hydrogenated Derivatives of Chemically Modified Curcumin CMC2.24 Are Potent Inhibitors of Melanogenesis in an In Vitro Model: Influence of Degree of Hydrogenation
title Novel Hydrogenated Derivatives of Chemically Modified Curcumin CMC2.24 Are Potent Inhibitors of Melanogenesis in an In Vitro Model: Influence of Degree of Hydrogenation
title_full Novel Hydrogenated Derivatives of Chemically Modified Curcumin CMC2.24 Are Potent Inhibitors of Melanogenesis in an In Vitro Model: Influence of Degree of Hydrogenation
title_fullStr Novel Hydrogenated Derivatives of Chemically Modified Curcumin CMC2.24 Are Potent Inhibitors of Melanogenesis in an In Vitro Model: Influence of Degree of Hydrogenation
title_full_unstemmed Novel Hydrogenated Derivatives of Chemically Modified Curcumin CMC2.24 Are Potent Inhibitors of Melanogenesis in an In Vitro Model: Influence of Degree of Hydrogenation
title_short Novel Hydrogenated Derivatives of Chemically Modified Curcumin CMC2.24 Are Potent Inhibitors of Melanogenesis in an In Vitro Model: Influence of Degree of Hydrogenation
title_sort novel hydrogenated derivatives of chemically modified curcumin cmc2.24 are potent inhibitors of melanogenesis in an in vitro model: influence of degree of hydrogenation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10304319/
https://www.ncbi.nlm.nih.gov/pubmed/37374155
http://dx.doi.org/10.3390/life13061373
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