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Cited by 21melanin and skin pigmentationBioactive natural compoundsPhytochemistry and Biological Activities

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Characterization of Phenethyl Cinnamamide Compounds from Hemp Seed and Determination of Their Melanogenesis Inhibitory Activity

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Kim, Jae Kwon, Heo, Hee-Young, Park, SeonJu, Kim, Haheon, Oh, Jeong Ju, Sohn, Eun-Hwa, Jung, Se-Hui, Lee, Kooyeon·2021·ACS Omega
DOI 10.1021/acsomega.1c04727PMC PMC8637947
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Abstract

High Resolution Image Download MS PowerPoint Slide Hyperpigmentation is induced by the overactivation of tyrosinase, which is a rate-limiting enzyme in melanogenesis. The defatted extract of hemp ( Cannabis sativa L.) seed is known to have inhibitory effects on melanogenesis; however, effective compounds in the extract have not been identified yet. In this study, three phenethyl cinnamamides present in hemp seed extract were prepared by purification and chemical synthesis and were assessed for their inhibitory effect on melanogenesis in B16F10 melanoma cells. A comparison of the anti-melanogenesis and anti-tyrosinase activity of hemp seed solvent fractions revealed that the ethyl acetate fraction possessed the greatest potential for suppressing melanogenesis in melanoma cells by decreasing tyrosinase activity. We tentatively identified 26 compounds in the ethyl acetate fraction by comparing spectroscopic data with the literature. Three phenethyl cinnamamides such as N - trans -caffeoyltyramine, N - trans -coumaroyltyramine, and N - trans -feruloyltyramine present abundantly in the ethyl acetate fraction were prepared and their anti-melanogenesis and anti-tyrosinase activities in melanoma cells were evaluated. We found that N - trans -caffeoyltyramine and N - trans -feruloyltyramine inhibited alpha melanocyte stimulating hormone (α-MSH)-induced melanogenesis without cytotoxicity, while N - trans -coumaroyltyramine inhibited melanogenesis with cytotoxicity. IC 50 values of N - trans -caffeoyltyramine, N - trans -feruloyltyramine, and N - trans -coumaroyltyramine for inhibition of α-MSH-mediated tyrosinase activation were 0.8, 20.2, and 6.3 μM, respectively. Overall, N - trans -caffeoyltyramine possessed the strongest anti-melanogenesis activity among the three phenethyl cinnamamides evaluated. The inhibitory effect of N - trans -caffeoyltyramine was verified by determining the melanin content and tyrosinase activity in melanoma after treating the cells with synthetic compounds. Thus, N - trans -caffeoyltyramine isolated from hemp seed extract could be useful in cosmetics as a skin-whitening agent.

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Crossref · 10.1021/acsomega.1c04727

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Figures

Figure 1 Investigation of inhibition potential of hemp seed solvent fractions on melanin synthesis. (A) ABTS radical scavenging activity was determined by measuring the absorbance of reaction mixtures of the ABTS radical and each solvent fraction. (B) Anti-tyrosinase activity of the solvent fractions was determined by L-DOPA oxidation assay. (C) Melanoma cell proliferation was determined by MTT assay. (D) Melanin content in B16F10 cells was determined using a photometric method, as described in the Materials and Methods section. (E) Cellular tyrosinase activity was determined by measuring dopachrome resulting from the enzymatic reaction of cell lysates with L-DOPA (HX: n-Hex, MC: CH2Cl2, EA: EtOAc, Bu: n-BuOH, and Ar: arbutin). (F) Total phenolic content of each solvent fraction was determined using the Folin-Ciocalteu method. Data are expressed as the mean ± SD of three independent experiments (*p < 0.05, **p < 0.01, and ***p < 0.001 vs control group; treated with only α-MSH).
Figure 1 Investigation of inhibition potential of hemp seed solvent fractions on melanin synthesis. (A) ABTS radical scavenging activity was determined by measuring the absorbance of reaction mixtures of the ABTS radical and each solvent fraction. (B) Anti-tyrosinase activity of the solvent fractions was determined by L-DOPA oxidation assay. (C) Melanoma cell proliferation was determined by MTT assay. (D) Melanin content in B16F10 cells was determined using a photometric method, as described in the Materials and Methods section. (E) Cellular tyrosinase activity was determined by measuring dopachrome resulting from the enzymatic reaction of cell lysates with L-DOPA (HX: n-Hex, MC: CH2Cl2, EA: EtOAc, Bu: n-BuOH, and Ar: arbutin). (F) Total phenolic content of each solvent fraction was determined using the Folin-Ciocalteu method. Data are expressed as the mean ± SD of three independent experiments (*p < 0.05, **p < 0.01, and ***p < 0.001 vs control group; treated with only α-MSH).CC BY-NC-ND · PubMed Central
Figure 2 UPLC-QTOF-MS total ion chromatogram of hemp seed EtOAc fractions in the negative ionization mode.
Figure 2 UPLC-QTOF-MS total ion chromatogram of hemp seed EtOAc fractions in the negative ionization mode.CC BY-NC-ND · PubMed Central
Figure 3 1H NMR spectra of (A) N-trans-caffeoyltyramine, (C) N-trans-feruloyltyramine, and (E) N-trans-coumaroyltyramine and 13C NMR spectra of (B) N-trans-caffeoyltyramine, (D) N-trans-feruloyltyramine, and (F) N-trans-coumaroyltyramine.
Figure 3 1H NMR spectra of (A) N-trans-caffeoyltyramine, (C) N-trans-feruloyltyramine, and (E) N-trans-coumaroyltyramine and 13C NMR spectra of (B) N-trans-caffeoyltyramine, (D) N-trans-feruloyltyramine, and (F) N-trans-coumaroyltyramine.CC BY-NC-ND · PubMed Central
Figure 4 Effects of three phenethyl cinnamamide derivatives on cell proliferation and melanogenesis in B16F10 cells. B16F10 cells were treated with 0.1% DMSO as a vehicle or with 50 μM of the three phenethyl cinnamamide compounds for 48 h. (A) Melanoma cell proliferation was determined by MTT assay. (B) Melanin content in B16F10 cells was determined using a photometric method, as described in the experimental section. (C) Cellular tyrosinase activity was determined by measuring dopachrome resulting from the enzymatic reaction of cell lysates with L-DOPA. Data are expressed as the mean ± SD of three independent experiments (*p < 0.05, ***p < 0.001 vs control group; treated with only α-MSH).
Figure 4 Effects of three phenethyl cinnamamide derivatives on cell proliferation and melanogenesis in B16F10 cells. B16F10 cells were treated with 0.1% DMSO as a vehicle or with 50 μM of the three phenethyl cinnamamide compounds for 48 h. (A) Melanoma cell proliferation was determined by MTT assay. (B) Melanin content in B16F10 cells was determined using a photometric method, as described in the experimental section. (C) Cellular tyrosinase activity was determined by measuring dopachrome resulting from the enzymatic reaction of cell lysates with L-DOPA. Data are expressed as the mean ± SD of three independent experiments (*p < 0.05, ***p < 0.001 vs control group; treated with only α-MSH).CC BY-NC-ND · PubMed Central
Figure 5 Molecular docking poses of the three phenethyl cinnamamides at the binding site of tyrosinase. Docked poses of (A) N-trans-caffeoyltyramine, (B) N-trans-feruloyltyramine, and (C) N-trans-coumaroyltyramine at the binding site of tyrosinase (Pdb code: 2Y9X).
Figure 5 Molecular docking poses of the three phenethyl cinnamamides at the binding site of tyrosinase. Docked poses of (A) N-trans-caffeoyltyramine, (B) N-trans-feruloyltyramine, and (C) N-trans-coumaroyltyramine at the binding site of tyrosinase (Pdb code: 2Y9X).CC BY-NC-ND · PubMed Central
Figure 6 Effects of N-trans-caffeoyltyramine on intracellular melanin synthesis. B16F10 cells were treated with 0.1% DMSO as a vehicle or with synthetic N-trans-caffeoyltyramine (2, 5, 10, 20, 50, and 100 μM) for 48 h. (A) Cell viability was determined by MTT assay. (B) Melanin content in B16F10 cells was determined using a photometric method, as described in the experimental section. (C) Cellular tyrosinase activity was determined by measuring dopachrome generated by the enzymatic reaction of cell lysates with L-DOPA. Data are expressed as the mean ± SD of three independent experiments (*p < 0.05, **p < 0.01, and ***p < 0.001).
Figure 6 Effects of N-trans-caffeoyltyramine on intracellular melanin synthesis. B16F10 cells were treated with 0.1% DMSO as a vehicle or with synthetic N-trans-caffeoyltyramine (2, 5, 10, 20, 50, and 100 μM) for 48 h. (A) Cell viability was determined by MTT assay. (B) Melanin content in B16F10 cells was determined using a photometric method, as described in the experimental section. (C) Cellular tyrosinase activity was determined by measuring dopachrome generated by the enzymatic reaction of cell lysates with L-DOPA. Data are expressed as the mean ± SD of three independent experiments (*p < 0.05, **p < 0.01, and ***p < 0.001).CC BY-NC-ND · PubMed Central

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Metadata

Authors
Kim, J. K., Heo, H.-Y., Park, S., Kim, H., Oh, J. J., Sohn, E.-H., Jung, S.-H., & Lee, K.
Affiliations
  • Kangwon National University (KR)
  • Korea Basic Science Institute (KR)
Corresponding author
  • Jung, Se-Hui
  • Lee, Kooyeon
ORCID
Venue
ACS Omega
Publisher
American Chemical Society (ACS)
Published
2021-11-19
Volume
6
Issue
47
Pages
31945-31954
ISSN
2470-1343 (ISSN-L)
DOI
10.1021/acsomega.1c04727
PMC
PMC8637947
OpenAlex
W3216645237
Cited by
20
References
35
Citations by year
2026: 4 · 2025: 6 · 2024: 4 · 2023: 4 · 2022: 2
FWCI
1.31
Type
journal article
Language
en
Open access
Licence
Locations
  • ACS Omega (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Ministry of Land, Infrastructure and Transport (B0070128000223)
  • Presidential Committee for Balanced National Development (B0070128000223)
  • Research and Development of Chuncheon Hemp
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › melanin and skin pigmentation
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Drug Discovery › Bioactive natural compounds
  • Life Sciences › Agricultural and Biological Sciences › Plant Science › Phytochemistry and Biological Activities
Keywords
hemp seeds, Cannabis sativa, melanogenesis inhibition, tyrosinase inhibition, N-trans-feruloyltyramine, alpha-melanocyte-stimulating hormone, B16F10 melanoma cells, skin whitening products, hyperpigmentation, ethyl acetate fraction, natural product isolation

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