(2E,5E)-2,5-Bis(3-hydroxy-4-methoxybenzylidene) cyclopentanone Exerts Anti-Melanogenesis and Anti-Wrinkle Activities in B16F10 Melanoma and Hs27 Fibroblast Cells

Abstract

Ultraviolet (UV) radiation exposure is the primary cause of extrinsic skin aging, which results in skin hyperpigmentation and wrinkling. In this study, we investigated the whitening effect of (2E,5E)-2,5-bis(3-hydroxy-4-methoxybenzylidene)cyclopentanone (BHCP) on B16F10 melanoma and its anti-wrinkle activity on Hs27 fibroblasts cells. BHCP was found to potently inhibit tyrosinase, with 50% inhibition concentration (IC50) values of 1.10 µM and 8.18 µM for monophenolase (l-tyrosine) and diphenolase (l-DOPA), and the enzyme kinetics study revealed that BHCP is a competitive-type tyrosinase inhibitor. Furthermore, BHCP significantly inhibited melanin content and cellular tyrosinase activity, and downregulated the levels of microphthalmia-associated transcription factor (MITF), phosphorylated levels of cAMP response element-binding (CREB) protein, and tyrosinase in α-melanocyte stimulating hormone (α-MSH)-induced B16F10 melanoma cells. Moreover, BHCP inhibited the phosphorylation of p65 and expression of matrix metalloproteinases (MMP-1, MMP-9, MMP-12, and MMP-13) in Hs27 fibroblasts stimulated with UV radiation. Therefore, our results demonstrate that BHCP may be a good candidate for the development of therapeutic agents for diseases associated with hyperpigmentation and wrinkling.

Natural and Bioinspired Phenolic Compounds as Tyrosinase Inhibitors for the Treatment of Skin Hyperpigmentation: Recent Advances

“…Apart from the direct inhibition of tyrosinase activity, the anti-melanogenic activity of resorcinol in B16F10 cells has been attributed to the inhibition of cAMP signaling and activation of p38 MAPK [179]. The same applies e.g., to moracin J [181], 4,5-dicaffeoylquinic acid [183], chrysin [187], casuarictin [178], and synthetic compounds [135,136,153,197], which have been reported to both inhibit intracellular tyrosinase activity and regulate melanogenesis-related protein expression.…”

“…In the last years several studies have been directed to the development of novel tyrosinase inhibitors inspired by natural scaffolds, which should overcome stability, efficacy, and isolation yield issues. One of the main exploited scaffolds is hydroxycinnamic acid: indeed several hydroxycinnamic acid analogues have been synthesized through the most disparate approaches [123][124][125][126][127][128][129][130][131][132][133][134][135][136][137][138][139][140][141], leading in some cases to very potent mushroom tyrosinase inhibitors (Figure 17), such as 2,4-dihydroxycinnamides (IC 50 = 0.0112-0.16 µM) [132,133]. A thiophenyl derivative of 2,4-dihydroxycinnamic acid has also exhibited a very low IC 50 value (0.013 µM) against the monophenolase activity of the enzyme [134].…”

“…A thiophenyl derivative of 2,4-dihydroxycinnamic acid has also exhibited a very low IC50 value (0.013 μM) against the monophenolase activity of the enzyme [134]. An IC50 value of 1.10 μM for the monophenolase activity of mushroom tyrosinase has been instead calculated for a cyclopentanone compound related to 3-hydroxy-4-methoxycinnamic acid [135]. Quite low IC50 values have been reported also for dihydrolipoic acid conjugates of caffeic acid and its methylester [136,137], as well as for thiochromanone compounds [138], diamides [139], or esters [140,141] related to p-coumaric acid.…”

“…In the last five years, several natural and synthetic phenolic compounds have been described also as inhibitors of tyrosinase from animal and human sources. Most of these studies used B16 murine melanoma cell lines as a model [52,55,75,85,95,96,99,114,122,123,[127][128][129][132][133][134][135]138,139,151,153,155,163,, although some papers using zebrafish as an in vivo whole animal model have also been published [55,116,206]. As to the human sources, data on inhibition of human recombinant or purified tyrosinase [9,207], human melanoma cells [130,136], normal human melanocytes [208][209][210][211], or human skin models consisting of reconstructed three-dimensional human epidermis [212][213][214][215] have been published (Figure 21).…”

A Potent Tyrosinase Inhibitor, (E)-3-(2,4-Dihydroxyphenyl)-1-(thiophen-2-yl)prop-2-en-1-one, with Anti-Melanogenesis Properties in α-MSH and IBMX-Induced B16F10 Melanoma Cells

“…Moreover, biological activities of chalcone-like derivatives are significantly determined based on the position and numbers of functional groups attached to benzene ring. In spite of diverse structural moiety of natural tyrosinase inhibitors and available methodology to reasonably design effective synthetic derivatives, many synthetic tyrosinase inhibitors with novel skeletons have been studied [ 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 ]. Especially, Hwang et al [ 27 ] reported the effects of heterocyclic chalcone derivatives containing heterocycles, such as thiophene or furan ring as an isostere of benzene ring on free radical scavenging activity.…”