Synthesis of cinnamic amide derivatives and their anti-melanogenic effect in α-MSH-stimulated B16F10 melanoma cells.

Of the three enzymes that regulate the biosynthesis of melanin, tyrosinase and its related proteins TYRP-1 and TYRP-2, tyrosinase is the most important because of its ability to limit the rate of melanin production in melanocytes. For treating skin pigmentation disorders caused by an excess of melanin, the inhibition of tyrosinase enzyme is by far the most established strategy. Cinnamic acid is a safe natural product with an (E)-β-phenyl-α,β-unsaturated carbonyl motif that we have previously shown to play an important role in high tyrosinase inhibition. Since cinnamic acid is relatively hydrophilic, which hinders its absorption on the skin, fifteen less hydrophilic cinnamic amide derivatives (1-15) were designed as safe and more potent tyrosinase inhibitors and were synthesized through a Horner-Wadsworth-Emmons reaction. The use of conc-HCl and acetic acid for debenzylation of the O-benzyl-protected cinnamic amides 40-54 produced the following three results. 1) Cinnamic amides 43, 48, and 53 with a 2,4-dibenzyloxyphenyl group, irrespective of the amine type of the amides, produced complex compounds with high polarity. 2) Cinnamic amides 40-42, 44, 50-52, and 54 with a benzylamino, or diethylamino group produced the desired debenzylated cinnamic amides 1-3, 5, 10-13, and 15. 3) Cinnamic amides 45-47, and 49 with an anilino moiety provided 3,4-dihydroquinolinones 16-19 through intramolecular Michael addition of the anilide group. Notably, the use of BBr

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