203571-40-8Relevant academic research and scientific papers
Synthesis of cinnamic amide derivatives and their anti-melanogenic effect in α-MSH-stimulated B16F10 melanoma cells
Ullah, Sultan,Kang, Dongwan,Lee, Sanggwon,Ikram, Muhammad,Park, Chaeun,Park, Yujin,Yoon, Sik,Chun, Pusoon,Moon, Hyung Ryong
, p. 78 - 92 (2018/10/24)
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 BBr3 as an alternative debenzylating agent for debenzylation of cinnamic amides 45–49 with the anilino moiety provided our desired cinnamic amides 6–10 without inducing the intramolecular Michael addition. Debenzylation of cinnamic amides 43, 48, and 53 with a 2,4-dibenzyloxyphenyl group was also successfully accomplished using BBr3 to give 4, 9, and 14. Among the nine compounds that inhibited mushroom tyrosinase more potently at 25 μM than kojic acid, four cinnamic amides 4, 5, 9, and 14 showed 3-fold greater tyrosinase inhibitory activity than kojic acid. The docking simulation using tyrosinase indicated that these four cinnamic amides (?6.2 to ?7.9 kcal/mol) bind to the active site of tyrosinase with stronger binding affinity than kojic acid (?5.7 kcal/mol). All four cinnamic amides inhibited melanogenesis and tyrosinase activity more potently than kojic acid in α-MSH-stimulated B16F10 melanoma cells in a dose-dependent manner without cytotoxicity. The strong correlation between tyrosinase activity and melanin content suggests that the anti-melanogenic effect of cinnamic amides is due to tyrosinase inhibitory activity. Considering that the cinnamic amides 4, 9, and 14, which exhibited strong inhibition on mushroom tyrosinase and potent anti-melanogenic effect in B16F10 cells, commonly have a 2,4-dihydroxyphenyl substituent, the 2,4-dihydroxyphenyl substituent appears to be essential for high anti-melanogenesis. These results support the potential of these four cinnamic amides as novel and potent tyrosinase inhibitors for use as therapeutic agents with safe skin-lightening efficiency.
Tyrosinase inhibition and anti-melanin generation effect of cinnamamide analogues
Ullah, Sultan,Park, Chaeun,Ikram, Muhammad,Kang, Dongwan,Lee, Sanggwon,Yang, Jungho,Park, Yujin,Yoon, Sik,Chun, Pusoon,Moon, Hyung Ryong
, p. 43 - 55 (2019/03/11)
Abnormal melanogenesis results in excessive production of melanin, leading to pigmentation disorders. As a key and rate-limiting enzyme for melanogenesis, tyrosinase has been considered an important target for developing therapeutic agents of pigment disorders. Despite having an (E)-β-phenyl-α,β-unsaturated carbonyl scaffold, which plays an important role in the potent inhibition of tyrosinase activity, cinnamic acids have not attracted attention as potential tyrosinase inhibitors, due to their low tyrosinase inhibitory activity and relatively high hydrophilicity. Given that cinnamic acids’ structure intrinsically features this (E)-scaffold and following our experience that minute changes in the chemical structure can powerfully affect tyrosinase activity, twenty less hydrophilic cinnamamide derivatives were designed as potential tyrosinase inhibitors and synthesised using a Horner-Wadsworth-Emmons reaction. Four of these cinnmamides (4, 9, 14, and 19) exhibited much stronger mushroom tyrosinase inhibition (over 90% inhibition) at 25 μM compared to kojic acid (20.57% inhibition); crucially, all four have a 2,4-dihydroxy group on the β-phenyl ring of the scaffold. A docking simulation using tyrosinase indicated that the four cinnamamides exceeded the binding affinity of kojic acid, and bound more strongly to the active site of tyrosinase. Based on the strength of their tyrosinase inhibition, these four cinnamamides were further evaluated in B16F10 melanoma cells. All four cinnamamides, without cytotoxicity, exhibited higher tyrosinase inhibitory activity (67.33 – 79.67% inhibition) at 25 μM than kojic acid (38.11% inhibition), with the following increasing inhibitory order: morpholino (9) = cyclopentylamino (14) cyclohexylamino (19) N-methylpiperazino (4) cinnamamides. Analysis of tyrosinase activity and melanin content in B16F10 cells showed that the four cinnamamides dose-dependently inhibited both cellular tyrosinase activity and melanin content and that their inhibitory activity at 25 μM was much better than that of kojic acid. The results of melanin content analysis well matched those of the cellular tyrosinase activity analysis, indicating that tyrosinase inhibition by the four cinnamamides is a major factor in the reduction of melanin production. These results imply that these four cinnamamides with a 2,4-dihydroxyphenyl group can act as excellent anti-melanogenic agents in the treatment of pigmentation disorders.
Design, synthesis and anti-melanogenic effect of cinnamamide derivatives
Ullah, Sultan,Park, Yujin,Ikram, Muhammad,Lee, Sanggwon,Park, Chaeun,Kang, Dongwan,Yang, Jungho,Akter, Jinia,Yoon, Sik,Chun, Pusoon,Moon, Hyung Ryong
, p. 5672 - 5681 (2018/10/24)
Pigmentation disorders are attributed to excessive melanin which can be produced by tyrosinase. Therefore, tyrosinase is supposed to be a vital target for the treatment of disorders associated with overpigmentation. Based on our previous findings that an (E)-β-phenyl-α,β-unsaturated carbonyl scaffold can play a key role in the inhibition of tyrosinase activity, and the fact that cinnamic acid is a safe natural substance with a scaffolded structure, it was speculated that appropriate cinnamic acid derivatives may exhibit potent tyrosinase inhibitory activity. Thus, ten cinnamamides were designed, and synthesized by using a Horner-Emmons olefination as the key step. Cinnamamides 4 (93.72% inhibition), 9 (78.97% inhibition), and 10 (59.09% inhibition) with either a 2,4-dihydroxyphenyl, or 4-hydroxy-3-methoxyphenyl substituent showed much higher mushroom tyrosinase inhibition at 25 μM than kojic acid (18.81% inhibition), used as a positive control. Especially, the two cinnamamides 4 and 9 having a 2,4-dihydroxyphenyl group showed the strongest inhibition. Docking simulation with tyrosinase revealed that these three cinnamamides, 4, 9, and 10, bind to the active site of tyrosinase more strongly than kojic acid. Cell-based experiments carried out using B16F10 murine skin melanoma cells demonstrated that all three cinnamamides effectively inhibited cellular tyrosinase activity and melanin production in the cells without cytotoxicity. There was a close correlation between cellular tyrosinase activity and melanin content, indicating that the inhibitory effect of the three cinnamamides on melanin production is mainly attributed to their capability for cellular tyrosinase inhibition. These results imply that cinnamamides having the (E)-β-phenyl-α,β-unsaturated carbonyl scaffolds are promising candidates for skin-lighting agents.
Total synthesis of 14C-labeled procyanidin B2
Viton, Florian,Landreau, Cyrille,Rustidge, David,Little, Gill,Robert, Fabien,Williamson, Gary,Barron, Denis
scheme or table, p. 371 - 374 (2011/05/05)
During the last decades, many in vitro and in vivo studies have shown the beneficial effects on health of procyanidins. However, their absorption and metabolism is still not fully understood and some aspects are still controversial. In order to have a clearer picture of the metabolism of procyanidins, the use of labelled compounds is essential. In this context, the enantioselective synthesis of 14C-radiolabelled procyanidin B2 was developed in our laboratories. It was achieved in fourteen 'hot' steps, involving as key steps the Sharpless dihydroxylation of an elaborated alkene, a stereoselective intramolecular cyclization to benzylated (+)-catechin and the condensation of two (-)-epicatechin units. 11 mCi of protected procyanidin B2 were obtained from 524 mCi of potassium [14C]cyanide. Copyright
First total synthesis of14C-labeled procyanidin B2 - A milestone toward understanding cocoa polyphenol metabolism
Viton, Florian,Landreau, Cyrille,Rustidge, David,Robert, Fabien,Williamson, Gary,Barron, Denis
supporting information; experimental part, p. 6069 - 6078 (2009/05/27)
The idea that foods consumed for pure pleasure could provide health benefits received much recognition in the recent years. Among these foods, cocoa and dark chocolate are particularly rich in procyanidins, one of the major dietary families of polyphenols. We developed the first asymmetric total synthesis of procyanidin B2 and applied it to the preparation of a regioselectively radiolabeled 14C-analogue, which will be used to strengthen our knowledge on the metabolism of procyanidins. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.
AMIDES AND METHOD FOR PLANT DISEASE CONTROL WITH THE SAME
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Page/Page column 68, (2010/11/08)
N-(α-cyanobenzyl)amide compounds represented by the formula (1): wherein R1 represents a hydrogen atom; a halogen atom; a C1-C6 alkyl group optionally substituted with a halogen atom or the like; or the like, R2 represents a hydrogen atom, a halogen atom, a C1-C6 alkyl group or the like, R3 represents a hydrogen atom or the like, R4 represents a C1-C4 alkyl group, a C3-C4 alkenyl group or the like, R5 represents a C1-C4 alkyl group, a C3-C4 alkenyl group, or the like, R6 represents a hydrogen atom or the like, R7 represents a hydrogen atom or the like, R8 represents a hydrogen atom or the like, R9 represents a hydrogen atom or the like, R10 represents a hydrogen atom or the like, R11 represents a hydrogen atom or the like, and R12 represents a hydrogen atom or the like, have excellent control activities against plant diseases.
Buffer-induced, selective mono-C-alkylation of phloroglucinol: Application to the synthesis of an advanced intermediate of catechin
Gissot, Arnaud,Wagner, Alain,Mioskowski, Charles
, p. 6807 - 6812 (2007/10/03)
A straightforward mono-selective and C-specific alkylation of phloroglucinol with activated alkyl halides is presented. The use of water as solvent limits the amount of over-alkylated by-products. Provided some minor changes in the experimental conditions, hydrophobic cinnamyl halides can also be reacted, thus giving a direct access to advanced intermediates of natural flavonoids.
Study of the green tea polyphenols catechin-3-gallate (CG) and epicatechin-3-gallate (ECG) as proteasome inhibitors
Wan, Sheng Biao,Chen, Di,Dou, Q. Ping,Chan, Tak Hang
, p. 3521 - 3527 (2007/10/03)
The green tea polyphenol catechin-3-gallate (CG) and epicatechin-3-gallate (ECG) were synthesized enantioselectively via a Sharpless hydroxylation reaction followed by a diastereoselective cyclization. Their potencies to inhibit the proteasome activity were measured. The unnatural enantiomers were found to be equally potent to the natural compounds.
A convenient synthesis of the Echinacea-derived immunostimulator and HIV-1 integrase inhibitor (-)-(2R,3R)-chicoric acid
Lamidey, Anne-Marie,Fernon, Lionel,Pouysegu, Laurent,Delattre, Charlotte,Quideau, Stephane,Pardon, Patrick
, p. 2328 - 2334 (2007/10/03)
The Echinacea-derived immunostimulator and HIV-1 integrase inhibitor (-)-chicoric acid (=2,3-bis{[3- (3,4-dihydroxyphenyl)-1-oxoprop-2-enyl]oxy}butanedioic acid; 1a) was conveniently prepared via a silane-promoted Pd-mediated chemoselective hydrogenolysis of its perbenzylated derivative 12a, which was generated from an efficient and reliable carbodiimide-mediated coupling reaction between the caffeic acid dibenzyl ether derivative 7 and commercially available (+)-dibenzyl L-tartrate (9a). The other naturally occurring dextrorotatory chicoric acid (1b) can be similarly prepared.
Synthesis of (±)-Rosmarinic Acid Methylester
Reimann,Maas,Pflug
, p. 995 - 1008 (2007/10/03)
Regioselective cleavage of the glycidic ester 3 by BF3/ether to pyruvic acid ester 4 followed by NaBH4 reduction affords the lactic acid derivative 5a which in turn can be acylated by caffeoyl chloride 8c to yield the O-protected rosmarinic acid ester 9a. Alternatively, 9a can be prepared by acylation of 5a with diethylphosphono acetyl chloride (6c) thus generating the Wadsworth-Emmons reagent 7a which is subsequently reacted with the aldehyde 1a. The analogous reaction using the silyl protected educts 7d and 1b failed to give 9d. Finally, 9a is debenzylated by BCl3 furnishing the title compound 10a in fair total yield.
