- Discovery of a New Inhibitor of Myeloid Differentiation 2 from Cinnamamide Derivatives with Anti-Inflammatory Activity in Sepsis and Acute Lung Injury
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Acute inflammatory diseases, including acute lung injury and sepsis, remain the most common life-threatening illness in intensive care units worldwide. Cinnamamide has been incorporated in several synthetic compounds with therapeutic potentials including anti-inflammatory properties. However, the possible mechanism and direct molecular target of cinnamamides for their anti-inflammatory effects were rarely investigated. In this study, we synthesized a series of cinnamamides and evaluated their anti-inflammatory activities. The most active compound, 2i, was found to block LPS-induced MD2/TLR4 pro-inflammatory signaling activation in vitro and to attenuate LPS-caused sepsis and acute lung injury in vivo. Mechanistically, we demonstrated that 2i exerts its anti-inflammatory effects by directly targeting and binding MD2 in Arg90 and Tyr102 residues and inhibiting MD2/TLR4 complex formation. Taken together, this work presents a novel MD2 inhibitor, 2i, which has the potential to be developed as a candidate for the treatment of sepsis, and provides a new lead structure for the development of anti-inflammatory agents targeting MD2.
- Chen, Gaozhi,Zhang, Yali,Liu, Xing,Fang, Qilu,Wang, Zhe,Fu, Lili,Liu, Zhiguo,Wang, Yi,Zhao, Yunjie,Li, Xiaokun,Liang, Guang
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- Tyrosinase inhibition and anti-melanin generation effect of cinnamamide analogues
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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.
- Ullah, Sultan,Park, Chaeun,Ikram, Muhammad,Kang, Dongwan,Lee, Sanggwon,Yang, Jungho,Park, Yujin,Yoon, Sik,Chun, Pusoon,Moon, Hyung Ryong
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- ANTI CANCER USE OF CAFFEIC ACID AND DERIVATIVES
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The present invention relates to the use of caffeic acid or a derivative thereof represented by the following general formula (1 ) wherein X is O, NH, or heterocyclyl; R may be present or absent and if present, is H, alkyl, aryl, or heterocyclyl; in all its stereoisomeric and tautomeric forms, and mixtures thereof in all ratios, and a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable polymorph or a prodrug, in the treatment of chronic myeloid leukemia (CML) which is resistant to treatment with Gleevec. The invention also relates to a method for reducing the proliferation of cells that are resistant to Gleevec by contacting the cells with a compound of general formula (1 ). The present invention also relates to pharmaceutical compositions (for the manufacture of the medicament) including caffeic acid or a derivative or a salt thereof represented by the general formula (1 ) for the treatment of chronic myeloid leukemia (CML) that is resistant to treatment with Gleevec, or for reducing the proliferation of cells that are resistant to Gleevec. The present invention further relates to a method of treatment of chronic myeloid leukemia (CML) that is resistant to treatment with Gleevec.
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Page/Page column 26
(2008/06/13)
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- Synthesis and evaluation of caffeic acid amides as antioxidants
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A series of amides of caffeic acid has been synthesised and their antioxidant properties evaluated as lipid peroxidation inhibitors. Anilides of caffeic acid were found to be very efficient antioxidants with IC50's of 0.3 μM.
- Rajan, Padinchare,Vedernikova, Irina,Cos, Paul,Vanden Berghe, Dirk,Augustyns, Koen,Haemers, Achiel
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p. 215 - 217
(2007/10/03)
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