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Semisynthesis, an Anti-Inflammatory Effect of Derivatives of 1?-Hydroxy Alantolactone from Inula britannica.

ABSTRACT: 1?-hydroxy alantolactone, a sesquiterpene lactone mainly isolated from Inula genus plants, exhibits potent anti-inflammatory and anticancer activities. In this work, 1?-hydroxy alantolactone was isolated and five derivatives were prepared through different reactions at the C1-OH and C13-methylene motifs. The structure-activity relationships (SAR) of anti-inflammatory effects against NO production in RAW264.7 cells showed that the ?-methylene-?-butyrolactone motif was essential for NO production suppression and that retaining the C1-OH group can remarkably improve this effect. The NF-?B signaling pathway plays a pivotal role in the regulation of NO expression. Moreover, the levels of p65 and p50 phosphorylation were investigated and active compound 1 inhibited phosphorylation of p65 and p50 in TNF-?-induced NF-?B signaling. Further molecular docking suggested that 1 may target the p65 of NF-?B.

SUBMITTER: Chen L

PROVIDER: S-EPMC6150205 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Semisynthesis, an Anti-Inflammatory Effect of Derivatives of 1β-Hydroxy Alantolactone from Inula britannica.

Chen Lin L Zhang Jian-Ping JP Liu Xin X Tang Jiang-Jiang JJ Xiang Ping P Ma Xing-Ming XM

Molecules (Basel, Switzerland) 20171027 11

1β-hydroxy alantolactone, a sesquiterpene lactone mainly isolated from <i>Inula</i> genus plants, exhibits potent anti-inflammatory and anticancer activities. In this work, 1β-hydroxy alantolactone was isolated and five derivatives were prepared through different reactions at the C1-OH and C13-methylene motifs. The structure-activity relationships (SAR) of anti-inflammatory effects against NO production in RAW264.7 cells showed that the α-methylene-γ-butyrolactone motif was essential for NO prod ...[more]

PMID: 29077042

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Project description:A series of diclofenac N-derivatives (2, 4, 6, 8c, 9c, 10a-c) were synthesized in order to test their anti-cancer and anti-inflammatory effects. The anticarcinogen activity has been assayed against three cancer cell lines: HT29, human colon cancer cells; Hep-G2, human hepatic cells; and B16-F10, murine melanoma cells. First, we determined the cytotoxicity of the different compounds, finding that the most effective compound was compound 8c against all cell lines and both compounds 4 and 6 in human Hep-G2 and HT29 cell lines. Compounds 4 and 8c were selected for the percentage of apoptosis determination, cell cycle distribution, and mitochondrial membrane potential measure because these products presented the lowest IC50 values in two of the three cancer cell lines assayed (B16-F10 and HepG2), and were two of the three products with lowest IC50 in HT29 cell line. Moreover, the percentages of apoptosis induction were determined for compounds 4 and 8c, showing that the highest values were between 30 to 60%. Next, the effects of these two compounds were observed on the cellular cycle, resulting in an increase in the cell population in G2/M cell cycle phase after treatment with product 8c, whereas compound 4 increased the cells in phase G0/G1, by possible differentiation process induction. Finally, to determine the possible apoptosis mechanism triggered by these compounds, mitochondrial potential was evaluated, indicating the possible activation of extrinsic apoptotic mechanism. On the other hand, we studied the anti-inflammatory effects of these diclofenac (DCF) derivatives on lipopolysaccharide (LPS) activated RAW 264.7 macrophages-monocytes murine cells by inhibition of nitric oxide (NO) production. As a first step, we determined the cytotoxicity of the synthesized compounds, as well as DCF, against these cells. Then, sub-cytotoxic concentrations were used to determine NO release at different incubation times. The greatest anti-inflammatory effect was observed for products 2, 4, 8c, 10a, 10b, and 9c at 20 µg·mL-1 concentration after 48 h of treatment, with inhibition of produced NO between 60 to 75%, and a concentration that reduces to the 50% the production of NO (IC50 NO) between 2.5 to 25 times lower than that of DCF. In this work, we synthesized and determined for the first time the anti-cancer and anti-inflammatory potential of eight diclofenac N-derivatives. In agreement with the recent evidences suggesting that inflammation may contribute to all states of tumorigenesis, the development of these new derivatives capable of inducing apoptosis and anti-inflammatory effects at very low concentrations represent new effective therapeutic strategies against these diseases.

Dataset Information

Semisynthesis, an Anti-Inflammatory Effect of Derivatives of 1?-Hydroxy Alantolactone from Inula britannica.

Publications

Semisynthesis, an Anti-Inflammatory Effect of Derivatives of 1β-Hydroxy Alantolactone from Inula britannica.

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