Synthesis and bio-evaluation of human macrophage migration inhibitory factor inhibitor to develop anti-inflammatory agent
Synthesis and bio-evaluation of human macrophage migration inhibitory factor inhibitor to develop anti-inflammatory agent
复制标题
DOI：
10.1016/j.bmc.2011.10.056
复制
发表时间：
2011-12-15
影响因子：
3.5
通讯作者：
Bandyopadhyay, Uday
中科院分区：
文献类型：
--
作者：
Alam, Athar;Pal, Chinmay;Bandyopadhyay, Uday
巨噬细胞迁移抑制因子（MIF）是一种促炎细胞因子，参与一系列炎症性疾病的发展，包括类风湿关节炎、炎症性肠病、牛皮癣、多发性硬化症和败血症。mif抑制剂的合成是开发新型抗炎药治疗多种炎症性疾病的基本途径。在这项工作中，我们合成并评价了一系列含有异恶唑啉骨架的小分子的mif抑制活性。通过对接研究确定了该抑制剂与人MIF （huMIF）的结合方式。合成的分子抑制了huMIF的互变酶活性。最有效的抑制剂4-（（3-（4-羟基-3-甲氧基苯基）- 4,5 -二氢异恶唑-5-基）甲氧基）苯甲醛（4b）在细胞模型（RAW 264.7细胞）中对humif诱导的炎症进行了抗炎活性评估。化合物4b显著抑制了humif介导的NF-kappa B向细胞核的易位、诱导型一氧化氮合酶的上调以及RAW 264.7细胞中作为炎症标志物的一氧化氮的产生。从细胞活力测定中可以看出，化合物4b没有细胞毒性。因此，化合物4b具有成为新型抗炎剂的潜力。(C) 2011 Elsevier Ltd.版权所有。
Macrophage migration inhibitory factor (MIF), a pro-inflammatory cytokine, is involved in the development of an array of inflammatory disorders including rheumatoid arthritis, inflammatory bowel disease, psoriasis, multiple sclerosis and sepsis. The synthesis of MIF-inhibitor is a rationale approach to develop novel anti-inflammatory agent to treat multitude of inflammatory diseases. In this work, we have synthesized and evaluated MIF-inhibitory activity of a series of small molecules containing isoxazoline skeleton. Mode of binding of this inhibitor to human MIF (huMIF) was determined by docking studies. The synthesized molecules inhibit tautomerase activity of huMIF. The anti-inflammatory activity of the most active inhibitor, 4-((3-(4-hydroxy-3-methoxyphenyl)-4, 5-dihydroisoxazol-5-yl) methoxy) benzaldehyde (4b) was evaluated against huMIF-induced inflammation in a cellular model (RAW 264.7 cell). Compound 4b significantly inhibits huMIF-mediated NF-kappa B translocation to the nucleus, up-regulation of inducible nitric oxide synthase and nitric oxide production in RAW 264.7 cell which are the markers for inflammation. The compound 4b is not cytotoxic as evident from cell viability assay. Hence, the compound 4b has potential to be a novel anti-inflammatory agent. (C) 2011 Elsevier Ltd. All rights reserved.