Abstract：
Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine with roles in innate and adaptive human immune responses, as well as inflammation. MIF exerts its biological activity by binding to the cell surface receptor CD74 as well as intracellular signalling proteins. MIF also possesses keto-enol tautomerase activity. Inhibition of the tautomerase activity has been associated with loss of biological activity of MIF and a potential anticancer target. Isothiocyanates (ITCs) are a class of compounds present in cruciferous vegetables that inhibit the MIF tautomerase activity via covalent modification of the N-terminal proline. A range of substituted ITCs featuring benzyl, phenethyl and phenyl propyl isothiocyanates were designed, synthesised and tested to determine any structure activity relationship for inhibiting MIF. Crystal structures of covalent compounds 8 and 9 in complex with rhMIF revealed key hydrogen bonding and edge-to-face π stacking interactions. Compound 9 and 11 with sub micromolar activity were tested in the NCI60 cancer cell lines panel. Both compounds showed tissue-specific reduced growth in colon and renal cancer cell lines, while one of these showed potent, dose-dependent inhibition of growth against all seven colon cancer cell lines (GI50 < 2.5 µM) and all eight renal cancer cell lines (GI50 < 2.2 µM).
摘要：
巨噬细胞迁移抑制因子（MIF）是一种在先天性和适应性人类免疫反应中发挥作用的促炎细胞因子，以及炎症。MIF通过与细胞表面受体CD74以及细胞内信号蛋白结合而发挥其生物活性。MIF还具有酮-烯醇互变异构酶活性。互变异构酶活性的抑制与MIF和潜在抗癌靶标的生物活性的丧失有关。异硫氰酸酯（ITC）是十字花科蔬菜中存在的一类化合物，可通过共价修饰N端脯氨酸来抑制MIF互变异构酶的活性。一系列具有苄基的取代ITCs，设计了苯乙基和苯基丙基异硫氰酸酯，合成并测试以确定抑制MIF的任何结构活性关系。与rhMIF复合的共价化合物8和9的晶体结构揭示了关键的氢键和边到面π堆积相互作用。在NCI60癌细胞系组中测试具有亚微摩尔活性的化合物9和11。两种化合物在结肠癌和肾癌细胞系中都显示出组织特异性降低的生长，虽然其中一个显示出了效力，对所有7种结肠癌细胞系（GI50<2.5µM）和所有8种肾癌细胞系（GI50<2.2µM）的生长的剂量依赖性抑制。
