作为潜在的结肠直肠癌治疗方法的细胞迁移抑制因子的共价异硫酸盐抑制剂
Lohitha Putha1, Liang K Kok1, Matthias Fellner2
1School of Pharmacy, University of Otago, PO Box 56, Dunedin, 9054, New Zealand.
ChemMedChem
|July 8, 2024
概括
来自十字花蔬菜的新型异硫酸 (ITC) 通过抑制巨细胞迁移抑制因子 (MIF) 相酶活性,显示出其作为抗癌剂的前景. 这些化合物有效地减少了结肠和癌细胞系的生长.
科学领域:
- 生物化学 生物化学
- 免疫学 免疫学 免疫学
- 药用化学 医学化学
背景情况:
- 巨细胞迁移抑制因子 (MIF) 是一种关键的促炎细胞因子,参与免疫反应和炎症.
- MIF的生物活性通过其受体CD74和细胞内信号传递以及其- tautomerase活性进行介导.
- 抑制MIF的顺相酶活性是一种潜在的抗癌策略.
研究的目的:
- 设计,合成和评估异硫酸盐 (ITC) 的结构-活性关系,以抑制MIF tautomerase活性.
- 通过针对MIF,探索ITC作为抗癌剂的潜力.
- 通过结构分析,研究ITC与MIF的约束相互作用.
主要方法:
- 各种替代ITC的合成,包括基,基和基基异硫酸酸盐.
- 生物化学测试以确定ITCs对MIF tautomerase的抑制活性.
- 进行X射线晶体学,以阐明ITC与rhMIF的结合方式.
- 使用NCI60癌细胞系面板对强大的ITC化合物进行抗癌活性查.
主要成果:
- 合成了几种替代ITC,并测试了它们抑制MIF tautomerase活性的能力.
- 晶体结构揭示了ITC和rhMIF之间的关键相互作用,包括键和pi堆叠.
- 化合物9和11显示出对MIF的亚微分子抑制活性.
- 这些化合物在结肠和癌细胞系中表现出组织特异性生长抑制,其中一种化合物表现出强大的剂量依赖性抑制 (结肠的GI50<2.5μM,的GI50<2.2μM).
结论:
- 异硫酸酸盐通过共价修饰有效抑制MIF tautomerase活动.
- 合成的ITC显示出作为抗癌剂的潜力,特别是针对结肠和癌.
- 结构洞察力为进一步优化基于ITC的MIF抑制剂提供了基础.
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