加强一个分子内非经典的键,以获得结合的形状
Norbert Varga1, Martin Smieško2, Xiaohua Jiang1
1Department of Pharmaceutical Sciences, Molecular Pharmacy, University of Basel, Klingelbergstrasse 50, 4056, Basel, Switzerland.
Angewandte Chemie (International ed. in English)
|July 29, 2024
概括
研究人员通过添加电子吸收组,加强了sialyl Lewis^x (sLe^x) 中的一个关键键. 这种修改增强了分子预组织,并改善了sLe^x模仿剂的稳定性和药理动力学特性.
科学领域:
- 药用化学 医学化学
- 碳水化合物化学 碳水化合物化学
- 结构生物学 结构生物学
背景情况:
- Sialyl Lewis ^ x (sLe ^ x) 是一个生理学E-选择因子连接体,对细胞粘附至关重要.
- 它的结合亲和力在很大程度上归因于结合形状中预先组织的有利.
- 对于这种预组织来说,在l-和d-银部分之间形成一种特定的非经典键 (C-H...O) 是至关重要的.
研究的目的:
- 为了研究在sLe^x衍生物中非经典键的强化.
- 增强其生物活性构成中的sLe^x模仿物的预组织.
- 改善sLe^x模仿剂的药理动力学特性,包括酸稳定性.
主要方法:
- 合成包含取电子组的sLe^x衍生物,特别是6,6,6-trifluoro-l-fucose.
- 高场核磁共振 (NMR) 谱学用于分析化学变化.
- 对与E-selectin.selectin.selectin.selectin.selectin.selectin.selectin.selectin.selectin.selectin.selectin.selectin.selectin.selectin.selectin.selectin.selectin.selectin.selectin.selectin.selectin.selectin.selectin.selectin.selectin.selectin.selectin.selectin.selectin.selectin.selectin.selectin.selectin.selectin.selectin.selectin.selectin.selectin.
- 异热定位热量计 (ITC) 用于量化结合热力学.
主要成果:
- 用6,6,6-trifluoro-l-fucose替换l-fucose显著加强了非经典的键,从7.4kJ/mol增加到14.9kJ/mol.
- 这种稳定导致了sLe^x模拟物的生物活性构成中改进的预组织.
- 核磁共振,X射线结晶学和ITC证实了增强的结合和预组织.
- 三甲基组改善了酸稳定性和其他药理动力学特性.
结论:
- 电子吸收组有效地强化了非经典的C-H...O键.
- 增强的键和预组织改善了sLe^x模拟物的亲和力和稳定性.
- 三化sLe^x衍生物由于其增强的稳定性,显示出改善治疗应用的潜力.
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