Lipophilicity Modulations by Fluorination Correlate with Membrane Partitioning
Lipophilicity Modulations by Fluorination Correlate with Membrane Partitioning
复制标题
氟化的亲脂性调节与膜分配相关
DOI：
10.1002/ange.202301077
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发表时间：
2023
影响因子：
--
通讯作者：
Wang Z
中科院分区：
文献类型：
--
作者：
Wang Z
生物活性化合物通常需要穿过膜到达其作用部位。辛醇-水分配系数（亲脂性，logPOW）已被证明是膜渗透性的一个很好的代表。在现代药物发现中，logPOWER和生物活性同时优化，其中优化是相关策略之一。由于辛醇和（各向异性）膜之间的分子环境存在差异，因此出现了以下问题：不同脂肪族氟基序引入导致的通常细微的logP修饰在多大程度上也会导致伴随的膜渗透性变化。研究发现，对于给定的化合物类别，logPW值与相应的膜摩尔分配系数（logKp）之间具有良好的相关性;该研究通过使用脂质囊泡的新型固态19 F NMR MAS方法实现。我们的研究结果表明，导致辛醇-水分配系数调制的因素同样影响膜渗透性。
Bioactive compounds generally need to cross membranes to arrive at their site of action. The octanol‐water partition coefficient (lipophilicity, logPOW) has proven to be an excellent proxy for membrane permeability. In modern drug discovery, logPOWand bioactivity are optimized simultaneously, for which fluorination is one of the relevant strategies. The question arises as to which extent the often subtle logPmodifications resulting from different aliphatic fluorine‐motif introductions also lead to concomitant membrane permeability changes, given the difference in molecular environment between octanol and (anisotropic) membranes. It was found that for a given compound class, there is excellent correlation between logPOWvalues with the corresponding membrane molar partitioning coefficients (logKp); a study enabled by novel solid‐state19F NMR MAS methodology using lipid vesicles. Our results show that the factors that cause modulation of octanol‐water partition coefficients similarly affect membrane permeability.