Abstract

The molecular mechanisms of action of dicyclohexyl-containing derivatives of O-iminoisourea, (E)-O-(N,N'-dicyclohexylcarbamimidoyl) oxime of cyclohexanone (1), (E)-O-(N,N'-dicyclohexylcarbodimide) oxime of propane-2-one (2) and (1-(E)-[(E)-(N,N'- dicyclohexylcarbamimidoyl)oxy]imino-1-(pyridine-4-yl)ethane (3), on model lipid membranes, unilamellar vesicles and planar lipid bilayers, were investigated. It was found that all the tested compounds did not affect the electrical properties of uncharged membranes of 1-palmitoyl-2-oleyl-sn-glycerol-3-phosphocholine (POPC), while oxime 2 at a concentration more than 0.2 mM increased the boundary potential of negatively charged membranes of 1-palmitoyl-2-oleyl-sn-glycerol-3-phospho-1'-rac-glycerol (POPG) by 40 mV. It was shown that the ability of the oximes to induce leakage of a fluorescent probe calcein from POPC liposomes at the equimolar oxime/lipid ratio decreased in the order 2 > 1 ≈ 3 from 25 to 15%. Compound 2 released up to 50% of the total calcein captured by POPG vesicles, while compounds 1 and 3 released no more than 15% of the probe. The observed differences in the ability of compound 2 to cause leakage of the probe from POPC and POPG liposomes can be explained by the formation of ion permeable pores in the POPG membranes. A higher efficiency of compound 2 compared to compounds 1 and 3 was due to the disordering effect of compound 2 on the lipid bilayers, which was confirmed by the data of differential scanning microcalorimetry. The results obtained are important in choosing a matrix for further chemical modification in the development of anticancer drugs based on dicyclohexylcarbamimidoyl.

中文翻译：

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二环己基氨基甲酰肟对模型脂质膜性质的影响

摘要

O-亚氨基异脲、( E )-O-(N,N'-二环己基氨基甲酰)肟环己酮( 1 )、( E )-O-(N,N'-二环己基碳二亚胺)的含二环己基衍生物的分子作用机制丙烷-2-酮 ( 2 ) 和 (1-( E )-[( E )-(N,N'-二环己基氨基甲酰) 氧基]亚氨基-1-(吡啶-4-基)乙烷 ( 3 )的肟，在对模型脂质膜、单层囊泡和平面脂质双层进行了研究。发现所有测试的化合物都不会影响 1-棕榈酰-2-油基-sn-甘油-3-磷酸胆碱 (POPC)不带电膜的电特性, 而肟2浓度超过 0.2 mM 时，1-palmitoyl-2-oleyl- sn -glycerol -3-phospho-1'-rac-glycerol (POPG)带负电荷膜的边界电位增加了40 mV。结果表明，在等摩尔肟/脂质比下，肟诱导荧光探针钙黄绿素从 POPC 脂质体泄漏的能力以2 > 1 ≈ 3的顺序从 25%降低到 15%。化合物2释放了多达 50% 的被 POPG 囊泡捕获的钙黄绿素，而化合物1和3释放的探针不超过 15%。观察到的化合物2的能力差异导致探针从 POPC 和 POPG 脂质体泄漏的原因可以通过 POPG 膜中离子渗透孔的形成来解释。与化合物1和3相比，化合物2 的效率更高是由于化合物2对脂质双层的无序作用，差示扫描微量热法的数据证实了这一点。获得的结果对于选择用于进一步化学修饰的基质在基于二环己基氨基甲酰氨基的抗癌药物的开发中具有重要意义。