The Effects of Dicyclohexylcarbamimidoyl Oximes on the Properties of Model Lipid Membranes

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.