Effects of Dicyclohexylcarbamimidoyl Oximes on the Properties of Model Lipid Membranes

In this work, we have investigated the mechanisms of action of dicyclohexyl containing derivatives of O-imino-isourea: oximes of (E)-O-(N,N'-dicyclohexylcarbamimidoyl)cyclohexanone oxime (1), (E)-O-(N,N'dicyclohexylcarbamimidoyl)propan-2-one oxime (2) and (1-(E)-[(E)-(N, N'-dicyclohexylcarbamimidoyl)oxy]imino-1-(pyridin-4-yl)ethane (3), on the model lipid membranes, planar lipid bilayers and liposomes. It was found that compounds 1-3 do not affect the electrical properties of uncharged palmitoyloleoylphosphocholine (POPC) membranes, while only derivative 2 at the concentration of 0.2 mM increases the boundary potential of the negatively charged palmitoyloleoylphosphoglycerol (POPG) bilayers by 40 mV. It was shown that the ability to induce the leakage of calcein from POPC liposomes at an equimolar oxime : lipid ratio decreases in the series 2 > 1 approximate to 3 from 25 to 15%. Compound 2 releases up to 50% of the total calcein captured by POPG vesicles, while derivatives 1 and 3 induce the release of no more than 15%. The observed differences in the ability of compound 2 to induce calcein leakage from POPC and POPG liposomes can be explained by the formation of ion-permeable pores in POPG membranes. The higher efficiency of compound 2 in comparison with 1 and 3 is associated with the disordering action of derivative 2 on lipid bilayers, which is confirmed by the data of differential scanning microcalorimetry. The results obtained are important for choosing a matrix for further chemical modification in the development of anticancer drugs based on dicyclohexylcarbamimidoyl.