Interaction between lipid bilayers and a new class of antineoplastic agents derived from arylchloroethylurea: a H-2 solid-state NMR study

We have investigated the interaction between a new class of antineoplastic agents derived from arylchloroethylurea (CEU) and model membrane of dimyris toylphosphatidylcholine by deuterium nuclear magnetic resonance spectroscop y. The results indicate that the drug incorporates in the bilayer and cause s an increase of the lipid acyl chain order, this effect being greater clos e to the interfacial region of the lipid bilayer. The increase in ordering is dependent on the nature (degree of ramification, length of the alkyl cha in, and presence of a sulfur atom) as well as on the position of the R subs tituent and is correlated with the cytotoxicity of the drugs. More specific ally, the more cytotoxic drugs, such as 4-sec-butyl CEU, are those having a bulky ramified substituent and those for which the ordering effect on the lipid bilayer is the smallest. On the other hand, the ordering effect is gr eater and seen all along the lipid acyl chains for the long-chain CEUs, suc h as n-hexadecyl CEU, which have been shown to have very weak cytotoxic act ivity. Finally, the results obtained as a function of the drug concentratio n indicate that the ordering effect is seen for lipid to drug molar ratios as low as 20:1.