Membrane interactions of a new class of anticancer agents derived from arylchloroethylurea: a FTIR spectroscopic study.
We have investigated the interaction between a new class of antineoplastic agents derived from arylchloroethylurea (CEU) and different lipids such as dimyristoylphosphatidylcholine (DMPC) in the absence and presence of 30 mol% of cholesterol, dimyristoylphosphatidylglycerol (DMPG) and a mixture made of 1-palmitoyl-2-oleylphosphatidylcholine (POPC) and DMPC by Fourier transform infrared (FTIR) spectroscopy. The results indicate that the drugs incorporate in the bilayer and cause a decrease of the phase transition temperature and an increase of the conformational disorder of the lipid acyl chains. These effects are dependent on the nature (degree of branching, length of the alkyl chain and presence of a sulfur atom), as well as on the position of the R substituent and are related to the cytotoxicity of the drugs. More specifically, the more cytotoxic drugs, such as 4-sec-butyl CEU, are those having a bulky branched substituent and those for which the disordering effect on the lipid bilayer is the greatest. On the other hand, the disordering effect is small for the long chain CEUs, such as 4-n-hexadecyl CEU, which have been shown to have weak cytotoxic activity.
Saint-Laurent
A
A
Département de chimie, CERSIM, Université Laval, Québec, G1K 7P4, Québec, Canada.
Boudreau
N
N
Larivière
D
D
Legault
J
J
Gaudreault
R C
RC
Auger
M
M
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000145:classification / Q000494:pharmacology; D002462:Cell Membrane / Q000737:chemistry / Q000187:drug effects; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D004134:Dimyristoylphosphatidylcholine / Q000737:chemistry; D066298:In Vitro Techniques; D008051:Lipid Bilayers / Q000737:chemistry; D008567:Membranes, Artificial; D010713:Phosphatidylcholines / Q000737:chemistry; D010715:Phosphatidylglycerols / Q000737:chemistry; D017550:Spectroscopy, Fourier Transform Infrared; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D014508:Urea / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology
D000970:Antineoplastic Agents; D008051:Lipid Bilayers; D008567:Membranes, Artificial; D010713:Phosphatidylcholines; D010715:Phosphatidylglycerols; C007685:ethylurea; D014508:Urea; C002773:dimyristoylphosphatidylglycerol; C028694:1-palmitoyl-2-oleoylphosphatidylcholine; D004134:Dimyristoylphosphatidylcholine