The conformational properties of the antineoplastic ether lipid 1-thiohexadecyl-2-O-methyl-S-glycero-3-phosphocholine.
Thio analogs of platelet activating factor (PAF) are of great interest because they exhibit antineoplastic properties both in vitro and in vivo. In contrast to most known anticancer agents, these lipids appear not to act through the synthesis and function of DNA and, therefore, offer a new avenue of approaching cancer chemotherapy. We have examined the conformational properties of 1-thiohexadecyl-2-O-methyl-S-glycero-3-phosphocholine (ET-S-16-OCH3) in organic solvents and in micelles. The conformational analysis was based on a combination of 1D, 2D NMR spectroscopy and molecular graphics. 1H and 13C spin lattice relaxation time (T1) experiments were also performed to study the dynamic properties of this molecule. The picture emerging from these studies is as follows. The alkyl chain of ET-S-16-OCH3 is the most mobile part of the molecule both in CDCl3/CD3OD and in micelles and exists as a mixture of interconverting conformers including an extended all trans and several low energy conformers with one or more gauche segments. This creates a twisting of the chain and facilitates a spatial communication between the alkyl chain and the glycerol backbone as well as between the alkyl chain and the headgroup. The methylene groups of the thioglycerol backbone and the headgroup are the least mobile while the methine group of the thioglycerol backbone appears to have an intermediate mobility. The conformation of the thioether lipid in the two media may be of relevance during its interaction with its site of action, the cellular membrane. Such a conformation may also play an important role in determining the selectivity of this interaction with different cell membranes.
Mavromoustakos
T
T
National Hellenic Research Foundation, Institute of Organic and Pharmaceutical Chemistry, Athens, Greece.
Theodoropoulou
E
E
Yang
D P
DP
Lin
S Y
SY
Koufaki
M
M
Makriyannis
A
A
D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D005990:Glycerol / Q000031:analogs & derivatives; D009682:Magnetic Resonance Spectroscopy; D008823:Micelles; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D010742:Phospholipid Ethers / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D010767:Phosphorylcholine / Q000031:analogs & derivatives*; D010972:Platelet Activating Factor / Q000031:analogs & derivatives
D000970:Antineoplastic Agents; D008823:Micelles; D010742:Phospholipid Ethers; D010972:Platelet Activating Factor; D010767:Phosphorylcholine; C009465:thioglycerol; D005990:Glycerol