Interaction of statins with phospholipid bilayers studied by solid-state NMR spectroscopy.

Statins are drugs that specifically inhibit the enzyme HMG-CoA reductase and thereby reduce the concentration of low-density lipoprotein cholesterol, which represents a well-established risk factor for the development of atherosclerosis. The results of several clinical trials have shown that there are important intermolecular differences responsible for the broader pharmacologic actions of statins, even beyond HMG-CoA reductase inhibition. According to one hypothesis, the biological effects exerted by these compounds depend on their localization in the cellular membrane. The aim of the current work was to study the interactions of different statins with phospholipid membranes and to investigate their influence on the membrane structure and dynamics using various solid-state NMR techniques. Using 1H NOESY MAS NMR, it was shown that atorvastatin, cerivastatin, fluvastatin, rosuvastatin, and some percentage of pravastatin intercalate the lipid-water interface of POPC membranes to different degrees. Based on cross-relaxation rates, the different average distribution of the individual statins in the bilayer was determined quantitatively. Investigation of the influence of the investigated statins on membrane structure revealed that lovastatin had the least effect on lipid packing and chain order, pravastatin significantly lowered lipid chain order, while the other statins slightly decreased lipid chain order parameters mostly in the middle segments of the phospholipid chains.

Sulfur-Containing Monoterpenoids as Potential Antithrombotic Drugs: Research in the Molecular Mechanism of Coagulation Activity Using Pinanyl Sulfoxide as an Example.

In this article we present the synthesis of enantiomerically pure sulfoxide and study the influence of this compound on hemostasis. Detailed NMR studies and molecular dynamics simulations using sodium dodecyl sulfate (SDS) membrane models indicated that the bicyclic fragment of sulfoxide was embedded into the SDS micelle whereas the -SO(CH2)2OH fragment remained on the surface of the micelle and was in contact with the solvent. We also found that the pro-coagulative activity of sulfoxide was due to its ability to inhibit platelet activation and inhibited the catalytic activity of phospholipid surface which was involved in formation of coagulation clotting factor complexes.

Dynamic NMR study of dinitrophenyl derivatives of seven-membered cyclic ketals of pyridoxine.

Two pyridoxine derivatives containing a dinitrophenyl moiety were investigated by (1)H NMR spectroscopy. Conformational dynamics in solution were studied for each compound using dynamic NMR experiments. It was shown that both compounds studied are involved into two conformational exchange processes. The first process is a transformation of the seven-membered cycle conformation between the enantiomeric P-twist and M-twist forms, and the second is a rotation of the dinitrophenyl fragment of the molecules around the C-O bond. Energy barriers of both conformational transitions were determined.