Effect of low molecular weight aliphatic alcohols and related compounds on platelet factor 4 subunit association.
Titration of platelet factor 4 (PF4) with increasing concentrations of various low molecular weight aliphatic alcohols disrupts dimer and tetramer quaternary structure while preserving tertiary structural integrity. Normally observed slow subunit exchange (1H NMR time scale) is shifted into the fast chemical exchange regime. The order of effectiveness is butanol > 2-propanol > propanol > ethanol > methanol. Fluorination of ethanol (trifluoroethanol) and 2-propanol (hexafluoro-2-propanol) increases effectiveness by approximately 2 orders of magnitude. Oxidation to 2-propanone or trifluoro-2-propanone produces a less effective compound, suggesting a mechanistic role for the hydroxyl group. Increasing the number of hydroxyls to three, as in glycerol, however, is relatively ineffective in disrupting aggregate states or modifying subunit exchange rates. While 19F NMR studies indicate that these alcohols specifically interact with PF4, binding alone can not explain their mechanism of action. Dimethyl sulfoxide, structurally similar to 2-propanol, disrupts PF4 aggregation by direct binding, but does not shift subunit exchange kinetics into the NMR fast-exchange regime. Although not fully understood, the effectiveness of these compounds appears to be related to the colligative properties of the solution.
Yang
Y
Y
Department of Pharmacology, Jefferson Cancer Institute, Thomas Jefferson University, Philadelphia, Pennsylvania 19107.
Barker
S
S
Chen
M J
MJ
Mayo
K H
KH
D000438:Alcohols / Q000494:pharmacology*; D001792:Blood Platelets / Q000378:metabolism; D005461:Fluorine; D006801:Humans; D006859:Hydrogen; D046911:Macromolecular Substances; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D010974:Platelet Aggregation / Q000187:drug effects; D010978:Platelet Factor 4 / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism*; D013329:Structure-Activity Relationship
D000438:Alcohols; D046911:Macromolecular Substances; D005461:Fluorine; D010978:Platelet Factor 4; D006859:Hydrogen