Interactions between trypanocidal drugs and membrane phospholipids. A surface pressure, surface potential and electrophoretic mobility study.

ABSTRACT

Amphiphilic diphenyl methane derivatives exhibiting both antiproliferative and trypanocidal effects were studied with respect to their interactions with phospholipids, in monolayers and bilayers. These compounds, namely (4-benzyl)-phenoxy-2 trimethylammonium ethane iodide (D1), (4-tertiobutyl)-phenoxy-2 morpholinium ethane chloride (D2), and (4-benzyl)-phenoxy-2 morpholinium ethane chloride (D3), were shown to interact with phosphatidylcholine (PC) and phosphatidylserine (PS) in monolayers, as monitored by surface pressure and surface potential measurements. The film expansion of monolayers, on 10 mM NaCl subphase at pH 7.1, was more pronounced in the presence of D2 and D3 in the subphase before spreading of the lipids than with the injection of the drugs underneath a preformed film. Apparent binding constants of 10(4) M-1 were determined for both drugs from monolayer experiments. With D2 in the presence of PS, results of monolayer compressions and electrophoretic mobility measurements indicate binding of the drug to the lipid molecules only when the molecular area was large. D3 was shown to interact with PS, both in monolayers and bilayers, with a drug-to-lipid binding constant of about 2 x 10(4)M-1, as evaluated from electrophoretic mobility measurements on PS liposomes. These results, which indicate binding of these drugs to phospholipids in the order D2 less than D3, correlate with the biological activity of the drugs, and may account for the discrepancy observed between the drug concentrations required for biological and binding activities.