Facilitated phospholipid flip-flop across bilayer membranes

This dissertation primarily explores the extraordinary ability of two classes of small organic molecules to alter transmembrane phospholipid distributions by facilitating bidirectional translocation (or flip-flop) without disrupting membrane integrity. The mechanism by which these synthetic scramblases facilitate flip-flop rests on their ability to complex with the phosphate portion of the head-group via hydrogen bonding, effectively masking the head-group polarity, and increasing the probability of the complex diffusing through the hydrophobic membrane core. The first class of synthetic scramblases described are based on the tripodal structure of tris(2-aminoethyl)amine (TREN). A sulfonamide derivative was shown to bind and translocate a phosphatidylcholine probe across surface differentiated vesicle and erythrocyte membranes. TREN-based compounds were also developed with a selectivity towards phosphatidylethanolamine in vesicle systems. A second class of steroid-derived scramblases with appended bis-urea functionalities was found to be superior translocators of phosphatidylcholine across vesicle and biological membranes. Finally, a series of cationic bis-urea scramblases were developed to translocate highly polar, anionic phosphatidylserine via a charge-neutral complex across vesicle and erythrocyte membranes. This produced increased levels of phosphatidylserine on the surface of erythrocytes which facilitated the conversion of prothrombin to thrombin. The synthetic scramblases described in this thesis have potential uses as tools for biological membrane research and as pharmaceutical agents.