Thermodynamics of the partitioning of 7-chloro-4-(4'-methoxy)anilinoquinoline and its cyclized analog in octanol-buffer and liposome systems

Abstract

The thermodynamics of the partitioning of 7-chloro-4-(4'-methoxy)anilinoquinoline (I) and its cyclized analogue, 3-chloro-8-methoxy-11H-indolo[3,2-c]quinoline (II) have been determined in octanol-buffer and liposome systems. Under the conditions of partitioning, the protonated forms of compounds I and II were predominant, but partitioning involved only the non-ionized species. The van't Hoff plots for both compounds were linear in the octanol-buffer system from 11° to 35°C. The log P of compound I increased with temperature, and partitioning was entropically controlled. In contrast, the partitioning of compound II decreased with temperature and was enthalpically driven. The Van't Hoff plots of compounds I and II in the dimyristoyl-L-α-phosphatidylcholine (DMPC) liposome-buffer were biphasic. A decrease in log P was observed from 13°C to approximately the T(c) of the phospholipid, followed by a subsequent increase in log P as temperature increased to about 32°C. In the case of compound I, partitioning was entropically controlled at temperatures below and above T(c). In contrast, the partitioning of compound II was enthalpically controlled below T(c) but entropically driven above T(c). The thermodynamics of the partitioning of compounds I and II in octanol and gel phase phospholipid (below T(c)) are similar. This may be attributed to their conformational differences. The planarity and rigidity of compound II allows it to interact well with the ordered matrices of octanol and phospholipid with an expected loss of enthalpy. In contrast, the twisted conformation of compound I would have disrupted the ordered matrices of the octanol and phospholipid phases, resulting in an entropy gain upon partitioning. This study shows that the molecular shape and conformational characteristics of solute molecules are important determinants in the partitioning process.