Role of desolvation energy in the nonfacilitated membrane permeability of dideoxyribose analogs of thymidine.

The ability of thymidine and four dideoxyribose analogs of thymidine to cross phase barriers, such as those encountered at the exo and endo faces of a membrane, has been studied in a two-phase water/chloroform system. The rate constants for entering, ka, and leaving, kb, the organic phase and the partition coefficient, Kp (ka/kb), were determined for each compound. The values of Kp were found to be proportional to the values of the rate constants for nonfacilitated diffusion, c, into human erythrocytes reported in the preceding paper [Mol. Pharmacol. 41:950-956 (1992)]. This linear relationship suggests that, in accord with the solubility-diffusion model of nonmediated membrane permeation, movement of the thymidine analogs across the potential energy barriers at the membrane interfaces is fast, relative to the rate of transbilayer diffusion. Because the compounds have similar molecular volumes and would, therefore, have similar rates of transbilayer diffusion, the differences in c reflect the differences in the distribution of the compounds across the interfaces, i.e., the Kp values. The magnitudes of the Kp values are dependent not only on the pi value of each substituent on the dideoxyribose ring but also on the position of the substituent. Analogs having a hydroxyl group in the 5'-position have a higher Kp and a higher c than the corresponding analogs with the hydroxyl group in the 3'-position. This increased lipophilicity is attributed to a decrease in desolvation energy, resulting from the ability of the 5'-hydroxyl analogs to assume a syn configuration in which a bifurcated, intramolecular, hydrogen bond can be formed to the O-4' and the C-2 carbonyl groups.