Measurements of ionization constants and partition coefficients of quanazole prodrugs.

A series of guanazole prodrugs, which are less water soluble than the parent compound and have relatively higher molecular weights, was recently synthesized, and their antineoplastic activities were measured in vitro. In present work, the ionization constants and partition coefficients of these compounds were measured for the first time. In contrast to guanazole, which is a weak base, guanazole prodrugs have been shown to be weak to moderate acids due to the electronic effects of the acyl group and the heterocyclic ring. Possible tautomeric and resonance structures are presented to account for the pKa values observed. Both the inductive and resonance effects of the substituent are important in determining the values of the ionization constant. The preparation of the prodrugs not only altered the lipophilicity but also drastically changed the acid-base property of the parent compound. The observed true partition coefficient values in most guanazole prodrugs studied were higher than those calculated from the pi-constants. Under highly ionized conditions, the small amount of water in the octanol layer has a significant effect in trapping a substantial amount of the ionized species in the octanol layer and gives rise to a higher log P value than expected. Under nonionized conditions, intramolecular hydrogen bonding plays an important factor in electron delocalization and reduction of hydrogen bonding with water molecules, causing the nonionized species of the guanazole prodrugs to be more lipophilic than expected.