Structure-Activity Relationships of 1-Substituted 2-Nitroimidazoles: Effect of Partition Coefficient and Side-Chain Hydroxyl Groups on Radiosensitization in Vitro

Abstract

Fourteen 1-substituted 2-nitroimidazoles that ranged in lipophilicity with partition coefficients (P) from 0.014 to 2.75 and that varied in the number of hydroxyl groups (0-3) on the side chain at the 1-position of the nitroimidazole ring were studied for their ability to radiosensitize hypoxic Chinese hamster ovary cells (HA-1) in vitro. The concentration (C/sub 1.6/) of each compound required for achieving an enhancement ratio (ER) of 1.6 was plotted as a function of P. Multiple linear regression analyses were performed to determine the influence of P and the number of hydroxyl groups according to the equation -log C/sub 1.6/ = b/sub 0/ + b/sub 1/ log P + b/sub 2/ (log P)/sup 2/ + b/sub 3/ (OH). It was found that either independent variable log P or (log P)/sup 2/ was significantly nonzero (P < 0.001), and, if used separately in the equation without the hydroxyl group term, could account for the explained variance (r/sup 2/) in the fit of the data. It was also shown that the number of hydroxyl groups on the side chain affected radiosensitization equally or to a greater extent than P in the range presently studied (r/sup 2/ for the hydroxyl term alone was 0.58).more » An increase in hydroxyl group number by one with no changes in lipophilicity resulted in an increase in drug concentration needed for the equivalent radiosensitization by a factor of 2. The use of either the log P or (log P)/sup 2/ terms together with the hydroxyl group term increased the r/sup 2/ value to 0.70. These data are relevant to the development of radiosensitizers potentially superior to misonidazole for clinical use, since they show that lipophilicity can only be decreased to about 1/10 of that of misonidazole without producing a loss of radiosensitizing effectiveness, and that independent of lipophilicity, the addition of OH groups to the molecule also reduces the radiosensitizing effectiveness.« less