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

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Abstract
Fourteen 1-substituted 2-nitroimidazoles that ranged in lipophilicity with partition coefficients (P) from 0.014-2.75 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 (C1.6) 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 C1.6 = b0 + b1 log P + b2 (log P)2 + b3 (OH). Either independent variable log P or (log P)2 was significantly nonzero (P < 0.001) and, if used separately in the equation without the hydroxyl group term, could account for 51% of the explained variance (r2) in the fit of the data. The number of hydroxyl groups on the side chain affected radiosensitization equally or to a greater extent than P in the range presently studied (r2 for the hydroxyl term alone was 0.58). An increase in hydroxyl group number by 1 with no change 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)2 terms together with the hydroxyl group term increased the r2 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 .apprx. 1/10 of that of misonidazole without producing a loss of radiosensitizing effectiveness, and that independent of lipophilicity, the addition of hydroxy groups to the molecule also reduces the radiosensitizing effectiveness.

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