Structure-activity relationships of 1-substituted 2- nitroimidazoles: effect of partition coefficient and side-chain hydroxyl groups on radiosensitization in vitro. [Hamsters]
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). 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.
- Research Organization:
- Stanford Univ., CA
- OSTI ID:
- 5500896
- Journal Information:
- Radiat. Res.; (United States), Vol. 90:1
- Country of Publication:
- United States
- Language:
- English
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Related Subjects
ANIMAL CELLS
RADIOSENSITIVITY
IMIDAZOLES
RADIOSENSITIVITY EFFECTS
STRUCTURAL CHEMICAL ANALYSIS
RADIOSENSITIZERS
BIOLOGICAL EFFECTS
EXTERNAL IRRADIATION
HAMSTERS
IN VITRO
OVARIES
PHYSICAL PROPERTIES
RESPONSE MODIFYING FACTORS
X RADIATION
ANIMALS
AZOLES
BODY
DRUGS
ELECTROMAGNETIC RADIATION
FEMALE GENITALS
GONADS
HETEROCYCLIC COMPOUNDS
IONIZING RADIATIONS
IRRADIATION
MAMMALS
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
ORGANS
RADIATIONS
RODENTS
VERTEBRATES
560121* - Radiation Effects on Cells- External Source- (-1987)
560114 - Radiation Effects on Biochemicals- In Animals- (-1987)