Radiosensitization by the 2,4-dinitro-5-aziridinyl Benzamide CB 1954: A Structure/Activity Study

Summary

CB 1954 (2,4-dinitro-5-aziridinyl benzamide) is a radiosensitizer which is up to 10 times more efficient in vitro than would be predicted on the basis of its electron affinity. In order to determine the contribution of the various functional groups comprising the molecule to overall sensitizing efficiency, nine structural analogues have been studied. The redox potential, E¹₇, and sensitizing efficiency, C_1·6, were obtained for each compound. The value of C_1·6 depends on both redox potential and the magnitude of an additional component defined by Ĉ_1·6/C_1·6, where Ĉ_1·6 is derived from a structure/activity relationship (Adams et al. 1979 b, Wardman 1982) described by the equation:

The magnitude of Ĉ_1·6/C_1·6 for CB 1954 and its analogues depends on alkyl substitution of the amide, the presence/absence and position of the nitro groups and is independent of the presence of the aziridine group. Holding cells in the presence of the drug post-irradiation marginally enhanced sensitization by CB 1954, CB 10–107 and by CB 10–092 but the largest effect was seen with the mononitro compound CB 7060 which also has a value of 26 for Ĉ_1·6/C_1·6. This compound was also interesting in that when combined with 2-phenyl-4(5)amino-5(4)-imidazole carboxamide (phenyl AIC) an enhancement of sensitization was obtained. In contrast, phenyl AIC protected against radiosensitization by CB 1954.

Taken together, the data suggest that multiple mechanisms of radiosensitization may contribute to the abnormal radiosensitizing efficiency of CB 1954 and its analogues. This has implications for the further design and development of novel radiosensitizing drugs.