| Abstract
| - DNA minor groove binders, Hoechst 33258 and Hoechst 33342, have been reported to protectagainst radiation-induced DNA-strand breakage, but their mutagenicity and cytotoxicity limittheir use as protectors of normal tissue during radiotherapy and as biological radioprotectorsduring accidental radiation exposure. On the basis of these observations, two new nontoxicdisubstituted benzimidazoles were synthesized, one having two methoxy groups (5-(4-methylpiperazin-1-yl)-2-[2‘-(3,4-dimethoxyphenyl)-5‘-benzimidazolyl]benzimidazole, 5) and another having a methoxy and a hydroxyl group (5-(4-methylpiperazin-1-yl)-2-[2‘{2‘ ‘-(4-hydroxy-3-methoxyphenyl)-5‘ ‘-benzimidazolyl}-5‘-benzimidazolyl]benzimidazole, 6) ortho to each otheron the phenyl ring. The radiomodifying effects of these nontoxic ligands were investigated witha human glioma cell line exposed to low linear energy transfer radiation by determining cellsurvival and cell proliferation compared with effects of the parent compound, Hoechst 33342.Cytotoxicity assayed by analyzing clonogenicity, cell growth, and metabolic viability showedthat both 5 and 6 were nontoxic at 100 μM after 72 h of exposure, whereas Hoechst 33342resulted in lysis of 77% of these cells in 24 h. Macrocolony assay (clonogenicity) showed that73%, 92%, and 10% of the cells survived when treated with 100 μM 5, 6, and Hoechst 33342,respectively. Both 5 and 6 did not affect the growth of BMG-1 cells. At 10 μM, 5 and 6 showed82% and 37% protection against radiation-induced cell death (macrocolony assay) while 100%protection was observed against growth inhibition. Disubstitution of the phenyl ring has notonly reduced cytotoxicity but also enhanced DNA-ligand stability, conferring high degree ofradioprotection.
|
