Ultraviolet light-induced cleavage of DNA in presence of iodoHoechst 33258: the sequence specificity of the reaction

Synthesis and evaluation of benzochalcogenazole-benzimidazole derivatives as potential DNA-binding radioprotectors

“…While M2PB 20 shows clear binding to the nucleotide containing an AATT binding site no strong conclusions can be made regarding the interactions of 6, 7 or 19 with DNA, either in the presence, or absence of an AATT binding site. Cell localisation assays on HeLa cells with one of these derivatives (7) shows that this molecule does not enter the nucleus, in contrast to M2PB (20), a known DNA-minor groove binder which was assessed for comparison and shows significant nuclear uptake. These results suggest that the proposed chalcogen bonding interactions involving S, Se and Te in 6, 7, and 20 are not strong enough to impart the DNA minor-groove binding behaviour which is displayed by corresponding bisbenzimidazoles such as 20.…”

“…13 C NMR (100 MHz, DMSO-d6) δ 49.3, 66.5, 106.9, 113.9, 114. 1, 116.6, 122.4, 122.6, 123.1, 125.9, 128.8, 132.8, 132.9, 136.6, 138.2, 147.7, 147.9, 149.7, 150.1, 152.8, 164. (7). Woollins' reagent (107.9 mg, 0.203 mmol) was stirred in pyridine (0.5 mL) at room temperature under nitrogen for 30 min.…”

“…Such radioprotection was first demonstrated for Hoechst 33258 1 and Hoechst 33342 2 in early studies on isolated plasmid DNA 1,2 and on the clonogenic survival of cultured cells, and in vivo, with the compounds present during and after irradiation. 3,4,5 These molecules bind in the minor groove of DNA in regions of three or more consecutive AT base pairs, 6,7,8 a mode of binding that is largely facilitated by hydrogen bonding of the benzimidazole N-H protons to hydrogen-bond acceptors at the floor of the minor groove in these regions. 9,10 Subsequently we designed more potent bisbenzimidazole based radioprotectors, such as proamine 3 and methylproamine 4.…”

DNA-Binding Radioprotectors

“…In vivo radioprotection by methylproamine has been demonstrated in mouse jejunum using the Withers assay with a DMF of 1.2 -1.3. Methylproamine, like other DNA binding bi-benzimidazoles, has a binding preference for AT-rich sequences, the consensus binding site being 3-4 consecutive AT base pairs as established by footprinting (Harshman & Dervan, 1985) and affinity cleavage (Martin & Holmes, 1983;Martin et al, 1990;Murray & Martin, 1994) studies, and confirmed by X-ray crystallography studies .…”

Selected Topics in DNA Repair

“…Assuming that base damage (BD) occurs more frequently than SSB (Ward, 1994b;Ward, 1994a), it is expected that the majority of OCDL are not frank DSB but contain two BD or BD and SSB in opposite strands . While isolated DNA lesions are generally repaired efficiently, OCDL are more difficult to resolve (Ward, 1981;Harrison et al, 1999;Georgakilas et al, established by footprinting (Harshman & Dervan, 1985) and affinity cleavage (Martin & Holmes, 1983;Martin et al, 1990;Murray & Martin, 1994) studies, and confirmed by X-ray crystallography studies (Martin et al, 2004).…”