Light-induced nicking of deoxyribonucleic acid by cobalt(III) bleomycins

Abstract

The anticancer drug bleomycin is a glycopeptide that causes strand scission of DNA both in vivo and in vitro. Cleavage of DNA by bleomycin has been studied extensively in vitro, with the findings that ferrous ion and molecular oxygen must be present and that addition of reducing agents greatly enhances the reaction. To date, only iron has been shown to be an effective metal cofactor for the cleavage of DNA by bleomycin. Here it is reported that two stable cobalt(III) complexes of bleomycin are strikingly effective in causing single-strand breaks (nicks) in supercoiled DNA in the presence of ultraviolet or visible radiation. For example, 366-nm light from an 18-W long-wavelength mercury lamp for 1 h causes 10(-6) M cobalt(III) bleomycin to completely convert supercoiled phi X174 DNA (10(-8) M DNA, 10(-4) M phosphate) into the nicked circular form. Furthermore, numerous alkali-labile sites are produced on the DNA during this treatment. The observed reactions are not caused by adventitious iron, and they occur only in the presence of cobalt(III) bleomycin and light.

Crystal structure of DNA-bound Co(III)·bleomycin B 2 : Insights on intercalation and minor groove binding

“…Facilitating structural studies, HOO-Co(III)⅐bleomycin ''green'' ( Fig. 1) (15) constitutes a stable structural analogue of O 2 activated Fe(II)⅐bleomycin, HOO-Fe(III)⅐bleomycin, that interacts with the same DNA site-selectivity (16)(17)(18)(19)(20) but requires photoactivation to cleave DNA. From 2D NMR derived models reported for DNA-bound HOO-Co(III)⅐bleomycin, the bithiazole is intercalated and the pyrimidinyl ring of the metal-binding domain interacts with the guanine of the 5Ј-GC site via the minor groove (21)(22)(23)(24)(25).…”

Light-dependent activity of the antitumor antibiotics ravidomycin and desacetylravidomycin

“…Recently, daunomycin has been observed to initiate DNA cleavage when visible light is applied to drug-DNA mixtures (10), while bleomycin, which initiates DNA damage without light, demonstrates enhanced activity if light at 300 to 350 nm is introduced (5). The poorly active cobalt (III) bleomycins efficiently introduce single-stranded breaks in DNA in the presence of UV or visible radiation (2).…”

New photocatalysts based on mixed-metal pyridine dicarboxylates

“…The use of cobalt molecular complexes in the selective homogeneous photocatalytic cleavage of DNA has been known [21][22][23][24][25]. According to these studies, the low-spin Co 3+ complexes, in general, show several types of excited states that include ligand-field (LF), intraligand (IL) and charge-transfer (CT) states.…”