Journal
JOURNAL OF INORGANIC BIOCHEMISTRY
Volume 87, Issue 3, Pages 129-135Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/S0162-0134(01)00338-5
Keywords
prodigiosin; tambjamine; copper; DNA cleavage
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The DNA-targeting activities of the 4-methoxypyrrolic natural products, that include prodigiosin (1). tambjamine E (2), and the blue pigment (3), have been compared using fluorescence spectroscopy to study DNA binding and agarose gel electrophoresis to assess their ability to facilitate oxidative copper-promoted DNA cleavage. Fluorescence emission titration of 3 with calf-thymus DNA (CT-DNA) shows that the natural product occupies a site size (n) of ca. two base pairs and possesses an affinity constant (K) of similar to6 x 10(5) M-1. Similar to prodigiosin (1), the blue pigment 3 was found to facilitate oxidative double-strand DNA (dsDNA) cleavage without the aid of an external reducing agent. Quantitation of ds- (n(2)) and ss- (n(1)) breaks provided n(1):n(2) ratios of similar to8-12, which were significantly greater than the number expected from the accumulation of ss-breaks (similar to 120). This was contrasted by the nicking activity of tambjamine E (2), which only generates ss-breaks in the presence of copper. The superior copper-nuclease activity of 1 and 3 also correlated with their superior anticancer properties against leukemia (HL-60) cells. These results are discussed with respect to the mode of cytotoxicity by the 4-methoxypyrrolic natural products. (C) 2001 Elsevier Science B.V. All rights reserved.
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