Conformational properties of topoisomerase II inhibitors and sequence specificity of DNA cleavage

• Published in: Journal of molecular recognition Vol. 7; no. 3; p. 227
• Main Authors: Palumbo, M, Mabilia, M, Pozzan, A, Capranico, G, Tinelli, S, Zunino, F
• Format: Journal Article
• Language: English
• Published: England 01-09-1994
• Subjects: Base Sequence; DNA - metabolism; DNA Topoisomerases, Type II - metabolism; Ellipticines - chemistry; Ellipticines - pharmacology; Genistein; Isoflavones - chemistry; Isoflavones - pharmacology; Molecular Structure; Substrate Specificity; Topoisomerase II Inhibitors
• ISSN: 0952-3499
• DOI: 10.1002/jmr.300070312

The sequence specificity of topoisomerase-II-mediated DNA cleavage, stimulated by 2-methyl-9-hydroxy ellipticinium and 4',5,7-trihydroxyflavone (genistein) was investigated by sequencing analysis of DNA cleavage sites and molecular modeling techniques. The former drug exhibits a marked preference for a T base at the position immediately preceding the cleavage site (-1). The latter shares the preference for the same base, with an additional preference for a thymine at position +1. The cleavage intensity patterns in the presence of the two drugs differ considerably. From a conformational point of view, ellipticinium and genistein exhibit similar overall shape and dimensions. However, the fused ring system in the former generates a planar structure whereas the single bond, connecting the two aromatic portions in the latter, allows internal rotation. The most stable conformation of genistein corresponds to a deviation of about 40 degrees from planarity. A computer-assisted analysis was carried out to compare the steric and electrostatic properties of the two compounds. Two types of preferred (energetically almost degenerate) alignment for the two molecules were found. One corresponds to overlapping of the 9-hydroxyl containing ring of ellipticinium with the 4'-hydroxyphenyl moiety of genistein, the other envisages the same moiety of ellipticine superimposed to the hydroxyl-benzopyrone portion of genistein. The structural similarities of the test drugs might account for the common preference for stimulation of DNA cleavage at position +1, whereas the different possible arrangements of genistein in the cleavable complex could explain both the additional +1 specificity exhibited by this compound and the differences in cleavage intensity patterns observed in comparison to ellipticinium.