Identification of anthracenyl-dipeptide conjugates as novel topoisomerase I and II inhibitors and their evaluation as potential anticancer drugs.

As part of an ongoing rational drug design programme aiming to develop monosubstituted anthracenyl-peptides as potential anticancer drugs, three novel dipeptide conjugates have been synthesized and evaluated as inhibitors of topoisomerase (topo) I and II. Each of the three conjugates (designated NU/ICRF 600-602) was shown to inhibit the catalytic activity of both topoisomerase I and II, of which NU/ICRF 602 was the most active [100% inhibition of both enzymes at 5 micrograms/ml (approximately 15 microM) or less]. In a topo I/DNA unwinding assay, none of the compounds bound to DNA, suggesting genuine inhibition of catalytic activity. NU/ICRF 600 stabilized topo I cleavable complexes, although none of the compounds induced topo II-mediated DNA cleavage. Using a panel of Chinese hamster ovary cell lines along with the human ovarian cancer cell line, A2780, none of the three compounds were actively cytotoxic at concentrations < 100 microM. Subsequent drug uptake studies with NU/ICRF 600 and 602, using a method developed to correlate the chemosensitivity of A2780 cells with the uptake of anthracenyl-amino acid conjugates, revealed a lack of cellular uptake for both dipeptide conjugates. The significance of this finding in relation to drug design and the future development of this series of compounds is discussed.