PEPTIDYL ANTHRAQUINONES AS POTENTIAL ANTINEOPLASTIC DRUGS - SYNTHESIS, DNA-BINDING, REDOX CYCLING, AND BIOLOGICAL-ACTIVITY

A series of new compounds containing a 9,10-anthracenedione moiety and one or two peptide chains at position 1 and/or 4 have been synthesize d. The amino acid residues introduced are glycine (Gly), lysine (Lys), and tryptophan (Trp), the latter two in both the L- and D-configurati ons. The peptidyl anthraquinones maintain the ability of intercalating efficiently into DNA, even though the orientation within the base-pai r pocket may change somewhat with reference to the parent drugs mitoxa ntrone (MX) and ametantrone (AM). The interaction constants of the mon o-, di-, and triglycyl derivatives are well comparable to those found for AM but 5-10 times lower than the value reported for MX. On the oth er hand, the glycyl-lysyl compounds bind DNA to the same extent as (L- isomer) or even better than (D-isomer) MX. As for the parent drugs wit hout peptidyl chains, the new compounds prefer alternating CG binding sites, although to different extents. The bis-Gly-Lys derivatives are the least sensitive to base composition, which may be due to extensive aspecific charged interactions with the polynucleotide backbone. As f ar as redox properties are concerned, all peptidyl anthraquinones show a reduction potential very close to that of AM and 60-80 mV less nega tive than that of MX; hence, they can produce free-radical-damaging sp ecies to an extent similar to the parent drugs. The biological activit y has been tested in human tumor and murine leukemia cell lines. Most of the test anthraquinones exhibit cytotoxic properties close to those of AM and considerably lower than those of MX. Stimulation of topoiso merase-mediated DNA cleavage is moderately present in representatives of the glycylanthraquinone family, whereas inhibition of the backgroun d cleavage occurs when Lys is present in the peptide chain. For most o f the test anthraquinones, the toxicity data are in line with the DNA affinity scale and the topoisomerase II stimulation activity. However, in the lysyl derivatives, for which lack of cytotoxicity cannot be re lated to poor binding to DNA, the steric and electronic properties of the side-chain substituent must impair an effective recognition of the cleavable complex.