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 synthesized. The amino acid residues introduced are glycine (Gly), lysine (Lys), and tryptophan (Trp), the latter two in both the L- and D-configurations. The peptidyl anthraquinones maintain the ability of intercalating efficiently into DNA, even though the orientation within the base-pair pocket may change somewhat with reference to the parent drugs mitoxantrone (MX) and ametantrone (AM). The interaction constants of the mono-, 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 other 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 without 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 far as redox properties are concerned, all peptidyl anthraquinones show a reduction potential very close to that of AM and 60-80 mV less negative than that of MX; hence, they can produce free-radical-damaging species to an extent similar to the parent drugs. The biological activity 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 topoisomerase-mediated DNA cleavage is moderately present in representatives of the glycylanthraquinone family, whereas inhibition of the background cleavage occurs when Lys is present in the peptide chain. For most of 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 related to poor binding to DNA, the steric and electronic properties of the side-chain substituent must impair an effective recognition of the cleavable complex.
Gatto
B
B
Department of Pharmaceutical Sciences, University of Padova, Italy.
Zagotto
G
G
Sissi
C
C
Cera
C
C
Uriarte
E
E
Palù
G
G
Capranico
G
G
Palumbo
M
M
D000818:Animals; D000880:Anthraquinones / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D002942:Circular Dichroism; D004247:DNA / Q000378:metabolism*; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D006801:Humans; D007364:Intercalating Agents / Q000138:chemical synthesis / Q000494:pharmacology; D051379:Mice; D008942:Mitoxantrone / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D008968:Molecular Conformation; D015394:Molecular Structure; D010084:Oxidation-Reduction; D010455:Peptides / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D013816:Thermodynamics; D014407:Tumor Cells, Cultured
D000880:Anthraquinones; D000970:Antineoplastic Agents; D007364:Intercalating Agents; D010455:Peptides; D004247:DNA; D008942:Mitoxantrone; D004250:DNA Topoisomerases, Type II