Aminoacyl-analogues of mitoxantrone as novel DNA-damaging cytotoxic agents

Abstract

Anthracenedione derivatives are widely used structures to target DNA in chemotherapy. One of the major problem related to their use is their lack of sequence selectivity along the genome. With the aim of favoring recognition of selected DNA sequences, we synthesized four novel aminoacyl derivatives. Two side chains carrying aminoacid residues different for charge and chirality have been introduced at positions 1 and 4 of 5,8-dihydroxyanthracene-9,10-dione. An aminoethylamino spacer was inserted between the planar ring system and the selected aminoacid residues. Investigations in DNA binding properties of these new derivatives showed a large modulation of the drugs affinities for the nucleic acid depending upon the charge of the aminoacid used but irrespective of its chirality. However, as shown by topoisomerase II poisoning, prominent DNA-binding properties did not grant superior topoisomerase inhibition due mainly to template effect. In turn, aminoacid chirality plays a critical role in the in vitro cytotoxicity, L enantiomers being much more effective than D enantiomers. These findings suggest that conjugation of the anthracenedione moiety to aminoacids/peptides can be a valuable tool to selectively target cancer cells.