Towards an understanding of the biological activity of naphthylisoquinoline alkaloids: DNA-binding properties of dioncophyllines A, B, and C

Abstract

To gain further insight into the mechanism of the promising cytotoxic and antitumoral actvities of naphthylisoquinoline (NIQ) alkaloids, the DNA-binding properties of three representative NIQ alkaloids, dioncophyllines A (1), B (2), and C (3), were, for the first time, investigated by means of spectroscopic studies. Thus, photometric and fluorimetric titrations as well as CD- and LD-spectroscopic analyses revealed an association of dioncophyllines A (1) and B (2) with duplex DNA and with abasic site-containing DNA (apurinic/apyrimidinic DNA:AP-DNA) with moderate affinity (K_b = 1–4 × 10⁴ M⁻¹). Notably, exemplary studies with dioncophylline A (1) also provided first evidence of a selectivity of this ligand towards AT-rich DNA sequences and abasic sites. Presumably, NIQs 1 and 2 bind to regular DNA in a half-intercalation mode, whereas they insert into the abasic site in AP-DNA. In contrast, dioncophylline C (3) does not bind to DNA, presumably because the 5,1′-connection of the biaryl unit in this NIQ leads to a sterically demanding structure that does not fit well into the DNA-binding sites. In summary, the results show that the DNA-binding properties of NIQ alkaloids should be considered in the assessment of their biological activities.