Abstract C279: Novel anthracenedione derivatives demonstrating several potential modes of actions.

DNA has been regarded as the primary target of numerous non-specific cytotoxic anticancer agents such as the nitrogen mustards and anthracycline antibiotics. The anthracyclines, most notably doxorubicin, proved to be highly potent and were thus incorporated into numerous chemotherapeutic regimens. However, their dose dependent redox activity that presumably contributes to their broad spectrum versatility is also associated with potentially lethal cardiotoxic adverse effects and thus, inspired the development of synthetic analogues including the anthracenediones. Like the anthracylines, their structural frame constitutes the DNA intercalating anthraquinone chromophore with functional amino groups stabilizing its insertion via hydrogen bonds and Van der Waal interactions. This interaction poisons the topoisomerase II cleavable complex which induces widespread DNA strand breaks culminating in the induction of apoptosis. We have shown that the availability of the methyl donating molecule, formaldehyde, generates adduct formation via a covalent aminal linkage between the exocyclic N2 amino group of guanine residue at specific CpG dinucleotides and an amino group on the anthracenediones side chains. The formaldehyde mediated DNA adduct formation, achievable via simultaneous formaldehyde-releasing prodrug administration, increases cancer cell toxicity and potentially endows general cardioprotective activity. Such cardioprotection has been associated with formaldehyde-mediated doxorubicin-DNA adducts We have synthesised a new series of anthracenediones that vary in their potential to induce covalent DNA adducts. We now show that the new anthracenediones including pixantrone (unlike the anthracyclines) also exhibits a preference for forming adducts with single stranded DNA and RNA, and these have similar characteristics to adducts that are formed with DNA. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C279. Citation Format: Paul P. Pumuye, Jelena E. Medan, Brad Sleebs, Keith Watson, Benny J. Evison, Donald R. Phillips, Suzanne M. Cutts. Novel anthracenedione derivatives demonstrating several potential modes of actions. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C279.