The anthracyclines (including daunomycin, doxorubicin, epirubicin and idarubicin) discovered over 25 years ago still remain amongst the most powerful anticancer agents used in the clinic. Primarily they act as topoisomerase II poisons, but can be also activated by formaldehyde leading to the formation of even more cytotoxic anthracycline-DNA adducts. The next generation of DNA intercalators were synthesized based on the structure on the anthracyclines and this lead to the identification of the synthetic anthracenedione known as mitoxantrone. The mode of action of mitoxantrone mimics the anticancer activity of the anthracyclines. Mitoxantrone is a DNA intercalating topoisomerase II poison that forms lesions in double-stranded DNA resulting in cell death. A novel mechanism was discovered whereby mitoxantrone can also be activated by formaldehyde. Mitoxantrone has lower toxicity when compared to other anthracyclines but still exerts toxic side-effects such as cardiotoxicity and myelosupression. The second generation anthracenedione, pixantrone exhibits great anticancer potency in mice models without cardiotoxicity. It can be activated by formaldehyde resulting in the formation of adducts with DNA specifically at CpG site. Currently, pixantrone has passed Phase III clinical trials and it has been approved for the treatments of aggressive non-Hodgkin B-cell lymphomas.
In summary, a novel mechanism has been discovered whereby such intercalating agents can be activated by formaldehyde or formaldehyde releasing prodrugs, forming covalent adducts with DNA.
Our focus is on the synthesis of the next generation DNA intercalators and on the development of the novel high-throughput assay for screening these compounds.