Brad Sleebs - New anthracenedione derivatives with improved biological activity by virtue of stable drug-DNA adduct formation

Version 1

      Publication Details (including relevant citation   information):

      Journal   of Medicinal Chemistry (2010),  53(19),   6851-6866

      Abstract:

      Mitoxantrone is an anticancer agent that acts as a topoisomerase   II poison, however, it can also be activated by formaldehyde to   form DNA adducts. Pixantrone, a 2-aza-anthracenedione with   terminal primary amino groups in its side chains, forms   formaldehyde-mediated adducts with DNA more efficiently than   mitoxantrone. Molecular modeling studies indicated that extension   of the “linker” region of anthracenedione side arms would allow   the terminal primary amino greater flexibility and thus access to   the guanine residues on the opposite DNA strand. New derivatives   based on the pixantrone and mitoxantrone backbones were   synthesized, and these incorporated primary amino groups as well   as extended side chains. The stability of DNA adducts increased   with increasing side chain length of the derivatives. A   mitoxantrone derivative bearing extended side chains   (7) formed the most stable adducts with   100-fold   enhanced stability compared to mitoxantrone. This finding is of   great interest because long-lived drug−DNA adducts are expected   to perturb DNA-dependent functions at all stages of the cell   cycle.

      Address (URL): http://10.1021/jm901894c