Planta Med 2013; 79 - PC7
DOI: 10.1055/s-0033-1348563

Structure Based Drug Design and Synthesis of Novel Topoisomerase IIα Inhibitors Based off the Marine Alkaloid Neoamphimedine

AD Abraham 1, J Ponder 1, H Ali 1, DV LaBarbera 1
  • 1Department of Pharmaceutical Sciences, The Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Denver, Anschutz Medical Campus, Aurora CO 80045, USA

The marine alkaloid, Neoamphimedine (neo), is a potent antitumor agent in vitro and in vivo. We have characterized neo as an ATP-competitive inhibitor of topoisomerase IIα (topoIIα), which is an important target for the treatment of various human cancers. Furthermore, we have shown that neo overcomes drug resistance observed with clinically used topoIIα drugs. Therefore, targeting topoIIα via ATP-competitive inhibition may be a more effective strategy to develop novel topoIIα drugs. Using the crystal structure of the N-terminal ATPase domain of human topoIIα, the pharmacophore of neo, and the Discovery Studio software (Accelrys), we have designed and synthesized a new class of topoIIα inhibitors and present our methodology herein.