The Synthesis of Novel Fluorinated 9-Amino Acridones as Potential Topoisomerase IIα Poisons

Our group is studying fluorinated acridone derivatives for the first time, for their potential as topoisomerase IIα poisons. Topoisomerases are nuclear enzymes, that are needed for replication, transcription, and recombination. Specifically, they are responsible for relaxing supercoiled DNA by removing knots and tangles prior to the above processes. Although there are two isoforms of topoisomerases (Topo I and Topo II), we are focusing on compounds that could act as topoisomerase poisons, which are among the most widely prescribed anticancer drugs. The proto-type drugs include amsacrine and etoposide. Our hypothesis is that small acridone molecules having a trifluoromethyl group on the eastern cyclohexane ring will enhance DNA cleavage and act as a topoisomerase poison. These acridone derivatives are structurally similar to amsacrine. Our preliminary data have demonstrated that 9-amino-7-chloro-3-trifluoromethylacridone is a topoisomerase IIα poison. We have synthesized derivatives with substituents on the leftmost aromatic ring, such as H, Cl, F, 4-Me, Br, and Nitro group. The analysis of the potential inhibitors were tested at a 20µM concentration and the fluorine derivative proved to be most active following its halogen counterparts and the nitro group. Though the unsubstituted and methyl species fell short, activity was present. There are two types of interactions that can lead to inhibition of the enzyme: covalent and noncovalent. Our drug interacts with the enzyme covalently. All compounds were characterized by H1NMR, C13NMR, FTIR, and MelTempII apparatus. Enzyme studies were conducted by drug-DNA-enzyme assay/gel electrophoresis and quantified by an AlphaImager from Alpha Innotech, through collaboration with the Osheroff group at Vanderbilt University School of Medicine