Anthracenyl amino acid analogues as topoisomerase I inhibitors

Topoisomerases are enzymes which alter the topological state of DNA. Mammalian type I and II topoisomerases (topo I and II) alter the linking number (L) of DNA by a factor of 1 and 2 respectively, thus reducing levels of supercoiling in mammalian DNA according to the equation L=T+W where T is the twisting number and W the writhing number. These enzymes are therefore essential for DNA metabolism and cell replication. A number of clinical useful anticancer drugs including camptothecin, doxorubicin and etoposide have been shown to inhibit the catalytic cycle of the topoisomerases, suggesting a mechanism of cell kill at least partially involving topo inhibition.A method for the synthesis of anthracenyl amino acid and peptide conjugates has been established. This class of compound has been reported to possess inhibitory activity against topo I. A range of novel compounds were therefore synthesised and evaluated as topoisomerase I inhibitors and structure activity relationships obtained. The amino acid conjugate 1-[Tyr]-4-hydroxy-anthraquinone was shown to be the most active compound in the series with regards to topo I inhibition. When compared to 0.1 μM camptothecin it was shown to possess similar activity to the known inhibitor at the higher concentration of 125 μM.