Anthracenyl amino acid analogues as topoisomerase I inhibitors

Giles, Gregory (2000) Anthracenyl amino acid analogues as topoisomerase I inhibitors. University of Southampton, Doctoral Thesis.

Record type: Thesis (Doctoral)

Abstract

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.

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