Synthesis of novel topoisomerase-I inhibiting naphtholo-xanthone derivatives as potential anti-cancer agents

The goal of this research is to synthesize novel naphtholo-xanthone derivatives (I & II) as possible topoisomerase inhibitors and therefore, potential anti-cancer agents. Topoisomerases are enzymes that solve conformational and topological changes that occur when DNA undergoes replication and transcription. It is hoped these derivatives will intercalate into DNA and act as inhibitors of either topoisomerase I or, less likely, II. These aromatic multi-ring compounds are ideal for intercalation because they are flat and can engage in stacking interactions with the DNA base pairs and distort the DNA helix. Topoisomerase inhibitors stabilize the cleavable reaction intermediate complex in which the topoisomerase is covalently bound to the DNA. These inhibitors interfere with the DNA breakage-rejoining step and lead to apoptosis. In order to synthesize these derivatives, a naphthalene (2) and an indole (3) must first be synthesized and utilized in coupling reactions. Two different routes were explored for the synthesis of the di-substituted naphthalene component 2. Substituted naphthalenes are difficult to isolate because mixtures of products may be formed even in mono-substitution. The Leimgruber-Batcho method was used for the synthesis of the hydroxyindole derivative 3. Copper catalyzed coupling reactions, followed by the final cyclization Friedal-Crafts aceylation reaction in polyphosphoric acid (PPA), will complete the synthesis of these novel derivatives. 1H NMR, 13 C NMR and IR spectroscopy characterized the intermediates and final products.