Waugh, TM; (2017) Synthesis of Quinone Anticancer Agents and Substituted Bicyclo[3.3.1]nonane-2,9-diones. Doctoral thesis , UCL (University College London).

Abstract

Current quinone anticancer agents such as the anthracyclines are polycyclic conjugated molecules which, whilst effective at treating many forms of cancer, their severe side effects such as cumulative heart toxicity often limit their use. A previously identified single ring anticancer quinone HU-331 was synthesised from cannabidiol and shown to be highly efficacious against several human cancer cell lines and in a comparative animal study was found to be less toxic and more effective than the commonly used doxorubicin. HU-331 has also been identified as a selective catalytic inhibitor of DNA topoisomerase II. HU-331 and a series of structurally related analogs were synthesised using a Friedel-Crafts alkylation and tested for inhibition of DNA relaxation against human DNA topoisomerase II. Initial focus was on making structural modifications on the terpene moiety and later on altering the n-pentyl chain. Although no significant improvement over HU-331 was identified. A series of simpler para-benzoquinone analogs were synthesised using a metalation strategy to identify the minimal structural requirements necessary for biological activity. A number of compounds were found to be more potent than HU-331 and were tested further in cell viability assays. The most potent compound contained a cyclohexyl ring in place of the terpene fragment and represents a basis for development of next generation DNA topoisomerase II inhibitors. The bicyclo[3.3.1]nonane system is a bridged bicyclic class of phloroglucinol products. The most famous being hyperforin a key constituent of St. John’s wort. The polyprenylated acylphloroglucinols (PPAP) family have shown multiple beneficial medicinal properties including anticancer, anti-HIV and anti-bacterial activities. A series of 1,6-disubstituted dihydroresorcinols were synthesised via a Michael-Claisen cyclocondensation and subsequently converted into their corresponding bicyclo[3.3.1]nonane-2,9 diones via a base-induced tandem Michael-Aldol annulation with acrolein/ methacrolein. All attempts to oxidise to a phloroglucinol ring were unsuccessful.

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