Synthesis and evaluation of quinoline-5,8-diones and isoquinoline-5,8-diones as anticancer agents

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Kruschel, Ryan D.
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University College Cork
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This thesis outlines the design and synthesis of novel chemical routes towards a nascent class of functionalised quinoline-5,8-diones and isoquinoline-5,8-diones. The structured approach adopted is predicted to lead to advancements in the two frameworks, expanding the structural diversity of both the quinoline-5,8-diones and isoquinoline-5,8-diones families with bioactivity evaluation. Chapters 4, 5, 6, 7 and 8 are focused on the development and biological screening of the quinoline-5,8-dione library; Chapters 9 and 10 construct and evaluate the isoquinoline-5,8-dione library. Initial route development furnished versatile quinoline-5,8-dione and isoquinoline-5,8-dione frameworks in high yields employing robust methodologies. Synthetic exploration into the regioselective addition of carbon, nitrogen, and oxygen to the quinone moiety was investigated yielding 85 novel analogues. The use of directing group strategies, Lewis acid coordination and blocking groups provided access to regioselective reactions. Antimicrobial screening was undertaken in collaboration with the Community for Open Antimicrobial Drug Discovery (CO-ADD). The quinoline-5,8-dione library exhibited potent antibacterial and antifungal MIC values, outperforming known antimicrobial agents’ vancomycin and fluconazole, respectively. Preliminary in vitro toxicology studies revealed that all analogues are not haemolytic, and multiple analogues are not cytotoxic to the human kidney cell line HEK293. Anticancer screening was undertaken in in collaboration with the National Cancer Institute (NCI) in Maryland US. Although the quinoline-5,8-dione library were not effective anticancer agents, the isoquinoline-5,8-dione family possessed nanomolar anticancer GI50 values across multiple human tumour cell lines. Multidrug resistant ovarian cancer cell lines NCI/ADR-RES and IGROV 1 were responsive to the series in the nanomolar range. Lead isoquinoline-5,8-dione N-oxide 10.21 exhibits a mean GI50 of 0.21 μM across 60 cancer cell lines. Extended mechanistic work incorporated molecular modelling, electrochemical assays and COMPARE analysis to rationalise the potent in vitro bioactivity and identities future biological targets.
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Anticancer , Antimicrobial , Chemistry , Quinone , Cytotoxicity , Bioactivity , Organic chemistry , Medicinal chemistry , Novel compound , Drug design , Drug discovery
Kruschel, R. D. 2020. Synthesis and evaluation of quinoline-5,8-diones and isoquinoline-5,8-diones as anticancer agents. PhD Thesis, University College Cork.
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