Synthesis and evaluation of novel functionalised indoles as anticancer agents

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dc.contributor.advisor McCarthy, Florence en Winfield, Hannah 2016-05-24T08:51:14Z 2015 2015
dc.identifier.citation Winfield, H. 2015. Synthesis and evaluation of novel functionalised indoles as anticancer agents. PhD Thesis, University College Cork. en
dc.identifier.endpage 314 en
dc.description.abstract This thesis outlines the design and application of new routes towards a range of novel bisindolylmaleimide and indolo[2,3-a]carbazole derivatives, and evaluation of their biological effects and their chemotherapeutic potential. A key part of this work focussed on utilising a hydroxymaleimide as a replacement for the prevalent lactam/maleimide functionality and forming a series of novel derivatives through substitution on the indole nitrogens. To achieve this, a robust synthetic strategy was developed which allowed access to key maleic anhydride intermediates using Perkin-type methodology. These hydroxymaleimides were further modified via a Lossen rearrangement to furnish a series of analogues containing a 6-membered F-ring. The theme of F-ring modulation was further expanded through the utilisation of a second route involving the design and synthesis of β-keto ester intermediates, which afforded novel derivatives containing pyrazolone and isocytosine headgroups, and various N-substituents. Work on a further route involving a dione intermediate resulted in the isolation of a bisindolyl derivative with a novel imidazole F-ring. Following the synthesis of 42 novel compounds, extensive screening was undertaken using the NCI-60 cell line screen, with twelve candidates progressing to evaluation via the five dose assay. This led to the identification of several lead compounds with high cytotoxicity and excellent selectivity profiles, which included derivatives with low nanomolar GI50 values against specific cancer cell lines, and also derivatives with selective cytotoxicity. Preliminary results from a kinase screen indicated noteworthy selectivity towards GSK3α/β and PIM1 kinases, with low micromolar IC50 values being observed for these enzymes. en
dc.description.sponsorship Irish Research Council for Science Engineering and Technology (EMBARK postgraduate scholarship) en
dc.format.mimetype application/pdf en
dc.language.iso en en
dc.publisher University College Cork en
dc.rights © 2015, Hannah Winfield. en
dc.rights.uri en
dc.subject Indolocarbazoles en
dc.subject Anticancer en
dc.subject Bisindolylmaleimides en
dc.subject Kinase inhibition en
dc.subject Heterocycles en
dc.subject Topoisomerase i en
dc.title Synthesis and evaluation of novel functionalised indoles as anticancer agents en
dc.type Doctoral thesis en
dc.type.qualificationlevel Doctoral en
dc.type.qualificationname PhD (Science) en
dc.internal.availability Full text not available en Restricted to everyone for five years en 2021-05-23T08:51:14Z
dc.description.version Accepted Version
dc.contributor.funder Irish Research Council for Science Engineering and Technology en
dc.description.status Not peer reviewed en Chemistry en
dc.check.reason This thesis is due for publication or the author is actively seeking to publish this material en
dc.check.opt-out Not applicable en
dc.thesis.opt-out false
dc.check.entireThesis Entire Thesis Restricted
dc.check.embargoformat E-thesis on CORA only en
dc.internal.conferring Summer 2016 en

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© 2015, Hannah Winfield. Except where otherwise noted, this item's license is described as © 2015, Hannah Winfield.
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