Synthesis and evaluation of novel functionalised indoles as anticancer agents

Winfield, Hannah

Restricted to everyone for five years. Restriction lift date: 2021-05-23T08:51:14Z

Synthesis and evaluation of novel functionalised indoles as anticancer agents

dc.check.date	2021-05-23T08:51:14Z
dc.check.embargoformat	E-thesis on CORA only	en
dc.check.entireThesis	Entire Thesis Restricted
dc.check.info	Restricted to everyone for five years	en
dc.check.opt-out	Not applicable	en
dc.check.reason	This thesis is due for publication or the author is actively seeking to publish this material	en
dc.contributor.advisor	McCarthy, Florence	en
dc.contributor.author	Winfield, Hannah
dc.contributor.funder	Irish Research Council for Science Engineering and Technology	en
dc.date.accessioned	2016-05-24T08:51:14Z
dc.date.issued	2015
dc.date.submitted	2015
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.description.status	Not peer reviewed	en
dc.description.version	Accepted Version
dc.format.mimetype	application/pdf	en
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.identifier.uri	https://hdl.handle.net/10468/2603
dc.language.iso	en	en
dc.publisher	University College Cork	en
dc.rights	© 2015, Hannah Winfield.	en
dc.rights.uri	http://creativecommons.org/licenses/by-nc-nd/3.0/	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.thesis.opt-out	false
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
ucc.workflow.supervisor	f.mccarthy@ucc.ie