Synthesis and evaluation of novel azaindolocarbazole derivatives as cancer chemotherapeutics

Cahill, Michael M.

Synthesis and evaluation of novel azaindolocarbazole derivatives as cancer chemotherapeutics

dc.check.chapterOfThesis	1,2,4,5,6,7,Appendices
dc.check.embargoformat	E-thesis on CORA only	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 O.	en
dc.contributor.author	Cahill, Michael M.
dc.date.accessioned	2013-07-30T09:12:05Z
dc.date.available	2013-07-30T09:12:05Z
dc.date.issued	2013
dc.date.submitted	2013
dc.description.abstract	This thesis details the design and implementation of novel chemical routes towards a series of highly propitious 7-azaindolyl derivatives of the indolocarbazole (ICZ) and bisindolylmaleimide (BIM) families, with subsequent evaluation for use as cancer chemotherapeutic agents. A robust synthetic strategy was devised to allow the introduction of a 7-azaindolyl moiety into our molecular template. This approach allowed access to a wide range of β-keto ester and β-keto nitrile intermediates. Critical analysis identified F-ring modulation as a major theme towards the advancement of ICZ and BIM derivatives in drug therapy. Thus, the employment of cyclocondensation methodology furnished a number of novel aminopyrazole, isoxazolone, pyrazolone and pyrimidinone analogues, considerably widening the scope of the prevalent maleimide functionality. Photochemical cyclisation provided for the first reported aza ICZ containing a six-membered F-ring. Another method towards achieving the aza ICZ core involved use of a Perkin-type condensation approach, with chemical elaboration of the headgroup instigated post-aromatisation. Subsequent use of a modified Lossen rearrangement allowed access to further analogues containing a six-membered F-ring. Extensive screening of the novel aza ICZ and BIM derivatives was carried out against the NCI-60 cancer cell array, with nine prospective candidates selected for continued biological evaluation. From these assays, a number of compounds were shown to inhibit cancer cell growth at concentrations of below 10 nM. Indeed, the most active aza ICZ tested is currently under assessment by the Biological Evaluation Committee of the NCI due to excellent antiproliferative activity demonstrated across the panel of cell lines, with a mean GI50 of 34 nM, a mean total growth inhibition (TGI) of 4.6 μM and a mean cytotoxicity (LC50) of 63.1 μM. Correlation to known topoisomerase I (topo I) inhibitors was revealed by COMPARE analysis, and subsequent topo I-mediated DNA cleavage assays showed inhibitory activity below 1 μM for several derivatives.	en
dc.description.status	Not peer reviewed	en
dc.description.version	Accepted Version
dc.format.mimetype	application/pdf	en
dc.identifier.citation	Cahill, M. 2013. Synthesis and evaluation of novel azaindolocarbazole derivatives as cancer chemotherapeutics. PhD Thesis, University College Cork.	en
dc.identifier.endpage	274
dc.identifier.uri	https://hdl.handle.net/10468/1202
dc.language.iso	en	en
dc.publisher	University College Cork	en
dc.rights	© 2013, Michael Cahill.	en
dc.rights.uri	http://creativecommons.org/licenses/by-nc-nd/3.0/	en
dc.subject	Indolocarbazole	en
dc.subject	Bisindolylmaleimide	en
dc.subject	Azaindole	en
dc.subject	Anti-cancer	en
dc.subject	Cell cycle	en
dc.subject.lcsh	Cancer--Chemotherapy	en
dc.subject.lcsh	Indole--Synthesis	en
dc.subject.lcsh	Indole--Therapeutic use	en
dc.thesis.opt-out	false
dc.title	Synthesis and evaluation of novel azaindolocarbazole derivatives as cancer chemotherapeutics	en
dc.type	Doctoral thesis	en
dc.type.qualificationlevel	Doctoral	en
dc.type.qualificationname	PhD (Science)	en
ucc.workflow.supervisor	cora@ucc.ie