Synthesis and evaluation of novel azaindolocarbazole derivatives as cancer chemotherapeutics

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dc.contributor.advisor McCarthy, Florence O. en Cahill, Michael M. 2013-07-30T09:12:05Z 2013-07-30T09:12:05Z 2013 2013
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.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.format.mimetype application/pdf en
dc.language.iso en en
dc.publisher University College Cork en
dc.rights © 2013, Michael Cahill. en
dc.rights.uri 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.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
dc.internal.availability Full text available en
dc.description.version Accepted Version
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.chapterOfThesis 1,2,4,5,6,7,Appendices
dc.check.embargoformat E-thesis on CORA only en

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© 2013, Michael Cahill. Except where otherwise noted, this item's license is described as © 2013, Michael Cahill.
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