Synthesis and antiproliferative activity of novel heterocyclic indole-trimethoxyphenyl conjugates

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dc.contributor.author Cahill, Michael M.
dc.contributor.author O'Shea, Kevin D.
dc.contributor.author Pierce, Larry
dc.contributor.author Winfield, Hannah
dc.contributor.author Eccles, Kevin S.
dc.contributor.author Lawrence, Simon E.
dc.contributor.author McCarthy, Florence O.
dc.date.accessioned 2017-10-18T09:40:12Z
dc.date.available 2017-10-18T09:40:12Z
dc.date.issued 2017
dc.identifier.citation Cahill, M., O’Shea, K., Pierce, L., Winfield, H., Eccles, K., Lawrence, S. and McCarthy, F. (2017) 'Synthesis and antiproliferative activity of novel heterocyclic indole-trimethoxyphenyl conjugates', Pharmaceuticals, 10(3), 62 (20pp). doi: 10.3390/ph10030062 en
dc.identifier.volume 10
dc.identifier.issued 3
dc.identifier.startpage 1
dc.identifier.endpage 20
dc.identifier.issn 1424-8247
dc.identifier.issn 1424-8247
dc.identifier.uri http://hdl.handle.net/10468/4879
dc.identifier.doi 10.3390/ph10030062
dc.description.abstract The synthesis and biological evaluation of a series of novel heterocyclic indole derivatives is described. The consolidation of the combretastatin and bisindolylmaleimide templates towards the inclusion of a novel heterocyclic ring proffered a versatile pharmacophore with which to pursue chemical diversification. Given literature precedent, maleimide was initially investigated in this role and the bioactivity assessed by measurement of NCI-60 cell panel growth. Subsequently, a range of 5-aminopyrazoles was designed and developed to explore the specific effect of heterocycle hydrogen bonding on cell growth. The unique electronic nature of the 5-aminopyrazole moiety allowed for regiospecific monosubstitution on different sites of the ring, such as thiourea substitution at the N(1) position for derivative 45 or trifluoroacetylation on the 5-amino position for 43. Further derivatisation led to the ultimate development of bicyclic pyrazolotriazinedione 41 and pyrimidine 42 systems. The antiproliferative activities of these 3,4-diaryl-5-aminopyrazoles were assessed using the NCI-60 cell screen, disclosing the discovery of distinct selectivity profiles towards a number of cell lines, such as SNB-75 CNS cancer, UO-31 and CAKI-1 renal cancer cells. A series of DNA topological assays discounted the interaction with topoisomerase II as a putative mechanism of action en
dc.format.mimetype application/pdf en
dc.language.iso en en
dc.publisher MDPI en
dc.relation.uri http://www.mdpi.com/1424-8247/10/3/62
dc.rights © 2017, the Authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/) en
dc.rights.uri https://creativecommons.org/licenses/by/4.0/
dc.subject Diarylmaleimide en
dc.subject Diaryl-aminopyrazole en
dc.subject 5-aminopyrazole regioselective substitution en
dc.subject Drug discovery en
dc.subject NCI anticancer screen en
dc.title Synthesis and antiproliferative activity of novel heterocyclic indole-trimethoxyphenyl conjugates en
dc.type Article (peer-reviewed) en
dc.internal.authorcontactother Florence McCarthy, Chemistry, University College, Cork, Ireland. +353-21-490-3000. Email: f.mccarthy@ucc.ie en
dc.internal.availability Full text available en
dc.description.version Published Version en
dc.contributor.funder National Cancer Institute
dc.contributor.funder Irish Research Council for Science, Engineering and Technology
dc.description.status Peer reviewed en
dc.identifier.journaltitle Pharmaceuticals en
dc.internal.IRISemailaddress f.mccarthy@ucc.ie en
dc.internal.IRISemailaddress simon.lawrence@ucc.ie en
dc.identifier.articleid 62


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© 2017, the Authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/) Except where otherwise noted, this item's license is described as © 2017, the Authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/)
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