Synthesis and antiproliferative activity of novel heterocyclic indole-trimethoxyphenyl conjugates

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dc.contributor.authorCahill, Michael M.
dc.contributor.authorO'Shea, Kevin D.
dc.contributor.authorPierce, Larry
dc.contributor.authorWinfield, Hannah
dc.contributor.authorEccles, Kevin S.
dc.contributor.authorLawrence, Simon E.
dc.contributor.authorMcCarthy, Florence O.
dc.contributor.funderNational Cancer Institute
dc.contributor.funderIrish Research Council for Science, Engineering and Technology
dc.date.accessioned2017-10-18T09:40:12Z
dc.date.available2017-10-18T09:40:12Z
dc.date.issued2017
dc.description.abstractThe 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 actionen
dc.description.statusPeer revieweden
dc.description.versionPublished Versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.articleid62
dc.identifier.citationCahill, 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/ph10030062en
dc.identifier.doi10.3390/ph10030062
dc.identifier.endpage20
dc.identifier.issn1424-8247
dc.identifier.issn1424-8247
dc.identifier.issued3
dc.identifier.journaltitlePharmaceuticalsen
dc.identifier.startpage1
dc.identifier.urihttps://hdl.handle.net/10468/4879
dc.identifier.volume10
dc.language.isoenen
dc.publisherMDPIen
dc.relation.urihttp://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.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectDiarylmaleimideen
dc.subjectDiaryl-aminopyrazoleen
dc.subject5-aminopyrazole regioselective substitutionen
dc.subjectDrug discoveryen
dc.subjectNCI anticancer screenen
dc.titleSynthesis and antiproliferative activity of novel heterocyclic indole-trimethoxyphenyl conjugatesen
dc.typeArticle (peer-reviewed)en
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