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Lead identification of conformationally restricted β-lactam type combretastatin analogues : synthesis, antiproliferative activity and tubulin targeting effects

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dc.contributor.authorCarr, M.
dc.contributor.authorGreene, L.M.
dc.contributor.authorKnox, A.J.S.
dc.contributor.authorLloyd, D.G.
dc.contributor.authorZisterer, D.M.
dc.contributor.authorMeegan, M.J.
dc.date.issued2010
dc.description.abstractThe synthesis and study of the structureeactivity relationships of a series of rigid analogues of combretastatin A-4 are described which contain the 1,4-diaryl-2-azetidinone (β-lactam) ring system in place of the usual ethylene bridge present in the natural combretastatin stilbene products. The 1,4-diaryl-2-azetidinones are unsubstituted at C-3, or contain methyl substituent(s) at C-3. The most potent compounds 12d and 12e display antiproliferative activity at nanomolar concentrations when evaluated against the MCF-7 and MDA-MB-231 human breast carcinoma cell lines. 12d exerts antimitotic effects through an inhibition of tubulin polymerisation and subsequent G2/M arrest of the cell cycle in human MDA-MB-231 breast cancer cells, with similar activity to that of CA-4. These novel β-lactam compounds are identified as potentially useful scaffolds for the further development of antitumour agents which target tubulin.
dc.identifier.citationEuropean Journal of Medicinal Chemistry, 2010; 45(12):5752-5766
dc.identifier.doi10.1016/j.ejmech.2010.09.033
dc.identifier.issn0223-5234
dc.identifier.issn1768-3254
dc.identifier.urihttps://hdl.handle.net/1959.8/151898
dc.language.isoen
dc.publisherElsevier Masson
dc.relation.fundingEnterprise Ireland
dc.relation.fundingHealth Research Board
dc.relation.fundingScience Foundation Ireland
dc.relation.fundingTrinity College IITAC research initiative
dc.relation.fundingWellcome Trust
dc.rightsCopyright 2010 Elsevier Masson
dc.source.urihttps://doi.org/10.1016/j.ejmech.2010.09.033
dc.subject2-azetidinon
dc.subjectcombrestatin A-4 analogues
dc.subjectcytotoxicity
dc.subjectstructure-activity
dc.subjecttubulin
dc.subjectβ-lactam
dc.titleLead identification of conformationally restricted β-lactam type combretastatin analogues : synthesis, antiproliferative activity and tubulin targeting effects
dc.typeJournal article
pubs.publication-statusPublished
ror.mmsid9915914143801831

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