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dc.contributor.authorLord, Rianne M.
dc.contributor.authorHebden, A.J.
dc.contributor.authorPask, C.M.
dc.contributor.authorHenderson, I.R.
dc.contributor.authorAllison, Simon J.
dc.contributor.authorShepherd, S.L.
dc.contributor.authorPhillips, Roger M.
dc.contributor.authorMcGowan, P.C.
dc.date.accessioned2016-09-28T15:51:14Z
dc.date.available2016-09-28T15:51:14Z
dc.date.issued2015-04-25
dc.identifier.citationLord RM, Hebden AJ, Pask CM, Henderson IR, Allison SJ, Shepherd SL, Phillips RM, McGowan PC (2015) Hypoxia-Sensitive Metal β‑Ketoiminato Complexes Showing Induced Single-Strand DNA Breaks and Cancer Cell Death by Apoptosis. Journal of Medicinal Chemistry 58(12): 4940–4953.en_US
dc.identifier.urihttp://hdl.handle.net/10454/9491
dc.descriptionyesen_US
dc.description.abstractA series of ruthenium and iridium complexes have been synthesized and characterized with 20 novel crystal structures discussed. The library of β-ketoiminato complexes has been shown to be active against MCF-7 (human breast carcinoma), HT-29 (human colon carcinoma), A2780 (human ovarian carcinoma), and A2780cis (cisplatin-resistant human ovarian carcinoma) cell lines, with selected complexes’ being more than three times as active as cisplatin against the A2780cis cell line. Selected complexes were also tested against the noncancerous ARPE-19 (retinal pigment epithelial cells) cell line, in order to evaluate the complexes selectivity for cancer cells. Complexes have also been shown to be highly active under hypoxic conditions, with the activities of some complexes increasing with a decrease in O2 concentration. The enzyme thioredoxin reductase is overexpressed in cancer cells, and complexes reported herein have the advantage of inhibiting this enzyme, with IC50 values measured in the nanomolar range. The anticancer activity of these complexes was further investigated to determine whether activity is due to effects on cellular growth or cell survival. The complexes were found to induce significant levels of cancer cell death by apoptosis with levels induced correlating closely with activity in chemosensitivity studies. As a possible cause of cell death, the ability of the complexes to induce damage to cellular DNA was also assessed. The complexes failed to induce double-strand DNA breaks or DNA cross-linking but induced significant levels of single-strand DNA breaks, indicating a mechanism of action different from that of cisplatin.en_US
dc.description.sponsorshipLord RM, Hebden AJ, Pask CM, Henderson IR, Allison SJ, Shepherd SL, Phillips RM, McGowan PCen_US
dc.language.isoenen_US
dc.relation.isreferencedbyhttp://dx.doi.org/10.1021/acs.jmedchem.5b00455en_US
dc.subjectRuthenium complexes; Iridium complexes; Cancer cell death; Chemotherapy; Anticancer agents;en_US
dc.titleHypoxia-Sensitive Metal β‑Ketoiminato Complexes Showing Induced Single-Strand DNA Breaks and Cancer Cell Death by Apoptosisen_US
dc.status.refereedyesen_US
dc.date.application2015-04-23
dc.typeArticleen_US
dc.type.versionAccepted manuscripten_US
refterms.dateFOA2018-07-25T14:32:32Z


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