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Hypoxia-Sensitive Metal β-Ketoiminato Complexes Showing Induced Single-Strand DNA Breaks and Cancer Cell Death by Apoptosis.

Authors
  • Lord, Rianne M1
  • Hebden, Andrew J1
  • Pask, Christopher M1
  • Henderson, Imogen R1
  • Allison, Simon J2
  • Shepherd, Samantha L3
  • Phillips, Roger M3
  • McGowan, Patrick C1
  • 1 †School of Chemistry, University of Leeds, Leeds LS2 9JT, United Kingdom. , (United Kingdom)
  • 2 ‡Institute of Cancer Therapeutics, University of Bradford, Bradford BD7 1DP, United Kingdom. , (United Kingdom)
  • 3 §Department of Pharmacy, School of Applied Sciences, University of Huddersfield, Huddersfield HD1 3DH, United Kingdom. , (United Kingdom)
Type
Published Article
Journal
Journal of Medicinal Chemistry
Publisher
American Chemical Society
Publication Date
Jun 25, 2015
Volume
58
Issue
12
Pages
4940–4953
Identifiers
DOI: 10.1021/acs.jmedchem.5b00455
PMID: 25906293
Source
Medline
License
Unknown

Abstract

A 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.

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