Lord Rianne M, Hebden Andrew J, Pask Christopher M, Henderson Imogen R, Allison Simon J, Shepherd Samantha L, Phillips Roger M, McGowan Patrick C
†School of Chemistry, University of Leeds, Leeds LS2 9JT, United Kingdom.
‡Institute of Cancer Therapeutics, University of Bradford, Bradford BD7 1DP, United Kingdom.
J Med Chem. 2015 Jun 25;58(12):4940-53. doi: 10.1021/acs.jmedchem.5b00455. Epub 2015 Jun 8.
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.
已合成了一系列钌和铱配合物，并对其进行了表征，讨论了20种新颖的晶体结构。已证明β-酮亚胺配合物库对MCF-7（人乳腺癌）、HT-29（人结肠癌）、A2780（人卵巢癌）和A2780cis（顺铂耐药人卵巢癌）细胞系具有活性，所选配合物对A2780cis细胞系的活性比顺铂高3倍以上。还对所选配合物针对非癌性ARPE-19（视网膜色素上皮细胞）细胞系进行了测试，以评估配合物对癌细胞的选择性。配合物在缺氧条件下也显示出高活性，一些配合物的活性随O2浓度降低而增加。硫氧还蛋白还原酶在癌细胞中过度表达，本文报道的配合物具有抑制该酶的优势，IC50值在纳摩尔范围内。进一步研究了这些配合物的抗癌活性，以确定活性是否归因于对细胞生长或细胞存活的影响。发现这些配合物通过凋亡诱导显著水平的癌细胞死亡，诱导的水平与化学敏感性研究中的活性密切相关。作为细胞死亡的可能原因，还评估了配合物诱导细胞DNA损伤的能力。这些配合物未能诱导双链DNA断裂或DNA交联，但诱导了显著水平的单链DNA断裂，表明其作用机制与顺铂不同。
