Abstract：
The search for novel anticancer agents to replace the current platinum-based treatments remains an ongoing process. Palladacycles have shown excellent promise as demonstrated by our previous work which yielded BTC2, a binuclear palladadycle with a non-ionisable polyethylene glycol (PEG) tether. Here, we explore the importance of the PEG-tether length on the anticancer activity of the binuclear palladacycles by comparing three analogous binuclear palladacycles, BTC2, BTC5 and BTC6, in the oestrogen receptor positive MCF7 and triple-negative MDA-MB-231 breast cancer cell lines. In addition, these are compared to another analogue with an ionisable morpholine tether, BTC7. Potent anticancer activity was revealed through cell viability studies (MTT assays) revealed that while BTC6 showed similar potent anticancer activity as BTC2, it was less toxic towards non-cancerous cell lines. Interestingly, BTC7 and BTCF were less potent than the PEGylated palladacycles but showed significantly improved selectivity towards the triple-negative breast cancer cells. Cell death analysis showed that BTC7 and BTCF significantly induced apoptosis in both the cancer cell lines while the PEGylated complexes induced both apoptosis and secondary necrosis. Furthermore, experimental and computational DNA binding studies indicated partial intercalation and groove binding as the modes of action for the PEGylated palladacycles. Similarly, experimental and computational BSA binding studies indicated and specific binding sites in BSA dependent on the nature of the tethers on the complexes.
摘要：
寻找新的抗癌剂来替代当前的基于铂的治疗仍然是一个正在进行的过程。Palladacycles已显示出出色的前景，正如我们先前的工作所证明的那样，该工作产生了BTC2，这是一种具有不可电离的聚乙二醇（PEG）系链的双核palladycle。这里,我们通过比较三个类似的双核palladacycles来探索PEG-tether长度对双核palladacycles抗癌活性的重要性，在雌激素受体阳性MCF7和三阴性MDA-MB-231乳腺癌细胞系中，BTC2，BTC5和BTC6。此外,将这些与具有可电离吗啉系链的另一种类似物进行比较，BTC7.通过细胞活力研究（MTT测定）揭示了有效的抗癌活性，表明尽管BTC6显示出与BTC2相似的有效抗癌活性，但对非癌细胞系的毒性较小。有趣的是,BTC7和BTCF的效力低于聚乙二醇化的钯环，但对三阴性乳腺癌细胞的选择性显着提高。细胞死亡分析表明，BTC7和BTCF均显着诱导两种癌细胞系的凋亡，而聚乙二醇化复合物则诱导凋亡和继发性坏死。此外，实验和计算DNA结合研究表明，部分嵌入和凹槽结合是PEG化的palladacycle的作用方式。同样，实验和计算BSA结合研究表明，BSA中的特异性结合位点取决于复合物上系链的性质。
