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Synthesis and biological evaluation of novel platinum complexes of imidazolyl-containing bisphosphonates as potential anticancer agents

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Abstract

Four novel platinum complexes, [Pt(en)]2ZL (1), [Pt(en)]2IPrBP (2), [Pt(en)]2MIBP (3) and [Pt(en)]2EIBP (4) [en = ethylenediamine; ZL = 1-hydroxy-3-(1H-imidazol-1-yl)ethane-1,1-diylbisphosphonic acid, commonly known as zoledronic acid; IPrBP = 1-hydroxy-3-(1H-imidazol-1-yl)propane-1,1-diylbisphosphonic acid; MIBP = 1-hydroxy-2-(2-methyl-1H-imidazol-1-yl)ethane-1,1-diylbisphosphonic acid; EIBP = 1-hydroxy-2-(2-ethyl-1H-imidazol-1-yl)ethane-1,1-diylbisphosphonic acid], were prepared and evaluated against five human cancer cell lines, including U2OS, A549, HCT116, MDA-MB-231 and HepG2. While exhibiting lower efficacy on the inhibition of cancer cell lines than cisplatin (CDDP), four complexes showed higher cytotoxicity than the corresponding ligands and relatively stronger cytotoxic effect on the hepatoma cell lines HepG2, and the complex 1 showed higher cytotoxicity than others on the whole. These complexes have better selectivity than the corresponding ligands in inhibiting hepatocarcinoma cells rather than normal liver cells, and the selective inhibitory effect of the complex 1 at the high concentration (100 μM) is better than that at the low concentration. Morphology studies exhibited typical characteristics of cell apoptosis and the cell cycle distribution analysis indicated that the complexes can inhibit cancer cells by inducing the cell cycle arrest at the G2/M phase, exhibiting a similar mechanism of action to CDDP. The binding interaction of complex with DNA has been explored by circular dichroism (CD) and UV–Vis absorption spectra, demonstrating these new complexes have moderate binding affinity for DNA.

Graphical Abstract

Four platinum complexes based on imidazolyl-containing bisphosphonates with effective antitumor activity and low hepatotoxicity were designed and evaluated.

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Acknowledgments

The authors are grateful to the financial support from National Natural Science Foundation of China (21371082 and 21001055), Natural Science Foundation of Jiangsu Province (BK20141102 and BK20151118), Key Medical Talent Project of Jiangsu Province (RC2011097), Science Foundation of Health Department of Jiangsu Province (Q201204) and Public Service Platform for Science and Technology Infrastructure Construction Project of Jiangsu Province (BM2012066).

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Authors and Affiliations

  1. Key Laboratory of Nuclear Medicine, Ministry of Health, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, 214063, People’s Republic of China

    Ling Qiu, Gaochao Lv, Yang Cao, Liping Chen, Hui Yang, Shineng Luo, Meifen Zou & Jianguo Lin

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  1. Ling Qiu
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  2. Gaochao Lv
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  3. Yang Cao
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  6. Shineng Luo
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  7. Meifen Zou
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  8. Jianguo Lin
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Correspondence to Shineng Luo or Jianguo Lin.

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Qiu, L., Lv, G., Cao, Y. et al. Synthesis and biological evaluation of novel platinum complexes of imidazolyl-containing bisphosphonates as potential anticancer agents. J Biol Inorg Chem 20, 1263–1275 (2015). https://doi.org/10.1007/s00775-015-1305-z

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  • DOI: https://doi.org/10.1007/s00775-015-1305-z

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