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J Inorg Biochem. 2017 Dec;177:328-334. doi: 10.1016/j.jinorgbio.2017.07.029. Epub 2017 Jul 29.

The influence of the ethane-1,2-diamine ligand on the activity of a monofunctional platinum complex.

Author information

1
School of Chemistry, The University of Sydney, NSW 2006, Australia.
2
The Florey Institute of Neuroscience and Mental Health, Parkville, Victoria 3052, Australia.
3
School of Life and Environmental Sciences, The University of Sydney, NSW 2006, Australia.
4
School of Chemistry, The University of Sydney, NSW 2006, Australia. Electronic address: trevor.hambley@sydney.edu.au.
5
School of Chemistry, The University of Sydney, NSW 2006, Australia. Electronic address: elizabeth.new@sydney.edu.au.

Abstract

The continued use of platinum-based chemotherapeutic drugs in the clinic mandates the need for further investigation of the biological activity of structural analogues of the clinically approved complexes. Of interest are monofunctional platinum(II) complexes, which bear only one labile ligand, for which it is believed that each complex binds to DNA only once. Pyriplatin ([PtCl(NH3)2(py)]+) and enpyriplatin ([PtCl(en)(py)]+) are both monofunctional platinum(II) complexes that bear a pyridine ligand and a labile chlorido ligand, differing in their cis‑ammine and ethane-1,2-diamine (en) ligands respectively. Despite their similar structure, the complexes exhibit dramatically different cytotoxicities. In this study, we synthesized and characterized both complexes in terms of their cytotoxicity, lipophilicity, DNA binding and cellular accumulation. There was no significant difference between the lipophilicities of the complexes and both complexes exhibited monofunctional type binding, but it was the temporal accumulation profiles of the two complexes which differed greatly. The complexes were further analyzed with size exclusion chromatography coupled with inductively coupled plasma mass spectrometry (SEC-ICP-MS) to determine the platination state of the proteins. Consistent with the accumulation studies, pyriplatin bound to proteins in far greater amounts than enpyriplatin, and this study also revealed some different protein targets between the bifunctional cisplatin and monofunctional pyriplatin. This study highlights the need for more sophisticated techniques, such as SEC-ICP-MS, to determine not only how much of a platinum complex accumulates in cells, but also the speciation and metabolites of platinum anticancer drugs.

PMID:
28789807
DOI:
10.1016/j.jinorgbio.2017.07.029
[Indexed for MEDLINE]

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