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Probing the Interactions of Cytotoxic [Pt(1 S ,2 S ‐DACH)(5,6‐dimethyl‐1,10‐phenanthroline)] and Its Pt IV Derivatives with Human Serum
Author(s) -
Harper Benjamin W. J.,
FriedmanEzra Aviva,
Sirota Roman,
Petruzzella Emanuele,
AldrichWright Janice R.,
Gibson Dan
Publication year - 2017
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201700092
Subject(s) - chemistry , tris , human serum albumin , phenanthroline , phosphate buffered saline , carboxylate , bovine serum albumin , phosphate , stereochemistry , in vitro , medicinal chemistry , biochemistry , crystallography , chromatography
The discrepancy between the in vitro cytotoxic results and the in vivo performance of Pt56MeSS prompted us to look into its interactions and those of its Pt IV derivatives with human serum (HS), human serum albumin (HSA), lipoproteins, and serum‐supplemented cell culture media. The Pt II complex, Pt56MeSS, binds noncovalently and reversibly to slow‐tumbling proteins in HS and in cell culture media and interacts through the phenanthroline group with HSA, with a K d value of ∼1.5×10 −6 m . All Pt IV complexes were found to be stable toward reduction in HS, but those with axial carboxylate ligands, cct ‐[Pt(1 S ,2 S ‐DACH)(5,6‐dimethyl‐1,10‐phenantroline)(acetato) 2 ](TFA) 2 (Pt56MeSS(OAc) 2 ) and cct ‐[Pt(1 S ,2 S ‐DACH)(5,6‐dimehtyl‐1,10‐phenantroline)(phenylbutyrato) 2 ](TFA) 2 (Pt56MeSS(PhB) 2 ), were spontaneously reduced at pH 7 or higher in phosphate buffer, but not in Tris buffer (pH 8). HS also decreased the rate of reduction by ascorbate of the Pt IV complexes relative to the reduction rates in phosphate buffer, suggesting that for this compound class, phosphate buffer is not a good model for HS.