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On the Stability of Pt IV Pro‐Drugs with Haloacetato Ligands in the Axial Positions
Author(s) -
Wexselblatt Ezequiel,
Raveendran Raji,
Salameh Sawsan,
FriedmanEzra Aviva,
Yavin Eylon,
Gibson Dan
Publication year - 2015
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201405467
Subject(s) - chemistry , ligand (biochemistry) , stereochemistry , hydrolysis , cytotoxicity , platinum , crystal structure , medicinal chemistry , combinatorial chemistry , crystallography , organic chemistry , receptor , in vitro , biochemistry , catalysis
The design of Pt IV pro‐drugs as anticancer agents is predicated on the assumption that they will not undergo substitution reactions before entering the cancer cell. Attempts to improve the cytotoxic properties of Pt IV pro‐drugs included the use of haloacetato axial ligands. Herein, we demonstrate that Pt IV complexes with trifluoroacetato (TFA) or dichloroacetato (DCA) ligands can be unstable under biologically relevant conditions and readily undergo hydrolysis, which results in the loss of the axial TFA or DCA ligands. The half‐lives for Pt IV complexes with two TFA or DCA ligands at pH 7 and 37 °C range from 6 to 800 min, which is short relative to the duration of cytotoxicity experiments that last 24–96 h. However, complexes with two monochloroacetato (MCA) or acetato axial ligands are stable under biologically relevant conditions. The loss of the axial ligands depends primarily on the electron‐withdrawing strength of the axial ligands, but also upon the nature of the equatorial ligands. We were unable to find obvious correlations between the structures of the Pt IV complexes and the rates of decay of the parent compounds. The X‐ray crystal structures of the bis‐DCA and bis‐MCA Pt IV derivatives of oxaliplatin did not reveal any significant structural differences that could explain the observed differences in stability.