Influence of Equatorial and
Axial Carboxylato Ligands on the Kinetic Inertness of Platinum(IV)
Complexes in the Presence of Ascorbate and Cysteine and within DLD‑1
Cancer Cells
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Abstract
The
rapid and premature reduction of platinum(IV) complexes in vivo is a significant impediment
to these complexes being successfully employed as anticancer prodrugs.
This study investigates the influence of the platinum(IV) coordination
sphere on the ease of reduction of the platinum center in various
biological contexts. In the presence of the biological reductants,
ascorbate and cysteine, platinum(IV) complexes with dicarboxylato
equatorial ligands were observed to exhibit lower reduction potentials
and slower reduction rates than analogous platinum(IV) complexes with
dichlorido equatorial ligands. Diaminetetracarboxylatoplatinum(IV)
complexes exhibited unusually long half-lives in the presence of excess
reductants; however, the complexes exhibited moderate potency in vitro,
indicative of rapid reduction within the intracellular environment.
By use of XANES spectroscopy, <i>trans</i>-[Pt(OAc)<sub>2</sub>(ox)(en)] and <i>trans</i>-[PtCl<sub>2</sub>(OAc)<sub>2</sub>(en)] were observed to be reduced at a similar rate within
DLD-1 cancer cells. This large variability in kinetic inertness of
diaminetetracarboxylatoplatinum(IV) complexes in different
biological contexts has significant implications for the design of
platinum(IV) prodrugs
