Probing the Interactions of Cytotoxic [Pt(1S,2S‐DACH)(5,6‐dimethyl‐1,10‐phenanthroline)] and Its Pt^IV Derivatives with Human Serum

Abstract

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 derivatives with human serum (HS), human serum albumin (HSA), lipoproteins, and serum-supplemented cell culture media. The Pt 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 value of ∼1.5×10 m. All Pt complexes were found to be stable toward reduction in HS, but those with axial carboxylate ligands, cct-[Pt(1S,2S-DACH)(5,6-dimethyl-1,10-phenantroline)(acetato) ](TFA) (Pt56MeSS(OAc) ) and cct-[Pt(1S,2S-DACH)(5,6-dimehtyl-1,10-phenantroline)(phenylbutyrato) ](TFA) (Pt56MeSS(PhB) ), 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 complexes relative to the reduction rates in phosphate buffer, suggesting that for this compound class, phosphate buffer is not a good model for HS.

A Subset of New Platinum Antitumor Agents Kills Cells by a Multimodal Mechanism of Action Also Involving Changes in the Organization of the Microtubule Cytoskeleton

“…The importance of the reduction of Pt­(IV) platinum compounds containing biologically active axial ligands also follows from the previously published results describing the MoA of closely related Pt­(IV) prodrugs (for review, see a recently published work) and those showing that Pt­(IV) derivatives of 5 very similar to those investigated in the present study were stable in human serum for 40 h at 37 °C, attesting to their extracellular stability . Also, importantly, the Pt­(IV) derivatives of 5 containing HDAC inhibitors (valproate (VPA) or PhB) in the axial positions exhibited cellular downregulation of HDACs that was absent when there were innocent ligands in the axial positions.…”

The effect of charge on the uptake and resistance to reduction of platinum(iv) complexes in human serum and whole blood models

“…The reduction of complex I by a ten-fold excess of ascorbate occurred rapidly, with a half-life of 7-8 minutes, with reduction being almost complete after 16 minutes (Figure 3). This is in agreement with the reduction of the complex Pt56MeSS(OAc)2 by ascorbate previously reported by Harper et al 34 Like the reduction of complex IV, the reduction of complex I occurred with the loss of its two axial acetate ligands resulting in the formation of one reduction product (Figure 3). This confirms the hypothesis that reduction accompanied by the loss of the bidentate ligand is less favourable.…”

Potent Chlorambucil-Platinum(IV) Prodrugs

“…This report followed the reduction in PCLB , 5CLB , and 56CLB using 1 H-NMR and 1D- 195 Pt-NMR spectroscopy. The method used for the reduction experiments was adapted from the literature with minor modifications [ 61 , 74 , 75 , 76 ]. A total of 10 mM PBS (~7.4 pH) was selected as media to mimic physiological conditions, while 10 mM AsA was used as the biological reducing agent.…”