The impact of highly electron withdrawing carboxylato ligands on the stability and activity of platinum(IV) pro-drugs

Recent developments in the design of platinum(IV) pro-drug candidates have demonstrated the importance of the coordination sphere of the complex in determining the resistance to reduction by endogenous reductants and the stability in biologically relevant environments. Diaminetetracarboxylatoplatinum(IV) complexes exhibit many desirable properties as platinum(IV) pro-drugs, exhibiting unusual resistance to reduction by endogenous reductants and in blood serum, but are rapidly reduced within cells. In this study, we used 19F NMR to monitor the aquation of complexes with highly electron withdrawing trifluoroacetato ligands in the axial positions of platinum(IV) and reinterpreted the reduction of these complexes by ascorbate and cysteine and their biological behaviour in the light of the aquation results. We concluded that the potential for aquation needs to be taken into account in interpreting reduction and cytotoxicity studies. While we show that this is possible for the reduction studies, we conclude that it is not possible for cytotoxicity studies and other studies in complex biological environments. We also note that the low stability of the complexes is not expected to be compatible with their use as pro-drugs

The reduction of cis-platinum(IV) complexes by ascorbate and in whole human blood models using 1H NMR and XANES spectroscopy

The efficacy of platinum(IV) prodrugs depends on their relative resistance to reduction in the extra- and intra-cellular environments. In the study reported here we investigated the influence of the nature of the axial and equatorial ligands on the pathway of reduction of the platinum(IV) complexes by the endogenous reductant, ascorbate, and their relative resistance to reduction in human blood serum and in a whole human blood model. The pathway of reduction of platinum(IV) complexes in the presence of excess ascorbate was found to be dependent on the nature of their axial and equatorial ligands in that complexes with chloride in the equatorial sites lost either both axial ligands or combinations of axial and equatorial ligands while those with oxalate occupying the equatorial sites lost both axial ligands only. Using XANES spectroscopy, complexes with axial hydroxide ligands were found to be highly resistant to reduction in blood serum and were only slowly and incompletely reduced in whole blood. The dihydroxide complex with an oxalate ligand occupying the equatorial leaving group sites was more resistant to reduction, both in serum and in whole blood, than the complex with chloride ligands in these sites. Cis, trans-[PtCl2(OAc)2(en)] and trans-[Pt(OAc)2(ox)(en)] were observed to be reduced rapidly and almost completely in whole blood but the latter was substantially resistant to reduction in human blood serum, and consequently demonstrates many of the features of an optimal platinum(IV) anticancer agent.ARC, Australian Synchrotro

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

cis- and trans-Platinum(IV) complexes with diaminetetracarboxylate coordination spheres possess the highly desirable property of exhibiting unusual resistance to reduction by blood serum components and endogenous reductants such as ascorbate. At the same time they are rapidly reduced in the intracellular environment of cancer cells. Consequently, they can potentially be tuned to remain intact in vivo until arrival at the tumour target where they are rapidly reduced to yield the active platinum(II) species. However, in order to achieve this, uptake must be largely restricted to tumour cells and therefore uptake by healthy cells including red blood cells must be prevented. In this proof of concept study, we report on the effect of net charge as a means of controlling the uptake by red blood cells. Using 1H NMR spectroscopy we found that modifying the net charge of the complex does not influence the rate of reduction of the complexes by an excess of ascorbate. Using XANES spectroscopy we found that modifying the net charge of the platinum(IV) complexes decreased the extent of reduction in whole blood, although probably not to the degree needed for the optimal delivery to tumours. Therefore, it is likely to be necessary to adopt higher charges and/or additional strategies to keep platinum(IV) prodrugs out of blood cells

The Assessment of Daily Energy Expenditure of Commercial Saturation Divers using Doubly Labelled Water

Commercial saturation divers are exposed to unique environmental conditions and are required to conduct work activity underwater. Consequently, divers’ physiological status is shown to be perturbed and therefore, appropriate strategies and guidance are required to manage the stress and adaptive response. This study aimed to evaluate the daily energy expenditure (DEE) of commercial saturation divers during a 21-day diving operation in the North Sea. Ten saturation divers were recruited during a diving operation with a living depth of 72 metres seawater (msw) and a maximum working dive depth of 81 msw. Doubly labelled water (DLW) was used to calculate DEE during a 10-day measurement period. Energy intake was also recorded during this period by maintaining a dietary log. The mean DEE calculated was 3030.9 ± 513.0 kcal/day, which was significantly greater than the mean energy intake (1875.3 ± 487.4 kcal; p = 0.005). There was also a strong positive correction correlation between DEE and total time spent performing underwater work (r = 0.7, p = 0.026). The results suggested saturation divers were in a negative energy balance during the measurement period with an intraindividual variability in the energy cost present that may be influenced by time spent underwater

Structural and anticancer properties of hydrogen bonded diphenyl phosphate adducts of Pt(IV) complexes: The importance of pKa matching

Co-crystallisation of diphenyl phosphate (Hdpp) with anticancer active Pt(IV) complexes of the type cis,trans,cis-[PtCl(2)(OH)(2)(am(m)ine)(2)] has produced a new type of supramolecular adduct with short hydrogen bonds from the Hdpp molecules to the hydroxide ligands in all cases. X-ray crystallographic analysis showed within the adduct cis,trans-[PtCl(2)(en)(OH(2))(2)](dpp)(2) (1) a hydrogen bond length of 2.341(6) Å; the shortest O ··· O distance reported in the literature. Similar, though longer hydrogen bonds were observed in three other complexes: [PtCl(2)(OH)(NH(3))(2)(OH(2))]dpp·3H(2)O (2), trans-[Pt(mal)(OH)(OH(2))(S,S-chxn)]dpp·3H(2)O (3), and trans-[Pt(ox)(OH)(OH(2))(S,S-chxn)]dpp·2H(2)O (4). Co-crystallisation with Hdpp leads to higher aqueous solubility than the parent complexes indicating the potential of the adducts for use as active pharmaceutical ingredients. Anticancer testing of [Pt(mal)(OH)(OH(2))(S,S-chxn)]dpp·3H(2)O (3) showed in vitro cytotoxicity is low, as expected for Pt(IV) prodrugs, yet substantial tumour growth inhibition was observed in an in vivo ADJ/PC6 tumour model, with activity retained at maximum tolerated dose (MTD)/2 and MTD/4

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

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)₂(ox)­(en)] and <i>trans</i>-[PtCl₂­(OAc)₂(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