Oxidation of the Platinum(II) Anticancer Agent [Pt{(p-BrC6F4)NCH2CH2NEt2}Cl(py)] to Platinum(IV) Complexes by Hydrogen Peroxide.

PtIV coordination complexes are of interest as prodrugs of PtII anticancer agents, as they can avoid deactivation pathways owing to their inert nature. Here, we report the oxidation of the antitumor agent [PtII(p-BrC6F4)NCH2CH2NEt2}Cl(py)], 1 (py = pyridine) to dihydroxidoplatinum(IV) solvate complexes [PtIV{(p-BrC6F4)NCH2CH2NEt2}Cl(OH)2(py)].H2O, 2·H2O with hydrogen peroxide (H2O2) at room temperature. To optimize the yield, 1 was oxidized in the presence of added lithium chloride with H2O2 in a 1:2 ratio of Pt: H2O2, in CH2Cl2 producing complex 2·H2O in higher yields in both gold and red forms. Despite the color difference, red and yellow 2·H2O have the same structure as determined by single-crystal and X-ray powder diffraction, namely, an octahedral ligand array with a chelating organoamide, pyridine and chloride ligands in the equatorial plane, and axial hydroxido ligands. When tetrabutylammonium chloride was used as a chloride source, in CH2Cl2, another solvate, [PtIV{(p-BrC6F4)NCH2CH2NEt2}Cl(OH)2(py)].0.5CH2Cl2,3·0.5CH2Cl2, was obtained. These PtIV compounds show reductive dehydration into PtII [Pt{(p-BrC6F4)NCH=CHNEt2}Cl(py)], 1H over time in the solid state, as determined by X-ray powder diffraction, and in solution, as determined by 1H and 19F NMR spectroscopy and mass spectrometry. 1H contains an oxidized coordinating ligand and was previously obtained by oxidation of 1 under more vigorous conditions. Experimental data suggest that oxidation of the ligand is favored in the presence of excess H2O2 and elevated temperatures. In contrast, a smaller amount (1Pt:2H2O2) of H2O2 at room temperature favors the oxidation of the metal and yields platinum(IV) complexes.

Electron Delocalization in Spectroelectrochemically and Computationally Characterized [Pt{(p-BrC6F4)NCH═C(Cl)NEt2}Cl(py)]+ Formed by Electrochemical Oxidation of [PtII{(p-BrC6F4)NCH═C(Cl)NEt2}Cl(py)].

[Pt{(p-BrC6F4)NCH═C(Cl)NEt2}Cl(py)] (1Cl) is the product of the hydrogen peroxide oxidation of the PtII anticancer agent [Pt{(p-BrC6F4)NCH2CH2NEt2}Cl(py)] (1). Insights into electron delocalization and bonding in [Pt{(p-BrC6F4)NCH═C(Cl)NEt2}Cl(py)]+ (1Cl+) obtained by electrochemical oxidation of 1Cl have been gained by spectroscopic and computational studies. The 1Cl/1Cl+ process is chemically and electrochemically reversible on the short time scale of voltammetry in dichloromethane (0.10 M [Bu4N][PF6]). Substantial stability is retained on longer time scales enabling a high yield of 1Cl+ to be generated by bulk electrolysis. In situ IR and visible spectroelectrochemical studies on the oxidation of 1Cl to 1Cl+ and the reduction of 1Cl+ back to 1Cl confirm the long-term chemical reversibility. DFT calculations indicate only a minor contribution to the electron density (13%) resides on the Pt metal center in 1Cl+, indicating that the 1Cl/1Cl+ oxidation process is extensively ligand-based. Published X-ray crystallographic data show that 1Cl is present in only one structural form, while NMR data on the dissolved crystals revealed the presence of two closely related structural forms in an almost equimolar ratio. Solution-phase EPR spectra of 1Cl+ are consistent with two closely related structural forms in a ratio of about 90:10. The average g value for the frozen solution spectra (2.0567 for the major species) is significantly greater than the 2.0023 expected for a free radical. Crystal field analysis of the EPR spectra leads to an estimate of the 5d(xz) character of around 10% in 1Cl+. Analysis of X-ray absorption fine structure derived from 1Cl+ also supports the presence of a delocalized singly occupied metal molecular orbital with a spin density of approximately 17% on Pt. Accordingly, the considerably larger electron density distribution on the ligand framework (diminished PtIII character) is proposed to contribute to the increased stability of 1Cl+ compared to that of 1+.

Quantifying the effects of not stirring between repetitive chronoamperometric experiments.

Electroanalytical protocols executed under quiescent conditions generally require that the analyte medium be stirred (or agitated) between repetitions to ensure reestablishment of identical initial conditions in the vicinity of the electrode surface. The present work examines what happens when experimental conditions preclude stirring. We consider two general schemes: Scheme 1 where the potential is stepped from E(start) to E(step) to oxidize the initially present reduced redox moiety, A, to B under diffusion control (i.e., [A](x=0) = 0) for 0 ≤ t ≤ τ(1) followed by a second potential step from E(step) back to E(start) and continuing for τ(1) < t ≤ τ(2) during which time species B is reduced back to the initially present species A under diffusion control (i.e., [B](x=0) = 0) and Scheme 2 where the potential is again stepped from E(start) to E(step) to oxidize A to B under diffusion control for 0 ≤ t ≤ τ(1) followed by a second potential step from E(step) back to E(start) and continuing for τ(1) < t ≤ τ(2) during which there is no electron transfer; i.e., the electrochemical conversion of B to A (or vice versa) does not occur, and the electrode is effectively at open circuit for time τ(1) < t ≤ τ(2). We define a recovery parameter which specifies the concentration of A at distance (D(A)τ(1))(1/2) from the electrode as a function of the recovery-time ratio τ(2)/τ(1) and the operative Scheme (J). We show that for any given level of recovery τ(2)/τ(1) for Scheme 2 is much larger than for Scheme 1.

Smart Nanozymes for Cancer Therapy: The Next Frontier in Oncology.

Nanomaterials that mimic the catalytic activity of natural enzymes in the complex biological environment of the human body are called nanozymes. Recently, nanozyme systems have been reported with diagnostic, imaging, and/or therapeutic capabilities. Smart nanozymes strategically exploit the tumor microenvironment (TME) by the in situ generation of reactive species or by the modulation of the TME itself to result in effective cancer therapy. This topical review focuses on such smart nanozymes for cancer diagnosis, and therapy modalities with enhanced therapeutic effects. The dominant factors that guide the rational design and synthesis of nanozymes for cancer therapy include an understanding of the dynamic TME, structure-activity relationships, surface chemistry for imparting selectivity, and site-specific therapy, and stimulus-responsive modulation of nanozyme activity. This article presents a comprehensive analysis of the subject including the diverse catalytic mechanisms of different types of nanozyme systems, an overview of the TME, cancer diagnosis, and synergistic cancer therapies. The strategic application of nanozymes in cancer treatment can well be a game changer in future oncology. Moreover, recent developments may pave the way for the deployment of nanozyme therapy into other complex healthcare challenges, such as genetic diseases, immune disorders, and ageing.

Diverse and unexpected outcomes from oxidation of the platinum(II) anticancer agent [Pt{(p-BrC6F4)NCH2CH2NEt2}Cl(py)] by hydrogen peroxide.

Oxidation of the anti-tumour agent [Pt{(p-BrC6F4)NCH2CH2NEt2}Cl(py)], 1 (py = pyridine) with hydrogen peroxide under a variety of conditions yields a range of organoenamineamidoplatinum(II) compounds [Pt{(p-BrC6F4)NCH=C(X)NEt2}Cl(py)] (X = H, Cl, Br) as well as species with shared occupancy involving H, Cl and Br. Thus, oxidation of the -CH2-CH2- backbone (dehydrogenation) occurs, often accompanied by substitution. Oxidation of 1 with H2O2 in acetone yielded 1:1 co-crystallized [Pt{(p-BrC6F4)NCH=CHNEt2}Cl(py)], 1H and [Pt{(p-BrC6F4)NCH=C(Cl)NEt2}Cl(py)], 1Cl. The former was obtained pure in low yield from the oxidation of 1 with (NH4)2[Ce(NO3)6] in acetone, and the latter was obtained from 1 and H2O2 in CH2Cl2 at near reflux. From the latter reaction under vigorous refluxing [Pt{(p-BrC6F4)NCH=C(Br)NEt2}Cl(py)], 1Br was isolated. In refluxing acetonitrile, oxidation of 1 with H2O2 yielded [Pt{(p-BrC6F4)NCH=C(H0.25Br0.75)NEt2}Cl(py)], 1H0.25Br0.75, in which the alkene is mainly substituted by Br in a dual occupancy. Treatment of 1 with H2O2 and tetrabutylammonium hydroxide in acetone at room temperature formed [Pt{(p-HC6F4)NCH2CH2NEt2}Cl(py)], 2. Oxidation of [Pt{(p-HC6F4)NCH2CH2NEt2}Br(py)], 3 with H2O2 in boiling acetonitrile gave the ligand oxidation product [Pt{(p-HC6F4)NCH=C(Br)NEt2}Br(py)], 3Br. All major products were identified by X-ray crystallography as well as by 1H and 19F NMR spectra. In cases of mixed crystals or dual occupancy compounds, the 19F and 1H NMR spectra showed dissociation into the components in the solution in the same proportions as in isolated crystalline material.

EPR spectroscopic characterization of a monomeric PtIII species produced via electrochemical oxidation of the anticancer compound trans-[PtII{(p-HC6F4)NCH2CH2NEt2}Cl(py)].

The bulk oxidative electrolysis of a 2mM solution of trans-[PtII{(p-HC6F4)NCH2CH2NEt2}Cl(py)] in highly non-coordinating dichloromethane (0.05M [Bu4N][B(C6F5)]) media leads to the formation of about 14% of the PtIII species trans-[PtIII{(p-HC6F4)NCH2CH2NEt2}Cl(py)]+. The EPR spectrum of this electro-synthesized formally PtIII species shows Pt-hyperfine coupling with gx~gy>gz~ge, and is broadly consistent with the simple crystal field theory prediction for 5d7 PtIII in an elongated tetragonal environment where the unpaired electron is in a 5d(z2) orbital. The crystal field calculations lead to an estimate of the 5d(z2) character of around 37% and indicate partial delocalization of the unpaired electron onto the orbitals of the surrounding ligands. Transient cyclic voltammetric and steady-state microelectrode studies in the same media as used for bulk electrolysis exhibit a chemically reversible one electron oxidation process under their shorter time scale conditions. Analysis of X-ray diffraction data obtained from a single crystal of trans-[PtII{(p-HC6F4)NCH2CH2NEt2}Cl(py)] shows the square planar geometry of the ligands around the Pt metal center and the 'W' arrangement of the ethyl groups on the ligand is explained in terms of agostic interactions.