On the Stability of PtIV Pro‐Drugs with Haloacetato Ligands in the Axial Positions

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.     

A Dogma in Doubt: Hydrolysis of Equatorial Ligands of PtIV Complexes under Physiological Conditions

Due to their high kinetic inertness and consequently reduced side reactions with biomolecules, Pt^IV complexes are considered to define the future of anticancer platinum drugs. The aqueous stability of a series of biscarboxylato Pt^IV complexes was studied under physiologically relevant conditions. Unexpectedly and in contrast to the current chemical understanding, especially oxaliplatin and satraplatin complexes underwent fast hydrolysis in equatorial position (even in cell culture medium and serum). Notably, the resulting hydrolysis products strongly differ in their reduction kinetics, a crucial parameter for the activation of Pt^IV drugs, which also changes the anticancer potential of the compounds in cell culture. The discovery that intact Pt^IV complexes can hydrolyze at equatorial position contradicts the dogma on the general kinetic inertness of Pt^IV compounds and needs to be considered in the screening and design for novel platinum‐based anticancer drugs.     

Dual‐Targeting Dual‐Action Platinum(IV) Platform for Enhanced Anticancer Activity and Reduced Nephrotoxicity

A novel and highly efficient dual‐targeting platform was designed to ensure targeted in vivo delivery of dual‐action Pt^IV prodrugs. The dual targeting was established by liposomal encapsulation of Pt^IV complexes, thereby utilizing the enhanced permeability and retention (EPR) effect as the first stage of targeting to attain a high accumulation of the drug‐loaded liposomes in the tumor. After the release of the Pt^IV prodrug inside cancer cells, a second stage of targeting directed a portion of the Pt^IV prodrugs to the mitochondria. Upon intracellular reduction, these Pt^IV prodrugs released two bioactive molecules, acting both on the mitochondrial and on the nuclear DNA. Our Pt^IV system showed excellent activity in vitro and in vivo, characterized by a cytotoxicity in a low micromolar range and complete tumor remission, respectively. Notably, marked in vivo activity was accompanied by reduced kidney toxicity, highlighting the unique therapeutic potential of our novel dual‐targeting dual‐action platform.     

A Multi-action and Multi-target RuII–PtIV Conjugate Combining Cancer-Activated Chemotherapy and Photodynamic Therapy to Overcome Drug Resistant Cancers

Pt^II complexes are commonly used to treat cancer. To reduce their side effects and improve their pharmacological properties, Pt^IV complexes are being developed as prodrug candidates that are activated by reduction in cancer cells. Concomitantly, Ru^II polypyridine complexes have gained much attention as photosensitizers for use in photodynamic therapy due to their attractive characteristics. In this article, a novel Pt^IV–Ru^II conjugate, which combines cancer activated chemotherapy with PDT, is presented. Upon entering the cancer cell, the Pt^IV centre is reduced to Pt^II and the axial ligands including the Ru^II complex and phenylbutyrate are released. As each component has its individual targets, the conjugate exerts a multi-target and multi-action effect with (photo-)cytotoxicity values upon irradiation up to 595 nm in the low nanomolar range in various (drug resistant) 2D monolayer cancer cells and 3D multicellular tumour spheroids.     

Multitargeted Platinum(IV) Anticancer Complexes Bearing Pyridinyl Ligands as Axial Leaving Groups

Although multitargeted Pt^IV anticancer prodrugs have shown significant activities in reducing drug resistance, the types of bioactive ligands and drugs that can be conjugated to the Pt center remain limited to O-donors. Herein, we report the synthesis of Pt^IV complexes bearing axial pyridines via ligand exchange reactions. Unexpectedly, the axial pyridines are quickly released after reduction, indicating their potential to be utilized as axial leaving groups. We further expand our synthetic approach to obtaining two multitargeted Pt^IV prodrugs containing bioactive pyridinyl ligands: a PARP inhibitor and an EGFR tyrosine kinase inhibitor; these conjugates exhibit great potential for overcoming drug resistance, and the latter conjugate inhibits the growth of Pt-resistant tumor in vivo. This research adds to the array of synthetic methods for accessing Pt^IV prodrugs and significantly increases the types of bioactive axial ligands that can be conjugated to a Pt^IV center.     

A Multi‐action and Multi‐target RuII–PtIV Conjugate Combining Cancer‐Activated Chemotherapy and Photodynamic Therapy to Overcome Drug Resistant Cancers

Pt^II complexes are commonly used to treat cancer. To reduce their side effects and improve their pharmacological properties, Pt^IV complexes are being developed as prodrug candidates that are activated by reduction in cancer cells. Concomitantly, Ru^II polypyridine complexes have gained much attention as photosensitizers for use in photodynamic therapy due to their attractive characteristics. In this article, a novel Pt^IV–Ru^II conjugate, which combines cancer activated chemotherapy with PDT, is presented. Upon entering the cancer cell, the Pt^IV centre is reduced to Pt^II and the axial ligands including the Ru^II complex and phenylbutyrate are released. As each component has its individual targets, the conjugate exerts a multi‐target and multi‐action effect with (photo‐)cytotoxicity values upon irradiation up to 595 nm in the low nanomolar range in various (drug resistant) 2D monolayer cancer cells and 3D multicellular tumour spheroids.     

Cycling a Tether into Multiple Rings: Pt-Bridged Macrocycles for Differentiated Guest Recognition,Pseudorotaxane Transformations,and Guest Capture and Release

Macrocycle engineering is a key topic in supramolecular chemistry. When synthesizing a ring, one can obtain either complex mixtures of macrocycles of different sizes or a single ring if a template is utilized. Here, we unite these approaches along with post-synthetic modifications to transform a single tether into multiple rings—up to five per tether. The macrocycles contain two bridged phenylpyridine ligands that are connected through a Pt atom, which defines the rings’ shape, size, and host activity. All rings undergo redox reactions (between Pt^II and Pt^IV) that allow for large conformational changes. Their reactivity, together with their host performance, is a convenient way to control the capture and release of guests, to mediate ring transformations, and to control pseudorotaxane-to-pseudorotaxane conversions. This novel approach could serve to assemble other libraries of small ring molecules, create cyclic polymers bridged by responsive-at-metal nodes, and produce processable mechanically interlocked molecules.     

Monochalcoplatin: An Actively Transported,Quickly Reducible,and Highly Potent PtIV Anticancer Prodrug

Recently, Pt^IV prodrugs have attracted much attention as the next generation of platinum‐based antineoplastic drug candidates. Here we report the discovery and evaluation of monochalcoplatin, a monocarboxylated Pt^IV prodrug that is among the most cytotoxic Pt^IV prodrugs to date. Compared with its dicarboxylated counterpart chalcoplatin, monochalcoplatin accumulates astonishingly effectively and rapidly in cancer cells, which is not ascribed to its lipophilicity. The prodrug is quickly reduced, causes DNA damage, and induces apoptosis, resulting in superior cytotoxicity with IC₅₀ values in the nanomolar range in both cisplatin‐sensitive and ‐resistant cells; these IC₅₀ values are up to 422‐fold higher than that of cisplatin. A detailed mechanistic study reveals that monochalcoplatin actively enters cells through a transporter‐mediated process. Moreover, monochalcoplatin shows significant antitumor activity in an in vivo colorectal tumor model. Our study implies a practical strategy for the design of more effective Pt^IV prodrugs to conquer drug resistance by tuning both cellular uptake pathways and activation processes.     

Monochalcoplatin: An Actively Transported,Quickly Reducible,and Highly Potent PtIV Anticancer Prodrug

Recently, Pt^IV prodrugs have attracted much attention as the next generation of platinum‐based antineoplastic drug candidates. Here we report the discovery and evaluation of monochalcoplatin, a monocarboxylated Pt^IV prodrug that is among the most cytotoxic Pt^IV prodrugs to date. Compared with its dicarboxylated counterpart chalcoplatin, monochalcoplatin accumulates astonishingly effectively and rapidly in cancer cells, which is not ascribed to its lipophilicity. The prodrug is quickly reduced, causes DNA damage, and induces apoptosis, resulting in superior cytotoxicity with IC₅₀ values in the nanomolar range in both cisplatin‐sensitive and ‐resistant cells; these IC₅₀ values are up to 422‐fold higher than that of cisplatin. A detailed mechanistic study reveals that monochalcoplatin actively enters cells through a transporter‐mediated process. Moreover, monochalcoplatin shows significant antitumor activity in an in vivo colorectal tumor model. Our study implies a practical strategy for the design of more effective Pt^IV prodrugs to conquer drug resistance by tuning both cellular uptake pathways and activation processes.     

Photoinduced Reduction of PtIV within an Anti‐Proliferative PtIV–Texaphyrin Conjugate

In an effort to increase the stability and control the platinum reactivity of platinum–texaphyrin conjugates, two Pt^IV conjugates were designed, synthesized, and studied for their ability to form DNA adducts. They were also tested for their anti‐proliferative effects using wild‐type and platinum‐resistant human ovarian cancer cell lines (A2780 and 2780CP, respectively). In comparison to an analogous first‐generation Pt^II chimera, one of the new conjugates provided increased stability in aqueous environments. Using a combination of ¹H NMR spectroscopy and FAAS (flameless atomic‐absorption spectrometry), it was found that the Pt^IV center within this conjugate undergoes photoinduced reduction to Pt^II upon exposure to glass‐filtered daylight, resulting in an entity that binds DNA in a controlled manner. Under conditions in which the Pt^IV complex is reduced to the corresponding Pt^II species, these new conjugates demonstrated potent anti‐proliferative activity in both test ovarian cancer cell lines.     

Primary photophysical and photochemical processes upon UV excitation of PtBr<Subscript>6</Subscript><Superscript>2–</Superscript> and PtCl<Subscript>6</Subscript><Superscript>2–</Superscript> complexes in water and methanol

Primary photophysical and photochemical processes were studied for Pt^IVBr₆ ^2– and Pt^IVCl₆ ^2– complexes in water and methanol by ultrafast kinetic spectroscopy upon excitation in the band region of charge transfer from the ligand-centered group π-orbitals to the e_g*-orbital of Pt^IV complex anion (LMCT bands). The data obtained earlier upon excitation in the region of d—d bands were compared. Irrespective of the excitation wavelength, the photochemical properties of complexes are caused by the reactions of intermediates proceeding in the picosecond time range. These intermediates were identified as Pt^IVBr₅ ^– upon photolysis of Pt^IVBr₆ ^2– and, presumably, the Adamson radical pair [Pt^IIICl₅ ^2–(C _4v )...Cl?] upon photolysis of Pt^IVCl₆ ^2–. The difference in the exciting light wavelengths has an impact only on the first step of these processes, i.e., transition from the Franck—Condon excited state to intermediates.     

Nickel(II) Analogues of Phosphorescent Platinum(II) Complexes with Picosecond Excited-State Decay

Square-planar Ni^II complexes are interesting as cheaper and more sustainable alternatives to Pt^II luminophores widely used in lighting and photocatalysis. We investigated the excited-state behavior of two Ni^II complexes, which are isostructural with two luminescent Pt^II complexes. The initially excited singlet metal-to-ligand charge transfer (¹MLCT) excited states in the Ni^II complexes decay to metal-centered (³MC) excited states within less than 1 picosecond, followed by non-radiative relaxation of the ³MC states to the electronic ground state within 9–21 ps. This contrasts with the population of an emissive triplet ligand-centered (³LC) excited state upon excitation of the Pt^II analogues. Structural distortions of the Ni^II complexes are responsible for this discrepant behavior and lead to dark ³MC states far lower in energy than the luminescent ³LC states of Pt^II compounds. Our findings suggest that if these structural distortions could be restricted by more rigid coordination environments and stronger ligand fields, the excited-state relaxation in four-coordinate Ni^II complexes could be decelerated such that luminescent ³LC or ³MLCT excited states become accessible. These insights are relevant to make Ni^II fit for photophysical and photochemical applications that relied on Pt^II until now.     

Activation of Platinum(IV) Prodrugs By Motexafin Gadolinium as a Redox Mediator

Water‐soluble platinum(IV) prodrugs, which proved kinetically stable to reduction in the presence of physiological concentration of ascorbate, were quickly reduced to their active form, oxaliplatin, when co‐incubated with a macrocycle metallotexaphyrin (i.e., Motexafin Gadolinium (MGd)). The reduction of Pt^IV to Pt^II promoted by MGd occurs in cell culture as well, leading to an increase in the antiproliferative activity of the Pt^IV species in question. The mediated effect is proportional to the concentration of MGd and gives rise to an enhancement when the prodrug is relatively hydrophilic. MGd is known to localize/accumulate preferentially in tumor tissues. Thus, the present “activation by reduction” approach may allow for the cancer‐selective enhancement in the cytotoxicity of Pt^IV prodrugs.     

Human Serum Albumin Conjugated Nanoparticles for pH and Redox‐Responsive Delivery of a Prodrug of Cisplatin

Platinum anticancer drugs are particularly in need of controlled drug delivery because of their severe side effects. Platinum(IV) agents are designed as prodrugs to reduce the side effects of platinum(II) drugs; however, premature reduction could limit the effect as a prodrug. In this work, a highly biocompatible, pH and redox dual‐responsive delivery system is prepared by using hybrid nanoparticles of human serum albumin (HSA) and calcium phosphate (CaP) for the Pt^IV prodrug of cisplatin. This conjugate is very stable under extracellular conditions, so that it protects the platinum(IV) prodrug in HSA. Upon reaching the acidic and hypoxic environment, the platinum drug is released in its active form and is able to bind to the target DNA. The Pt–HSA/CaP hybrid inhibits the proliferation of various cancer cells more efficiently than cisplatin. Different cell cycle arrests suggest different cellular responses of the Pt^IV prodrug in the CaP nanocarrier. Interestingly, this delivery system demonstrates enhanced cytotoxicity to tumor cells, but not to normal cells.     

Development of a Pre‐assembled Through‐Bond Energy Transfer (TBET) Fluorescent Probe for Ratiometric Sensing of Anticancer Platinum(ll) Complexes

Fluorescence microscopy has emerged as an attractive technique to probe the intracellular processing of Pt‐based anticancer compounds. Herein, we reported the first through‐bond energy transfer (TBET) fluorescent probe NPR1 designed for sensitive detection and quantitation of Pt^II complexes. The novel TBET probe was successfully applied for ratiometric fluorescence imaging of anticancer Pt^II complexes such as cisplatin and JM118 in cells. Capitalizing on the ability of the probe to discriminate between Pt^II complexes and their Pt^IV derivatives, the probe was further applied to study the activation of Pt^IV prodrug complexes that are known to release active Pt^II species after intracellular reduction.     

Inorganic and organometallic chemistry of PtIII complexes having a delocalized PtIII—PtIII bond

Amidate-bridged dinuclear Pt^III complexes having a Pt^III—Pt^III bond react with ketones and alkenes. In the reaction with alkenes in water, 1,2-diols are obtained. In the reactions with conjugated dienes, stereospecific 1,4-diols are formed selectively. A kinetic study revealed that at each intermediate step of the reaction with alkenes the electronic state of the Pt—Pt bond changes between Pt^III—Pt^III and Pt^II—Pt^IV and stabilizes the reaction intermediates.     

A Ratiometric Fluorescent Probe for Cisplatin: Investigating the Intracellular Reduction of Platinum(IV) Prodrug Complexes

The Pt^IV prodrug strategy has emerged as an excellent alternative to tackle the problems associated with conventional Pt^II drug therapy. However, there is a lack of tools to study how this new class of Pt^IV drugs are processed at the cellular level. Herein, we report the first ratiometric probe for cisplatin detection and use it to investigate Pt^IV anticancer complexes in biological systems. The probe was able to distinguish between cisplatin and its Pt^IV derivatives, allowing us to probe the intracellular reduction of Pt^IV prodrug complexes. The correlation between the amount of active Pt^II species available after intracellular reduction of Pt^IV complexes and their cytotoxicity and the role glutathione plays in the reduction of Pt^IV complexes were investigated.     

195Pt-Kernresonanz in PtII-und PtIV-Verbindungen

The ¹⁹⁵Pt-nmr spectra of several Pt^IV- and Pt^II-complexes have been measured in aqueous solutions. It has been shown that this method has great potentialities for the evaluation of the bonding character in platinum complexes. The ¹⁹⁵Pt-resonance spectra of solutions containing mixed chloro-bromo-complexes of Pt^IV have been used for the estimation of relative stabilities of these complexes. It is pointed out that this method is generally applicable to determine equilibrium constants of platinum compounds.     

Primary reactions in the photochemistry of hexahalide complexes of platinum group metals: A minireview

We review the results obtained for Pt^IVCl₆²⁻, Pt^IVBr₆²⁻, Ir^IVCl₆²⁻, Ir^IVBr₆²⁻, and Os^IVBr₆²⁻ complexes in aqueous and alcoholic solutions using ultrafast pump–probe spectroscopy, laser flash photolysis, ESR, and photoelectron spectroscopy. We discuss the correlations between the photophysics and the photochemistry of these complexes. The key reaction for Pt^IVCl₆²⁻ is the inner-sphere electron transfer, which results in an Adamson radical pair that lives for several picoseconds, and the subsequent photoaquation in aqueous solutions and photoreduction in alcohols. The chlorine atom formed as the primary product escapes the solvent cage in aqueous solutions or oxidizes a solvent alcohol molecule via secondary electron transfer, producing secondary intermediates that react on the microsecond time scale. The photoexcitation of Pt^IVBr₆²⁻ results in the formation of pentacoordinated Pt^IV intermediates, i.e. ³Pt^IVBr₅⁻ and ¹Pt^IVBr₅⁻, with characteristic lifetimes of approximately 1 and 10 ps, respectively. Subsequent reactions of these intermediates result in the complexation of a solvent molecule. Photoreduction is also possible in alcohols. Similar reactions occur with rather low quantum yields for Ir^IVCl₆²⁻, therefore, only the ground-state recovery could be monitored in ultrafast experiments, which occur on the 10-ps time scale. The photochemical behaviours of the Ir^IVBr₆²⁻ and Os^IVBr₆²⁻ complexes are similar to those of Ir^IVCl₆²⁻ and Pt^IVBr₆²⁻, respectively.     

A Simple Route to the Synthesis of Pt Nanobars and the Mechanistic Understanding of Symmetry Reduction

Noble-metal nanocrystals with anisotropic shapes have received increasing interest owing to their unique properties. Here, a facile route to the preparation of Pt nanobars with aspect ratios tunable up to 2.1 was reported by simply reducing a Pt^IV precursor in N,N-dimethylformamide (DMF) at 160 °C in the presence of poly(vinyl pyrrolidone) (PVP). In addition to its commonly observed roles as a solvent and a reductant, DMF could also decompose to generate CO, a capping agent capable of selectively passivating Pt{100} facets to promote the formation of nanobars. The size and aspect ratio of the nanobars could be tuned by varying the amount of Pt^IV precursor involved in the synthesis, as well as the concentration of PVP because of its dual roles as a stabilizer and a co-reductant. Our mechanistic study indicated that the anisotropic growth resulted from both particle coalescence and localized oxidative etching followed by preferential growth.