Organoplatinum Research Articles

Immobilisation of Platinum by Cupriavidus metallidurans

The metal resistant bacterium Cupriavidus metallidurans CH34, challenged with aqueous platinous and platinic chloride, rapidly immobilized platinum. XANES/EXAFS analysis of these reaction systems demonstrated that platinum binding shifted from chloride to carboxyl functional groups within the bacteria. Pt(IV) was more toxic than Pt(II), presumably due to the oxidative stress imparted by the platinic form. Platinum immobilisation increased with time and with increasing concentrations of platinum. From a bacterial perspective, intracellular platinum concentrations were two to three orders of magnitude greater than the fluid phase, and became saturated at almost molar concentrations in both reaction systems. TEM revealed that C. metallidurans was also able to precipitate nm-scale colloidal platinum, primarily along the cell envelope where energy generation/electron transport occurs. Cells enriched in platinum shed outer membrane vesicles that were enriched in metallic, colloidal platinum, likely representing an important detoxification strategy. The formation of organo-platinum compounds and membrane encapsulated nanophase platinum, supports a role for bacteria in the formation and transport of platinum in natural systems, forming dispersion halos important to metal exploration.

Influence of ancillary ligands on the photophysical properties of cyclometalated organoplatinum(ii) complexes

The photophysical properties of three series of cyclometalated organoplatinum(ii) complexes were studied and the influence of changing the ancillary ligands and substituents on their luminescence properties were investigated.

Successive alkylation of PtII by RI to form bis-organoplatinum(IV) derivatives as key steps for cross-electrophile coupling

A solvent-specific reduction of PtIV iodo complexes into PtII by iodide ions was found: in acetone, PtIV iodo complexes are almost quantitatively reduced into PtII, and iodine, which is formed upon the reduction, is bound in a poorly soluble polymeric complex with NaI and acetone.The revealed solvent-specific reduction of PtIV into PtII was used for sequential alkylation of PtII iodo complexes with iodoacetone to form mono-, bis-, and tris-acetonyl PtIV derivatives and also with iodoacetic acid to give mono- and bis-carboxymethyl PtIV complexes. The reaction of iodoacetic acid is accompanied by its catalytic reduction into acetic acid.The organic ligands in the formed organoplatinum compounds are mutually cis, which is essential for further accomplishment of C-C coupling reactions.

Singly and Doubly N-Confused Calix[4]phyrin Organoplatinum(II) Complexes as Near-IR Triplet Sensitizers

Organoplatinum(II) complexes of calix[4]phyrin analogues, singly N-confused calix[4]phyrin (Pt-2), and doubly N-confused calix[4]phyrin (Pt-3), were synthesized and characterized. The explicit structures of these organoplatinum(II) complexes were elucidated by single-crystal X-ray diffraction and spectroscopic studies. The introduction of N-confused pyrrole rings to the parent calix[4]phyrin scaffold was found to have profound effects on the photophysical properties, such as the bathochromic shifts of both the absorption and phosphorescence maxima. The triplet excited state properties of these platinum complexes were analyzed by DFT calculations at the B3LYP level. The organoplatinum(II) complexes derived from the deformed scaffolds can serve as potent triplet sensitizers for singlet oxygen generation under aerobic conditions.

Producing irreversible topoisomerase II-mediated DNA breaks by site-specific Pt(II)-methionine coordination chemistry.

Human type II topoisomerase (Top2) isoforms, hTop2α and hTop2β, are targeted by some of the most successful anticancer drugs. These drugs induce Top2-mediated DNA cleavage to trigger cell-death pathways. The potency of these drugs correlates positively with their efficacy in stabilizing the enzyme-mediated DNA breaks. Structural analysis of hTop2α and hTop2β revealed the presence of methionine residues in the drug-binding pocket, we therefore tested whether a tighter Top2-drug association may be accomplished by introducing a methionine-reactive Pt2+ into a drug to further stabilize the DNA break. Herein, we synthesized an organoplatinum compound, etoplatin-N2β, by replacing the methionine-juxtaposing group of the drug etoposide with a cis-dichlorodiammineplatinum(II) moiety. Compared to etoposide, etoplatin-N2β more potently inhibits both human Top2s. While the DNA breaks arrested by etoposide can be rejoined, those captured by etoplatin-N2β are practically irreversible. Crystallographic analyses of hTop2β complexed with DNA and etoplatin-N2β demonstrate coordinate bond formation between Pt2+ and a flanking methionine. Notably, this stable coordinate tether can be loosened by disrupting the structural integrity of drug-binding pocket, suggesting that Pt2+ coordination chemistry may allow for the development of potent inhibitors with protein conformation-dependent reversibility. This approach may be exploited to achieve isoform-specific targeting of human Top2s.

Spectroscopic Characterization on the Interaction Between Synthesized Platinum(II)-Based Drug and Human Serum Albumin

The interaction of a new organoplatinum(II) complex [Pt(pr-dtc)(bpy)]NO3 (where pr-dtc = propyldithiocarbamate and bpy = 2,2′-bipyridine), as anticancer agent with human serum albumin (HSA) in aqueous solution at pH 7.4 has been studied by fluorescence, UV–Vis absorption, and CD spectroscopy. The quenching constants and binding parameters were determined by fluorescence quenching method. The obtained results revealed that there is a strong binding interaction between Pt(II) complex and HSA. The calculated thermodynamic parameters (ΔG, ΔH, and ΔS) confirmed that the binding reaction is mainly entropy driven, and hydrophobic forces played a major role in the reaction. The binding distance (r) between the Pt(II) complex (acceptor) and HAS (donor) was obtained based on Forsters theory of non-radiation energy transfer. Finally, the results of CD and UV–Vis spectroscopy showed that the binding of this complex to HSA induced conformational changes in protein. We hope that such spectroscopic studies will indeed be helpful in studying the pharmacological response of drugs and design of dosage forms.

Producing irreversible topoisomerase II-mediated DNA breaks by site-specific Pt(II)-methionine coordination chemistry.

Human type II topoisomerase (Top2) isoforms, hTop2α and hTop2β, are targeted by some of the most successful anticancer drugs. These drugs induce Top2-mediated DNA cleavage to trigger cell-death pathways. The potency of these drugs correlates positively with their efficacy in stabilizing the enzyme-mediated DNA breaks. Structural analysis of hTop2α and hTop2β revealed the presence of methionine residues in the drug-binding pocket, we therefore tested whether a tighter Top2-drug association may be accomplished by introducing a methionine-reactive Pt2+ into a drug to further stabilize the DNA break. Herein, we synthesized an organoplatinum compound, etoplatin-N2β, by replacing the methionine-juxtaposing group of the drug etoposide with a cis-dichlorodiammineplatinum(II) moiety. Compared to etoposide, etoplatin-N2β more potently inhibits both human Top2s. While the DNA breaks arrested by etoposide can be rejoined, those captured by etoplatin-N2β are practically irreversible. Crystallographic analyses of hTop2β complexed with DNA and etoplatin-N2β demonstrate coordinate bond formation between Pt2+ and a flanking methionine. Notably, this stable coordinate tether can be loosened by disrupting the structural integrity of drug-binding pocket, suggesting that Pt2+ coordination chemistry may allow for the development of potent inhibitors with protein conformation-dependent reversibility. This approach may be exploited to achieve isoform-specific targeting of human Top2s.

Organophosphines in organoplatinum complexes: structural aspects of PtPCX2 (X = OL, NL, Cl, SL, SeL, SiL, Br or I) derivatives

In this review are classified and analyzed the structural parameters of eighty monomeric organoplatinum complexes with inner coordination spheres of PtPCX2 (X = OL, NL, Cl, SL, SeL, SiL, Br or I). These complexes crystallized in four crystal systems: cubic, orthorhombic, monoclinic and triclinic. Distorted square planar environments about the Pt(II) atoms are built up from monodentate, homobidentate, heterobidentate and heterotridentate donor ligands. The chelating ligands create wide varieties of metallocycles. These are discussed in terms of the coordination about the platinum atom, and correlations are drawn between donor atoms, bond lengths and interbond angles, with particular attention to any trans-influence. There are complexes with cis- as well as trans-configurations, but the former by far prevail. The Pt–L bonds in the complexes with cis-configuration appear to be more polar and presumably weaker than those in their trans-partners.

Reaction of dimethylplatinum(II) complexes with PhCH2CH2Br: Comparative reactivity with CH3CH2Br and PhCH2Br and synthesis of Pt(IV) complexes

Oxidative addition of 2‐phenylethylbromide (PhCH2CH2Br) to dimethylplatinum(II) complexes [PtMe2(NN)] (1a, NN = 2,2′‐bipyridine (bpy); 1b, NN = 1,10‐phenanthroline (phen)) afforded the new organoplatinum(IV) complexes [PtMe2(Br)(PhCH2CH2)(bpy)], as a mixture of trans (2a) and cis (3a) isomers, and [PtMe2(Br)(PhCH2CH2)(phen)], as a mixture of trans (2b) and cis (3b) isomers, respectively. The new Pt(IV) complexes were readily characterized using multinuclear (1H and 13C) NMR spectroscopy and elemental microanalysis. The crystal structure of 2a was further determined using X‐ray crystallography indicating an octahedral geometry around the platinum centre. A comparison of reactivity of RCH2Br reagents (R = CH3, Ph or PhCH2) in their oxidative addition reactions with complex 1a, with an emphasis on the effects of the R groups of alkyl halides, was also conducted using density functional theory.

A nanohybrid of organoplatinum(II) complex and graphene oxide as catalyst for reduction of p-nitrophenol

In this study, a organoplatinum(II) complex, [Pt(ppy)Cl(dmso)], dmso = dimethylsulfoxide and ppy = deprotonated 2-phenylpyridine, has been covalently immobilized on the graphene oxide (GO) surface through coordination interaction with 3-(aminomethyl)pyridine (3-ampy) ligand spacers (3-ampy-GO), which was synthesized through covalent bonds between NH2 functional groups of 3-ampy and the epoxy groups of GO. The synthesis of Pt(0)/3-ampy- reduced-graphene oxide (RGO) nanohybrid by the reduction of [Pt(ppy)Cl(3-ampy)]/GO nanohybrid with hydrazine in an aqueous solution was studied. Nanohybrids were characterized by transmission electron microscopy (TEM), X-ray diffraction (XRD), energy dispersive X-ray analysis (EDAX), X-ray photoelectron spectroscopy (XPS), Raman spectroscopy, and Fourier transform infrared spectroscopy (FT-IR). Catalytic activities of these nanohybrids were investigated in the p-nitrophenol reduction. On the basis of comparative kinetic studies, the following trend was obtained for the effect of the related nanohybrid catalyst on the rate of reaction: [Pt(ppy)Cl(3-ampy)]/GO > Pt(0)/3-ampy-RGO.

Fine Dispersion of Pt4–5 Subnanoclusters and Pt Single Atoms over Porous Carbon Supports and Their Structural Analyses with X-ray Absorption Spectroscopy

We demonstrate the fine dispersion of Pt4–5 subnanoclusters or Pt single atoms on two types of porous carbon supports, Ketjen black (KB) and zeolite-templated carbon (ZTC). The loading amount of Pt4–5 subnanoclusters reached as much as ca. 4 and 13 wt % for KB and ZTC, respectively. For the fine dispersion of Pt subnanoclusters, simply filling an organoplatinum complex, (COD)PtMe2, as a Pt precursor into the micropores is found to be crucial to prevent agglomeration or sintering of Pt subnanoclusters. Moreover, it is possible to disperse Pt single atoms on ZTC, simply by decreasing the Pt loading amount down to ca. 0.9 wt %, owing to some stabilization effect by oxygen-containing functional groups. The detailed structural insights into the supported Pt subnanoclusters and Pt single atoms were analyzed by X-ray absorption spectroscopy (XAS). Extended X-ray absorption fine structure (EXAFS) analysis for Pt subnanoclusters reveals that the Pt–Pt bond is contracting to a large extent (∼2.8%) relative to balk ...

Exploring the Influence of the Aromaticity on the Anticancer and Antivascular Activities of Organoplatinum(II) Complexes

A series of new organometallic PtII complexes of the type [Pt(C^N)Cl(DMSO)] (C^N=N,N-dimethyl-1-(2-aryl)methanamine-κ2 C2,N; aryl=phenyl 2 a, biphenyl 2 b, p-terphenyl 2 c, naphthyl 2 d, anthracenyl 2 e, or pyrenyl 2 f) have been synthesized to explore the influence of the aromaticity on their anticancer activity. The best performers, 2 b and d, are more active than cisplatin (CDDP) in epithelial ovarian carcinoma cells A2780, with 2 d having a higher selectivity factor than CDDP in all the tested cell lines. In addition, all the new compounds overcome the acquired resistance in A2780cisR cells and interestingly, show low micromolar IC50 values towards the triple negative breast cancer cell line MDA-MB-231 and the highly metastatic 518A2 melanoma cells. This study shows that the hydrophobicity, accumulation into cells, and metal levels on nuclear DNA for the complexes are consistent with their cytotoxicity. Complexes 2 b and d induce apoptosis in a caspase-independent manner and suppress the intracellular ROS generation without modifying the mitochondria membrane potential. In addition, 2 a-f effectively inhibit angiogenesis in the endothelial cell line EA.hy926 at sub-cytotoxic concentrations and 2 b and d show in vivo antivascular effects on the chorioallantoic membrane (CAM) of fertilized SPF-eggs (SPF=specific-pathogen-free). Inhibition of tubulin polymerization and degeneration of cytoskeleton organization in 518A2 melanoma cells are presented as a preliminary mechanism of its antimetastatic activity.

Melatonin prevents mitochondrial dysfunction and promotes neuroprotection by inducing autophagy during oxaliplatin-evoked peripheral neuropathy.

Oxaliplatin, an organoplatinum compound, is used in the treatment of colorectal cancer, but its clinical use can be limited due to the development of peripheral neuropathy. Whilst mitochondrial dysfunction has been implicated as a major pathomechanism for oxaliplatin-induced neurotoxicity, the prevention of autophagy may also aggravate neuronal cell death. Melatonin, a well-known mitoprotectant and autophagy inducer, was used to examine its neuroprotective role in oxaliplatin-induced peripheral neuropathy (OIPN). Melatonin prevented the loss of mitochondrial membrane potential (Ψm) and promoted neuritogenesis in oxaliplatin-challenged neuro-2a cells. It did not interfere with the cytotoxic activity of oxaliplatin in human colon cancer cell line, HT-29. Melatonin treatment significantly alleviated oxaliplatin-induced pain behavior and neuropathic deficits in rats. It also ameliorated nitro-oxidative stress mediated by oxaliplatin, thus prevented nitrosylation of proteins and loss of antioxidant enzymes, and therefore, it improved mitochondrial electron transport chain function and maintained cellular bioenergetics by improving the ATP levels. The protective effects of melatonin were attributed to preventing oxaliplatin-induced neuronal apoptosis by increasing the autophagy pathway (via LC3A/3B) in peripheral nerves and dorsal root ganglion (DRG). Hence, it preserved the epidermal nerve fiber density in oxaliplatin-induced neuropathic rats. Taken together, we provide detailed molecular mechanisms for the neuroprotective effect of melatonin and suggest it has translational potential for oxaliplatin-induced neuropathy.

Organophosphines in organoplatinum complexes: structural aspects of trans-PtP2C2 derivatives

AbstractThis review summarized and analyzed the structural parameters of 174 monomeric organoplatinum complexes with an inner coordination sphere of trans-PtP2C2. These complexes crystallized in four crystal systems: hexagonal (x2), orthorhombic (x13), triclinic (x76), and monoclinic (x84). These complexes, on the basis of the coordination mode of the respective donor ligands, can be divided into the seven sub-groups: Pt(PL)2(CL)2, Pt(PL)2(η2-C2L), Pt(η2-P2L)(CL)2, Pt(PL)(η2-P,CL)(CL), Pt(η2-P,CL)2, Pt(η3-P,C,PL)(CL), and Pt(η3-C,P,CL)(PL). The chelating ligands create 4-, 5-, 6-, 16-, 17-, 18-, and 19-membered rings. The total mean values of Pt-L bond distances are 2.055 Å (C) and 2.300 Å (P). There are examples that exist in two isomeric forms and are examples of distortion isomerism. The structural parameters of trans-PtP2C2 are discussed with those of cis-PtP2C2 derivatives.

Photophysical study on unsymmetrical binuclear cycloplatinated(ii) complexes

A general synthetic method has been designed to prepare a new series of unsymmetrical binuclear cyclometalated organoplatinum(ii) complexes and the effect of each part on their luminescence properties were investigated.

Reactivity of organoplatinum complexes containing appended alcohol functional groups: Activation of dioxygen and hydrogen peroxide

The oxidative addition reactions of platinum(II) complexes [PtMe2(RN=CH-2-C5H4N)], especially when R = CH2CH2OH or CH2CH2CH2OH, have been studied. Both complexes react with R’X (MeI or PhCH2Br) by trans oxidative addition to give [PtXMe2R′(RN=CH-2-C5H4N)]. They also react with oxygen in methanol solution or with hydrogen peroxide to give [Pt(OH)(OMe)Me2(RN=CH-2-C5H4N)] or [Pt(OH)2Me2(RN=CH-2-C5H4N)], respectively, but the reactions are complicated in the case with R = (CH2)3OH by partial cyclization of the imine ligand to give the corresponding oxazine complex. When R = CH2CH2OH, the complex [PtMe2(RN=CH-2-C5H4N)] reacts with oxygen in acetone solution to give the platinum(IV) complex [Pt(OH)Me2{κ3-N,N,O-RNH-CH(2-C5H4N)(CHCMeO)}], but no reaction occurs when R = CH2CH2CH2OH or CH2CH2NMe2. It is suggested that the hydroxyethyl substituent plays a key role in the dioxygen activation and subsequent reactions of a coordinated acetone molecule.

Design of alkyl- and haloalkyl complexes of dimethylplatinum(IV) via oxidative addition: Reactivity, characterization and crystal structures

Dimethylplatinum(II) complexes [PtMe2(NN)] {NN=5,5′-Me2bpy (5,5′-dimethyl-2,2′-bipyridine; phen (1,10-phenanthroline)} were reacted with benzyl bromide to yield the organoplatinum(IV) complexes [PtMe2(PhCH2)Br(NN)] {NN=5,5′-Me2bpy (1), phen (2)}. On the basis of NMR data, the Pt(IV) products of 1–2 contain almost exclusively the trans isomer and small traces of the cis isomers are also observed. Oxidative addition of dimethylplatinum(II) complexes [PtMe2(NN)] with dihaloalkanes CH2Cl2 and Br(CH2)4Br have also been investigated. The reactions of complexes [PtMe2(NN)] {NN=4,4′-Me2bpy (4,4′-dimethyl-2,2′-bipyridine); 5,5′-Me2bpy; phen} with dihaloalkanes CH2Cl2 and Br(CH2)4Br resulted in the formation of the new organoplatinum(IV) complexes [PtMe2(CH2Cl)Cl(NN)] {NN=4,4′-Me2bpy (3); 5,5′-Me2bpy (4)} and [PtMe2{(CH2)4Br}Br(NN)] {NN=4,4′-Me2bpy (5); 5,5′-Me2bpy (6); phen (7)}, respectively. The products have been characterized by elemental analysis, 1H, 13C, HH-COSY and DEPT-135 NMR spectroscopy. On the basis of NMR data, in the case of CH2Cl2, the platinum(IV) products of the reaction contain a mixture of cis and trans isomers, while small traces of the cis isomer are observed in the case of Br(CH2)4Br. NMR data indicates that the trans influence of bpy, 4,4′-Me2bpy and 5,5′-Me2bpy is the same. The crystal structures of [PtMe2(CH2Cl)Cl(4,4′-Me2bpy)] and [PtMe2{(CH2)4Br}Br(4,4′-Me2bpy)] reveal a slightly distorted octahedral geometry of the platinum(IV) metal center with haloalkyl group trans to halide. The haloalkyl chains of CH2Cl and (CH2)4Br units are twisted respect to the 4,4′-Me2bpy ligand with a syn arrangement. Therefore, the steric hindrance can be partially relieved.

Photophysical Properties of Organoplatinum(II) Compounds and Derived Self-Assembled Metallacycles and Metallacages: Fluorescence and its Applications.

Over the past couple of decades, coordination-driven self-assembly has evolved as a broad multidisciplinary domain that not only covers the syntheses of aesthetically pleasing supramolecular architectures but also emerges as a method to form new optical materials, chemical sensors, theranostic agents, and compounds with light-harvesting and emissive properties. The majority of these applications depend upon investigations that reveal the photophysical nature and electronic structure of supramolecular coordination complexes (SCCs), including two-dimensional (2D) metallacycles and three-dimensional (3D) metallacages. As such, well-defined absorption and emission spectra are important for a given SCC to be used for sensing, bioimaging, and other applications with molecular fluorescence being an important component. In this Account, we summarize the photophysical properties of some bis(phosphine)organoplatinum(II) compounds and their discrete SCCs. The platinum(II) based organometallic precursors typically display spectral red-shifts and have low fluorescence quantum yields and short fluorescence lifetimes compared to their organic counterparts because the introduction of metal centers enhances both intersystem crossing (ISC) and intramolecular charge transfer (ICT) processes, which can compete with the fluorescence emissions. Likewise ligands with conjugation can also increase the ICT process; hence the corresponding organoplatinum(II) compounds undergo a further decrease in fluorescence lifetimes. The use of endohedral amine functionalized 120°-bispyridyl ligands can dramatically enhance the emission properties of the resultant organoplatinum(II) based SCCs. As such these SCCs display emissions in the visible region (ca. 400-500 nm) and are significantly red-shifted (ca. 80-100 nm) compared to the ligands. This key feature makes them suitable as supramolecular theranostic agents wherein these unique emission properties provide diagnostic spectroscopic handles and the organoplatinum(II) centers act as potential anticancer agents. Using steady state and time-resolved-spectroscopic techniques and quantum computations in concert, we have determined that the emissive properties stem from the ligand-centered transitions involving π-type molecular orbitals with modest contributions from the metal-based orbitals. The self-assembly and the photophysics of organoplatinum(II) ← 3-substituted pyridyl based SCCs are highly diverse. Subtle changes in the ligands' structures can form molecular congener systems with distinct conformational and photophysical properties. Furthermore, the heterometallic SCCs described herein possess rich photophysical properties and can be used for sensing based applications. Tetraphenylethylene (TPE) based SCCs display emissions in the aggregated state as well as in dilute solutions. This is a unique phenomenon that bridges the aggregation caused quenching (ACQ) and aggregation induced emission (AIE) effects. Moreover, a TPE based metallacage exhibits solvatoluminescence, including white light emission in THF solvent, and can act as a fluorescence-sensor for structurally similar ester compounds.

Metal effects on the asymmetric syntheses of chiral P−N bidentate ligands

The organoplatinum complex containing ortho-metalated (S)-[1-(dimethylamino)ethyl]naphthalene as the chiral auxiliary has been used to promote the asymmetric cycloaddition reactions between 3,4-dimethyl-1-phenyl phosphole and (E)-1-phenyl-3-pyridin-2-yl-2-propenone or (E)-1-methyl-3-pyridin-2- yl-2-propenoate in high selectivity under mild condition. However, the corresponding palladium complex didn't show similar reactivity. This Diels−Alder reaction generated five new stereogenic centers in a single step. The naphthylamine auxiliary could be removed chemoselectively from the template products by treatment with concentrated hydrochloric acid to form the corresponding dichloro platinum complexes [(P−N)PtCl2]. The molecular structure and absolute configuration of the major dichloro platinum complex have been resolved by single-crystal X-ray diffraction. Finally, the enantiomerically pure P−N ligands can be readily liberated from the corresponding dichloro platinum complexes as air-sensitive solids by treatment with aqueous potassium cyanide in quantitative yield.

ChemInform Abstract: Advances on Supramolecular Assembly of Cyclometalated Platinum(II) Complexes

AbstractReview: 66 refs.