Novel Nickel(II), Palladium(II), and Platinum(II) Complexes with O,S Bidendate Cinnamic Acid Ester Derivatives: An In Vitro Cytotoxic Comparison to Ruthenium(II) and Osmium(II) Analogues

(1) Background: Since the discovery of cisplatin’s cytotoxic properties, platinum(II) compounds have attracted much interest in the field of anticancer drug development. Over the last few years, classical structure–activity relationships (SAR) have been broken by some promising new compounds based on platinum or other metals. We focus on the synthesis and characterization of 17 different complexes with β-hydroxydithiocinnamic acid esters as O,S bidendate ligands for nickel(II), palladium(II), and platinum(II) complexes. (2) Methods: The bidendate compounds were synthesized and characterized using classical methods including NMR spectroscopy, MS spectrometry, elemental analysis, and X-ray crystallography, and their cytotoxic potential was assessed using in vitro cell culture assays. Data were compared with other recently reported platinum(II), ruthenium(II), and osmium(II) complexes based on the same main ligand system. (3) Results: SAR analyses regarding the metal ion (M), and the alkyl-chain position (P) and length (L), revealed the following order of the effect strength for in vitro activity: M > P > L. The highest activities have Pd complexes and ortho-substituted compounds. Specific palladium(II) complexes show lower IC₅₀ values compared to cisplatin, are able to elude cisplatin resistance mechanisms, and show a higher cancer cell specificity. (4) Conclusion: A promising new palladium(II) candidate (Pd3) should be evaluated in further studies using in vivo model systems, and the identified SARs may help to target platinum-resistant tumors.     

Synthesis, structural characterization, and pro-apoptotic activity of 1-indanone thiosemicarbazone platinum(II) and palladium(II) complexes: potential as antileukemic agents

In the search for alternative chemotherapeutic strategies against leukemia, various 1‐indanone thiosemicarbazones, as well as eight novel platinum(II) and palladium(II) complexes, with the formula [MCl₂(HL)] and [M(HL)(L)]Cl, derived from two 1‐indanone thiosemicarbazones were synthesized and tested for antiproliferative activity against the human leukemia U937 cell line. The crystal structure of [Pt(HL1)(L1)]Cl^.2M eOH, where L1=1‐indanone thiosemicarbazone, was solved by X‐ray diffraction. Free thiosemicarbazone ligands showed no antiproliferative effect, but the corresponding platinum(II) and palladium(II) complexes inhibited cell proliferation and induced apoptosis. Platinum(II) complexes also displayed selective apoptotic activity in U937 cells but not in peripheral blood monocytes or the human hepatocellular carcinoma HepG2 cell line used to screen for potential hepatotoxicity. Present findings show that, in U937 cells, 1‐indanone thiosemicarbazones coordinated to palladium(II) were more cytotoxic than those complexed with platinum(II), although the latter were found to be more selective for leukemic cells suggesting that they are promising compounds with potential therapeutic application against hematological malignancies.     

Carbenes Made Easy: Formation of Unsymmetrically Substituted N‐Heterocyclic Carbene Complexes of Palladium(II), Platinum(II) and Gold(I) from Coordinated Isonitriles and their Catalytic Activity

From palladium(II) or platinum(II) bis(isonitrile) complexes and from gold(I) isonitrile complexes, both easily available from simple precursors, the corresponding mono‐N‐heterocyclic carbene (NHC) complexes could be obtained selectively in good yields under very mild conditions. The reagents are simple β‐chloroammonium salts in the presence of a weak base. Unsymmetric NHC complexes are accessible. Thus over only two steps from simple metal precursors a broad variety of NHC complexes is available, the method is ideal to quickly assemble catalyst libraries. The palladium complexes are active pre‐catalysts in Suzuki cross‐coupling even with the additional isonitrile ligand on palladium.     

Reduction of nitroaromatics with poly(vinylpyridine) complexes of palladium(II) and platinum(II)

Palladium(II) and platinum(II) anchored to 2- and 4-vinylpyridine polymers of different molecular weights were used for the dihydrogen reduction of various nitroaromatics and benzaldehyde in ethanol at 50°C. Palladium(II) complexes were far more effective than their platinum(II) analogues and the activity decreased with increasing molecular weights of the polymers. The nitroaromatics were selectively and almost completely reduced to the corresponding anilines. During reduction, the orange palladium(II) complexes changed to voluminous green precipitates, which could be used repeatedly and preserved for a long time without any loss of activity. A rate equation of the type: rate = K[Cat] [H₂] has been derived and a reduction mechanism has been proposed on the basis of experimental results and kinetic data.     

The syntheses,characterization and fluorescence spectra of novel,octakis(alkylthiophthalocyanato) nickel(II) and palladium(II) complexes

The syntheses, characterization and fluorescence studies of several {octakis(alkylthio)phthalocyanato} palladium(II) and nickel(II) complexes are presented. The absorption spectra of some of the complexes showed extra peaks which are attributable to non-planar distortion, the extent of which, was found to dependent on alkyl chain length. The fluorescence excitation spectra of the nickel(II) derivatives were not in agreement with their absorption spectra, owing to structural changes upon excitation. Fluorescence quantum yields were very low (<1%) for all complexes as a consequence of the open-shell electronic structures of nickel(II) and palladium(II).     

Synthesis and cytotoxicity of enantiomerically pure [1,2-diamino-1-(4-fluorophenyl)-3-methylbutane]platinum(II) complexes

A series of leaving group derivatives of enantiomerically pure [1,2-diamino-1-(4-fluorophenyl)-3-methylbutane]platinum(II) complexes were synthesized and tested for cytotoxicity. The enantiomeric purity was determined by 1H NMR spectroscopy on the final diamines after derivation with (1R)-myrtenal. For coordination to platinum, the diamines were reacted with K2PtI4. The treatment of diiodoplatinum(II) complexes (4F-Ph/iProp-PtI2) with Ag2SO4 resulted in the sulfatoplatinum(II) complexes (4F-Ph/iProp-PtSO4), which can be easily transformed to dichloroplatinum(II) complexes (4F-Ph/iProp-PtCl2) with 2 n HCl. The importance of the leaving groups and the configuration at the diamine ligand on the antiproliferative effects was evaluated on the hormone-dependent MCF-7 and the hormone-independent MDA-MB 231 breast cancer cell lines as well as the LNCaP/FGC prostate cancer cell line. (R,R)-4F-Ph/iProp-PtCl2 was identified as the most active platinum(II) complex. The 3-methyl group increased antiproliferative effects relative to the [1,2-diamino-1-(4-fluorophenyl)butane]platinum(II) complexes described in an earlier study.     

Synthesis and Properties of Hydrazino Amino Acyclic Carbenes of Gold(I), Platinum(II), Palladium(II) and Rhodium(III)

The nucleophilic addition of protected and substituted hydrazine derivatives to isonitrile complexes of gold(I), platinum(II), palladium(II) and rhodium(III) provides the corresponding hydrazino amino acyclic carbene complexes. These are characterized by their spectroscopic data, four different X‐ray single crystal structure analyses and their catalytic activity in the gold(I)‐catalyzed cycloisomerization of N‐propargylcarboxamides to alkylideneoxazolines is investigated.

     

Methods for correction of selectivity of N-(2-sulfoethyl)chitosan-based materials towards platinum(IV) and palladium(II) ions

In this paper, we report methods for correction of selectivity of sorbents based on N-(2-sulfoethyl)chitosan towards platinum(IV) and palladium(II) in HCl solutions. The common method for correction of selectivity of the sorbents is variation of their modification degree with complexing groups. An increase in the degree of sulfoethylation of the chitosan leads to the significant increase in selectivity of sorption of palladium(II) over platinum(IV). Application of the N-(2-sulfoethyl)chitosan with the highest degree of sulfoethylation allows for selective separation palladium(II) from platinum(IV) (рН = 5.0). Palladium is quantitatively desorbed from the surface of the N-(2-sulfoethyl)chitosans by 3.5 mol/dm³ solution of HCl.     

Facile synthesis of new Pd(II) and Cu(II) based metallomesogens from ligands containing thiophene rings

Very simple synthetic procedures, involving use of tin/amine complex afford two new mesogenic thiophene derivatives. These can chelate palladium(II) or copper(II) producing the corresponding metallomesogens. The liquid crystal properties of all compounds were investigated by calorimetry, polarizing microscopy and X-ray diffraction techniques. Molecular and crystal structure of one ligand and two complexes were analyzed by single crystal X-ray diffraction. Connections between structural features and phase behaviour are discussed.     

Antiandrogen and Antimicrobial Aspects of Coordination Compounds of Palladium(II), Platinum(II) and Lead(II)

Synthesis, characterization and antimicrobial activities of an interesting class of biologically potent macrocyclic complexes have been carried out. All the complexes have been evaluated for their antimicrobial effects on different species of pathogenic fungi and bacteria. The testicular sperm density, testicular sperm morphology, sperm motility, density of cauda epididymal spermatozoa and fertility in mating trails and biochemical parameters of reproductive organs have been examined and discussed. The resulting biologically active [M(MaL(n))(R(2))]Cl(2) and [Pb(MaL(n))(R(2))X(2)] (where, M = Pd(II) or Pt(II) and X = Cl or NO(3)) type of complexes have been synthesized by the reactions of macrocyclic ligands (MaL(n)) with metal salts and different diamines in 1:1:1 molar ratio in methanol. Initially the complexes were characterized by elemental analyses, molecular weight determinations and conductivity measurements. The mode of bonding was established on the basis of IR, (1)H NMR, (13)C NMR, (195)Pt NMR, (207)Pb NMR, XRD and electronic spectral studies. The macrocyclic ligand coordinates through the four azomethine nitrogen atoms which are bridged by benzil moieties. IR spectra suggest that the pyridine nitrogen is not coordinating. The palladium and platinum complexes exhibit tetracoordinated square-planar geometry, whereas a hexacoordinated octahedral geometry is suggested for lead complexes.     

Solvent-Extraction Behavior of Cobalt(II), Nickel(II), Copper(II), and Palladium(II) with Tri-n-butylphosphate

Abstract

A systematic study of the extraction behavior of cobalt(II), nickel(II), copper(II), and palladium(II) with TBP from thiocyanate system in various ranges of acid concentrations has been performed. The thiocyanate medium leads to enhanced extractions in all these cases compared to those in the previously used chloride medium. For palladium, the chloride and nitrate systems have been critically examined. Sixty-two per cent extraction occurs from 4 M hydrochloric acid using 100% TBP in a single run and the extraction becomes quantitative (>99%) after four successive equilibrations. A simpler method has been proposed for rapid extraction of palladium(II) as the thiocyanate complex. Quantitative extraction occurs in the presence of 1.2% thiocyanate solution from 0.5 to 2 M hydrochloric acid (initial) up to pH 8.0. The extractable species of cobalt(II), nickel(II), copper(II), and palladium(II) from thiocyanate medium are probably similar and of the type [M(CNS)₄]^2? [K·TBP·3H₂O]₂ ⁺ (buffer solution) and [M(CNS)₄]^2? [H·TBP·3H₂O]⁺ ₂ (acid solution). A simple extraction scheme has been worked out for the separation of palladium(II) from iron(III), cobalt(II), nickel, manganese(II), copper(II), and platinum.     

Chiral Homobimetallic Palladium(II) Complexes Composed of Chirality-Organized Quinonediimines Bearing Amino Acid Moieties

The chirality-organized quinonediimine derivatives bearing amino acid moieties were demonstrated to react with 2 molar equiv. of Pd(OAc)₂, resulting in the formation of the chiral homobimetallic palladium(II) complexes. The crystal structures of the chiral conjugated complexes revealed the coordination of the quinonediimine nitrogen to a palladium center and a chiral propeller twist conformation of the π-conjugated backbone. The mirror image relationship of the CD signals around the quinonediimine moieties in acetonitrile was observed between l- and d-derivatives, indicating the preservation of the chirality-organized structures even in a solution.     

Solid-Phase Extraction of Pt(IV) with Dialkyl-(hexane-1,6-diyl) Phosphate Modified Merrifield Resins from Aqueous Chloride Media in Column Operations

A series of three dialkyl phosphate resins with a Merrifield resin support was used to extract platinum from acidic media. In column operations total capacities of 85-130 mg/g were gained. The presence of palladium and rhodium results in the order: Pt(IV) > Pd(II) >> Rh(III). From a leach liquor gained from spent automotive catalysts metals forming anionic chloro complexes are co-extracted only to a small extent. However, in order to separate and enrich platinum a selective back-extraction can be done with a sodium thiocyanate solution. A second elution step with acidic thiourea leads to a mixed solution of palladium and rhodium.     

Well-defined N-heterocyclic carbenes-palladium(II) precatalysts for cross-coupling reactions

Metal-catalyzed cross-coupling reactions, notably those permitting C-C bond formation, have witnessed a meteoritic development and are now routinely employed as a powerful synthetic tool both in academia and in industry. In this context, palladium is arguably the most studied transition metal, and tertiary phosphines occupy a preponderant place as ancillary ligands. Seriously challenging this situation, the use of N-heterocyclic carbenes (NHCs) as alternative ligands in palladium-catalyzed cross-coupling reactions is rapidly gaining in popularity. These two-electron donor ligands combine strong sigma-donating properties with a shielding steric pattern that allows for both stabilization of the metal center and enhancement of its catalytic activity. As a result, the number of well-defined NHC-containing palladium(II) complexes is growing, and their use in coupling reactions is witnessing increasing interest. In this Account, we highlight the advantages of this family of palladium complexes and review their synthesis and applications in cross-coupling chemistry. They generally exhibit high stability, allowing for indefinite storage and easy handling. The use of well-defined complexes permits a strict control of the Pd/ligand ratio (optimally 1/1), avoiding the use of excess costly ligand that usually requires end-game removal. Furthermore, it partly removes the "black box" character often associated with cross-coupling chemistry and catalyst formation. In the present Account, four main classes of NHC-containing palladium(II) complexes will be presented: palladium dimers with bridging halogens, palladacycles, palladium acetates and acetylacetonates, and finally pi-allyl complexes. These additional ligands are best described as a protecting shell that will be discarded going from the palladium(II) precatalyst to the palladium(0) true catalyst. The synthesis of all these precatalysts generally requires simple and short synthetic procedures. Their catalytic activity in different cross-coupling reactions is discussed and put into context. Remarkably, some NHC-containing catalytic systems can achieve extremely challenging coupling reactions such as the formation of tetra-ortho-biphenyl compounds and perform reactions at very low loadings of palladium (ppm levels). The chemistry described here, combining fundamental organometallic, catalysis, and pure organic methodology, remains rich in opportunities considering that only a handful of palladium(II) architectures have been studied. Hence, en route to an "ideal catalyst", [(NHC)Pd(II)] compounds exhibit remarkable stability and allow for fine-tuning of the NHC and of surrounding ligands in order to control the activation and the catalytic activity. Finally, unlike [Pd(PPh(3))(4)], [(NHC)Pd(II)] compounds have so far been examined only in palladium-mediated reactions (most often cross-coupling such as the Suzuki-Miyaura and Heck reactions), leaving a treasure trove of exciting discoveries to come.     

EQUILIBRIUM OF PALLADIUM(II) EXTRACTION WITH 1-OCTYLTHEOBROMINE

ABSTRACT

1-Octyltheobromine was synthesized to study extraction equiliburium of palladium(II). To evaluate its efficiency as an extractant, the extraction of palladium(II) from acidic chloride media was studied at 303K using toluene. The extraction of palladium(II) from hydrochloric acid media by 1-octyltheobromine exhibited high selectivity for palladium(II) over the platinum group metals. The stoichiometrics of the extraction of palladium(II) with 1-octyltheobromine was elucidated by examining the effects of hydrochloric acid, chloride ion, hydrogen ion, extractant and metal ion concentrations on its extractability. Palladium(II) was found to be extracted as two molecules of 1-octyltheobromine reacted with PdCl₂ as follows: PdCl₂ +{2}¯RN ? ¯PdCl₂(RN)₂. The extraction equilibrium constant was K=2.72?×?10⁸(mol?dm^?3)^?2. The complex of 1-octyltheobromine with PdCl₂ was confirmed by mass spectrometric analysis. The stripping of palladium(II) was performed over 60% by a single batchwise treatment with an aqueous solution of thiourea or ammonia.     

SOLVENT EXTRACTION OF COPPER (II) WITH AN ALDOXIME FROM HYDROCHLORIC AND HYDROBROMIC ACIDS

2-ethylhexanal oxime was synthesized to examine the selectivities for various metals in the extractions from hydrochloric acid. It was found to be highly selective for palladium(II) over platinum(II and IV) and other base metals including copper(II), zinc and aluminum, especially in the low concentration region of chloride ions.     

The Development of Palladium(II)-Specific Amine-Functionalized Silica-Based Microparticles: Adsorption and Column Separation Studies

The adsorption and separation of platinum(IV) and palladium(II) chlorido species ([PtCl₆]^2? and [PdCl₄]^2?) on silica-based microparticles functionalized with ammonium centers based on ethylenediamine (EDA), diethylenetriamine (DETA), triethylenetriamine (TETA) and tris-(2-aminoethyl)amine (TAEA) were investigated. The functionalized sorbent materials were characterized using SEM, XPS, BET, and FTIR. The sorbents were used in the batch and column study for adsorption and selective separation of [PtCl₆^2? and PdCl₄]^2?. The adsorption model for both [PtCl₆]^2? and [PdCl₄]^2? on the different sorbent materials fitted the Freundlich isotherm with R² values > 0.99. The S-TETA sorbent material was palladium(II) specific. Pd(II) loaded on the silica column was recovered using 3% m/v thiourea solution as the eluting agent. Separation of platinum and palladium was achieved by selective stripping of [PtCl₆]^2? with 0.5 M of NaClO₄ in 1.0 M HCl while Pd(II) was eluted with 0.5 M thiourea in 1.0 M HCl. The separation of palladium (Pd) from a mixture containing platinum (Pt), iridium (Ir), and rhodium (Rh) was successful on silica functionalized with triethylenetriamine (TETA) showing specificity for palladium(II) and a loading capacity of 0.27 mg/g. S-TETA showed potential for use in the recovery of palladium from platinum group metals such as from solutions of worn out automobile emission control catalytic convertors and other secondary sources.     

Stereo-regulated methyl methacrylate (MMA) polymerization catalyzed by asymmetric Salen-type Schiff-base Cu(II) complexes

A series of mononuclear asymmetric Salen-type Schiff-base complexes [Cu(Lⁿ)] (n = 1–5, 1–5) were obtained by the Cu(II)-templated approach in the presence of one of five salicylaldehyde derivatives, respectively. These complexes could effectively catalyze the metal-coordinative polymerization of MMA for the formation of the syndio-enriched PMMAs (poly(methyl methacrylates)) in the presence of AIBN, where the Cu(II)-to-chelate-plane distances are positively relative to the catalytic activity. Moreover, the introduction of the encumbering substituent ortho to the phenoxide ring of the ligands plays a much more important and influential role on the tacticity and chain-growth of the obtained PMMAs than the variation of reaction conditions under the controllable polymerization.     

Polymers containing metal chelate units. V Modification of a polyethylene surface by post-grafting polymerization of palladium(II) chelate monomers

The synthesis of palladium(II) chelate monomers involving 1-phenyl-4-methylpent-4-en-1,3-dione and 1 phenyl-3-anilino-4-methylpent-4-en-1-one has been developed. New polymer-containing metal chelate units have been prepared by post-grafting polymerization of these monomers and the products characterized by elemental analysis and IR spectroscopy. The catalytic properties of the immobilized complexes in chloronitrobenzene hydrogenation have been studied.     

Synthesis,Cytotoxicity, Induction of Apoptosis,and Interaction with DNA of Dinuclear Platinum(II) Complexes

Six dicarboxylato‐bridged dinuclear platinum(II) complexes S1 – S6 , with a newly designed chiral ligand, 2‐{[(1R,2R)‐2‐aminocyclohexyl]amino}propanoic acid ( HL ), were prepared and spectrally characterized. The in vitro cytotoxicity of all resulting platinum(II) complexes was evaluated against human HCT‐116, MCF‐7, and HepG‐2 tumor cell lines. The results show that all compounds exhibit positive biological activity toward HCT‐116 and MCF‐7 cell lines, of which complexes S3 , S4 , and S5 , with succinate and its derivatives as bridges, showing better activity than the positive controls. Moreover, double‐dyeing flow cytometric resection experiments indicate that the target compounds inhibit tumor cell growth by inducing apoptosis; gel electrophoresis experiments demonstrate the compounds′ ability to prompt pET22b plasmid DNA degradation in almost the same way as oxaliplatin.