Methimazole complexes of platinum(II): Synthesis, characterization and redox behavior

A variety of platinum(II) complexes of methimazole (2-mercapto-1-methylimidazole; HImS = neutral form and ImS = thiolate form), coordinated in both thione and thiolate forms, have been isolated by reacting methimazole with [PtCl(terpy)]Cl (terpy = 2,2′:6′,2″ terpyridine), [PtCl₂(bipy)] (bipy = bipyridine), [PtCl₂(o-phen)] (o-phen = o-phenanthroline), [PtCl₂(CH₃CN)₂] and [PtCl₂(COD)] (COD = 1,5-cyclooctadiene). These complexes were characterized by electronic absorption, IR and NMR (¹H, ¹³C, ¹⁹⁵Pt) spectroscopies. Molecular structure of [Pt(bipy)(HImS)₂]Cl₂·3H₂O (3a·3H₂O) has been established by single crystal X-ray crystallography. Platinum thiolate complex, [Pt(ImS)₂(HImS)₂] (5), could be obtained by treatment of [Pt(HImS)₄]Cl₂ with sodium methoxide in methanol. The solution of 5 in organic solvents yielded bi- and tri-nuclear platinum complexes. The effect of diimine ligands on oxidation of methimazole moiety in the complexes has been studied by electrochemical oxidation and pulse radiolytic oxidation employing specific one-electron oxidant, radical.     

Synthesis and characterization of heteroscorpionate dioxo-tungsten(VI) complexes

Twelve new dioxo W(VI) complexes of a family of heteroscorpionate ligands of the type [(L)WO₂Y], where L = N₂X ligand and Y = Cl or OR, have been synthesized and characterized. With the more sterically bulky ligands we show that these complexes exist as isolable cis and trans isomers and compare the rate of such isomerization with their corresponding dioxo Mo(VI) analogs.     

Modulation of transplanaramine platinum complex reactivity by systematic modification of carrier and leaving groups

Transplatinum planaramine complexes with carboxylate ligands as leaving groups, trans-[Pt(O₂CR)₂(L)(L′)] (L = L′ = pyridine; L = NH₃, L′ = pyridine, isoquinoline, thiazole, quinoline, etc.), are potential anticancer complexes with cytotoxicity in some cases equivalent to that of cisplatin. The carboxylate complexes are, as a family, very water-soluble and surprisingly stable towards hydrolysis - resembling carboplatin in their reactivity. Their pharmacological properties can be systematically modified by steric and electronic effects of the donor groups as well as in the leaving carboxylate ligands. Previously, we have recognized the leaving group formate as having appropriate kinetics for bioligand substitution [1]. In this paper we directly compared the effect on biological properties of a pyridine versus isoquinoline-based carrier group. Binding to calf thymus DNA was similar for both compounds but the distortions produced on DNA, as assessed by T_m (melting temperature) and an ethidium bromide fluorescence reporter assay, were more marked for the isoquinoline ligand. Model studies with 5′-GMP (5′-guanosinemonophosphate) confirmed these trends, with the product trans-[Pt(5′-GMP)₂(NH₃)(isoquinoline)] showing evidence of restricted rotation caused by steric hinderance of three rigid planar rings on the central platinum. A cross-linking assay on pUC19 plasmid confirmed a higher % of interstrand adducts for the isoquinoline compound. This “enhanced” reactivity was matched by higher cytotoxicity in HCT116 human colon tumor cells, and also with enhanced cellular accumulation. Thus, a combination of systematic biophysical and biological studies indicates that trans-[Pt(O₂CH)₂(NH₃)(isoquinoline)] has the most promising range of chemical and biological properties for further development and examination.     

Synthesis of the donor-acceptor ligand 2-(4-dimethylaminobenzylidene)-4,5-bis(diphenylphosphino)-4-cyclopenten-1,3-dione (dbpcd) and X-ray diffraction structure of the platinum(II) compound PtCl2(dbpcd)·1.5CH2Cl2

Knoevenagel condensation of 4-(dimethylamino)benzaldehyde with 4,5-bis(diphenylphosphino)-4-cyclopenten-1,3-dione (bpcd) gives the donor-acceptor ligand 2-(4-dimethylaminobenzylidene)-4,5-bis(diphenylphosphino)-4-cyclopenten-1,3-dione (dbpcd). The reaction of dbpcd with PtCl₂(cod) affords the platinum(II) complex PtCl₂(dbpcd) in high yield. The free dbpcd ligand and PtCl₂(dbpcd) have been isolated and fully characterized in solution by IR and NMR spectroscopies, and the solid-state structure of PtCl₂(dbpcd) determined by X-ray diffraction analysis. PtCl₂(dbpcd), as the 1.5CH₂Cl₂ solvate, crystallizes in the triclinic space group , a = 11.7412(7) Å, b = 12.0486(7) Å, c = 14.4781(9) Å, α = 82.866(1), β = 75.049(1), γ = 83.905(1), V = 1957.6(2) Å³, Z = 2, and D_calc = 1.678 mg/m³, R = 0.0291 and wR₂ = 0.0723 for 8315 reflections with I > 2σ(I). The molecular structure of PtCl₂(dbpcd)·1.5CH₂Cl₂ consists of a square-planar platinum architecture containing two chlorines and the ancillary dbpcd diphosphine ligand. The redox properties of the dbpcd ligand and PtCl₂(dbpcd) have been explored by cyclic voltammetry, and these data are discussed with respect to extended Hückel MO calculations.     

Synthesis, characterization, and cytotoxicities of platinum(II) complexes bearing pyridinecarboxaldimines containing bulky aromatic groups

Condensation of 2-pyridinecarboxaldehyde with several primary amines containing bulky aryl groups gave the corresponding pyridinecarboxaldimines (N-N′). Addition of these ligands to [PtCl₂(coe)]₂ (coe = cis-cyclooctene) gave complexes of the type cis-PtCl₂(N-N′) in moderate yields. The platinum complexes have been examined for their potential cytotoxicities against OV2008 (human ovarian carcinoma) and the analogous cisplatin-resistant cell line C13.     

Novel C,N-chelate platinum(II) antitumor complexes bearing a lipophilic ethisterone pendant

The novel steroidal carrier ligand 17-α-[4′-ethynyl-dimethylbenzylamine]-17-β-testosterone (ET-dmba 1) and the steroid — C,N-chelate platinum(II) derivatives [Pt(ET-dmba)Cl(L)] (L = DMSO (2) and PTA (3; PTA = 1,3,5-triaza-7-phosphaadamantane)) have been prepared. Values of IC₅₀ were calculated for the new platinum complexes 2 and 3 against a panel of human tumor cell lines representative of ovarian (A2780 and A2780cisR) and breast cancers (T47D). At 48 h incubation time complexes 2 and 3 show very low resistance factors (RF of < 2) against an A2780 cell line which has acquired resistant to cisplatin and were more active than cisplatin (about 4-fold for 3) in T47D (AR+, AR = androgen receptor). Compound 1 retains a moderate degree of relative binding affinity (RBA = 0.94%) for androgen receptors. The cytotoxicity of the non steroidal platinum analogues [Pt(dmba)Cl(L)] (dmba = dimethylbenzylamine; L = DMSO (4) and PTA (5)) has also been studied for comparison purposes. Theoretical calculations at the BP86/def2-TZVP level of theory on complex 3 have been undertaken.     

Structure and solution behaviour of cyclooctadiene complexes of platinum(II)

The substitution behaviour of [PtCl(R)(COD)] (R⁻ = Me and Fc) complexes, by the stepwise addition of phosphine ligands, L (L = PPh₃, PEt₃ and P(NMe₂)₃), were investigated in situ by ¹H and ³¹P NMR spectroscopy. Addition of less than two equivalents of the phosphine ligand results in the formation of dimeric molecules with the general formula trans-[Pt(R)(μ-Cl)(L)]₂ for the sterically demanding systems where R⁻ = Me/L = P(NMe₂)₃ and R⁻ = Fc/L = PEt₃, PPh₃ and P(NMe₂)₃ while larger quantities resulted in cis- and trans mixtures of mononuclear complexes being formed. In the case of the relatively small steric demanding, strongly coordinating, PEt₃ ligand the trans-[PtCl(R)(PEt₃)₂] mononuclear complexes were exclusively observed in both cases. The crystal structures of the two substrates, [PtCl(R)(COD)] (R⁻ = Me or Fc), as well as the cis-[PtCl(Fc)(PPh₃)₂] substitution product are reported.     

Probing the electronic factors responsible for the cyclic electron-transfer induced isomerism fac ? mer: Synthesis, electrochemical and spectroscopic studies of fac-[Mn(CO)3(L′-L′)L] complexes

Spectroscopic (IR, ³¹P NMR and UV-Vis) and electrochemical studies on fac-[Mn(CO)₃(L′-L′)(L)]^0/+,where L′-L′ = 1,2-bis(diphenylphosphino)ethane (dppe) or 1,10-phenanthroline (phen) and L = bromide, triflate, imidazole (im), isonicotinamide (isn) or N-(2-hydroxyethyl)isonicotinamide (heisn), were undertaken to understand the effect of various ligands on the CO-Mn-L and CO-Mn-(L′-L′) bonding characteristics of these complexes. Crystal structures for L = triflate/L′-L′ = dppe, L = triflate/L′-L′ = phen and L = isn/L′-L′ = phen are reported and they show that the two Mn-O(OSO₂CF₃) and Mn-N(isn) distances are similar. The tricarbonyl complexes exhibit two major bands in the 250-300 and 350-450 nm region of the UV-Vis spectrum. The lowest energy bands have been assigned as a contribution from both the metal-centered (MC) and metal to ligand (d_π → L′-L′) charge transfer (MLCT) transitions. The energy of this maximum absorption decreases in the order Br⁻ ∼ triflate > im > isn ∼ heisn. The cyclic four-component mechanism was observed at room temperature by voltammetric techniques for all the cases. On the basis of d metal orbital splitting, an electronic molecular orbital diagram is proposed. In this model, the ligands along the z-axis play a relevant role in the reverse of the HOMO energies of the fac/mer isomers by stabilizing the metal d_z² orbital relative to d_xy in mer-Mn(II).     

Synthesis and characterisation of new N1-alkyl-3,5-dipyridylpyrazole derived ligands. Study of their reactivity with Pd(II) and Pt(II)

Two new pyrazole-derived ligands, 1-ethyl-3,5-bis(2-pyridyl)pyrazole (L¹) and 1-octyl-3,5-bis(2-pyridyl)pyrazole (L²), both containing alkyl groups at position 1 were prepared by reaction between 3,5-bis(2-pyridyl) pyrazole and the appropriate bromoalkane in toluene using sodium ethoxide as base.The reaction between L¹, L² and [MCl₂(CH₃CN)₂] (M = Pd(II), Pt(II)) resulted in the formation complexes of formula [MCl₂(L)] (M = Pd(II), L = L¹ (1); M = Pd(II), L = L² (2); M = Pt(II), L = L¹ (3); M = Pt(II), L = L² (4)). These complexes were characterised by elemental analyses, conductivity measurements, infrared, ¹H, ¹³C{¹H} NMR and HMQC spectroscopies. The X-ray structure of the complex [PtCl₂(L²)] (4) was determined. In this complex, Npyridine and Npyrazole donor atoms coordinate the ligand to the metal, which complete its coordination with two chloro ligands in a cis disposition.     

Synthesis, spectroscopy, structure and photophysical properties of dinaphthylmethylarsine complexes of palladium(II) and platinum(II)

Dinaphthylmethylarsine complexes of palladium(II) and platinum(II) with the formulae [MX₂L₂] (M = Pd, Pt; L = di(1-naphthyl)methylarsine = Nap₂AsMe and X = Cl, Br, I), [M₂Cl₂(μ-Cl)₂L₂], [PdCl(S₂CNEt₂)L], [Pd₂Cl₂(μ-OAc)₂L₂] and [MCl₂(PR₃)L] (PR₃ = PEt₃, PPr₃, PBu₃, PMePh₂) have been prepared. These complexes have been characterized by elemental analyses, IR, Raman, NMR (¹H, ¹³C, ³¹P) and UV-vis spectroscopy. The stereochemistry of the complexes has been deduced from the spectroscopic data. The crystal structures of trans-[PdCl₂(PEt₃)(Nap₂AsMe)] and of [Pd(S₂CNEt₂)₂], a follow-up product, were determined. The UV-vis spectra of [MX₂L₂] complexes show a red shift on going from X = Cl to X = I. The complexes [PdX₂L₂] and [PtX₂L₂] are strongly luminescent in fluid solution and in the solid at ambient temperature.     

Synthesis and reactivity of osmium (VI) nitrido complexes containing pyridine-carboxylato ligands

A series of osmium(VI) nitrido complexes containing pyridine-carboxylato ligands Os^VI(N)(L)₂X (L = pyridine-2carboxylate (1), 2-quinaldinate (2) and X = Cl (a), Br (1b and 2c) or CH₃O (2b)) and [Os^VI(N)(L)X₃]⁻ (L = pyridine-2,6-dicarboxylate (3) and X = Cl (a) or Br (b)) have been synthesised. Complexes 1 and 2 are electrophilic and react readily with various nucleophiles such as phosphine, sulfide and azide. Reaction of Os^VI(N)(L)₂X (1 and 2) with triphenylphosphine produces the osmium(IV) phosphiniminato complexes Os^VI(NPPh₃)(L)₂X (4 and 5). The kinetics of nitrogen atom transfer from the complexes Os^VI(N)(L)₂Br (2c) (L = 2-quinaldinate) with triphenylphosphine have been studied in CH₃CN at 25.0 °C by stopped-flow spectrophotometric method. The following rate law is obtained: −d[Os(VI)]/dt = k₂[Os(VI)][PPh₃]. Os^VI(N)(L)₂Cl (L = 2-quinaldinate) (2a) reacts also with [PPN](N₃) to give an osmium(III) dichloro complex, trans-[PPN][Os^III(L)₂Cl₂] (6). Reaction of Os^VI(N)(L)₂Cl (L = 2-quinaldinate) (2a) with lithium sulfide produces an osmium(II) thionitrosyl complex Os^II(NS)(L)₂Cl (7). These complexes have been structurally characterised by X-ray crystallography.     

Platinum(II) phosphonate complexes derived from endo-8-camphanylphosphonic acid

The reactions of cis-[PtCl₂L₂] [L = PPh₃, PMe₂Ph or L₂ = Ph₂P(CH₂)₂PPh₂ (dppe)] with endo-8-camphanylphosphonic acid (CamPO₃H₂) and Ag₂O in refluxing dichloromethane gave platinum(II) phosphonate complexes [Pt(O₃PCam)L₂]. The X-ray crystal structure of [Pt(O₃PCam)(PPh₃)₂]·2CHCl₃ shows that the bulky camphanyl group, rather than being directed away from the platinum, is instead directed into a pocket formed by the Pt and the two PPh₃ ligands. This allows the O₃P-CH₂ group to have a preferred staggered conformation. The complexes were studied in detail by NMR spectroscopy, which demonstrates non-fluxional behaviour for the sterically bulky PPh₃ and dppe derivatives, which contain inequivalent phosphine ligands in their ³¹P NMR spectra. These findings are backed up by theoretical calculations on the PPh₃ and PPhMe₂ derivatives, which show, respectively, high and low energy barriers to rotation of the camphanyl group in the PPh₃ and PPhMe₂ complexes. The X-ray crystal structure of CamPO₃H₂ is also reported, and consists of hydrogen-bonded hexameric aggregates, which assemble to form a columnar structure containing hydrophilic phosphonic acid channels surrounded by a sheath of bulky, hydrophobic camphanyl groups.     

Synthesis, structures and in vitro cytotoxicity of some cationic cis-platinum(II) complexes containing chelating thiocarbamates

The thiocarbamates 4-RC₆H₄NHC(S)NR₂′ (R = H, Cl; R′ = Me, Et), 4-ClC₆H₄NHC(S)NR (NR = 2-pyridylpiperazine) react with cis-[PtCl₂(PTA)₂] (PTA = 1,3,5-triaza-7-phosphaadamantane) in the presence of base to afford the monocationic platinum(II) complexes cis-[Pt{SC(NR₂′) = NC₆H₄R}(PTA)₂]⁺ (R = H, Cl; R′ = Me, Et), cis-[Pt{SC(NR) = NC₆H₄Cl}(PTA)₂]⁺ (NR = 2-pyridylpiperazine), which were isolated as their PF₆ salts in high yields. The complexes were fully characterised spectroscopically and also by X-ray crystallography. Cytotoxicity of these complexes was studied in vitro in three human cancer cell lines (CH1, A549 and SW480) using the MTT assay.     

Synthesis, characterization and equilibrium study of the dinuclear adducts formation between nickel(II) Salen-type complexes with diorganotin(IV) dichlorides in chloroform

Adduct formation between R₂SnCl₂ (R = methyl and n-butyl) as acceptors, and nickel(II) complexes of tetradentate Schiff base ligands ([NiL]) where L = [3-methoxysalen, N,N′-bis(3-methoxysalicylidene)ethylenediamine], [4-methoxysalen, N,N′-bis(4-methoxysalicylidene)ethylenediamine], [5-methoxysalen, N,N′-bis(5-methoxysalicylidene)ethylenediamine], [salen, N,N′-bis(salicylaldehydo)ethylenediamine], [5-chlorosalen, N,N′-bis(5-chlorosalicylidene)ethylenediamine] and [5-bromosalen, N,N′-bis(5-bromosalicylidene)ethylenediamine] as donors have been investigated in chloroform as a solvent by means of UV-Vis spectrophotometeric analysis. Adducts have been characterized by ¹H NMR, IR and electronic spectroscopy. The formation constants and the thermodynamic free energies were measured using UV-Vis spectrophotometry titration for 1:1 adduct formation at various temperatures (T = 278-308 K). The trend of the adduct formation of the nickel Schiff base complexes with a given tin acceptor decreases as follow:

Ni(3-MeOSalen)>Ni(5-MeOSalen)>Ni(4-MeOSalen)     

The microwave synthesis of platinum(II) phosphine complexes

The microwave synthesis of a series of platinum(II) phosphine complexes is reported. The complexes dppePtCl₂ (dppe = bis(diphenylphosphino)ethane), dpppPtCl₂ (dppp = bis(diphenylphosphino)propane), dppmPtCl₂ (dppm = bis(diphenylphosphino)methane) and cis-(Ph₃P)₂PtCl₂ are synthesized from the reaction of potassium tetrachloroplatinate(II) and the phosphine. The isolated yields are 65% or better.     

Preparation and separation of asymmetric tripodal iron complexes of tren and selected aldehydes

Reaction of iron salts with the tripodal ligands formed from the condensation of tris-(2-aminoethyl)amine (tren) with the following mixtures of aldehydes, 2-pyridinecarboxaldehyde (py) and 6-methyl-2-pyridinecarboxaldehyde (6-CH₃py), salicylaldehyde (sal) and 2-hydroxy-5-methylbenzaldehyde (5-CH₃sal), salicylaldehyde and pyrrole-2-carboxaldehyde (pyr), and 4-methyl-5-imidazolecarboxaldehyde (4-CH₃ImH) and salicylaldehyde yielded mixtures of all four possible iron complexes, [Fe(tren)L_xL′_y]^z (x +y = 3), where L and L′ represent different aldehydes. Preliminary indication of mixtures of products was provided by IR and UV-Vis spectroscopy. Conclusive proof of the existence of all four components (x = 0-3) in each of the reaction mixtures is provided by mass spectroscopy. Separation of the [Fetren(sal)_x(4-CH₃ImH)_y](ClO₄)_y mixture can be achieved using a Sephadex ion exchange column. Treatment of the two observed fractions with base yields greatly enriched [Fetren(sal)₂(4-CH₃Im)] and [Fetren(sal)(4-CH₃Im)₂], which were identified by mass spectroscopy.     

Synthesis, characterization and photophysical properties of mixed ligand tris(polypyridyl)chromium(III) complexes, [Cr(phen)2L]

A series of new heteroleptic, tris(polypyridyl)chromium(III) complexes, [Cr(phen)₂L]³⁺ (L = substituted phenanthrolines or bipyridines), has been prepared and characterized, and their photophyical properties in a number of solvents have been investigated. X-ray crystallography measurements confirmed that the cationic (3+) units contain only one ligand L plus two phenanthroline ligands. Electrochemical and photophysical data showed that both ground state potentials and lifetime decays are sensitive to ligand structure and the nature of the solvent with the exception of compounds containing L = 5-amino-1,10-phenanthroline (aphen) and 2,2′-bipyrimidine (bpm). Addition of electron-donating groups in the ligand structure shifts redox potentials to more negative values than those observed for the parent compound, [Cr(phen)₃]³⁺. Emission decays show a complex dependence with the solvent. The longest lifetime was observed for [Cr(phen)₂(dip)]³⁺ (dip = 4,7-diphenylphenanthroline) in air-free aqueous solutions, τ = 273 μs. Solvent effects are explained in terms of the affinity of hydrophobic complexes for non-polar solvent molecules and the solvent microstructure surrounding chromium units.     

Hydrogen bonding patterns in pyrazole Pt(II- and IV) chloride complexes

The solid-state packing arrays of the platinum(II) trans- and cis-[PtCl₂(PzH)₂] (1 and 2) and platinum(IV) trans- and cis-[PtCl₄(PzH)₂] (3 and 4) complexes have been examined and the occurrence of N-H ? Cl hydrogen-bonding associations in those structures has been discussed. Although different packing motifs are observed, in all cases molecules are interacting mostly via NH ? Cl and CH ? Cl associations. The square planar 1 and 2 form stacked arrays of PtCl₂(PzH)₂, which are supported by NH ? Cl and CH ? Cl hydrogen bonding. The isomeric structure of the complexes and orientation of the PzH rings determine NH ? Cl bonding mode (intermolecular or intramolecular) and also the extent of the platinum-platinum interaction. The synthetic procedures for the preparation of 1-4 along with elemental and X-ray analyses, TG/DTA, FAB⁺-MS, IR, and ¹H and ¹³C{¹H} NMR data are also given in this article.     

Cytotoxicity studies of [PtCl2(H2bim)] (H2bim = 2,2′-biimidazole): Study of its interaction with a small protein PCI (potato carboxypeptidase inhibitor)

The effect of the platinum compound [PtCl₂(H₂bim)] (H₂bim = 2,2′-biimidazole) on the plasmid DNA conformation was previously studied by electrophoresis in agarose gel and on calf thymus DNA by circular dichroism spectroscopy. The effect of this compound on pBR322 plasmid DNA has now been visualized by atomic force microscopy, which shows that the complex modifies the DNA in the same way as cisplatin does. The cytotoxic activity of [PtCl₂(H₂bim)] in HeLa-229, HL-60, A2780 and A2780cisR cell lines has also been evaluated. Likewise, the interaction of [PtCl₂(H₂bim)] with the small protein potato carboxypeptidase inhibitor (PCI) and a PCI mutant in which glycine 39 was substituted by methionine has been followed by HPLC/mass spectrometry. The interaction with the mutant protein PCI showed the formation of monofunctional adducts that ultimately gave bifunctional adducts. PCI mutant protein could be a good carrier of this platinum compound to the tumour cells in which the antiproliferative behaviour was demonstrated.     

The structural definition of adducts of stoichiometry MX:dppx (1:1) M = Cu, Ag, X = simple anion, dppx=Ph2P(CH2)xPPh2, x = 3-6

Single crystal X-ray structural characterizations are recorded for a wide range of adducts of the form MX:dppx (1:1)_(n), M = silver(I) (predominantly), copper(I), X = simple (pseudo-) halide or oxy-anion (the latter spanning, where accessible, perchlorate, nitrate, carboxylate - a range of increasing basicity), dppx=bis(diphenylphosphino)alkane, Ph₂P(CH₂)_xPPh₂, x = 3-6. Adducts are defined of two binuclear forms: (i) [LM(μ-X)₂L], with each ligand chelating a single metal atom, and (ii) [M(μ-X)₂(μ-(P-L-P′))₂M′] where both ligands L and halides bridge the two metal atoms; a few adducts are defined as polymers, the ligands connecting M(μ-X)₂M′ kernels, this motif persisting in all forms. Synthetic procedures for all adducts have been reported. All compounds have been characterized both in solution (¹H, ¹³C, ³¹P NMR, ESI MS) and in the solid state (IR).