Ammine Ligands Research Articles

Structure of duplex DNA containing the cisplatin 1,2-{Pt(NH 3) 2} 2+-d(GpG) cross-link at 1.77 Å resolution

We report the 1.77-Å resolution X-ray crystal structure of a dodecamer DNA duplex with the sequence 5′-CCTCTGGTCTCC-3′ that has been modified to contain a single engineered 1,2- cis-{Pt(NH 3) 2} 2+-d(GpG) cross-link, the major DNA adduct of cisplatin. These data represent a significant improvement in resolution over the previously published 2.6-Å structure. The ammine ligands in this structure are clearly resolved, leading to improved visualization of the cross-link geometry with respect to both the platinum center and to the nucleobases, which adopt a higher energy conformation. Also better resolved are the deoxyribose sugar puckers, which allow us to re-examine the global structure of platinum-modified DNA. Another new feature of this model is the location of four octahedral [Mg(H 2O) 6] 2+ ions associated with bases in the DNA major groove and the identification of 124 ordered water molecules that participate in hydrogen-bonding interactions with either the nucleic acid or the diammineplatinum(II) moiety.

Density functional theory calculations on Fe–O and O–O cleavage of ferric hydroperoxide species: Role of axial ligand and spin state

Density functional theory (DFT) calculations are performed on thiolate bound hydroperoxide complexes. O–O and Fe–O cleavage reaction coordinates, relevant to the active sites of cytochrome P450 and superoxide reductase enzymes, were investigated for both high and low spin states and for cis and trans orientations of the thiolate ligand with respect to the hydroperoxide ligand. The results indicate that the presence of a thiolate ligand produces significant elongation of the Fe–O bond and reduction of Fe–O vibrational frequency. While the fate of the O–O cleavage reaction is not significantly altered, the presence of a thiolate induces a heterolytic Fe–O cleavage irrespective of the spin state and orientation which is very different from results obtained with a trans ammine ligand.

Bis[diamminesilver(I)] 5-nitroisophthalate monohydrate

In the title compound, [Ag(NH3)2]2(C8H3NO6)·H2O, the cations have an almost linear coordination geometry with two ammine ligands and inter­act with the water mol­ecules [Ag⋯Owater = 2.725 (4) and 2.985 (4) Å]. In the crystal, N—H⋯O and O—H⋯O hydrogen bonds, combined with weak (lone pair)⋯π [O⋯centroid distance = 3.401 (4) Å] and π–π stacking [centroid–centroid distance = 3.975 (3) Å] inter­actions, stabilize the three-dimensional supra­molecular network.

Ammine(2,2′-bipyridine-κ2N,N′)silver(I) nitrate: a dimer formed by π–π stacking and ligand-unsupported Ag...Ag interactions

Reaction of AgNO(3) and 2,2'-bipyridine (bipy) under ultrasonic treatment gave the title compound, [Ag(C(10)H(8)N(2))(NH(3))]NO(3). The crystal structure consists of dimers formed by two symmetry-related Ag(I)-bipy monomers connected through intra-dimer pi-pi stacking and ligand-unsupported Ag...Ag interactions. A crystallographic C2 axis passes through the mid-point of and is perpendicular to the Ag...Ag(i)(-x + 1, y, -z + 1/2) axis. In addition, each Ag(I) cation is coordinated by one chelating bipy ligand and one ammine ligand, giving a trigonal coordination environment capped by the symmetry-equivalent Ag atom. Molecules are assembled by Ag...Ag, pi-pi, hydrogen-bond (N-H...O and C-H...O) and weak Ag...pi interactions into a three-dimensional framework. Comparing the products synthesized under different mechanical treatments, we found that reaction conditions have a significant influence on the resulting structures. The luminescence properties of the title compound are also discussed.

Reaction of human metallothionein-3 with cisplatin and transplatin

Human metallothioneins, small cysteine- and metal-rich proteins, play an important role in the acquired resistance to platinum-based anticancer drugs. These proteins contain a M(II)4(CysS)11 cluster and a M(II)3(CysS)9 cluster localized in the alpha-domain and the beta-domain, respectively. The noninducible isoform metallothionein-3 (Zn7MT-3) is mainly expressed in the brain, but was found overexpressed in a number of cancer tissues. Since the structural properties of this isoform substantially differ from those of the ubiquitously occurring Zn7MT-1/Zn7MT-2 isoforms, the reactions of cis-diamminedichloridoplatinum(II) (cisplatin) and trans-diamminedichloridoplatinum(II) (transplatin) with human Zn7MT-3 were investigated and the products characterized. A comparison of the reaction kinetics revealed that transplatin reacts with cysteine ligands of Zn7MT-3 faster than cisplatin. In both binding processes, stoichiometric amounts of Zn(II) were released from the protein. Marked differences between the reaction rates of cisplatin and transplatin binding to Zn7MT-3 and the formation of the Pt-S bonds suggest that the binding of both Pt(II) compounds is a complex process, involving at least two subsequent binding steps. The electrospray ionization mass spectrometry characterization of the products showed that whereas all ligands in cisplatin were replaced by cysteine thiolates, transplatin retained its carrier ammine ligands. The 113Cd NMR studies of Pt1 113Cd6MT-3 revealed that cisplatin binds preferentially to the beta-domain of the protein. The rates of reaction of cisplatin and transplatin with Zn7MT-3 were much faster than those of cisplatin and transplatin with Zn7MT-2. The biological consequences of a substantially higher reactivity of cisplatin toward Zn7MT-3 than Zn7MT-2 in the acquired resistance to platinum-based drugs are discussed.

Visualization of Metal-to-Ligand and Ligand-to-Ligand Charge Transfer in Metal-Ligand Complexes

Three methods including the atomic resolved density of state, charge difference density, and the transition density matrix are used to visualize metal to ligand charge transfer (MLCT) in ruthenium(II) ammine complex. The atomic resolved density of state shows that there is density of Ru on the HOMOs. All the density is localized on the ammine, which reveals that the excited electrons in the Ru complex are delocalized over the ammine ligand. The charge difference density shows that all the holes are localized on the Ru and the electrons on the ammine. The localization explains the MLCT on excitation. The transition density matrix shows that there is electron-hole coherence between Ru and ammine. These methods are also used to examine the MLCT in Os(bpy)2(p0p)Cl (Osp0p"; bpy = 2,2-bipyridyl; p0p = 4,4-bipyridyl) and the ligand-to-ligand charge transfer (LLCT) in Alq3. The calculated results show that these methods are powerful to examine MLCT and LLCT in the metal-ligand system.

The neutral cluster amminehexa-μ2-chlorido-μ4-oxido-tris(1,4,6-triazabicyclo[3.3.0]oct-4-ene)tetracopper(II)

The title compound, [Cu(4)Cl(6)O(C(5)H(9)N(3))(3)(NH(3))], is a neutral conformationally chiral cluster which crystallizes under the conditions described in this paper as a racemic conglomerate. It contains four Cu(II) atoms in a tetrahedral coordination with a central O atom lying on a crystallographic threefold axis. Six chloride anions bridge the four Cu(II) atoms. Three Cu(II) atoms are bound by an N atom of a monodentate 1,4,6-triazabicyclo[3.3.0]oct-4-ene (Htbo) ligand and the remaining Cu(II) atom is bound by a terminal ammine ligand. The geometry at each copper center is trigonal bipyramidal, produced by the bound N atom of Htbo or ammonia, the O atom in the axial position, and three chloride ions in the equatorial plane. The chloride anions form an octahedron about the oxygen center. The copper-ammonia bond lies along the crystallographic threefold axis, along which the molecules are packed in a polar head-to-tail fashion.

Intramolecular MLOH/π and MLNH/π interactions in crystal structures of metal complexes

AbstractIntramolecular metal-ligand OH/π (MLOH/π) and metal-ligand NH/π (MLNH/π) interactions in transition metal complexes between aqua or ammine ligand and ligand containing a C6-aromatic ring were investigated in crystal structures deposited in the Cambridge Structural Database (CSD). These intramolecular interactions appear in 38 structures with aqua ligand as the hydrogen atom donor and in 10 structures with ammine ligand as the hydrogen atom donor. Among all these complexes only one is negatively charged, 14 are positively charged and 33 are neutral indicating that the overall charge of the molecule has an influence on the XH/π (X = O or N) interactions. Energy estimated by DFT calculations is approximately 19 kJ mol−1 for the MLOH/π interactions and approximately 15 kJ mol−1 for the MLNH/π interactions.

A chemical preformulation study of a host–guest complex of cucurbit[7]uril and a multinuclear platinum agent for enhanced anticancer drug delivery

Single crystal and powder X-ray diffraction have been used to examine the host-guest complex of cucurbit[7]uril (CB[7]) and the model dinuclear platinum anticancer complex trans-[{PtCl(NH(3))(2)}(2)mu-dpzm](2+) (di-Pt, dpzm= 4,4'-dipyrazolylmethane). The single crystal structure shows that the host-guest complex forms with the di-Pt dpzm ligand within the CB[7] cavity and with the platinum groups just beyond the macrocycle portals. Binding is stabilised through hydrophobic interactions and six hydrogen bonds between the platinum ammine ligands and the dpzm pyrazole amine to the CB[7] carbonyls. Each host-guest complex crystallises with two chloride counterions and 5.5 water molecules. The unit cell comprises four asymmetric units, each of which contains three crystallographically independent CB[7]-di-Pt moieties. X-Ray powder diffraction demonstrated structural consistency of the bulk crystals with a single polycrystalline phase that is identical with the single crystal structure. Finally, the effect of CB[7] encapsulation of the thermal stability of di-Pt was examined by thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC). From the TGA experiments it was found that free CB[7] and the CB[7]-di-Pt complex lose 11 and 3.5% of their mass respectively, through the loss of water molecules, upon heating to 160 degrees C. The DSC results showed that the free dpzm ligand melts between 186 and 199 degrees C, with a standard enthalpy of fusion of 27.92 kJ mol(-1). As a 2+ inorganic salt the metal complex does not melt but undergoes several decomposition events between 140 and 290 degrees C. Encapsulation by CB[7] completely stabilises di-Pt with no decomposition of either the macrocycle or metal complex at temperatures up to 290 degrees C.

Influence of (Hydroxymethyl)pyridine and Pyridine‐carboxylic Acids, in trans‐Position to the Isopropylamine and Ammine Ligands, on the Cytotoxicity of Platinum Complexes

trans-Pt(II) Complexes with aliphatic amines and planar amines such as (hydroxymethyl)pyridines, and pyridine-3- and pyridine-4-carboxylic acids were synthesized and screened for their potential cytotoxic activity in different cancer cell lines used at the NCI for in vitro screens, i.e., MCF7, NCIH460, and SF268. The complexes studied were designed to differ in geometrical parameters such as the position of the phenyl-group substituents and the nature of the substituents themselves for gathering information about the structure-activity relationships in the trans-complexes. The variation of the substituents turns to be crucial for their biological activity, as both pyridine-3- and pyridine-4-carboxylic acids in trans-position to both amine and isopropylamine ligands provided complexes which displayed no specificity toward any type of cell tested, while (hydroxymethyl)pyridine in trans-position to isopropylamine ligands led to complexes that were clearly more effective against the cell lines tested.

Synthesis, Characterization, and In Vitro Antitumor Activity of New Amidineplatinum(II) Complexes Obtained by Addition of Ammonia to Coordinated Acetonitrile

AbstractNew cis‐ and trans‐dichloridoplatinum(II) complexes, which contain two amidine ligands or one amidine and one ammine ligand, cis‐ and trans‐[PtCl2{(Z)‐HN=C(NH2)CH3}2] (1) and cis‐ and trans‐[PtCl2(NH3){(Z)‐HN=C(NH2)CH3}] (2), have been prepared from the corresponding nitrile complexes by amminolysis in thf solution. All synthesized compounds were characterized by elemental analysis, ESI‐MS, and IR and NMR spectroscopy. Amidines are isosters of iminoethers and ketimines. The trans isomers of the platinum complexes of the latter are endowed with an unexpectedly high antitumor activity. An important feature of complexes 1 and 2, as compared to iminoethers, is the exclusive preference for the Z configuration of the amidine ligand(s). The tumor cell growth inhibitory potency of the amidine compounds was tested towards a pair of human ovarian tumor cell lines A2780 (cancer cells sensitive to cisplatin) and A2780cisR (cancer cells with acquired resistance to cisplatin), and compared to that of cisplatin. From the obtained results it appears that the resistance factor is lower for cis‐amidine complexes as compared to cisplatin, and for trans compounds it is lower as compared to cis compounds.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)

Platinated Copper(3‐Clip‐Phen) Complexes as Effective DNA‐Cleaving and Cytotoxic Agents

The synthesis and biological activity of three heteronuclear platinum-copper complexes based on 3-Clip-Phen are reported. These rigid complexes have been designed to alter the intrinsic mechanism of action of both the platinum moiety and the Cu(3-Clip-Phen) unit. The platinum centers of two of these complexes are coordinated to a 3-Clip-Phen moiety, an ammine ligand and two chlorides, which are either cis or trans to each other. The third complex comprises two 3-Clip-Phen units and two chloride ligands bound in a trans fashion to the platinum ion. DNA-cleavage experiments show that the complexes are highly efficient nuclease agents. In addition, a markedly difference in their aptitude to perform direct double-strand cleavage is observed, which appears to be strongly related to the ability of the platinum unit to coordinate to DNA. Indeed, complex 6 is unable to coordinate to DNA, which is reflected by its incapability to carry out double-strand breaks. Nonetheless, this complex exhibits efficient DNA-cleavage activity, and its cytotoxicity is high for several cell lines. Complex 6 shows better antiproliferate activity than both cisplatin and Cu(3-Clip-Phen) toward most cancer cell lines. Furthermore, the cytotoxicity observed for 1 is for most cell lines close to that of cisplatin, or even better. Cu(3-Clip-Phen) induces very low cytotoxic effects, but a marked migratory activity. Complex 6 presents DNA-cleavage properties comparable to the one of Cu(3-Clip-Phen), but it does not show any migratory activity. Interestingly, both Cu(3-Clip-Phen) and 6 induces vacuolisation processes in the cell in contrast to complex 1 and cisplatin. Thus, the four complexes cisplatin tested, Cu(3-Clip-Phen), 1 and 6 stimulate different cellular responses.

Unusual silver coordination by mono-carboxylate utilization of a poly-carboxylate anion, solid-state structures of silver-tetrachlorophthalate with phthalazine and amine ligands

Silver carboxylate coordination with the tetrachlorophthalate anion, in combination with neutral donor ligands, has been found to deviate from other known poly-carboxylate complexes. Both complexes reported here, bis-[tetrachlorophthalato-silver phthalazine] and bis-[ammino-tetrachlorophthato-silver di-ammino-silver], utilize mixed carboxylate bonding types for silver coordination. In the case of the phthalazine ligand, both chelating and monodentate carboxylates form the framework for the oligomeric structure. In the case of the ammine ligand, one carboxylate forms a monodentate connection to a silver-ammine group, while the other is simply involved with hydrogen bonding to lock in a [(Ag–NH 3) 2–Ag–NH 3] substructure with an adjacent tetrachlorophthalato-silver unit. Both structures exhibit supramolecular connections via hydrogen bonding and π–π interactions.

New trans-Platinum Drugs with Phosphines and Amines as Carrier Ligands Induce Apoptosis in Tumor Cells Resistant to Cisplatin

Cisplatin resistance observed in some human tumors has prompted research in platinum derivatives that can circumvent this effect. Despite initial works reporting lack of activity of trans-platinum derivatives, complexes with the general formula PtCl2(L)(L') exhibit cytotoxic activity in cisplatin-sensitive and -resistant cell lines. Here we reported the chemical and biological properties of seven platinum complexes with PPh3 or PMe2Ph in trans to several amines. They show important antitumoral properties in tumor cell lines. Among the compounds, those with a replacement of an ammine ligand in the inactive trans-DDP by a phosphine ligand have an important enhancement of their cytotoxic activity. In SKOV3, no G1 nor G2/M accumulation was observed after treatments, and apoptosis was launched probably by a mechanism independent of classical checkpoints activation. Our data indicate that our compounds are not cross-resistant with cisplatin and might be promising agents in the treatment of tumors unresponsive to cisplatin.

Bifunctional binding of cisplatin to DNA: why does cisplatin form 1,2-intrastrand cross-links with ag but not with GA?

The bifunctional binding of the anticancer drug cisplatin to two adjacent nucleobases in DNA is modeled using density functional theory. Previous experimental studies revealed that cisplatin binding to adjacent guanine and adenine is sensitive to nucleobase sequence. Whereas AG 1,2-intrastrand cross-links are commonly observed, the analogous GA adducts are not known. This study focuses on understanding this directional preference by constructing a full reaction profile using quantum chemical simulation methods. Monofunctional and bifunctional cisplatin adducts were generated, and the transition states that connect them were located for the dinucleotides d(pApG) and d(pGpA), assuming that initial platination takes place at the guanine site. Our computer simulations reveal a significant kinetic preference for formation of the AG over the GA adduct. The activation free energies of approximately 23 kcal/mol for AG and approximately 32 kcal/mol for GA suggest that bifunctional closure is approximately 6 orders of magnitude faster for AG than for GA. A strong hydrogen bond between one of the ammine ligands of cisplatin and the 5' phosphate group of the DNA backbone is responsible for the stabilization of the transition state that affords the AG adduct. This interaction is absent in the transition state that leads to the GA adduct because the right-handed helix of the DNA backbone places the phosphate out of reach for the ammine ligand. We found only an insignificant thermodynamic difference between AG and GA adducts and conclude that the preference of AG over GA binding is largely under kinetic control. The puckering of the deoxyribose ring plays an important role in determining the energetics of the bifunctional platination products. Whereas the 3'-nucleoside remains in the native C2'-endo/C3'-exo form of B-DNA, the deoxyribose of the 5'-nucleoside always adopts the C2'-exo/C3'-endo puckering in our simulations. A detailed analysis of the energies and structures of the bifunctional adducts revealed that the observed sugar puckering patterns are necessary for platinum to bind in a relaxed coordination geometry.

Ligand Influence on Metathesis Activity of Ruthenium Carbene Catalysts: A DFT Study

AbstractA survey of the concept of active and inactive ligand conformations in ruthenium alkene carbene complexes of the Grubbs catalyst type is presented. This concept is extended to a variety of anionic ligand atoms. Density functional theory calculations at the B3LYP/LACV3P**+//B3LYP/LACVP* level of theory were performed on the precatalyst, 14 valence‐electron intermediate, alkene carbene conformers and ruthena(IV)cyclobutane model intermediates for several ligands, such as methoxide, methanethiolate, fluoride, mesylate, water, and ammonia. The rule of the superiority of metathesis catalysts with small and electron‐withdrawing halogens does not apply to fluoride ligands. Alkoxides and thiolates also destabilize active carbene conformations, while mesylate ligands lead to a balanced energetic relation of active and inactive carbene orientations. Cationic ruthenium carbene species with aqua or ammine ligands are limited by unfavored ligand dissociation to 14 valence‐electron intermediates. A guideline for the design of novel ligand systems for ruthenium carbene complexes as metathesis catalysts is proposed.

Platination of superoxide dismutase with cisplatin: tracking the ammonia ligands using Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR MS)

The high mass accuracy of FT-ICR MS combined with (15)N-labelling shows that mono- and di- platinated products from the reaction of erythrocyte superoxide dismutase with the anticancer drug cisplatin in solution retain their ammine ligands, in contrast to a recent X-ray crystallographic study.

Trans-Platinum Complexes in Cancer Therapy

The research of new platinum drugs active towards cisplatin refractory/resistant tumors has been mostly focussed on compounds with cis geometry because transplatin, the trans-isomer of cisplatin, is inactive. It is widely accepted that transplatin inactivity stems from two major factors: i) the kinetic instability promoting its deactivation and ii) the formation of DNA adducts characterized by a regioselectivity and a stereochemistry different from those of cisplatin. However, several exceptions to the general rule that the presence of two leaving groups in cis positions is necessary for antitumor activity of platinum complexes, have been reported. Substitution of transplatin ammine ligands by aromatic N-donor heterocycles, branched aliphatic amines, or imino ligands has lead to compounds with relevant in vitro tumor cell growth inhibitory potency, often active towards cisplatin refractory/resistant tumor cells, and in some cases endowed with significant activity also in vivo. From a mechanistic point of view, substitution of bulky ligands for ammines can retard substitution of the two chloride ligands, thus reducing the kinetic instability of the trans-platinum compounds. On the other hand, the formation of DNA adducts qualitatively and quantitatively different from those of cisplatin strongly supports the hypothesis that antitumor-active trans-platinum complexes can have a different spectrum of activity. It is hoped that the increasing knowledge of the biochemical and cellular processes underlying the antitumor-activity of trans-platinum complexes will foster their clinical development.

Diamminebis(tri-tert-butoxysilanethiolato)cadmium(II) acetonitrile solvate

The title compound, [Cd(C12H27O3SSi)2(NH3)2]·C2H3N, is a mol­ecular heteroleptic cadmium thiol­ate with two ammine ligands and contains a tetra­hedrally coordinated CdII ion with an S2N2 environment. All ammine H atoms and one of the H atoms of the acetonitrile methyl group participate in the formation of intra- and inter­molecular hydrogen bonds, which link adjacent mol­ecules into infinite chains.

Preparation of Supported Gold Nanoparticles by a Modified Incipient Wetness Impregnation Method

In this work, we show that if the mere procedure of impregnation of oxide supports with chloroauric acid, which is well-known to lead to large gold particles, is followed by a step of washing with ammonia, small gold particles (3-4 nm) can be obtained after a treatment of calcination at 300 degrees C on any type of oxide supports (alumina, titania, silica). Moreover, gold leaching is very limited during the washing step, and a large range of gold loadings (0.7-3.5 wt %) can be achieved. Elemental analysis, Raman spectroscopy, and temperature programmed desorption under argon show that this ammonia posttreatment results in the removal of chloride ligands from the coordination sphere of Au(III) precursor and their replacement by ammine ligands, leading to an ammino-hydroxo or an ammino-hydroxo-aquo gold complex and not to gold hydroxide. The Au/TiO(2) catalysts prepared with this modified procedure of impregnation are almost as active as those prepared by deposition-precipitation with urea in the CO oxidation reaction performed at room temperature.