Ag Adducts Research Articles

SERS detection of 1,4-bis(2-aminoethyl)piperazine functionalized GO (AEP-GO) on X60 carbon steel surface in 15% HCl solution

In this study, a silver nanoparticle anchored transparent tape sensor was used to detect 1,4-bis(2-aminoethyl)piperazine functionalized GO (AEP-GO) adsorbed on carbon steel surface utilizing the surface-enhanced Raman scattering (SERS) technique. SERS detection enabled the extreme amplification of Raman signals emitted by inhibitor molecules in order to describe their adsorption behavior on metallic/alloy surfaces. The strong corrosion inhibition performance of AEP-GO against carbon steel corrosion in 15 % HCl solution was proven by weight loss, electrochemical measurements and surface characterization techniques in a previous study. The SERS analysis showed the Raman peaks intensity of AEP-GO on the carbon surface gradually increases with increasing AEP-GO concentration. The increasing intensity with concentration correlated well with the previously reported weight loss and electrochemical results. DFT calculation was also carried out to understand the nature of interaction between the adsorbed AEP-GO molecules and the silver nanoparticles. The AEP-GO_Ag adduct's optimized structure reveals the silver metals approached the oxygen atom at the GO epoxy group in AEP-GO rather than the oxygen atoms at the carbonyl and hydroxyl groups. With no restrictions on substrate materials, the fabricated SERS sensor created in this study can be employed as a versatile sensor to characterize corrosion adsorption processes on metal surfaces.

Tunable Signal-Off and Signal-On Electrochemical Cisplatin Sensor

We report the first electrochemical cisplatin sensor fabricated with a thiolated and methylene blue (MB)-modified oligo-adenine (A)-guanine (G) DNA probe. Depending on the probe coverage, the sensor can behave as a signal-off or signal-on sensor. For the high-coverage sensor, formation of intrastrand Pt(II)-AG adducts rigidifies the oligo-AG probe, resulting in a concentration-dependent decrease in the MB signal. For the low-coverage sensor, the increase in probe-to-probe spacing enables binding of cisplatin via the intrastrand GNG motif (N = A), generating a bend in the probe which results in an increase in the MB current. Although both high-coverage signal-off and low-coverage signal-on sensors are capable of detecting cisplatin, the signal-on sensing mechanism is better suited for real time analysis of cisplatin. The low-coverage sensor has a lower limit of detection, wider optimal AC frequency range, and faster response time. It has high specificity for cisplatin and potentially other Pt(II) drugs and does not cross-react with satraplatin, a Pt(IV) prodrug. It is also selective enough to be employed directly in 50% saliva and 50% urine. This detection strategy may offer a new approach for sensitive and real time analysis of cisplatin in clinical samples.

In-Depth Study on Chloride Abstractions from (NHC)Ir(COD)Cl Complexes

While attempting to prepare a series of cationic NHC-Ir complexes of general formula [(NHC)Ir(COD)]+ via the silver salt metathesis reaction of its precursor (NHC)Ir(COD)Cl in dichloromethane, we unexpectedly synthesized [(μ-Cl){(2,7-SICyNap)Ir(COD)}·{Ag(OTf)}], a chloride-bridged Ir–Ag adduct. This result led us to investigate the chloride abstraction from the (NHC)Ir(COD)Cl system in detail. We show how the outcome of this ubiquitous reaction is dependent on a fine balance between the nucleophilicity of the weakly coordinating anion (WCA) and the polarity/coordinating ability of the reaction medium. A frequently encountered alternative to using silver salts is also presented and compared. The experimental difference in the reactivities of cationic catalysts in a representative intramolecular hydroamination reaction shows how a cationic Ir–Ag adduct can fail to deliver the reaction product through what appears to be a stabilization of the catalytically inactive iridium–silver intermediate by the educt.

Solvent-free silver-nanoparticle surface-assisted laser desorption/ionization imaging mass spectrometry of the Irganox 1010 coated on polystyrene

Imaging mass spectrometry (IMS) of the antioxidant Irganox 1010 coated on a polystyrene (PS) was conducted using solvent-free silver-nanoparticle surface-assisted laser desorption/ionization (Ag-NP SALDI). The lateral resolution and probing depth of Ag-NP SALDI-IMS, which are important factors in determining the surface sensitivity, were investigated. Direct Ag vapor deposition produced a 10-nm-thick homogenous layer of Ag-NPs on the Irganox 1010/PS thin film. Ag adduct ions of Irganox 1010 and PS repeating structures, and Ag cluster ions appeared in the mass spectrum, which showed that Ag-NPs on the sample surface enhanced the ionization efficiency by functioning as cationization agents. At the lateral resolution of this method (20μm), complementary grid patterns (55 lines per inch) of Irganox 1010 on the PS were observed. The probing depth was investigated with Irganox 1010 layers of different thicknesses, the detection of silver adduct ions of PS indicated Ag-NP SALDI could ionize the PS layer beyond the Irganox 1010 layer. The probing depth was 50–100nm for 10-nm-thick Ag-NP SALDI.

Nanoporous GaN–Ag Composite Materials Prepared by Metal-Assisted Electroless Etching for Direct Laser Desorption-Ionization Mass Spectrometry

Three-dimensional nanoporous gallium nitride(PGaN) produced by metal-assisted electroless etching is chemically embedded with silver nanoparticles via electroless deposition, forming a metallized semiconductor membrane with large surface area and nanoscale metal features. A new application utilizing the unique chemical and morphological features of these composite nanostructures is described here, laser induced desorption-ionization(LDI) of biomolecules(e.g., cholesterol and nucleotides) for direct mass analysis, without use of additional organic matrix. Although PGaN itself is a poor matrix for direct LDI mass spectrometry, the combination of Ag and PGaN greatly improves ion signals relative to PGaN or Ag nanostructure surfaces alone. This behavior is attributed to the combination of strong UV absorption, enhanced surface area, and favorable thermal properties of PGaN. Importantly, Ag-PGaN is shown to facilitate the formation of Ag adduct ions in some cases, for example adenine, where adducts are not observed from either porous anodic aluminum membranes or surfaces presenting Ag nanoparticles in isolation. Nanopore-embedded Ag nanostructures serve a dual role: as cationization agents and to assist thermal desorption under UV laser irradiation. The results reported here suggest that the combination of Ag nanostructures embedded in PGaN has the capacity for high quality matrix-free LDI mass analysis.

Binding of Silver Nanoparticles to Bacterial Proteins Depends on Surface Modifications and Inhibits Enzymatic Activity

Here we describe results from a proteomic study of protein-nanoparticle interactions to further the understanding of the ecotoxicological impact of silver nanoparticles (AgNPs) in the environment. We identified a number of proteins from Escherichia coli that bind specifically to bare or carbonate-coated AgNPs. Of these proteins, tryptophanase (TNase) was observed to have an especially high affinity for both surface modifications despite its low abundance in E. coli. Purified TNase loses enzymatic activity upon associating with AgNPs, suggesting that the active site may be in the vicinity of the binding site(s). TNase fragments with high affinities for both types of AgNPs were identified using matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry. Differences in peptide abundance/presence in mass spectra for the two types of AgNPs suggest preferential binding of some protein fragments based on surface coating. One high-binding protein fragment contained a residue (Arg103) that is part of the active site. Ag adducts were identified for some fragments and found to be characteristic of strong binding to AgNPs rather than association of the fragments with ionic silver. These results suggest a probable mechanism for adhesion of proteins to the most commonly used commercial nanoparticles and highlight the potential effect of nanoparticle surface coating on bioavailability.

Monomeric Copper(I), Silver(I), and Gold(I) Alkyne Complexes and the Coinage Metal Family Group Trends

A series of thermally stable, easily isolable, monomeric, and isoleptic coinage metal alkyne complexes have been reported. Treatment of [N{(C(3)F(7))C(Dipp)N}(2)]Li (the lithium salt of the 1,3,5-triazapentadiene [N{(C(3)F(7))C(Dipp)N}(2)]H) with AuCl, CF(3)SO(3)Ag or CF(3)SO(3)Cu in the presence of 3-hexyne led to the corresponding coinage metal alkyne complex [N{(C(3)F(7))C(Dipp)N}(2)]M(EtC[triple bond]CEt) in good yield (M = Au, Ag, Cu; Dipp = 2,6-diisopropylphenyl). X-ray crystal structures of the three coinage metal alkynes are remarkably similar, and show the presence of trigonal-planar metal sites with eta(2)-bonded 3-hexyne. The M-C and M-N bond distances vary in the order Cu < Au < Ag. The bending of the C-C[triple bond]C bond angle is largest for the gold, followed by Cu and Ag adducts. The gold adduct also shows the largest decrease in C[triple bond]C stretching frequency in Raman, while the Ag adduct shows the smallest change compared to that of the uncoordinated alkyne. DFT calculations on [N{(CF(3))C(Ph)N}(2)]M(EtC[triple bond]CEt) and the related ClM(EtC[triple bond]CEt) predict that the M-alkyne bond energy varies in the order Ag < Cu < Au. The gold adducts are also predicted to have the longest C[triple bond]C, largest deviation of C-C[triple bond]C bond angle from linearity, and smallest C[triple bond]C stretching frequency, followed by the Cu and Ag adducts. In these triazapentadienyl coinage metal adducts, the sigma-donation from alkyne --> M dominates over the M --> alkyne pi-back-donation.

Cutting Edge: Complement (C3d)-Linked Antigens Break B Cell Anergy

C3dg adducts of Ag can coligate complement receptor type 2 (CR2; CD21) and the B cell Ag receptor. This interaction significantly amplifies BCR-mediated signals in Ag-naive wild-type mice, lowering the threshold for B cell activation and the generation of humoral immune responses as much as 1000-fold. In this study we demonstrate that CR2-mediated complementation of BCR signals can also overcome B cell anergy. Unlike Ag alone, BCR/CR2 costimulation (Ars-CCG/C3dg complexes) of anergic Ars/A1 B cells led to Ca(2+) mobilization in vitro and the production of autoantibodies in vivo. Interestingly, the in vivo immune response of anergic cells occurs without the formation of germinal centers. These results suggest that the Ag unresponsiveness of anergic B cells can be overcome by cross-reactive (self-mimicking) Ags that have been complement-opsonized. This mechanism may place individuals exposed to complement-fixing bacteria at risk for autoimmunity.

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.

Activation of the C–I and C–OH bonds of 2-iodoethanol by gas phase silver cluster cations yields subvalent silver-iodide and -hydroxide cluster cations

The gas phase ion-molecule reactions of silver cluster cations (Ag(n)(+)) and silver hydride cluster cations (Ag(m)H(+)) with 2-iodoethanol have been examined using multistage mass spectrometry experiments in a quadrupole ion trap mass spectrometer. These clusters exhibit size selective reactivity: Ag(2)H(+), Ag(3)(+), and Ag(4)H(+) undergo sequential ligand addition only, while Ag(5)(+) and Ag(6)H(+) also promote both C-I and C-OH bond activation of 2-iodoethanol. Collision induced dissociation (CID) of Ag(5)HIO(+), the product of C-I and C-OH bond activation by Ag(5)(+), yielded Ag(4)OH(+), Ag(4)I(+) and Ag(3)(+), consistent with a structure containing AgI and AgOH moieties. Ag(6)H(+) promotes both C-I and C-OH bond activation of 2-iodoethanol to yield the metathesis product Ag(6)I(+) as well as Ag(6)H(2)IO(+). The metathesis product Ag(6)I(+) also promotes C-I and C-OH bond activation.DFT calculations were carried out to gain insights into the reaction of Ag(5)(+) with ICH(2)CH(2)OH by calculating possible structures and their energies for the following species: (i) initial adducts of Ag(5)(+) and ICH(2)CH(2)OH, (ii) the subsequent Ag(5)HIO(+) product, (iii) CID products of Ag(5)HIO(+). Potential adducts were probed by allowing ICH(2)CH(2)OH to bind in different ways (monodentate through I, monodentate through OH, bidentate) at different sites for two isomers of Ag(5)(+): the global minimum "bowtie" structure, 1, and the higher energy trigonal bipyramidal isomer, 2. The following structural trends emerged: (i) ICH(2)CH(2)OH binds in a monodentate fashion to the silver core with little distortion, (ii) ICH(2)CH(2)OH binds to 1 in a bidentate fashion with some distortion to the silver core, and (iii) ICH(2)CH(2)OH binds to 2 and results in a significant distortion or rearrangement of the silver core. The DFT calculated minimum energy structure of Ag(5)HIO(+) consists of an OH ligated to the face of a distorted trigonal bipyramid with I located at a vertex, while those for both Ag(4)X(+) (X = OH, I) involve AgX bound to a Ag(3)(+) core. The calculations also predict the following: (i) the ion-molecule reaction of Ag(5)(+) and ICH(2)CH(2)OH to yield Ag(5)HIO(+) is exothermic by 34.3 kcal mol(-1), consistent with the fact that this reaction readily occurs under the near thermal experimental conditions, (ii) the lowest energy products for fragmentation of Ag(5)HIO(+) arise from loss of AgI, consistent with this being the major pathway in the CID experiments.

Gold(I) and silver(I) complexes of 2,3-bis(diphenylphosphino)maleic acid: Structural studies and antitumour activity

The 2:1 and 1:2 adducts of Au(I) and 1:2 adducts of Ag(I) with the diphosphine 2,3-bis(diphenylphosphino)maleic acid (dpmaa) have been prepared in high yields. Crystal structures have been determined for the neutral digold complex (AuCl) 2(dpmaa) · 2thf ( 1) and the bis-chelated complex [Au(dpmaa) 2]Cl · H 2O · CH 3OH ( 2). For 1, conformational rigidity imposed by the ethylenic bridge facilitates the formation of short intramolecular Au–Au contacts with no evidence of similar intermolecular contacts. Complex 2 crystallizes with [Au(dpmaa) 2] + cations hydrogen bonded through the carboxyl groups to a water molecule and chloride anion to form a H-bonded chain along the a axis. 31P NMR titration of 1 with dpmaa in acetone shows conversion to 2 at Au:P–P ratios less than 1:1 indicating similar high thermodynamic and kinetic stabilities to other bis-chelated [Au(P–P) 2] + complexes containing 5- or 6-membered chelate rings. The ionic Au(I) complex 2 and the analogous Ag(I) complex [Ag(dpmma) 2]NO 3 ( 3) are highly water soluble. The in vitro cytotoxic activity of 2 was assessed against eight different cell lines and no significant activity was found. The solubility properties and solution behaviour of the complexes are compared to the analogous 1,2-bis(diphenylphosphino)ethane (dppe) complexes and the potential significance of these results to the antitumour properties of chelated 1:2 Au(I)diphosphine complexes are discussed.

Syntheses, spectroscopic and structural characterization of some (solvated) binuclear adducts of the form Ag(oxyanion):dpem(:S) (1:1(: x)) 2 (oxyanion = ClO 4, F 3CCO 2, F 3CSO 3; dpem = Ph 2E(CH 2)EPh 2 (E = P, As))

Syntheses, spectroscopic (IR, NMR and ESI MS) and single crystal X-ray structural characterizations are reported for a wide variety of adducts of Ag(oxyanion):dpem(:S) (1:1(: n)) 2 (oxyanion = ClO 4, F 3CCO 2 (tfa) F 3CSO 3 (tfs); dpem = Ph 2E(CH 2)EPh 2) stoichiometry among which the basic Ag(Ph 2E(CH 2)EPh 2) 2Ag core is diversely perturbed by interactions with anions and solvent molecules. ESI MS and 31P NMR spectroscopy indicated that dinuclear species also exist in solution.

DNA binding of the anti-cancer platinum complex trans-[{Pt(NH3)2Cl}2μ-dpzm]2+

The DNA binding of the dinuclear platinum complex trans-[{Pt(NH3)2Cl}2μ-dpzm]2+ (di-Pt), linked with the 4,4′-dipyrazolylmethane (dpzm) linker, was examined by 1H and 195Pt NMR and transcription assays. At 60 °C, di-Pt reacts with guanosine two-fold slower (t1/2: 1 h) than cisplatin (t1/2: 0.5 h). With adenosine, the di-Pt complex reacts much slower (t1/2: 7 h) forming a range of different adducts through the N7 and either the N1 or N3 positions of the nucleoside. From 1H NMR analysis of the major product of the reaction of di-Pt with the oligonucleotide d(ATGCAT)2, purified by HPLC, it was determined that the dinuclear platinum complex can readily form a 1,2-GG interstrand DNA cross-link. Transcription assays using di-Pt and the lac UV5 promoter indicated that the metal complex forms an array of adducts vastly different from cisplatin. The two greatest blockages occurred at adenine residues, with possible interstrand and intrastrand AA and AG adducts being formed. These results indicate that unlike other platinum based anti-cancer agents, di-Pt binds to DNA with a preference for adenine bases.

A study of complexes Mg(NH 3) n+· and Ag(NH 3) n+, where n = 1–8: competition between direct coordination and solvation through hydrogen bonding

Density functional calculations at B3LYP/6-31+G(d) and B3LYP/DZVP are reported for Mg(NH 3) n +·, where n = 1–6 and for some solvated ions Mg(NH 3) n +· … NH 3 ( n = 1–3, 6). After correction for basis set superposition errors, the enthalpies for sequential addition of NH 3 to Mg +· resulting from direct coordination to the metal are 38.1, 26.6, 21.2, 13.7, 12.1, and 11.3 kcal mol −1. The free energies for these same addition reactions are all negative, although for complexes with n ≥ 4 the values are very small. Attempts at optimising structures with higher coordination numbers all resulted in the formation of solvated octahedral complexes. Enthalpies for solvation through hydrogen bonding to one of the ligated NH 3 molecules are all less than 16 kcal mol −1 and decrease rapidly as the number of ligated NH 3 molecules increases. Molecular orbital calculations at B3LYP/DZVP have been used to optimise structures for ions Ag(NH 3) n +, where n = 1–6. The five-coordinate and six-coordinate structures have very small binding enthalpies (4.3 and 2.6 kcal mol −1) and the free energies for formation of these ions are positive. The binding energies for the addition of the first and second NH 3 molecules added to Ag + are 40.1 and 36.1 kcal mol −1, while those for the third and fourth additions are much smaller (15.1 and 11.0 kcal mol −1). Adducts up to n = 3 have been detected in electrospray experiments. The first three adducts of Ag + with NH 3 have been formed in the selected ion flow tube apparatus and multicollision induced dissociation experiments show Ag(NH 3) 3 + to have a lower binding enthalpy than both Ag(NH 3) 2 + and Ag(NH 3) +.

Antimony as a Donor Atom in Silver Coordination Chemistry: Synthesis, IR Spectra and Structure of the Silver(I) Cyanoximate Complexes with Triphenylstibine and Triphenylphosphine Model Compounds

Silver(I) cyanoximate complexes Ag{ONC(CN)-R} (R = COPh, {L1}; COC(CH3)3, {L2}; benzothiazol-2-yl, {L3}) with triphenylphosphine and -stibine of compositions Ag(PPh3)n{L} (n = 2, 4) and Ag(SbPh3)n{L} (n = 3 for {L1} and {L2}, n = 2 for {L3}) were synthesized by the reaction of the components in acetonitrile solution and characterized by elemental analyses and IR spectroscopy. The crystal structures of Ag(SbPh3)3{L} (L = {L1} (1), {L2} (2), Ag(SbPh3)2{L3} ∙ CH3CN (3) and Ag(PPh3)2{L1} ∙ CH3CN (4), have been determined by X-ray diffraction. For all the compounds examined the coordination environment of the silver atom has the geometry of a distorted terahedron ([AgP2NO] (4); [AgSb3N] (1), (2); [AgSb2N2] (3)). The bis adducts Ag(EPh3)n{L} adopt molecular structures, in which the organic anions are coordinated in bidentate chelate fashion via the nitroso nitrogen atom and the oxygen (nitrogen for {L3}) atom of the substituent R. In the tris-stibino complexes (Ag-Sb 2.670(4) - 2.7748(8) Å; Sb-Ag-Sb 108.87(4) - 115.00(2)°) the cyanoximates are unidentate ligands and coordinated via the nitroso nitrogen atoms (Ag-N ca. 2.35(1) Å). The different behaviour of N ,O and N,N chelating cyanoximes under the same conditions suggests, that the Sb donor triphenylstibine is able to substitute the oxygen atoms in the silver(I) coordination sphere, but not the nitrogen ones. This causes the formation of 1:3 adducts of Ag{L} with SbPh3 for N ,O donors {L1} and {L2}, and only 1:2 for N,N donor anionic {L3}.

Structural and solution chemistry of gold(I) and silver(I) complexes of bidentate pyridyl phosphines: selective antitumour agents

The 1:2 adducts of Ag(I) and Au(I) with 1,2-bis(di- n-pyridylphosphino)ethane (d npype) for n=2, 3 and 4 have been synthesised and solution properties characterised by multinuclear NMR spectroscopy. The complexes are hydrophilic analogs of the lipophilic Au(I) antitumour complex [Au(dppe) 2] + and the degree of hydrophilicity depends critically on the position of the N atom in the pyridyl ring. The complexes of d3pype and d4pype are simple monomeric [M(d3pype) 2] + and [M(d4pype) 2] + species which have a much higher water solubility than the 2-pyridyl complexes which crystallise in the solid state as dimeric [{M(d2pype) 2} 2] 2+. In solution these 1:2 M:d2pype species exist as equilibrium mixtures of monomeric, dimeric and trimeric (Ag) or tetrameric (Au) clusters. The Au(I) and Ag(I)pyridyl phosphine complexes have been evaluated for antitumour activity against a panel of cultured human ovarian carcinoma cell lines. The results show both potent and selective activity for the compounds with IC 50 values ranging from 0.18 to 1500 μM. There is a correlation between the degree of antitumour selectivity and the octanol/water partition coefficients with the greatest selectivity (500-fold range) found for the most hydrophilic complex [Au(d4pype) 2]Cl. Clinical development of the parent compound [Au(dppe) 2] + was halted by liver toxicity and the hydrophilic pyridylphosphine analogs are significantly less toxic than [Au(dppe) 2] + when exposed to isolated rat hepatocytes. Convenient synthetic routes to the bidentate pyridyl phosphines d2pype, d3pype and d4pype are also described.

Pharmacodynamics of cisplatin in human head and neck cancer: correlation between platinum content, DNA adduct levels and drug sensitivity in vitro and in vivo.

Total platinum contents and cisplatin–DNA adduct levels were determined in vivo in xenografted tumour tissues in mice and in vitro in cultured tumour cells of head and neck squamous cell carcinoma (HNSCC), and correlated with sensitivity to cisplatin. In vivo, a panel of five HNSCC tumour lines growing as xenografts in nude mice was used. In vitro, the panel consisted of five HNSCC cell lines, of which four had an in vivo equivalent. Sensitivity to cisplatin varied three- to sevenfold among cell lines and tumours respectively. However, the ranking of the sensitivities of the tumour lines (in vivo), also after reinjection of the cultured tumour cells, did not coincide with that of the corresponding cell lines, which showed that cell culture systems are not representative for the in vivo situation. Both in vitro and in vivo, however, significant correlations were found between total platinum levels, measured by atomic absorption spectrophotometry (AAS), and tumour response to cisplatin therapy at all time points tested. The levels of the two major cisplatin–DNA adduct types were determined by a recently developed and improved32P post-labelling assay at various time points after cisplatin treatment. Evidence is presented that the platinum–AG adduct, in which platinum is bound to guanine and an adjacent adenine, may be the cytotoxic lesion because a significant correlation was found between the platinum–AG levels and the sensitivities in our panel of HNSCC, in vitro as well as in vivo. This correlation with the platinum–AG levels was established at 1 h (in vitro) and 3 h (in vivo) after the start of the cisplatin treatment, which emphasizes the importance of early sampling. © 1999 Cancer Research Campaign

In vitro formation of DNA adducts by cisplatin, lobaplatin and oxaliplatin in calf thymus DNA in solution and in cultured human cells.

Two interesting representatives of a new generation of platinum-based cytostatic drugs that are currently being tested in clinical trials are lobaplatin [1,2-diaminomethylcyclobutane platinum(II) lactate] and oxaliplatin [1,2-diaminocyclohexane platinum (II) oxalate]. Since little is known about the DNA adduct formation of these compounds, we studied their formation in DNA in vitro in calf thymus DNA and in cells. The major adducts formed in vitro were the Pt-GG and Pt-AG intrastrand crosslinks. The latter adducts could be detected using a recently developed 32P-postlabelling method. Using both this assay and atomic absorption spectroscopy, it was shown that there is a substantially higher rate of the in vitro adduct formation by cisplatin, compared with lobaplatin and oxaliplatin. Platinum concentrations required to obtain 90% cell kill during a 2 h incubation of A2780 cells were 15 microM for cisplatin and oxaliplatin and 22 microM for lobaplatin. Using an antiserum originally raised against cisplatin-treated DNA, we were also able to detect platinum-DNA adducts induced by lobaplatin and oxaliplatin. Maximal nuclear staining for all three compounds was observed after a 4 h post-incubation period. The nuclear staining level induced by cisplatin was about 10-fold higher than after lobaplatin and oxaliplatin treatment. GG and AG adducts, measured by 32P-postlabelling, also showed maximum levels at about 4 h after treatment. Relative GG peak levels were 4:1:3 for cisplatin, lobaplatin and oxaliplatin, respectively. The ratios of GG over AG intrastrand crosslinks in the A2780 cells were not significantly different for the various compounds. In conclusion, the 32P-postlabelling technique has been shown to be appropriate for adduct analysis, not only for the classical Pt compounds cisplatin and carboplatin but also for novel platinum compounds like lobaplatin and oxaliplatin. Results indicated large differences in reactivity of the latter compounds to DNA in vitro, compared with cisplatin. This difference was smaller in cells, suggesting enhancement of adduct formation by certain cellular mechanisms and/or compounds. From these studies, no conclusions can be drawn with respect to the cytotoxicity of the different Pt-GG and Pt-AG intrastrand crosslinks formed by these compounds.

Exchange Coupling in Niobocene Trihydrides, Nb(C5H3RR‘)2H3, and Their Adducts with Copper Triad Cations, [{Nb(C5H3RR‘)2H3}2M]+(R = R‘ = H; R = H, R‘= SiMe3; R = R‘ = SiMe3; M = Cu, Ag, Au)

The reactions of Nb(C5H3RR‘)2Cl2 with Red−Al followed by hydrolysis yield Nb(C5H3RR‘)2H3 (R = R‘ = H, 1; R = H, R‘ = SiMe3, 2; R = R‘ = SiMe3, 3). These compounds react with Lewis acidic coinage cationic species, namely, [Cu(MeCN)4]PF6, AgBF4, and “Au(THT)PF6”, prepared in situ from AuCl(THT) and TlPF6 in a 2 to 1 ratio to yield the adducts [{Nb(C5H3RR‘)2H3}2M]+ (M = Cu, R = R‘ = H, 7; R = H, R‘ = SiMe3, 8; R = R‘ = SiMe3, 9; M = Ag, R = H, R‘ = SiMe3, 10; R = R‘ = SiMe3, 11; M = Au, R = R‘ = H, 12; R = H, R‘ = SiMe3, 13; R = R‘ = SiMe3, 14). Like 1, but unlike the corresponding tantalum derivatives Ta(C5H3RR‘)2H3 (R = R‘ = H, 4; R = H, R‘ = SiMe3, 5; R = R‘ = SiMe3, 6), 2 and 3 show exchange couplings in their high-field 1H NMR spectra due to a hydride tunneling phenomenon. The magnitudes of exchange couplings are larger in the cases of 2 and 3 than in the case of 1 as a result of the decrease of electron density upon increasing the number of SiMe3 substituents on the Cp ring. The addition of a Lewis acidic cation results in the observation of an AB2 pattern for the hydrides at room temperature, which splits at low temperature into an ABC one in agreement with a fluxional behavior of the cation which binds to two hydrides of each niobium center. The activation energy of these fluxional processes are close to 42−45 kJ·mol-1 in the case of Cu adducts, 37 kJ·mol-1 in the case of Ag adducts, and 40 kJ·mol-1 in the case of Au adducts. The magnitude of exchange couplings is reduced upon addition of copper cation to 1−3, is of the same order of magnitude after addition of a silver cation, and is greatly increased by addition of a gold cation. A model is proposed to explain these variations which involves two isomeric states that are close in energy, one involving two bridging and one terminal hydrides on niobium and one involving one bridging hydride and a dihydrogen molecule. A line shape analysis experiment carried out on 14 allows determination of the parameters of the classical exchange, the coupling constants at various temperatures which reach 550 Hz at 347 K, and the parameters of the quantum mechanical exchange according to our proposed model. The structure of 14 has been studied by X-ray diffraction. The structure has been solved from diffractometer data by Patterson method and refined by blocked full-matrix least squares on the basis of 3082 observed reflections to R and Rw values of 0.0346 and 0.0381, respectively. The structure shows the presence of two bridging hydrides between the niobium and gold atoms; one of them is found close to the terminal hydride.

Isonitrile-containing platinum-gold phosphine clusters

PtAu-phosphine clusters with an isonitrile ligand on Pt or both Pt and Au can be synthesized from [Pt(AuPPh3)8]2+. The reaction of one equivalent of RNC (R = i-Pr,t-Bu) with [Pt(AuPPh3)8]2+ results in the addition of RNC to the central Pt, to form [Pt(RNC)(AuPPh3)8]2+. The addition of an excess of RNC results in the replacement of one of the Au-bonded PPh3 ligands to give [Pt(RNC)(AuRNC)(AuPPh3)7]2+. Treatment of [Pt(CO)(AuPPh3)8]2+ with an excess of RNC does not result in displacement of the Pt-bonded CO ligand but only one of the Au-bonded PPh3 ligands, to yield [Pt(CO)(AuRNC)(AuPPh3)7]2+. Ag adducts of all of these compounds can be prepared by the addition of one equivalent of AgNO3. The compounds have been characterized by IR and NMR (1H, 31P and 195Pt) spectroscopy and elemental analysis. The structures are thought to be isostructural with the reported [Pt(AgNO3)x(CO)y(AuPPh3)8](NO3)2 compounds, with x, y = 0, 1. NMR and IR data for these clusters are compared, and observed trends analysed in terms of σ-donor and π-acceptor considerations. A fragment molecular orbital analysis of [Pt(CO)(AuPPh3)8](NO3)2 is presented. The changes in bonding characteristics upon addition of CO to [Pt(AuPPh3)8](NO3)2 are examined and the decrease of the radial 2J(PtP) coupling constant is explained in terms of the results.