Effects of amine ligand bulk and hydrogen bonding on the rate of reaction of platinum(II) diamine complexes with key nucleotide and amino acid residues

NMR spectroscopy has been used to observe the effects of the amine ligand on the rate of reaction of platinum diamine and triamine complexes with DNA and protein residues. Whereas [Pt(dien)Cl]Cl and [Pt(dien)(D(2)O)](2+) have been known to react faster with thioether residues such as N-AcMet than with 5'-GMP, we found that [Pt(Me(4)en)(D(2)O)(2)](2+) appeared to react faster with 5'-GMP. To quantitatively assess the factors influencing the rates of reaction, rate constants at pH 4 were determined for the reactions of [Pt(en)(D(2)O)(2)](2+) [en = ethylenediamine] and [Pt(Me(4)en)(D(2)O)(2)](2+) with N-AcMet, N-AcHis, 5'-GMP, and Guo (guanosine). In each case the less bulky complex ([Pt(en)(D(2)O)(2)](2+)) reacts more quickly than does the bulkier [Pt(Me(4)en)(D(2)O)(2)](2+), as expected. Both complexes reacted faster with 5'-GMP; however, analysis of the rate constants suggests that the [Pt(en)(D(2)O)(2)](2+) complex favors reaction with 5'-GMP due to hydrogen bonding with the 5'-phosphate, whereas [Pt(Me(4)en)(D(2)O)(2)](2+) disfavors reaction with N-AcMet due to steric clashes. Bulk had relatively little effect on the rate constant with N-AcHis, suggesting that peptides or proteins that coordinate via His residues would not have their reactivity affected by bulky diamine ligands.     

Study of the reactions between platinum(II) complexes and L-methionine in the presence and absence of 5'-GMP

The reactions of the platinum(II) complexes, [Pt(dien)(H(2)O)](2+), [PtCl(dien)](+) and [PtBr(dien)](+) (dien is diethylenetriamine) with some biologically relevant ligands such as inosine (INO), inosine-5'-monophosphate (5'-IMP), guanosine-5'-monophosphate (5'-GMP), glutathione (GSH) and l-methionine (S-meth), have been studied by UV-Visible spectrophotometry and (1)H NMR spectroscopy. Kinetic and thermodynamic parameters of these reactions were determined. Competitive reactions of [PtCl(dien)](+) with l-methionine and 5'-GMP demonstrated initially rapid formation of [Pt(dien)(S-meth)](2+) followed by displacement of l-methionine by 5'-GMP. In the later stages the concentration of [Pt(dien)(N7-GMP)](2+) is predominant. The results are analyzed in reference to the anti-tumour activity of Pt(II) complexes.     

A bulky platinum triamine complex that reacts faster with guanosine 5′-monophosphate than with N-acetylmethionine

A bulky platinum triamine complex, [Pt(Me₅dien)(NO₃)]NO₃ (Me₅dien = N,N,N′,N′,N′′-pentamethyldiethylenetriamine) has been prepared and reacted in D₂O with N-acetylmethionine (N-AcMet) and guanosine 5′-monophosphate (5′-GMP); the reactions have been studied using ¹H NMR spectroscopy. Reaction with 5′-GMP leads to two rotamers of [Pt(Me₅dien)(5′-GMP-N7)]⁺. Reaction with N-AcMet leads to formation of [Pt(Me₅dien)(N-AcMet-S)]⁺. When a sample with equimolar mixtures of [Pt(Me₅dien)(D₂O)]²⁺, 5′-GMP, and N-AcMet was prepared, [Pt(Me₅dien)(5′-GMP-N7)]⁺ was the dominant product observed throughout the reaction. This selectivity is the opposite of that observed for a similar reaction of [Pt(dien)(D₂O)]²⁺ with 5′-GMP and N-AcMet. To our knowledge, this is the first report of a platinum(II) triamine complex that reacts substantially faster with 5′-GMP than with N-AcMet; the effect is most likely due to steric clashes between the methyl groups of the Me₅dien ligand and the N-AcMet.     

Pt(II) complexes with N-(3-pyridyl)-2-(4-(trifluoromethyl)phenyl)diazenecarboxamide and their reactions with glutathione

The reaction between [PtCl(dmso)(en)]Cl (dmso=dimethyl sulfoxide, en=ethylenediamine) and N-(3-pyridyl)-2-(4-(trifluoromethyl)phenyl)diazenecarboxamide (L) was studied using multinuclear NMR spectroscopy. The water-soluble complexes [PtCl(en)(L-N1)](+) (1) and [Pt(en)(L-N1)(2)](2+) (2) were isolated and their reactions with glutathione (GSH) were investigated to assess the oxidation properties of coordinated L. Both species 1 and 2 oxidized GSH to GSSG, while the reduced form of L (semicarbazide, SL) remained coordinated to Pt(2+). In complex 1 the labile chloride ion was substituted by the thiol moiety of GSH, which gave rise to the release of en in excess GSH over a period of 7 days. Complexes [PtCl(dmso)(en)]Cl, 1, 2 and ligand L were tested against T24 bladder carcinoma cells. Ligand L and complexes 1 and 2 showed higher cytotoxicity than [PtCl(dmso)(en)]Cl.     

Sulfur K-edge extended X-ray absorption fine structure spectroscopy of homoleptic thiolato complexes with Zn(II) and Cd(II)

The sulfur K-edge extended X-ray absorption fine structure (EXAFS) spectroscopy is applied to homoleptic thiolato complexes with Zn(II) and Cd(II), (Et(4)N)[Zn(SAd)(3)] (1), (Et(4)N)(2)[{Zn(ScHex)(2)}(2)(mu-ScHex)(2)] (2), (Et(4)N)(2)[{Cd(ScHex)(2)}(2)(mu-ScHex)(2)] (3), (Et(4)N)(2)[{Cd(ScHex)}(4)(mu-ScHex)(6)] (4), [Zn(mu-SAd)(2)](n) (5), and [Cd(mu-SAd)(2)](n) (6) (HSAd=1-adamantanethiol, HScHex=cyclohexanethiol). The EXAFS results are consistent with the X-ray crystal data of 1-4. The structures of 5 and 6, which have not been determined by X-ray crystallography, are proposed to be polynuclear structures on the basis of the sulfur K-edge EXAFS, far-IR spectra, and elemental analysis. Clear evidences of the S...S interactions (between bridging atoms or neighboring sulfur atoms) and the S...C(far) interactions (in which C(far) atom is next to carbon atom directly bonded to sulfur atom) were observed in the EXAFS data for all complexes and thus lead to the reliable determination of the structures of 5 and 6 in combination with conventional zinc K-edge EXAFS analysis for 5. This new methodology, sulfur K-edge EXAFS, could be applied for the structural determination of in vivo metalloproteins as well as inorganic compounds.     

Convenient synthesis of human calcitonin and its methionine sulfoxide derivative

The human calcitonin peptide chain was assembled using Fmoc solid-phase peptide synthesis chemistry. The combinations of cleavage Reagent H with trans-[Pt(en)(2)Cl(2)](2+) and Reagents B, K, and R with trans-[Pt(CN)(4)Cl(2)](2-) provide convenient methods for the synthesis of human calcitonin and its methionine sulfoxide derivative; the formation of intramolecular disulfide bonds by the above Pt(IV) oxidants is essentially quantitative.     

Reaction of platinum(II) diamine and triamine complexes with selenomethionine

We have reacted [Pt(dien)Cl]Cl, [Pt(en)(D₂O)₂]²⁺, and [Pt(Me₄en)(D₂O)₂]²⁺ [Me₄en = N,N,N′,N′-tetramethylethylenediamine] with selenomethionine (SeMet). When [Pt(dien)Cl]Cl is reacted with SeMet, [Pt(dien)(SeMet-Se)]²⁺ is formed; two Se-CH₃ resonances are observed due to the different chiralities at the Se atom upon platination. In a reaction of [Pt(dien)Cl]Cl with an equimolar mixture of SeMet and Met, the SeMet product forms more quickly though a slow equilibrium with approximately equal amounts of both products is reached. [Pt(Me₄en)(D₂O)₂]²⁺ reacts with SeMet to form [Pt(Me₄en)(SeMet-Se)(D₂O)]²⁺ initially but forms [Pt(Me₄en)(SeMet-Se,N)]⁺ ultimately. One stereoisomer of the chelate, assigned to the R chirality at the Se atom, dominates within the first few minutes of reaction. [Pt(en)(D₂O)₂]²⁺ forms a variety of products depending on reaction stoichiometry; when one equivalent or less of SeMet is added, the dominant product is [Pt(en)(SeMet-Se,N)]⁺. In the presence of excess SeMet, [Pt(en)(SeMet-Se)₂]²⁺ is the dominant initially, but displacement of the en ligand occurs leading to [Pt(SeMet-Se,N)₂] as the eventual product. Displacement of the en ligand from [Pt(en)(SeMet-Se,N)]⁺ does not occur. In reactions of K₂PtCl₄ with two equivalents of SeMet, [Pt(SeMet-Se,N)₂] is formed, and three sets of resonances are observed due to different chiralities at the Se atoms. Only the cis geometric isomers are observed by ¹H and ¹⁹⁵Pt NMR spectroscopy.     

Reactions of cisplatin hydrolytes with methionine, cysteine, and plasma ultrafiltrate studied by a combination of HPLC and NMR techniques

The reactions of cis-[PtCl(NH3)2(H2O)]+ with L-methionine have been studied by 1D 195Pt and 15N NMR, and by 2D[1H, 15N] NMR. When the platinum complex is in excess, the initial product, cis-[PtCl(NH3)2(Hmet-S)]+ undergoes slow ring closure to [Pt(NH3)2(Hmet-N,S)]2+. Slow ammine loss then occurs to give the isomer of [PtCl(NH3)(Hmet-N,S)]+ with chloride trans to sulfur. When methionine is in excess, a reaction sequence is proposed in which trans-[PtCl(NH3)(Hmet-S)2]+ isomerises to the cis-isomer, with subsequent ring closure reactions leading to cis-[Pt(Hmet-N,S)2]2+. Near pH 7, methionine is unreactive toward cis-[PtCl(OH)(NH3)2]. By contrast, L-cysteine reacts readily with cis-[PtCl(OH)(NH3)2] at pH 7, but there were many reaction products, including bridged species. Cis-[PtCl(OH)(NH3)2] reacts with reduced thiols in ultrafiltered plasma but these are oxidized if the plasma is not fresh or appropriately stored. With very low concentrations of the platinum complexes (35.5 microM), HPLC experiments (UV detection at 305 nm) indicate that the thiolate (probably cysteine) reactions become simpler as bridging becomes less important.     

Cytotoxicity studies of chromium(III) complexes on human dermal fibroblasts

The cytotoxicity of certain Cr(III) complexes, such as [Cr(salen)(H(2)O)(2)](+), [Cr(edta)(H(2)O)](-), [Cr(en)(3)](3+), [Cr(ox)(3)](3-), [Cr(pic)(3)], and CrCl(3), which differ in ionic character and ligand environment in human dermal skin fibroblasts, has been studied. After 72 h of exposure to 100 microM doses of chromium(III) complexes, the order in which the complexes had an inhibitory effect on cell viability was [Cr(en)(3)](3+) > [Cr(salen)(H(2)O)(2)](+) > [Cr(ox)(3)](3-) > [Cr(edta)(H(2)O)](-) > [Cr(pic)(3)] > CrCl(3). Based on viability studies it was confirmed that [Cr(en)(3)](3+), a triply charged cation, inhibits cell proliferation, and therefore, it was chosen to carry out further investigations. [Cr(en)(3)](3+), at a dose of 50 microM, was found to bring about surface morphological changes, evidenced by cellular blebbing and spike formation accompanied by nuclear damage. TEM analysis revealed substantial intracellular damage to fibroblasts in terms of the formation of apoptotic bodies and chromatin condensation, thus reflecting cell death. FACS analysis further revealed DNA damage by formation of a sub-G(1) peak with 84.2% DNA as aneuploid DNA and arrest of the G(2) / M phase of the cell cycle. Cellular DNA damage was confirmed by agarose gel electrophoresis with the characteristic appearance of a DNA streak in DNA isolated from [Cr(en)(3)](3+)-treated fibroblasts. The proposed mechanism suggests the plausible role of Cr(V), formed as a result of oxidation of Cr(III) by cellular oxidative enzymes, in the cytotoxic response. Consequently, any Cr(III) complex that is absorbed by cells and can be oxidized to Cr(V) must be considered a potential carcinogen. This has potential implications for the increased use of Cr(III) complexes as dietary supplements and highlights the need to consider the cytotoxicity and genotoxicity of a variety of Cr(III) complexes and to understand the potential hazards of Cr(III) complexes encountered in research laboratories.     

Guanine binding of a cytotoxic platinum-acridin-9-ylthiourea conjugate monitored by 1-D 1H and 2-D [1H,15N] NMR spectroscopy: hydrolysis is not the rate-determining step

The reaction of [PtCl(en)(ACRAMTU)](NO(3))(2) (PT-ACRAMTU, 1; ACRAMTU=1-[2-(acridin-9-ylamino)ethyl]-1,3-dimethylthiourea, en=ethane-1,2-diamine) and the [(15)N]-en labeled analogue, 1', with 2'-deoxyguanosine (dG) was studied by (1)H NMR and two-dimensional [(1)H,(15)N] HSQC (heteronuclear single quantum coherence) spectroscopy. Reactions were performed in phosphate buffered solution at 37 degrees C at various ratios and total concentrations of reactants. The (1)H NMR data suggest that the hydrolyzed form of the drug, [Pt(H(2)O)(en)(ACRAMTU)](3+) (1a), forms at a rate (k(1)) similar to that observed in classical platinum chloroam(m)ines but to only a minor extent ( approximately 15%). Attempts to detect and characterize 1'a by two-dimensional NMR spectroscopy, however, were unsuccessful, and 1' and dG( *) were the only species observed in the HSQC spectra. Reaction of the putative aqua intermediate 1a with dG to yield [Pt(en)(dG-N7)(ACRAMTU)](3+) (dG( *)) is slow and is highly dependent on the initial concentrations of the reactants. This unusual observation is consistent with a mechanism in which a second-order term becomes rate-determining (k(2)相似文献   

Synthesis, structure, and reactivity of monofunctional platinum(II) and palladium(II) complexes containing the sterically hindered ligand 6-(methylpyridin-2-yl)acetate

Three complexes containing the novel, sterically hindered ligand 6-(methylpyridin-2-yl)acetate (PICAC) have been synthesized and characterized: [Pt(NH3)2(PICAC-N,O)]NO3 (1), [Pt(en)(PICAC-N,O)]NO3 (2), and [Pd(en)(PICAC-N,O)]NO3 (3) (en = ethane-1,2-diamine). The crystal structures of 2 and 3 have been determined. The two complexes are isostructural and exhibit a mixed [N3O] coordination. In both cases, PICAC forms a sterically crowded six-membered chelate. Signal multiplicities in 1H NMR spectra of 1-3 indicate that the N,O chelates are conformationally rigid on the NMR timescale as a result of the steric bulk of the pyridine derivative. Complex 2 undergoes facile ring opening in 0.1M NaCl solution at neutral pH, resulting in a zwitterionic species in which carboxylate oxygen has been replaced with chloride. The complex was identified by X-ray crystallography as [PtCl(en)(PICAC-N)] x H2O (4), which contains a "dangling" carboxylate group. In 4, the pyridine moiety adopts an almost perpendicular orientation relative to the platinum coordination plane. Likewise, complex 2 reacts rapidly with 5'-guanosine monophosphate (5'-GMP) to form the monofunctional adduct [Pt(en)(PICAC)(5'-GMP)] (5) (NMR, 25 degrees C, t(1/2) approximately 24 min). 2-D nuclear Overhauser enhancement spectroscopy (NOESY) and double quantum-filtered correlated spectroscopy (dqf-COSY) experiments (500 MHz) and variable temperature NMR spectroscopy confirm that adduct 5 exists as a 1:1 mixture of rotamers in solution as a result of the mutual repulsion between the cis-oriented pyridine and guanine bases. While 2 readily reacts with DNA nitrogen, its monofunctional adducts show no significant effect on the conformation of native DNA. Circular dichroism (CD) spectra recorded of platinum-modified calf-thymus DNA suggest that the structural damage produced by complex 2 does not mimic that produced by the clinical agent. Both the unusual reactivity and the inability to induce cisplatin-like DNA conformational changes are proposed to be responsible for the marginal biological activity of the new complexes.     

The influence of methionine-containing peptides on the reaction of carboplatin with 5'-guanosine monophosphate: a comparison with cisplatin

The pH- and time-dependent reaction of the anticancer drug carboplatin, [Pt(cbdca-kappa(2)O,O')(NH(3))(2)] (cbdca=cyclobutane-1,1-dicarboxylate), with the tripeptides H-glyglymet-OH (glycylglycyl-L-methionine) and Ac-glyglymet-OH at 313 K was investigated by high-performance liquid chromatography, NMR and mass spectrometry. The relative stability of the initial ring-opened kappaS complex [Pt(cbdca-kappaO)(Ac-glyglymet-OH-kappaS)(NH(3))(2)] leads to increased formation of the kinetically favoured kappaS:kappaS' bis-adduct [Pt(Ac-glyglymet-OH-kappaS)(2)(NH(3))(2)](2+) in comparison with cisplatin. As a result a second 1:2 reaction pathway kappaS-->kappaS:kappaS'-->kappa(2)N(M), S:kappaS'-->kappa(3)N(G2),N(M), S:kappaS', where N(M) and N(G2) represent, respectively, metallated methionine and glycine nitrogen atoms, competes with the 1:1 route kappaS-->kappa(2)N(M), S-->kappa(3)N(G2),N(M), S also observed for cisplatin. Cleavage of N-acetylglycine at the backbone C(O)-N bond to the second gly residue (G2) is observed after 100 h for the respective tridentate complexes [Pt(Ac-glyglyH(-1)metH(-1)-OH-kappa(3)N(G2),N(M), S) (Ac-glyglymet-OH-kappaS)] and [Pt(Ac-glyglyH(-1)metH(-1)-OH-kappa(3)N(G2),N(M), S)(NH(3))] at pH <5.2. The longevity of the initial kappaS complex leads to about an eight-fold increase in the rate of formation of the kappaN7:kappaN7' bis-adduct [Pt(5'-GMP-kappaN7)(2)(NH(3))(2)](2-) for the reaction of carboplatin with 5'-GMP(2-) at pH 7 in the presence of Ac-glyglymet-OH. A mixed-ligand kappaS:kappaN7 species [Pt(5'-GMP-kappaN7)(Ac-glyglymet-OH-kappaS)(NH(3))(2)] provides the major precursor for this 1:2 nucleotide complex and kappaN7 coordination of 5'-GMP(2-) is also observed in the kappa(2)N(M),S:kappaN7 complex [Pt(5'-GMP-kappaN7)(Ac-glyglymetH(-1)-OH-kappa(2)N(M),S)(NH(3))(2)](-) formed by substitution of the ammine ligand trans to the methionine sulphur. As the intermediate kappaS:kappaN7 species is formed rapidly within the first 10 h of reaction, these results suggest that the transfer reaction pathway kappaS-->kappaS:kappaN7-->kappaN7:kappaN7' involving kappaS platinated peptides could play an important role in accelerating the rate of DNA binding for carboplatin.     

Preparation of platinum(IV) complexes with dipeptide and diimine. X-ray crystal structure and 195Pt NMR spectra

We prepared platinum(IV) complexes containing dipeptide and diimine or diamine, the [PtCl(dipeptide-N,N,O)(diimine or diamine)]Cl complex, where -N,N,O means dipeptide coordinated as a tridentate chelate, dipeptide=glycylglycine (NH(2)CH(2)CON(-)CH(2)COO(-), digly, where two protons of dipeptide are detached when the dipeptide coordinates to metal ion as a tridentate chelate), glycyl-L-alanine (NH(2)CH(2)CON(-)CHCH(3)COO(-), gly-L-ala), L-alanylglycine (NH(2)CH CH(3)CON(-)CH(2)COO(-), L-alagly), or L-alanyl-L-alanine (NH(2)CHCH(3)CON(-)CHCH(3)COO(-), dil-ala), and diimine or diamine=bipyridine (bpy), ethylenediamine (en), N-methylethylenediamine (N-Me-en), or N,N'-dimethylethylenediamine (N,N'-diMe-en). In the complexes containing gly-L-ala or dil-ala, two separate peaks of the (195)Pt NMR spectra of the [PtCl(dipeptide-N,N,O)(diimine or diamine)]Cl complexes appeared in, but in the complexes containing digly or L-alagly, one peak which contained two overlapped signals appeared. One of the two complexes containing gly-L-ala and bpy, [PtCl(gly-L-ala-N,N,O)(bpy)]NO(3), crystallized and was analyzed. This complex has the monoclinic space group P2(1)2(1)2(1) with unit cell dimensions of a=9.7906(3)A, b=11.1847(2)A, c=16.6796(2)A, Z=4. The crystal data revealed that this [PtCl(gly-L-ala-N,N,O)(bpy)]NO(3) complex has the near- (Cl, CH(3)) configuration of two possible isomers. Based on elemental analysis, the other complex must have the near- (Cl, CH(3))-[PtCl(gly-L-ala-N,N,O)(bpy)]NO(3) configuration. The (195)Pt NMR chemical shifts of the near- (Cl, CH(3))-[PtCl(gly-L-ala-N,N,O)(bpy)]NO(3) complex and the far- (Cl, CH(3))-[PtCl(gly-L-ala-N,N,O)(bpy)]NO(3) complex are 0 ppm and -19 ppm, respectively (0 ppm for the Na(2)[PtCl(6)] signal). The additive property of the (195)Pt NMR chemical shift is discussed. The (195)Pt NMR chemical shifts of [PtCl(dipeptide-N,N,O)(bpy)]Cl appeared at a higher field when the H attached to the dipeptide carbon atom was replaced with a methyl group. On the other hand, the (195)Pt NMR chemicals shifts of [PtCl(dipeptide-N,N,O)(diamine)] appeared at a lower field when the H attached to the diamine nitrogen atom was replaced with a methyl group, in the order of [PtCl(digly-N,N,O)(en)]Cl, [PtCl(digly-N,N,O)(N-Me-en)]Cl, and [PtCl(digly-N,N,O)(N,N'-diMe-en)]Cl.     

Identification of platination sites on human serum transferrin using 13C and 15N NMR spectroscopy

 Reactions between various apo and metal-bound forms of human serum transferrin (80 kDa) and the recombinant N-lobe (40 kDa) with [Pt(en)Cl₂] or cis-[PtCl₂(NH₃)₂] have been investigated in solution via observation of [¹H,¹⁵N] NMR resonances of the Pt complexes, [¹H,¹³C] resonances of the eCH₃ groups of the protein methionine residues, and by chromatographic analysis of single-site methionine mutants. For the whole protein, the preferred Pt binding site appears to be Met256. Additional binding occurs at the other surface-exposed methionine (Met499), which is platinated at a slower rate than Met256. In contrast, binding of similar Pt compounds to the N-lobe of the protein occurs at Met313, rather than Met256. Met313 is buried in the interlobe contact region of intact transferrin. After loss of one chloride ligand from Pt and binding to methionine sulfur of the N-lobe, chelate-ring closure appears to occur with binding to a deprotonated backbone amide nitrogen, and the loss of the other chloride ligand. Such chelate-ring closure was not observed during reactions of the whole protein, even after several days. Received: 5 May 1999 / Accepted: 26 July 1999     

Kinetics and mechanism of the substitution reactions of [PtCl(bpma)]<Superscript>+</Superscript>, [PtCl(gly-met-<Emphasis Type="Italic">S,N,N</Emphasis>)] and their aqua analogues with <Emphasis Type="SmallCaps">l</Emphasis>-methionine,glutathione and 5′-GMP

The substitution reactions of [PtCl(bpma)]+, [PtCl(gly-met-S,N,N)], [Pt(bpma)(H(2)O)](2+) and [Pt(gly-met-S,N,N)(H(2)O)](+) [where bpma is bis(2-pyridylmethyl)amine and gly-met-S,N,N is glycylmethionine] with L-methionine, glutathione and guanosine 5'-monophosphate (5'-GMP) were studied in aqueous solutions in 0.10 M NaClO(4) under pseudo-first-order conditions as a function of concentration and temperature using UV-vis spectrophotometry. The reactions of the chloro complexes were followed in the presence of 10 mM NaCl and at pH approximately 5, whereas the reactions of the aqua complexes were studied at pH 2.5. The [PtCl(bpma)]+ complex is more reactive towards the chosen nucleophiles than [PtCl(gly-met-S,N,N)]. Also, the aqua complexes are more reactive than the corresponding chloro complexes. The activation parameters for all the reactions studied suggest an associative substitution mechanism. The reactions of [PtCl(bpma)]+ and [PtCl(gly-met-S,N,N)] with 5'-GMP were studied by using (1)H NMR spectroscopy at 298 K. The pK (a) value of the [Pt(gly-met-S,N,N)(H(2)O)]+ complex is 5.95. Density functional theory calculations (B3LYP/LANL2DZp) show that in all cases guanine coordination to the L(3)Pt fragment (L(3) is terpyridine, bpma, diethylenetriamine, gly-met-S,N,N) is much more favorable than the thioether-coordinated form. The calculations collectively support the experimentally observed substitution of thioethers from Pt(II) complexes by N7-GMP. This study throws more light on the mechanistic behavior of platinum antitumor complexes.     

Sulfur K-edge XAS of WVO vs. MoVO bis(dithiolene) complexes: contributions of relativistic effects to electronic structure and reactivity of tungsten enzymes

Molybdenum- or tungsten-containing enzymes catalyze oxygen atom transfer reactions involved in carbon, sulfur, or nitrogen metabolism. It has been observed that reduction potentials and oxygen atom transfer rates are different for W relative to Mo enzymes and the isostructural Mo/W complexes. Sulfur K-edge X-ray absorption spectroscopy (XAS) and density functional theory (DFT) calculations on [Mo(V)O(bdt)(2)](-) and [W(V)O(bdt)(2)](-), where bdt=benzene-1,2-dithiolate(2-), have been used to determine that the energies of the half-filled redox-active orbital, and thus the reduction potentials and MO bond strengths, are different for these complexes due to relativistic effects in the W sites.     

Intermediates formed by laser flash photolysis of [PtCl(6)](2-) in aqueous solutions.

The stationary photolysis of [PtCl(6)](2-) in aqueous solutions (10(-5)-10(-4) M) at the region of 313 nm leads to its photoaquation with a quantum yield of 0.19. Laser flash photolysis experiments (308 nm) provided evidence of the formation of Pt(iii) intermediates, namely [PtCl(4)(OH)(H(2)O)](2-) and [PtCl(4)](-), and Cl(2) (-) radical anions. The Pt(iii) complexes formed as a result of an intrasphere electron transfer from Cl(-) ligands to the excited Pt(iv) ion. However, the main ( approximately 90%) photolysis channel was not accompanied by the transfer of Cl atoms to the solvent bulk. The photoaquation of [PtCl(6)](2-) results from the back electron transfer in the secondary geminate pair, [PtCl(5)(H(2)O)](2-)-Cl. The relative yield of Pt(iii) intermediates, recorded after the completion of all processes in the geminate pair, was less than 10% of the number of disappearing initial [PtCl(6)](2-) complexes.     

Modulation of the chemical and biological properties of trans platinum complexes: monofunctional platinum complexes containing one nucleobase as potential antiviral chemotypes

Replacement of one of the chloride leaving groups in trans-[PtCl2(NH3)(L)] by the nucleobase 9-ethylguanine gives the nucleobase cations [SP-4-2]-[PtCl(9-ethylguanine)(NH3)(L)]+ (L = NH3, 1; L = quinoline, 3), which are models for the monofunctional adduct on DNA. Displacement of Cl- in 1 and 3 by either 5'-guanosine monophosphate (5'-GMP) or N-acetyl-L-methionine (N-AcMet) showed clear kinetic preference for the sulfur (estimated half-lives of 1.5 and 4 h with N-AcMet against 7 and 17 h for 5'-GMP for 1 and 3, respectively). To further examine the kinetic preference, 1-methylcytosine (1-MeCyt) analogs were prepared, [SP-4-2]-[PtCl(1-Me-Cyt)(NH3)(L)]+ (L=NH3, 2; L=quinoline, 4). The -MeCyt compounds, 2 and 4, resulted in slower rates of substitution by both 5'-GMP and N-AcMet in comparison to 1 and 3 (estimated half-lives for N-AcMet of 5 and 13.5 h and for 5'-GMP of 6 and 14 h for 2 and 4, respectively). Interestingly in this case, however, no selectivity for the sulfur site was observed, a possible explanation being that molecular recognition across the square plane enhances the rate of reaction with 5'-GMP. The affinity of 3 towards S-donor ligands was exploited to remove zinc from the zinc-finger site of the C-terminal finger of the HIV-nucleocapsid protein, NCp7. The ability to eject zinc further suggested the biological antiviral application of [SP-4-2]-[PtCl(nucleobase)(NH3)(L)]+. A preliminary survey against HIV and herpes viruses indeed showed encouraging results with some antiviral specificity, dependent on the exact nature of the compound. The initial results suggest consideration of [SP-4-2]-[PtCl(nucleobase)(NH3)(L)]+ as a novel antiviral chemotype.     

Synthesis,characterization and in vitro cytotoxicity of new organotin(IV) derivatives of N-methylglycine

The synthesis and characterization of new coordination compounds of some diorganotins(IV) with N-methylglycine (sarcosine) are reported; all these derivatives mainly tend to assume a chelate structure. As single crystals were not obtained, a large number of experimental techniques were used to accomplish a definitive characterization and determination of their structure. Results obtained by (1)H/(119)Sn NMR, FT-IR and (119)mSn-M?ssbauer spectroscopy and thermogravimetric analysis allow us to deduce the pentacoordination for 1:1 (Sn/sarcosine) derivatives [R(2)SnCl(2)(Sar)](+)Cl(-) (R=Me, n-Bu) in a trigonal-bipyramidal structure, and the hexacoordination for 1:2 complexes [R'(2)Sn(Sar)(2)](2+)2Cl(-) (R'=Me, n-Bu, Ph) in an octahedral structure; however, the probability of partially or totally non-chelate structures for some adducts increases with the steric hindrance of the R/R' groups and the number of the sarcosine molecules bound to the tin atom, so that they give rise to fluxional equilibria in solution. Finally, the synthesized compounds have been tested for in vitro cytotoxic activity against human adenocarcinoma HeLa cells showing, in some cases, strong activity even at low concentration.     

Fixing the conformations of diamineplatinum(II)-GpG chelates: NMR and CD signatures of individual rotamers

The bulky, asymmetric analog of the antitumor drug cisplatin, [PtCl(2)(tmen)] (tmen = N,N,N'-trimethylethylenediamine), was used to produce crosslinks with the dinucleotide d(GpG), modeling the most frequent lesions that cisplatin and its analogs cause to DNA. The ligand tmen was chosen because it is expected to constrain the guanine cis to the NMe(2) group in the adduct [Pt(tmen){d(GpG)}](+) to an orientation perpendicular to the coordination plane and to stabilize the other guanine in an oblique orientation, thus maintaining a head-to-head geometry typical of cisplatin-d(GpG) crosslinks within single- and double-stranded DNA. Of the four possible combinations of tmen chirality (R or S symmetry of the coordinated NHMe group) and crosslink direction (5'-G bound cis to the secondary or the tertiary amino group of tmen), two isomers were preponderantly formed, [Pt(R-tmen){d(GpG)}](+) with 5'-G bound cis to NMe(2) and [Pt(S-tmen){d(GpG)}](+) with 5'-G bound cis to NHMe. The former was shown to have a right-handed R2 orientation of guanines similar to that found in duplex DNA, whereas the latter had a left-handed L1 orientation that modeled cisplatin-d(GpG) adducts within single-stranded DNA. The R2 rotamer was found to be in an equilibrium (as observed using EXSY spectroscopy) with a minor fraction (< or =4%) of a Delta-HT rotamer related to R2 by rotation of the 3'-G about the Pt-N7 bond. The major rotamers R2 and L1 were isolated using reverse-phase HPLC, and their NMR and CD signatures were compared to those of the corresponding rotamers of the less hindered adduct [Pt(dmen)(GpG)](+) (dmen = N,N-dimethylethylenediamine). From this and other comparisons with previously reported platinum dinucleotide complexes, and from molecular modeling, it could be concluded that both steric repulsion between guanine and substituents of the cis amino group and N-H...O6 hydrogen bonding are significant effects favoring the oblique orientation of one guanine base typical of the HH rotamers of [Pt(diamine){d(GpG)}](+) and [Pt(diamine)(GpG)](+) complexes.