Interaction of cis-[Pt(NH3)2(H2O)2](NO3)2 with ribose deoxyribose diguanosine phosphates

The three diguanosine phosphates GpG (4 X 10(-4) M), d(GpG) (10(-5) M), and d(pGpG) (10(-5) M) have been reacted with cis-[Pt(NH3)2(H2O)2](NO3)2 (1 Pt/dinucleotide) in water at pH 5.5 and 37 degrees C. In each case a single product is formed. The three complexes have been characterized by proton nuclear magnetic resonance (1H NMR) and circular dichroism (CD) analyses. They are N(7)-N(7) chelates of the metal with an anti-anti configuration of the bases. They present a conformational change upon deprotonation of guanine N(1)H whose pKa is ca. 8.7 (D2O). Their CD spectra, compared to those of the free dinucleotides, exhibit an increase of ellipticity in the 275-nm region, which can be qualitatively related to the characteristic increase reported for platinated DNA and poly(dG) . poly(dC). These results are in favor of the hypothesis of intrastrand cross-linking of adjacent guanines, by the cis-PtII(NH3)2 moiety, after a local denaturation of DNA.     

Crystal structures and cytotoxicity of isopropylamine Pt(II) complexes: a trinuclear squarato-bridged [Pt3(mu2-C4O4)3(H2NPri)6].3H2O and a mononuclear cis-[Pt(NO3)2(H2NPri)2

Crystals of a novel platinum(II) complex with squarato ligand, [Pt(3)(mu(2)-C(4)O(4))(3)(H(2)NPr(i))(6)].3H(2)O (1) (H(2)NPr(i)=ipa), have been isolated from the aqueous solution of cis-[Pt(H(2)O)(2)(H(2)NPr(i))(2)]SO(4) and barium squarate. Slow evaporation of methanol solution of cis-[Pt(NO(3))(2)(H(2)NPr(i))(2)] (2) resulted in crystallization of nitrato complex. The single crystal X-ray diffraction method was used to determine structures of 1 and 2. Complex 1 crystallizes in a triclinic space group P1 with a=11.17380(10)A, b=14.4535(2)A, c=14.8010(2)A, alpha=86.0901(10) degrees , beta=78.4343(11) degrees , gamma=69.1915(5) degrees , and complex 2 in a monoclinic space group P2(1)/n, with a=10.1161(2)A, b=9.9188(2)A, c=13.3766(2)A, beta=102.7360(7) degrees . The X-ray structure analysis revealed that three platinum atoms in 1 are connected with three squarates which adopt bis(unidentate) binding modes. The squarato ligands span relatively long intramolecular Ptcdots, three dots, centeredPt distances (4.8842(3)-5.2699(3)A). A pair of cis positioned isopropylamine ligands completes a square planar coordination sphere of each Pt(II) ion. The square-planar coordination of complex 2 consists of two cis positioned isopropylamine ligands and two nitrato ligands. The results of cytotoxicity assay of trimer 1, monomer 2 and cis-diamminedichloroplatinum(II) (cisplatin) performed on human bladder tumor cell line T24 provide evidence that complex 2 is less cytotoxic compared to cisplatin and that the survival of tumor cells after exposure to 1 was minimally reduced.     

Reaction of DNA oligonucleotides with [Pt(dien)GSMe]2+ (GSMe =S-methylated glutathione) and cis-[Pt(NH3)2(GSMe)2]2+: evidence of oligonucleotide platination via sulfur-coordinated platinum intermediates

To study the possibility of DNA platination via platinum-sulfur coordinated intermediates, the reactions of the complexes [Pt(dien)GSMe]2+ (GSMe=S-methylated glutathione) and cis-[Pt(NH3)2(GSMe)2]2+ with the synthetic oligonucleotides d(ATATGCATAT), d(ATTACCGGTAAT), and d(ATCCTATTTTTTTTAGGAT) have been investigated. The reactions were studied using FPLC, NMR, and mass spectrometry. It was found that the sulfur atom of the platinum-thioether adduct is substituted by these oligonucleotides. For the reactions with [Pt(dien)GSMe]2+ at 310 K, half-lives were determined to be t 1/2 =147+/-7 h for d(ATATGCATAT), t 1/2 =84+/-4 h) for d(ATTACCGGTAAT), and t 1/2 = 21+/-1 h for d(ATCCTATTTTTTTTAGGAT. This study clearly shows that it is indeed possible for oligonucleotides to be platinated via Pt-thioether coordinated intermediates. The rates at which such substitutions occur, however, makes it improbable that such a mechanism contributes significantly to the antitumor activity of cisplatin.     

Specific platinum chelation by the guanines of the deoxyhexanucleotide d(T-G-G-C-C-A) upon reaction with cis-[Pt(NH3)2(H2O)2](NO3)2

The stoichiometric reaction between d-TpGpGpCpCpA (d(T-G-G-C-C-A)) and $\text{cis}$-[Pt(NH₃)₂(H₂O)₂](NO₃)₂ (8.4 × 10^?6 to 1.3 × 10^?4M in water at pH 5.5–6) gives a single complex. High pressure gel permeation chromatography and pH-dependent ¹H NMR analyses of the nonexchangeable base protons, show that it is a platinum chelate with the $\text{cis}$-Pt^II(NH₃)₂ moiety bound to the two N7 atoms of the adjacent guanines. A 3 × 10^?3M reaction gives the same platinum chelate, via the formation of intermediate complexes, together with unsoluble adducts.     

Molecular structure, bioavailability and bioactivity of [Cu(o-phen)2(cnge)](NO3)2.2H2O and [Cu(o-phen)(cnge)(H2O)(NO3)2] complexes

Two Cu(II) complexes with cyanoguanidine (cnge) and o-phenanthroline, [Cu(o-phen)(2)(cnge)](NO(3))(2).2H(2)O (1) and [Cu(o-phen)(cnge)(H(2)O)(NO(3))(2)] (2), have been synthesized using different experimental techniques and characterized by elemental analyses, FTIR, diffuse and UV-vis spectra and EPR and magnetic moment measurements techniques. The crystal structures of both complexes were solved by X-ray diffraction methods. Complex (1) crystallizes in the monoclinic space group C2/c with a=12.621(5), b=31.968(3), c=15.39(1)A, beta=111.68(4) degrees, and Z=8 and complex (2) in the monoclinic space group P2(1)/n with a=10.245(1), b=13.923(2), c=12.391(2)A, beta=98.07(1) degrees, and Z=4. The environments of the copper(II) center are trigonal bipyramidal (TBP) for [Cu(o-phen)(2)(cnge)](2+) and an elongated octahedron for [Cu(o-phen)(cnge)(H(2)O)(NO(3))(2)]. Solution studies have been performed to determine the species distribution. The superoxide dismutase (SOD) activities of both complexes have also been tested in order to determine if these compounds mimic the enzymatic action of the enzyme SOD that protects cells against peroxide radicals.     

A coordination polymer formed by cis-[(PMePh2)2Pt(NO3)2] and 2,5-bis(4-pyridyl)-1,3,4-thiadiazole

The 1:1 adduct formed from cis-[(PMePh₂)₂Pt(NO₃)₂] and 2,5-bis(4-pyridyl)-1,3,4-thiadiazole (bpytdz) in chloroform crystallizes out as a 1D coordination polymer built up of cis-(PMePh₂)₂Pt units connected by the bpytdz ligand, an unusual self-assembly for a complex formed from a (phosphine)₂Pt^II entity and a N,N linker.     

Bending studies of DNA site-specifically modified by cisplatin, trans-diamminedichloroplatinum(II) and cis-[Pt(NH3)2(N3-cytosine)Cl]+

Duplex oligonucleotides containing a single intrastrand [Pt(NH3)2]2+ cross-link or monofunctional adduct and either 15 or 22 bp in length were synthesized and chemically characterized. The platinum-modified and unmodified control DNAs were polymerized in the presence of DNA ligase and the products studied on 8% native polyacrylamide gels. The extent of DNA bending caused by the various platinum-DNA adducts was revealed by their gel mobility shifts relative to unplatinated controls. The bifunctional adducts cis-[Pt(NH3)2[d(GpG)]]+, cis-[Pt(NH3)2[d(ApG)]]+, and cis-[Pt(NH3)2[d(G*pTpG*)]], where the asterisks denote the sites of platinum binding, all bend the double helix, whereas the adduct trans-[Pt(NH3)2[d(G*pTpG*)]] imparts a degree of flexibility to the duplex. When modified by the monofunctional adduct cis-[Pt(NH3)2(N3-cytosine)(dG)]Cl the helix remains rod-like. These results reveal important structural differences in DNAs modified by the antitumor drug cisplatin and its analogs that could be important in the biological processing of the various adducts in vivo.     

Similar binding of the carcinostatic drugs cis-[Pt(NH3)2Cl2] and [Ru(NH3)5Cl] Cl2 to tRNAphe and a comparison with the binding of the inactive trans-[Pt(NH3)2Cl2] complex - reluctance in binding to Watson-Crick base pairs within double helix.

A comparative study of the binding of square planar cis- and trans-[Pt(NH3)2Cl2] complexes and the octahedral [Ru(NH3)5(H2O)]3+ complex to tRNAphe from yeast was carried out by X-ray crystallography. Both of the carcinostatic compounds, cis-[Pt(NH3)2Cl2] and [Ru(NH3)5(H2O)]3+ show similarities in their mode of binding to tRNA. These complexes bind specifically to the N(7) positions of guanines G15 and G18 in the dihydrouridine loop. [Ru(NH3)5(H2O)]3+ has an additional binding site at N(7) of residue G1 after extensive soaking times (58 days). A noncovalent binding site for ruthenium is also observed in the deep groove of the acceptor stem helix with shorter (25 days) soaking time. The major binding site for the inactive trans-[Pt(NH3)Cl2] complex is at the N(1) position of residue A73, with minor trans-Pt binding sites at the N(7) positions of residues Gm34, G18 and G43. The similarities in the binding modes of cis-[Pt(NH3)2Cl2] and [Ru(NH3)5(H2O)]3+ are expected to be related to their carcinostatic properties.     

Ruthenium-modified proteins. Reactions of cis-[ Ru(NH3)4(OH2)2]2+ and cis-[ Ru(en)2(OH2)2]2+ with azurin,myoglobin and cytochrome c

Reactions of cis-[Ru(en)₂(OH₂)₂]²⁺ (or cis-[Ru (NH₃)₄(OH₂)₂]²⁺) with Pseudomonas aeruginosa azurin (Az), horse heart myoglobin (Mb^h), and horse heart cytochrome c (cyt c) give Ru-labelled proteins. The ruthenium binding sites in the singly modified derivatives are His-83 (Az), His-81 (Mb^h), and His-33 (cyt c). Spectroscopic and electrochemical measurements indicate that the structures of the proteins are not perturbed by the surface-bound ruthenium complexes. The E°_f values of the Ru(III)/(II) couple in these Ru-modified proteins fall between −0.07 and −0.13 V vs. NHE.     

The reaction of Pt-antitumor drugs with selected nucleophiles. I. The reaction of cis-[Pt(NH3)2Cl2] with glycine

Various Pt(II)-glycine coordination compounds were characterized by 1H and 13C NMR spectroscopy, some of them also by electrophoretic and chromatographic behavior. The results were applied to the analysis of the reaction mixtures of cis-[Pt(NH3)2Cl2] and glycine obtained under various conditions. Cis-[Pt(NH3)2Cl2] reacts with glycine to give cis-diammine-(glycine-N,O)-Pt(II) and cis-diammine-bis(glycine-N-)Pt(II). Their ratio depends primarily on the pH of the reaction medium. Conformation of these compounds is discussed based on the observed Pt-C and Pt-H NMR coupling constants.     

Effect of serum on inhibition of DNA synthesis in leukemia cells by cis- and trans-(Pt (NH3) 2C1(2))

We examined the inhibition of DNA synthesis by cis- and trans-diamminedichloroplatinum (II) (cis- and trans-Pt) in leukemia cells, YAC-1 and RADA1. The degree of inhibition by trans-Pt was about the same as that by cis-Pt in vitro in the absence of serum, but the former was much lower than the latter in vivo or in the presence of serum in vitro. Atomic absorption studies showed that the amount of trans-Pt trapped by the serum in vitro is much larger than that of cis-Pt. Therefore, the amount of trans-Pt bound to DNA in vivo must be considerably smaller than that of cis-Pt, which eventually results in the antitumor-inactive nature of trans-Pt.     

A high melting cis-[Pt(NH3)2[d(GpG)]]adduct of a decanucleotide duplex

The [cis-Pt(NH3)2(d(GCCGGATCGC)-N7(4), N7(5))]-d(GCGATCCGGC) duplex has been prepared with Tm = 49 degrees C (vs 58 degrees C for the unplatinated form). NMR of the ten observable imino protons supports a kinked structure with intact base pairing of the duplex on the 3'-side of the d(GpG).cis-Pt chelate (relative to the platinated strand) The modification of the B-DNA type CD spectrum, due to the platinum chelate, is comparable to that observed for the platination (at a 0.05 Pt:base ratio) of the Micrococcus Lysodeikticus DNA (72% GC).     

PtL3 X-ray absorption studies of Pt model compounds and [(NH3)2Pt(OH)2Pt(NH3)2]2+ bound to DNA

The Pt L₃ X-ray absorption spectra of a series of Pt compounds have been recorded and their extended fine structure (EXAFS) analysed to investigate the sensitivity of EXAFS to non-first-shell PtPt distances. The Pt L₃ EXAFS spectra of complexes formed between [(NH₃)₂Pt(OH)₂Pt(NH₃)₂]²⁺ and calf thymus DNA were also recorded. PtPt vectors could not be detected in these spectra. When combined with the model compound studies, this result rules out Pt dimer structures for the PtDNA complex which involve rigidly bridged, adjacent Pt atoms. Such structures, based on dimeric bonding of a hydroxo dimer intermediate to DNA, have been proposed as models for cisplatin antitumor activity. These types of models now seem unlikely.     

Synthesis and characterization of bis[salicylideneaminato] palladium(II) complexes. Molecular structure of bis[N-(n-butyl)(3-benzyloxy)-2-salicylideneaminato]-palladium(II), pd(C18H20NO2)2]

Transition metal compounds having liquid crystalline properties can be interesting materials for practical applications. Attempting to correlate mesomorphic properties with molecular structure and crystal packing mode, we have investigated some complexes obtained from Schiff bases of long chain aliphatic amines and salicylaldehyde or 2,3-dihydroxybenzaldehyde derivatives. The X-ray structural analysis of bis[N-(n-butyl)(3-benzyloxy)-2-salicylideneaminato] palladium [II] is also reported.     

Electrochemical investigations of platinum-methyluracil-blue and the related binuclear complex [(NH3)2Pt(MeU)2Pt(NH3)2](NO3)2

The redox behavior of the head-to-head bis(μ- (1-methyluracilato-N³,O²)-bis(cis-diammine platinum(II)) dinitrate, PtMeU, and platinum 1-methyluracil blue, PtMeUB, was studied by cyclic voltammetry (CV), rotating disk voltammetry (RDV), and controlled-potential coulometry (CPC). Redox titrimetry, electrochemistry/electron paramagnetic resonance spectroscopy (EPR), and liquid chromatography (LC) served as complementary techniques. The former reactant exhibits two-step electro-oxidation, consistent with the formation of a mixed-valence Pt(II, III) state en route to Pt(III, III). The latter also appears to oxidize to a uniform Pt(III) state. Although the oxidative-reductive electrochemistry of both reactants exhibits chemical reversibility, the heterogeneous electron-transfer kinetics are notably sluggish. The latter appears to be associated with the formation of an inhibiting film on the electrode surface. A slow conversion of PtMeU to a PtMeUB-like state was revealed by CV and LC. The complex, oligomeric nature of PtMeUB was revealed by means of gradient LC examination. Comparing oxidative and reductive electrolysis curves for PtMeUB yielded an average platinum oxidation state of 2.08. All observed behavior for PtMeUB, as well as for PtMeU, is accounted for by invoking +2 and +3 oxidation states for platinum; redox titrimetry using Ce(IV) revealed inconsequential oxidation of both of these systems beyond the III state. An estimate of molecular weight for the platinum blue was made by employing RDV in conjunction with the Einstein-Stokes equation.     

Instability of the monofunctional adducts in cis-[Pt(NH3)2(N7-N-methyl-2-diazapyrenium)Cl](2+)-modified DNA: rates of cross-linking reactions in cis-platinum-modified DNA.

Single- and double-stranded oligonucleotides containing a single monofunctional cis-[Pt(NH3)2(dG)(N7-N-methyl-2-diazapyrenium)]3+ adduct have been studied at two NaCl concentrations. In 50 mM and 1 M NaCl, the adducts within the single-stranded oligonucleotides are stable. In contrast, they are unstable within the corresponding double-stranded oligonucleotides. In 50 mM NaCl, the bonds between platinum and guanine or N-methyl-2,7-diazapyrenium residues are cleaved and subsequently, intra- or interstrand cross-links are formed as in the reaction between DNA and cis-DDP. In 1 M NaCl, the main reaction is the replacement of N-methyl-2,7-diazapyrenium residues by chloride which generates double-stranded oligonucleotides containing a single monofunctional cis-[Pt(NH3)2(dG)Cl]+ adduct. The rates of closure of these monofunctional adducts to bifunctional cross-links have been studied in 60 mM NaClO4. Within d(TG.CT/AGCA), d(CG.CT/AGCG) and d(AG.CT/AGCT) (the symbol.indicates the location of the adducts in the central sequences of oligonucleotides), the half-lifes (t1/2) of the cis-[Pt(NH3)2(dG)Cl]+ adducts are respectively 12, 6 and 2.8 hr and the cross-linking reactions occur between guanine residues on the opposite strands. Within d(AG.TC/GACT), d(CG.AT/ATCG) and d(TGTG./CACA) or d(TG.TG/CACA) t1/2 are respectively 1.6, 8 and larger than 20 hr and the intrastrand cross-links are formed at the d(AG), d(GA) and d(GTG) sites, respectively. The conclusion is that the rates of conversion of cis-platinum-DNA monofunctional adducts to minor bifunctional cross-links are dependent on base sequence. The potential use of the instability of cis-[Pt(NH3)2(dG)(N7-N-methyl-2-diazapyrenium)]3+ adducts is discussed in the context of the antisense strategy.     

Modeling the effect of H-bonding interactions and molecular packing on the molecular structure of [Ag(ethylnicotinate)2]NO3 complex

The gas phase molecular structure of a single isolated molecule of [Ag(Etnic)₂NO₃];1 where Etnic = Ethylnicotinate was calculated using B3LYP method. The H-bonding interaction between 1 with one (complex 2) and two (complex 3) water molecules together with the dimeric formula [Ag(Etnic)₂NO₃]₂;4 and the tetrameric formula [Ag(Etnic)₂NO₃]₄;5 were calculated using the same level of theory to model the effect of intermolecular interactions and molecular packing on the molecular structure of the titled complex. The H-bond dissociation energies of complexes 2 and 3 were calculated to be in the range of 12.220–14.253 and 30.106–31.055 kcal?mol^?1, respectively, indicating the formation of relatively strong H-bonds between 1 and water molecules. The calculations predict bidentate nitrate ligand in the case of 1 and 2, leading to distorted tetrahedral geometry around the silver ion with longer Ag–O distances in case of 2 compared to 1, while 3 has a unidentate nitrate ligand leading to a distorted trigonal planar geometry. The packing of two [Ag(Etnic)₂NO₃] complex units; 4 does not affect the molecular geometry around Ag(I) ion compared to 1. In the case of 5, the two asymmetric units of the formula [Ag(Etnic)₂NO₃] differ in the bonding mode of the nitrate group, where the geometry around the silver ion is distorted tetrahedral in one unit and trigonal planar in the other. The calculations predicted almost no change in the charge densities at the different atomic sites except at the sites involved in the C–H?O interactions as well as at the coordinated nitrogen of the pyridine ring.

Mechanism and biological implications of the NO release of cis-[Ru(bpy)2L(NO)](n+) complexes: a key role of physiological thiols

Nitric oxide (NO) has a critical role in several physiological and pathophysiological processes. In this paper, the reactions of the nitrosyl complexes of [Ru(bpy)₂L(NO)]ⁿ⁺ type, where L = SO₃²⁻ and imidazole and bpy = 2,2′-bipiridine, with cysteine and glutathione were studied. The reactions with cysteine and glutathione occurred through the formation of two sequential intermediates, previously described elsewhere, [Ru(bpy)₂L(NOSR)]ⁿ⁺ and [Ru(bpy)₂L(NOSR)₂] (SR = thiol) leading to the final products [Ru(bpy)₂L(H₂O)]ⁿ⁺ and free NO. The second order rate constant for the second step of this reaction was calculated for cysteine k₂(SR⁻) = (2.20 ± 0.12) × 10⁹ M^− 1 s^− 1 and k_2(RSH) = (154 ± 2) M^− 1 s^− 1 for L = SO₃²⁻ and k₂(SR⁻) = (1.30 ± 0.23) × 10⁹ M^− 1 s^− 1 and k₂(RSH) = (0.84 ± 0.02) M^− 1 s^− 1 for L = imidazole; while for glutathione they were k₂(SR⁻) = (6.70 ± 0.32) × 10⁸ M^− 1 s^− 1 and k₂(RSH) = 11.8 ± 0.3 M^− 1 s^− 1 for L = SO₃²⁻ and k₂(SR⁻) = (2.50 ± 0.36) × 10⁸ M^− 1 s^− 1 and k₂(RSH) = 0.32 ± 0.01 M^− 1 s^− 1 for L = imidazole. In all reactions it was possible to detect the release of NO from the complexes, which it is remarkably distinct from other ruthenium metallocompounds described elsewhere with just N₂O production. These results shine light on the possible key role of NO release mediated by physiological thiols in reaction with these metallonitrosyl ruthenium complexes.     

Triboluminescence and crystal structure of the centrosymmetric complex [Tb(NO3)2(Acac)(Phen)2]·H2O

The atomic structure of crystals of the complex [Tb(NO₃)₂(Acac)(Phen)₂]·H₂O, (AA – acetylacetonate anion, Phen – 1,10‐phenanthroline) characterized by an intensive luminescence and triboluminescence has been determined by means of an X‐ray structural analysis method. Centrosymmetric crystals have a monoclinic syngony: a = 11.2298(1), b = 9.6492(1), c = 13.2745(1) Å, β = 101.290(1), space group P2/n, Z = 2, ρ_calc = 1.790 g/cm³. The crystal structure is represented by individual С₂₉Н₂₅N₆O₉Tb complexes linked through van der Waals interactions with clearly expressed cleavage planes. The Tb(III) atom coordination polyhedron reflects the state of a distorted square antiprism. The structural aspects of the suggested model of formation of the triboluminescent properties were considered and the role of the cleavage planes discussed. Copyright © 2016 John Wiley & Sons, Ltd.     

The interaction of [Ru(NH3)5Cl]2+ and [Ru(NH3)6]3+ ions with DNA

The interaction of [Ru(NH3)5Cl]2+ and [Ru(NH3)6]3+ complex ions with calf thymus DNA has been studied at various r values (r = [Mn+]/[DNA-P]). Electronic spectra of metal-DNA solutions have been recorded and compared to the spectra of metal, as well as of DNA, solutions. Melting curves have been taken for the determination of DNA melting temperature (Tm) in the presence of the above complex ions. The results showed a biphasic melting of the DNA strands for relatively high r values. The Tm for the first phase increased with increasing r values, indicating metal ion interaction with the phosphate moieties of the DNA. The appearance of a second-phase melting, in connection with electronic spectra, pH values, and conductivity measurements of metal ion solutions, is indicative of the initial complexes' transformation to [Ru(NH3)5OH]2+, which binds preferentially to double-stranded rather than single-stranded DNA, thus leading to a second melting curve at a higher temperature than the first one.