Studies on the metal—amide bond. XVIII. The crystal and molecular structure of [N,N′-bis(2′-pyridinecarboxamido)-1,3-propane] nickel(II) monohydrate

[N,N′-bis(2′-pyridinecarboxamido)-1,3-propane] - nickel(II) monohydrate, C₁₅H₁₆N₄O₃Ni is monoclinic, space group P2₁/c, with a = 7.174(4), b = 18.590(3), c = 11.641(5) Å, β = 110.69(2)°, Z = 4. The structure was refined to R = 0.030 for 1826 diffractometer data using full-matrix least-squares methods. The N₄-ligand coordinates to the nickel atom in an irregular square plane [average Ni-N_amide 1.864(4), Ni-N_pyridine 1.912(3) Å and N_amide-Ni-N_amide 96.0(1), N_pyridine-Ni-N_pyridine 98.7(1)°] with a tetrahedral twist of 15.9° at the nickel atom. The two picolinamide units are related by an approximate two-fold axis and the enforced strain in the molecule results in significant non-planar distortions in the amide chelate rings and the pyridyl rings. The plane of the chelate molecule lies approximately perpendicular to [100] and the lattice water molecule hydrogen bonds amide oxygen atoms to form chains parallel to [101]     

A study of cis-dichlorobis(methylamine)platinum(II): Crystal and molecular structures of two crystal forms

A new synthesis of cis-dichlorobis(methylamine)platinum(II) is described. It appears that during the crystallization process at least two types of crystals are formed. Form A is monoclinic with space group P2 ₁/n and unit cell dimensions a = 6.272, b = 15.726, c = 7.419Å, β = 99.86°, V = 721Å ³, Z = 4, R = 0.055. Form B is monoclinic, with space group P2 ₁/c and unit cell dimensions a = 16.078, b = 6.372, c = 21.459Å, β = 92.7°, V = 2196Å ³, Z = 12, R = 0.057. The two forms can be readily distinguished by IR spectroscopy.     

The crystallochemistry of tetracyanocomplexes. The crystal and molecular structures of tris(1,2-diaminoethane)zinc(II) tetracyanoniccolate(II) monohydrate and tris(1,2-diaminoethane)zinc(II) tetracyanoniccolate(II)

C₁₀H₂₆N₁₀ONiZn, tris(1,2-diaminoethane) zinc(II) tetrakis(cyano)niccolate(II) monohydrate (I), orthorhombic, Pbca, a = 1.1680(4), b = 1.5844(3), c = 1.9981(6) nm, Z = 8 d(meas) = 1.54, d(calc) = 1.53 g cm^?3. C₁₀H₂₄N₁₀NiZn, tris(1,2-diaminoethane) zinc(II) terakis(cyano)niccolate(II), (II), monoclinic, P2₁/n, a = 0.7957(2), b = 1.5170(5), c = 1.4932(4) nm, β = 96.41(2)°, Z = 4, d(meas) = 1.49, d(calc) = 1.51 g cm^?3. Both the structures (I) and (II) have been solved by the heavy atom method and refined by full-matrix least-squares to R(I) = 0.086 for 1890 independent reflections and R(II) = 0.058 for 1689 independent reflections, respectively. In the case of (II) the superlattice structure problem was solved. The crystal structure of (I) consists of [Zn(en)₃]²⁺ cations, [Ni(CN)₄]^2? anions and water molecules. Two of the cyano groups in trans positions are bonded to water molecules by hydrogen bonds, the distances CN?O being 0.289 and 0.291 nm, respectively. The crystal structure of (II) is constituted by [Zn(en)₃]²⁺ cations and [Ni(CN)₄]^2? anions.     

[H,N] NMR studies of the aquation of cis-diamine platinum(II) complexes

Two ¹⁵N-labelled cis-Pt(II) diamine complexes with dimethylamine (¹⁵N-dma) and isopropylamine (¹⁵N-ipa) ligands have been prepared and characterised. [¹H,¹⁵N] HSQC NMR spectroscopy is used to obtain the rate and equilibrium constants for the aquation of cis-[PtCl₂(¹⁵N-dma)₂] at 298 K in 0.1 M NaClO₄ and to determine the pK_a values of cis-[PtCl(H₂O)(¹⁵N-dma)₂]⁺ (6.37) and cis-[Pt(H₂O)₂(¹⁵N-dma)₂]²⁺ (pK_a1 = 5.17, pK_a2 = 6.47). The rate constants for the first and second aquation steps (k₁ = (2.12 ± 0.01) × 10⁻⁵ s⁻¹, k₂ = (8.7 ± 0.7) × 10⁻⁶ s⁻¹) and anation steps (k₋₁ = (6.7 ± 0.8) × 10⁻³ M⁻¹ s⁻¹, k₋₂ = 0.043 ± 0.004 M⁻¹ s⁻¹) are very similar to those reported for cisplatin under similar conditions, and a minor difference is that slow formation of the hydroxo-bridged dimer is observed. Aquation studies of cis-[PtCl₂(¹⁵N-ipa)₂] were precluded by the close proximity of the NH proton signal to the ¹H₂O resonance.     

Synthesis, characterization and antiproliferative studies of the enantiomers of cis-[(1,2-camphordiamine)dichloro]platinum(II) complexes

The platinum(II) complex cis-[(1S,2R,3S)-1,7,7-trimethylbicyclo[2.2.1]heptane-2,3-diamine]dichloroplatinum(II) (1) and its enantiomer (2) have been synthesized and physically and spectroscopically characterized. To obtain the enantiopure complexes the chiral pool approach was applied. The synthetic pathway has four steps, starting from (+/-)-diphenylethylenediamine (DPEDA) (3) and the natural products (1S)-camphorquinone or (1R)-camphorquinone to obtain enantiomers 1 and 2, respectively. The interaction of the Pt(II) complexes with DNA was studied by several techniques: circular dichroism, electrophoresis on agarose gel and atomic force microscopy (AFM). These studies showed differences in the degree of interaction between both enantiomers and DNA (calf thymus DNA and plasmid pBR322 DNA). The cytotoxicity of enantiomers 1 and 2 against the HL-60 cell line was studied by in vitro tests of antiproliferative activity, incubating during both 24 h and 72 h. An important difference of activity was found between both enantiomers regarding the IC50 data at 24 h of incubation. Thus, complex 1 showed to be much more active than its enantiomer 2.     

Synthesis and anticancer activity of [2-hydroxy-1,3-diaminopropane-kappa 2N,N'] platinum(II) complexes

A series of novel platinum(II) complexes involving a carrier with HO- peripheral functional group, 2-hydroxy-1,3-propanediamine (HO-pda), cis-[Pt(HO-dpa)X₂] (X₂ = 2Cl⁻ (1), (2), malonate (3), 1,1-cyclobutane dicarboxylate (CBDCA) (4), 3-hydroxy-1,1-cyclobutanedicarboxylate (HO-CBDCA) (5)), have been synthesized and characterized by elemental analysis and spectroscopic data along with X-ray diffraction for three representative complexes 1, 4 and 5. The Pt(II) is in a square planar environment and is coordinated in cis position by a chelating HO-pda and 2Cl⁻ for 1 and CBDCA for 4 and 5. Pt-N, Pt-Cl and Pt-O distances and coordinate bond angles of N-Pt-N, Cl-Pt-Cl and O-Pt-O are in the normal range. There are two independent molecules in the asymmetric unit of 5, held together by intermolecular hydrogen bonded chain. All the complexes show significant cytotoxicity on the sensitive cell lines SGC-7901, LNcap and A549, and are more active than carboplatin. 4 is also found to be active against the resistant cell A549/ATCC, which suggests that it has less cross-resistance with cisplatin than carboplatin. Moreover 4 shows much greater inhibition of tumor growth than carboplatin in S180-bearing mice, and is therefore worthy of further development as a potential anti-tumor platinum drug.     

Synthesis and single crystal structures of first examples of tridentate ligands of (Te, N, S) type and their complexes with palladium(II), platinum(II) and ruthenium(II)

The First examples of (Te, N, S) type ligands, 2-CH₃SC₆H₄CHNCH₂CH₂TeC₆H₄-4-OCH₃ (L¹) and 2- CH₃SC₆H₄CHNHCH₂CH₂TeC₆H₄-4-OCH₃ (L²), and their metal complexes, [PdCl(L¹)]PF₆ · CHCl₃ · 0.5H₂O (4), [PtCl(L¹)]PF₆ (5), [PdCl(L²)]ClO₄.CHCl₃ (6), [PtCl(L²)]ClO₄ (7), and [Ru(p-cymene)(L²)](PF₆)₂ · CHCl₃ (8), have been synthesized and characterized. The single crystal structures of 4, 6 and 8 have revealed that both the ligands coordinate in them in a tridentate (Te, N, S) mode. The geometry around Pd in both the complexes has been found to be square planar, whereas for Ru in a half sandwich complex 8, it is found to be octahedral. Between two molecules of 4 there are intra and inter molecular weak Te?Cl [3.334(3) and 3.500(3) Å, respectively] interactions along with weak intermolecular Pd?Te [3.621(2) Å] interactions. The Pd-Te bond lengths are between 2.517(6) and 2.541(25) Å and the Ru-Te bond length is 2.630(6) Å. The crystal structure of [PdCl₂(4-MeO-C₆H₄- TeCH₂CH₂NH₂)] (9) is also determined. It is formed when KPF₆ is not added in the synthesis of 4 and Pd-complex of L¹ is recrystallized. Apart from Te?Cl secondary interactions, C-H?π interactions also exist in the crystal of 9.     

The crystal and molecular structures of dioxo mo(VI) complexes of tripodal,tetradentate N,S-donor ligands

The crystal and molecular structures of the complexes MoO₂((SCH₂CH₂)₂NCH₂CH₂SCH₃), I and MoO₂((SCH₂CH₂)₂NCH₂CH₂N(CH₃)₂), II, have been determined from X-ray intensity data collected by counter methods. Compound I crystallizes in two forms, Ia and Ib. In form Ia the space group is P2₁/n with cell parameters a = 7.235(2), b = 7.717(2), c = 24.527(6) Å, β = 119.86(2)°, V = 1188(1) ų, Z = 4. In form Ib the space group is P2₁/c with cell parameters a = 14.945(5), b = 11.925(5), c = 14.878(4) Å, β = 114.51(2)°, V = 2413(3) ų, Z = 8. The molecules of I in Ia and Ib are very similar having an octahedral structure with cis oxo groups, trans thiolates (cis to both oxo groups) and N and thioether sulfur atoms trans to oxo groups. Average ditances are MoO = 1.70, MoS (thiolate) = 2.40, MoN = 2.40 and MoS (thioether) = 2.79 Å. Molecule II crystallizes in space group P2₁2₁2₁ with a = 7.188(1), b = 22.708(8), c = 7.746(2) Å, V = 1246(1) ų and Z = 4. The coordination about Mo is octahedral with cis oxo groups, trans thiolates and N atoms trans to oxo. Distances in the first coordination sphere are MoO = 1.705(2), 1.699(2), MoS = 2.420(1), 2.409(1) and MoN = 2.372(2), 2.510(2) Å. The conformational features of the complexes are discussed. Complex I displays MoO and MoS distances which are very similar to those found by EXAFS in sulfite oxidase. This similarity is discussed.     

Analysis and quantitation of the DNA damage produced in cells by the cisplatin analog cis-[3H]dichloro(ethylenediamine)platinum (II).

The anticancer drug cisplatin elicits its cytotoxicity through damaging DNA. A sensitive method for following this interaction involves the use of an analog cis-[3H]dichloro(ethylenediamine)platinum(II) (cis-[3H]DEP). Cells are incubated with this analog, the DNA is purified, the enzyme is digested, and the deoxyribonucleoside-bound adducts are separated by HPLC. Other radioactive peaks can be detected by HPLC. These have been identified as arising from contaminating RNA and from the incorporation of tritium into unmodified nucleosides. A rapid DNA purification procedure that overcomes the first problem is presented. The latter problem is overcome by incubation of cells in hypoxanthine, aminopterin, and thymidine (HAT medium). Direct quantitation of levels of DNA platination can be determined in a single HPLC run by comparing the radioactivity in a specific adduct peak to the absorbance of the unmodified deoxyribonucleosides. Modifications to the synthesis of cis-[3H]DEP, the enzyme digestion of DNA, and the HPLC methodology are also described.     

The crystal and molecular structures of cellulose I and II

The paper describes molecular dynamics (MD) simulations on the crystal structures of the Iβ and II phases of cellulose. Structural proposals for each of these were made in the 1970s on the basis of X-ray diffraction data. However, due to the limited resolution of these data some controversies remained and details on hydrogen bonding could not be directly obtained. In contrast to structure factor amplitudes in X-ray diffraction, energies, as obtained from MD simulations, are very sensitive to the positions of the hydroxyl hydrogen atoms. Therefore the latter technique is very suitable for obtaining such structural details. MD simulations of the Iβ phase clearly shows preference for one of the two possible models in which the chains are packed in a parallel orientation. Only the parallel-down mode (in the definition of Gardner and Blackwell (1974) J Biopolym 13: 1975-2001) presents a stable structure. The hydrogen bonding consists of two intramolecular hydrogen bonds parallel to the glycosidic linkage for both chains, and two intralayer hydrogen bonds. The layers are packed hydrophobically. All hydroxymethyl group are positioned in the tg conformation. For the cellulose II form it was found that, in contrast to what seemed to emerge from the X-ray fibre diffraction data, both independent chains had the gt conformation. This idea already existed because of elastic moduli calculations and 13C-solid state NMR data. Recently, the structure of cellotetraose was determined. There appear to be a striking similarity between the structure obtained from the MD simulations and this cellotetraose structure in terms of packing of the two independent molecules, the hydrogen bonding network and the conformations of the hydroxymethyl group, which were also gt for both molecules. The structure forms a 3D hydrogen bonded network, and the contribution from electrostatics to the packing is more pronounced than in case of the Iβ structure. In contrast to what is expected, in view of the irreversible transition of the cellulose I to II form, the energies of the Iβ form is found to be lower than that of II by 1 kcal mol-1 per cellobiose. This revised version was published online in November 2006 with corrections to the Cover Date.     

Crystal structures and coordination-site exchange reactions of palladium(II) and platinum(II) complexes containing tris[2-(tert-butylthio)ethyl]amine

Palladium(II) and platinum(II) complexes, [PdX(NS₃ ¹Bu)]BPh₄ (X=Cl, Br, I; NS₃ ¹Bu=tris[2-(tert-butylthio)ethyl]amine) and [PtCl(NS₃ ¹Bu)]BPh₄, were prepared, and their structures were determined by X-ray analyses. The geometry around the palladium and platinum atoms is square planar. The NS₃ ¹Bu ligand functions as a tridentate ligand and one sulfur atom is not coordinated to the metal. The ¹H NMR spectrum of [PdCl(NS₃ ¹Bu)]BPh₄ in acetone-d₆ exhibited a dynamic behavior. At 20°C the spectrum showed a singlet signal at 1.60 ppm that can be assigned to tert-butyl protons, whereas at −70°C three singlet signals were observed at 1.36, 1.61, and 1.70 ppm with an intensity ratio of 1: 0.25: 2. The signals at 1.36 and 1.70 ppm are assigned to the tert-butyl protons in the square-planar structure, and these signals are consistent with the X-ray structure. The signal at 1.61 ppm can be assigned to the tert-butyl protons in a trigonal-bipyramidal structure where the three tert-butyl groups are magnetically equivalent. Thus, we concluded that the coordination-site exchange occurred via a trigonal-bipyramidal intermediate. The square-planar and trigonal-bipyramidal species of [PdCl(NS₃ ¹Bu)]BPh₄ are in equilibrium in acetone-d₆. The equilibrium was shifted toward the square-planar species on decreasing the temperature. The ¹H NMR spectra for [PdX(NS₃ ¹Bu)]BPh₄ (X=Cl, Br, and I) were similar to one another at the same temperature, suggesting that the site-exchange process is insensitive to the kind of coexisting halogen ligand. The site exchange reaction of [PtCl(NS₃ ¹Bu)]BPh₄ seems to occur more slowly than that of the palladium(II) analogue.     

N-{2-(4-methoxyphenyltelluro)ethyl}morpholine (L1) and its platinum(II) and ruthenium(II) complexes. Synthesis and crystal structure of L1 and trans-[PtCl2(L1)2]

The first tellurated derivative of morpholine, N-{2-(4-methoxyphenyltelluro)ethyl}morpholine (L¹) has been synthesized by reacting in situ generated ArTe⁻ with 4-(2-chloroethyl)morpholine hydrochloride under N₂ atmosphere. The compound L¹ gives molecular ion peak at m/z 351 and is characterized structurally. The donor atoms N and Te in compound L¹ are rightly oriented for its ligation in bidentate mode. The TeC(alkyl) is 0.02 Å longer than TeC(aryl). The complexes of ligand L¹ having composition [PtCl₂(L¹)₂] (1) and [RuCl₂(p-cymene)L¹] (2) have been synthesized. The compound 1 has been characterized structurally. The Pt has a square planar geometry in complex 1 and two molecules of ligand L¹ bonded through Te alone are trans to each other (PtTe=2.583(2) Å). The ¹³C{¹H} NMR spectrum of complex 1 is as expected. The ¹H NMR spectrum of single crystals of complex 1 shows multiplication of signals, which is supported by HETCOR experiments. The complex 2 also has ligand L¹ in a monodentate coordination mode, bonded through Te alone. This is supported by deshielded CH₂Te and ArCTe signals in ¹H and ¹³C{¹H} NMR spectra of complex 2 with respect to those of free ligand L¹. The HETCOR spectrum of complex 2 has been used to authenticate the assignments of CH₂Te group, as its two protons appear to be magnetically non-equivalent.     

Dichloro(6-aminoethylaminopurine)platinum(II) and its hydroxy analogues: Synthesis and preliminary evaluation

The synthesis, chemical characterization and functional evaluation are reported for dichloro(6-aminoethylaminopurine)platinum(II) and dichloro(6-hydroxyethylaminopurine)platinum(II) and dichloro(6-hydroxyethylamethylaminopurine)platinum(II) (i.e. Pt(6-AEAP), Pt(6-HEAP) and Pt(6-MHEAP) new complexes of platinum(II). Certain reaction conditions favored the formation of the tripurine platinum complex, but the monopurine complex could be obtained either by hydrolysis of the tripurine or by reacting at reduced temperature and concentration. Although neither compound was as effective as cis-diamminedichloroplatinum(II) (i.e. DDP) at reducing tumor cell viability or proliferation, both were associated with much less renal toxicity than DDP in the mouse kidney (i.e. Pt(6-AEAP):～20 × less; Pt(6-MHEAP): ～100 × less).     

The crystal and molecular structure of cyclo-[-(D-Val-Hyi-Val-D-Hyi)3-] (meso-valinomycin,C60H102N6O18)

The crystal structure of the valinomycin analog, cyclo-[(-D -Val-Hyi-Val-D -Hyi-)₃-] (meso-valinomycin, C₆₀H₁₀₂N₆O₁₈) has been determined by direct x-ray diffraction procedures. The crystals are triclinic, space group P1 , number of molecules per unit cell Z = 1, and cell parameters a = 11.831, b = 13.815, c = 14.889 Å, α = 109.54°, β = 116.10°, γ = 98.89°. The atomic coordinates for the C,N,O atoms were refined in the anisotropic thermal motion approximation and for the H atoms in the isotropic approximation to R = 0.07. The structure is centrosymmetric and has a threefold axis of pseudosymmetry. The depsipeptide chain is in the form of a bracelet stabilized by six identical intramolecular 4 → 1 hydrogen bonds between the amide C?O and NH groups. The ester carbonyls are oriented towards the symmetry axis, their O atoms forming an ellipsoidal molecular cavity. The isopropyl side chains are located on the molecular periphery. The structure found differs considerably from the conformation of the crystalline naturally occurring antibiotic, valinomycin, but completely resembles that of valinomycin and meso-valinomycin in nonpolar solvents. In the crystal, meso-valinomycin molecules form stacks. The molecular cavities situated in the stacks one above the other along the pseudo-C₃ axis form a continuous channel, the internal surface of which is lined by O atoms. The possible conformations of depsipeptides of the valinomycin series and their mode of action in membranes are discussed in the light of the data obtained.     

Aqueous solution chemistry of dichloro[S-methylcysteine(N,S)]platinum(II) isomers and their hydrolysis products

Rate and equilibrium constants at 25 °C, pH ∼ 1, and ionic strength 0.10 for hydrolysis of the two non-equivalent chlorides of dichloro[S-methyl-l-cysteine(N,S)]platinum(II) isomers, denoted [PtCl₂(SmecysH)], and the resultant chloro-aqua species have been determined by NMR, potentiometric, and spectrophotometric methods. Though hydrolysis constants, K_h, for the two chlorides are similar (pK_h = 4-5), the rate of hydrolysis of the chloride trans to coordinated S, k_h = 3.4 × 10⁻³ s⁻¹, is 2-3 orders of magnitude faster than the k_h for the other chloride, 2.3 × 10⁻⁶ s⁻¹, and for the cancer drug cisplatin, cis-[PtCl₂(NH₃)₂], 5.2 × 10⁻⁵ s⁻¹. Relative rates of hydrolysis determined under three different experimental conditions (pH ∼ 1 in 0.10 M HNO₃, high pH in 0.10 M NaOH, and at low pH with Ag⁺ assistance) are consistent: the Cl trans to S is 100-1000 times more labile than the Cl cis to S. Potentiometric and NMR methods were also used to estimate pK_a values of all aqua species, which are comparable to values reported for corresponding aqua species derived from cisplatin.