Interactions of bis-[μ-chloro-chlorotricarbonylruthenium(II)] and poly-[μ-dichloro-dicarbonylruthenium(II)] with nucleosides

The interactions of dimeric complex bis-[μ-chloro-chlorotricarbonylruthenium(II)], [Ru(CO)₃Cl₂]₂, and the polymeric complex poly-[μ-dichlorodicarbonylruthenium(II)], [Ru(CO)₂Cl₂]_x, with nucleosides (Nucl) in a 1:1 Ru:Nucl molar ratio for the dimer and 1:2 Ru:Nucl for the polymer, resulted in formation of the monomeric mononucleoside [Ru(CO)₃(Nucl)Cl₂] and bis-nucleoside [Ru(CO)₂(Nucl)₂Cl₂] complexes, respectively. The dimer [Ru(CO)₃Cl₂]₂ also gave the ionic bis-nucleoside complexes [Ru(CO)₃(Nucl)₂Cl]Cl in the molar ratio 1:2 Ru:Nucl. The mononucleoside complexes are stable in solution while the bis-nucleoside complexes tend to lose one nucleoside in strong complexing solvents, probably by solvent substitution. The complexes [Ru(CO)₃(Nucl)Cl₂] and [Ru(CO)₂(Nucl)₂Cl₂] with one N(1)H ionizable imino proton undergo ionization in alkaline solution and the complexes [Ru(CO)₃(NuclH⁺)Cl] and [Ru(CO)₂(NuclH⁺)₂], respectively, were isolated. In these deprotonated complexes the nucleosides behave as bidentate ligands, while in the protonated ones they act as monodentate. All Complexes were characterized by elemental analyses and various spectroscopic methods.     

The synthesis and structural properties of [M(dippe)(η2-C4H4S)] complexes of Pd and Pt and comparison with their Ni analog

X-ray structural and NMR spectroscopic data for the ring-opened thiophene complexes [Pd(dippe)(T)] (2), and [Pt(dippe)(T)] (3) are now presented. The complex [Ni(dippe)(T)] (1), where T = (η²-C,S-C₄H₄S), was reported by our group, previously.The structural and bonding properties of complexes 2 and 3 were compared with those of complex 1. DFT calculations were carried out to rationalize their relative stabilities and structural properties. Compound 1 loses thiophene at ambient temperature in solution, while compound 2 decomposes rapidly in both acetone-d₆ and THF-d₈ with k_obs = 7.15(9) × 10⁻⁵ and 7.7(3) × 10⁻⁵ s⁻¹, respectively, to give products that varied by solvent. Complex 3 does not lose thiophene at temperatures below 100 °C. The ΔG⁰ values determined from DFT calculations are consistent with the observed stabilities of the complexes. The single crystal X-ray structures of all three complexes contain a disordered thienyl fragment in the asymmetric unit due to the interchange of the position of sulfur in the metal-inserted thiophenic ring. The thiophenic moiety is relatively flat in 1, 2 and 3, which is attributed to the open ligand environment at the M(dippe) fragment. All three complexes possess square-planar geometry around the metal center and have bond-length alternation among the thiophenic carbons, which indicates double bond localization. The calculated bond lengths are in good agreement with experimental data. Molecular orbital (MO) and natural bonding orbital (NBO) analyses were carried out to rationalize the results.     

A kinetic model for the B–Z transition of poly[d(G-C)]·poly[d(G-C)] and poly[d(G-m5C)]·poly[d(G-m5C)]

The analysis of the kinetic data of the B-Z conformational changes induced by salt in sized double-stranded poly[d(G-C)].poly[d(G-C)] and poly[d(G-m5C)].poly[d(G-m5C)] polymers indicated that there exists a salt threshold which reveals some largely, as yet, unrecognised characteristics of the transition. It was observed that there is a direct correlation between the length of the polymer and the rate of the B-Z transition when the salt concentration in the polymer solution is lower than the salt threshold. The correlation is inverse when the salt concentration is higher than the salt threshold. Thus, the molecular mechanism of the B- to Z-DNA transition varies depending on whether the salt concentration is higher or lower than the threshold. In this context, we have found that the contrasting results reported in the literature describing the rate of the B-Z transition are not contradictory but complementary. The finding of a salt threshold leads to the establishment of a relationship between the cooperativity index of the B-Z transition and the polymer chain length. That relationship is dependent on the chemical structure of the polymer but is temperature independent.     

Complex-Formation of Ethidium Bromide with Poly[d(A-T)]·Poly[d(A-T)]

Abstract

The interaction of Ethidium Bromide (EtBr) with double-stranded (ds-) and single-stranded (ss-) poly[d(A-T)] was studied in different ionic strengths solutions. Optical spectroscopy and Scatchard analysis results indicate that the ligand interacts to both helix and coiled structures of the polynucleotide by “strong” and “weak” binding modes. The association parameters (binding constant—K—and the number of nucleotides corresponding to a binding site—n) of the strong type of interaction were found to be independent of Na+ concentration. Weak interaction occurs at low ionic strength and/or high EtBr concentration. Estimated binding parameters of EtBr with ss- and ds-polynucleotide are in good agreement with those for EtBr-B-DNA complexes. Data obtained provided an evidence for a stacking interaction of EtBr with single stranded poly[d(A-T)].     

Solution behaviour and relative stability of the complexes [MCl2(RNCHCHNR)] and [MCl2(py-2-CHNR)] (M=Pd,Pt;R=C6H4OMe-p)

Even though the α-diimino complexes [MCl₂(RNCHCHNR)] and [MCl₂(py-2-CHNR)] (M=Pd, Pt;R=C₆H₄OMe-p) are poorly soluble in chlorinated solvents, such as chloroform and 1,2-dichloroethane, or in acetonitrile, the electronic and ¹H NMR spectra indicate that these compounds are generally present as undissociate monomers with σ, σ′-N,N′ chelate N-ligands in dilute solutions. Only for [PdCl₂(RNCHCHNR)], some dissociation of the α-diimine occurs in acetonitrile. In dimethylsulfoxide, where the solubility is much higher, no dissociation is observed for the pyridine-2-carbaldimine complexes [MCl₂(py-2-CHNR)], whereas the 1,2-bis(imino) ethane derivatives [MCl₂(RNCHCHNR)] are extensively dissociated through a step-wise process involving intermediates with a σ-N monodentate α-diimino group. As is shown by the course of substitution reactions with 2,2′-bipyridine, the higher stability of [MCl₂(py-2-CHNR)] in dimethylsulfoxide is mainly due to thermodynamic factors (ground state stabilization for the presence of stronger MN bonds) rather than by kinetic factors (higher activation energy for steric strain in the activation states or transients).     

The effect of protonation on [Mn(IV)(μ2-O)]2 complexes

The series of complexes [Mn(IV)(X-SALPN)(₂-O)]₂, 1: X=5-OCH₃; 2: X=H; 3: X=5-Cl; 4: X=3,5-diCl; 5: X=5-NO₂, contain [Mn₂O₂]⁴⁺ cores with Mn-Mn separations of 2.7 . These molecules can be protonated to form [Mn(IV)(X-SALPN)(₂-O,OH)]₂ ⁺ in which a bridging oxide is protonated. The pK_a values for the series of [Mn(IV)(X-SALPN)(₂-O,OH)]₂ ⁺ track linearly versus the shift in redox potential with a slope of 84 mV/pKa. This observation suggests that the [Mn₂O₂]⁴⁺ core can be considered as a unit in which the free energy of protonation is directly related to the ability to reduce the Mn(IV) ion. The marked sensitivity of the reduction potential to the presence of protons presents a mechanism in which an enzyme can control the oxidizing capacity of an oxo manganese cluster by the degree and timing of oxo bridge protonation.Abbreviations AnH⁺CF₃SO₃ ^- anilinium triflate - DMA N,N-dimethyl acetamide - H₂SALPN 1,3-bis(salicylideneiminato)propane - H₂(5-Cl-SALPN) 1,3-bis(5-chlorosalicylideneiminato)propane; - H₂(3,5-diCl-SALPN) 1,3-bis(3,5-dichlorosalicylideneiminato)propane - H₂(5-NO₂-SALPN) 1,3-bis(5-nitorosalicylideneiminato)propane - H₂(5-OMe-SALPN) 1,3-bis(5-methoxysalicylideneiminato)propane - LuH⁺CF₃SO₃ ^- 2,4-lutidinium triflate - ME₃NH⁺Ph₄B^- trimethylammonium tetraphenylborate - OEC oxygen evolving complex - PyH⁺ClO₄ ^- pyridinium perchlorate - SCE saturated calomel electrode     

The mechanism of antimalarial action of the ruthenium(II)–chloroquine complex [RuCl2(CQ)]2

The mechanism of antimalarial action of the ruthenium-chloroquine complex [RuCl(2)(CQ)](2) (1), previously shown by us to be active in vitro against CQ-resistant strains of Plasmodium falciparum and in vivo against P. berghei, has been investigated. The complex is rapidly hydrolyzed in aqueous solution to [RuCl(OH(2))(3)(CQ)](2)[Cl](2), which is probably the active species. This compound binds to hematin in solution and inhibits aggregation to beta-hematin at pH approximately 5 to a slightly lower extent than chloroquine diphosphate; more importantly, the heme aggregation inhibition activity of complex 1 is significantly higher than that of CQ when measured at the interface of n-octanol-aqueous acetate buffer mixtures under acidic conditions modeling the food vacuole of the parasite. Partition coefficient measurements confirmed that complex 1 is considerably more lipophilic than CQ in n-octanol-water mixtures at pH approximately 5. This suggests that the principal target of complex 1 is the heme aggregation process, which has recently been reported to be fast and spontaneous at or near water-lipid interfaces. The enhanced antimalarial activity of complex 1 is thus probably due to a higher effective concentration of the drug at or near the interface compared with that of CQ, which accumulates strongly in the aqueous regions of the vacuole under those conditions. Furthermore, the activity of complex 1 against CQ-resistant strains of P. falciparum is probably related to its greater lipophilicity, in line with previous reports indicating a lowered ability of the mutated transmembrane transporter PfCRT to promote the efflux of highly lipophilic drugs. The metal complex also interacts with DNA by intercalation, to a comparable extent and in a similar manner to uncomplexed CQ and therefore DNA binding does not appear to be an important part of the mechanism of antimalarial action in this case.     

Syntheses and characterization of Cp2Ce[η3-N(QPPh2)2] (Q = S,Se) and Cp2Ce[η3-N(SPiPr2)(SePPh2)]

The compounds Cp₂Ce[η³-N(QPPh₂)₂] (Q = S (1), Se (2)) and Cp₂Ce[η³-N(SPⁱPr₂)(SePPh₂)] (3) have been synthesized from the protonolysis reactions between Cp₃Ce and HN(QPPh₂)₂ or HN(SPⁱPr₂)(SePPh₂) in THF. The structures of these compounds have been determined by X-ray crystallographic methods. The three compounds have similar structures in which the ligands are coordinated to Cp₂Ce moiety in an η³ fashion through the two chalcogen atoms and an N atom. Whereas the ⁷⁷Se NMR resonances are normal the ³¹P NMR resonances are shifted to much lower frequencies than in similar rare-earth compounds.     

Protonation,alkylation, addition and redox reactions of 16, 17 and 18 valence electron [Mo(L)(NO)('S4')] complexes [L = SPh,PMe3, NO; 'S4'2– = 1,2-Bis-(2-mercaptophenylthio)ethane(2-)]

In the quest for complexes modelling functional characteristics of metal sulfur oxidoreductases, a series of molybdenum nitrosyl complexes with sulfur-dominated coordination sphere was synthesized. Treatment of the 16, 17 and 18 valence electron (VE) complexes [Mo(L)(NO)('S₄')] (1–3) [L?=?SPh (1), PMe₃ (2), NO (3), 'S₄'^2–?=?1,2-bis-(2-mercaptophenylthio) ethane(2-)] with the Brönsted acid HBF₄ resulted in formation of different types of products. 1 and 3 were reversibly protonated at one thiolate atom of the 'S₄'^2– ligand;2, however, yielded the phosphonium salt [HPMe₃]BF₄ and the dinuclear [Mo(NO)('S₄')]₂. Alkylation of 1, 2 and 3 by Me₃OBF₄ or Et₃OBF₄ uniformly resulted in high yields of [Mo(L)(NO)(R-'S₄')]BF₄ complexes [L?=?SPh: R?=?Me (5), Et (6); L?=?PMe₃: R?=?Me (7); L?=?NO: R?=?Me (8), Et (9)] in which one thiolate atom of the 'S₄'^2– ligand had become alkylated; the NMR spectra of 5, 6, 8 and 9 indicated that only one out of four theoretically possible diastereoisomers had formed. 5 and 6 were characterized also by single-crystal X-ray structure analyses. A comparison of ν(NO) bands and redox potentials (cyclic voltammetry) of parent complexes and alkylated derivatives showed that alkylation leads to a decrease in electron density at the molybdenum center and to a positive shift in redox potentials. The 16 VE complex 1 could be reduced, also chemically, to give the corresponding 17 VE anion [1]^–, and inserted elemental sulfur into the Mo-SPh bond, forming the 18 VE phenylperthio complex [Mo(η²–SSPh)(NO)('S₄')] (11) which, upon reaction with PPh₃, gave SPPh₃ and regenerated the parent complex 1. These results are discussed with regard to the sequence of proton and electron transfer steps occurring in substrate conversions catalyzed by metal sulfur oxidoreductases.     

Synthesis and structures of porphyrin complexes of scandium: ClSc(TTP)·2(C 10H 7Cl) and O[Sc(TTP)] 2·6THF

A facile, high yield metallation procedure is reported for the insertion of Sc into H ₂(TTP) (TTP= dianion of meso-tetratolylporphyrin) using anhydrous ScCl ₃. Single crystal X-ray structures are reported for ClSc(TPP)·2(C ₁₀H ₇Cl) ( 1) and O[Sc(TTP)] ₂·6THF ( 2). Compound 1: space group P2 ₁/c with a = 19.850(17), b = 28.822(24), c = 9.954(9)Å, β = 95.71(7)°, Z = 4; 2: space group P2/n, a = 16.952(9), b = 16.737(5), c = 19.93(1)Å, β = 112.56(5)°, Z = 4. Compounds 1 and 2 both had large amounts of poorly ordered solvents in the lattice which resulted in rather high R factors in the range of 12–14%. In 1, the Sc is five-coordinate (4N and 1Cl) and is centered 0.68Åabove the plane defined by the four porphyrin nitrogens. For 2, the Sc is 0.82Åfrom the plane and contains a non-linear μ-oxide bridge with a ScO Sc angle of 109(3)°, but with essentially coplanar porphyrin rings.     

Synthesis and anticancer activity of 3′-[4-fluoroaryl-(1,2,3-triazol-1-yl)]-3′-deoxythymidine analogs and their phosphoramidates

Abstract

A series of novel 4-chlorophenyl N-alkyl phosphoramidates of 3′-[4-fluoroaryl-(1,2,3-triazol-1-yl)]-3′-deoxythymidines (20–49) was synthesized by means of phosphorylation of 3′-[4-aryl-(1,2,3-triazol-1-yl)]-3′-deoxythymidines (7–11) with 4-chlorophenyl phosphoroditriazolide (14), followed by a reaction with the appropriate amine. The synthesized compounds 7–11 and 20–49 were evaluated along with four known anticancer compounds for their cytotoxic activity in human cancer cell lines: cervical (HeLa), nasopharyngeal (KB), breast (MCF-7), osteosarcoma (143B) (only selected compounds 20, 24, 28, 32–36, 38, 40, 46) and normal human dermal fibroblast cell line (HDF) using the sulforhodamine B (SRB) assay. Among 3′-[4-aryl-(1,2,3-triazol-1-yl)]-3′-deoxythymidines (7–11) the highest activity in all the investigated cancer cells was displayed by 3′-[4-(3-fluorophenyl)-(1,2,3-triazol-1-yl)]-3′-deoxythymidine (9) (IC₅₀ in the range of 2.58–3.61?μM) and its activity was higher than that of cytarabine. Among phosphoramidates 20–49 the highest activity was demonstrated by N-n-propyl phosphoramidate of 3′-[4-(3-fluorophenyl)-(1,2,3-triazol-1-yl)]-3′-deoxythymidine (35) in all the cancer cells (IC₅₀ in the range of 0.97–1.94?μM). Also N-ethyl phosphoramidate of 3′-[4-(3-fluorophenyl)-(1,2,3-triazol-1-yl)]-3′-deoxythymidine (33) exhibited good activity in all the used cell lines (IC₅₀ in the range of 4.79–4.96?μM).     

Solution structures and dynamics of [HOs3(CO)10(σ,π vinyl)] complexes

No interconversion has been found to occur on the NMR time scale between the structural arrangements found in the solid state. The σ, π motion of the vinyl group does not cause a cis-trans interconversion of the terminal hydrogens in [HOs₃(CO)₁₀(CHCH₂)] which simply takes place by alternating the π-electron cloud to opposite osmium centres.The ¹H chemical shift of the =C

moieties is a useful probe to assess the coordination mode of the vinyl ligand.In [HOs₃(CO)₁₀(CPhC(H)Ph)], a trigonal twist process has been shown to occur at the Os(CO)₄ unit. For the same unit ²J_c−c trans have been obtained for all the reported derivatives and their magnitude is almost unchanged along the series. Further J_cc information has been obtained from a sample of [HOs₃(CO)₁₀(CHCH₂)] C-13 labelled in the vinyl ligand.     

Bh-DNA: Variations of the Poly[d(A)] · Poly[d(T)] Structure within the Framework of the Fibre Diffraction Studies

Abstract

A refinement of the recent results for poly[d(A)] · poly[d(T)] (Alexeev et al., J. Biomol. Struct. Dyn. 4, 989 (1987)) involving additional parameters of the base-pair structure and of the sugar- phosphate backbone expands the conformational potential of this polynucleotide of the B type to include the possibility of bifurcated hydrogen bonds of the kind recently discovered in crystalline deoxyoligonucleotide with lone d(A)_n · d(T)_n stretch (Nelson et al., Nature 330, 221 (1987)).

Still, analysis of the available data and energy calculations do not seem to indicate that the bifurcated H-bonds are a crucial factor responsible for the anomalous structure of the d(A)_n · d(T)_n sequence. The unique structural properties of poly [d(A)] · poly[d(T)] can hardly be explained without taking into account its interactions with the double-layer hydration spine in the minor groove. In view of the hydration mechanism stabilizing poly [d(A)] · poly [d(T)] and of the polynucleotide's heteronomous prehistory (Arnott et al., Nucleic Acids Res. 11, 4141 (1983)) we suggest that this B-type structure be called B_h.     

Synthesis and structure of μ-3,3′-[ 1,2-ethanediyl-bis(nitrilomethylidyne)-bis(2-hydroxybenzoato)] aquadicopper(II) hydrate

The complex μ-3,3′-[1,2-ethanediyl-bis(nitrilome- thylidyne)-bis(2-hydroxybenzoato)] aquadicopper(II) hydrate, C₁₈H₁₆N₂O₈Cu₂, was isolated from an attempted preparation of a copper lanthanum binuclear complex. The dark purple crystals are monoclinic, space group P2₁/n, with 4 molecules per unit cell; dimensions a = 13.961(5), b = tl.787(3), c = 11.622(3) Å and β = 113.09(2)°. The final R was 0.046 for the 2062 reflections used in the analysis. The Cu atom in the N₂O₂ cavity is five coordinate with CuN distances of 1.879 and 1.880 Å and CuO distances of 1.898 and 1.900 Å. A water molecule at 2.557 Å completes the square pyramidal arrangement. The second Cu in the O₄ cavity is square planar, with CuO distances to the bridging oxygens of 1.914 and 1.909 Å and to the carboxy oxygens of 1.871 and 1.882 Å. A survey of copper complexes in a square planar N₂O₂ arrangement has led to the equation δCu from the N₂O₂ plane = 0.822 – 0.275 (CuO axial distance) with a correlation coefficient of 0.98 for the 12 structures in which the Cu atom is bonded to a fifth oxygen atom. A model for the transition from square planar to square pyramidal geometry is proposed.     

Reactivity of [PdCl(μ-med)]2 with monodentate or bidentate ligands. Structure of the dinuclear complexes [Pd(μ-med)(PPh3)]2(BF4)2 and [Pd(μ-med)(bpy)]2(BF4)2. [Hmed=N-(2-mercaptoethyl)-3,5-dimethylpyrazole]

Treatment of the ligand N-(2-mercaptoethyl)-3,5-dimethylpyrazole with [Pd(CH₃COO)₂]₃ and reaction of [PdCl(μ-med)]₂ with pyridine (py) or triphenylphosphine (PPh₃) in the presence of AgBF₄ produced the following complexes: [Pd(CH₃COO)(μ-med)]₂, [Pd(μ-med)(py)]₂(BF₄)₂ and [Pd(μ-med)(PPh₃)]₂(BF₄)₂. Similar reactions carried out with 2,2^′-bipyridine (bpy) or 1,3-bis(diphenylphosphino)propane (dppp) produced [Pd(μ-med)(bpy)]_x(BF₄)_x (x=1 or 2) and [Pd(μ-med)(dppp)]_x(BF₄)_x (x=1 or 2). Treatment of [Pd(μ-med)(bpy)]_x(BF₄)_x with [PdCl₂(CH₃CN)₂] produced [Pd₃Cl₂(μ-med)₂(bpy)₂](BF₄)₂. Treatment of [Pd(μ-med)(dppp)]_x(BF₄)_x with [PdCl₂(CH₃CN)₂] produced a mixture of [Pd(μ-Cl)(dppp)]₂(BF₄)₂ and [Pd(μ-med)₂(dppp)]²⁺. X-ray crystal structures of [Pd(μ-med)(PPh₃)]₂(BF₄)₂ · 2CH₃CN and [Pd(μ-med)(bpy)]₂(BF₄)₂ · 0.5CH₃OH are presented.     

On the nature of mutual inactivation between [Cp*Rh(bpy)(H2O)]2+ and enzymes – analysis and potential remedies

Pentamethylcyclopentadienyl rhodium bipyridine ([Cp*Rh(bpy)(H₂O)]²⁺) is a versatile catalyst to promote biocatalytic redox reactions. However, its major drawback lies in the mutual inactivation of [Cp*Rh(bpy)(H₂O)]²⁺ and the biocatalyst. This interaction was investigated using the alcohol dehydrogenase from Thermus sp. ATN1 (TADH) as model enzyme. TADH binds 4 equiv. of [Cp*Rh(bpy)(H₂O)]²⁺ without detectable decrease in catalytic activity and stability. Higher molar ratios lead to time-, temperature-, and concentration-dependent inactivation of the enzyme suggesting [Cp*Rh(bpy)(H₂O)]²⁺ to function as an ‘unfolding catalyst’. This detrimental activity can be circumvented using strongly coordinating buffers (e.g. (NH₄)₂SO₄) while preserving its activity as NAD(P)H regeneration catalyst under electrochemical reaction conditions.     

Four- versus five-coordination in platinum(II) complexes of α-diimines and the crystal structure of [PtClMe(i-PrNCHCHNi-Pr)]

The complex [PtCIMe(i-PrNCHCHNi-Pr)] and its unstable five-coordinate ethylene adduct have been prepared and characterized by ¹H NMR. The crystal and molecular structure of the former has been determined. The complex crystallizes in the orthorhombic space group Pca2 ₁, with a = 12.138(6), b = 9.601(6), c = 10.586(6)Å, Z = 4. Refinement converged to a final R index of 0.059. The geometrical parameters of the structure are compared with those of a related complex and discussed in relation to the stability of the five-coordinate olefin adducts.     

Synthesis, characterisation and structural studies of [Cu(dach)(μ-NCS)(NCS)]n and [Cu(dach)2(N3)]ClO4 (dach=1,4-diazacycloheptane)

A new singly bridging complex [Cu(dach)(μ-NCS)(NCS)]_n (dach=1,4-diazacycloheptane) has been synthesised and its crystal structure determined. There are many examples of double NCS bridged polymeric chains, but fewer singly bridged ones. IR, ESR and temperature variable magnetic studies are described but no magnetic interaction was found between the copper centres. [Cu(dach)₂(N₃)]ClO₄ has also been characterised by IR, ESR spectra and magnetic studies. The crystal structure determination shows that it is a penta-coordinated monomeric species with an axially coordinated azide linked to the perchlorate counterion by hydrogen bonding.