Bioinspired nonheme iron complexes derived from an extended series of N,N,O-ligated BAIP ligands.

A series of mononuclear Fe(II) triflate complexes based on the 3,3-bis(1-alkylimidazole-2-yl)propionate ester (BAIP) ligand scaffold are reported. In these complexes, the tripodal N,N,O-BAIP ester ligand is varied by (i) changing the ester moiety (i.e., n-Pr, tert-Bu esters, n-Pr amide), (ii) changing the methylimidazole moieties to methylbenzimidazole moieties, and (iii) changing the methylimidazole moieties to 1-ethyl-4-isopropylimidazole moieties. The general structure of the resulting complexes comprises two facially capping BAIP ligands around a coordinatively saturated octahedral Fe(II) center, with either a transoid or cisoid orientation of the N,N,O-donor manifold that depends on the combined steric and electronic demand of the ligands. In the case of the sterically most encumbered ligand, a four-coordinate all N-coordinate complex is formed as well, which cocrystallizes with the six-coordinate complex. In combination with the catalytic properties of the new complexes in the epoxidation/cis-dihydroxylation of cyclooctene with H2O2, in terms of turnover number and cis-diol formation, these studies provide a number of insights for further ligand design and catalyst development aimed at Fe-mediated cis-dihydroxylation.

Mono- and dinuclear iron complexes of bis(1-methylimidazol-2-yl)ketone (bik): structure, magnetic properties, and catalytic oxidation studies.

The newly synthesized dinuclear complex [Fe(III)(2)(µ-OH)(2)(bik)(4)](NO(3))(4) (1) (bik, bis(1-methylimidazol-2-yl)ketone) shows rather short Fe···Fe (3.0723(6) Å) and Fe-O distances (1.941(2)/1.949(2) Å) compared to other unsupported Fe(III)(2)(µ-OH)(2) complexes. The bridging hydroxide groups of 1 are strongly hydrogen-bonded to a nitrate anion. The (57)Fe isomer shift (δ = 0.45 mm s(-1)) and quadrupole splitting (ΔE(Q) = 0.26 mm s(-1)) obtained from Mössbauer spectroscopy are consistent with the presence of two identical high-spin iron(III) sites. Variable-temperature magnetic susceptibility studies revealed antiferromagnetic exchange (J = 35.9 cm(-1) and H = JS(1)·S(2)) of the metal ions. The optimized DFT geometry of the cation of 1 in the gas phase agrees well with the crystal structure, but both the Fe···Fe and Fe-OH distances are overestimated (3.281 and 2.034 Å, respectively). The agreement in these parameters improves dramatically (3.074 and 1.966 Å) when the hydrogen-bonded nitrate groups are included, reducing the value calculated for J by 35%. Spontaneous reduction of 1 was observed in methanol, yielding a blue [Fe(II)(bik)(3)](2+) species. Variable-temperature magnetic susceptibility measurements of [Fe(II)(bik)(3)](OTf)(2) (2) revealed spin-crossover behavior. Thermal hysteresis was observed with 2, due to a loss of cocrystallized solvent molecules, as monitored by thermogravimetric analysis. The hysteresis disappears once the solvent is fully depleted by thermal cycling. [Fe(II)(bik)(3)](OTf)(2) (2) catalyzes the oxidation of alkanes with t-BuOOH. High selectivity for tertiary C-H bond oxidation was observed with adamantane (3°/2° value of 29.6); low alcohol/ketone ratios in cyclohexane and ethylbenzene oxidation, a strong dependence of total turnover number on the presence of O(2), and a low retention of configuration in cis-1,2-dimethylcyclohexane oxidation were observed. Stereoselective oxidation of olefins with dihydrogen peroxide yielding epoxides was observed under both limiting oxidant and substrate conditions.

Quinoxaline-2-carboxamide as a carrier ligand in two new platinum(II) compounds: Synthesis, crystal structure, cytotoxic activity and DNA interaction.

The search for platinum compounds structurally different from cisplatin has led to two new platinum(II) compounds containing quinoxaline-2-carboxamide as a carrier ligand, i.e. cis-[Pt(qnxca)(MeCN)Cl2] (1) and the [Pt(qnxca-H)(dmso)Cl] (2). Both compounds have been synthesized and characterized using different spectroscopic methods. In addition, single-crystal structures have been determined by X-Ray diffraction for both compounds. In each case a square planar Pt(II) is present; in (1) the qnxca is monodentate and neutral, whereas in (2) the ligand has lost a hydrogen, to form the anionic chelating ligand abbreviated as qnxca-H. The biological activity of both compounds has been investigated in a panel of seven human tumour cells, displaying poor cytotoxic activity, compared to cisplatin. The interaction of the new compounds with 1 or 2 equiv. of 9-ethylguanine has been studied using (1)H NMR, (195)Pt NMR and ESI-MS spectroscopy, finding poor reactivity of 1 towards the model base, forming only the monosubstituted adduct. Surprisingly, compound 2, which is more sterically crowded, interacts more efficiently with the 9-EtG, forming a bifunctional adduct with two 9-EtG with substitution of the dmso and the chloride ligand. Unwinding studies of pUC19 plasmid DNA by compound 1 show similar unwinding properties to cisplatin.

A novel ruthenium(III) complex with a tridentate dianionic P,O,O-ligand showing high cytotoxic activity.

Tris(o-anisyl)phosphane was reacted with ruthenium(III) chloride forming a novel Ru(III) complex of formula [Ru(PAn(3))(P(An)(phenolate)(2))Cl] containing a tridentate dianionic P,O,O-ligand and a bidentate neutral P,O ligand. The tridentate ligand was formed by elimination of two methyl groups from the starting ligand in the reaction with the ruthenium salt. The molecular structure was determined by single crystal X-ray diffraction analysis. The compound shows a high cytotoxic activity in ovarian cancer cell lines comparable with cisplatin and overcoming cisplatin-resistance.

Mono- and dinuclear platinum(II) compounds with 5,7-dimethyl-1,2,4-triazolo[1,5-a]pyrimidine. Structure, cytotoxic activity and reaction with 5'-GMP.

Mono- and dinuclear platinum(II) coordination compounds of formula cis-[PtCl(2)(NH(3))(dmtp)], 1, cis-[PtCl(2)(dmtp)(2)], 2 and {H(+)[C(28)H(32)Cl(2)N(16)Pt(2)](2+)(NO(3))(3)(H(2)O)(6)}, 3, in which dmtp is 5,7-dimethyl-1,2,4-triazolo[1,5-a]pyrimidine have been synthesized and characterized by infrared and by (1)H, (13)C, (195)Pt NMR spectroscopy. The coordination units of the cationic species of formula [Pt(2)(mu-dmtp)(2)Cl(2)(dmtp)(2)](2+) are built up by two platinum atoms in a square-planar environment. Two sites are occupied by two 5,7-dimethyl-1,2,4-triazolo[1,5-a]pyrimidine (dmtp) bridging ligands which are linked to both metal atoms through their nitrogen atoms in positions 3 and 4. The other two positions are occupied by one monodentate 5,7-dimethyl-1,2,4-triazolo[1,5-a]pyrimidine (dmtp) molecule and a coordinated chloride. This compound is the first in which the same triazolopyrimidine ligand (dmtp) coordinates to a metal ion in two different ways, i.e. bridging bidentate and non-bridging monodentate. In addition, the interaction of compounds 1 and 2 with 5'-GMP was investigated in solution by (1)H NMR spectroscopy. The cytotoxicity of all the new platinum(II) compounds were studied by using two different cell lines: T47D (breast cancer) and HCV29T (bladder cancer).

DNA cleavage and antitumour activity of platinum(II) and copper(II) compounds derived from 4-methyl-2-N-(2-pyridylmethyl)aminophenol: spectroscopic, electrochemical and biological investigation.

The reaction of the redox-active ligand, Hpyramol (4-methyl-2-N-(2-pyridylmethyl)aminophenol) with K(2)PtCl(4) yields monofunctional square-planar [Pt(pyrimol)Cl], PtL-Cl, which was structurally characterised by single-crystal X-ray diffraction and NMR spectroscopy. This compound unexpectedly cleaves supercoiled double-stranded DNA stoichiometrically and oxidatively, in a non-specific manner without any external reductant added, under physiological conditions. Spectro-electrochemical investigations of PtL-Cl were carried out in comparison with the analogue CuL-Cl as a reference compound. The results support a phenolate oxidation, generating a phenoxyl radical responsible for the ligand-based DNA cleavage property of the title compounds. Time-dependent in vitro cytotoxicity assays were performed with both PtL-Cl and CuL-Cl in various cancer cell lines. The compound CuL-Cl overcomes cisplatin-resistance in ovarian carcinoma and mouse leukaemia cell lines, with additional activity in some other cells. The platinum analogue, PtL-Cl also inhibits cell-proliferation selectively. Additionally, cellular-uptake studies performed for both compounds in ovarian carcinoma cell lines showed that significant amounts of Pt and Cu were accumulated in the A2780 and A2780R cancer cells. The conformational and structural changes induced by PtL-Cl and CuL-Cl on calf thymus DNA and phiX174 supercoiled phage DNA at ambient conditions were followed by electrophoretic mobility assay and circular dichroism spectroscopy. The compounds induce extensive DNA degradation and unwinding, along with formation of a monoadduct at the DNA minor groove. Thus, hybrid effects of metal-centre variation, multiple DNA-binding modes and ligand-based redox activity towards cancer cell-growth inhibition have been demonstrated. Finally, reactions of PtL-Cl with DNA model bases (9-Ethylguanine and 5'-GMP) followed by NMR and MS showed slow binding at Guanine-N7 and for the double stranded self complimentary oligonucleotide d(GTCGAC)(2) in the minor groove.

A molecular cage of nickel(II) and copper(I): a [{Ni(L)2}2(CuI)6] cluster resembling the active site of nickel-containing enzymes.

A new mononuclear low-spin nickel(II) dithiolato complex, [NiL(2)] (1), reacts with copper iodide to form the hetero-octanuclear cluster [{Ni(L)(2)}(2)(CuI)(6)] (2) with four trigonal-planar CuI(2)S and two tetrahedral CuI(2)S(2) sites; anagostic interactions between the nickel(II) ions and aromatic protons have been demonstrated by variable-temperature NMR studies to pertain in solution.

A phosphorus analogue of Bis(eta4-cyclobutadiene)iron(0).

P makes it possible: The convenient oxidative synthesis of the 16-electron organophosphorus iron sandwich complex [Fe(eta(4)-P(2)C(2)tBu(2))(2)] (see structure) suggests that the elusive all-carbon complex [Fe(eta(4)-C(4)H(4))(2)] is a viable synthetic target.

N-donor functionalized N-heterocyclic carbene nickel(II) complexes in the Kumada coupling.

The synthesis and characterization of novel nickel(II) complexes bearing two bidentate N-heterocyclic carbene ligands functionalized with anionic N-donor moieties are described. Two different N-donor groups are employed, namely amido and benzimidazolato moieties. The solid-state structures of three of these complexes have been determined by X-ray crystallography. The amido-functionalized low-spin, square-planar Ni(II) complexes exhibit a cis geometry around the metal centre, while the benzimidazolato-functionalized complex crystallizes as the trans isomer. The activity of these novel complexes in the Kumada cross-coupling of phenylmagnesium chloride with 4-chloroanisole and 4-fluoroanisole was investigated. One of the benzimidazolato-functionalized complexes shows the highest activity in this reaction reported to date, yielding the desired product in quantitative yields within 30 min (4-chloroanisole), or 150 min (4-fluoroanisole) with only 1 mol% catalyst.

Synthesis of conformationally constrained peptidomimetics using multicomponent reactions.

A novel modular synthetic approach toward constrained peptidomimetics is reported. The approach involves a highly efficient three-step sequence including two multicomponent reactions, thus allowing unprecedented diversification of both the peptide moieties and the turn-inducing scaffold. The turn-inducing properties of the dihydropyridone scaffold were evaluated by molecular modeling, X-ray crystallography, and NMR studies of a resulting peptidomimetic. Although modeling studies point toward a type IV beta-turn-like structure, the X-ray crystal structure and NMR studies indicate an open turn structure.

Synthesis, crystal structure, studies in solution and cytotoxicity of two new fluorescent platinum(II) compounds containing anthracene derivatives as a carrier ligand.

Two new cytotoxic fluorescent platinum(II) compounds, cis-[Pt(A9opy)Cl2] (1) and cis-[Pt(A9pyp)(DMSO)Cl2] (2),have been designed, synthesized, and characterized by IR, 1H NMR, and 195Pt NMR spectroscopy; electrospray ionization mass spectrometry (ESI-MS); and single-crystal X-ray diffraction. The carrier ligands selected for thesynthesis of these fluorescent platinum(II) compounds are E-2-[1-(9-anthryl)-3-oxo-3-prop-2-enylpyridine] (abbreviatedas A9opy) and E-1-(9-anthryl)-3-(2-pyridyl)-2-propenone (abbreviated as A9pyp). The compound cis-[Pt(A9opy)Cl2](1) comprises a peculiar cis-platinum(II) organometallic compound, in which the platinum(II) ion is bound to the photoisomerizable carbon-carbon double bond of the carrier ligand. The effects of the metal-ion coordination on the photoisomerization of the carbon-carbon double bond of the ligand have been studied. In contrast, the carrier ligand A9pyp used for the synthesis of the cis-[Pt(A9pyp)(DMSO)Cl2] compound (2) does not undergo such anisomerization process and remains in the E conformation, while coordinated to the platinum(II) ion through the nitrogen of the pyridine ring. In addition to the synthesis and characterization, solution studies of both compounds have also been performed in detail, including NMR and ESI-MS spectroscopy. Moreover, a high degree of cytotoxicactivity of compound 1 was found, as compared to cisplatin and its corresponding platinum-free molecule, in a series of human tumor cell lines. Compound 2 was also found to be highly active against these cell lines but appeared less active compared to the platinum-free molecule.

A two-step spin crossover mononuclear iron(II) complex with a [HS-LS-LS] intermediate phase.

The two-step spin crossover of a new mononuclear iron(ii) complex is studied by magnetic, crystallographic and calorimetric methods revealing two successive first-order phase transitions and an ordered intermediate phase built by the repetition of the unprecedented [HS-LS-LS] motif.

Ruthenium(III) chloride complex with a tridentate bis(arylimino)pyridine ligand: synthesis, spectra, X-ray structure, 9-ethylguanine binding pattern, and in vitro cytotoxicity.

The synthetic, spectroscopic, structural, and biological studies of a bis(arylimino)pyridine Ru(III) chloride compound containing the ligand, 2,6-bis(2,4,6-trimethylphenyliminomethyl)pyridine are reported. The bis(arylimino)pyridine ligand, with three donor nitrogen atoms, was synthesized by condensation of 2,6-pyridinedicarboxaldehyde with 2,4,6-trimethylaniline. The Ru(III) complex, with formula [RuCl 3(L1)](H 2O) (RuL1), where L1 = 2,6-bis(2,4,6-trimethylphenyliminomethyl)pyridine, was structurally determined on the basis of analytical and spectroscopic (IR, UV-vis, ESI-MS) studies. A straightforward strategy to fully characterize the paramagnetic compound using advanced (1)H NMR is reported. This new complex is a prototype for a series of new anticancer Ru(III) and Ru(II) compounds with improved cytostatic properties; likely to be modified in a desirable manner due to the relatively facile ligand modification of the bis(imino)pyridines and their molecular architecture. The present Ru(III) complex is the first example of this family of Ru(III)/Ru(II) anticancer compounds with the aimed physicochemical characteristics. Although the ligand itself is moderately active in selected cell lines (EVSA-T and MCF-7), the activity of the [Ru(L1)Cl 3] complex has increased significantly for a broad range of cancer cell lines tested in vitro (IC 50 values = 11 approximately 17 microM). Reaction of the RuL1 species with the DNA model base 9-ethylguanine (9EtGua) was found to produce in a redox reaction the species trans-[Ru(II)(L1)(9EtGua) 2(H 2O)](ClO 4) 2 (abbreviated as RuL1-9EtGua), which was studied in solution and also in the solid state, by X-ray crystallography. The structure comprises the as yet unknown trans-bis(purine)Ru(II) unit.

Phenanthroline derivatives with improved selectivity as DNA-targeting anticancer or antimicrobial drugs.

Phenanthroline derivatives are of interest due to their potential activity against cancer, and viral, bacterial, and fungal infections. In a search for highly specific antitumor and antibacterial compounds, we report the activities of 1,10-phenanthroline-5,6-dione (phendione or L(1)), dipyrido[3,2-a:2',3'-c]phenazine (dppz or L(2)), and their corresponding platinum complexes ([PtL(1)Cl2] and [PtL(2)Cl2]), and provide the solid-state 3D structure for [PtL(1)Cl2]. It is generally known that a toxic metal ion coordinated to an active organic moiety leads to a synergistic effect; however, we report herein that the platinum complexes [PtL(1)Cl2] and [PtL(2)Cl2] have weaker activities relative to those of the free ligands, especially against bacteria. Testing these agents against a variety of human cancer cell lines revealed that L(1) and [PtL(1)Cl2] were at least as active as cisplatin against several of the cell lines (including a cisplatin-resistant cell line). The absence of antibacterial activity of [PtL(1)Cl2] removes the detrimental effect of phenanthrolines toward intestinal flora, suggesting a highly promising new strategy for the development of anticancer drugs with reduced side effects.

Iron(II) complexes with bio-inspired N,N,O ligands as oxidation catalysts: olefin epoxidation and cis-dihydroxylation.

The Rieske dioxygenases are a group of non-heme iron enzymes, which catalyze the stereospecific cis-dihydroxylation of its substrates. Herein, we report the iron(II) coordination chemistry of the ligands 3,3-bis(1-methylimidazol-2-yl)propionate (L1) and its neutral propyl ester analogue propyl 3,3-bis(1-methylimidazol-2-yl)propionate (PrL1). The molecular structures of two iron(II) complexes with PrL1 were determined and two different coordination modes of the ligand were observed. In [Fe(II)(PrL1)(2)](BPh(4))(2) (3) the ligand is facially coordinated to the metal with an N,N,O donor set, whereas in [Fe(II)(PrL1)(2)(MeOH)(2)](OTf)(2) (4) a bidentate N,N binding mode is found. In 4, the solvent molecules are in a cis arrangement with respect to each other. Complex 4 is a close structural mimic of the crystallographically characterized non-heme iron(II) enzyme apocarotenoid-15-15'-oxygenase (APO). The mechanistic features of APO are thought to be similar to those of the Rieske oxygenases, the original inspiration for this work. The non-heme iron complexes [Fe(II)(PrL1)(2)](OTf)(2) (2) and [Fe(II)(PrL1)(2)](BPh(4))(2) (3) were tested in olefin oxidation reactions with H(2)O(2) as the terminal oxidant. Whereas 2 was an active catalyst and both epoxide and cis-dihydroxylation products were observed, 3 showed negligible activity under the same conditions, illustrating the importance of the anion in the reaction.

Iron(III)-catecholato complexes as structural and functional models of the intradiol-cleaving catechol dioxygenases.

The structural and spectroscopic characterization of mononuclear iron(III)-catecholato complexes of ligand L4 (methyl bis(1-methylimidazol-2-yl)(2-hydroxyphenyl)methyl ether, HL4) are described, which closely mimic the enzyme-substrate complex of the intradiol-cleaving catechol dioxygenases. The tridentate, tripodal monoanionic ligand framework of L4 incorporates one phenolato and two imidazole donor groups and thus well reproduces the His2Tyr endogenous donor set. In fact, regarding the structural features of [FeIII(L4)(tcc)(H2O)] (5.H2O, tcc = tetrachlorocatechol) in the solid state, the complex constitutes the closest structural model reported to date. The iron(III)-catecholato complexes mimic both the structural features of the active site and its spectroscopic characteristics. As part of its spectroscopic characterization, the electron paramagnetic resonance (EPR) spectra were successfully simulated using a simple model that accounts for D strain. The simulation procedure showed that the observed g = 4.3 line is an intrinsic part of the EPR envelope of the studied complexes and should not necessarily be attributed to a highly rhombic impurity. [FeIII(L4)(dtbc)(H2O)] (dtbc = 3,5-di-tert-butylcatechol) was studied with respect to its dioxygen reactivity, and oxidative cleavage of the substrate was observed. Intradiol- and extradiol-type cleavage products were found in roughly equal amounts. This shows that an accurate structural model of the first-coordination sphere of the active site is not sufficient for obtaining regioselectivity.

The synthesis, chemical and biological properties of dichlorido(azpy)gold(III) chloride (azpy=2-(phenylazo)pyridine) and the gold-induced conversion of the azpy ligand to the chloride of the novel tricyclic pyrido[2,1-c][1,2,4]benzotriazin-11-ium cation.

A new Au(III) coordination compound with the ligand 2-(phenylazo)pyridine has been synthesized and fully characterized by means of elemental analysis, IR, UV-visible, conductivity measurements, NMR, electrospray ionization (ESI-MS) and inductively coupled plasma optical emission spectrometry (ICP-OES). The chemical stability of the cation in this compound, [Au(azpy)Cl(2)](+) (abbreviated: Au-azpy), was analyzed by means of several physicochemical methods. While stable in the solid state, stability studies performed with the gold compound in solution showed an unexpected and unprecedented reactivity. A cationic organic derivative of 2-(phenylazo)pyridine, (abbreviated: pyrium), was produced from the solution and has been isolated as its chloride salt and characterized by crystal structure determination, elemental analysis, NMR, ESI-MS and conductivity studies in solution. This cyclization reaction is reported for the first time in the case of gold coordination compounds. The Au adduct and the pyrium cation were investigated as potential cytotoxic and anticancer agents, and both show moderate to high cytotoxic properties in cisplatin-sensitive and cisplatin-resistant ovarian carcinoma cell lines, A2780; and cisplatin-sensitive and cisplatin-resistant murine lymphocytic leukemia cell lines, L1210. Significant anticancer activity against the cisplatin resistant cell lines was found for the pyrium salt, ruling out the occurrence of cross resistance phenomena.

alpha-Tris(2,4-pentanedionato-kappa(2)O,O')aluminum(III) at 240, 210, 180, 150 and 110 K: a new delta phase at 110 K.

The crystal structure of the title compound, [Al(C(5)H(7)O(2))(3)], has been investigated by a multi-temperature measurement to provide information on thermal vibrations and disorder in the structure. At 110 K, the structure of a new delta polymorph could be determined. A disorder-order phase transition takes place between 150 and 110 K and is klassengleich. The unit-cell volume increases by a factor of three and the diffraction pattern shows weak supercell reflections.