CO-releasing molecule (CORM) conjugate systems.

The development of CORMs (CO-releasing molecules) as a prodrug for CO administration in living organisms has attracted significant attention. CORMs offer the promising possibility of a safe and controllable release of CO in low amounts triggered by light, ligands, enzymes, etc. For the targeting of specific tissues or diseases and to prevent possible side effects from metals and other residues after CO release, these CORMs are attached to biocompatible systems, like peptides, polymers, nanoparticles, dendrimers, protein cages, non-wovens, tablets, and metal-organic frameworks. We discuss in this review the known CORM carrier conjugates, in short CORM conjugates, with covalently-bound or incorporated CORMs for medicinal and therapeutic applications. Most conjugates are nontoxic, show increasing half-lives of CO release, and make use of the EPR-effect, but still show problems because of a continuous background of CO release and the absence of an on/off-switch for the CO release.

Synthesis of oxime-based CO-releasing molecules, CORMs and their immobilization on maghemite nanoparticles for magnetic-field induced CO release.

Oxime-based CO-releasing molecules (oximeCORMs) were immobilized with a catechol-modified backbone on maghemite iron oxide nanoparticles (IONPs) to give oximeCORM@IONP. The CO release from the free and immobilized oximeCORMs was measured using the standard myoglobin assay. The oximeCORM-nanoparticles were coated with dextran for improved water solubility and confined into an alginate shell for protection and separation from the surrounding myoglobin assay to allow for CO release studies by UV/Vis absorption without interference from highly-absorptive oximeCORM@IONP. Half-lifes of the oxime-based polymer-confined alginate@dextran@oximeCORM@IONPs were estimated at 20 °C to 814 ± 23 min, at 37 °C to 346 ± 83 min and at 50 °C to 73 ± 1 min. The alginate@dextran@oximeCORM@IONP composite showed a further decrease of the half-life of CO release to 153 ± 27 min at 37 °C through local magnetic heating of the susceptible iron oxide nanoparticles with application of an external alternating magnetic field (31.7 kA m(-1), 247 kHz, 39.9 mTesla). The activation energy for the CO release from molecular dicarbonylchlorido(imidazole-2-carbaldehydeoxime)(alkoxycarbonyl)ruthenium(ii) complexes is determined to be ∼100 kJ mol(-1) for five different imidazole-oxime derivatives.

Metal carbonyls supported on iron oxide nanoparticles to trigger the CO-gasotransmitter release by magnetic heating.

Magnetic iron oxide, maghemite (Fe2O3) nanoparticles with covalent surface-bound CO-releasing molecules (CORMs) can be triggered to release CO through heating in an alternating magnetic field. In the proof-of-concept study the rate of CO-release from [RuCl(CO3)(µ-DOPA)]@maghemite nanoparticles was doubled upon exposure to an external alternating magnetic field (31.7 kAm(-1), 247 kHz, 25 °C, 39.9 mTesla, DOPA = dioxyphenyl-alaninato).

Tricarbonyl[tris(1-methyl-1H-imidazol-2-yl-κN(3))methanol]manganese(I) trifluoromethanesulfonate.

In the title compound, [Mn(C(13)H(16)N(6)O)(CO)(3)](CF(3)O(3)S), the Mn(I) atom has a slightly distorted octa-hedral geometry. The three CO ligands have C-Mn-C angles in the range 89.44 (10)-92.31 (9)°, while the three N atoms of the tripodal ligand form significantly smaller N-Mn-N angles of 82.76 (2)-85.51 (6)°. The three N atoms of the tripodal ligand and the three carbonyl ligands coordinate facially. In the crystal, the trifluoro-methane-sulfonate counter anion is connected by a medium-strength O-H⋯O hydrogen bond to the hydroxyl group of the manganese complex.

(Picolinato-κN,O)[tris(2-isopropyl-1H-imidazol-4-yl-κN)phosphane]cobalt(II) nitrate.

Single crystals of the title compound, [Co(C(6)H(4)NO(2))(C(18)H(27)N(6)P)]NO(3), were obtained from the reaction of nitrato[tris-(2-isopropyl-imidazol-4-yl)phosphane]cobalt(II) nitrate with picolinic acid in the presence of potassium tert-butoxide as base. The coordination polyhedron around the central Co(II) ion is about halfway between square-pyramidal and trigonal-bipyramidal geometry. In the structure, the nitrate counter-anion is connected by N-H⋯O hydrogen bonding to the complex cation. Additionally, the complex cations form one-dimensional chains along [010] by hydrogen bonding of the NH group of an imidazole ring to the picolinate group of a neighbouring complex cation.

Stabilisation of water-soluble platinum nanoparticles by phosphonic acid derivatives.

Sodium 2-(diphenylphosphino)ethyl phosphonate (1) was investigated as a stabilising agent for platinum nanoparticles (Pt-NPs) in aqueous solution. This phosphino phosphonate is known to stabilise rhodium nanoparticles (NPs) in water. Here we report that in the case of Pt-NPs this ligand is indirectly involved in the stabilisation mechanism and the actual stabilisation agent is the platinum complex Na(2)[Pt(1)(2)] (2). The reduction of platinum(II) salts in the presence of the phosphonates 1, 2, sodium 2-(diphenylphosphoryl)ethyl phosphonate (3) and 3,3,3-triphenylpropyl phosphonate (4) leads to stable platinum NPs with a remarkably narrow particle size distribution. These platinum NPs show high catalytic activity in the hydrogenation of 1-hexene and 1-chloro-3-nitrobenzene under biphasic as well as heterogeneous (supported on charcoal) conditions. The activity of the supported NPs was 30 times higher than the commercially available catalyst Pt(0) EnCat®. Furthermore, the single-crystal X-ray structures of (1)(MeOH)(2)(H(2)O)(2), (3)(H(2)O)(4), and (4)(2)(H(2)O)(17) have been determined.

Gold(I) complexes of water-soluble diphos-type ligands: synthesis, anticancer activity, apoptosis and thioredoxin reductase inhibition.

Gold(I) complexes of imidazole and thiazole-based diphos type ligands were prepared and their potential as chemotherapeutics investigated. Depending on the ligands employed and the reaction conditions complexes [L(AuCl)(2)] and [L(2)Au]X (X = Cl, PF(6)) are obtained. The ligands used are diphosphanes with azoyl substituents R(2)P(CH(2))(2)PR(2) {R = 1-methylimidazol-2-yl (1), 1-methylbenzimidazol-2-yl (4), thiazol-2-yl (5) and benzthiazol-2-yl (6)} as well as the novel ligands RPhP(CH(2))(2)PRPh {R = 1-methylimidazol-2-yl (3)} and R(2)P(CH(2))(3)PR(2) {R = 1-methylimidazol-2-yl (2)}. The cytotoxic activity of the complexes was assessed against three human cancer cell lines and a rat hepatoma cell line and correlated to the lipophilicity of the compounds. The tetrahedral gold complexes [(3)(2)Au]PF(6) and [(5)(2)Au]PF(6) with intermediate lipophilicity (logD(7.4) = 0.21 and 0.25) showed significant cytotoxic activity in different cell lines. Both compounds induce apoptosis and inhibit the enzymes thioredoxin reductase and glutathione reductase.

Gold(I) catalysts with bifunctional P, N ligands.

A series of phosphanes with imidazolyl substituents were prepared as hemilabile PN ligands. The corresponding gold(I) complexes were tested as bifunctional catalysts in the Markovnikov hydration of 1-octyne, as well as in the synthesis of propargylamines by the three component coupling reaction of piperidine, benzaldehyde, and phenylacetylene. While the activity in the hydration of 1-octyne was low, the complexes are potent catalysts for the three component coupling reaction. In homogeneous solution the conversions to the respective propargylamine were considerably higher than under aqueous biphasic conditions. The connectivity of the imidazolyl substituents to the phosphorus atom, their substitution pattern, as well as the number of heteroaromatic substituents have pronounced effects on the catalytic activity of the corresponding gold(I) complexes. Furthermore, formation of polymetallic species with Au(2), Au(3), and Au(4) units has been observed and the solid-state structures of the compounds [(5)(2)Au(3)Cl(2)]Cl and [(3c)(2)Au(4)Cl(2)]Cl(2) (3c = tris(2-isopropylimidazol-4(5)-yl phosphane, 5 = 2-tert-butylimidazol-4(5)-yldiphenyl phosphane) were determined. The gold(I) complexes of imidazol-2-yl phosphane ligands proved to be a novel source for bis(NHC)gold(I) complexes (NHC = N-heterocyclic carbene).

[(C3H4N2)2Au]Cl--a bis protic gold(I)-NHC.

The gold(I) bis-NHC (NHC = imidazol-2-ylidene) parent compound was synthesised in high yield by a three step reaction starting from imidazole. The compound is highly water soluble and stable in concentrated hydrochloric acid.

The betainic form of (imidazol-2-yl)phenylphosphinic acid hydrate.

Single crystals of the title compound, (imidazolium-2-yl)phenyl-phosphinate monohydrate, C(9)H(9)N(2)O(2)·H(2)O, were ob-tained from methanol/water after deprotection and oxidation of bis-(1-diethoxy-methyl-imidazol-2-yl)phenyl-phosphane. In the structure, several N-H⋯O and P-O⋯H-O hydrogen bonds are found. π-π inter-actions between the protonated imidazolyl rings [centroid-centroid distance = 3.977 (2) Å] help to establish the crystal packing. The hydrate water mol-ecule builds hydrogen bridges to three mol-ecules of the phosphinic acid by the O and both H atoms.

A new crystal modification of diammonium hydrogen phosphate, (NH(4))(2)(HPO(4)).

The addition of hexa-fluorido-phosphate salts (ammonium, silver, thallium or potassium) is usually used to precipitate complex cations from aqueous solutions. It has long been known that PF(6) (-) is sensitive towards hydrolysis under acidic conditions [Gebala & Jones (1969 ▶). J. Inorg. Nucl. Chem.31, 771-776; Plakhotnyk et al. (2005 ▶). J. Fluorine Chem.126, 27-31]. During the course of our investigation into coinage metal complexes of diphosphine ligands, we used ammonium hexa-fluorido-phosphate in order to crystallize [Ag(diphos-phine)(2)]PF(6) complexes. From these solutions we always obtained needle-like crystals which turned out to be the title compound, 2NH(4) (+)·HPO(4) (2-). It was received as the hydrolysis product of NH(4)PF(6). The crystals are a new modification of diammonium hydrogen phosphate. In contrast to the previously published polymorph [Khan et al. (1972 ▶). Acta Cryst. B28, 2065-2069], Z' of the title compound is 2. In the new modification of the title compound, there are eight mol-ecules of (NH(4))(2)(HPO(4)) in the unit cell. The structure consists of PO(3)OH and NH(4) tetra-hedra, held together by O-H⋯O and N-H⋯O hydrogen bonds.

Imidazole-based phosphane gold(I) complexes as potential agents for cancer treatment: synthesis, structural studies and antitumour activity.

The reaction of the imidazolyl-4(5)-phosphane ligands 2-isopropylimidazol-4(5)yl-diphenylphosphane (4-MIP(iPr)) and tris(2-isopropylimidazol-4(5)yl)phosphane (4-TIP(iPr)) towards gold(I) has been explored and compared to those of analogous 1-methylimidazol-2-ylphosphane ligands. The structure of [(4-MIP(iPr))AuCl] () shows a linear P-Au-Cl coordination, whereas the 4-TIP(iPr) ligand forms a dinuclear complex [{(4-TIP(iPr))Au}(2)]Cl(2) (). Here, 4-TIP(iPr) bridges two gold(I) atoms in a head-to-tail P,N fashion. Complex forms in the presence of the hard Lewis acid ZnCl(2) the bimetallic complex [AuCl(4-TIP(iPr))ZnCl]Cl (), in which 4-TIP(iPr) bridges the two metal centers. In accordance with the HSAB concept the Au(I) atom is coordinated by the P atom and the zinc(II) by three N atoms in a N,N,N fashion. The solid-state structures of the complexes have been elucidated by single-crystal X-ray analysis. The Au(I)-Au(I) contact in is 2.8821(15) A. The biological activities of all imidazol-2-yl- and imidazol-4(5)-ylphosphane gold(I) complexes towards nine human cancer cell lines including seven ovarian cancer cell lines of different sensitivity towards cisplatin and two leukemia cell lines have been explored.