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A previous Delphi survey from the Rational Use of Analgesics (RUA) project involving Italian palliative care specialists revealed some discrepancies between current guidelines and clinical practice with a lack of consensus on items regarding the use of strong opioids in treating cancer pain. Those results represented the basis for a new Delphi study addressing a better approach to pain treatment in patients with cancer. The study consisted of a two-round multidisciplinary Delphi study. Specialists rated their agreement with a set of 17 statements using a 5-point Likert scale (0 = totally disagree and 4 = totally agree). Consensus on a statement was achieved if the median consensus score (MCS) (expressed as value at which at least 50% of participants agreed) was at least 4 and the interquartile range (IQR) was 3–4. This survey included input from 186 palliative care specialists representing all Italian territory. Consensus was reached on seven statements. More than 70% of participants agreed with the use of low dose of strong opioids in moderate pain treatment and valued transdermal route as an effective option when the oral route is not available. There was strong consensus on the importance of knowing opioid pharmacokinetics for therapy personalization and on identifying immediate-release opioids as key for tailoring therapy to patients’ needs. Limited agreement was reached on items regarding breakthrough pain and the management of opioid-induced bowel dysfunction. These findings may assist clinicians in applying clinical evidence to routine care settings and call for a reappraisal of current pain treatment recommendations with the final aim of optimizing the clinical use of strong opioids in patients with cancer.

J. CHEM. SOC., DALTON TRANS.

In the present study, energy densities of 80 adult brown trout (Salmo trutta), seasonally sampled in an alpine stream in the eastern Alps and energy densities of their main prey items, were determined. The energy density (J/g wet mass) and dry weight content (%) of fish were highly correlated (p

The monocarbonyl Ru(II)–dmso precursor cis,cis,trans-RuCl2(dmso-S)2(dmso-O)(CO) (1) equilibrates slowly in light protected chloroform solution with two new geometrical isomers of formula cis,cis,cis-RuCl2(dmso-S)2(dmso-O)(CO) (2) and cis,mer-RuCl2(dmso-S)3(CO) (3). The three isomers have similar stabilities in solution. In 2 and 3 the three sulfoxides are in a meridional geometry, with the CO ligand coordinated trans to one of the cis chlorides. The new complexes 2 and 3 differ only in the coordination mode of one of the two trans sulfoxides: they are both S-bonded in 3, while one is S-bonded and the other O-bonded in 2. Thus 2 and 3 are linkage isomers of each other. The three isomers 1–3 are also obtained as a mixture by treatment of cis-RuCl2(dmso)4 with CO. The spectroscopic characterization of the new compounds 2 and 3 is reported, together with the X-ray structure of 2. Isomer 2 is the first example of a Ru(II)–CO complex in which coordination through the oxygen atom is found for a dmso that is not trans to CO; isomer 3 is the first example of a Ru(II)–dmso complex featuring three S-bonded dmso ligands with a meridional geometry. Considerations relating the stability of the three isomers to their geometry and to the binding mode of the dmso ligands are reported.

The stereochemistry of a new class of models of the vitamin B12 system, containing tridentate pyridyl-imino-oxime [C6H5N(CH2)nNC(CH3)C(CH3)NO−; n = 1, L1; n = 2, L2] and pyridyl-amino-oxime [C6H5N(CH2)nNHCH(CH3)C(CH3)NO−; n = 1, L3; n = 2, L4] ligands, has been investigated through molecular mechanics calculations based on a specific force field. It is shown that, among all the possible diastereomers of the imino complexes [Co(L1,2)2]+, the minimum strain energy is exhibited in a mer configuration. For the amino complexes [Co(L3,4)(HL3,4)]2+, the minimum is exhibited in a fac configuration, with the amino nitrogen atoms all having the same chirality, opposite to that of the adjacent carbon atoms. Furthermore, comparison of the effect of five- (L1, L3) or six-membered (L2, L4) chelate rings on the complexes indicates that the strain energy decreases upon passing from L1 to L2 complexes, while it increases upon passing from L3 to L4 complexes. The effect of rotation around the axial pyridyl Co−N bond on the coordination geometry has also been studied through a conformational analysis of the methyl (R = Me) and adamantyl (R = Adam) organocobalt derivatives [RCo(L4)(HL4)]+. The most important result is that the rotation is rather hindered in the case of the bulky Adam group, while in the Me case the pyridyl group can rotate across a wide angular range. In both cases, the rotation causes a significant change in the Co−N bond length, while the Co−C distance is almost unaffected. It is also shown that the aromatic base is oriented with respect to the equatorial ligand in a fashion quite different from other B12 models. (© Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002)

Compounds with hydroxyl ammonium cations, [RR′NHOH][ fac -RuCl 3 (dmso–S) 3 ], with R=R′=H ( 1 ), R=Me, R′=H ( 2 ) and R=R′=Et ( 3 ), have been prepared and structurally characterized by X-ray analyses. The three compounds display chain-like structures, formed by hydrogen bonding between the hydroxyl ammonium cations and the chlorine and oxygen atoms of the ruthenium anion. H-bonding involving the dmso oxygen atoms causes a lengthening of the S–O bonds. The comparison of the solid state structures with results of Molecular Mechanics calculations show that the arrangement of the fac -dmso–S ligands is not determined by H-bonding or packing effects, but from intramolecular steric and electrostatic interactions. These give rise to hindered rotation about the Ru–S bonds.

The first crystal structure of a copper(II) complex containing a disulfoxide is reported. The 1,3-bis(n-propylsulfinyl)propane ligand acts as a bis(monodentate) ligand bridging the metal ions through its oxygen atoms to form layers of distorted square planar CuO4 groups (Cu–O, 1.942(3) A) connected by nPrS(CH2)3SnPr bridges (S–O, 1.533(5) A), with homochiral sulfur atoms. Each copper atom achieves a square pyramidal coordination, interacting with the oxygen atom of one perchlorate ion (Cu–O, 2.36(2) A). Crystals consist of a racemic mixture of layers of opposite chirality, held together essentially by van der Waals forces.

The three-dimensional structures of the native cytochrome c(2) from Rhodopseudomonas palustris and of its ammonia complex have been obtained at pH 4.4 and pH 8.5, respectively. The structure of the native form has been refined in the oxidized state at 1.70 A and in the reduced state at 1.95 A resolution. These are the first high-resolution crystal structures in both oxidation states of a cytochrome c(2) with relatively high redox potential (+350 mV). The differences between the two oxidation states of the native form, including the position of internal water molecules, are small. The unusual six-residue insertion Gly82-Ala87, which precedes the heme binding Met93, forms an isolated 3(10)-helix secondary structural element not previously observed in other c-type cytochromes. Furthermore, this cytochrome shows an external methionine residue involved in a strained folding near the exposed edge of the heme. The structural comparison of the present cytochrome c(2) with other c-type cytochromes has revealed that the presence of such a residue, with torsion angles phi and psi of approximately -140 and -130 degrees, respectively, is a typical feature of this family of proteins. The refined crystal structure of the ammonia complex, obtained at 1.15 A resolution, shows that the sulphur atom of the Met93 axial ligand does not coordinate the heme iron atom, but is replaced by an exogenous ammonia molecule. This is the only example so far reported of an X-ray structure with the heme iron coordinated by an ammonia molecule. The detachment of Met93 is accompanied by a very localized change in backbone conformation, involving mainly the residues Lys92, Met93, and Thr94. Previous studies under typical denaturing conditions, including high-pH values and the presence of exogenous ligands, have shown that the detachment of the Met axial ligand is a basic step in the folding/unfolding process of c-type cytochromes. The ammonia adduct represents a structural model for this important step of the unfolding pathway. Factors proposed to be important for the methionine dissociation are the strength of the H-bond between the Met93 and Tyr66 residues that stabilizes the native form, and the presence in this bacterial cytochrome c(2) of the rare six-residue insertion in the helix 3(10) conformation that increases Met loop flexibility.

Diastereomeric meso and rac forms of 1,3-bis(n-propylsulfinyl)propane (BPSP) and 1,2-bis(methylsulfinyl)ethane (BMSE) have been separated and treated with Cu(ClO4)2 to obtain [trans-Cu(meso-BPSP)2(H2O)2](ClO4)2 (2) trans-Cu(meso-BMSE)2(ClO4)2 (3) and trans-Cu(rac-BMSE)2(ClO4)2 (4). The configurational assignment to BPSP has been performed by single crystal X-ray analysis, showing that the α (m.p. 139.0–139.9 °C) and β (m.p. 107.0–107.6 °C) forms correspond to the meso and rac isomers, respectively. Enthalpies of fusion, determined by differential scanning calorimetry techniques, are 34.3 (meso-BMSE), 22.2 (rac-BMSE), 40.6 (meso-BPSP), and 35.1 kJ mol−1 (rac-BPSP). Single crystals, acceptable for X-ray diffraction studies, were grown by the hanging-drop method of vapor diffusion and micro-seeding techniques. The crystal structure of meso-BPSP (1) is characterized by an anti conformation of the propane bridge. The two sulfinyl bonds (av. SO bond distance, 1.487(4) A) are nearly parallel. In fact, the S→O vectors form an angle of 2.3° and the pseudo-torsion angle OS⋯SO is of 2.2°. Crystals belong to the C2/c space group, with a=32.285(11), b=5.315(5), c=15.232(7) A, β=109.98(3)°. The structure was refined to R=0.092. Crystal data for the copper complexes are space group P2/n, a=13.914(7), b=7.834(4), c=14.805(11) A, β=96.61(5)° for 2; space group P21/c, a=7.348(7), b=17.892(4), c=8.620(2) A, β=113.06(2)° for 3; space group P21/a, a=8.343(3), b=12.337(6), c=9.390(3) A, β=97.35(3)° for 4. The structures were refined to R=0.066, 0.062, and 0.097 for 2, 3, and 4, respectively. The crystal structures of the meso Cu(II) complexes 2 and 3 are characterized by linear chains of copper atoms, bridged by two disulfoxide molecules acting as bis-monodentate O-ligands. In the rac complex 4, BMSE acts again as a μ2-O,O ligand, but forms layers with a net structure containing four copper atoms per mesh, and each layer contains sulfur atoms with both R and S chirality. In the copper complexes the mean SO bond length is of 1.520(3) A, confirming the already observed increase in comparison to free sulfoxides.

Reaction of trans-[OsCl2(Me2SO)4] 1 with excess N2H4·2HCl leads to the osmium(III) compound mer-[OsCl3(NH3)2(Me2S)] 2 in the course of concerted reactions, i.e. oxidation of the metal, deoxygenation of the sulfoxide, disproportionation of hydrazine and substitution by NH3. In contrast, interaction of cis-[RuCl2(Me2SO)4] cis-3 with hydrazine dihydrochloride brings about easy substitution (without redox conversion) leading to mer-[RuCl3(N2H5)(Me2SO)2] 4 which is a rare example of a hydrazinium complex. X-Ray single-crystal diffraction analyses were performed on 1, 2 and 4. In 4, one Ru–S bond is unusually short due to the enhanced π bonding contribution as a result of an intramolecular H-bond between the Me2SO and the cis N2H5+ group. The complexes show anodic oxidations and 4, that in aqueous medium undergoes spontaneous dehydrochlorination, exhibits by controlled potential electrolysis a multi-electron oxidation process with anodically-induced H+ loss, oxidation of the hydrazine ligand to N2 and N-oxides, and of Me2SO to SO2. The anodic waves of Me2SO or H2O solutions of cis-3 were assigned to trans-[RuCl2(Me2SO-S )4] trans-3 and [RuCl(H2O)2(Me2SO-S )3]+, respectively. The oxidation potential values were interpreted on the basis of redox potential–structure relationships and the Lever electrochemical parameter EL was tentatively estimated for both S- and O-coordinated Me2SO and for the hydrazinium ligand, showing that Me2SO-S in our complexes behaves as a significant π-electron acceptor and N2H5+ as a rather weak net electron donor, and applied to predict the oxidation potential of some Ru and Os complexes.