Nanoparticles derived from amphiphilic γ-cyclodextrins

Three alkylcarbonates of γ-cyclodextrin, i.e. hexyl, octyl and dodecylcarbonate, were synthesized and characterized, with the goal of formulating solid nanoparticles. The series of alkylcarbonates showed amphiphilic properties and were capable of forming micelles and nanoparticles. Blank and drug-loaded alkylcarbonate nanoparticles were prepared with each alkylcarbonate, using the solvent injection technique. Progesterone was chosen as model drug. The sizes of both unloaded and loaded nanoparticles were in the 80–200 nm range, with narrow size distribution and spherical shape, as shown by TEM analysis. The zeta potentials of unloaded nanoparticles were in the −20 to −24.0 mV range, and were slightly decreased in loaded nanoparticles. Drug-loading capacity was good; DSC analysis did not detect the progesterone melting peak, indicating the drug had interacted with the cyclodextrin alkylcarbonates. In vitro release kinetics of progesterone from the three types of nanoparticles were slow. These results indicate that γ-CD alkylcarbonate nanoparticles might be used as prolonged drug delivery system.     

New Bimetallic Ni–Rh Carbonyl Clusters: Synthesis and X-ray Structure of the [Ni7Rh3(CO)18]3?, [Ni3Rh3(CO)13]3? and [NiRh8(CO)19]2? Cluster Anions

The reaction of the [Ni₆(CO)₁₂]²⁻ dianion with [Rh(COD)Cl]₂ (COD = cyclooctadiene) in acetone affords a mixture of bimetallic Ni–Rh clusters, mainly consisting of the new [Ni₇Rh₃(CO)₁₈]³⁻ and [Ni₈Rh(CO)₁₈]³⁻ trianions. A study of the reactivity of [Ni₇Rh₃(CO)₁₈]³⁻ led to isolation of the new [Ni₃Rh₃(CO)₁₃]³⁻ and [NiRh₈(CO)₁₉]²⁻ anions. All these new bimetallic Ni–Rh carbonyl clusters have been isolated in the solid state as tetrasubstituted ammonium salts and have been characterised by elemental analysis, X-ray diffraction studies, ESI-MS and electrochemistry. The unit cell of the [NEt₄]₃[Ni₇Rh₃(CO)₁₈] salt contains two orientationally-disordered ν₂-tetrahedral [Ni₇Rh₃(CO)₁₈]³⁻ trianions with occupancy factors of 0.75 and 0.25. Besides, their inner Ni₃Rh₃ octahedral moieties show two cis sites purely occupied by Rh atoms, two trans sites purely occupied by Ni atoms and the remaining two cis sites are disordered Ni and Rh sites with respective occupancy fraction of 0.5. At difference from the parent [Ni₇Rh₃(CO)₁₈]³⁻, the octahedral [Ni₃Rh₃(CO)₁₃]³⁻ displays an ordered distribution of Ni and Rh atoms in two staggered triangles. The [NiRh₈(CO)₁₉]²⁻ dianion adopts an isomeric metal frame with respect to that of the [PtRh₈(CO)₁₉]²⁻ congener. As a fallout of this work, new high-yield synthesis of the known [Ni₆Rh₃(CO)₁₇]³⁻ and [Ni₆Rh₅(CO)₂₁]³⁻, as well as other currently-investigated bimetallic Ni–Rh clusters have been obtained.     

Novel Hydroxyicosatetraenoic and Hydroxyicosapentaenoic Acids and a 13-Oxo Analog. Isolation from a Mixture of the Calcareous Red Algae Lithothamnion corallioides and Lithothamnion calcareum of Brittany Waters

A mixture of the red calcareous algae Lithothamnion corallioides CROUAN and Lithothamnion calcareum (PALLAS ) ARESCHOUGH , from Brittany waters, gives, on ethanolic extraction, the novel icosanoids ethyl 13-hydroxy-arachidonate (=(+)-all-Z-ethyl 13-hydroxyicosa-5,8, 11,14,-tetraenoate; (+)- 1 )), ethyl 13-hydroxytimnodonate (=(+)-(all-Z)-ethyl 13-hydroxyicosa-5,8,11,14,17-pentaenoate ((+)- 2 ), and (5Z,9E,11E,14E)-ethyl 8-hydroxy-13-oxoicosa-5,9,11,14-tetraenoate ( 3 ). Moreover, the ethyl esters of four known icosatetraenoic acids are contained in the above algae. Structural elucidations of these metabolites are based mainly on NMR data.     

New approach to the chemistry of technetium(V) and rhenium(V) phenylimido complexes: novel [M(NPh)PNP]3+ metal fragments (M = Tc, Re; PNP = aminodiphosphine) suitable for the synthesis of stable mixed-ligand compounds

Ligand-exchange reactions of the aminodiphosphine ligand bis[(2-diphenylphosphino)ethyl]amine hydrochloride (PNHP x HCl) with labile M(NPh)Cl3(PPh3)2 precursors (M = Re, Tc) in the presence of triethylamine yield monocationic phenylimido mer,cis-[M(NPh)Cl2(PNHP)]Cl (M = Re, 1; Tc, 2) intermediate complexes. X-ray analyses show that in both compounds the aminodiphosphine acts as a tridentate ligand dictating a mer,cis arrangement. Two chloride ligands, respectively in an equatorial and in the axial position trans to the linear M-NPh moiety, fill the remaining positions in a distorted-octahedral geometry. The chloride trans to the metal-imido core is labile, and is replaced by an alcoholate group, without affecting the original geometry, as established in mer,cis-[Re(NPh)(OEt)Cl(PNHP)]Cl 4. Otherwise, ligand-exchange reactions involving the aminodiphosphine bis[(2-diphenylphosphino)ethyl]methylamine (PNMeP), in which the central secondary amine has been replaced by a tertiary amine function, or its hydrochloride salt (PNMeP x HCl) give rise to three different species, depending on the experimental conditions: fac,cis-[Re(NPh)Cl2(PNMeP)]Cl 3a, cis,fac-Re(NPh)Cl3(PNMeP) x HCl 3b, and mer,trans-[Re(NPh)Cl2(PNMeP)]Cl 3c, which are characterized in solution by multinuclear NMR studies. The monodentate groups incorporated in these intermediate compounds, either halides and/or ethoxide, undergo substitution reactions with bidentate donor ligands such as catechol, ethylene glycol, and 1,2-aminophenol to afford stable mixed ligand complexes of the type [M(NPh)(O,O-cat)(PNP)]Cl [PNP = PNHP M = Re 5, Tc 6; PNP = PNMeP M = Re 7], [Re(NPh)(O,O-gly)(PNP)]Cl [PNP = PNHP 8, PNMeP 9] and [Re(NPh)(O,N-ap)(PNMeP)]Cl 10. X-ray diffraction analyses of the representative compounds 5 and 8 reveal that the aminodiphosphine switches from the meridional to the facial coordination mode placing the heteroatom of the diphosphine trans to the phenylimido unit and the bidentate ligand in the equatorial plane. Solution-state NMR studies suggest an analogous geometry for 6, 7, 9, and 10. Comparison with similar mixed ligand complexes including the terminal nitrido group is discussed.     

Ion–molecule reactions by chemical ionization: Determination of rate constants

Tungsten hexacarbonyl was studied by chemical ionization mass spectrometry using carbon monoxide as reagent gas. The variation of the relative abundances of ions as a function of reactant gas pressure was used for evaluating the relative rate constants for consecutive reactions. The results are in agreement with the rate constant ratios obtained from ion trap mass spectrometric data.     

Electrospray ionization mass spectrometry for identification and structural characterization of pregnane glycosides

Pregnane glycosides are a class of naturally occurring substances characterized by some interesting biological activities and widely distributed in the plant kingdom and in some marine organisms. Their toxicity and use in herbal drugs and folk medicines has generated great interest in the chemical characterization of these molecules. In the study reported here the potential of electrospray ionization mass spectrometry (ESI-MS) in the identification and structural characterization of pregnane glycosides was examined. ESI-MS/MS and ESI-MS(n) analyses were performed on 27 different compounds employing two mass spectrometers equipped with a triple-quadrupole or an ion-trap analyzer. The data illustrate the ability of the ESI techniques in the identification of pregnane glycosides, including the nature of the pregnane core, the kind of ester substituents, the types of sugar residues (hexose, deoxyhexose, dideoxyhexose, O-methyldeoxyhexose and O-methyldideoxyhexose), and the primary structure of the saccharide chain. From these data, a generalized fragmentation pathway was proposed by comparing the spectra acquired for all the compounds. Interestingly, similar results were obtained from the two instruments, thus demonstrating that detailed analyses of product ion spectra obtained using a triple-quadrupole mass spectrometer led to structural information comparable to those obtainable in MSn experiments using an ion trap. Different and complementary information was deduced by fragmenting the [M+H]+ or the [M+Na]+ ions, or the protonated aglycone [Agl+H]+ generated by in-source fragmentation. The present evidence clearly suggests that, in order to obtain a complete characterization of pregnane glycosides by MS, all three of these species should be accurately analyzed.     

Determination of endogenous and synthetic glucocorticoids in human urine by gas chromatography-mass spectrometry following microwave-assisted derivatization

A complete screening and confirmation analytical method for the direct determination of six endogenous (cortisol, cortisone, deoxycorticosterone, tetrahydrocortisol, tetrahydrocortisone, tetrahydro-S) and 17 synthetic (amcinonide, betamethasone, desoximethasone, dexamethasone, fludrocortisone, flumethasone, flunisolide, flucinolone acetonide, flucinonide, fluprednisolone, flurandrenolide, fluorometholone, 6-methylprednisolone, prednisolone, prednisone, triamcinolone, triamcinolone acetonide) glucocorticoids in human urine by gas chromatography with mass spectrometric detection (GC-MS) is presented.The analytical technique comprises a pre-treatment procedure and the instrumental analysis of the trimethylsilyl (TMS) derivatives, performed by GC-MS (quadrupole) with electron impact (EI) ionization. The derivatization yields obtained by two different derivatizing mixtures, namely N-methyl-N(trimethylsilyl)trifluoroacetamide (MTSFA):NH₄I:dithioerythritol (DTE) 1000:2:4 (usually indicated as TMSiodine); and N-trimethylsilylimidazole (TMSim):N,O-bis(trimethylsilyl)acetamide (BSA):trimethylchlorosilane (TMCS) 3:3:2, both under direct thermal heating and with microwave (MW) irradiation, were evaluated, also as a function of the temperature, of the MW power and of the incubation time.The highest yields of the derivatization process were obtained, for most of the compounds here considered, by a two-step procedure: a microwave-assisted derivatization stage (40 min in a microwave oven at 900 W emitted power), followed by a traditional heat transfer derivatization (1.5 h in a thermostated bath at 70 °C) with the derivatization mixture TMSim:BSA:TMCS 3:3:2. In these operating conditions, diagnostic EI-MS spectra of all considered glucocorticoids were obtained. Limits of detection (LOD) of synthetic glucocorticoids in urine ranged from 3 to 25 μg/l. The effectiveness of the method for the determination of glucocorticoids in urine was evaluated on spiked urine samples and on real samples obtained from patients under pharmacological treatment with synthetic glucocorticoids.Apart from the clinical monitoring of glucocorticoids in urine, the method can be applied as a complete screening + confirmation analytical protocol in antidoping tests for the detection of illicit administration of glucocorticoids by the athletes.     

Complexes of zinc(II), cadmium(II) and mercury(II) halides with ethylenselenourea

Summary Reaction of zinc(II), cadmium(II) and mercury(II) halides with ethylenselenourea yields complexes of general formula ML₂X₂ where X = Cl, Br, I. On the basis of an i.r. comparison of these complexes and their ethylenthiourea analogues in the 4000-200 cm^–1 range, it appears that the ethylenselenourea complexes are monomeric, tetrahedral and Se-bonded to the metals. The metal-halogen and metal-ligand vibrations above 200 cm^–1 are identified.This work was supported by the National Research Council (C.N.R.) of Italy.     

Cytotoxic trans-oriented platinum complexes only form adducts with single-stranded oligodeoxynucleotides

The reactions of the anticancer complex trans-[PtCl(2)[(E)-HN==C(OMe)Me](2)] (trans-EE) with both single-stranded and double-stranded deoxyribonucleotides have been studied by HPLC and 2D [(1)H,(15)N] HMQC NMR spectroscopy and compared with those of cis-[PtCl(2)(NH(3))(2)] (cis-DDP). Reactions of trans-EE with the single-stranded oligonucleotides d(CCTCGCTCTC) and d(CCTGGTCC) proceed rapidly through solvolysis of the starting substrate and subsequent formation of G-N7/monochloro trans-EE adducts. The rate of reaction is comparable to that of formation of an adduct from trans-EE and the dinuclotide d(ApG). Quite unexpectedly, the double-helical duplexes, d(TATGGTACCATA)(2) and d(TATGGCCATA)(2), with no terminal G residues, are practically inert towards trans-EE, and only minor species (< 5 % as estimated from HPLC traces) appear during 24 h reaction time. However, the duplexes d[(CCTCGCTCTC). (GAGAGCGAGG)] and d(GATAGGCCTATC)(2), which contain both terminal and central G residues, undergo platination only at the terminal, solvent-exposed, G residues, thereby confirming that the interior of the duplex is not accessible to trans-EE due to steric hindrance. In contrast, cis-DDP was found to bind exclusively to the central GG pair in d(GATAGGCCTATC)(2).     

Photoinduced Double Addition of Acetylene to 3-Oxocyclopent-1-ene-1-carbonitrile or 3-oxocyclopent-1-enyl acetate leading to 2,3-dihydro-1H-inden-1-one and other rearranged products

UV Irradiation of 3-oxocyclopent-1-enyl acetate ( 17 ) and acetylene in MeCN at 0° gives, besides the product of normal enone-alkyne [2 + 2] cycloaddition (cis-4-oxobicyclo[3.2.0] hept-6-en-1-yl acetate, 18 ) and its product of oxa-di-π-methane rearrangement (5-oxotricyclo[4.1.0.0^2,7]hept-2-yl acetate, 19 ), unexpected products of further addition of a molar equivalent of acetylene. These are indanone ( = 2,3-dihydro-1H-inden-1-one, 16 ), in 21% yield, cis-1-cisoid-1,2-cis-2- ( 20 ) and cis-1-transoid-1,2-cis-2-7-oxotricyclo[4.3.0.0^2,5]non-3-en-1-yl acetate ( 21 ), 4-oxo-7-‘exo’-vinyltricyclo[3.2.0.0^2,6]hept-2-yl acetate ( 22 ), cis-4-oxo-6-‘endo’- ( 23 ) and cis-4-oxo-6-‘exo’-vinylbicyclo[3.2.0]hept-1-yl acetate ( 24 ), and cis-4-oxo-7-‘exo’-vinylbicyclo[3.2.0]hept-1-yl acetate ( 25 ). At least in part, indanone must be formed via intermediates 20 and 21 . In fact, on heating a 9:1 mixture 20/21 , indanone is obtained quantitatively. With 3-oxocyclopent-1-ene-1-carbonitrile ( 15 ) in place of 17 , indanone is formed in lower (8%) yield besides much tars.