Synthesis and characterization of [Pt(COD)Cl(NO3)] and [Pt(COD)(NO3)2] and the use of [Pt(COD)Clx(NO3)2−x] in the preparation of cis[Pt(PPh3)2Clx(NO3)2−x] (x=0, 1, 2) and [Pt(PPh3)3L](NO3) (L=Cl,NO3)

[Pt(COD)Cl₂] (COD=1,5-cyclooctadiene) is a versatile starting material for the synthesis of Pt(II) compounds. The preparations of the new compounds [Pt(COD)Cl(NO₃)], [Pt(COD)(NO₃)₂] and [Pt(PPh₃)₃(NO₃)](NO₃) and also of the known compounds cis[Pt(PPh₃)₂Cl₂], cis [Pt(PPh₃)₂Cl(NO₃)], cis[Pt(PPh₃)₂(NO₃)₂] and [Pt(PPh₃)₃Cl](NO₃)are reported. The compounds are characterized by elemental analysis, ³¹P{¹H} NMR spectroscopy and IR spectroscopy.     

Antagonists of 5-HT₆ receptors. Substituted 3-(phenylsulfonyl)pyrazolo[1,5-a]pyrido[3,4-e]pyrimidines and 3-(phenylsulfonyl)pyrazolo[1,5-a]pyrido[4,3-d]pyrimidines-Synthesis and 'structure-activity' relationship

Synthesis and biological evaluation of a new series of structurally unrestricted and intramolecular hydrogen bond restricted derivatives of 3-(phenylsulfonyl)pyrazolo[1,5-a]pyrido[3,4-e]pyrimidines (angular tricyclics) and 3-(phenylsulfonyl)pyrazolo[1,5-a]pyrido[4,3-d]pyrimidines (linear tricyclics) are described. Structurally restricted derivatives are highly potent and selective blockers of 5-HT(6) receptors with little difference between angular or linear shape of the tricyclic core, the angular species being only slightly more potent. The angular representative of 3-(phenylsulfonyl)pyrazolo[1,5-a]pyrido[3,4-e]pyrimidines, 5, can be considered as more favorable candidate for further development as it shows only weak 5-HT(2B) blocking activity (IC(50)=6.16 μM as compared with IC(50)=1.8 nM for 5-HT(6) receptors) and very low hERG potassium channel blocking potency (IC(50)=54.2 μM). The linear analog, 11, is less favorable as while showing no binding to the 5-HT(2B) receptor at concentrations of up to 10 μM, it exhibits quite a high potency to block the hERG channel (IC(50)=0.5 μM).     

The tungsten(IV) aqua ion; reduction studies and detection of aquachloro complexes of [W3(μ3-O)(μ2-O)3]4+ by oxygen-17 and tungsten-183 NMR spectroscopy

Oxygen-17 and tungsten-183 NMR studies on solutions of orange tungsten(IV), prepared in 2 M p-toluenesulphonic acid (Hpts) solution via acid catalyzed hydrolysis of potassium hexachlorotungstate(IV) in 2 M Hpts followed by treatment with a single DOWEX 50W X2 cation-exchange column, confirm the formation of the species; [W₃(μ₃-O)(μ₂-O)₃(OH₂)₈Cl]³⁺ as major product in addition to [W₃(μ₃-O)(μ₂-O)₃(OH₂)₉]⁴⁺ under these conditions in a manner not possible by spectrophotometric means. Further characterization of the green W(III,III,IV) mixed-valence reduction product has also been carried out with in addition an estimation of the formal reduction potential for the W(IV)₃/W(III,III,IV) redox couple.     

Synthesis of novel spiro[pyrazolo[4,3-d]pyrimidinones and spiro[benzo[4,5]thieno[2,3-d]pyrimidine-2,3′-indoline]-2′,4(3H)-diones and their evaluation for anticancer activity

An efficient and novel method for the preparation of spiro[pyrazolo[4,3-d]pyrimidin]-7′(1′H)-ones by the condensation of 4-amino-1-methyl-3-propylpyrazole-5-carboxamide with ketones under mild conditions using catalytic InCl₃ was reported. This method has been extended for the synthesis of novel spiro[benzo[4,5]thieno[2,3-d]pyrimidine-2,3′-indoline]-2′,4(3H)-dione which are having potential applications in medicinal chemistry. All the synthesized compounds were evaluated for their anti-proliferative properties in vitro against cancer cell lines and several compounds were found to be active. Further in vitro studies revealed that inhibition of sirtuins could be the possible mechanism of action of these molecules.     

Speciation of dimethyltin(IV) – and trimethyltin(IV) – carbocysteinate and – glutamate systems in aqueous media

Abstract

The formation of complex species in the dimethyltin(IV) and trimethyltin(IV)-carboxymethyl-L-cysteinate (carbocysteinate) systems in NaCl_aq, at different ionic strengths, and in a multicomponent Na⁺, K⁺, Ca²⁺ ,Mg²⁺, Cl^? and SO₄^2-? medium representative of the seawater major composition, is discussed. Experimental results give evidence for the formation of the following species (L = carbocysteinate): [(CH₃)₂Sn(L)]⁰, [(CH₃)₂Sn(HL)]⁺, [(CH₃)₂Sn(OH)(L)]^?, [(CH₃)₂Sn(OH)₂(L)]^2? in the DMT–CCYS system, and [(CH₃)₃Sn(HL)]⁰, [(CH₃)₃Sn(L)]^? and [(CH₃)₃Sn(OH)(L)]^2? in the TMT-CCYS system. The ionic strength dependence of formation constants was taken into account by an extended Debye Hückel type equation and by the SIT (Specific ion Interaction Theory). Measurements were carried out also on the dimethyltin(IV)-glutamate and trimethyltin(IV)-glutamate systems in NaCl_aq, owing the strict similarity of glutamate and carbocysteinate. Results obtained show the formation of complex species having the same stoichiometry as those formed in the DMT- and TMT-carbocysteinate systems, with very similar stability, confirming that carbocysteinate behaves as a dicarboxylic amino acid without involving the sulfur-bridge potential binding site in metal coordination.     

Synthesis and spectral properties of Zr(IV) and Hf(IV) phthalocyanines with β-diketonates as axial ligands

The series of new zirconium(IV) and hafnium(IV) phthalocyanines with various β-dicarbonyl ligands were prepared via direct interaction between di(chloro)zirconium(IV) or hafnium(IV) phthalocyanines and free β-diketones and also with 4-benzoyl-3-methyl-1-phenyl-2-pyrazolin-5-one. The structure of the obtained bis(β-dicarbonilato) zirconium(IV) and hafnium(IV) phthalocyanines was studied by two dimension ¹H NMR spectroscopy (COSY, NOESY, ROESY). Absorption and fluorescence spectroscopic studies have been investigated in various solvents. Analyzed compounds of concentration range below 10^?5 mol/dm³ do not aggregate in the organic solvents. Fluorescence quantum yields (Φ_F) and natural life times (τ) of zirconium phthalocyanine complexes have been calculated in toluene, DMSO and THF.     

Synthesis and characterization of tris(β-diketonato)technetium(III) and -(IV) complexes

The preparations and properties of tris(dipivaloylmethanato)technetium(III), tris(trifluoroacetylacetonato)technetium(III), and tris(hexafluoroacetonato)technetium(III) are described. The oxidation of the dipivaloyl derivative to tris(dipivaloyl)technetium(IV) hexafluorophosphate was shown to take place readily. Voltammetric studies and magnetic resonance results on the new complexes are reported. The large shifts observed for the complexes seem to be due to a contact interaction.     

RNA Modified Uridines VI: Conformations of 3-[3-(S)-Amino-3-Carboxypropyl]Uridine (acp3U) from tRNA and 1-Methyl-3-[3-(S)-Amino-3-Carboxypropyl]Pseudouridine (m1acp3Ψ) from rRNA

Abstract

The conformation of chemically synthesized acp³U is 60& 3′-endo, gauche⁺, whereas that of m¹acp³Ψ is 60& 2′-endo, gauche⁺. We conclude that the difference in conformation probably imparts important local structures to their respective tRNA and rRNA.     

Haloalkyl complexes of the transition metals. Part 5. The synthesis and reactions of some new pentamethylcyclopentadienyl halomethyl and methoxymethyl complexes of molybdenum(II) and tungsten(II) and the X-ray crystal structure of the cationic ylide complex [η-C5Me5W(CO)3CH2PPh3]I

Synthetic routes are described for the new halo- methyl complexes of the type [η-C₅Me₅M(CO)₃- CH₂X]. The complexes where M = Mo, X = Cl or OMe and M = W, X = Cl, I, OMe have been fully characterized. Reaction of [η-C₅Me₅Mo(CO)₃CH₂Cl] with PPh₃ in methanol under reflux or acetonitrile at room temperature gives [η-C₅Me₅Mo(CO)₂(PPh₃)- Cl], whereas reaction of [η-C₅Me₅W(CO)₃CH₂I] with PPh₃ under similar conditions gives the cationic phosphorus ylide complex [η-C₅Me₅W(CO)₃CH₂- PPh₃]I. The structure of this ylide complex has been determined by X-ray crystallography. The complex crystallizes with half a molecule of CH₂Cl₂ in the monoclinic space group P2₁/n with a = 16.616- (8), b = 11.738(6), c = 18.126(9) Å, β = 101.74(2)° and Z = 4. The structure was solved and refined to R = 0.076. It confirms the formulation of the compound and the presence of the ylide ligand, WC_ylide 2.34(2) Å, PC_ylide 1.82(2) Å and the WC_ylideP angle of 119(1)°.     

A new hydroxo-bridged thorium(IV) dimer: Preparation and structure of di-μ-hydroxo-bis[aquanitrato(2,6-diacetylpyridinedisemicarbazone)thorium(IV)] nitrate tetrahydrate

The pentadentate ligand 2,6-diacetylpyridinedisemicarbazone, DAPSC, reacts with Th(NO₃)₄ in ethanolwater mixture and a di-μ-hydroxo Th(IV) dimer is formed. The compound [Th₂(OH)₂(DAPSC)₂(NO₃)₂(H₂O)₂](NO₃)₄·4H₂O (I) is monoclinic, space group P2₁/n with a = 10.705(1), b = 19.008(2), c = 11.782(1) Å, β = 107.82(2)°, V = 2282(1) ų and Z = 2. Detailed X-ray structural analysis showed that each thorium atom in the complex is coordinated to one pentadentate DAPSC ligand, which is subjected to a considerable distortion, one bidentate nitrate group, one water ligand and two bridging hydroxo groups. The coordination number is ten and the best presentation of the polyhedron is that of a distorted bicapped square antiprism. The ThTh separation is 4.0181(6) Å and the average ThO(H) bridge is 2.366 Å. The structure was refined using 3185 reflections to an R value of 5.0%.     

The formation and reactivity of sulfito complexes of tetraethylenepentamine-cobalt(III): X-ray structure of αα-[co(tetren)SO3]ClO4

The synthesis of complexes of the type Co(tetren)-OH₂³⁺ (tetren = tetraethylenepentamine) and their reactions with sulfite to produce O- and S-bonded isomers were studied in detail. The linkage isomerization reaction of αβS-Co(tetren)OSO₂⁺ to αβS-Co(tetren)SO₃⁺ is accompanied by a geometrical isomerization to αα-Co(tetren)SO₃⁺. The latter species was isolated as pure crystals and an X-ray structure was determined. The structure data clearly show the strong trans effect of the sulfito ligand, which may account for the geometrical isomerization process.     

Comparison of Effects of DL-Threo-β-Benzyloxyaspartate (DL-TBOA) and L-Trans-Pyrrolidine-2,4-Dicarboxylate (t-2,4-PDC) on Uptake and Release of [3H]D-Aspartate in Astrocytes and Glutamatergic Neurons

Uptake and release processes in cerebellar astrocytes and granule neurons (glutamatergic) for glutamate were investigated by the use of [³H]D-aspartate, a non-metabolizable glutamate analog. The effects of DL-threo--benzyloxyaspartate (DL-TBOA) and L-trans-pyrrolidine-2,4-dicarboxylate (t-2,4-PDC) on uptake and release of [³H]D-aspartate were studied. Both compounds inhibited potently uptake of [³H]D-aspartate in neurons and astrocytes (IC₅₀ values 10-100 M), DL-TBOA being slightly more potent than t-2,4-PDC. Release of preloaded [³H]D-aspartate from neurons or astrocytes could be stimulated by addition of excess t-2,4-PDC whereas addition of DL-TBOA had no effect on [³H]D-aspartate efflux. Moreover, DL-TBOA inhibited significantly the depolarization-induced (55 mM KCl) release of preloaded [³H]D-aspartate in the neurons. The results reflect the fact that DL-TBOA is not transported by the glutamate carriers while t-2,4-PDC is a substrate which may heteroexchange with [³H]D-aspartate. It is suggested that DL-TBOA may be used to selectively inhibit depolarization coupled glutamate release mediated by reversal of the carriers.     

Differential expression of ·1(IV), ·2(IV), ·5(IV) and ·6(IV) collagen chains in the basement membrane of basal cell carcinoma

Type IV collagen, the major component of basement membrane, consists primarily of ·1(IV) and ·2(IV) chains. Recently, other types of collagen IV chains, i.e. ·3(IV), ·4(IV), ·5(IV) and ·6(IV) chains, have been identified by protein chemistry and molecular cloning. We have examined the diversity of the assembly of ·(IV) chains of the basement membrane surrounding tumour nests of basal cell carcinomas, in tissues from 11 patients, by immunohistochemical analysis using specific monoclonal antibodies to six ·(IV) chain. The immunostaining profile of each chain differed with respect to the histological subtypes of basal cell carcinoma. In the morphea-like subtype, which was more invasive, ·1(IV) and ·2(IV) chains were discontinuously stained, and ·5(IV) and ·6(IV) chains were entirely absent. However, in the superficial subtype, which was non-aggressive, ·1(IV), ·2(IV), ·5(IV) and ·6(IV) chains were well stained compared with the other subtypes of basal cell carcinoma. In addition, in the solid subtype, which showed slow growth and ulceration, ·1(IV) and ·2(IV) chains were continuously stained, and ·5(IV) and ·6(IV) chains were discontinuous or absent. The assembly of ·5(IV) and ·6(IV) chains into the basement membrane was inhibited in the solid and morphea subtypes of BCC. This differential expression of type IV collagen chains seems to be associated with the invasive potential of basal cell carcinoma This revised version was published online in November 2006 with corrections to the Cover Date.     

Synthesis and Biological Evaluation of 4-Amino-1-β-D-Ribofuranosylpyrrolo[3,2-c]Pyriding (3-Deazatubercidin)

Abstract

4-Amino-1-β-D-ribofuranosylpyrrolo[3,2-c]pyridine (3-deazatubercidin) has been synthesized in four steps by glycosylation of the anion of the 4,6-dichloro-1H-pyrrolo[3,2-c]pyridine with 1-chloro-2,3-O-isopropylidene-5-O-(t-butyl)dimethylsily 1-α-D-ribofuranose. 3-Deaza-tubercidin was found devoid of antitumor activity in vitro.     

Crystal structure and properties of [TTF]2.5[V(mnt)3 ]·0.5CH2ClCH2Cl[TTF = tetrathiafulvalene and mnt = 1,2-dicyanoethylene-1,2-dithiolate(2−)]

The title salt was obtained by a reaction of [TTF]₃ [BF₄]₂ (TTF = tetrathiafulvalene) with [NMe₄]₂ [V(mnt)₃] [mnt = 1,2-dicyanoethylene-1,2- dithiolate(2−)] in a mixture of 1,2-dichloroethane and acetonitrile (3:2 ν/ν). A single crystal X-ray analysis of it revealed a TTF columnar structure consisting of both TTF⁰ and the TTF^·+ radical cation and the distorted octahedral geometry of the [V(mnt)₃]²⁻ anion. The salt crystallizes in a monoclinic system, space group C2/c with unit cell constants a = 25.428(3), b = 12.434(2), c = 25.477(3) Å, β = 92.428(3)° and Z = 8. The structure was solved by the direct method and refined, on the basis of 3854 [|F_o| > 3σ(F)] observed data, to an R value of 0.078. The salt e`xhibits electrical conductivity of 1.7 x 10⁻⁴ S cm⁻¹ at 25°C for a compacted pellet.     

Synthesis and Biological Activity of the Novel Adenosine Analogs; 3-Amino-6-(β-D-ribofuranosyl)pyrazolo[3,4-c]pyrazole and 3-Amino-1-methyl-6-(β-D-ribofuranosyl)pyrazolo[3,4-c]pyrazole

Abstract

Chemical modification of the 4-nitrile group in 5-amino-1-(2,3,5-tri-O-benzyl-β-D-ribofuranosyl)pyrazole-4-carbonitrile (1) afforded 5-amino-4-(5-methyl-1,2,4-oxadiazol-3-yl)-1-(2,3,5-tri-O-benzyl-β-D-ribofuran osyl)pyrazole (3). The methylation of 3, via a three step procedure, gave 5-methylamino-4-(5-methyl-1,2,4-oxadiazol-3-yl)-1-(2,3,5-tri-O-benzyl-β-D-ribofuranosyl)pyrazole (3a). The mononuclear heterocyclic rearrangement (m.h.r) of 3 and 3a, provided a convenient route to the novel azapentalene adenosine analogs 3-amino-6-(β-D-ribofuranosyl)pyrazolo[3,4-c]pyrazole (6) and 3-amino-1-methyl-6-(β-D-ribofuranosyl)pyrazolo[3,4-c]pyrazole (6a), respectively. Compound 6 exhibited no cytotoxicity when screened in vitro against either mouse L1210 leukemic cells or human foreskin fibroblasts. Nor was it active against human cytomegalovirus. Compound 6a was designed and prepared to investigate the possibility that the lack of biological activity of 6 might be due to annular tautomerization limiting the ability of 6 to serve as a substrate for the activating enzyme adenosine kinase. This hypothesis was neither supported nor disproved by the results, as compound 6a was also inactive in both the antiproliferative and antiviral test systems.     

Complexes of large ring macrocycles. The preparation of the C-meso- and C-racemic-diastereoisomers of Me6[18]aneN4 and characterisation of their ‘blue’ and ‘red’ copper(II) complexes

The reaction of 1,4-diaminobutane monohydroperchlorate with acetone gives trans-Me₆[18]- dieneN₄·2HClO₄·2H₂O. The diene can be reduced with NaBH₄ under basic conditions to give a mixture of C-meso Me₆[18]aneN₄ (melting point (m.p.) 119–120 °C) and C-racemic Me₆[18]aneN₄ (m.p. 79 °C) which can be separated by fractional crystallisation from xylene (Me₆[18]aneN₄=2,4,4,11,13, 13-hexamethyl-1,5,10,14-tetraazacyclooctadecane). The free base form of Me₆[18]dieneN₄ has been characterised and molecular weight measurements by vapour pressure osmometry confirm the 18-membered tetraaza structure rather than the alternative 9- membered diaza structure. Blue copper(II) complexes [CuL](ClO₄)₂ have been characterised with both C- meso and C-racemic Me₆[18] aneN₄ which have a dd band at 680 nm. These blue complexes are converted to the more thermodynamically stable red isomers (λ_max 488 nm) on stirring aqueous suspensions of the blue perchlorate salts. The red isomers are believed to have the trans III or RSSR configuration of the sec- NH centres.     

Kinetics of [3H]prazosin and [3H]dihydroalprenolol binding to α1- and β-adrenoreceptors in rat brain cortex membranes

The binding of nonselective α₁- and β-adrenoreceptor antagonists [³H]prazosin and [³H]dihydroalprenolol ([³H]DHA) to rat cerebral cortex synaptosomal membranes has been studied. It is found that ligand-receptor interactions of α₁-adrenoreceptors fit into a single receptor pool model, which assumes the binding of two ligand molecules to one receptor molecule. The parameters of [³H]prazosin binding to α₁-adrenoreceptors are as follows: K _d = 2.58 ± 0.20 nM; B _m = 2.95 ± 1.12 fmol/mg protein; Hill coefficient, n = 2. For β-adrenoreceptors, ligand-receptor interactions fit into a model assuming the presence of two receptor pools in the same effector system and binding of two ligand molecules to one receptor molecule. The corresponding parameters of the [³H]DHA binding to β-adrenoreceptors are as follows: K _d1 = 0.74 ± 0.09 nM; K _d2 = 7.63 ± 0.70 nM; B _m1 = 25 ± 2 fmol/mg, B _m2 = 48 ± 2 fmol/mg, n ₁ = 2; n ₂ = 2. We suggest that in rat cerebral cortex membranes α-and β-adrenoreceptors exist as dimers.     

The structures and inhibitory effects of Buame [N-(3-hydroxy-1,3,5(10)-estratrien-17β-yl)-butylamine] and Diebud [N,N'-bis-(3-hydroxy-1,3,5(10)-estratrien-17β-yl)-1,4-butanediamine] on platelet aggregation

Compounds with estrogenic effects that also inhibit platelet aggregation might be useful in reducing thrombotic events associated with estrogenic therapy. In this study, two aminoestrogens, Buame [N-(3-hydroxy-1,3,5(10)-estratrien-17β-yl)-butylamine] and Diebud [N,N'-bis-(3-hydroxy-1,3,5(10)-estratrien-17β-yl)-1,4-butanediamine], were synthesized and characterized using common analytical methods and spectrophotometric analyses. The location and orientation of these molecules on the estrogenic receptor α (ERα) were also evaluated. Platelet inhibitory effects were elucidated ADP-induced platelet aggregation and ADP- and collagen-induced ATP release. Molecular docking demonstrated that Buame can reach and bind to the ERα in the ligand binding domain (LBD) similar to 17β-estradiol (co-crystallized ligand). On the other hand, Diebud binds only to the surface of ERα due to its high molecular volume compared to 17β-estradiol and Buame.