1-Benzyloxy-5-phenyltetrazole derivatives highly active against androgen receptor-dependent prostate cancer cells.

A series of 1-benzyloxy-5-phenyltetrazole derivatives and similar compounds were synthesized and evaluated for their in vitro inhibitory activity against androgen-receptor-dependent (22Rv1) and androgen-receptor independent (PC3) prostate cancer cells. The most active compounds had in vitro IC50 values against 22Rv1 cells of <50 nM and showed apparent selectivity for this cell type over PC3 cells; however, these active compounds had short half-lives when incubated with mouse liver microsomes and/or when plasma concentration was monitored during in vivo pharmacokinetic studies in mice or rats. Importantly, lead compound 1 exhibited promising inhibitory effects on cell proliferation, expression of AR and its splicing variant AR-v7 as well as AR regulated target genes in 22Rv1 cells, which are so called castration-resistant prostate cancer (CRPC) cells, and a 22Rv1 CRPC xenograft tumour model in mice. Structural changes which omitted the N-O-benzyl moiety led to dramatic or total loss of activity and S-benzylation of a cysteine derivative, as a surrogate for in vivo S-nucleophiles, by representative highly active compounds, suggested a possible chemical reactivity basis for this "activity cliff" and poor pharmacokinetic profile. However, representative highly active compounds did not inhibit a cysteine protease, indicating that the mode of activity is unlikely to be protein modification by S-benzylation. Despite our efforts to elucidate the mode of action, the mechanism remains unclear.

Inter-molecular hydrogen bonding in N-methyl-N'-(pyridin-2-yl)benzene-1,2-di-amine.

The structure of N-methyl-N'-(pyridin-2-yl)benzene-1,2-di-amine, C12H13N3, at 123 K has ortho-rhom-bic (Pna21) symmetry. The title compound displays an unexpected proton-splitting pattern when studied by 1H NMR spectroscopy. The X-ray crystallography analysis determined this to be caused by strong dual N-H⋯N hydrogen bonding.

Carbodiphosphorane-Stabilized Parent Dioxophosphorane: A Valuable Synthetic HO2P Source.

Introducing a small phosphorus-based fragment into other molecular entities via, for example, phosphorylation/phosphonylation is an important process in synthetic chemistry. One of the approaches to achieve this is by trapping and subsequently releasing extremely reactive phosphorus-based molecules such as dioxophosphoranes. In this work, electron-rich hexaphenylcarbodiphosphorane (CDP) was used to stabilize the least thermodynamically favorable isomer of HO2P to yield monomeric CDP·PHO2. The title compound was observed to be a quite versatile phosphonylating agent; that is, it showed a great ability to transfer, for the first time, the HPO2 fragment to a number of substrates such as alcohols, amines, carboxylic acids, and water. Several phosphorous-based compounds that were generated using this synthetic approach were also isolated and characterized for the first time. According to the initial computational studies, the addition-elimination pathway was significantly more favorable than the corresponding elimination-addition route for "delivering" the HO2P unit in these reactions.

The Synthesis of a Bis(thiosemicarbazone) Macrocyclic Ligand and the Mn(II), Co(II), Zn(II) and 68Ga(III) Complexes.

A 1,4,7,10-tetraazacyclododecane (cyclen) variant bearing two thiosemicarbazone pendant groups has been prepared. The ligand forms complexes with Mn2+, Co2+ and Zn2+. X-ray crystallography of the Mn2+, Co2+ and Zn2+ complexes showed that the ligand provides a six-coordinate environment for the metal ions. The Mn2+ and Zn2+ complexes exist in the solid state as racemic mixtures of the Δ(δ,δ,δ,δ)/Λ(λ,λ,λ,λ) and Δ(λ,λ,λ,λ)/Λ(δ,δ,δ,δ) diastereomers, and the Co2+ complex exists as the Δ(δ,δ,δ,δ)/Λ(λ,λ,λ,λ) and Δ(λ,λ,λ,δ)/Λ(δ,δ,δ,λ) diastereomers. Density functional theory calculations indicated that the relative energies of the diastereomers are within 10 kJ mol-1. Magnetic susceptibility of the complexes indicated that both the Mn2+ and Co2+ ions are high spin. The ligand was radiolabelled with gallium-68, in the interest of developing new positron emission tomography imaging agents, which produced a single species in high radiochemical purity (>95%) at 90 °C for 10 min.

Diverse and unexpected outcomes from oxidation of the platinum(II) anticancer agent [Pt{(p-BrC6F4)NCH2CH2NEt2}Cl(py)] by hydrogen peroxide.

Oxidation of the anti-tumour agent [Pt{(p-BrC6F4)NCH2CH2NEt2}Cl(py)], 1 (py = pyridine) with hydrogen peroxide under a variety of conditions yields a range of organoenamineamidoplatinum(II) compounds [Pt{(p-BrC6F4)NCH=C(X)NEt2}Cl(py)] (X = H, Cl, Br) as well as species with shared occupancy involving H, Cl and Br. Thus, oxidation of the -CH2-CH2- backbone (dehydrogenation) occurs, often accompanied by substitution. Oxidation of 1 with H2O2 in acetone yielded 1:1 co-crystallized [Pt{(p-BrC6F4)NCH=CHNEt2}Cl(py)], 1H and [Pt{(p-BrC6F4)NCH=C(Cl)NEt2}Cl(py)], 1Cl. The former was obtained pure in low yield from the oxidation of 1 with (NH4)2[Ce(NO3)6] in acetone, and the latter was obtained from 1 and H2O2 in CH2Cl2 at near reflux. From the latter reaction under vigorous refluxing [Pt{(p-BrC6F4)NCH=C(Br)NEt2}Cl(py)], 1Br was isolated. In refluxing acetonitrile, oxidation of 1 with H2O2 yielded [Pt{(p-BrC6F4)NCH=C(H0.25Br0.75)NEt2}Cl(py)], 1H0.25Br0.75, in which the alkene is mainly substituted by Br in a dual occupancy. Treatment of 1 with H2O2 and tetrabutylammonium hydroxide in acetone at room temperature formed [Pt{(p-HC6F4)NCH2CH2NEt2}Cl(py)], 2. Oxidation of [Pt{(p-HC6F4)NCH2CH2NEt2}Br(py)], 3 with H2O2 in boiling acetonitrile gave the ligand oxidation product [Pt{(p-HC6F4)NCH=C(Br)NEt2}Br(py)], 3Br. All major products were identified by X-ray crystallography as well as by 1H and 19F NMR spectra. In cases of mixed crystals or dual occupancy compounds, the 19F and 1H NMR spectra showed dissociation into the components in the solution in the same proportions as in isolated crystalline material.

Pyrazolium Phase-Change Materials for Solar-Thermal Energy Storage.

Thermal energy storage technology utilizing phase-change materials (PCMs) can be a promising solution for the intermittency of renewable energy sources. This work describes a novel family of PCMs based on the pyrazolium cation, that operate in the 100-200 °C temperature range, offering safe, inexpensive capacity and low supercooling. Thermal stability and extensive cycling tests of the most promising PCM candidate, pyrazolium mesylate (Tm =168±1 °C, ΔHf =160 J g-1 ±5 %, ΔHtotal v =495 MJ m-3 ±5 %) show potential for its use in thermal storage applications. Additionally, this work discusses the molecular origins of the high thermal energy storage capacity of these ionic materials based on their crystal structures, revealing the importance of hydrogen bonds in PCM performance.

New examples of triangular terbium(iii) and holmium(iii) and hexagonal dysprosium(iii) single molecule toroics.

The structural, magnetic and theoretical aspects are described for three triangular lanthanide complexes, [Tb(OH)(teaH2)3(paa)3]Cl2 (1), [Dy(OH)(teaH2)3(paa)3]Cl2 (2) and [Ho(OH)(teaH2)3(paa)3]Cl2 (3), and a hexanuclear wheel of formula [Dy(pdeaH)6(NO3)6] (4) [teaH3 = triethanolamine, paaH = N-(2-pyridyl)-acetoacetamide and pdeaH3 = 3-[bis(2-hydroxyethyl)amino]propan-1-ol]. Each complex displays single molecule toroidal behaviour as rationalised using high-level ab initio calculations. Complexes 2 and 3 are the first examples of mixed moment single molecule toroidal complexes featuring non-Kramers ions.

Cadmium tris(dithiocarbamate) ionic liquids as single source, solvent-free cadmium sulfide precursors.

The first cadmium-based ionic liquids (ILs) have been developed, along with a family of cadmium dialkyldithiocarbamate salts, (cation)[Cd(R2dtc)3], in the pursuit of single source molecular precursors that thermolyse to form cadmium sulfide. Pyrrolidinium cadmium dialkyldithiocarbamate salts, (C4C1py)[Cd(R2dtc)3], salts were established to be ILs through thorough thermal and structural investigation.

Rationalizing the sign and magnitude of the magnetic coupling and anisotropy in dinuclear manganese(iii) complexes.

We have synthesised twelve manganese(iii) dinuclear complexes, 1-12, in order to understand the origin of magnetic exchange (J) between the metal centres and the magnetic anisotropy (D) of each metal ion using a combined experimental and theoretical approach. All twelve complexes contain the same bridging ligand environment of one µ-oxo and two µ-carboxylato, that helped us to probe how the structural parameters, such as bond distance, bond angle and especially Jahn-Teller dihedral angle affect the magnetic behaviour. Among the twelve complexes, we found ferromagnetic coupling for five and antiferromagnetic coupling for seven. DFT computed the J and ab initio methods computed the D parameter, and are in general agreement with the experimentally determined values. The dihedral angle between the two Jahn-Teller axes of the constituent MnIII ions are found to play a key role in determining the sign of the magnetic coupling. Magneto-structural correlations are developed by varying the Mn-O distance and the Mn-O-Mn angle to understand how the magnetic coupling changes upon these structural changes. Among the developed correlations, the Mn-O distance is found to be the most sensitive parameter that switches the sign of the magnetic coupling from negative to positive. The single-ion zero-field splitting of the MnIII centres is found to be negative for complexes 1-11 and positive for complex 12. However, the zero-field splitting of the S = 4 state for the ferromagnetic coupled dimers is found to be positive, revealing a significant contribution from the exchange anisotropy - a parameter which has long been ignored as being too small to be effective.

Tetracarboxylate Bis-Bipyridine Ruthenium Dyes: Synthesis, Structural and Electronic Characterisation.

The preparation of ruthenium complexes with novel 2,2'-bipyridine (bpy) ligands bearing four carboxylic acid groups was investigated with a view to creating dyes containing more than two potential anchoring groups per bpy unit for attachment to a titania surface. Synthetic challenges are encountered upon using the 2,2'-bipyridine-3,3',4,4'-tetracarboxylic acid ligand because it readily decarboxylates. The use of the methyl esterified derivative (3) proved to be more successful for complex preparation, with a robust preparation of the [Ru(3)2 Cl2 ] complex identified with diglyme as the solvent. This complex was further converted into the thiocyanato complex, [Ru(3)2 (NCS)2 ], which could not be completely de-esterified. X-ray analysis of crystals obtained from a mixture of isomers for this complex provided data for the S,S- and N,S-coordinated isomers; both showed a twisted arrangement of the pyridine rings in the 2,2'-bipyridine-3,3',4,4'-tetracarboxylic acid ligand, owing to steric hinderance. Conversely, the isosteric 2,2'-bipyridine-4,4',5,5'-tetracarboxylic acid ligand was easily converted into the desired [Ru(2)2 (NCS)2 ] complex through a standard one-pot procedure in N,N-dimethylformamide solvent. All of the complexes presented herein exhibit a significant redshift for the metal to ligand charge-transfer bands, relative to the benchmark ruthenium dye N719 and derivatives thereof. All complexes exhibit a quasi-reversible process for the ruthenium(II/III) couple at approximately 0.4 V versus the ferrocene couple, comparable to analogous ruthenium dyes.

Use of the TCNQF4 2- Dianion in the Spontaneous Redox Formation of [FeIII (L- )2 ][TCNQF4 ⋠- ].

The reaction of [FeII (L. )2 ](BF4 )2 with Li2 TCNQF4 results in the formation of [FeIII (L- )2 ][TCNQF4 . - ] (1) where L. is the radical ligand, 4,4-dimethyl-2,2-di(2-pyridyl)oxazolidine-N-oxide and TCNQF4 is 2,3,5,6-tetrafluoro-7,7,8,8-tetracyanoquinodimethane. This has been characterised by X-ray diffraction, Raman and Fourier transform infrared (FTIR) spectroscopy, variable-temperature magnetic susceptibility, Mössbauer spectroscopy and electrochemistry. X-ray diffraction studies, magnetic susceptibility measurements and Raman and FTIR spectroscopy suggest the presence of low-spin FeIII ions, the anionic form (L- ) of the ligand and the anionic radical form of TCNQF4 ; viz. TCNQF4 . - . Li2 TCNQF4 reduces the [FeII (L. )2 ]2+ dication, which undergoes a reductively induced oxidation to form the [FeIII (L- )2 ]+ monocation resulting in the formation of [FeIII (L- )2 ][TCNQF4 . - ] (1), the electrochemistry of which revealed four well-separated, diffusion-controlled, one-electron, reversible processes. Mössbauer spectroscopy and electrochemical measurements suggest the presence of a minor second species, likely to be [FeII (L. )2 ][TCNQF4 2- ].

Crystal structures of two 2,3-di-ethyl-naphtho-[2,3-g]quinoxaline-6,11-dione derivatives.

Two new 5,12-disubstituted 2,3-di-ethyl-naphtho-[2,3-g]quinoxaline-6,11-dione compounds were readily synthesized from the commercial dye quinizarin. For 2,3-diethyl-5,12-di-hydroxy-naphtho-[2,3-g]quinoxaline-6,11-dione, (II), C20H16N2O4, the mol-ecule displays a near planar conformation and both hy-droxy groups participate in intra-molecular O-H⋯O(carbon-yl) hydrogen bonds. In the crystal, π-π ring inter-actions [minimum ring centroid separation = 3.5493 (9) Å] form stacks of co-planar mol-ecules down the c axis, while only minor inter-molecular C-H⋯O inter-actions are present. In contrast, in 2,3-diethyl-5,12-bis-(piperidin-1-yl)naphtho-[2,3-g]quinoxaline-6,11-dione, (IV), C30H34N4O2, which contains two independent, but similar, mol-ecules in the asymmetric unit, the polycyclic cores have a significant twist, with dihedral angles of 29.79 (6) and 29.31 (7)° between the terminal rings and only minor inter-molecular C-H⋯O hydrogen-bonding inter-actions are present. Electron density associated with additional solvent mol-ecules disordered about a fourfold axis was accounted for using the SQUEEZE procedure in PLATON [Spek (2015 ▸). Acta Cryst. C71, 9-18].

Structural elucidation of a hy-droxy-cineole product obtained from cytochrome P450 monooxygenase CYP101J2 catalysed transformation of 1,8-cineole.

1,8-Cineole is an abundant natural product that has the potential to be transformed into other building blocks that could be suitable alternatives to petroleum-based chemicals. Mono-hydroxy-lation of 1,8-cineole can potentially occur at eight different carbon sites around the bicyclic ring system. Using cytochrome P450 monooxygenase CYP101J2 from Sphingobium yanoikuyae B2, the hy-droxy-lation can be regioselectively directed at the C atom adjacent to the methyl-substituted quaternary bridgehead atom of 1,8-cineole. The unambiguous location of the hydroxyl functionality and the stereochemistry at this position was determined by X-ray crystal analysis. The mono-hydroxy-lated compound derived from this microorganism was determined to be (1S)-2a-hy-droxy-1,8-cineole (trivial name) or (1S,4R,6S)-1,3,3-trimethyl-2-oxabi-cyclo-[2.2.2]octan-6-ol (V) (systematic), C10H18O2. In the solid state this compound exhibits an inter-esting O-H⋯O hydrogen-bonding motif.

Phosphasalen Indium Complexes Showing High Rates and Isoselectivities in rac-Lactide Polymerizations.

Polylactide (PLA) is the leading bioderived polymer produced commercially by the metal-catalyzed ring-opening polymerization of lactide. Control over tacticity to produce stereoblock PLA, from rac-lactide improves thermal properties but is an outstanding challenge. Here, phosphasalen indium catalysts feature high rates (30±3 m-1 min-1 , THF, 298 K), high control, low loadings (0.2 mol %), and isoselectivity (Pi =0.92, THF, 258 K). Furthermore, the phosphasalen indium catalysts do not require any chiral additives.

Enantioselective N-Heterocyclic Carbene Catalyzed Diene Regenerative (4 + 2) Annulation.

An enantioselective N-heterocyclic carbene (NHC)-catalyzed diene regenerative (4 + 2) annulation has been achieved through the use of highly nucleophilic morpholinone-derived catalysts. The reaction proceeds with good to excellent yields, high enantioselectivity (most >92% ee), and good diastereoselectivity (most >7:1). The generality of the reaction is high, with 19 examples reported. The utility of the products has been examined with subsequent derivatization in Diels-Alder reactions using electron-poor dienophiles. Furthermore, interception of the proposed ß-lactone intermediate has been achieved, allowing the synthesis of compounds bearing four contiguous stereocenters with high levels of enantio- and diastereoselectivity.

Redox Levels of a closo-Osmaborane: A Density Functional Theory, Electron Paramagnetic Resonance and Electrochemical Study.

A closo-type 11-vertex osmaborane [1-(η(6)-pcym)-1-OsB10H10] (pcym = para-cymene) has been synthesized and characterized by single-crystal X-ray diffraction and elemental analysis, as well as by (11)B and (1)H NMR, UV-visible, and mass spectrometry. The redox chemistry has been probed by dc and Fourier transformed ac voltammetry and bulk reductive electrolysis in CH3CN (0.10 M (n-Bu)4NPF6) and by voltammetry in the ionic liquid N-butyl-N-methylpyrrolidinium bis(trifluoromethylsulfonyl)amide (Pyrr1,4-NTf2), which allows the oxidative chemistry of the osmaborane to be studied. A single-crystal X-ray diffraction analysis has shown that [1-(η(6)-pcym)-1-OsB10H10] is isostructural with other metallaborane compounds of this type. In CH3CN (0.10 M (n-Bu)4NPF6), [1-(η(6)-pcym)-1-OsB10H10] undergoes two well-resolved one-electron reduction processes with reversible potentials separated by ca. 0.63-0.64 V. Analysis based on a comparison of experimental and simulated ac voltammetric data shows that the heterogeneous electron transfer rate constant (k(0)) for the first reduction process is larger than that for the second step at GC, Pt, and Au electrodes. k(0) values for both processes are also larger at GC than metal electrodes and depend on the electrode pretreatment, implying that reductions involve specific interaction with the electrode surface. EPR spectra derived from the product formed by one-electron reduction of [1-(η(6)-pcym)-1-OsB10H10] in CH3CN (0.10 M (n-Bu)4NPF6) and electron orbital data derived from the DFT calculations are used to establish that the formal oxidation state of the metal center of the original unreduced compound is Os(II). On this basis it is concluded that the metal atom in [1-(η(6)-pcym)-1-OsB10H10] and related metallaboranes makes a 3-orbital 2-electron contribution to the borane cluster. Oxidation of [1-(η(6)-pcym)-1-OsB10H10] coupled to fast chemical transformation was observed at 1.6 V vs ferrocene(0/+) in Pyrr1,4-NTf2. A reaction scheme for the oxidation involving formation of [1-(η(6)-pcym)-1-OsB10H10](+), which rearranges to an unknown electroactive derivative, is proposed, and simulations of the voltammograms are provided.

A fluoride bridged {Cr(III)4Dy(III)4} single molecule magnet.

The synthesis of a heterometallic octanuclear {Cr(III)4Dy(III)4} complex containing fluoride bridges displays SMM behaviour, with highly coercive magnetic hysteresis loops. Intriguingly multiple relaxation processes are revealed and the relaxation times are found to be longer compared to those of an analogous complex with the same metallic core topology.

2-(10',10'-Dimethyl-3'-sulfanyl-idene-4'-aza-tri-cyclo-[5.2.1.0(1,5)]decan-2'--yl)-10,10-dimethyl-4-aza-tri-cyclo-[5.2.1.0(1,5)]decane-3-thione.

The title compound, C28H40N2O2S2, was obtained as a minor product from an anti-aldol reaction between the corresponding N-propionyl-thiol-actam and benzaldehyde. The asymmetric unit contains one half-molecule, which is completed by inversion symmetry. The molecule displays a nearly eclipsed conformation along the central C-C bond with a C-C-C-C- torsion angle of 20.4 (3)°.

Anti-leishmanial activity of heteroleptic organometallic Sb(v) compounds.

In seeking new drugs for the treatment of the parasitic disease Leishmaniasis, an extensive range of organometallic antimony(v) dicarboxylates of the form [SbR3(O2CR')2] have been synthesised, characterised and evaluated. The organometallic moieties (R) in the complexes vary in being Ph, tolyl (o, m or p), or benzyl. The carboxylates are predominantly substituted benzoates with some compounds incorporating acetato or cinnamato ligands. The crystal structures of [Sb(p-Tol)3(O2CC6H2-3,4,5-(OMe)3)2]·0.5PhMe and [SbPh3(m-CH3C6H4CH2CO2)2] were determined and shown to adopt a typical trigonal pyramidal geometry, being monomeric with a five coordinate Sb centre. In total, the biological activity of 26 Sb(v) compounds was assessed against the Leishmania major parasite, and also human fibroblast skin cells to give a measure of general toxicity. Of these, 11 compounds (predominantly substituted benzoates with m- or p-tolyl ligands) proved to be highly effective against the parasite amastigotes at concentrations of 0.5-3.5 µM, while being non-toxic towards the mammalian cells at levels below 25 µM, making them highly promising drug candidates.