Umbelliferyloxymethyl phosphonate compounds-weakly binding zinc ionophores with neuroprotective properties.

Umbelliferone is a member of the coumarin family of compounds which are known for diverse pharmacological activity including in targets relevant to Alzheimers disease, AD. The toxicity associated with some forms of the amyloid protein, Aß, and the role of Zn2+ (and other biometals) dyshomeostasis in this, are of great interest in AD and make metal ionophore capability desirable in so called multi target drug ligands MTDLs. A new series of umbelliferyloxymethyl phosphonic acid diethylester compounds (umbelliferyloxymethyl phosphonates) bearing a phosphonate at the 7-position (compounds 1, 3-6), hydrolysis products 2, 2a and 2b from 1 and analogues 7 and 8 of 1 with 7-O to 7-S and 1-O to 1-NH substitutions, are reported. Single crystal X-ray structures of compounds 1, 2 and 2a were determined. In terms of neuroprotective properties, the compounds 1, 2, 3, 4, 5 and 6 at 1 µM concentration, inhibited the toxicity of Aß1-42 (Aß42) in both toxic Amyloid Derived Diffusible Ligand (ADDL) and fibrillar (fibril) forms towards rat hippocampal cells. Compound 7 displayed cytotoxicity and 8 failed to inhibit Aß42 toxicity. Concerning compound-metal ionophore activity (assessed using chemical experiments), despite weak binding to Zn2+ determined from 31P NMR titration of 1 and 2 by ZnCl2, compounds 1, 3, 4, 5 and 6 demonstrated ionophore assisted partition of Zn2+ from water to octanol at micromolar concentrations with efficacy on a par with or better than the chelator MTDL clioquinol (5-chloro-7-iodo-8-hydroxyquinoline). Partition was assessed using furnace Atomic Absorption Spectroscopy (AAS). In further experiments interaction of compound 1 with Zn2+ or it's pathways was inferred by (i) delayed fluorescence response with added Zn2+ in cells treated with FluoZin-3 and (ii) by suppression of Zn2+ promoted aggregation of Aß42.

Crystal structure of bromido-nitro-syl-bis(tri-phenyl-phosphane-κP)nickel(II).

The asymmetric unit of the title complex, [NiBr(NO){P(C6H5)3}2], comprises two independent mol-ecules each with a similar configuration. The Ni(II) cation is coordinated by one bromide anion, one nitrosyl anion and two tri-phenyl-phosphane mol-ecules in a distorted BrNP2 tetra-hedral coordination geometry. The coordination of the nitrosyl group is non-linear, the Ni-N-O angles being 150.2 (5) and 151.2 (5)° in the two independent mol-ecules. In the crystal, mol-ecules are linked by weak C-H⋯Br hydrogen bonds and weak C-H⋯π inter-actions into a three-dimensional supra-molecular architecture.

Catalytic and mechanistic studies into the epoxidation of styrenes using manganese complexes of structurally similar polyamine ligands.

Two structurally similar polyamine ligands (7 and 8) have been prepared, which differ only by the presence of either a secondary or tertiary nitrogen donor within their N5 donor set. The ligands, in combination with iron and manganese salts, have been screened for their efficacy as catalysts for the epoxidation of styrene, using both hydrogen peroxide and peracetic acid as oxidants. Clear differences in activity between the two systems were observed, with 7 proving most effective in the presence of MnSO4 with H2O2, whereas ligand 8 proved to be effective with Mn(OTf)2, MnCl2 and Mn(ClO4)2 using peracetic acid as the oxidant. A Hammett analysis of the initial rate kinetics of the optimal systems, combined with analysis by UV-vis spectroscopy, indicates that the small structural differences in the ligands elicit profound changes in the nature of the active species formed.

Visible-Range Sensitization of Er(3+)-Based Infrared Emission from Perfluorinated 2-Acylphenoxide Complexes.

Five new fully fluorinated acylphenoxide ligands, which are aromatic analogues of ß-diketonates, provide visible photosensitization of the Er(3+4)I13/2 → (4)I15/2 emission at ∼1540 nm (of interest for telecommunications) via the "antenna effect", as observed in Cs[ErL4] compounds. Depending on the chemical functionalization, the excitation wavelength can be tuned in the 400-650 nm range. Decay times for the solids are in the range of 7-16 µs, proving that the complexes can be of interest for a number of optoelectronic and photonic applications.

Efficient sensitized emission in Yb(III) pentachlorotropolonate complexes.

New Yb(III) complexes based on the pentachlorotropolonate (pctrop) ligand show enhanced infrared emission when excited in the orange organic chromophore. Yb(pctrop)(3)(DMF-d(7))(2) presents the highest reported quantum yield for a nonfluorinated infrared-emitting organolanthanide complex.

Luminescent zinc(II) complexes of fluorinated benzothiazol-2-yl substituted phenoxide and enolate ligands.

Zn(II) complexes of the following new, fluorine-containing, benzothiazole-derived ligands have been synthesized and characterized crystallographically: 2-(3,3,3-trifluoro-2-oxopropyl)benzothiazole (3), 4,5,6,7-tetrafluoro-2-(3,3,3-trifluoro-2-oxopropyl)benzothiazole (4), 4,5,6,7-tetrafluoro-2-(2-hydroxyphenyl)benzothiazole (12), 2-(3,4,5,6-tetrafluoro-2-hydroxyphenyl)-4,5,6,7-tetrafluorobenzothiazole (13), and 2-(3,4,5,6-tetrafluoro-2-hydroxyphenyl)benzothiazole (16); the Cu(II) complex of ligand 4 is also reported. These are analogs of the important photo- and electroluminescent material [Zn(BTZ)(2)](2), where H-BTZ = 2-(2-hydroxyphenyl)benzothiazole. DFT calculations indicate that HOMO and LUMO energy levels in these materials are substantially lowered by fluorination. The fluorinated ZnL(2) complexes are mononuclear (in contrast to the dinuclear, nonfluorinated material [Zn(BTZ)(2)](2)). They easily sublime and show broad visible photoluminescence. A common crystallographic feature is the existence of pairs of fluorinated ZnL(2) molecules related by inversion centers, with their π systems facing one another.

A novel approach to isoindolo[2,1-a]indol-6-ones.

A convenient route to isoindolo[2,1-a]indol-6-ones has been developed starting from the appropriate 2-(N-phthaloyl)benzoic acids. Formation of the acid chlorides with thionyl chloride followed by heating with triethyl phosphite in a suitable solvent resulted in a multistep reaction giving tetracyclic ß-ketophosphonates that on reduction with sodium borohydride gave the required indolones in good overall yields. Analogous ß-ketophosphonates were also prepared starting with N,N-(1,8-naphthaloyl)-2-aminobenzoic acid and 2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)benzoic acids although of these only the naphthaloyl product could be reduced with sodium borohydride without cleaving the amide bond in the ring system.

Studies of the reactions of tripodal pyridine-containing ligands with Re(CO)5Br leading to rheniumtricarbonyl complexes with potential biomedical applications.

The complexes formed from the reaction of N-acylated tris-(pyridin-2-yl)methylamine (LH) with [Re(CO)(5)Br] depend on the structure of the ligand and the reaction conditions. Thus, while N-[1,1,1-tris-(pyridin-2-yl)methyl]acetamide coordinates through the three pyridine nitrogens to give a stable cationic complex [LHRe(CO)(3)Br], the analogous N-benzoyl ligand reacts under similar conditions to give a neutral complex [LRe(CO)(3)] with coordination through two pyridine nitrogens and a deprotonated amide. To try to explain these different outcomes, the reactions of some structurally related N-acylated [1,1-bis(pyridin-2-yl)]methylamines (L'H) with [Re(CO)(5)Br] have been studied and the reaction pathways identified. These studies indicate that a neutral complex [L'HRe(CO)(3)Br] is initially formed in which the amide portion of the ligand is uncoordinated, but that this complex under appropriate conditions then rearranges to give a cationic complex [L'HRe(CO)(3)]Br in which the coordinated amide nitrogen either remains protonated or is present in its imidic acid tautomeric form. Elimination of HBr from these complexes either thermally or in the presence of base then gives stable neutral complexes [L'Re(CO)(3)]. The impact of the N-acyl group and any substituent at the apex of the tripodal ligands (L''H) on the relative stabilities of intermediate complexes on the reaction pathway helps provide an explanation for the observed difference in behaviour of the N-acylated tris(pyridin-2-yl)methylamines (LH).

Modular 'click' sensors for zinc and their application in vivo.

Although the central role that zinc plays in many biological processes and important disease states is now well-established, there remains a pressing need to develop an absolute understanding of the underlying biology of zinc trafficking in terms of its dynamic and quantitative processing in specific organelles. Here we describe the modular synthesis of zinc sensors using a 'click' approach and demonstrate the applicability of our new sensors in vivo using a zebrafish model.

Synthesis and characterization of fused pyrrolo[3,2-d:4,5-d']bisthiazole-containing polymers.

The synthesis of a novel electron-deficient fused pyrrolo[3,2-d:4,5-d']bisthiazole is reported from 2-bromothiazole. This was copolymerized with thiophene, selenophene, thienothiophene, and bithiophene by microwave-assisted Stille polycondensation. The resulting polymers exhibited small optical band gaps combined with low-lying HOMO energy levels and demonstrated semiconducting behavior in organic field effect transistors.

Cyclam-based "clickates": homogeneous and heterogeneous fluorescent sensors for Zn(II).

In an effort to improve upon the recently reported cyclam based zinc sensor 1, the "click"-generated 1,8-disubstituted analogue 2 has been prepared. The ligand shows a 2-fold increase in its fluorescence emission compared to 1 exclusively in the presence of Zn(II) that is typical of switch-on PET fluorescent sensors. Single crystal X-ray diffraction of complexes of model ligand 10 reveals that the configuration adopted by the macrocyclic framework is extremely sensitive to the metal ion to which it coordinates. For Zn(II), Mg(II), and Li(I) the metal ions adopt an octahedral geometry with a trans III configuration of the cyclam ring. In contrast for Ni(II) the ligand adopts the rare cis V configuration, while for Cu(II) a clear preference for five-coordinate geometry is displayed with a trans I configuration of the macrocyclic ring being observed in two essentially isostructural compounds prepared via different routes. The ligand displays an increased selectivity for Zn(II) compared to 1 in the majority of cases with excellent selectivity upheld over Na(I), Mg(II), Ca(II), Mn(II), Ni(II), Co(II), and Fe(III). In contrast for Cu(II) and Hg(II) little improvement was observed for 2 compared to 1 and for Cd(II) the selectivity of the new ligand was inferior. In the light of these findings and the slower response times for ligand 2, our original "click"-generated cyclam sensor system 1 was employed in a proof of concept study to prepare a heterogeneous sol-gel based material which retains its PET response to Zn(II). The versatile nature of the sol-gel process importantly allows the simple preparation of a variety of nanostructured materials displaying high surface area-volume ratio using fabrication methods such as soft lithography, electrospinning, and nanopipetting.

Unexpected formation of a novel pyridinium-containing catecholate ligand and its manganese(III) complex.

Nucleophilic aromatic substitution of tetrachloro-o-benzoquinone by pyridine and reduction of the o-quinone to the catechol by hydroxylamine forms 1,2-dihydroxy-3,5,6-trichlorobenzene-4-pyridinium chloride. This compound reacts with manganese(II) acetate in air to form chlorobis(3,5,6-trichlorobenzene 4-pyridinium catecholate)manganese(III), which represents the first complex of this ligand class to be structurally characterized by X-ray diffraction; this complex is active in the catalytic reduction of dioxygen to hydrogen peroxide under ambient conditions and turnover frequencies (TOFs) >10,000 h(-1) can be obtained.

Is there really a diagnostically useful relationship between the carbon-oxygen stretching frequencies in metal carboxylate complexes and their coordination mode?

An investigation into the relationship between the asymmetric and symmetric stretching modes of ancillary carboxylate ligands and their mode of binding in a family of manganese(III) complexes of tetradentate N(2)O(2) Schiff base ligands, which includes comparison of an (18)O isotopically labelled derivative, has been undertaken. The results suggest that caution should be employed in using this technique to assign the binding mode of the carboxylate ligands in these complexes despite its very extensive use in the literature.

Responsive metal complexes: a click-based "allosteric scorpionate" complex permits the detection of a biological recognition event by EPR/ENDOR spectroscopy.

Chemical sensing is a mature field, and many effective sensors for small anions and cations have been devised. Metal complexes have been used widely for this purpose, but there are fewer reports of their use in the detection of organic and biological analytes. To date metal complexes have been used in sensing via the direct displacement of a pre-existing ligand by an analyte, or by an adventitious complementarity between the complex and analyte. These strategies do not permit a general approach to the sensing of biological molecules with metal complexes because of the demands to engineer molecular recognition into the complex architecture. We describe a fundamentally new approach to this field-the "allosteric scorpionate" metal complex. The binding partner of a biological analyte is attached to a scorpionate ligand on a metal complex, remote from the metal centre. Binding of the analyte causes a change in the primary coordination sphere at the metal, thereby revealing the presence of the biological molecule. We show that azamacrocyclic complexes with a triazole scorpion ligand may be easily assembled with the [3+2] Huisgens 'click' cycloaddition. We demonstrate the synthesis of a biotin-functionalised cyclam derivative using this methodology. This, and our previously communicated zinc sensor, are to the best of our knowledge the first examples of a triazole being employed as a scorpion ligand on an azamacrocycle. Coordination by the triazole to the metal is perturbed by the binding of avidin to the pendant ligand. This event can be sensitively detected with EPR spectroscopy, and the details of the coordination change probed with ENDOR spectroscopy, confirming the loss of the axial triazole nitrogen donor upon binding to avidin. This represents the first metal complex where remote, 'allosteric' coordination of an analyte has been shown to cause a change in the primary coordination sphere of the metal. Since the synthesis is modular and straightforward, other biological ligands may easily be introduced, and the associated binding events may be probed.

Quenching of IR luminescence of erbium, neodymium, and ytterbium beta-diketonate complexes by ligand C-H and C-D bonds.

The effect of CH and CD quenching on the luminescence lifetime of Er(3+) Nd(3+) and Yb(3+) in the Cs[Ln(HFA)(4)] system has been quantified, and we have shown that for Er(3+) ions the quenching is dominated by the nearest neighbor CH oscillators, whereas for Nd(3+) ions the roles of more distant CH oscillators and nearest neighbor CD oscillators are important.

Stereoselective synthesis of (E)-mannosylidene derivatives using the Wittig reaction.

Stabilized ylides Bu(3)P=CH(EWG), where EWG is an ester or nitrile group, react with 2,3,4,6-tetra-O-benzylmannono-1,5-lactone giving high yields of mannosylidene derivatives; in contrast to the glucose and galactose analogues, the (E)-mannosylidenes are predominant (E:Z > 9:1), thus minimizing dipole-dipole repulsions in the Wittig reactions. NMR indicates chair-like conformations for solutions of the (E)-mannopyranosylidenes, but not for those (Z)-isomers where data are available (EWG = CN or CO(2)Et). X-ray crystallography shows an approximately twist-boat conformation for the tetra-O-benzyl-protected (Z)-mannosylideneacetonitrile.

Synthesis, structural characterization, experimental, and computational spectrophotometric studies of 8-quinolinyloxymethyphosphonate compounds.

The synthesis of diethyl-8-quinolinyloxymethylphosphonate 1 and 8-quinolinyloxymethylphosphonic acid hemihydroiodide 2 is reported along with their spectroscopic and analytical characteristics (NMR, infrared, mass spectra, and elemental analysis). The single-crystal X-ray structure of 2 is described. Solutions of the disodium phosphonate 3, from 2 and sodium hydroxide, were prepared and used in situ. The coordination complex between 1 and zinc chloride 4 is described according to its single-crystal X-ray structure. The spectrophotometric features (absorption and emission) of 1, 2, 3, and 4 are reported along with the fluorescence response and affinity of 3 to some metal cations. The origin of the fluorescence from compounds 1 and 4 is investigated using density functional theory and the oscillator strength for each transition is computed. Two deactivation pathways, one of which is only weakly emissive, are identified in 4. In contrast to 4, which is only moderately more emissive than 1 a strong zinc-activated fluorescence response is observed from aqueous solutions of 3.

Synthesis of phenazine derivatives for use as precursors to electrochemically generated bases.

1,6-Disubstituted phenazine derivatives for use as precursors to electrochemically generated bases have been synthesized from readily available starting materials. Reaction of 1,6-dihydroxyphenazine with 1,10-diododecane, 1,11-diiodo-3,6,9-trioxaundecane or (R,R)-(-)-1,2-bis(3-iodopropoxy)cyclohexane gave planar chiral phenazinophanes containing ether-linked bridges; molecular structures of all these compounds have been determined by X-ray crystallography. Substituted 1,6-diaminophenazines were prepared by palladium-mediated amination of 1,6-dichlorophenazine and acylation of 1,6-diaminophenazine followed by reduction. Reaction of 1,6-bis(alkylamino)phenazines with sebacoyl chloride gave planar chiral phenazinophanes containing amide-linked bridges.

The reactivity, as electrogenerated bases, of chiral and achiral phenazine radical-anions, including application in asymmetric deprotonation.

Radical-anions, electrochemically generated in aprotic solvent from C(2) symmetric homochiral phenazine derivatives, act as chiral electrogenerated bases (EGBs) in the desymmetrisation by selective deprotonation of a prochiral epoxide (3,4-epoxy-2,3,4,5-tetrahydrothiophene-1,1-dioxide); the anion produced is trapped by mesitoic anhydride. The phenazines may be recovered in high yield by air oxidation. Enantiomeric excesses are modest (8-34%) but this is to our knowledge the first demonstration of such stereoselective electrochemically-initiated deprotonation. The reactivity of phenazine radical-anions as EGBs has also been explored by measurements of the rates of proton transfer; the prochiral epoxide was found to have a kinetic acidity similar to that of the methyltriphenylphosphonium cation.

Synthesis of planar chiral phosphapalladacycles by highly enantioselective transcyclopalladation.

The first highly enantioselective synthesis of planar chiral ferrocene phosphapalladacycles was performed by high-yielding asymmetric transcyclopalladation with cobalt oxazoline palladacycles (COP). Use of di-mu-acetatobis[(eta5-(S)-(pR)-2-(2'-(4'-isopropyl)oxazolinyl)cyclopentadienyl-C1,N3')(eta4-tetraphenylcyclobutadiene)cobalt]dipalladium(II), followed by acetate/chloride ligand exchange, gave (pS)-di-mu-chloro[2-(2-dicyclohexylphosphino)phenylferroene-C1,P)dipalladium(II) (95% ee). Similarly, diastereomeric di-mu-acetatobis[(eta5-(S)-(pS)-2-(2'-(4'-tert-butyl)oxazolinyl)cyclopentadienyl-C1,N3')(eta4-tetraphenylcyclobutadiene)cobalt]dipalladium(II) led to the enantiomeric (pR)-phosphapalladacycle (95% ee), revealing the control of these reactions by the element of planar chirality in COP. The reactions were extended to the synthesis of (pS)- and (pR)-di-mu-chloro[2-(2-diphenylphosphino)phenylferroene-C1,P)dipalladium(II) (78 and 92% ee, respectively). In all cases, the palladium-free precursors to COP were recovered for recycling.