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1.  Expanding the scope of Metal-Free enantioselective allylic substitutions: Anthrones 
Scientific Reports  2015;5:16886.
The highly enantioselective asymmetric allylic alkylation of Morita–Baylis–Hillman carbonates with anthrones is presented. The reaction is simply catalyzed by cinchona alkaloid derivatives affording the final alkylated products in good yields and excellent enantioselectivities.
PMCID: PMC4655356  PMID: 26592555
2.  Interaction of serum amyloid P component with hexanoyl bis(d-proline) (CPHPC) 
Serum amyloid P component is a pentameric plasma glycoprotein that recognizes and binds to amyloid fibres in a calcium-dependent fashion and is likely to contribute to their deposition and persistence in vivo. Five molecules of the drug CPHPC avidly cross-link pairs of protein pentamers and the decameric complex is rapidly cleared in vivo. Crystal structures of the protein in complex with a bivalent drug and cadmium ions, which improve crystal quality, allow the definition of the preferred bound drug isomers.
Under physiological conditions, the pentameric human plasma protein serum amyloid P component (SAP) binds hexanoyl bis(d-proline) (R-1-{6-[R-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl}pyrrolidine-2-carboxylic acid; CPHPC) through its d-proline head groups in a calcium-dependent interaction. Cooperative effects in binding lead to a substantial enhancement of affinity. Five molecules of the bivalent ligand cross-link and stabilize pairs of SAP molecules, forming a decameric complex that is rapidly cleared from the circulation by the liver. Here, it is reported that X-ray analysis of the SAP complex with CPHPC and cadmium ions provides higher resolution detail of the interaction than is observed with calcium ions. Conformational isomers of CPHPC observed in solution by HPLC and by X-ray analysis are compared with the protein-bound form. These are discussed in relation to the development of CPHPC to provide SAP depletion for the treatment of amyloidosis and other indications.
PMCID: PMC4118831  PMID: 25084341
serum amyloid P component; CPHPC; amyloidosis
3.  Aldol elaboration of 4,5,6,7-tetrahydroisoxazolo[4,3-c]pyridin-4-ones, masked precursors to acylpyridones 
A core 4,5,6,7-tetrahydroisoxazolo[4,3-c]pyridine-4-one scaffold is elaborated at C-3(Me) by base-mediated aldol condensation to give new 3-alkenyl-4,5,6,7-tetrahydroisoxazolo[4,3-c]pyridine-4-ones, which are masked forms related to the acylpyridone natural products.
PMCID: PMC3302094  PMID: 22423299
aldol reaction; fused-ring systems; heterocycles; isoxazole; metalation; pyridone
4.  NMR studies of anion-induced conformational changes in diindolylureas and diindolylthioureas 
The conformational properties of 1,3-diindolylureas and thioureas were studied by a combination of heteronuclear NMR spectroscopy and quantum mechanics calculations. NOE experiments showed that the anti–anti conformer along the C7–N7α bonds was predominant in DMSO-d 6 solution in the absence of anions. Anion-induced changes in the 1H and 15N chemical shifts confirm the weak binding of chloride anions with negligible conformational changes. Strong deshielding of ureido protons and moderate deshielding of indole NH was observed upon the addition of acetate, benzoate, bicarbonate and dihydrogen phosphate, which indicated that the predominant hydrogen bond interactions occurred at the urea donor groups. Binding of oxo-anions caused conformational changes along the C7–N7α bonds and the syn–syn conformer was preferred for anion–receptor complexes. The conformational changes upon anion binding are in good agreement with energetic preferences established by ab initio calculations.
PMCID: PMC3182429  PMID: 21977204
anion recognition; conformation analysis; host–guest systems; NMR spectroscopy
5.  Bis-cation salt complexation by meso-octamethylcalix[4]pyrrole: linking complexes in solution and in the solid state† 
Pyridinium and imidazolium bis-cations are shown to link calix[4]pyrrole anion complexes both in solution and in the solid state. This is accomplished by binding of the bis-cations to the electron-rich bowl shaped cavities formed by two separate calixpyrrole–anion complexes. These resulting sandwich-type structures provide a new way of organising calix[4]pyrrole anion complexes in space.
PMCID: PMC2871009  PMID: 20024138
6.  Conformational control of HCl co-transporter: imidazole functionalised isophthalamide vs. 2,6-dicarboxamidopyridine 
Replacement of the central isophthalamide core in a synthetic HCl receptor, with a 2,6-dicarboxamidopyridine, leads to a more preorganized molecular structure that exhibits higher chloride affinity and membrane transport flux.
PMCID: PMC2864111  PMID: 17457425
7.  Synthesis and anion binding properties of N,N’-bis-pyrrol-2-yl-2,5-diamidopyrrole 
Organic letters  2006;8(8):1593-1596.
A bis-pyrrol-2-yl-2,5-diamidopyrrole has been synthesized and shown to have a significantly higher affinity for oxo-anions than previous generation 2,5-diamidopyrroles.
PMCID: PMC2712661  PMID: 16597118
8.  Calix[4]pyrrole as a Chloride Anion Receptor: Solvent and Counter-Cation Effects 
Journal of the American Chemical Society  2006;128(37):12281-12288.
The interaction of calixpyrrole with several chloride salts has been studied in the solid state by X-ray crystallography as well as in solution by isothermal titration calorimetry (ITC) and 1H NMR spectroscopic titrations. The titration results in dimethylsulfoxide, acetonitrile, nitromethane, 1,2-dichloroethane and dichloromethane, carried out using various chloride salts, specifically tetraethylammonium (TEA), tetrapropylammonium (TPA), tetrabutylammonium (TBA), tetraethylphosphonium (TEP), tetrabutylphosphonium (TBP), and tetraphenylphosphonium (TPhP) showed no dependence on method of measurement. The resulting affinity constants (Ka's), on the other hand, were found to be highly dependent on the choice of solvent with Ka's ranging from 102−105 being recorded in the test solvents used for this study. In dichloromethane a strong dependence on the counter-cation was also seen, with the Ka's for the interaction with chloride ranging from 102−104. In the case of TPA, TBA and TBP the ITC data could not be fit to a 1:1 binding profile.
PMCID: PMC2572717  PMID: 16967979
anion binding; calixpyrrole; NMR titrations; isothermal titration calorimetry (ITC)
9.  Crystal Structure and Antitumor Activity of the Novel Zwitterionic Complex of tri-n-Butyltin(IV) with 2-Thiobarbituric Acid 
A novel tri-n-butyl(IV) derivative of 2-thiobarbituric acid (HTBA) of formula [(n-Bu)3Sn(TBA) H2O] (1) has been synthesized and characterized by elemental analysis and 119Sn-NMR and FT-IR spectroscopic techniques. The crystal structure of complex 1 has been determined by single crystal X-ray diffraction analysis at 120(2) K. The geometry around Sn(IV) is trigonal bipyramidal. Three n-butyl groups and one oxygen atom from a deprotonated 2-thiobarbituric ligand are bonded to the metal center. The geometry is completed with one oxygen from a water molecule. Compound 1 exhibits potent, in vitro, cytotoxicity against sarcoma cancer cells (mesenchymal tissue) from the Wistar rat, polycyclic aromatic hydrocarbons (PAH, benzo[a]pyrene) carcinogenesis. In addition, the inhibition caused by 1, in the rate of lipoxygenase (LOX) catalyzed oxidation reaction of linoleic acid to hyperoxolinoleic acid, has been also kinetically and theoretically studied. The results are compared to that of cisplatin.
PMCID: PMC2288696  PMID: 18401456
10.  Characterisation of temperature-dependent phase transitions in 2,2-trimethylenedioxy-4,4,6,6-tetrachlorocyclotriphosphazene, N3P3Cl4[O(CH2)3O] 
The crystal structure of 2,2-trimethylenedioxy-4,4,6,6-tetrachlorocyclo triphosphazene has been determined at 120, 274 and 293 K. The result at 293 K confirms the room temperature Cmc21 structure, but at the lower temperatures the space group is Pna21. Nevertheless the basic structure remains the same, with only small displacements of the atoms, amounting to an average of 25 pm between 120 and 293 K.
X-ray diffraction and DSC results indicate that the phase transition takes place in two steps between 274 – 293 K and provides an understanding of previous NQR results. In the intermediate temperature range the molecules are displaced from their room temperature positions in such a way as to give an average structure with Cmc21 symmetry.
The overall phase transition is consistent with the occurrence of a soft lattice mode at room temperature in which a large displacement of the molecule in the x-direction is coupled with a flexing motion about an axis defined by the nitrogen atoms in the N1 and N3 positions.
PMCID: PMC1989690  PMID: 17880672
11.  Structure–Activity Relationships in Tripodal Transmembrane Anion Transporters: The Effect of Fluorination 
Journal of the American Chemical Society  2011;133(35):14136-14148.
A series of easy-to-make fluorinated tripodal anion transporters containing urea and thiourea groups have been prepared and their anion transport properties studied. Vesicle anion transport assays using ion-selective electrodes show that this class of compound is capable of transporting chloride through a lipid bilayer via a variety of mechanisms, including chloride/H+ cotransport and chloride/nitrate, chloride/bicarbonate, and to a lesser extent an unusual chloride/sulfate antiport process. Calculations indicate that increasing the degree of fluorination of the tripodal transmembrane transporters increases the lipophilicity of the transporter and this is shown to be the major contributing factor in the superior transport activity of the fluorinated compounds, with a maximum transport rate achieved for clog P = 8. The most active transporter 5 contained a urea functionality appended with a 3,5-bis(trifluoromethyl)phenyl group and was able to mediate transmembrane chloride transport at receptor to lipid ratios as low as 1:250000. Proton NMR titration and single crystal X-ray diffraction revealed the ability of the tripodal receptors to bind different anions with varying affinities in a 1:1 or 2:1 stoichiometry in solution and in the solid state. We also provide evidence that the most potent anion transporters are able to induce apoptosis in human cancer cells by using a selection of in vitro viability and fluorescence assays.
PMCID: PMC3436094  PMID: 21846096

Results 1-11 (11)