Adenophostin A and analogues modified at the adenine moiety: synthesis, conformational analysis and biological activity

The synthesis of adenophostin A (2) and two analogues [etheno adenophostin (4) and 8-bromo adenophostin (5)] modified at the adenine moiety, is reported. A combination of NMR analysis and molecular modelling was used to compare their structures in solution and determined that they all adopt very similar conformations. The analogues were tested for their ability to mobilise Ca(2+) from DT40 cells expressing recombinant Type 1 rat Ins(1,4,5)P(3)R which reveals etheno adenophostin as a high affinity fluorescent probe of the Ins(1,4,5)P(3)R. 8-Bromo adenophostin was only slightly less potent. The biological results support our current hypothesis regarding the binding mode of adenophostin A at the Ins(1,4,5)P(3)R, i. e. that a cation-pi interaction between the base moiety and Arg 504 of the receptor in combination with H-bonding may be responsible for the high potency of adenophostin A relative to Ins(1,4,5)P(3).     

Antagonist binding in the rat muscarinic receptor A study by docking and X-ray crystallography

A series of agonists to the rat muscarinic receptor have been docked computationally to the active site of a homology model of rat M1 muscarinic receptor. The agonists were modelled on the X-ray crystal structure of atropine, which is reported here and the docking studies are shown to reproduce correctly the order of experimental binding affinities for the agonists as well as indicate where there appear to be inconsistencies in the experimental data. The crystal and molecular structure of atropine (tropine tropate; -[hydroxymethyl]benzeneacetic acid 8-methyl[3.2.1]oct-3-yl ester C₁₇H₂₃NO₃) has been determined by X-ray crystallography using an automated Patterson search method, and refined by full-matrix least-squares to a final R of 0.0452 for 2701 independent observed reflections and 192 parameters using Mo K radiation, λ = 0.71073 Å at 150 K. The compound crystallises in space group Fdd2 with Z = 16 molecules per unit cell.     

Rapid synthetic route toward structurally modified derivatives of cyclic adenosine 5'-diphosphate ribose

A concise synthesis of five new analogues of the second messenger cADPR (cyclic adenosine 5'-diphosphate ribose) is presented. The synthetic plan centered around the key derivative 8-Br-N1-cIDPR (cyclic 8-Br-inosine 5'-diphosphate ribose, 2), which was prepared in only three steps from IMP (inosine 5'-monophosphate) via an unusual enzymatic cyclization reaction. The enhanced stability of 2 allowed for the direct modification of this cyclic dinucleotide at the 8 position, providing the unsubstituted parent N1-cIDPR (4) as well as the 8-phenyl (5), 8-azido (6), and 8-amino (7) N1-cIDPR analogues. In Jurkat T-lymphocytes, N1-cIDPR 4 induced Ca2+ release with an almost identical profile as the natural agonist cADPR, illustrating the value of this approach.     

Crystal structures of CsFe2S3 and RbFe2S3: synthetic analogs of rasvumite KFe2S3

The isostructural alkali thioferrate compounds CsFe₂S₃, RbFe₂S₃ and KFe₂S₃ have been synthesized by reacting Fe and S with their corresponding AFeS₂ (A=K, Rb, Cs) precursors. The crystal structures of these and binary compounds of intermediate composition were determined by Rietveld analysis of laboratory powder X-ray diffraction patterns. All of the synthesized compounds adopt the space group Cmcm (#63), Z=4 with: a=9.5193(8) Å, b=11.5826(10) Å, c=5.4820(4) Å for CsFe₂S₃; a=9.2202(7) Å, b=11.2429(9) Å, c=5.4450(3) Å for RbFe₂S₃; and a=9.0415(13) Å, b=11.0298(17) Å, c=5.4177(6) Å for KFe₂S₃. These mixed valence alkali thioferrates show regular changes in cell dimensions, AS₁₀ (A=K, Rb, Cs) polyhedron volumes, polyhedron distortion parameters, and calculated oxidation state of Fe with respect to increasing size of the alkali element cation. The calculated empirical oxidation state of iron varies from +2.618 (CsFe₂S₃), through +2.666 (RbFe₂S₃) to +2.77 (KFe₂S₃).     

Vibrational analysis of 1,2-dichloroalkanes

IR and Raman spectra have been obtained for 1,2-dichlorobutane and 1,2-dichloro- pentane. The butane crystallizes in the P_XS_XH conformation, but the pentane could not be made to crystallize. Normal coordinate calculations were made for the P_XS_XH, P_CS_HH, and P_HS_HH conformers of these two compounds and for 1,2-dichloropropane. The ob- served spectra were interpreted with the aid of these calculations, and it was concluded that all three conformers exist for each of these compounds. The force field that was obtained should be applicable to other 1,2-dichloroalkanes.     

Detection of substituted benzenes in water at the pg/ml level using solid-phase microextraction and gas chromatography-ion trap mass spectrometry.

Solid-phase microextraction (SPME) is combined with gas chromatography-ion trap mass spectrometry (GC-IT-MS) for the analysis of benzene, toluene, ethyl benzene and xylene isomers (BTEX) in water. SPME is a recent technique for extracting organics from an aqueous matrix into a stationary phase immobilized on a fused-silica fiber. The analytes are thermally desorbed directly in the injector of a gas chromatograph. The wide linear dynamic range (five orders of magnitude) and pg sensitivity of the ion trap mass spectrometer in its full scan mode is an ideal detector for identifying and quantifying the analytes extracted with an SPME device. The combined method SPME-GC-IT-MS, using fibers coated with a 100-microns polydimethylsiloxane coating, showed a limit of quantitation (LOQ) of 50 pg/ml benzene in water. This corresponds to 5 pg of benzene absorbed onto the fiber. The limit of detection (LOD) was 15 pg/ml benzene. For o-xylene spiked at 50 pg/ml in water 50 pg were absorbed by the fiber indicating an LOQ and LOD 10 times better than for benzene. The detection limits obtained exceed the requirements of both the United States Environmental Protection Agency method 524.2 and the Ontario Municipal/Industrial Strategy for Abatement program, which range from 30 to 80 pg/ml and 500 to 1100 pg/ml, respectively. The linearity of the method extended over five orders of magnitude. Relative standard deviation ranged from 2.7 to 5.2% for 15 ng/ml BTEX in water and from 5.5 to 7.5% for 50 pg/ml BTEX in water. SPME-GC-IT-MS was used to evaluate the contamination level in laboratory, potable and wastewater sources.     

Structure of 3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine isethionate solvate (lamotrigine isethionate)

The crystal and molecular structure of lamotrigine isethionate, C₉H₈Cl₂N₅ ⁺ .HOC₂H₄SO₃ ^– has been determined by direct methods. The compound crystallizes in the tetragonal space group I4₁/a. The isethionate moiety forms multiple hydrogen bonds to the lamotrigine nucleus, three from one isethionate, two from a symmetry related isethionate and a further two from two different symmetry related molecules. Protonation of N(2) in the triazine ring, not observed in the native lamotrigine structure is presumably associated with the interaction of the isethionate moiety. Both rings in the lamotrigine moiety are essentially planar, with a dihedral angle of 66.08(7)° compared to 80.70° in native lamotrigine. The connecting bond length C(1)—C(6) = 1.493(3) Å also correlates well with values in related compounds (1.480(3) Å) in the native structures.     

Stability criterion for radial wave equation in finite-differencetime-domain method

A relaxed time-step stability criterion is derived for the radial wave equation in Schelkunoff form approximated by a finite-difference time-domain (FDTD) method. The criterion is established by comparing with the Cartesian Laplacian operator. This is the first step in developing stability analysis for a spherical wave implementation in FDTD