Backbone Conformation Shifts in X-ray Structures of Human Acetylcholinesterase upon Covalent Organophosphate Inhibition

Conformations of Cα backbones in X-ray structures of most organophosphate (OP)-inhibited human acetylcholinesterases (hAChEs) have been previously shown to be similar to that of the native hAChE. One of the exceptions is the structure of the diethylphosphoryl-hAChE conjugate, where stabilization of a large ethoxy group into the acyl pocket (AP) of hAChE-triggered notable loop distortions and consequential dissociation of the hAChE homodimer. Recently, six X-ray structures of hAChE conjugated with large OP nerve agents of the A-type, Novichoks, have been deposited to PDB. In this study we analyzed backbone conformation shifts in those structures, as well as in OP-hAChE conjugates formed by Paraoxon, Soman, Tabun, and VX. A Java-based pairwise alpha carbon comparison tool (PACCT 3) was used for analysis. Surprisingly, despite the snug fit of large substituents on phosphorus, inside Novichok-conjugated hAChEs only minor conformational changes were detected in their backbones. Small magnitudes of observed changes were due to a 1.2–2.4 Å shift of the entire conjugated OP away from the AP. It thus appears that the small AP of AChEs can accommodate, without distortion, substituents of the size of ethoxy or butyryl groups, provided that conjugated OP is “pulled” away from the AP. This observation has practical consequences in the structure-based design of nucleophilic reactivation antidotes as well as in the definition of the AChE specificity that relies on the size of its AP.

Bioinspired Total Synthesis of Marine Anti-Cancer Meroterpenoids Dysideanone B and Dysiherbol A and Structure Revision of Dysiherbol A

Our recent progress on the total synthesis of marine anti-cancer sesquiterpene quinone/hydroquinone dysideanone B and dysiherbol A was briefly highlighted. This success relied on some key transformations. The union of the terpene and quinone/hydroquinone moieties was realized through a site and stereoselective α-position alkylation of Wieland–Miescher ketone derivative with a bulky benzyl bromide. The 6/6/6/6-tetracycle of dysideanone B was constructed using an intramolecular radical cyclization and the 6/6/5/6-fused core structure of dysiherbol A was forged by an intramolecular Heck reaction, respectively. The possible origin of ethoxy group in dysideanone B was revealed by mimicking the isolation conditions at a late-stage. The structure of dysiherbol A was revised through the total synthesis of this natural product. Schmalz’s synthesis of dysiherbol A was also included.

Syntheses and structures of two benzoyl amides: 2-chloro-4-ethoxy-3,5-dimethoxy-N-(3-oxocyclohex-1-en-1-yl)benzamide and 2-chloro-N-(5,5-dimethyl-3-oxocyclohex-1-en-1-yl)-4-ethoxy-3,5-dimethoxybenzamide

The first title benzoyl amide, C17H20ClNO5 (3a), crystallizes in the monoclinic space group P21/c with Z = 4 and the second, C19H24ClNO5 (3b), also crystallizes in P21/c with Z = 8 (Z′ = 2), thus there are two independent molecules in the asymmetric unit. In 3a, the phenyl ring makes a dihedral angle of 50.8 (3)° with the amide moiety with the C=O group on the same side of the molecule as the C—Cl group. One methoxy group is almost in the plane of the benzene ring, while the ethoxy and other methoxy substituent are arranged on opposite sides of the ring with the ethoxy group occupying the same side of the ring as the C=O group in the amide moiety. For one of the two molecules in 3b, both the amide and 5,5-dimethyl-3-oxocyclohex-1-en-1-yl moieties are disordered over two sets of sites with occupancies of 0.551 (2)/0.449 (2) with the major difference between the two conformers being due to the conformation adopted by the cyclohex-2-en-1-one ring. The three molecules in 3b (i.e., the undisordered molecule and the two disorder components) differ in the arrangement of the subsituents on the phenyl ring and the conformation adopted by their 5,5-dimethyl-3-oxocyclohex-1-en-1-yl moieties. In the crystal of 3a, N—H...O hydrogen bonds link the molecules into a zigzag chain propagating in the [001] direction. For 3b a combination of C—H...O and N—H...O intermolecular interactions link the molecules into a zigzag ribbon propagating in the [001] direction.

Influence of Halogen Substituent on the Self-Assembly and Crystal Packing of Multicomponent Crystals Formed from Ethacridine and Meta-Halobenzoic Acids

In order to determine the influence of halogen substituent on the self-assembly of the 6,9-diamino-2-ethoxyacridinium cations and 3-halobenzoate anions in the crystals formed from ethacridine and halobenzoic acids, the series of ethacridinium meta-halobenzoates dihydrates: ethacridinium 3-chlorobenzoate dihydrate (1), ethacridinium 3-bromobenzoate dihydrate (2), and ethacridinium 3-iodobenzoate dihydrate (3), were synthesized and structurally characterized. Single-crystal X-ray diffraction measurements showed that the title compounds crystallized in the monoclinic P21/c space group and are isostructural. In the crystals of title compounds, the ions and water molecules interact via N–H⋯O, O–H⋯O and C–H⋯O hydrogen bonds and π–π stacking interactions to produce blocks. The relationship between the distance X⋯O between the halogen atom (X=Cl, Br, I) of meta-halobenzoate anion and the O-atom from the ethoxy group of cation from neighbouring blocks and crystal packing is observed in the crystals of the title compounds.

Synthesis, characterization, aggregation and electrochemical properties of peripheral octa-2-{[4-(2-benzylphenoxy]benzyl]thio} ethoxy group substituted cobalt(II) phthalocyanine

We were reported here, the synthesis, characterization, aggregation and electrochemical properties of 4,5-bis(2-{[4-(2- benzyl)phenoxy)benzyl]thio}ethoxy)phthalonitrile and 2,3,9,16, 17,23,24-octa[(2-{[4-(2-benzyl)phenoxy)benzyl]thio}ethoxy)] phthalociyaninatocobalt(II). CoPc were prepared by the reaction of 4,5-bis(2-{[4-(2-benzyl)phenoxy)benzyl]thio}ethoxy) phthalonitrile with the corresponding anhydrous metal salt in n-pentanol and DBU. The structures of the original compounds were identified by using elemental analysis, 1 H-NMR, 13C-NMR, IR, mass and UVvis spectroscopic data. Electrochemical redox characteristics of the compounds were determined by electroanalytical techniques such as cyclic voltammetry, square wave voltammetry. The aggregation tendencies and electrochemical redox properties of all phthalocyanines were investigated on the basis of central metal, solvent medium and substituent effects, using UV-Vis spectral.

A Computational and Experimental Study of the Conformers of Pyrrolidinium Ionic Liquid Cations Containing an Ethoxy Group in the Alkyl Side Chain

We investigate the conformers of the N-methoxyethyl-N-methylpyrrolidinium (PYR1(2O1)) and N-ethoxyethyl-N-methylpyrrolidinium (PYR1(2O2)) ionic liquid cations by means of DFT calculations at the B3LYP/6-31G⁎⁎ level and we calculate their infrared vibration frequencies. The comparison with the absorbance spectra of two ionic liquids containing these ions indicates good performance of such a combination of theory and basis set. The lowest energy conformer of each pyrrolidinium cation displays equatorial-envelope geometry; however, in contrast with the prototypical PYR14, the main alkyl side chain is not in an all-trans configuration, but it tends to be bent. Moreover, calculations indicate that the LUMO orbital extends more along the alkyl side chain in PYR1(2O1) and PYR1(2O2) than in the parent ion 1-butyl-1-methylpyrrolidinium (PYR14).

(E)-4-(4-Ethoxyphenyl)but-3-en-2-one

In the title compound, C12H14O2, the benzene ring makes dihedral angles of 5.03 (8) and 5.37 (15)° with the mean planes of the but-3-en-2-one group and the ethoxy group, respectively. In the crystal, molecules are linked by two pairs of C—H...O hydrogen bonds forming inversion dimers, which enclose anR22(8) ring motif flanked by twoR21(7) loops.

2-Dimethylamino-1-(2-ethoxy-2-oxoethyl)-3-methyl-4,5-dihydroimidazolium tetraphenylborate

In the crystal structure of the title salt, C10H20N3O2+·C24H20B−, the C—N bond lengths in the cation are 1.327 (3), 1.339 (3) and 1.342 (3) Å, indicating partial double-bond character. The central C atom is bonded to the three N atoms, indicating only a slight deviation from a trigonal–planar geometry. The positive charge is delocalized in the CN3plane. The ethoxy group is disordered over two orientations, with an occupancy ratio of 0.60 (1):0.40 (1). C—H...π interactions are present between the guanidinium H atoms and the phenyl C atoms of the tetraphenylborate ions. The phenyl rings form aromatic pockets, in which the cations are embedded. This leads to the formation of a two-dimensional supramolecular pattern along theacplane.