Bis[S-octyl 3-(2-methyl-propyl-idene)di-thio-carb-az-ato-κ2N3,S]nickel(II).

The central NiII atom in the title complex, [Ni(C13H25N2S2)2], is located on an inversion center and adopts a roughly square-planar coordination environment defined by two chelating N,S donor sets of two symmetry-related ligands in a trans configuration. The Ni-N and Ni-S bond lenghts are 1.9193 (14) and 2.1788 (5) Å, respectively, with a chelating N-Ni-S bond angle of 86.05 (4)°. These data are compared with those measured for similar di-thio-carbazato ligands that bear n-octyl or n-hexyl alkyl chains. Slight differences are observed with respect to the phenyl-ethyl-idene derivative where the ligands are bound cis relative to one another.

Crystal structure of bis-{S-octyl-3-[(thio-phen-2-yl)methyl-idene]di-thio-carbazato-κ2N3,S}nickel(II).

In the title complex, [Ni(C14H21N2S3)2], the nickel(II) atom is located on a crystallographic inversion center and exhibits a square-planar coordination environment, being coordinated by two negatively charged N,S-chelating ligands in a trans configuration. In the crystal, the non-H atoms of the complex are practically coplanar (r.m.s. deviation of fitted atoms = 0.135 Å), and the angle between the thienyl and the chelating rings is 6.7 (1)°. The mol-ecules stack at a distance of 3.623 (2) Šalong the b-axis direction.

Crystal structure of 4-[(4-methyl-benz-yl)-oxy]-N'-(4-nitro-benzyl-idene)benzohydrazide: a new hydrazone derivative.

The mol-ecular structure of the title compound, C22H19N3O4, shows a non-coplanar conformation, with dihedral angles between the phenyl rings of 73.3 (1) and 80.9 (1)°. These deformations are induced by the crystal packing that is mainly governed by N-H⋯O and C-H⋯O hydrogen bonds, forming a mono-periodic arrangement parallel to the b axis.

Crystal structure of bis-[4-(all-yloxy)-N'-(but-2-en-1-yl-idene)benzohydrazidato]nickel(II).

In the title complex, [Ni(C14H15N2O2)2], the nickel(II) atom exhibits a square-planar coordination geometry, being coordinated by two negatively charged N,O chelating ligands in a trans configuration, with the metal located on a crystallographic center of symmetry. The X-ray structural characterization showed the complex to be disordered over two orientations with refined occupancies of 0.898 (2) and 0.102 (2). The whole mol-ecule is close to planar, the five- and six-membered rings subtending a dihedral angle of 7.5 (2)°. The crystal packing is supported by C-H⋯π and C-H⋯O inter-actions that form a di-periodic layered network.

Crystal structures of 4-[(4-methyl-benz-yl)-oxy]benzohydrazide and its N'-[(thio-phen-2-yl)-methyl-idene]- derivative.

The mol-ecular and crystal structures of a benzoyl-hydrazine bearing an ether group, 4-[(4-methyl-benz-yl)-oxy]benzohydrazide, C15H16N2O2, (I), and of the corresponding N'-[(thio-phen-2-yl)-methyl-idene]- derivative, 4-[(4-methyl-benz-yl)-oxy]-N'-[(thio-phen-2-yl)-methyl-idene]benzohydrazide, C20H18N2O2S, (II), are described. The supra-molecular structures of both compounds are governed by N-H⋯N and N-H⋯O hydrogen-bonding inter-actions. The hydrazine compound (I) shows a crystal packing with a more complex hydrogen-bonding scheme because of the NH-NH2 entity, forming a di-periodic supra-molecular structure extending parallel to (100). Hydrazone mol-ecules in (II) are hydrogen-bonded through N-H⋯O inter-actions, giving rise to the formation of ribbons parallel to [010]. Mol-ecules of (I) and (II) show a different orientation of the carbohydrazide moiety likely to favor the crystal packing and thus hydrogen-bonding inter-actions.

4-(All-yloxy)benzohydrazide.

The non-H atoms of the title compound, C10H12N2O2, are approximately coplanar with the exception of those at the ends: the terminal allyl carbon atom and terminal hydrazide nitro-gen atom are displaced from the mean plane by 0.67 (2) and 0.20 (2) Å, respectively. In the crystal, the mol-ecules are linked by N-H⋯O and N-H⋯N hydrogen bonds, which give rise a two-dimensional network propagating in the (001) plane.

Crystal structure of S-n-octyl 3-(1-phenyl-ethyl-idene)di-thio-carbazate and of its bis-chelated nickel(II) complex.

The nitro-gen-sulfur Schiff base proligand S-n-octyl 3-(1-phenyl-ethyl-idene)di-thio-carbazate, C17H26N2S2 (HL), was prepared by reaction of S-octyl di-thio-carbamate with aceto-phenone. Treatment of HL with nickel acetate yielded the complex bis-[S-n-octyl 3-(1-phenyl-ethyl-idene)di-thio-carbazato]nickel(II), [Ni(C17H25N2S2)2] (NiL 2), which was shown to adopt a tetra-hedrally distorted cis-square-planar coordination geometry, with the NiSN planes of the two ligands forming a dihedral angle of 21.66 (6)°. Changes in the geometry of the L ligand upon chelation of Ni2+ are described, involving a ca 180° rotation around the N(azomethine)-C(thiol-ate) bond.

Crystal structure of bis-{4-[(4-methyl-benz-yl)-oxy]-N'-(4-methyl-benzyl-idene)benzohydrazidato}nickel(II).

In the title complex, [Ni(C23H21N2O2)2], the central NiII atom is located on an inversion centre and exhibits a slightly distorted square-planar N2O2 coordination environment. A trans-configuration of the N,O chelating ligands results from the imposed site symmetry of the central NiII atom. In the crystal, individual mol-ecules stack along the a axis through weak π-π stacking inter-actions between the phenyl rings.

Crystal structure of ethyl 4-[(4-methyl-benz-yl)-oxy]benzoate.

The title compound, C17H18O3, crystallizes with three mol-ecules in the asymmetric unit. The mol-ecules differ in the conformation related to the eth-oxy group and in the orientation of the two phenyl rings, one of which has the eth-oxy group disordered over two positions with refined occupancies of 0.735:0.265 (9). In the crystal packing, the mol-ecules are connected by weak C-H⋯π inter-actions.

Cis versus trans arrangement of di-thio-carbazate ligands in bis-chelated Ni and Cu complexes.

The structures are described of two bis-chelated metal complexes of nickel(II) and copper(II) with S-n-hexyl 3-(1-phenyl-ethyl-idene)di-thio-carbazate Schiff bases in a cis configuration, namely, bis-[S-n-hexyl 3-(1-phenyl-ethyl-idene)di-thio-carbazato-κ2 N 3,S]nickel(II), [Ni(C15H21N2S2)2], and bis-[S-n-hexyl 3-(1-phenyl-ethyl-idene)di-thio-carbazato-κ2 N 3,S]copper(II), [Cu(C15H21N2S2)2]. In both complexes, the metals have distorted square-planar geometries. A search in the Cambridge Structural Database [Groom et al. (2016 ▸). Acta Cryst. B72, 171-179] for bis-chelated nickel(II) and copper(II) complexes with similar Schiff bases retrieved 55 and 36 hits for the two metals, respectively. An analysis of the geometrical parameters of complexes showing cis and trans configurations is reported and the values compared with those for the complexes described in this work.

Novel biosensor system model based on fluorescence quenching by a fluorescent streptavidin and carbazole-labeled biotin.

In the present study, a novel molecular biosensor system model was designed by using a couple of the fluorescent unnatural mutant streptavidin and the carbazole-labeled biotin. BODIPY-FL-aminophenylalanine (BFLAF), a fluorescent unnatural amino acid was position-specifically incorporated into Trp120 position of streptavidin by four-base codon method. On the other hand, carbazole-labeled biotin was synthesized as a quencher for the fluorescent Trp120BFLAF mutant streptavidin. The fluorescence of fluorescent Trp120BFLAF mutant streptavidin was decreased as we expected when carbazole-labeled biotin was added into the mutant streptavidin solution. Furthermore, the fluorescence decrease of Trp120BFLAF mutant streptavidin with carbazole-labeled biotin (100 nM) was recovered by the competitive addition of natural biotin. This result demonstrated that by measuring the fluorescence quenching and recovery, a couple of the fluorescent Trp120BFLAF mutant streptavidin and the carbazole-labeled biotin were successfully applicable for quantification of free biotin as a molecular biosensor system. Copyright © 2016 John Wiley & Sons, Ltd.

Site-selective chemical modification of chymotrypsin using peptidyl derivatives bearing optically active diphenyl 1-amino-2-phenylethylphosphonate: Stereochemical effect of the diphenyl phosphonate moiety.

Diphenyl (α-aminoalkyl)phosphonates act as mechanism-based inhibitors against serine proteases by forming a covalent bond with the hydroxy group of the active center Ser residue. Because the covalent bond was found to be broken and replaced by 2-pyridinaldoxime methiodide (2PAM), we employed a peptidyl derivative bearing diphenyl 1-amino-2-phenylethylphosphonate moiety (Phe(p) (OPh)2 ) to target the active site of chymotrypsin and to selectively anchor to Lys175 in the vicinity of the active site. Previously, it was reported that the configuration of the α-carbon of phosphorus in diphenyl (α-aminoalkyl)phosphonates affects the inactivation reaction of serine proteases, i.e., the (R)-enantiomeric diphenyl phosphonate is comparable to l-amino acids and it effectively reacts with serine proteases, whereas the (S)-enantiomeric form does not. In this study, we evaluated the stereochemical effect of the phosphonate moiety on the selective chemical modification. Epimeric dipeptidyl derivatives, Ala-(R or S)-Phe(p) (OPh)2 , were prepared by separation with RP-HPLC. A tripeptidyl (R)-epimer (Ala-Ala-(R)-Phe(p) (OPh)2 ) exhibited a more potent inactivation ability against chymotrypsin than the (S)-epimer. The enzyme inactivated by the (R)-epimer was more effectively reactivated with 2PAM than the enzyme inactivated by the (S)-epimer. Finally, N-succinimidyl (NHS) active ester derivatives, NHS-Suc-Ala-Ala- (R or S)-Phe(p) (OPh)2 , were prepared, and we evaluated their action when modifying Lys175 in chymotrypsin. We demonstrated that the epimeric NHS derivative that possessed the diphenyl phosphonate moiety with the (R)-configuration effectively modified Lys175 in chymotrypsin, whereas that with the (S)-configuration did not. These results demonstrate the utility of peptidyl derivatives that bear an optically active diphenyl phosphonate moiety as affinity labeling probes in protein bioconjugation. © 2015 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 106: 521-530, 2016.

Crystal structure of bis-[S-hexyl 3-(4-methyl-benzyl-idene)di-thio-carbazato-κ(2) N (3),S]palladium(II).

The whole mol-ecule of the title complex, [Pd(C15H21N2S2)2], is generated by twofold rotational symmetry. The palladium(II) atom exhibits a square-planar coordination geometry, and is located on the crystallographic twofold axis that induces a cis configuration of the N,S chelating ligands. In the crystal, mol-ecules stack along the c-axis direction and there are no significant inter-molecular inter-actions present. The structure was refined as an inversion twin with a final BASF parameter of 0.34 (2).

(+)-Grandifloracin, an antiausterity agent, induces autophagic PANC-1 pancreatic cancer cell death.

Human pancreatic tumors are known to be highly resistant to nutrient starvation, and this prolongs their survival in the hypovascular (austere) tumor microenvironment. Agents that retard this tolerance to nutrient starvation represent a novel antiausterity strategy in anticancer drug discovery. (+)-Grandifloracin (GF), isolated from Uvaria dac, has shown preferential toxicity to PANC-1 human pancreatic cancer cells under nutrient starvation, with a PC50 value of 14.5 µM. However, the underlying mechanism is not clear. In this study, GF was found to preferentially induce PANC-1 cell death in a nutrient-deprived medium via hyperactivation of autophagy, as evidenced by a dramatic upregulation of microtubule-associated protein 1 light chain 3. No change was observed in expression of the caspase-3 and Bcl-2 apoptosis marker proteins. GF was also found to strongly inhibit the activation of Akt, a key regulator of cancer cell survival and proliferation. Because pancreatic tumors are highly resistant to current therapies that induce apoptosis, the alternative cell death mechanism exhibited by GF provides a novel therapeutic insight into antiausterity drug candidates.

Uvaridacols E-H, highly oxygenated antiausterity agents from Uvaria dac.

Chemical investigation of the stems of Uvaria dac yielded four new highly oxygenated cyclohexene derivatives named uvaridacols E-H (1-4). Their structures were established through NMR and circular dichroism spectroscopic analysis. Uvaridacols E (1), F (2), and H (4) displayed weak preferential cytotoxicity against PANC-1 human pancreatic cancer cells under nutrition-deprived conditions in a concentration-dependent manner, without causing toxicity in normal nutrient-rich conditions.

Antiausterity agents from Uvaria dac and their preferential cytotoxic activity against human pancreatic cancer cell lines in a nutrient-deprived condition.

Human pancreatic cancer cell lines are known for their inherent tolerance to nutrition starvation, which enables them to survive under a hypovascular (austerity) tumor microenvironment. The search for agents that preferentially retard the survival of cancer cells under low nutrition conditions (antiausterity agent) is a novel approach to anticancer drug discovery. In this study, it was found that a dichloromethane extract of the stem of Uvaria dac preferentially inhibited PANC-1 human pancreatic cancer cells survival under nutrition-deprived conditions at a concentration of 10 µg/mL. Workup of this bioactive extract led to the discovery of (+)-grandifloracin (8) as a potent antiausterity agent as evaluated in a panel of four human pancreatic cancer cell lines, PANC-1 (PC(50), 14.5 µM), PSN-1 (PC(50), 32.6 µM), MIA PaCa-2 (PC(50), 17.5 µM), and KLM-1 (32.7 µM). (+)-Grandifloracin (8) has been isolated from a natural source for the first time. Its absolute stereochemistry was established by single-crystal X-ray crystallography and circular dichroism spectroscopic analysis. In addition to this, seven other new highly oxygenated cyclohexene derivatives, named uvaridacanes A (1) and B (2), uvaridacols A-D (3, 4, 6, 7), and uvaridapoxide A (5), were also isolated and structurally characterized.

Dicyclopenta[a,d]cyclooctene: A [14]Annulene Containing Two Zero-Atom Cross-Links.

14π-Electrocyclization across the two pentafulvenoid moieties of pentafulvene 1 occurs upon heating to provide dicyclopenta[a,d]cyclooctene 2 [Eq. (1)]. The nonalternant hydrocarbon 2 shows diatropic character and a distinctive absorption spectrum with the longest wavelength maximum at 767 nm.

Structure and Properties of 3-(Diethylboryl)pyridines(1).

3-(Diethylboryl)pyridine (1a), a versatile starting material for the preparation of arylpyridines, is notable for its stability under ambient conditions, in spite of little steric hindrance on the boron atom. (1)H and (13)C spectra of 1a indicated that the boryl group does not act as a mere pi-acceptor and that the boron atom is shielded by ca. 50 ppm even when compared with trivalent boron atoms conjugated with the pi-donor. A single-crystal X-ray crystallographic study for 1a revealed formation of a cyclic-tetramer with a void via the intermolecular boron-nitrogen coordination bond. Vapor pressure osmometry in various solvents suggested that 1a comprises the tetramer in these solutions. In order to know the actual structure, synthesis of 3-(2-methoxyethoxy)-5-(diethylboryl)pyridine (1b) and its scrambling experiment with 1a were carried out. Heating at 100 degrees C for 24 h was required to attain the equilibrium of the scrambling of the component molecules in the tetramers. This means that 3-(diethylboryl)pyridines 1a and 1b comprise the rigid cyclic-tetramer in solution at ambient temperature. Compound 1b is stable in aerated tetrahydrofuran containing up to 33 % water.