Metabolomics Study of Type 2 Diabetes Mellitus and the AntiDiabetic Effect of Berberine in Zucker Diabetic Fatty Rats Using Uplc-ESI-Hdms.

The present study aimed to evaluate the pathogenesis of type 2 diabetes mellitus (T2DM) and the anti-diabetic effect of berberine in Zucker diabetic fatty (ZDF) rats. A urinary metabolomics analysis was performed with ultra-performance liquid chromatography/electrospray ionization synapt high-definition mass spectrometry. Pattern recognition approaches were integrated to discover differentiating metabolites. We identified 29 ions (13 in negative mode and 16 in positive mode) as 'differentiating metabolites' with this metabolomic approach. A functional pathway analysis revealed that the alterations were mainly associated with glyoxylate and dicarboxylate metabolism, pentose and glucuronate interconversions and sphingolipid metabolism. These results indicated that the dysfunctions of glycometabolism and lipometabolism are involved in the pathological process of T2DM. Berberine could decrease the serum levels of glycosylated hemoglobin, total cholesterol and triglyceride and increase the secretion of insulin. The urinary metabolomics analysis showed that berberine could reduce the concentrations of citric acid, tetrahydrocortisol, ribothymidine and sphinganine to a near-normal state. These results suggested that the anti-diabetic effect of berberine occurred mainly via its regulation of glycometabolism and lipometabolism and activation of adenosine 5'-monophosphate-activated protein kinase. Our work not only provides a better understanding of the anti-diabetic effect of berberine in ZDF rats but also supplies a useful database for further study in humans and for investigating the pharmacological actions of drugs. Copyright © 2016 John Wiley & Sons, Ltd.

Diethyl 2,2'-bis-(hy-droxy-imino)-3,3'-(hydrazinediyl-idene)dibutano-ate.

Each mol-ecule of the title compound, C(12)H(18)N(4)O(6), is located on an inversion centre at the mid-point of the central N-N bond. The azo groups C=N of the Schiff base group have an E conformation and the azo groups in the oxime C=N-O groups have a Z conformation. O-H⋯O hydrogen bonds link neighbouring mol-ecules into infinite monolayers perpendicular to the a axis.

Trinuclear and mononuclear copper(II) complexes incorporating tetradentate 2,2'-[1,1'-(ethylenedioxydinitrilo)diethylidyne]diphenol ligand: Syntheses, crystal structures, spectral and thermal behaviors.

Mononuclear and trinuclear Cu(II) complexes with chemical formula [CuL].CH3OH (1) and [{(Cu(mu-L))2(OAc)2}Cu] (2), where H2L = 2,2'-[1,1'-(ethylenedioxydinitrilo)diethylidyne]diphenol, have been synthesized and characterized by elemental analyses, 1H NMR, IR and UV-vis spectra et al. Crystallographic data of complex 1 reveal the formation of an asymmetric mononuclear structure and a slight distortion toward tetrahedral geometry from the square planar structure, in which the introduction of the non-coordinated methanol molecule lead to the assembly of the 1D chains by hydrogen bonding, Cu...pi and pi...pi interactions. Complex 2 have the elongated square pyramidal geometries for the two terminal Cu(II) ions and an octahedral coordinated geometry for the central Cu(II) ion. In complex 2, two acetate ions coordinate to three Cu(II) ions adopting a familiar syn-syn (muM-O-C-O-M) coordinated fashion. The central Cu(II) ion sits in a crystallographic inversion centre. Therefore, the whole molecule of complex 2 is rigorously centrosymmetric, and forms a 3D supramolecular networks through intermolecular C-H...O and C-H..pi interactions.

6,6'-Dieth-oxy-2,2'-[propane-1,3-diyl-dioxy-bis(nitrilo-methyl-idyne)]diphenol.

The complete mol-ecule of the title compound, C(21)H(26)N(2)O(6), is generated by a crystallographic twofold axis and adopts a trans configuration with respect to the azomethine group. The two benzene rings are almost perpendicular to one another, making a dihedral angle of 89.53 (3)°. In the mol-ecular structure, pairs of intra-molecular O-H⋯N hydrogen bonds generate two six-membered rings. The crystal structure is further stabilized by inter-molecular C-H⋯O hydrogen bonds, which link four adjacent mol-ecules into a network structure.

1,3-Bis[(4-nitro-benzyl-idene)amino-oxy]propane.

The complete molecule of title compound, C(17)H(16)N(4)O(6), is generated by a crystallographic twofold axis. Within the mol-ecule, the two benzene units are approximately perpen-dicular, making a dihedral angle of 85.91 (4)°. In the crystal, mol-ecules are linked into a three-dimensional network by C-H⋯O hydrogen bonds and short O⋯O and N⋯O inter-actions, with distances of 2.998 (2) and 2.968 (3) Å, respectively.

2,2'-[1,1'-(Octane-1,8-diyldioxy-dinitrilo)diethyl-idyne]diphenol.

The title compound, C(24)H(32)N(2)O(4), has a crystallographic inversion centre at the mid-point of the central C-C bond. At each end of the mol-ecule, intra-molecular O-H⋯N hydrogen bonds generate six-membered S(6) ring motifs. The crystal structure is stabilized by pairs of weak inter-molecular C-H⋯O hydrogen bonds that link neighbouring mol-ecules into R(2) (2)(40) ring motifs, which in turn form infinite one-dimensional supra-molecular ribbon structures.

Bis[(E)-4-bromo-2-(ethoxy-imino-meth-yl)phenolato-κN,O]copper(II).

The title compound, [Cu(C(9)H(9)BrNO(2))(2)], is a centrosymmetric mononuclear copper(II) complex. The Cu atom is four-coordinated in a trans-CuN(2)O(2) square-planar geometry by two phenolate O and two oxime N atoms from two symmetry-related N,O-bidentate (E)-4-bromo-2-(ethoxy-imino-meth-yl)phenolate oxime-type ligands. An inter-esting feature of the crystal structure is the centrosymmetric inter-molecular Cu⋯O inter-action [3.382 (1) Å], which establishes an infinite chain structure along the b axis.

(E)-2-{4-[1-(Hydroxyimino)ethyl]phenyl-iminomethyl}-6-methoxyphenol mono-hydrate.

In the title compound, C(16)H(16)N(2)O(3)·H(2)O, the benzene rings are nearly coplanar with each other, forming a dihedral angle of 4.46 (3)°. There is a strong intra-molecular O-H⋯N hydrogen bond which results in a six-membered ring. In the crystal, the mol-ecules are connected into a three-dimensional network via O-H⋯O and O-H⋯N inter-molecular hydrogen bonds, forming a centrosymmetric ring along the b axis with graph-set motif R(4) (4)(10). In addition, the short distances between the centroids of six-membered rings [3.555 (1) Å], indicate the existence of π-π stacking inter-actions, which may stabilize the crystal structure.

1,3-Bis[(4-methylbenzylidene)amino-oxy]propane.

The title bis-oxime compound, C(19)H(22)N(2)O(2), synthesized by the reaction of 4-methyl-2-hydroxy-benzaldehyde with 1,3-bis-(amino-oxy)propane in ethanol, adopts a V-shaped conformation. The dihedral angle between the rings is 84.59 (3)°. The mol-ecule is disposed about a crystallographic twofold rotation axis, with one C atom lying on the axis. In the crystal, mol-ecules are packed by C-H⋯π(Ph) inter-actions, forming chains.

4-({4-[1-(Methoxy-imino)eth-yl]anilino}(phen-yl)methyl-ene)-3-methyl-2-phenyl-1H-pyrazol-5(4H)-one.

In the title compound, C(26)H(24)N(4)O(2), the dihedral angles between the central pyrazole ring and the other three benzene rings are 40.02 (3), 77.51 (5) and 55.72 (3)°. A strong intra-molecular N-H⋯O hydrogen bond forms a six-membered ring with an S(6) motif. In the crystal structure, a weak inter-molecular C-H⋯N inter-action with graph-set motif R(2) (2)(8) and C-H⋯O hydrogen bonds link each mol-ecule to three others, forming an infinite two-dimensional supra-molecular structure.

2,2'-[Octane-1,8-diyldioxy-bis(nitrilo-methyl-idyne)]diphenol.

The complete mol-ecule of the title compound, C(22)H(28)N(2)O(4), is generated by a crystallographic inversion centre at the mid-point of the central C-C bond. The two benzene rings are parallel to each other with a perpendicular inter-planar spacing of 1.488 (2) Å. Intra-molecular O-H⋯N hydrogen bonds generate two six-membered rings with S(6) motifs. In the crystal, weak inter-molecular C-H⋯O hydrogen bonds link neighbouring mol-ecules into an infinite three-dimensional network, which is further stabilized by weak C-H⋯π inter-actions.

{2,2'-[1,1'-(Ethyl-enedioxy-dinitrilo)diethyl-idyne]di-1-naphtholato}copper(II).

The title complex, [Cu(C(26)H(22)N(2)O(4))], is isostructural with its Ni analogue. All intramolecular distances and angles are very similar for the two structures, whereas the packing of the molecules, including C-H⋯O and C-H⋯π interactions, are slightly different.

{2,2'-[1,1'-(Ethyl-enedioxy-dinitrilo)diethyl-idyne]di-1-naphtholato}nickel(II).

In the title complex, [Ni(C(26)H(22)N(2)O(4))], the Ni(II) atom has a slight distortion toward tetra-hedral geometry from a square-planar structure, coordinated by two O and two N atoms of the tetra-dentate salen-type bis-oxime 2,2'-[1,1'-(ethyl-enedioxy-dinitrilo)diethyl-idyne]di-1-naphtholate (L(2-)) unit, with a mean deviation of 0.022 Šfrom the N(2)O(2) plane. The N- and O-donor atoms are mutually cis. The dihedral angle between two naphthalene systems of the L(2-) ligand is 67.59 (4)°. The crystal structure is stabilized by inter-molecular C-H⋯O and C-H⋯π inter-actions, which link neighbouring mol-ecules into extended chains along the b axis.

2,2'-[1,1'-(Heptane-1,7-diyldioxy-dinitrilo)diethyl-idyne]di-1-naphthol.

The mol-ecule of the title compound, C(31)H(34)N(2)O(4), adopts an L-shaped configuration, in which the naphthalene units are approximately perpendicular, making a dihedral angle of 87.89 (3)°. Intramolecular H-bonds are formed between the OH substituents and the N atoms at each end of the molecule. In the crystal structure, each mol-ecule links six other mol-ecules into an infinite three-dimensional network supra-molecular structure, which is built from one-dimensional zigzag chains via weak C-H⋯π stacking and inter-molecular C-H⋯O hydrogen bonds.

2,2'-{1,1'-[Pentane-1,5-diylbis(oxy-nitrilo)]diethylidyne}di-1-naphthol.

The title compound, C(29)H(30)N(2)O(4), adopts a distorted Z configuration with respect to the oxime group, which is almost coplanar with the adjacent naphthalene ring [dihedral angle = 4.11 (2)°]. There is one half-mol-ecule in the asymmetric unit, with a crystallographic twofold rotation axis passing through the central C atom of the -CH=N-O-(CH)(5)-O-N=CH- bridge. Within the mol-ecule, the dihedral angle formed by the two naphthalene rings is 79.08 (3)°, and there are two intra-molecular O-H⋯N hydrogen bonds.

2,2'-{1,1'-[Butane-1,4-diyl-bis(oxy-nitrilo)]di-ethylidyne}di-1-naphthol.

The title compound, C(28)H(28)N(2)O(4), was synthesized by the reaction of 2-acetyl-1-naphthol with 1,4-bis-(amino-oxy)butane in ethanol. The molecule, which lies about an inversion centre, adopts a linear structure, in which the oxime groups and naphthalene ring systems assume an anti conformation. The intra-molecular inter-planar distance between parallel naphthalene rings is 1.054 (3) Å. Intra-molecular O-H⋯N hydrogen bonds are formed between the oxime nitro-gen and hydr-oxy groups.

Bis{(E)-4-chloro-2-[(2-chloro-3-pyrid-yl)imino-methyl-κN]phenolato-κO}copper(II).

In the title complex, [Cu(C(12)H(7)Cl(2)N(2)O)(2)], the Cu(II) center is tetra-coordinated by two phenolic O and two azomethine N atoms from two bidentate 4-chloro-2-[(2-chloro-3-pyrid-yl)imino-meth-yl]phenolate (L) ligands. In the crystal structure, the Cu(II) atom has a distorted square-planar coordination environment. The dihedral angles between the benzene and pyridyl rings are 54.39 (3) and 80.14 (4)°, indicating that the pyridine ring has a considerably weaker steric hindrance. The packing of the mol-ecule is controlled by C-H⋯π(Ph) inter-actions and short O⋯Cl inter-actions [3.196 (4) Å], linking the mol-ecules into a chain-like structure along the c axis.

Bis{(E)-4-bromo-2-[(2-chloro-3-pyrid-yl)imino-meth-yl]phenolato-κN,O}copper(II).

In the title complex, [Cu(C(12)H(7)BrClN(2)O)(2)], the Cu(II) center is tetra-coordinated by two phenolate O and two azomethine N atoms from two independent bidentate 4-bromo-2-[(2-chloro-3-pyrid-yl)imino-meth-yl]phenolate (L) ligands. In the crystal structure, the Cu(II) atom has a distorted square-planar coordination environment. The inter-planar dihedral angles between the benzene and pyridine rings in the individual ligands are 63.83 (4) and 54.43 (3)°, indicating the pyridine ring to have considerably weaker steric hindrance.

N-Benzoyl-N'-(2-chloro-3-pyrid-yl)thio-urea.

The title compound, C(13)H(10)ClN(3)OS, was prepared by the reaction of 3-amino-2-chloropyridine with benzoyl isothio-cyanate at room temperature. The thio-urea group makes dihedral angles of 47.17 (5) and 51.88 (4)°, respectively, with the benzene and pyridyl rings, while the angle between the benzene and pyridine rings is 8.91 (3)°. Inter-molecular hydrogen-bond inter-actions link neighbouring mol-ecules into an infinite supra-molecular structure.

2,2'-Dichloro-1,1'-[(pentane-1,5-diyldi-oxy)bis-(nitrilo-methyl-idyne)]dibenzene.

The mol-ecule of the title compound, C(19)H(20)Cl(2)N(2)O(2), which lies across a crystallographic inversion centre, adopts a linear configuration. The dihedral angle between the two halves of the mol-ecule is 5.14 (2)°. In the crystal structure, inter-molecular C-H⋯O hydrogen bonds link neighbouring mol-ecules into an infinite zigzag chain supra-molecular structure.