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Following the finding of in vitro insulinominetic activities of new prepared Zn(II) complexes with amide ligands (2-picolinamide (pa-a) and 6-methyl-2-picolinmethylamide (6mpa-ma)) in isolated rat adipocytes treated with epinephrine in terms of inhibition of free fatty acid release, their blood glucose normalizing effects were observed on daily intraperitoneal injections for 14 d in a type 2 diabetes mellitus model animal, KK-Ay mice. The blood glucose levels of KK-Ay mice were maintained in a normal range during the administration of both complexes. After the administration of each complex for 14 d, the improvement of glucose metabolism was confirmed as judged by the glucose tolerance test.

Summary: In order to understand the insulinomimetic activity of zinc(II) complexes, we studied the metallokinetic features of zinc in the blood of normal rats given the zinc complexes, bis(maltolato)zinc(II) (Zn(mal) 2 ) and bis(6-methylpicolinato)zinc(II) (Zn(6mpa) 2 ) by comparing each of them with an ionic form of zinc chloride (ZnCl 2 ). The bioavailability of the zinc(II) complexes following oral administration was enhanced to 1.4-1.5-fold that of ZnCl 2 with respect to zinc level. Based on the results of a metallokinetic analysis and administration method in normal rats, we examined the antidiabetic ability of the zinc(II) complexes in GK rats, a model animal of type 2 diabetes mellitus. High blood glucose levels of GK rats were normalized following intraperitoneal injections and oral administration of the zinc(II) complexes, in which the Zn(6mpa) 2 complex was found to be more effective than Zn(mal) 2 . The present results are noteworthy, not only due to their potential relevance for clinical application, but also for the development of new zinc(II) complexes.

Several workers have synthesized chiral and achiral N, N'-ethylene-bridged dipeptides (piperazin-2-one derivatives), and used them mainly as units of biologically active pseudopeptides such i : as enkephalin analogs because these structurally constrained and lipophilic dipeptides afford the character resisting enzymatic hydrolysis to biologically active peptides. However, their synthetic methods have some problems (nonstereoselective, multi-steps, troublesome techniques, expensive reagents etc.) Therefore; we have developed more convenient procedures for preparing N, N'-ethylene-bridged dipeptides. This article reports four kinds of synthetic methods of chiral N, N'-ethylene-bridged dipeptides, in which various (R) or (S) -α-amino acids are used as starting materials. Moreover, a series of studies on the structures and the functionalities (enantioselective inclusion and transport of (R) - and (S) -ammonium salts, complexing of metal ions) of macrocyclic pseudopeptides and on the enkephalin- and dermorphin-like biological activities of linear pseudopeptides containing these dipeptides as their units are introduced and discussed. Also, the synthesis of a macrocyclic polyamine obtained by the BH3 reduction of macrocyclic pseudopeptide and the structure of its metal complex ion are described.

The amide and ester carbonyl groups of four piperazin-2-one derivatives (N,N'-ethylene-bridged dipeptide ethyl esters) constructed from (R)- or (S)-phenylalanine and glycine were reduced with borane-tetrahydrofuran complex to produce the corresponding piperazine derivatives in 70-80% yields. These piperazin-2-one or piperazine derivatives were used as the carboxyl-terminal residues of eight dermorphin analogues (H-tyrosyl-D-alanyl-piperazine derivatives were used as the carboxyl-terminal residues of eight dermorphin analogues (H-tyrosyl-D-alanyl-piperazin-2-one or piperazine derivatives) whose opiate activities were examined in vitro by use of the guinea pig ileum and the mouse vas deferens assays. It was found in the guinea pig ileum assay that the configuration of pheylalanine and the replacement of the piperazin-2-one ring with a piperazine ring are important for enhancing or reducing the opiate activities of these analogues.

In vitro insulinomimetic activities of Zn(II) complexes with three natural products, betaine, L-lactic acid, and D-(-)-quinic acid (qui), were found in rat adipocytes treated with epinephrine in terms of the inhibition of free fatty acid release. Based on the results, the blood glucose lowering effect in KK-A(y) mice with type 2 diabetes mellitus was observed by daily i.p. injections of a monomeric zinc(II) complex, Zn(qui)(2), for 13 d.

Conformations of 24-Membered Ring Pseudopeptides Containing N,N′-Ethylene-Bridged Dipeptides Constructed from ( S )-Alanine, -Leucine, -Isoleucine, and -Phenylalanine

Macrocyclic Peptides VI. Complex Formations and Conformations of an Ionophorous Cyclic Octapeptide Containing N , N ′-Ethylene-Bridged ( S )-Leucyl-( S )-leucine and Glycine in Acetonitrile

Zinc(II) complexes of alpha-amino acids and their derivatives with a Zn(N2O2) coordination mode were found to have in vitro insulinomimetic activity as estimated with the inhibition of free fatty acid release in isolated rat adipocytes treated with epinephrine. It was revealed that the insulinomimetic activities of zinc(II) complexes with over-all stability constants (log beta) less than 10.5 are higher than those of ZnSO4 and VOSO4. The high blood glucose level of KK-Ay mice with type 2 diabetes mellitus was lowered by daily intraperitoneal injections of a zinc(II) complex, cis-[Zn(L-Thr)2(H2O)2], for 14 d. The improvement of diabetes mellitus was confirmed with the oral glucose tolerance test.

We found alpha-glucosidase inhibitory effect of Zn(II) complex with 6-methyl-2-picolinmethylamide (6mpa-ma) which showed the highest blood glucose lowering effect in Zn(II) complexes with picolinamide derivatives in KK-A(y) mice. The Zn(II) complex showed strong alpha-glucosidase inhibitory activity greater by about eighty times (substrate: maltose) and forty times (substrate: sucrose) compared with acarbose.

X-Ray structure analysis has elucidated that the reaction of Nδ-salicylidene-L-ornithine and palladium(II) acetate in DMF results in the amine exchange and racemization of the ligand, yielding (Nα-salicylidene-D-ornithinato)(Nα-salicylidene-L-ornithinato)dipalladiuna(II). The yellow crystals are monoclinic, a=15.15(2), b=9.80(1), c=15.67(2) A, β=111.3(1)°, space group P21⁄c, and Z=2. The structure was solved by the Patterson and Fourier techniques and was refined by the least-squares method to R=0.105. The complex molecule has a center of symmetry by which D- and L-Schiff-base ligands are interrelated. Each Pd atom has a square-planar coordination by means of two O and Nα atoms of one ligand, and the Nδ atom of the other one, the two N atoms being in the trans position. The H2Nδ–(CH2)3–CH–Nα fragments of the two ligands bridge the two Pd atoms, giving a 14-membered ring.

The title compound was prepared, and its structure then determined by X-ray structure analysis. The crystal is trigonal with the space group P3221, a=8.450(3), c=42.00(6)A, and Z=3. The crystal structure has been determined from the diffractometer data and refined by a least-squares method to an R value of 0.103 for 1349 independent reflections with I>3σ(I). The cyclo-L-histidyl-L-histidyl is coordinated to the Cu atom via the N atoms of the respective imidazolyl groups. The coordination of Cu is not planar but distorted toward the tetrahedral configuration, the interplanar angle betweent (Remark: Graphics omitted.) planes being 29°. The complex has virtually D2 symmetry: there are two pseudo two-fold axes and one crystallographically imposed two-fold axis which relates two chelate rings. The chelate rings assume the δ conformation, and the ligating cyclo-L-histidyl-L-histidyl is of a folded form with a bowsprit-boat 2,5-piperazinedione ring. The electronic and circular dichroism spectra in the visible re...

The crystal structure of the title compound has been determined by a three-dimensional X-ray structure analysis, using 4563 counter intensity data. The crystals are monoclinic, with a=22.97(2), b=15.89(1), c=10.00(1) A, β=100.1(1)°, space group P21, and Z=4. The structure was solved by the Patterson and Fourier technique and was refined by the block-diagonal least-squares method to R=0.061. The unit cell contains two crystallographically independent complex cations, the structure of which are very similar to each other. The complex cation is dimeric; there are two Cu atoms, and each of the two cyclo-L-histidyl-L-histidylato ligands bridges two metal atoms. Except for the aqua ligand, the main body of the complex has an approximate twofold axis which passes through the two metal atoms and relates the ligands to each other. The two Gu atoms have different coordination geometries. One Gu atom has a flattened tetrahedral coordination by 4N atoms, whereas the other is surrounded by 2N and 3O atoms and is inter...

The crystal structure of a zinc(II) complex with cyclo(L-methionyl-L-histidyl) shows that all four ligands coordinated tetrahedrally to a Zn2+ ion have a folded conformation, with the imidazole ring facing the piperazine ring in each ligand. The calculation from α-β coupling constant data (obtained by 1H NMR measurement) of the histidyl residue of cyclo(L-methionyl-L-histidyl) linked to a Zn2+ ion shows that the ratio of a folded conformation to an unfolded one is 61:39 in D2O.

The crystal structure of cyclo(L-histidyl-L-histidyl) was determined by X-ray diffraction techniques, and was refined to a final R index of 0.066 for 680 reflections. This showed that one imidazolyl group of this compound faces the piperazine ring(folded) whereas the other is kept away from the ring(unfolded). A calculation using the α-β coupling-constant data of this peptide obtained by an 1H NMR measurement shows that the ratio of a folded conformation to an unfolded one is 49:51 in D2O. Also, NMR investigations of zinc(II) and silver(I) complexes with this peptide were carried out in D2O.

The reaction between acetone and methanol to form acetone dimethylacetal attains equilibrium quickly under the influence of copper(II) bromide. Reaction of both acetone and acetone dimethylacetal with copper(II) bromide thus proceed simultaneously to produce copper(I) bromide, hydrogen bromide, and brominated substrates. The mass balances of these reactions were established. On account of the retarding effect of copper(I) bromide and the enhancing effect of hydrogen bromide, the time course of reaction is too complicated to be analyzed, and the initial rate formula was determined. Two reaction pathways were suggested and copper(II) bromide was considered to play dual roles as a catalyst and a brominating agent in either case. The acid catalyzed reactions were also found to follow a two-term rate law, one being independent of and the other first order with respect to copper(II) bromide.

When the copper(II) chelate of ethyl acetoacetate reacts with bromine in dry dichloromethane, the chelate is broken, forming the α-bromoester and copper(I) or copper(II) bromide depending on the reactants’ mole ratio. However, in the reaction between bromine and the chelate at a mole ratio of 1 : 1 in dichloromethane saturated with water, copper-(I) bromide is not produced primarily; instead copper(II) hydroxide is formed, as is copper-(II) bromide. In the reactions of the copper(II) chelate of acetylacetone or ethyl acetoacetate with dry hydrogen bromide at the mole ratio of 1 : 1 or 1 : 1.5, more than 98% of the total copper precipitated as copper(I) bromide. Even when 2 mol. of hydrogen bromide was employed against 1 mol. of the chelate, more than 90% of the original copper changed to copper(I) bromide, in contrast with the results obtained in a similar reaction with bromine. The entire reaction pattern has been suggested employing a presumed intermediate binuclear complex containing a bromine double b...

Because of a long induction period, the reaction between acetone and copper(II) bromide does not occur readily in pure DMF. However, in the presence of an acid, it proceeds readily. The initial rate is proportional to the product of the concentration of acetone and perchloric acid, but independent of the concentration of copper(II) bromide. The acid-catalyzed bromination of acetone by bromine has also been studied in DMF and found to obey the same second-order rate law as that in water. Both bromination reactions of acetone in DMF by copper(II) bromide and bromine were interpreted to be controlled by the enolization process of acetone.

The structures of silver(I) complexes with cyclo(glycyl-L-histidyl), cyclo(L-methionyl-L-histidyl), and cyclo(L-histidyl-L-histidyl) were examined using 1H and 13C NMR. The NMR measurements suggest...

The crystal structure of the title complex, [H2O Cu2(C12H13N6O2)2](ClO4)2·3.5H2O, was determined from X-ray diffraction data. The unit cell contains two independent complex cations which have similar structures. The complex cation consists of a dimer in which one Cu atom is pseudo tetrahedral and the other one distorted square pyramidal.