Yoshitane Kojima’s research while affiliated with Seikei University and other places

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.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

The solution conformations of novel dipeptides, methyl (2S, 3′S)-3-methyl-2-(2′-oxo-3′-isopropyl-1′-piperazinyl)-butanoate (EVV-OCH3), methyl (2S, 3′S)-3-phenyl-2-(2′-oxo-3′-benzyl-1′-piperazinyl) propionate (EFF-OCH3), and their derivatives (Boc-Gly-EW-OH, Boc-Gly-EVV-Gly-OH, and Boc-Gly-EFF-OH), were studied by ‘H NMR measurements and molecular mechanics calculations (1). The molecular structures of Boc-Gly-EVV-OH, Boc-Gly-EFF-OH, and the hydrochloride of EVV-OCH3 were determined by X-ray analyses. The conformations of the piperazinone rings and the side chains of these oligopeptides were clarified.

A new cyclic compound [(2S,3′S)-2-(2′-oxo-3′-methylpiperazin-1′-yl)-propanoic acid] obtained using (2S,7S)-2,7-dimethyl-3,6-diazaoctanedioic acid as a starting material was derived from N-t-butyloxycarbonyl-(2S,3′S)-2-(2′-oxo-3′-methylpiperazin-1′-yl)-propanoic acid in order to determine the molecular structure by X-ray crystal analysis. Two new macrocyclic peptides were prepared using the above cyclic compound and sarcosine as peptide units.

We prepared zinc(II) complexes with a series of monomethyl-substituted pyridine-2-sulfonic acid derivatives to clarify the relationship between the structure and insulinomimetic activity. Towards in vitro insulinomimetic activity, bis(3-methylpyridine-2-sulfonato)zinc(II) gave the best result among the zinc(II) complexes with methylpyridine-2-sulfonates.

Several metal ions and their complexes have been known to mimic the action of insulin in in vitro and in vivo systems. We prepared a family of Zn(II) complexes derived from amino ligands with Zn(Nn) (n=3 and 4) coordination modes, the insulinomimetic activity being estimated by an inhibitory effect of free fatty acid release from isolated rat adipocytes treated with epinephrine. In comparison with the positive controls VOSO(4) and ZnSO(4), Zn(II)-amine complexes with stability constants (log beta) lower than 11.5 exhibited higher insulinomimetic activities. Among them, a bis(2-aminomethyl pyridinato)Zn(II) (Zn(2-ampy)(2)(2+)) complex with the highest insulinomimetic activity and a higher stability constant but lower than 11.5 was selected, and subjected to in vivo evaluation in KK-A(y) mice with a genetically type 2 diabetes mellitus. The high blood glucose level of the mice was lowered by daily intraperitoneal injections of Zn(2-ampy)(2)(2+) at a dose of 2 mg Zn/kg body weight for 14 days. Based on the results, Zn(2-ampy)(2)(2+) with Zn(N(4)) coordination mode was proposed to have both a high in vitro insulinomimetic activity and an in vivo blood glucose lowering effect.

The insulinomimetic activity of zinc(II) complexes Zn(gln-m)(2) and Zn(gln-e)(2), respectively, with L-gamma-glutamyl-methylamide (gln-m) and -ethylamide (theanine: gln-e), components of green tea, were compared to that of Zn(gin)(2) with L-glutarnine (gin) in an in vitro study using isolated rodent adipocytes treated with epinephrine in the presence of glucose, expressed as the IC50 value (50% inhibition concentration) of free fatty acids (FFA) released from fat cells. The former were found to have higher inslinomimetic activity than that of the latter. The IC50 values of the former were 0.61 and 0.56, respectively. Then, the anti-diabetic activity of a zinc(II) complex, Zn(gin-e)(2), was examined in an in vivo experiment on KK-A(y) mice, model animals of type-2 DM, by the intraperitoneat (ip) injection of 3-4 mg Zn/kg b.w./day for 13 days. The blood-glucose level of a group treated with a Zn complex, Zn(gin-e)(2), decreased significantly after 13 days compared to those of non-treated and gln-e treated groups. The serum concentrations of triglyceride (TG) and HbA(1c), decreased significantly in Zn(gln-e)(2) treated KK-Ay mice compared to those of the gln-e treated group, respectively. Furthermore, the improvement in glucose tolerance was confirmed by an 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.