Yoshitane Kojima

Antidiabetic vanadium(IV) and zinc(II) complexes

Abstract Diabetes mellitus (DM), which develops many secondary complications such as atherosclerosis, microangiopathy, renal dysfunction and failure, cardiac abnormality, diabetes retinopathy and ocular disorders, is classified as either insulin-dependent type 1 or non-insulin-dependent type 2, according to the definition of WHO. Although several types of insulin preparations for type 1 DM and those of synthetic drugs for type 2 DM have been developed and clinically used, they have several problems such as physical and mental pain due to daily insulin injections and defects involving side effects, respectively. In the 21st century, a new class of pharmaceuticals should be introduced. For this reason, metallopharmaceutical compounds containing vanadium and zinc ions are expected to treat both types of DM, by making effective use of unique characteristics of the metals. In this article, the current state of development of insulin-mimetic vanadium and zinc complexes with different coordination modes are reviewed, focusing on the preparations and coordination structures of the complexes and in vitro and in vivo evaluations as well as the possible mechanism.

A new insulin-mimetic bis(allixinato)zinc(II) complex: structure-activity relationship of zinc(II) complexes.

During the investigation of the development of insulin-mimetic zinc(II) complexes with a blood glucose-lowering effect in experimental diabetic animals, we found a potent bis(maltolato)zinc(II) complex, Zn(ma)2, exhibiting significant insulin-mimetic effects in a type 2 diabetic animal model. By using this Zn(ma)2 as the leading compound, we examined the in vitro and in vivo structure–activity relationships of Zn(ma)2 and its related complexes. The in vitro insulin-mimetic activity of these complexes was determined by the inhibition of free fatty acid release and the enhancement of glucose uptake in isolated rat adipocytes treated with epinephrine. A new Zn(II) complex with allixin isolated from garlic, Zn(alx)2, exhibited the highest insulin-mimetic activity among the complexes analyzed. The insulin-mimetic activity of the Zn(II) complexes examined strongly correlated (correlation coefficient=0.96) with the partition coefficient (logP) of the ligand, indicating that the activity of Zn(ma)2-related complexes depends on the lipophilicity of the ligand. The blood glucose-lowering effects of Zn(alx)2 and Zn(ma)2 were then compared, and both complexes were found to normalize hyperglycemia in KK-Ay mice after a 14-day course of daily intraperitoneal injections. However, Zn(alx)2 improved glucose tolerance in KK-Ay mice much more than did Zn(ma)2, indicating that Zn(alx)2 possesses greater in vivo anti-diabetic activity than Zn(ma)2. In addition, Zn(alx)2 improved leptin resistance and suppressed the progress of obesity in type 2 diabetic KK-Ay mice. On the basis of these observations, we conclude that the Zn(alx)2 complex is a novel potent candidate for the treatment of type 2 diabetes mellitus.

Bis(6-ethylpicolinato)oxovanadium(IV) complex with normoglycemic activity in KK-Ay mice

A novel bis(6-ethylpicolinato)(H(2)O)oxovanadium(IV) complex (VO(6epa)(2) x (H(2)O)) was prepared and its structure was revealed by X-ray analysis (space group Pc(#7), a=10.838(2), b=11.148(5), c=16.642(3) A, and Z=2). Because VO(6epa)(2) x (H(2)O) exhibited higher in vitro insulinomimetic activity compared to that of vanadyl sulfate in terms of inhibition of free fatty acid (FFA) release from isolated rat adipocytes in the presence of epinephrine, its in vivo effect on whether the complex has a blood glucose normalizing effect was examined in KK-A(y) mice, a model animal of type 2 diabetes mellitus. VO(6epa)(2) x (H(2)O) was found to normalize the high blood glucose levels of KK-A(y) mice when given intraperitoneally at doses of 49 micromol/kg body weight for the first 4 days and then 39 micromol/kg body weight for 10 days. In addition, VO(6epa)(2) x (H(2)O) improved glucose tolerance ability as examined by the oral glucose test and seemed to have little toxicity in terms of serum parameters. VO(6epa)(2) x (H(2)O) showed higher normoglycemic activity than bis(6-methylpicolinato)oxovanadium(IV) (VO(6mpa)(2)) at the same dose. These results indicated that greater enhancement of the blood glucose normalizing effect in KK-A(y) mice by ethyl substitution compared to methyl substitution may be due to its being more strongly lipophilic.

Macrocyclic pseudopeptides containing N,N′-ethylene-bridged-dipeptide units: synthesis, binding properties toward metal and organic ammonium cations, and conformations. The first step in designing artificial metalloproteins

Abstract To design a metalloprotein and metalloenzyme model, macrocyclic pseudopeptides containing N,N′-ethylene-bridged-dipeptides were synthesized and their conformations estimated. Piperazin-2-one rings in this type of macrocyclic pseudopeptide provide a hydrophobic wall and deep cavity as shown in the structure of valinomycin. A 24-membered cyclic pseudopeptide was able to include metal cations, and a 36-membered one was able to bind organic ammonium cations enantioselectively. This offers a new type of host-guest chemistry.

Enantioselective transport of amino acid ester salts by macrocyclic pseudopeptides containing N, N′-ethylene-bridged-dipeptide units

Macrocyclic pseudopeptides containing N,N′-ethylene-bndged-dipeptide units exhibited specific transport properties toward several amino acid ester salts, while they rarely transported K− or other metal cations. In particular, a 36-membered pseudopeptide extracted amino acid ester salts in an enantioselective fashion and mediated their enantioselective transport.

Synthesis of met- and leu-enkephalin analogues containing chiral N,N′-ethylene-bridged phenylalanyl-methionine and -leucine

Conformationally constrained N,N′-ethylene-bridged dipeptides (eXX′) were conveniently synthesized in two steps using (R)- or (S)-phenylalanine (X = F) and -methionine (X′= M)[-leucine (X′= L)] as starting materials.These dipeptides are diastereoisomeric or enantiomeric, and were used as the carboxyl terminal residues of enkephalin analogues [H–tyrosyl–D-alanyl–glycyI–eXX′–OEt]. The opiate activities of these pentapeptides were examined preliminarily by the mouse vas deferens assay, suggesting that these enkephalin analogues possess receptor- binding affinities.

Syntheses and crystal structures of oxovanadium(IV) complexes with N,N′-ethylenebis(amino acids)

Abstract The oxovanadium(IV) complexes with N,N′-ethylenebis(amino acids) ([VO(XeX)(H2O)], where X=A ((S)-Ala), V ((S)-Val) and P ((S)-Pro)) are synthesized and characterized by X-ray analyses and IR spectra. The crystal structure analyses reveal that the geometry around the vanadium cation of each complex is distorted octahedral and is coordinated by a water molecule and the tetradentate N,N′-ethylenebis(amino acidate) anion with Δ-cis-α configuration, in which the water oxygen atom occupies equatorial coordination position and one of the two secondary or tertiary nitrogen atoms of each tetradendate ligand is bound trans to the vanadyl oxo moiety. The compilation of bond lengths for present and previous VO complexes containing nitrogen and oxygen donating ligands shows that the tertiary amine groups of PeP ligand elongate VN bonds. Comparison of the sum of the bond angles of three five-membered rings (one ethylenediamine ring and two amino acidate rings) indicates that the ring strain is mostly concentrated in the ethylenediamine ring and the strain of amino acidate ring lying in the equatorial plane of V(IV) ion is more pronounced than that in another amino acidate ring. The IR observations of the present complexes are well consistent with the crystallographic studies of them.

Preparations ofN, N′-ethylene-bridged dipeptides(eXX) constructed from (S)-methionine, -tryptophan, -tyrosine and-N(ɛ)-benzyloxycarbonyllysine through acid-catalyzed cyclization

SummaryN, N′-Ethylene-bridged bis-(S)-methionine[(2S, 7S)-2, 7-bis(2-methyl-thioethyl)-3,6-diazaoctanedioic acid] derived from (S)-methionine and 1,2-dibromoethane was cyclized and esterified simultaneously in boiling ethanol in the presence of an appropriate amount of strong acid such asp-toluenesulfonic acid, affording a cyclic compound,N, N′-ethylene-bridged (S)-methionyl-(S)-methionine ethyl ester {ethyl(2S, 3′S)-4-(methylthio)-2-[2′-oxo-3′-(2-methylthioethyl)-1′-piperazinyl] butanoate}, exclusively in 80–90% yields. It was also found that, by applying this method, 70–80% yields of the otherN, N′-ethylenebridged dipeptides containing (S)-tryptophan, -tyrosine and -N(ɛ)-benzyloxycarbonyllysine were obtained.

Novel optically-active bis(amino acid) ligands and their complexation with gadolinium

A condensation reaction of glyoxal with (S)-histidine and (S)-aspartic acid yielded a new optically-active bis(amino acid) ligand, N-[(S)-1-carboxy-2-(imidazol-4-yl)ethyl]-N′-[(S)-1,2-dicarboxyethyl]ethylenediamine. Two bis(amino acid) ligands with picolyl (pyridylmethyl) groups were synthesized by condensation reactions of glyoxal with the picolyl derivative of (S)-histidine and that of (S)-aspartic acid: the obtained ligands are N,N′-bis(2-pyridylmethyl)-N-[(S)-1-carboxy-2-(imidazol-4-yl)ethyl]-N′-[(S)-1,2-dicarboxyethyl]ethylenediamine and N,N′-bis(2-pyridylmethyl)-N,N′-bis[(S)-1-carboxy-2-(imidazol-4-yl)ethyl]ethylenediamine. The protonation constants of these ligands were determined by potentiometry, and the corresponding protonation sites were located on the basis of 1H NMR spectra obtained at different pD values. The formation constants of the Gd3+ complexes were determined by potentiometric titrations, and the NMR relaxivities r1 and r2 by the measurements of the NMR relaxation times.

Coordination abilities of amide oxygens in a 24-membered ring pseudopeptide toward several transition metal ions in acetonitrile

Abstract Stability constants of a cyclic octapseudopeptide, cyclo (Gly-eLL-Gly) 2 (eLL N , N ′-ethylene-bridged ( S )-leucyl-( S )-leucine, Gly=glycine), for eleven kinds of transition metal ions were investigated by CD spectra in acetonitrile at 25 °C. The stability constants toward bivalent ions of first transition metal are in the order of Mn 2+ > Fe 2+ > Co 2+ > Ni 2+ 2+ 2+ and those toward Group XII are Zn 2+ 2+ >Hg 2+ . This trend may be explained by the cavity size of cyclo (Gly-eLL-Gly) 2 , but not the hard and soft acids and bases principle. The titration curves obtained from CD data indicated the presence of only a PC (peptide:cation=1:1) complex for Mn 2+ , Fe 2+ , Co 2+ , Cu 2+ , Zn 2+ and Hg 2+ , both PC and P 2 C (peptide:cation=2:1) complexes for Fe 3+ , and both PC and PC 2 (peptide:cation=1:2) complexes for Fe 2+ and Cd 2+ . But ligand/metal ion interactions are considered to be very weak for Ag + and Ni 2+ because of undetectable CD spectral changes. Moreover, 13 C NMR studies revealed that six amide oxygens in cyclo (Gly-eLL-Gly) 2 coordinate to Cu 2+ and Fe 3+ in CD 3 CN.