Keiichi Yamada

Phosphodiester bond cleavage mediated by a cyclic β-sheet peptide-based dinuclear zinc(II) complex

A dinuclear Zn(II) complex of nN2δ,N2δ,N n2′δ,N2′δ-tetra nkis(2-pyridylmethyl) derivative of cyclic peptide gramicidin S markedly naccelerated the cleavage of the phosphodiester linkage of the RNA model nsubstrate 2-hydroxypropyl p-nitrophenyl phosphate.

Optical resolution and absolute configuration of N-Benzyloxycarbonyl-α-alkoxyglycines

Optical resolution of racemic N-benzyloxycarbonyl-protected alpha-alkoxyglycines, (+/-)-Cbz-Gly(OR)-OH (R = Et and Pr(i)), was achieved by means of fractional crystallization of diastereomeric salts with (+)-(1S,2S)-2-amino-1-phenyl-1,3-propanediol or diastereomeric esters of (+)- or (-)-menthol. The D- and L-configurations were assigned to the (+)- and (-)-Cbz-Gly(OR)-OH, respectively, based on L-enantioselective enzymatic hydrolysis of (+/-)-Cbz-Gly(OR)-OR (R = Me, Et, and Pr(i); R = CH(2)CF(3) and Me) using porcine pancreatic lipase and papain. Chiroptical properties and HPLC retention times of D- and L-Gly(OR)-residue (R = Me and Pr(i))-containing peptides were compared in relation to their configurational assignments. Copyright 1999 Wiley-Liss, Inc.

Stereochemistry of protected ornithine side chains in gramicidin S derivatives and their resistance to N-methylation

Derivatives of gramicidin S (GS) and its mono- and di-d-cyclohexylalanined-Cha) analogs possessing various protecting groups on Orn side chains were prepared.1H NMR spectra of the unsymmetrically protected analogs [Orn(X)2, Orn(X′)2′,d-Cha4]GS were similar to the composites of the spectra of the symmetrical derivatives [Orn(X)2,2′,d-Cha4,4′]GS and [Orn(X′)2,2′]Gs, revealing the proximity of the protecting groups of NδH of Orn residues at the 2 and 2′ positions to the side chains ofd-Phe (ord-Cha) residues at the 4 and 4′ positions, respectively. The results indicated the presence of H-bonds between the N°H of Orn and the carbonyl ofd-Phe residues in the i→i+2 sense and not in i→i-3, which was also supported by the ROESY analysis. The substantially strong H-bonds can explain the observed resistance of the urethane NH of the Orn side chains in the GS derivatives to the N-methylation with CH3I−Ag2O in DMF.

Preparation and metal ion-binding properties of gramicidin S derivatives carrying picolinoyl groups on the ornithine side chains

Derivatives of gramicidin S (GS) in which one or both of the two ornithine side chains were picolinoylated were prepared. The dipicolinoyl derivative [Orn(PyCO)2,2′]GS 1 formed a 1∶1 complex with Cu2+ and Zn2+ in MeOH, while in the case of the monopicolinoyl derivative [Orn(Boc)2,Orn(PyCO)2′]GS (2) stepwise formation of 1∶1 and 2∶1 (2∶Cu2+) complexes was observed. The formation constant of the Cu2+-mediated dimeric species of compound 2 was larger than those of the corresponding linear compounds possessing the partial structure of macrocycle 2. The corresponding tetra-N-methyl derivative [MeOrn(Boc)2,MeOrn(PyCO)2′,D-MePhe4,4′]GS 3 also showed lower stability of the 2∶1 complex compared with compound 2, which suggested the presence of a β-sheet-type intermolecular H-bonding interaction between the two molecules of macrocycle 2 in the 2∶1 complex.

Dinuclear Zinc(II) Complexes of Linear and Cyclic Peptides Containing Two Bis(2-pyridylmethyl)amino Groups as Catalysts for Hydrolysis of RNA Model Substrate

Various enzymes possess two metal ions in their active center and many models of the metalloenzymes were reported. Dinuclear Zn(II) complex of 2-pyridylmethyl (PyCH2) derivative of 2-hydroxypropanediamine, (PyCH2)2NCH2CH(OH)CH2N(CH2Py)2, was reported to promote cleavage of phosphodiester linkage of diribonucleotides, where synergistic effect of the two metal centers was considered to be essential [1]. Since the cyclic decapeptide gramicidin S (GS), cyclo(-Val-Orn-Leu-D-Phe-Pro-)2, possesses two Orn side chains located on one side of the stable antiparallel β-sheet plane, we prepared a GS derivative containing two bis(2-pyridylmethyl)amino groups, namely [Orn(PyCH2)2 2,2′]GS (1, R′ = R″ = H). As expected, dinuclear Zn(II) complex of it effectively enhanced the cleavage of the phosphodiester linkage of 2-hydroxypropyl p-nitrophenyl phosphate (HPNP) as an RNA model substrate [2]. Here we will report the synthesis, Zn(II) ion-chelating behavior, and phosphodiester bond-cleaving activity for HPNP of the Zn(II) complexes of related cyclic and linear peptide derivatives.