PubMed Health⌕ Search

Biomedical subjects

Ayumu Niida

Publications and source records attributed to Ayumu Niida.

13 recordsLinked to original sources
PubMed2007

Fmoc-based solid-phase synthesis of GPR54-agonistic pentapeptide derivatives containing alkene- and fluoroalkene-dipeptide isosteres.

Fmoc-protected Phe-Gly-type (Z)-alkene dipeptide isostere (ADI) and (E)-fluoroalkene dipeptide isostere (FADI) were synthesized and applied to Fmoc-based solid-phase peptide synthesis (SPPS). These cis-peptide bond mimetics were introduced into a bioactive pentapeptide [H-Amb-Phe-Gly-Leu-Arg-Trp-NH(2); Amb = 4-(aminomethyl) benzoic acid], which has potent GPR54 agonistic activity. The resulting pentapeptide derivatives showed low GPR54 agonistic activity, as compared with the parent peptide and (E)-ADI-containing derivative. This suggests that the trans-amide conformer of Phe-Gly peptide bond of the parent peptide would be significantly important for bioactivity. Contrary to our expectations, a (Z)-FADI-containing derivative exhibited essentially no activity, revealing the necessity of critical validation of FADI-bioisosterism.

Alkenes↗
PubMed2006

Structure-activity relationship study on small peptidic GPR54 agonists.

Metastin (kisspeptin-54) is an endogenous ligand that modulates gonadotropin-releasing hormone (GnRH) secretion through the interaction with a G protein-coupled receptor (GPCR), GPR54. The short-chain C-terminal decapeptide amide, metastin (45-54) (kisspeptin-10), exerts the identical bioactivities to metastin, such as metastasis suppression of cancer cells and inhibition of trophoblast migration and invasion. In order to understand the structural requirement for GPR54 agonistic activity, structure-activity relationship (SAR) study on pentapeptide-based C-terminal metastin analogues was carried out. As a result, H-Amb-Nal(2)-Gly-Leu-Arg-Trp-NH2 34 was identified as a novel GPR54 agonist that possessed the most potent GPR54 agonistic activity reported so far.

Alkylation↗
PubMed2006

Stereoselective synthesis of (Z)-alkene-containing proline dipeptide mimetics.

In peptides and proteins, the peptide bond between an amino acid and proline exists as an equilibrium mixture of the cis-imide and trans-imide due to the low energy barrier in their interconversion. This feature greatly influences the structure and function of the proline-containing peptides and proteins. Therefore, restricting the amide bond with an (E)- or (Z)-alkene should provide a promising method for elucidating the structure-activity relationships of the peptide and the proteins. In this report, the regio- and stereoselective synthesis of cis-alanylproline (Ala-Pro) type (Z)-alkene dipeptide mimetic is described. The key steps of this synthesis are to introduce a C3 unit onto a gamma-phosphoryloxy-alpha,beta-unsaturated-delta-lactam with an organocopper-mediated anti-S(N)2' reaction and subsequently construct a five-membered proline-like cyclic structure with an intramolecular Suzuki coupling reaction. Hydrolysis of the amide bond in the resulting bicyclic lactam yields the desired cis-Ala-Pro type (Z)-alkene dipeptide isostere. The presented synthetic methodology should be applicable to the general syntheses of other cis-aminoacylproline type (Z)-alkene dipeptide mimetics.

Alkenes↗
PubMed2006

Synthesis of (Z)-alkene and (E)-fluoroalkene-containing diketopiperazine mimetics utilizing organocopper-mediated reduction-alkylation and diastereoselectivity examination using DFT calculations.

We have carefully examined the organocopper-mediated reduction-alkylation of gamma-acetoxy or gamma,gamma-difluoro-alpha,beta-unsaturated-delta-lactams for the synthesis of (Z)-alkene- or (E)-fluoroalkene-containing diketopiperazine mimetics. Reduction of acetates 2, 12, 14, and difluorolactam 18 with higher-order cuprate reagents (Me3CuLi2 x LiI x 3 LiBr), followed by trapping the resulting metal dienolate with an electrophile in a one-pot procedure gave alpha-alkylated-beta,gamma-unsaturated-delta-lactams in good yields. Because of side-chain steric repulsion, we found that alkylation using relatively large electrophiles such as BnBr gave mostly 3,6-trans isomers by kinetic trapping of metal enolates. On the other hand, MeI-mediated alkylations predominantly provided the unexpected 3,6-cis isomers despite the presence of a bulky benzyl side chain. Based on density functional theory calculations, we concluded that formation of the 3,6-cis isomers was due to the occurrence of oxa-pi-allyllithium complexes 29 and 31.

Alkenes↗
PubMed2006

Stereoselective synthesis of 3,6-disubstituted-3,6-dihydropyridin-2-ones as potential diketopiperazine mimetics using organocopper-mediated anti-SN2' reactions and their use in the preparation of low-molecule CXCR4 antagonists.

Organocopper-mediated anti-SN2' reactions of gamma-phosphoryloxy-alpha,beta-unsaturated-delta-lactams were used to prepare highly functionalized diketopiperazine mimetics. The substrate phosphates 24, 32, and 47 were prepared from alpha-amino acid-derived allylic alcohols 10 by a sequence of reactions that included ring-closing metathesis. In the reactions of phosphates with organocopper reagents, the addition of LiCl dramatically improved anti-SN2' selectivity, indicating that an organocopper cluster containing lithium chloride plays an important role in the determination of regioselectivity. This reaction system was applied to the preparation of novel low molecular weight CXCR4-chemokine receptor antagonists.

Copper↗
PubMed2006

Transport characteristics of a novel peptide transporter 1 substrate, antihypotensive drug midodrine, and its amino acid derivatives.

Midodrine is an oral drug for orthostatic hypotension. This drug is almost completely absorbed after oral administration and converted into its active form, 1-(2',5'-dimethoxyphenyl)-2-aminoethanol) (DMAE), by the cleavage of a glycine residue. The intestinal H+-coupled peptide transporter 1 (PEPT1) transports various peptide-like drugs and has been used as a target molecule for improving the intestinal absorption of poorly absorbed drugs through amino acid modifications. Because midodrine meets these requirements, we examined whether midodrine can be a substrate for PEPT1. The uptake of midodrine, but not DMAE, was markedly increased in PEPT1-expressing oocytes compared with water-injected oocytes. Midodrine uptake by Caco-2 cells was saturable and was inhibited by various PEPT1 substrates. Midodrine absorption from the rat intestine was very rapid and was significantly inhibited by the high-affinity PEPT1 substrate cyclacillin, assessed by the alteration of the area under the blood concentration-time curve for 30 min and the maximal concentration. Some amino acid derivatives of DMAE were transported by PEPT1, and their transport was dependent on the amino acids modified. In contrast to neutral substrates, cationic midodrine was taken up extensively at alkaline pH, and this pH profile was reproduced by a 14-state model of PEPT1, which we recently reported. These findings indicate that PEPT1 can transport midodrine and contributes to the high bioavailability of this drug and that Gly modification of DMAE is desirable for a prodrug of DMAE.

Amino Acids↗
PubMed2006

Unequivocal synthesis of (Z)-alkene and (E)-fluoroalkene dipeptide isosteres to probe structural requirements of the peptide transporter PEPT1.

[reaction: see text] Described is a novel synthetic route for dipeptide isosteres containing (Z)-alkene and (E)-fluoroalkene units as cis-amide bond equivalents via organocopper-mediated reduction of gamma-acetoxy- or gamma,gamma-difluoro-alpha,beta-unsaturated-delta-lactams. The synthesized isosteres were evaluated in terms of their affinities for the peptide transporter PEPT1. trans-Amide isosteres tended to possess higher affinities for PEPT1 as compared to the corresponding cis-amide bond equivalents.

Alkenes↗
PubMed2005

Design and synthesis of downsized metastin (45-54) analogs with maintenance of high GPR54 agonistic activity.

Metastin has been identified as a metastasis suppressor gene product that mediates its function through a G protein coupled receptor, GPR54. To refine insight into the critical pharmacophore for the activation of GPR54, we have conducted alanine and d-amino acid scanning on a biologically active metastin fragment (45-54). Based on these data and structures of peptides previously reported to activate GPR54, a series of shortened metastin (45-54) derivatives were synthesized and tested for the ability to induce GPR54 signaling. These biological experiments were performed in yeast containing human GPR54 that was coupled to the pheromone response pathway and a pheromone responsive lacZ reporter gene. Compounds 32, 33, and 39, which possess an N-terminal basic group and a C-terminal RW-amide motif, were strong agonists, similar to the level of metastin. This may provide an approach to reverse the pro-metastatic effect of metastin deletion in multiple malignant tumors.

Amino Acid Motifs↗
PubMed2004

Metastin and its variant forms suppress migration of pancreatic cancer cells.

Metastin, a post-translationally modified variant of KiSS1, was recently identified as an endogenous peptide agonist for a novel G-protein coupled receptor, hOT7T175 (AXOR12, GPR54). In this study, we analyzed the role of KiSS1 and hOT7T175 in both pancreatic cancer tissues and pancreatic cancer cell lines. Furthermore, we synthesized novel short variant forms of metastin and tested the inhibitory effect of those variants on in vitro cell functions that are relevant to metastasis. Pancreatic cancer tissues showed significantly lower expression of KiSS1 mRNA than normal tissues (p=0.018), while cancer tissues showed significantly higher expression of hOT7T175 mRNA than normal pancreatic tissues (p=0.027). In human pancreatic cancer cell lines, KiSS1 mRNA was highly expressed in 2 out of 6 pancreatic cancer cell lines, while hOT7T175 mRNA was expressed in all cell lines at various degrees. PANC-1 cells showed the highest expression of hOT7T175. Exogenous metastin did not suppress cell proliferation but significantly reduced the in vitro migration of PANC-1 cells (p<0.01). Metastin induced activation of ERK1 in PANC-1 and AsPC-1 cells. Finally, we synthesized 3 novel short variant forms of metastin, FM053a2TFA, FM059a2TFA, and FM052a4TFA. These metastin variants significantly suppressed the migration of PANC-1 cells and activated ERK1. These data suggest that the metastin receptor, hOT7T175, is one of the promising targets for suppression of metastasis, and that small metastin variants could be an anti-metastatic agent to pancreatic cancer.

Cell Line, Tumor↗
PubMed2002

Diastereoselective synthesis of new psi[(E)-CH=CMe]- and psi[(Z)-CH=CMe]-type alkene dipeptide isosteres by organocopper reagents and application to conformationally restricted cyclic RGD peptidomimetics.

Diastereoselective synthesis of new psi[(E)-CH=CMe]- and psi[(Z)-CH=CMe]-type alkene dipeptide isosteres corresponding to dipeptides having one N-methylamino acid, and application to bioactive peptides, are described. In a key reaction introducing the chiral alpha-alkyl group of the isosteres, organocopper-mediated alkylation of syn-beta-methylated gamma-mesyloxy-alpha,beta-enoate 26a afforded E- and Z-isomers of anti-S(N)2' products in a solvent-dependent manner. The resulting two isosteres, D-Phe-psi[(E)-CH=CMe]-L-Val 27a and D-Phe-psi[(Z)-CH=CMe]-L-Val 28b, which corresponded to trans- and cis-conformers of D-Phe-L-MeVal, respectively, were utilized in a structure-activity relationship study on cyclic RGD peptides 1 and 2, in company with a psi[(E)-CH=CH]-type alkene dipeptide isostere, D-Phe-psi[(E)-CH=CH]-L-Val. The cyclic isostere-containing pseudopeptides 3, 4, and 40 were synthesized and biological activity against integrin alpha(V)beta(3) and alpha(IIb)beta(3) receptors were also evaluated.

Alkenes↗
PubMed2002

Diastereoselective synthesis of psi[(E)-CH=CMe]- and psi[(Z)-CH=CMe]-type dipeptide isosteres by organocopper-mediated anti-S(N)2' reaction.

[reaction: see text] Acyclic psi[(E)-CH=CMe]- and psi[(Z)-CH=CMe]-type dipeptide isosteres were efficiently synthesized. In a key reaction, alpha-alkylation of gamma-mesyloxy-beta-methyl-alpha,beta-unsaturated esters with organocyanocuprates in diethyl ether or tetrahydrofuran preferentially afforded the psi[(E)-CH=CMe]- or psi[(Z)-CH=CMe]-isomer, respectively, via anti-S(N)2' mechanism.

Alkylation↗
PubMed2002

Diastereoselective synthesis of psi[(E)-CMe=CH]- and psi[(E)-CMe=CMe]- type dipeptide isosteres based on organocopper-mediated anti-S(N)2' reaction.

[reaction: see text] A straightforward synthetic route for the synthesis of diastereomerically pure psi[(E)-CMe=CH]- and psi[(E)-CMe=CMe]-type dipeptide isosteres was developed on the basis of regio- and stereoselective anti-S(N)2' alkylation of 3-(N-Boc-5-methyl-4-substituted-oxazolidin-2-on-5-yl)acrylates with organocopper reagents.

Alkylation↗