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Nobutaka Fujii

Publications and source records attributed to Nobutaka Fujii.

83 records · Page 5Linked to original sources
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↗
PubMed2002

A point mutation that confers constitutive activity to CXCR4 reveals that T140 is an inverse agonist and that AMD3100 and ALX40-4C are weak partial agonists.

CXCR4 is a G protein-coupled receptor for stromal-derived factor 1 (SDF-1) that plays a critical role in leukocyte trafficking, metastasis of mammary carcinoma, and human immunodeficiency virus type-1 infection. To elucidate the mechanism for CXCR4 activation, a constitutively active mutant (CAM) was derived by coupling the receptor to the pheromone response pathway in yeast. Conversion of Asn-119 to Ser or Ala, but not Asp or Lys, conferred autonomous CXCR4 signaling in yeast and mammalian cells. SDF-1 induced signaling in variants with substitution of Asn-119 to Ser, Ala, or Asp, but not Lys. These variants had similar cell surface expression and binding affinity for SDF-1. CXCR4-CAMs were constitutively phosphorylated and present in cytosolic inclusions. Analysis of antagonists revealed that exposure to AMD3100 or ALX40-4C induced G protein activation by CXCR4 wild type, which was greater in the CAM, whereas T140 decreased autonomous signaling. The affinity of AMD3100 and ALX40-4C binding to CAMs was less than to wild type, providing evidence of a conformational shift. These results illustrate the importance of transmembrane helix 3 in CXCR4 signaling. Insight into the mechanism for CXCR4 antagonists will allow for the development of a new generation of agents that lack partial agonist activity that may induce toxicities, as observed for AMD3100.

Amino Acid Substitution↗
PubMed2002

Synthesis and evaluation of pseudopeptide analogues of a specific CXCR4 inhibitor, T140: the insertion of an (E)-alkene dipeptide isostere into the betaII'-turn moiety.

A 14-residue peptide, T140, strongly inhibits the T-cell line-tropic HIV-1 (X4-HIV-1) infection, since this peptide functions as a specific antagonist against a chemokine receptor, CXCR4. T140 takes an antiparallel beta-sheet structure with a type II' beta-turn. In the present paper, we have designed and synthesized several T140 analogues, in which an (E)-alkene dipeptide isostere was inserted into the type II' beta-turn moiety, as a bridging study to develop nonpeptidic CXCR4 inhibitors. It has been proven that the turn region of T140 can be replaced by the above surrogate with the maintenance of strong anti-HIV activity.

Anti-HIV Agents↗
PubMed2002

Synthesis of allenes from allylic alcohol derivatives bearing a bromine atom using a palladium(0)/diethylzinc system.

A general and efficient synthesis of allenes using a palladium(0)/diethylzinc system is described. Treatment of mesylates or trichloroacetates of (E)- or (Z)-2-bromoalk-2-en-1-ols with diethylzinc in the presence of a catalytic amount of palladium(0) affords allenes bearing an aminoalkyl, alkyl, or aryl substituent(s) in good to high yields. No transfer of chirality from the stereogenic center carrying the mesyloxy group to the allene was observed.

Journal Article↗
PubMed2002

Susceptibility of diverse primary HIV isolates with varying co-receptor specificity's to CXCR4 antagonistic compounds.

The chemokine receptors CCR5 and CXCR4 are an obvious target for HIV therapies. Two compounds, T-22 and AMD-3100, have been shown to inhibit infection of CXCR4-using HIV-1 isolates. The specificity of T-22 and AMD-3100 was further confirmed by their ability to block entry of HIV-1 in GHOST-CXCR4 transfected cells with no effect on viral entry in the GHOST-CCR5 cells. The ability of T-22 to block replication of diverse HIV-1 isolates (group M, subtypes A, B, D, E, and F as well as group O) and HIV-2 primary isolates with varying coreceptor specificities ranging from exclusive CCR5 usage to multiple coreceptor usage was examined in detail. T-22 was found to be highly effective (>90%) at blocking infection of diverse HIV-1 (subtypes A-F, and group O) and HIV-2 isolates that use multiple coreceptors in human PBMCs homozygous for a 32-bp deletion in CCR5 (CCR5-/-), but less effective in CCR5 +/+ PBMCs. Additionally, sequential primary HIV-1 isolates obtained from a longitudinal cohort who had switched from single coreceptor usage to a broad range of multiple receptors could be blocked effectively by both T-22 and AMD-3100 in CCR5-/- PBMCs. Our data suggest that CXCR4 antagonistic compounds are highly effective in blocking the entry of X4-tropic HIV-1, and that these compounds could be a useful additive to current anti-retroviral therapy for clinical management of HIV disease.

Anti-HIV Agents↗
PubMed2002

Certification of the critical importance of L-3-(2-naphthyl)alanine at position 3 of a specific CXCR4 inhibitor, T140, leads to an exploratory performance of its downsizing study.

We have previously found that a 14-amino acid residue-peptide, T140, inhibits infection of target cells by T cell line-tropic HIV-1 (X4-HIV-1) through its specific binding to a chemokine receptor, CXCR4. Here, the importance of an L-3-(2-naphthyl)alanine (Nal) residue at position 3 in T140 for high anti-HIV activity and inhibitory activity against Ca(2+) mobilization induced by stromal cell-derived factor (SDF)-1alpha-stimulation through CXCR4 has initially been shown by the synthesis and biological evaluation of several analogues, where Nal(3) is substituted by diverse aromatic amino acids. Next, the order of the N-terminal 3 residues (Arg(1)-Arg(2)-Nal(3)) has been proved to be important from the structure--activity relationship (SAR) study shuffling these residues. Based on these results, we have found 10-residue peptides possessing modest anti-HIV activity by systematic antiviral evaluation of a series of synthetic, shortened analogues of T140.

Alanine↗
PubMed2002

Trojan p16 peptide suppresses pancreatic cancer growth and prolongs survival in mice.

PURPOSE: The tumor suppressor gene p16INK4A is inactivated frequently in a large number of human cancers, and many investigators have attempted to restore the function of p16 using the p16 wild-type gene and viral vectors. In this study, we treated the tumor-bearing animals with the p16-derived synthetic peptide coupled with the Antennapedia carrier sequence, which we designated as Trojan p16 peptide. EXPERIMENTAL DESIGN: Injections (i.p.) of the Trojan p16 peptide (100 microg/mouse/day) were given for 3 weeks in the AsPC-1 and BxPC-3 s.c. tumor models. Tumor growth, histopathology, and TUNEL staining of the tumor and toxicity of the animals were evaluated. To examine its influence on the survival of tumor-bearing mice, Trojan p16 was administered in the AsPC-1 peritoneal dissemination model. RESULTS: In the AsPC-1 s.c. tumor model, a significant growth inhibition was obtained by the Trojan p16 treatment when compared with the three control treatments, i.e., vehicle, unconjugated form of p16, or Trojan peptide alone. Tumor growth inhibition was almost complete in the BxPC-3 tumor, a relatively slow growing tumor. Neither hematological cytotoxicity or body weight loss were observed. Histopathology of the BxPC-3 s.c. tumor in the Trojan p16 treatment group revealed marked vacuole formation and apoptotic death of cancer cells. In the AsPC-1 peritoneal dissemination model, the survival curve of mice treated with Trojan p16 was significantly longer than that of control. CONCLUSIONS: These results provide evidence that the Trojan p16 peptide system, a gene-oriented peptide coupled with a peptide vector, functions for experimental pancreatic cancer therapy.

Amino Acid Sequence↗
PubMed1998

Reactions of N-Arylsulfonyl-2,3-cis- and N-Arylsulfonyl-2,3-trans-3-alkyl-2-vinylaziridines with Organocopper Reagents: Importance of 2,3-cis-Stereochemistry in Controlling Regio- and Stereoselectivity.

Although reactions of 2,3-trans-N-arylsulfonyl-3-alkyl-2-alkenylaziridines with organocopper reagents give a mixture of two or three products, the corresponding 2,3-cis-isomers provide a highly efficient route to synthetically important nonracemic (E)-allylamines. It is also found that the reaction proceeds via the well-known anti-S(N)2' pathway.

Journal Article↗
PubMed1997

Palladium(0)-Catalyzed Isomerization Reactions of Aziridines Bearing an alpha,beta-Unsaturated Ester Group: A Thermodynamic Preference for Chiral Alkyl (2E)-4,5-cis-4,5-Epimino-N-(alkyl- or arylsulfonyl) 2-Enoates over the Other Three Stereoisomers.

Palladium(0)-catalyzed reactions of five sets of four stereoisomeric 4,5-epimino-N-(methanesulfonyl) or -N-(arylsulfonyl) 2-enoates reveal that 4,5-cis-(2E)-isomers are thermodynamically more stable than other isomers, in accord with calculations. A highly stereoselective synthesis of (E)-alkene dipeptide isosteres having the desired stereochemistries from unwanted stereoisomeric 4,5-epimino-N-(arylsulfonyl) 2-enoates is also presented.

Journal Article↗