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Hiroaki Ohno

Publications and source records attributed to Hiroaki Ohno.

At least 19 recordsLinked to original sources
PubMed2007

Structure-activity relationships of cyclic peptide-based chemokine receptor CXCR4 antagonists: disclosing the importance of side-chain and backbone functionalities.

Previously, we have identified a highly potent CXCR4 antagonist 2 [cyclo(-D-Tyr1-Arg2-Arg3-Nal4-Gly5-)] and its Arg2 epimer 3 [cyclo(-D-Tyr1-D-Arg2-Arg3-Nal4-Gly5-)] by the screening of cyclic pentapeptide libraries that were designed based on the structure-activity relationship studies on 14-residue peptidic CXCR4 antagonist 1. In the present study, a new series of analogues of 2 and 3 were synthesized to evaluate the influences of peptide side-chain and backbone modification on bioactivities. Based on the Ala-scanning study, in which each residue in 2 and 3 was replaced with Ala having the identical chirality, substitution of Arg3 and Nal4 [Nal = L-3-(2-naphthyl)alanine] with Ala (compounds 6, 7, 10, 11) led to significant loss of the potency, indicating these amino acids are more important contributors to the bioactivity. For the cyclic peptide backbone, several modifications including d/l-Ala or cyclic amino acids substitution at the Gly5 position and sequential N-methylation on amide nitrogens were conducted. Among the analogues, compounds 13 [cyclo(-D-Tyr1-Arg2-Arg3-Nal4-D-Ala5-)] and 32 [cyclo(-D-Tyr1-D-MeArg2-Arg3-Nal4-Gly5-)] were close in potency to the most potent lead 2. NMR and conformational analysis indicated that both of these analogues favor the same backbone conformation as 2, whereas similar analysis of less potent analogues indicates that an altered backbone conformation is favored. The conformational analysis showed that steric repulsion by a 1,3-allylic strain-like effect across the planar peptide bond might contribute to the conformational preferences of cyclic pentapeptides.

Alanine↗
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↗
PubMed2007

Bromoallenes as allyl dication equivalents in the presence or absence of palladium(0): direct construction of bicyclic sulfamides containing five- to eight-membered rings by tandem cyclization of bromoallenes.

A highly regioselective synthesis of bicyclic sulfamides is described. Based on our recent discovery that bromoallenes can act as allyl dication equivalents in the presence of a palladium catalyst and alcohol, we investigated tandem cyclization of bromoallenes bearing a sulfamide group. It is found that some bromoallenes act as allyl dication equivalents even in the absence of a palladium(0) catalyst to afford cyclosulfamides containing five- or six-membered rings. While the palladium-free cyclization is dependent on the substrate structure affording the bicyclic sulfamides through the first cyclization onto the proximal or central carbon atom of the bromoallenes, the palladium-catalyzed reaction strongly promotes the first cyclization onto the central allenic carbon atom to afford bicyclic sulfamides containing a seven- or eight-membered ring. Formation of two types of bicyclic sulfamides from single bromoallenes by simply changing the reaction conditions is also described.

Alkadienes↗
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

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

Potassium carbonate-promoted stereospecific 5-endo-trig cyclization of unactivated allenes in the absence of any transition metals.

Formation of 3-pyrrolines from simple unactivated allenes bearing a protected amino group under basic conditions is described. Treatment of alpha-amino allenes with potassium carbonate in DMF under reflux in the absence of any transition-metal catalysts gave the corresponding 3-pyrrolines in good to excellent yields, by 5-endo-trig mode cycloisomerization. The reaction of internal allenes with an axial chirality afforded the corresponding 3-pyrrolines in a stereoselective manner.

Journal Article↗
PubMed2006

A c-fms tyrosine kinase inhibitor, Ki20227, suppresses osteoclast differentiation and osteolytic bone destruction in a bone metastasis model.

In bone metastatic lesions, osteoclasts play a key role in the development of osteolysis. Previous studies have shown that macrophage colony-stimulating factor (M-CSF) is important for the differentiation of osteoclasts. In this study, we investigated whether an inhibitor of M-CSF receptor (c-Fms) suppresses osteoclast-dependent osteolysis in bone metastatic lesions. We developed small molecule inhibitors against ligand-dependent phosphorylation of c-Fms and examined the effects of these compounds on osteolytic bone destruction in a bone metastasis model. We discovered a novel quinoline-urea derivative, Ki20227 (N-{4-[(6,7-dimethoxy-4-quinolyl)oxy]-2-methoxyphenyl}-N'-[1-(1,3-thiazole-2-yl)ethyl]urea), which is a c-Fms tyrosine kinase inhibitor. The IC(50)s of Ki20227 to inhibit c-Fms, vascular endothelial growth factor receptor-2 (KDR), stem cell factor receptor (c-Kit), and platelet-derived growth factor receptor beta were found to be 2, 12, 451, and 217 nmol/L, respectively. Ki20227 did not inhibit other kinases tested, such as fms-like tyrosine kinase-3, epidermal growth factor receptor, or c-Src (c-src proto-oncogene product). Ki20227 was also found to inhibit the M-CSF-dependent growth of M-NFS-60 cells but not the M-CSF-independent growth of A375 human melanoma cells in vitro. Furthermore, in an osteoclast-like cell formation assay using mouse bone marrow cells, Ki20227 inhibited the development of tartrate-resistant acid phosphatase-positive osteoclast-like cells in a dose-dependent manner. In in vivo studies, oral administration of Ki20227 suppressed osteoclast-like cell accumulation and bone resorption induced by metastatic tumor cells in nude rats following intracardiac injection of A375 cells. Moreover, Ki20227 decreased the number of tartrate-resistant acid phosphatase-positive osteoclast-like cells on bone surfaces in ovariectomized (ovx) rats. These findings suggest that Ki20227 inhibits osteolytic bone destruction through the suppression of M-CSF-induced osteoclast accumulation in vivo. Therefore, Ki20227 may be a useful therapeutic agent for osteolytic disease associated with bone metastasis and other bone diseases.

Acid Phosphatase↗
PubMed2006

Construction of tricyclic enone, a common precursor for aphidicolane and stemodane B/C/D-ring system.

Synthesis of a tricyclic enone (B/C/D ring system), a common key precursor for the aphidicolane- and stemodane-type diterpene, is described. The key reaction for the construction of the quaternary carbon center is allylation of epoxide at the more substituted carbon with an organotitanium reagent. Asymmetric reduction with DIP-Cl followed by stereoselective cyclization of spirocyclic ketone and the functional group modification gave the desired tricyclic enone in good yield.

Acetals↗
PubMed2005

Palladium(0)-catalyzed tandem cyclization of allenenes: direct construction of tricyclic heterocycles through aromatic C--H activation.

Palladium(0)-catalyzed tandem cyclization of allenenes is described. Treatment of allenenes with an aryl halide, potassium carbonate, and catalytic [Pd(PPh(3))(4)] in dioxane afforded tri- or tetracyclic heterocycles in moderate to good yields through insertion of arylpalladium(II) halide into the allenic moiety, intramolecular carbopalladation, and aromatic C--H bond activation. The substituent on the olefin terminus has proven to be essential for the success of the tandem cyclization. The reaction with heterocyclic aryl halides such as iodopyrazine or 4-bromo-1-methylindole afforded tri- or tetracyclic heteroaromatic products in good yields.

Alkenes↗
PubMed2005

Nicotinamide prevents the development of hyperphosphataemia by suppressing intestinal sodium-dependent phosphate transporter in rats with adenine-induced renal failure.

BACKGROUND: Nicotinamide has been shown to inhibit intestinal sodium-dependent phosphate transport activity in normal rats. It was reported recently that type IIb sodium-dependent phosphate co-transporter (NaPi-2b) is a carrier of intestinal phosphate absorption, and that its expression level is regulated by serum 1,25-dihydroxyvitamin D [1,25(OH)(2)D] and Pi levels in normal rats. However, in chronic renal failure (CRF), serum 1,25(OH)(2)D and Pi levels are often abnormal. In a rat model of CRF, we investigated whether short-term nicotinamide administration was effective in reducing intestinal phosphate absorption and, if so, whether the effect was mediated by intestinal NaPi-2b. METHODS: Adenine-induced CRF rats were given a single daily intrapenitoneal administration of nicotinamide or vehicle solution for 6 days, and time course changes in serum Pi, Ca, blood urea nitrogen (BUN) and creatinine levels were monitored. Intestinal phosphate absorption was examined by oral administration of radiolabelled phosphate on the final day. In addition, NaPi-2b protein content in jejunum brush border membranes was determined. RESULTS: Nicotinamide prevented the progressive increase in serum Pi associated with renal failure and significantly inhibited intestinal Pi absorption as assessed by the influx of orally administered radiolabelled phosphate into the circulation. This effect was accompanied by a decrease in NaPi-2b expression in jejunum brush border membranes. In addition, nicotinamide treatment was also associated with less marked elevations in BUN and serum creatinine and a higher creatinine clearance. CONCLUSIONS: Nicotinamide inhibited intestinal Pi absorption in a rat model of CRF, at least in part by inhibiting the expression of NaPi-2b, and appeared to protect against the deterioration of renal function.

Adenine↗
PubMed2005

Development of useful reactions involving tandem cyclizations based on the novel reactivities of allenic compounds.

This review highlights author's recent study on allenic compounds. In the first section, organocopper-mediated ring-opening reaction of ethynylaziridines and palladium-catalyzed reductive synthesis of allenes including those which are not accessible by other means, are described. In the second section, palladium-catalyzed stereoselective cyclization of allenes and tandem reaction leading to aziridines, pyrrolidines, benzoisoindoles, and cyclopropanes are presented. The final section presents aziridination and medium-ring formation by intramolecular reaction of bromoallenes, which are scarcely investigated until quite recently. The latter reaction is based on our recent discovery that bromoallenes can act as allylic dication equivalents in the presence of a palladium catalyst and alcohol.

Alkadienes↗
PubMed2005

Development of useful reactions based on the novel reactivities of allenic compounds and their application to tandem cyclizations.

This review highlights a recent study on allenic compounds by the author's group. In the first section, the organocopper-mediated ring-opening reaction of ethynylaziridines and palladium-catalyzed reductive synthesis of allenes are described. In the second section, palladium-catalyzed stereoselective cyclization of allenes, including the tandem reaction, leading to aziridines, pyrrolidines, benzoisoindoles, and cyclopropanes is presented. The final section reviews aziridination and medium-ring formation due to the intramolecular reaction of bromoallenes. The latter reaction is based on the author's recent discovery that bromoallenes can act as allylic dication equivalents in the presence of a palladium catalyst and alcohol.

Alkadienes↗