Concentration-dependence of specific rotation of optically active glycerol analogues and structurally related compounds: The significance of intermolecular hydrogen bonding

Specific rotation of optically active glycerol analogues, (S)-3-(benzyloxy)propane-1,2-diol [(S)-1], (S)-3-methoxypropane-1,2-diol [(S)-6] and (S)-3-phenoxypropane-1,2-diol [(S)-13], changed its sign from (+) to () with increasing concentration in CHCl3, whereas no significant concentration-dependent change was observed in MeOH. The 1H NMR spectrum of (S)-1 showed concentration-dependent changes of the chemical shift in CDCl3. Intermolecular interaction by OHOH hydrogen bonds was suggested by single crystal X-ray crystallography of (S)-13. The concentration-dependent changes of specific rotation of (S)-1, (S)-6, and (S)-13 in CHCl3 can therefore be presumed to be due to self-assembly of these compounds via intermolecular hydrogen bonding at high concentration. The remarkable concentration-dependent changes in specific rotation were also observed to occur in the compounds with related chemical structures, such as (S)-3-hydroxy-4-methoxy-4-oxobutanoic acid [(S)-10], (S)-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carboxylic acid [Boc-L-Pro-OH, (S)-14], (R)-3-hydroxy-4,4-dimethylhydrofran-2(3H)-one [(R)-15], (R)-tetrahydrofuran-2-carboxylic acid [(R)-16], (S)-3-methyl-2-[(2-methylpropan-2-yl)oxycarbonylamino]butanoic acid [Boc-L-Val-OH, (S)-17], (R)-oxiran-2-ylmethanol [(R)-18], and (4S)-4-isopropyloxazolidin-2-one [(S)-19]. The existence of intermolecular interaction by C=OHO hydrogen bonds was suggested by single crystal X-ray crystallography of (S)-10, (S)-13, and (S)-14. Thus, this series of chiral compounds have multiple functional groups in appropriate positions that serve as hydrogen-bond donors and/or acceptors, resulting in significant concentration-dependent changes of specific rotation.


Synthesis of Novel Phosphorus-Substituted Stable Isoindoles by a Three-Component Coupling Reaction of ortho-Phthalaldehyde, 9,10-Dihydro-9-oxa-10-phosphaphenanthrene 10-Oxide, and Primary Amines

A three-component coupling reaction of ortho-phthalaldehyde, 9,10-dihydro-9-oxa-10-phosphaphenanthrene 10-oxide, and various primary amines readily afforded novel phosphorus-substituted stable isoindoles in good to excellent yields. The importance of the reversible ring-opening of 9,10-dihydro-9-oxa-10-phosphaphenanthrene 10-oxide by methanolysis in the three-component coupling reaction became apparent.


Efficient One-Pot, Three-Step Synthesis of 1,2,3,5-Tetrasubstituted Pyrroles via Aza-Michael Addition of Methyl 3-Iminoacrylates

An efficient one-pot, three-step procedure for the aza-Michael addition of methyl 3-iminoacrylates with secondary amines followed by intramolecular cyclization and silylation successfully afforded novel 1,2,3,5-tetrasubstituted pyrroles in high yields.


Novel antimyeloma therapeutic option with inhibition of the HDAC1-IRF4 axis and PIM kinase

Multiple myeloma (MM) preferentially expands and acquires drug resistance in the bone marrow (BM). We herein examined the role of histone deacetylase 1 (HDAC1) in the constitutive activation of the master transcription factor IRF4 and the prosurvival mediator PIM2 kinase in MM cells. The knockdown or inhibition of HDAC1 by the class I HDAC inhibitor MS-275 reduced the basal expression of IRF4 and PIM2 in MM cells. Mechanistically, the inhibition of HDAC1 decreased IRF4 transcription through histone hyperacetylation and inhibiting the recruitment of RNA polymerase II at the IRF4 locus, thereby reducing IRF4-targeting genes, including PIM2. In addition to the transcriptional regulation of PIM2 by the HDAC1-IRF4 axis, PIM2 was markedly upregulated by external stimuli from BM stromal cells and interleukin-6 (IL-6). Upregulated PIM2 contributed to the attenuation of the cytotoxic effects of MS-275. Class I HDAC and PIM kinase inhibitors cooperatively suppressed MM cell growth in the presence of IL-6 and in vivo. Therefore, the present results demonstrate the potential of the simultaneous targeting of the intrinsic HDAC1-IRF4 axis plus externally activated PIM2 as an efficient therapeutic option for MM fostered in the BM.


Only one carbon difference determines the pro-apoptotic activity of α-tocopheryl esters

α-Tocopheryl succinate (TS), a redox-silent succinyl ester of natural α-Tocopherol, has emerged as a novel anti-cancer agent. However, the underlying mechanism is unclear. We found that the terminal dicarboxylic moiety of tocopheryl esters contributes to apoptosis induction and thus cytotoxicity. To further examine this relationship, we compared the pro-apoptotic activity of TS, which has four carbon atoms in the terminal dicarboxylic moiety, to that of a newly synthesized, tocopheryl glutarate (Tglu), which has five. Cytotoxicity assays in vitro confirmed that TS stimulated apoptosis, while Tglu was non-cytotoxic. In investigating biological mechanisms leading to these opposing effects, we found that TS caused an elevation of intracellular superoxide, but Tglu did not. TS increased intracellular Ca in cultured cells, suggesting induction of endoplasmic reticulum (ER) stress; however, Tglu did not affect Ca homeostasis. 1,4,5-trisphosphate (IP ) receptor antagonist 2-Aminoethyl diphenylborinate (2-APB) decreased TS-induced intracellular Ca , restored mitochondrial activity and cell viability in TS-treated cells, establishing the ER-mitochondria relationship in apoptosis induction. Moreover, real-time PCR, immunostaining and Western blotting assays revealed that TS downregulated glucose-regulated protein 78 (GRP78), which maintains ER homeostasis and promotes cell survival. Conversely, Tglu upregulates GRP78. Taken together, our results suggest a model in which TS-mediated superoxide production and GRP78 inhibition induce ER stress, which elevates intracellular Ca and depolarizes mitochondria, leading to apoptosis. Because Tglu does not affect superoxide generation and increases GRP78 expression, it inhibits ER stress and is thereby non-cytotoxic. Our research provides insight into the structure-activity relationship of tocopheryl esters regarding the induction of apoptosis.


Molecular species profiles of plasma ceramides in different clinical types of X-linked adrenoleukodystrophy

X-linked adrenoleukodystrophy (X-ALD) is a genetic disorder associated with peroxisomal dysfunction. Patients with this rare disease accumulate very long-chain fatty acids (VLCFAs) in their bodies because of impairment of peroxisomal VLCFA ?-oxidation. Several clinical types of X-ALD, ranging from mild (axonopathy in the spinal cord) to severe (cerebral demyelination), are known. However, the molecular basis for this phenotypic variability remains largely unknown. In this study, we determined plasma ceramide (CER) profile using liquid chromatography-tandem mass spectrometry. We characterized the molecular species profile of CER in the plasma of patients with mild (adrenomyeloneuropathy;AMN) and severe (cerebral) X-ALD. Eleven X-ALD patients (five cerebral, five AMN, and one carrier) and 10 healthy volunteers participated in this study. Elevation of C26:0 CER was found to be a common feature regardless of the clinical types. The level of C26:1 CER was significantly higher in AMN but not in cerebral type, than that in healthy controls. The C26:1 CER level in the cerebral type was significantly lower than that in the AMN type. These results suggest that a high level of C26:0 CER, along with a control level of C26:1 CER, is a characteristic feature of the cerebral type X-ALD. J. Med. Invest. 70 : 403-410, August, 2023.

The Journal of Medical Investigation : JMI


Development of a novel tocopheryl ester for suppression of lipid accumulation without cytotoxicity by optimization of dicarboxylic ester moiety


Synthesis of Novel 2,3-Disubstituted Thiophenes via Tandem Thia-Michael/Aldol Reaction of Allenyl Esters

A tandem thia-Michael/aldol reaction of allenyl esters and mercaptoacetaldehyde in the presence of triethylamine provided 2,3,4-trisubstituted tetrahydrothiophenes. Novel 2,3-disubstituted thiophenes were obtained in high yield by the subsequent dehydration of the 2,3,4-trisubstituted tetrahydrothiophenes using p-toluenesulfonic acid monohydrate as an effective catalyst.


Catalytic Asymmetric Ring-Opening of σ-Symmetric Cyclic Carbonates with Chiral Sulfonamide-Amine Catalysts

Enantioselective ring-opening of σ-symmetric six-membered cyclic carbonates with benzyl alcohol catalyzed by 20 mol% of chiral amino sulfonamide catalysts afforded chiral acyclic carbonates in up to 79% ee.


Indocyanine green-labeled dasatinib as a new fluorescent probe for molecular imaging of gastrointestinal stromal tumors.

It is difficult to differentiate gastrointestinal stromal tumors (GISTs) from other subepithelial lesions under gastrointestinal endoscopy. Because most GISTs express tyrosine kinase receptor c-KIT, fluorescence-labeled c-KIT-specific tyrosine kinase inhibitors seem to be useful agents for molecular imaging of GIST. We aimed to develop a near-infrared fluorescent imaging technology for GIST targeting c-KIT using the novel fluorescent probe indocyanine green-labeled dasatinib (ICG-dasatinib) and to investigate the antitumor effect of ICG-dasatinib on GIST cells. Indocyanine green-labeled dasatinib was synthesized by labeling linker-induced dasatinib with ICG derivative 3-indocyanine-green-acyl-1,3-thiazolidine-2-thione. Human GIST cell lines GIST-T1 and GIST-882M were incubated with ICG-dasatinib and observed by fluorescent microscopy. GIST cells were incubated with ICG-dasatinib, unlabeled dasatinib, or imatinib, and cell viabilities were evaluated. Subcutaneous GIST model mice or orthotopic GIST model rats were intravenously injected with ICG-dasatinib and observed using an IVIS Spectrum. Strong fluorescent signals of ICG-dasatinib were observed in both GIST cell lines in vitro. IC50 values for ICG-dasatinib, unlabeled dasatinib, and imatinib were 13.9, 1.17, and 16.2 nM in GIST-T1 and 26.6, 3.63, and 47.6 nM in GIST-882M cells, respectively. ICG-dasatinib accumulated in subcutaneous xenografts in mice. Fluorescent signals were also observed in liver and gallbladder, indicating biliary excretion; however, fluorescence intensity of tumors was significantly higher than that of intestine after washing. Strong fluorescent signals were observed in orthotopic xenografts through the covering normal mucosa in rats. Indocyanine green-labeled dasatinib could visualize GIST cells and xenografted tumors. The antitumor effect of ICG-dasatinib was preserved to the same degree as imatinib.

Journal of Gastroenterology and Hepatology


Tandem Thia-Michael/Dieckmann Condensation of Allenyl Esters for the Regioselective Synthesis of Trisubstituted Thiophenes

Tandem thia-Michael/Dieckmann condensation of allenyl esters with methyl mercaptoacetate in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene afforded 2,3,5-trisubstituted thiophenes regioselectively. On the other hand, 2,3,4-trisubstituted thiophenes were obtained as the sole product by tandem thia- Michael/Dieckmann condensation employing magnesium bromide and triethylamine.


Synthesis of Three Stereoisomers of Erythrochelin, a Hydroxamate-Type Tetrapeptide Siderophore from Saccharopolyspora erythraea

Details of the synthesis of three stereoisomers of erythrochelin, a hydroxamate-type tetrapeptide siderophore produced by Saccharopolyspora erythraea, were described. Both enantiomers of protected δ-N-hydroxyornithine were used as key intermediates in the synthesis of stereoisomers of erythrochelin containing a (3S,6S)-3,6-disubstituted-2,5-diketopiperazine ring. From comparisons of 1H and 13C NMR spectra, neither of stereoisomers provided a match for the erythrochelin spectral data, and the absolute configuration of erythrochelin was unambiguously reconfirmed to be (R,R,S,S).


Facile Two-Step Synthesis of Methyl Bis(2,2,2-trifluoroethyl)phosphonoacetate by Exploiting GareggSamuelsson Reaction Conditions


Synthesis of Sterically Protected Isoindoles from ortho-Phthalaldehyde

o-Phthalaldehyde (OPA) reacts with O-protected tris(hydroxyalkyl)aminomethanes in the presence of 1-propanethiol to afford a novel class of stable isoindoles. Steric protection provided by the bulkiness of C 3-symmetric primary amines derived from tris(hydroxymethyl)aminomethane could be significant for the stabilization of 1-alkylthio-2-alkyl-substituted isoindoles derived from OPA. A plausible reaction mechanism is proposed to explain the formation of the isoindole and an isoindolin-1-one by-product.


Unique anti-myeloma activity by thiazolidine-2,4-dione compounds with Pim inhibiting activity.

Proviral Integrations of Moloney virus 2 (PIM2) is overexpressed in multiple myeloma (MM) cells, and regarded as an important therapeutic target. Here, we aimed to validate the therapeutic efficacy of different types of PIM inhibitors against MM cells for their possible clinical application. Intriguingly, the thiazolidine-2,4-dione-family compounds SMI-16a and SMI-4a reduced PIM2 protein levels and impaired MM cell survival preferentially in acidic conditions, in contrast to other types of PIM inhibitors, including AZD1208, CX-6258 and PIM447. SMI-16a also suppressed the drug efflux function of breast cancer resistance protein, minimized the sizes of side populations and reduced in vitro colony-forming capacity and in vivo tumourigenic activity in MM cells, suggesting impairment of their clonogenic capacity. PIM2 is known to be subject to ubiquitination-independent proteasomal degradation. Consistent with this, the proteasome inhibitors bortezomib and carfilzomib increased PIM2 protein levels in MM cells without affecting its mRNA levels. However, SMI-16a mitigated the PIM2 protein increase and cooperatively enhanced anti-MM effects in combination with carfilzomib. Collectively, the thiazolidine-2,4-dione-family compounds SMI-16a and SMI-4a uniquely reduce PIM2 protein in MM cells, which may contribute to their profound efficacy in addition to their immediate kinase inhibition. Their combination with proteasome inhibitors is envisioned.


Synthesis of Fluorine-Containing Analogues of 1-Lysoglycerophospholipids via HornerWadsworthEmmons Reaction

An efficient method of synthesizing fluorine-containing analogues of 1-lysoglycerophospholipids (1-LPLs) by introducing a palmitoyl moiety starting from bis(2,2,2-trifluoroethyl)phosphonoacetate (StillGennari reagent) is described. The method effectively employs HornerWadsworthEmmons reagents as masked 1-LPL derivatives to prepare a series of analogues of 1-lysophosphatidic acid (1-LPA), 1-lysophosphatidylethanolamine (1-LPE), and 1-lysophosphatidylcholine (1-LPC).


Antibacterial and antibiofilm effects of Reuterin-Related Compounds to periodontopathic bacteria


Novel reuterin-related compounds suppress odour by periodontopathic bacteria

Halitosis is caused by volatile sulphur compounds including methyl mercaptan (CH3 SH) in the oral cavity and is a serious problem that limits interpersonal social communication. The aim of study was to evaluate the effects of reuterin-related compounds (RRCs) on halitosis-related periodontopathic bacteria in vitro. RRC-01, RRC-02 and RRC-03 (32 and 64 g ml(-1) ) in culture media containing Fusobacterium nucleatum JCM8523 and Porphyromonas gingivalis ATCC33277 were used. The effects of RRCs on CH3 SH production and detectable odour by F. nucleatum and P. gingivalis were examined by CH3 SH production assay and organoleptic test, respectively. The number of bacterial cells was also measured using an ATP assay. In P. gingivalis treated with RRCs, the expression of mgl gene, which is responsible for CH3 SH production, was examined by qRT-PCR. CH3 SH production and the score of detectable odour from F. nucleatum and P. gingivalis culture media containing RRCs were significantly lower than that without RRCs (P < 0.05). The expression of mgl gene in P. gingivalis was significantly downregulated by RRC-01 (P < 0.01), but not by RRC-02 or RRC-03. RRCs are potent oral care products for preventing halitosis via reducing CH3 SH production.


Enzymatic Synthesis of Chiral P-Stereogenic Phosphonoacetates

In this data article, we describe the enzymatic kinetic resolution of a series of racemic mixed phosphonoacetates, which were successfully prepared from methyl bis(2,2,2-trifluoroethyl)phosphonoacetate (Still-Gennari reagent) by alcoholysis with -symmetrical secondary alcohols in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). Porcine liver esterase (PLE)-catalyzed kinetic resolution of some of these racemic mixed phosphonoacetates proceeded in a highly stereoselective manner to furnish the chiral P-stereogenic phosphonoacetates (up to > 99% ee).


Synthesis of Erythrochelin: A Hydroxamate-Type Siderophore from Saccharopolyspora erythraea

Erythrochelin, a hydroxamate-type siderophore produced by Saccharopolyspora erythraea, is synthesized for the first time. A key building block of erythrochelin containing the 2,5-diketopiperazine ring is prepared by intramolecular cyclization of the corresponding dipep- tide precursor derived from two kinds of protected -N-hydroxy-L-orni- thines. Consecutive condensation of the building block with protected D-serine and protected -N-hydroxy-D-ornithine, followed by deprotec- tion, furnishes erythrochelin.


N4-Methylation Changes the Conformation of (3S,6S)-3-Alkyl-6-benzylpiperazine-2,5-diones from Folded to Extended

N4-Methylation of (3S,6S)-3-alkyl-6-benzylpiperazine-2,5-diones (S,S)-1ac was found to change their folded conformation to an extended conformation. Conformational aspects of N1- and/or N4-methylated (S,S)-1ac were revealed by single crystal X-ray crystallography and 1H NMR spectroscopy.


Asymmetric Synthesis of cis-4a,5,8,8a-Tetrahydrophthalazin-1(2H)-one Derivatives Based on Organocatalytic Alcoholysis of Cyclic Dicarboxylic Anhydride

Asymmetric synthesis of optically active cis-4-phenyl-4a,5,8,8a- tetrahydrophthalazin-1(2H)-one and its N-alkylated derivatives based on an organocatalytic enantioselective alcoholysis of cyclic dicarboxylic anhydride was described.


Analysis of molecular species profiles of ceramide-1-phosphate and sphingomyelin using MALDI-TOF mass spectrometry

Ceramide-1-phosphate (C1P) is a potential signaling molecule that modulates various cellular functions in animals. It has been known that C1P with different N-acyl lengths induce biological responses differently. However, molecular species profiles of the C1P in animal tissues have not been extensively examined yet. Here, we developed a method for determination of the molecular species of a C1P using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry with Phos-tag, a phosphate capture molecule. The amounts of total C1P in skin, brain, liver, kidney and small intestine of mice were determined to be 344, 151, 198, 96 and 90 pmol/g wet weight, respectively. We found a C1P species having an α-hydroxypalmitoyl residue (h-C1P, 44 pmol/g wet weight) in mouse skin. The h-C1P was detected only in the skin, and not other tissues of mice. The same analysis was applied to sphingomyelin after conversion of sphingomyelin to C1P by Streptomyces chromofuscus phospholipase D. We found that molecular species profiles of sphingomyelin in skin, kidney and small intestine of mice were similar to those of C1P in corresponding tissues. In contrast, molecular species profiles of sphingomyelin in liver and brain were quite different from those of C1P in these tissues, indicating selective synthesis or degradation of C1P in these tissues. The method described here will be useful for detection of changes in molecular species profiles of C1P and sphingomyelin.


Synthesis of Allenyl Esters by Horner-Wadsworth-Emmons Reactions of Ketenes Mediated by Isopropylmagnesium Bromide


A Novel Synthetic Approach to Glycerophospholipid via Horner-Wadsworth-Emmons Reaction of Mixed Phosphonoacetate

A novel synthetic approach to glycerophospholipids featuring the use of Horner-Wadsworth-Emmons reagents as masked glycerophospholipids has been developed. Based on the method, phosphatidic acid (PA), phosphatidylethanolamine (PE), and phosphatidylcholine (PC) containing palmitoyl moieties were readily synthesized from a mixed phosphonoacetate as a common key intermediate.


Synthesis of Rhodotorulic Acid and Its 1,4-Dimethylated Derivative


Z-Selective HornerWadsworthEmmons Reaction of 2-TOM-cyclopentanone for the Synthesis of rac-N-Cbz-Gly-[(Z)-CF=C]-Pro-OH Dipeptide Isostere


E-Selective Horner-Wadsworth-Emmons Reaction of 2-OBO-cyclopentanone for the Synthesis of rac-N-Cbz-Gly-[(E)-CF=C]-Pro-OH Dipeptide Isostere


Pim-2 kinase is an important target of treatment for tumor progression and bone loss in myeloma.

Pim-2 kinase is overexpressed in multiple myeloma (MM) cells to enhance their growth and survival, and regarded as a novel therapeutic target in MM. However, the impact of Pim-2 inhibition on bone disease in MM remains unknown. We demonstrated here that Pim-2 expression was also upregulated in bone marrow stromal cells and MC3T3-E1 preosteoblastic cells in the presence of cytokines known as the inhibitors of osteoblastogenesis in MM, including interleukin-3 (IL-3), IL-7, tumor necrosis factor-, transforming growth factor- (TGF-) and activin A, as well as MM cell conditioned media. The enforced expression of Pim-2 abrogated in vitro osteoblastogenesis by BMP-2, which suggested Pim-2 as a negative regulator for osteoblastogenesis. Treatment with Pim-2 short-interference RNA as well as the Pim inhibitor SMI-16a successfully restored osteoblastogenesis suppressed by all the above inhibitory factors and MM cells. The SMI-16a treatment potentiated BMP-2-mediated anabolic signaling while suppressing TGF- signaling. Furthermore, treatment with the newly synthesized thiazolidine-2,4-dione congener, 12a-OH, as well as its prototypic SMI-16a effectively prevented bone destruction while suppressing MM tumor growth in MM animal models. Thus, Pim-2 may have a pivotal role in tumor progression and bone loss in MM, and Pim-2 inhibition may become an important therapeutic strategy to target the MM cell-bone marrow interaction.Leukemia advance online publication, 30 May 2014; doi:10.1038/leu.2014.147.


Synthesis and Conformational Characterization of Diketopiperazines Bearing a Benzyl Moiety

Diketopiperazines bearing a benzyl moiety with different para-substituents were synthesized and analyzed by 1H NMR spectroscopy. All of these diketopiperazines were found to adopt a folded conformation according to the upfield chemical shift of the cis-proton (cis to the benzyl moiety) due to a shielding effect in the 1H NMR spectra. An intramolecular CH- interaction appears to be an important factor for the folded conformation due to the effects of para-substituents on the benzyl group.


Reinvestigation of 1,3,4-Thiadiazol-2(3H)-Iminium Bromide in the Two-Step Synthesis of Imdazo[2,1-b][1,3,4]-Thiadiazoles


Catalytic Asymmetric Ring-Opening of -Symmetric Cyclic Carbonates with Chiral Brønsted Acid Catalysts


Deconjugative Esterification of 2-(4-Phenylcyclohexylidne)acetic Acid via Intramolecular Chirality Transfer


A Microwave-Assisted Deconjugative Esterification of α,β-Unsaturated Carboxylic Acids through alpha,beta-Unsaturated Ketene Intermediates


Reinvestigation of the Synthesis of Isoliquiritigenin (ILG): Application of Horner-Wadsworth-Emmons Reaction and Claisen-Schmidt Condensation

Isoliquiritigenin [ILG, (E)-1] was readily prepared via the Horner-Wadsworth-Emmons reactions using β-ketophosphonates 5a, b. An improved protocol for the synthesis of (E)-1 via the Claisen-Schmidt condensation was also presented.


Intragastrically administrered lysophospatidic acid protect against gastric ulcer in rats under water-immersion restraint stress

Lysophosphatidic acid exerts important physiological effects on many types of animal cells through its specific binding to several G protein-coupled receptors. In particular, its potent wound-healing effect has attracted much attention. To determine whether lysophosphatidic acids in a foodstuff and Chinese medicine are effective in protecting against gastric ulcer, we subjected rats to water-immersion restraint stress. Three direct administrations of a solution of lysophosphatidic acid with a C18 fatty acyl group to the rat stomach in a concentration range of 0.001-0.1 mM resulted in a significant reduction in the number of gastric ulcers induced during water-immersion restraint stress, and the potencies were as follows: linoleoyl species=α-linolenoyl species>oleoyl species. Intragastric administrations of a solution of highly purified lysophosphatidic acid from soybean lecithin significantly protected against the stress-induced gastric ulcers at lower concentrations than partially purified lysophosphatidic acid from soybean lecithin did. In addition, administration of a decocted solution of antyu-san, and lysophosphatidic acid-rich Chinese medicine, to the stomach was more effective in protecting against stress-induced ulcer than decoctations of antyu-san lacking the corydalis tuber component that is rich in lysophosphatidic acid. These results clearly show that lysophosphatidic acid is the effective component of soybean lecithin and antyu-san in protection against stress-induced gastric ulcer in the rat model, and suggest that daily intake of lysophosphatidic acid-rich foods or Chinese medicines may be beneficial for prevention of stress-induced gastric ulcer in human subjects.


Evaluation of inhibitory actions of flavonols and related substances on lysophospholipase d activity of serum autotaxin by a convenient assay using a chromogenic substrate.

Overproduction of lysophosphatidic acid (LPA) by lysophospholipase D/autotaxin (lysoPLD/ATX) is postulated to be involved in the promotion of cancer and atherosclerosis. A lysoPLD inhibitor may be utilized to ameliorate the LPA-related pathological conditions. In this study, a new assay was devised to quantify p-nitrophenol from hydrolysis of chromogenic substrate by serum lysoPLD without tedious lipid extraction procedures. Flavonols, phenolic acids, free fatty acids, and N-acyltyrosines inhibited lysoPLD activity in a micromolar range. They were classified into competitive, noncompetitive, or mixed type inhibitors. The results show that the low hydrophobicity of an inhibitor is a critical factor in its preference for the binding to a noncatalytic binding site over a catalytic binding site. Considering its reported bioavailability and the low dependency of its inhibitory activity on serum dilution, flavonol is likely to be a more effective lysoPLD inhibitor in human blood circulation in vivo than the other inhibitors including LPA.

Journal of Agricultural and Food Chemistry


Modified Cinchona Alkaloid-Zinc Complex Catalysts: Enantioselective Monoacetylation of Glycerol Derivatives with Acetic Anhydride


A Chiral Bifunctional Sulfonamide as an Organocatalyst: Alcoholysis of -Symmetric Cyclic Dicarboxylic Anhydrides


Synthesis and Reaction of 1-Azabicyclo[3.1.0]hexane

The effective formation of 1-azabicyclo[3.1.0]hexane (5) by treatment of 2-(bromomethyl)pyrrolidine hydrobromide (4) with n-BuLi was established, with the reaction occurring by a rational reaction pathway via the open chain transition state 8 based on intermolecular Br...Li(+) coordination (SN2 process). The reaction of 5 with electrophiles 13a-n gave the corresponding pyrrolidines 14a-n and piperidine 6, 15a-g, i-n. The selectivity of the products in this reaction appeared to be controlled by equilibrium.


Reaction of 1-Azabicyclo[1.1.0]butane with Activated Amides


Use of Diketopiperazines for Determining Absolute Configurations of α-Substituted Serines by 1H-NMR Spectroscopy


Chemoenzymatic Synthesis of α-Substituted Serines via Enantiodivergent Transformation


Intramolecular Nonbonded S---N Interaction in Rabeprazole

Intramolecular nonbonded S...N interactions in the crystal structures of the derivatives (7a-d) of sodium rabeprazole (1) and an intermolecular nonbonded S...N interaction between ethylmethylsulfoxide and pyridine in a solution were recognized. These results made us estimate that the intramolecular nonbonded S...N interaction existed in 1 and its derivatives in a solution, and formed the 4-membered quasi-ring in 2 (Fig. 1) followed by the increase of the reactivity of 2 to give the putative spiro sulfoxide 3, which is the key intermediate in the reaction cascade of 1 (Chart 1).


Synthesis of New Quinolone Antibiotics Utilizing Azetidine Derivatives Obtained from 1-Azabicyclo[1.1.0]butane

A series of 3-sulfenylazetidine derivatives 5a-f were synthesized via the ring-opening reactions of 1-azabicyclo[1.1.0]butane (ABB, 3) with thiols 4a-f in 50-92% yields. Treatment of ABB (3) with aromatic amines 9a-e and dibenzylamine (9f) in the presence of Mg(ClO4)2 afforded the corresponding 3-aminoazetidine derivatives 10a-f in 24-65% yields. N-Benzyl-3-bromoazetidine (13), which was obtained by the reaction of ABB (3) with benzyl bromide, gave 3-aliphatic amino-substituted azetidine derivatives 15a, b. Novel fluoroquinolones 7a-f, 11a-f, 16a, b and 25a-c were obtained by the introduction of these azetidine derivatives into the C7 position of a quinolone nucleus 6 and N1-heterocyclic quinolones 21a-c in 21-83% yields. Some of them exhibited a greater antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) in comparison with that of clinically used fluoroquinolone, levofloxacin (LVFX).


Effects of Magnesium Salts and Amines on the Stereoselectivity in the Imine Aldol Reaction

In the imine aldol reactions of 1 with aromatic aldehydes using magnesium salts in the presence of amines, the threo/erythro ratios of products increased in the order Mg(ClO4)2>MgI2>MgBr2>MgCl2>Mg(OTf)2 and N,N,N',N'-tetramethylethylenediamine (TMEDA)>Et3N. This increase in the threo/erythro ratios of products was estimated to be caused by a retro-imine aldol reaction under thermodynamic control.


Nonenzymatic Enantioselective Monoacetylation of Prochiral 2-Protectedamino-2-alkyl-1,3-propanediols Utilizing a Chiral Sulfonamide-Zn Complex Catalyst

[structure: see text] Treatment of a chiral sulfonamide with Et(2)Zn gave quantitatively its Zn complex and then the structure was determined by X-ray crystallographic analysis. Reaction of prochiral N-Boc-2-amino-2-alkyl-1,3-propanediols with Ac(2)O in the presence of 5 mol % of chiral sulfonamide-Zn complex catalyst afforded the corresponding chiral monoacetyl products in 70-92% yields with 70-88% ee values. The proposed mechanism for the catalytic monoacetylation of a prochiral 1,3-propanediol was presented on the basis of CSI-MS analysis.


Stereoselective Synthesis of Unsymmetrical Conjugated Dienes and Trienes Utilizing Silacyclobutenes


Synthesis and Antibacterial Activities of New Quinolone Derivatives Utilizing 1-Azabicyclo[1.1.0]butane

The ring-opening reactions of 1-azabicyclo[1.1.0]butane 3 with thiols 6a-f gave 3-sulfenylazetidine derivatives 7a-f in 50-92% yields. Treatment of 3 with aromatic amines 11a-e and dibenzylamine 11f in the presence of Mg(ClO(4))(2) afforded the corresponding 3-aminoazetidine derivatives 12a-f in 24-53% yields. These azetidine derivatives were introduced into the C7 position of a quinolone nucleus 8 to afford the corresponding fluoroquinolones 9a-f and 13a-f in 21-83% yields. Some of them exhibited superior antibacterial activity against quinolone-susceptible MRSA in comparison with clinically used fluoroquinolones, such as levofloxacin, ciprofloxacin, and gatifloxacin.

Bioorganic & Medicinal Chemistry Letters


Synthesis of Novel Silacyclobutene Derivatives Utilizing Zirconocene- and Titanocene-ethylene Complexes


Tandem Reduction Olefination of Triethyl 2-Aceyl-2-fluoro-2-phosphonoacetates and a Synthetic Approach to Cbz-Gly-Ψ[(Z)-CF=C]-Gly Dipeptide Isostere


Novel Deconjugative Esterification of 2-Cyclohexylidneacetic Acids through 4-(Pyrrolidin-1-yl)pyridine Catalyzed Carbodiimide Couplings


Diastereoselective Horner-Wadsworth-Emmons Reaction for the Synthesis of Tetrasubstituted Alkenes with an Axis of Chirality


Practical Synthesis of New Chiral cis-Phthalazinones with Potential for High Phosphodiesterase (PDE-4) Inhibitory Activity


Lipase-catalyzed Enantioselective Acetylation of Prochiral N-Cbz-2-Alkyl-2-amino-1,3-propanediols and Enantiodivergent Synthesis of α-Benzylserine


Fab fragment labeled with ICG-derivative for detecting digestive tract cancer


A Novel and Efficient Darzens Reaction Catalyzed by Magnesium Bromide


Optimal Labeling Condition of Antibodies Available for Immunofluorescence Endoscopy

In recent years, labeled antibodies have been used for diagnostic imaging in many studies. In this study, we investigated the mode of binding in antibodies labeled with ICG derivatives newly developed for the diagnosis of microcarcinomas, and evaluated the optimal binding molar ratio between the labeling compounds and antibody. MUC 1 antibody and ICG derivatives (ICG-ATT and ICG-sulfo-OSu) were used. ICG derivatives non-covalently bound to the antibody were removed with ethyl acetate, and the ratio of ICG derivatives covalently bound to the labeled antibody was confirmed. During purification of the labeled antibody, the amount of each labeling compound reacting with 1 molecule of the antibody varied as follows: 4, 8, 16, and 32 molar equivalents. Subsequently, the intensity of fluorescence was evaluated by spectroscopy and infrared fluoroscopy. The ratio of residual ICG derivative labeling the antibody was 67.4% for ICG-ATT and 65.0% for ICG-sulfo-OSu. When fluorescent antibody labeled with ICG-ATT at an F/P ratio of 2.94 or 4.18 was used, specific and clear fluorescent images of the antigen were obtained. When ICG-ATT-labeled antibody at an F/P ratio of 6.50 or 6.75 was used, the fluorescence intensity decreased and the fluorescent images of antigen became unclear. It was found that the ICG-ATT-labeled antibody was a more specific and sensitive marker than ICG-sulfo-OSu-labeled antibody, and that lower binding molar ratios of ICG-ATT were more useful for labeling the antibody.

The Journal of Medical Investigation : JMI


Expeditious Syntheses of Conjugated Allenyl Esters and Oxazoles through a Cascade Reaction of α-Alkynyl Malonates under Alkaline Conditions

Diethyl alpha-alkynyl-alpha-methoxymalonates (2a--e) were smoothly hydrolyzed and then decarboxylated under alkaline conditions employing 1 N KOH in EtOH to give conjugated allenyl esters (6a--e) in high yields, and similar alkaline treatment of diethyl alpha-alkynyl-alpha-acetylaminomalonates (5a, b, d, e) furnished unexpectedly the oxazoles (7a, b, d, e) having three substituent groups in excellent yields.


Highly Stereoselective Asymmetric Pummerer Reactions That Incorporate Intermolecular and Intramolecular Nonbonded S---O Interactions

New chiral sulfoxides (R(S),S)-3, (S(S),S)-3, (R(S),S)-4, and (S(S),S)-4 and known chiral sulfoxides (R(S))-5, (R(S))-6, and (R(S))-7 were synthesized, and the stereochemistry of the new sulfoxides (R(S),S)-3 and (R(S),S)-4 was determined by X-ray crystallographic analysis. In their crystallographic structures, the intramolecular nonbonded S...O close contacts were recognized. Analyses of several sulfoxide complexes including rac-11 with N,N-dimethylacetamide (DMAC) or N-methyl-2-pyrrolidone (NMP) in a MeOH solution utilizing cold-spray ionization mass spectrometry provided, for the first time, direct information for intermolecular nonbonded S...O interactions between sulfoxides and amide (or lactam) in a solution. Highly diastereoselective and enantioselective Pummerer reactions based on the concept of intermolecular and intramolecular nonbonded S...O interactions were performed by treatment of several chiral sulfoxides (R(S), S)-3, (S(S), S)-3, (R(S), S)-4, (S(S), S)-4, (R(S))-5, (R(S))-6, and (R(S))-7 with acetic anhydride and trimethylsilyl triflate (TMSOTf) in DMAC, NMP, N,N-dimethylformamide, and N-formylpiperidine. Mechanistic studies on these facile stereoselective Pummerer reactions revealed the necessity for the amide/TMSOTf complex, such as 26 or 27, to be an efficient activation reagent for Ac(2)O and a trapping reagent for the released acetate ion, and that DMAC and NMP had a positive effect on this highly stereoselective chiral transfer reaction.

Journal of the American Chemical Society


Highly Enantioselective Catalytic Thiolysis of Prochiral Cyclic Dicarboxylic Anhydrides Utilizing a Bifunctional Chiral Sulfonamide


Practical Synthesis of Chiral cis-Cyclohex-4-ene-1,2-dicarboxylic Acid Derivatives by Utilizing (4S)-Isopropyl-1,3-thiazolidine-2-thione


A Facile Synthesis of Novel Chiral Phosphonoacetates Bearing a Stereogenic Phosphorus Atom

Novel chiral phosphonoacetates bearing a stereogenic phosphorus atom were successfully synthesized by enzyme-catalyzed kinetic resolution of racemic phosphonoacetates.


Trimethylaluminum-Induced Diastereoselective Methylation onto Ethyl 2-Oxocyclopentane-1-carboxylate and Isomerization between Both of the Dimethylaluminium-Alkoxide Products


Facile Generation Method for Conjugated Allenyl Esters Based on retro-Dieckmann Type Ring-Opening Reactions


New Ring-Expansion Reactions of Hydroxy Propenoyl Cyclic Compounds under Palladium(0)/Phosphine-Catalyzed Conditions

[reaction: see text] Palladium(0)-catalyzed one-atom ring-expansion of 1-hydroxy-2,2-dialkyl-1-propenoylindan derivatives has been achieved in the presence of P(o-tolyl)(3) giving 2-hydroxy-3,3-dialkyl-2-vinyl-1-tetralone derivatives in excellent yields. This ring-expansion reaction was applied to a 17-(1-oxo-2-propenyl)-beta-estradiol derivative and furnished a similar ring-expanded product in an excellent yield.


New Synthetic Methods for Seven- and Eight-Membered Cyclic Ethers Based on the Ring-Expansion Reactions of Hydroxy or Lithioxy Methoxyallenylisochroman Derivatives


Intramolecular Nonbonded S---O Interaction in Acetazolamide and Thiadiazolinethione Molecules in Their Dimeric Crystalline Structures and Complex Crystalline Structures with Enzymes


A New Infrared Fluorescent-Labeling Agent and Labeled Antibody for Diagnosing Microcancers

We have developed infrared fluorescent labeling agents and infrared-ray fluorescence endoscopes to establish a novel diagnostic technique. Since the fluorescence intensity of the initial labeled antibody (ICG-sulfo-OSu-labeled antibody) was not sufficient for practical use, we synthesized indocyanine green acylthiazolidinethione (ICG-ATT), which was expected to label various target molecules having amino groups efficiently. To confirm imaging of infrared fluorescence intensity of ICG-ATT- and ICG-sulfo-OSu-labeled anti-MUC1 antibodies, cotton thread was soaked in various concentrations of the antibody solution in 0.1M PBS, and observed under the epi-illumination infrared fluorescence microscope. Localization and the intensity of infrared fluorescence and DAB coloring was compared in paraffin sections of human gastric mucosa. In the study of cotton threads, both labeled antibodies showed relatively clear infrared fluorescence, and significant difference was not observed between the two antibodies. ICG-ATT-labeled anti-MUC1 antibody produced stronger staining than that by ICG-sulfo-OSu-labeled antibody. Localization pattern of infrared fluorescent staining was in good agreement with that by the conventional method with oxidized DAB staining. ICG-ATT is useful as a fluorescent-labeling agent for diagnosis of microcancers by infrared fluorescence endoscopes.


Asymmetric Horner-Wadsworth-Emmons Reaction Utilizing Isomannide and Isosorbide Derivatives as Chiral Auxiliaries


Tandem Reduction-Olefination for the Stereoselective Synthesis of (Z)-α-Fluoro-α,β-unsaturated Esters


(E)-Selective Horner Wadsworth Emmons reaction of aldehydes with bis-(2,2,2-trifluoroethyl)phosphonoacetic acid


A New Convenient Method for Synthesis of 3-(2-Oxoethylidene)isoindolin-1-ones Employing Palladium(II) Acetate and DDQ


(E)-Selective Horner-Wadsworth-Emmons Reaction of Aryl Alkyl Ketones with Bis(2,2,2-trifluoroethyl)phosphonoacetic Acid


A Facile Method for the Stereoselective Horner-Wadsworth-Emmons Reaction of Aryl Alkyl Ketones

Excellent Z or E selectivity was observed in the Horner-Wadsworth-Emmons (HWE) reactions of methyl bis(2,2,2-trifluoroethyl)phosphonoacetate or ethyl 2-fluoro-2-diethylphosphonoacetate with aryl alkyl ketones bearing substituents on an aromatic moiety employing Sn(OSO_2CF_3)_2 in the presence of N-ethylpiperidine.


Synthesis of New Chiral Sulfinyldiacetic Acid Derivatives and Attempt at Chemoselective Asymmetric Pummerer Reaction

(R_s)-1 (85% ee) was prepared by utilizing a porcin pancreatic lipase-promoted hydrolysis of sulfinyldiacetic acid dimethyl ester (8) which was derived from thiodiacetic acid (7). (R_s)-1 (99% ee) and (S_s)-1 (99% ee) were readily obtained by methanolysis of (R_s,S)-12 and (S_s,S)-12 with MeONa in MeOH. (R_s,S)-12 and (S_s,S)-12 were furnished by chromatographic separation of the diastereomeric mixture, obtained by oxidation of thiodiacetic mono-carboxylic acid (11) with 30% H_2O_2 followed by dehydrative condensation of the resultant sulfinyldiacetic mono-carboxylic acid with 4(S)-isopropyl-1,3-thiazolidine-2-thione. (R_s)-1 (99% ee) was successively treated with (TMS)_2NLi, Ac_2O, and TMSOTf to give a major chiral-3 product in 75% ee and in a highly chemoselective manner (chiral-3 : chiral-2=93 : 7).


Remarkable Discrepancy in the Predominant Structures of Acyl(or Thioacyl)aminothiadiazoles, Acyl(or Thioazyl)aminooxadiazoles and Related Compounds Having the Potential for Rotational, Geometrical and Tautomeric Isomerism


Facile Palladium(0)-Catalyzed Ring Expansion Reactions of Hydroxy Methoxyallenyl Cyclic Compounds via Hydropalladation

Palladium(0)-catalyzed one-atom ring expansion of various hydroxy methoxyallenyl compounds has been achieved in excellent yields without the use of aryl halides. Hydroxy methoxyallenylisoindolinones, -indanones, and -phthalans have been readily converted to the corresponding isoquinolones, naphthoquinones, and isochromanones in the presence of P(o-tolyl)(3).


Highly Chemoselective Pummerer Reactions of Sulfinyldiacetic Acid Derivative


Enantioselective Horner-Wadsworth-Emmons Reaction for the Asymmetric Synthesis of α-Fluoro-α,β-unsaturated Esters


Stereoselective Synthesis of Tetrasubstituted (Z)-Alkenes form Aryl Alkyl Ketones Utilizing the Horner-Wadsworth-Emmons Reaction


Toward (Z)-Selective Horner-Wadsworth-Emmons Reaction of Aldehydes with 2-Fluoro-2-diethylphosphonoacetic Acid


Synthesis and Antibacterial Activity of New 1β-Methylcarbapenems Having the Potential for Intramolecular Nonbonded S---O Interactions

Mercaptoacetyliminothiadiazoline derivatives (19, 20) useful for the pendant moiety of 1beta-methylcarbapenem antibiotics were efficiently synthesized. Acetyl derivative (18) of 20 was submitted to X-ray analysis, and a significant nonbonded S...O close contact was recognized in the crystallographic structure. New 1beta-methylcarbapenems (5, 6) were synthesized by exploiting 19 and 20, and exhibited considerable antibacterial activities in vitro.


Copper(I) Iodine-Promoted Hydroxylation onto the Lithium or Potassium Enolate of Lactones and Lactams


Chemoenzymatic Total Synthesis of (+)-Conagenin, a Low-molecular-weight Immunomodulator


Asymmetric Syntheses of (+)-Camptothecin and (+)-7-Ethyl-10-methoxycamptothecin


Synthesis of a New Class of Cathepsin B Inhibitors Exploiting a Unique Reaction Cascade


Desulfurilative Self-Coupling Reaction of 1,3-Thiazolidine-2-thiones and Intramolecular Non-Bonded S---S Interaction in the Crystallographic Structure of the Products


Tin-Mediated Enantioselective Aldol-Type Reaction for the Asymmetric Synthesis of α-Substituted Serines Utilizing an External Chiral Ligand, (-)-Sparteine


Novel hetrocyclic ring-expansion and/or dehydration-hydration reactions of propargylic and allenylic hydroxy γ-lactams in the presence of strong base or Lewis acid


New Reaction Mode of the Horner-Wadsworth-Emmons Reaction for the Preparation of α-Fluoro-α,β-unsaturated Esters


Intramolecular Nonbonded S---O Interaction Recognized in (Acylimino)thiadiazoline Derivatives as Angiotensin II Receptor Antagonists and Related Compounds

Journal of the American Chemical Society


Synthesis and Antibacterial Activity of New, Non-natural 1β-Methylcarbapenem Bearing a σ-Symmetric Bicyclopyrazoliumthio Group as the Pendant Moiety


New Enantiodivergent Procedure for the Syntheses of Chiral α-Substituted Serines from α-Alkyl-α-aminomalonates Utilizing Enzymatic Hydrolysis


Synthesis and Reactivities of 3-Indocyanine-green-acyl-1,3-thiazolidine-2-thione (ICG-ATT) as a New Near-Infrared Fluorescent-labeling Reagent


Tin- or Magnesium-Mediated Diastereoselective Aldol-Type Reactions for the Asymmetric Synthesis of α-Substituted Serines


Efficient, Direct Synthesis of Novel Racemic Trimethoxy-Substituted [6] and


New Reaction Mode of the Horner-Wadsworth-Emmons Reaction Using Sn(OSO2CF3)2


Asymmetric Dihydroxylation onto the α,β-Unsaturated Carboxylic Ester Derivatives of Camptothecin


Variable Stereoselectivity in the Imine Aldol Reactions Employing MgBr2 and Et3N


A New Ring Enlargement Reaction of γ-Lactones to Seven-Membered Cyclic Ethers via


Syntheses and Reactions of the Diethyl α-Alkynylmalonates Involving the Generation of


A New Enantiodivergent Procedure Utilising the Chemoselective Dieckmann-Type


New Reaction Mode of the Dieckmann-Type Cyclization under the Lewis Acid-Et3N


Asymmetric Total Synthesis of ISP-I (Myriocin, Thermozymocidin), a Potent


Lewis Acid- and Cationic Lithium-Mediated Diastereoselective Aldol-Type Reaction Based


New Six- to Eight-Membered-Ring Formation Based on the Intramolecular Endo- Mode


Enzymatic Hydrolyses of the σ-Symmetric Dicarboxylic Diesters Bearing a Sulfinyl Group


A Facile Synthesis of New Prostaglandin Analogues by Utilizing the Characteristics of the


One-Pot Synthesis of New 1,3-Imidazolidines Possessing Three Aryl Groups via a 1,3-


Synthesis of New Molecules Adopting a Unique Sigmoid Conformation with Stacked


Characterization of the Sulfonic Esters Adopting a Folded Conformation with Stacked


Different Mechanisms of Action of Long Chain Fatty Acid Esters of Podophyllotoxin and


Biomimetic, Chemical, and Spectroscopic Evaluations for the Radiosensitizing Potential of


Radiosensitizing Hypoxic Cells with New 3-Nitro-1,2,4-triazole Derivatives in Vitro and


Effect of Oridonin, a Rabdosia Diterpenoid, on Radiosensitization with Misonidazole


Synthetic Development of Hypoxic Cell Sensitizers Having 3-Nitrotriazole Moiety


Evaluation of the Affinity of New N Atom-Containing Tumor Inhibitors for Nucleic Acids

Nucleic Acids Research, Symposium Series