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The absolute stereochemistry of the aglycon part of an antitumor antibiotic vicenistatin (1) was determined by a synthetic approach. Two relevant components degradatively derived from natural 1 were compared with the corresponding... more
The absolute stereochemistry of the aglycon part of an antitumor antibiotic vicenistatin (1) was determined by a synthetic approach. Two relevant components degradatively derived from natural 1 were compared with the corresponding synthetic standards prepared from known compounds by stereochemically defined chemistry. The absolute configuration of 1 turned out to be 6S,7S,18S.
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ABSTRACT Pinthunamide (1), a sesquiterpene metabolite produced by a fungus Ampliferina sp., was synthesized by starting from (1R,4S,6S)-6-hydroxy-1-methylbicyclo[2,2]octan-2-one (4), which could readily be prepared by yeast reduction of... more
ABSTRACT Pinthunamide (1), a sesquiterpene metabolite produced by a fungus Ampliferina sp., was synthesized by starting from (1R,4S,6S)-6-hydroxy-1-methylbicyclo[2,2]octan-2-one (4), which could readily be prepared by yeast reduction of the corresponding β-diketone 5.
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... Yoshitaka Matsushimaa, Takuya Nakayamaa, Shigehiro Tohyamab, Tadashi Eguchib and Katsumi Kakinuma*a. a Department of Chemistry, Tokyo ... Furthermore, the undesired compound 8′ could be converted into 8 by Mitsunobu inversion and... more
... Yoshitaka Matsushimaa, Takuya Nakayamaa, Shigehiro Tohyamab, Tadashi Eguchib and Katsumi Kakinuma*a. a Department of Chemistry, Tokyo ... Furthermore, the undesired compound 8′ could be converted into 8 by Mitsunobu inversion and hydrolysis of the resulting p ...
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Research Interests: Molecular Biology, Biology, Medicine, Enzymes, Humans, and 14 moreFemale, Gastric Cancer, Male, DNA demethylation, Tandem Mass Spectrometry, High Performance Liquid Chromatography, Aged, Middle Aged, Single Nucleotide Polymorphism, IDH, DNA binding proteins, Stomach neoplasms, cytosine, and deoxycytidine
Trichloroacetimidates, generated either in situ or prepared and isolated from methyl 3‐hydroxycycloalk‐1‐enecarboxylates, undergo stereoselective intramolecular conjugate addition reactions to produce oxazolines. These oxazolines lead, in... more
Trichloroacetimidates, generated either in situ or prepared and isolated from methyl 3‐hydroxycycloalk‐1‐enecarboxylates, undergo stereoselective intramolecular conjugate addition reactions to produce oxazolines. These oxazolines lead, in a novel, simple way, to 2‐amino‐3‐hydroxycycloalkanecarboxylic acids and their derivatives. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)
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Objective: China has among the highest incidence and mortality rates of esophageal cancer in the world. Cixian, one of the high-incidence areas, demonstrates a much higher incidence when compared with other rural or urban areas in China.... more
Objective: China has among the highest incidence and mortality rates of esophageal cancer in the world. Cixian, one of the high-incidence areas, demonstrates a much higher incidence when compared with other rural or urban areas in China. To address the etiology of esophageal cancer in Cixian, we carried out a comprehensive DNA adduct analysis (DNA adductome) using surgical specimens that were collected from esophageal cancer patients living in Cixian and Shijiazhuang (low-incidence area for esophageal cancer). Methods: Both tumorous and nontumorous tissues were collected from patients who underwent surgical procedures at Cixian Cancer Hospital and the Fourth Hospital of Hebei Medical University. A peripheral blood sample was also collected in each hospital. DNA adductome analysis was performed with LC-QTOF mass spectrometer by using DNA derived from surgical specimen. Whole-exome sequencing analysis was also conducted using esophageal tumor/peripheral blood paired samples. Mutation analyses of candidate chemical substance, which was predicted by DNA adductome analysis, were performed with Ames assay and gpt delta transgenic rats. Results: Multiple DNA adducts were detected in samples from both areas in the DNA adductome analysis. The 2D-PCA scores plot of the DNA adducts showed a clear clustering of the high- and low-incidence areas, and the associated loadings plot demonstrated that several DNA adducts made a greater contribution to the high-incidence area. By referring to an in-house DNA adduct database, N2-(3,4,5,6-tetrahydro-2H-pyran-2-yl)deoxyguanosine (THP-dG), which was derived from N-nitrosopiperidine (NPIP), emerged as a major DNA adduct. In order to confirm the DNA adduct that was highly correlated to the high-incidence area, we synthesized authentic 15N5-THP-dG and analyzed it by quantitative LC-MS/MS apparatus. An elution peak, which appeared at the same position of authentic 15N5-THP-dG, was observed in the surgical specimens collected from the high-incidence area. Examination of THP-dG adduct in peripheral blood samples demonstrated that the adduct levels were significantly higher in the high-incidence area than in the low-incidence area. Moreover, NPIP exhibited a strong mutagenic activity under metabolic activation in the Ames test and a significant dose-dependent increase in mutation frequency during in vivo mutagenicity tests with gpt delta rats. The NPIP-induced mutation was dominated by A:T to C:G transversions, followed by G:C to A:T and A:T to G:C transitions, in both liver and esophagus of animal samples. Similar mutational patterns were observed in the mutational signatures of esophageal cancer patients, which demonstrated weak correlation with THP-dG levels. Conclusion: This is the first study that used DNA adductome analysis to reveal the etiology of esophageal cancer in Cixian. These findings suggested that NPIP exposure is partly involved in the development of esophageal cancer in Cixian residents. Citation Format: Hitoshi Nakagama, Yukari Totsuka, Yingsong Lin, Yutong He, Haruna Sato, Tomonari Matsuda, Yoshitaka Matsushima, Mamoru Kato, Asmaa Elzawahry, Yasushi Totoki, Tatsuhiro Shibata, Baoen Shan. Exploration of esophageal cancer etiology using comprehensive DNA adduct analysis (DNA adductome analysis) [abstract]. In: Proceedings of the AACR Special Conference on Environmental Carcinogenesis: Potential Pathway to Cancer Prevention; 2019 Jun 22-24; Charlotte, NC. Philadelphia (PA): AACR; Can Prev Res 2020;13(7 Suppl): Abstract nr A24.
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(E)- endo-Bergamoten-12-oic acids (α-form: 1, β-form: 2), moth oviposition stimulants isolated from wild tomato leaves, were synthesized starting from the lactone 7.
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ABSTRACT Amicoumacins are a family of antibiotics with a variety of important bioactivities. A concise and efficient method was developed for synthesizing the amino acid component of amicoumacins via the corresponding dihydrooxazine... more
ABSTRACT Amicoumacins are a family of antibiotics with a variety of important bioactivities. A concise and efficient method was developed for synthesizing the amino acid component of amicoumacins via the corresponding dihydrooxazine intermediate. The dihydrooxazine ring was formed with complete stereoselectivity through an intramolecular conjugate addition of a δ-trichloroacetimidoyloxy-α,β-unsaturated ester, which was obtained from a known 4,6-O-p-methoxybenzylidene-protected d-glucose. The synthesis developed in this study can be used to synthesize the building blocks of amicoumacins and can likely be adapted for the synthesis of other types of molecules possessing dihydrooxazine rings or amino alcohol moieties.
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ABSTRACT (S)-Phosphonothrixin is a phosphonate natural product produced by Saccharothrix sp. ST-888 that exhibits herbicidal activity. The previously reported asymmetric synthesis of (S)-phosphonothrixin is laborious and difficult to... more
ABSTRACT (S)-Phosphonothrixin is a phosphonate natural product produced by Saccharothrix sp. ST-888 that exhibits herbicidal activity. The previously reported asymmetric synthesis of (S)-phosphonothrixin is laborious and difficult to reproduce. In this study, we developed a scalable and concise enantioselective total synthesis of (S)-phosphonothrixin via two different synthetic routes by the enzymatic resolution of a known racemic epoxy alcohol. The second-generation synthesis was more efficient in terms of the overall yield (15%) and the number of steps (7) and afforded a unique cyclic phosphonate (phostone) as the product of the C–P bond formation reaction, which was converted to (S)-cyclic phosphonothrixin. Both (S)-phosphonothrixin and (S)-cyclic phosphonothrixin induced chlorosis in the plant Arabidopsis thaliana. However, (S)-cyclic phosphonothrixin exhibited lower activity than (S)-phosphonothrixin owing to its fixed conformation, as evidenced by a structure–activity relationship study. This study paves the way for the elucidation of the detailed mode of action of (S)-phosphonothrixin.
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We established a novel, concise synthetic route for obtainingnoviose, the deoxy sugar component of aminocoumarin antibiotics. L-(+)-Noviose was successfullysynthesized by utilizing a palladium-catalyzed epoxide-opening reactionand the... more
We established a novel, concise synthetic route for obtainingnoviose, the deoxy sugar component of aminocoumarin antibiotics. L-(+)-Noviose was successfullysynthesized by utilizing a palladium-catalyzed epoxide-opening reactionand the subsequent lactone formation as key reactions, startingfrom a nonsugar chiral epoxide, which is easily available in bothenantiomeric forms.
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Methylcyclohexanedione (I) is converted to the aldehyde (V) as shown in the scheme.
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ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select... more
ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
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Amicoumacins are a family of antibiotics with a variety of important bioactivities. A concise and efficient method was developed for synthesizing the amino acid component of amicoumacins via the corresponding dihydrooxazine intermediate.... more
Amicoumacins are a family of antibiotics with a variety of important bioactivities. A concise and efficient method was developed for synthesizing the amino acid component of amicoumacins via the corresponding dihydrooxazine intermediate. The dihydrooxazine ring was formed with complete stereoselectivity through an intramolecular conjugate addition of a δ-trichloroacetimidoyloxy-α,β-unsaturated ester, which was obtained from a known 4,6-O-p-methoxybenzylidene-protected d-glucose. The synthesis developed in this study can be used to synthesize the building blocks of amicoumacins and can likely be adapted for the synthesis of other types of molecules possessing dihydrooxazine rings or amino alcohol moieties.
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Background: Field cancerization is a popular concept regarding where cancer cells arise in a plane, such as the opened-up gastrointestinal mucosa. The geospatial distribution of DNA adducts, some of which are believed to initiate... more
Background: Field cancerization is a popular concept regarding where cancer cells arise in a plane, such as the opened-up gastrointestinal mucosa. The geospatial distribution of DNA adducts, some of which are believed to initiate mutation, may be a clue to understanding the landscape of the preferred occurrence of gastric cancer in the human stomach, such that the occurrence is much more frequent in the lesser curvature than in the greater curvature. Methods: Seven DNA adducts, C5-methyl-2′-deoxycytidine, 2′-deoxyinosine, C5-hydroxymethyl-2′-deoxycytidine, N6-methyl-2′-deoxyadenosine, 1,N6-etheno-2′-deoxyadenosine, N6-hydroxymethyl-2′-deoxyadenosine, and C8-oxo-2′-deoxyguanosine, from different points and zones of the human stomach were semi quantitatively measured by liquid chromatography/tandem mass spectrometry. The differences in the quantity of these DNA adducts from the lesser and greater curvature, the upper, middle and lower third zones, the anterior and posterior wall of th...
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Additional file 2 Supplementary Table S1: Mass transitions of DNA adducts. Seven mass transitions that assume a neutral loss of 116 units of deoxyribose in DNA adducts of deoxyribonucleosides were monitored by mass spectrometry.... more
Additional file 2 Supplementary Table S1: Mass transitions of DNA adducts. Seven mass transitions that assume a neutral loss of 116 units of deoxyribose in DNA adducts of deoxyribonucleosides were monitored by mass spectrometry. Supplementary Table S2: Estimated molar ratios of DNA adducts in samples. As described in the Materials and Methods, the molar ratios of DNA adducts and three pairs of peak boundaries, namely, broad, best retention time (Best) and background (BG), were listed for each DNA adduct. A total of 341 samples were classified as GC (Case No. 1–59) and non-GC (Case No. 60–66). Samples from GC were also categorized as tumor or nontumor and are indicated in the Group Status column. Supplementary Table S3: Numbers of sampling sites. The number of samples per individual and its frequency are listed in the table of the nontumor portions of 59 GC cases. This is used to draw the histogram in Fig. 1b. Supplementary Table S4: Representative molar ratio of DNA adducts in indiv...
Additional file 1. Supplementary Figure S1: Chromatograms of standard compounds of DNA adducts. Representative chromatograms of blank (left panel) and standard compounds (right panel) in each mass transition and column retention times are... more
Additional file 1. Supplementary Figure S1: Chromatograms of standard compounds of DNA adducts. Representative chromatograms of blank (left panel) and standard compounds (right panel) in each mass transition and column retention times are shown (a: C5-methyl-dC, b: dI, c: C5-hydroxymethyl-dC, d: N6-methyl-dA, e: etheno-dA, f: N6-hydroxymethyl-dA, g: C8-oxo-dG). Supplementary Figure S2: Histogram of the quantity of each DNA adduct. The distributions according to the various amounts (molar ratios; horizontal axis) of DNA adducts (a: C5-methyl-dC, b: dI, c: C5-hydroxymethyl-dC, d: N6-methyl-dA, e: etheno-dA, f: N6-hydroxymethyl-dA, g: C8-oxo-dG) in nontumor sites of gastric cancer cases are shown. We assigned a zero value in some of the cases with considerably low or undetectable levels of adducts and depicted the histograms of molar ratios among 306 samples.
Objective: China has among the highest incidence and mortality rates of esophageal cancer in the world. Cixian, one of the high-incidence areas, demonstrates a much higher incidence when compared with other rural or urban areas in China.... more
Objective: China has among the highest incidence and mortality rates of esophageal cancer in the world. Cixian, one of the high-incidence areas, demonstrates a much higher incidence when compared with other rural or urban areas in China. To address the etiology of esophageal cancer in Cixian, we carried out a comprehensive DNA adduct analysis (DNA adductome) using surgical specimens that were collected from esophageal cancer patients living in Cixian and Shijiazhuang (low-incidence area for esophageal cancer). Methods: Both tumorous and nontumorous tissues were collected from patients who underwent surgical procedures at Cixian Cancer Hospital and the Fourth Hospital of Hebei Medical University. A peripheral blood sample was also collected in each hospital. DNA adductome analysis was performed with LC-QTOF mass spectrometer by using DNA derived from surgical specimen. Whole-exome sequencing analysis was also conducted using esophageal tumor/peripheral blood paired samples. Mutation ...
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Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA DNA adducts are recognized as an initiative step of mutagenesis, but the measurement of them is still a technical challenge. So-called adductome approach,... more
Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA DNA adducts are recognized as an initiative step of mutagenesis, but the measurement of them is still a technical challenge. So-called adductome approach, based on LC-MS/MS, is a popular procedure to identify multiple DNA adducts in various tissues at a single experiments. Recently we reported 7 lipid peroxidation-induced DNA adducts in human gastric mucosa resected for gastric cancer in two countries for the first time, and showed the profile of these DNA adducts could indicate geo-pathological background of gastric mucosa (Matsuda 2013). Though DNA adductome approach posesses the high throghput potential in terms of finding numerous specis of DNA adducts having different molecular weights, there are still challenges to overcome. First of all, the numbers of the standards of DNA adducts molecules available are less than the species with identified molecular weight. This implies there are much more DNA modifications in human tissues than previously characterized. The other challaenge is that the absolute quantifications of these adducts requires isotopic standard chemicals. In this study, we strengthened DNA adductome method by including as many as known adducts in the assay system. Mass/Charge value and liquid chromatography retention time of known 254 DNA addcuts were collected and incoporated into LC-MS/MS machine (4000-QTRAP; Thermo). By this procedure we could measure the 254 DNA adducts at one time in MRM mode. Using this system, we measured 254 DNA adducts in the following human gastric mucosa. Written informed consents were obtained from the patients who took gastrectomy for gastric cancer. Under the hypothesis of field cancerization of gastric mucosa, in order to analyze the spatial influence of the exposure of the potential carcinogens toward cancer site, muocsal tissue at multiple sites with different distance to cancer, (10cm and more distant from the tumor site in the stomach to the site adjacent to the tumor) were taken. Three to 10 sites/case were investigated for DNA adducts measurements. Totally 11 cases and 77 sites are analyzed. Considerable numbers of known DNA adducts were present in human gastric mucosa in different quantities. Among them, tobacco-related and lipid-peroxidation-induced DNA adducts were noted. We also did the same measurements in proximal, middle, and distal gastric mucosa from autospy cases without gastric cancer and compared them to those of the cancer cases. Among them, etheno-dA was able to be quantitatively measured using isotopic standard. The mean level of etheno dA in the gastric mucosa of autopsy cases without gastric cancer was 8.02/107 nucleotides, while that of gastric cancer patients mucosae was 4.80/107 nucleotides. These comprehensive identifications in adducts in human gastric mucosa will provide the basic information for dosimetry and risk assessment of environmental chemicals toward gastric cancer. Citation Format: Nobuya Kurabe, Ippei Ohnishi, Masako Suzuki, Yusuke Inoue, Tomoaki Kahyo, Moriya Iwaizumi, Yoshitaka Matsushima, Yukari Totsuka, Hitoshi Nakagama, Masako Kasami, Hideto Ochiai, Keigo Matsumoto, Shioto Suzuki, Fumihiko Tanioka, Haruhiko Sugimura. DNA adductome analyses at multiple sites of human gastric mucosa, resected for gastric cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4619. doi:10.1158/1538-7445.AM2015-4619
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Background A comprehensive understanding of DNA adducts, one of the most plausible origins of cancer mutations, is still elusive, especially in human tissues in clinical settings. Recent technological developments have facilitated the... more
Background A comprehensive understanding of DNA adducts, one of the most plausible origins of cancer mutations, is still elusive, especially in human tissues in clinical settings. Recent technological developments have facilitated the identification of multiple DNA adducts in a single experiment. Only a few attempts toward this “DNA adductome approach” in human tissues have been reported. Geospatial information on DNA adducts in human organs has been scarce. Aim Mass spectrometry of human gastric mucosal DNA was performed to identify DNA adducts associated with environmental factors. Materials and methods From 59 subjects who had received gastrectomy for gastric cancer, 306 samples of nontumor tissues and 15 samples of tumors (14 cases) were taken for DNA adductome analysis. Gastric nontumor tissue from autopsies of 7 subjects without gastric cancer (urothelial cancer, hepatocellular carcinoma, lung cancer each; the other four cases were without any cancers) was also investigated. B...
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ABSTRACT
ABSTRACT (+/-)-cis,cis-Spiro[4.4]nonane-1,6-diol (1), which has axial chirality, was efficiently resolved by lipase-catalyzed enantioselective esterification in diisopropyl ether.