著者

瀬戸 治男 Tanabe Masato

出版者

天然有機化合物討論会実行委員会

雑誌

天然有機化合物討論会講演要旨集

巻号頁・発行日

vol.18, pp.264-270, 1974

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The biosynthetic pathway of sterigmatocystine, a metabolite of Aspergillus versicolor, was studied by labeling the metabolite with ^<13>CH_3^<13>CO_2Na. The ^<13>C-nmr spectrum revealed that sterigmatocystine is formed from tetraketide through pathway (b) as shown in Fig. 1. The same technique was also applied to investigate the biosynthesis of penicillic acid. The result shown in Fig.3, pathway (a), was completely in agreement with the conclusion obtained by Mosbach.

著者

チャンサカオ スニー 石川 勉 関 宏子 関根 啓子 岡田 峯明 樋口 義洋 チャイチャンティピュース チャイヨー

出版者

天然有機化合物討論会実行委員会

雑誌

天然有機化合物討論会講演要旨集

巻号頁・発行日

vol.42, pp.49-54, 2000

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"Kwao Keur." which had been identified as Puraria mirifica (Leguminosae), has long been used in Thailand and Burma as a rejuvenating folk medicine and has a fascinating history. A potent estrogenic principle has been known to be an unusual phenol miroestrol (1). Although the possible presence of an alternative active component was suggested, there has been no isolation of any other powerful phytoestrogens. with further studies leading instead to the isolation of isoflavonoids. These situation made us re-investigate the estrogenic principles of P. mirifica. The bioassay-guided separation of the ethyl acetate extract of the tuberous roots of P. mirifica by chromatographic techniques resulted in the successful isolation of a new phytoestrogen. (+)-deoxymiroestrol (4). together with (+)-1 and (+)-isomiroestrol (7). The structure of (+)-1 had been determined by X-ray crystallographic analysis and its enantioselective total synthesis was recently reported. Thus. the structure of (+)-deoxymiroestrol (4) was established by comparison of its NMR data with those of (+)-1. The growth-promoting effect of them on MCF-7 human breast cancer cells showed the strongest activity with 4. Interestingly. 4 was easily converted into 1 and 7 by aerial oxidation. suggesting that 4 may be the actual phytoestrogen of P. mirifica. On the other hand daidzein (2), genistein (3), and coumestrol (6) belong to isoflavonoids were isolated as phytoestrogens with lower activity. In addition, it was found that kwakhurin (5). a characteristic isoflavonoid in this plant. also showed the same activity as 2.

著者

通 和夫 十倉 一也 岡部 啓 江幡 光雄 大塚 英夫 松下 和弘 Lukacs G.

出版者

天然有機化合物討論会実行委員会

雑誌

天然有機化合物討論会講演要旨集

巻号頁・発行日

vol.20, pp.24-31, 1976

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Sulfur-containing peptide antibiotics, siomycins (SIM) A, B, and C isolated from Streptomyces sioyaensis are known to have structures quite similar to that of thiostrepton (TST) isolated from S. azureus. The 25-MHz ^<13>C FT NMR and 220-MHz ^1H NMR spectra of TST and SIM's were determined in CDCl_3-CD_3OD (8: 2) at various temperatures to obtain structural relationships between these antibiotics. ^<13>C signals were tentatively assigned by ^1H noise decoupling, single-frequency and noise off-resonance decouplings, and partially-relaxed FT techniques and using known chemical-shift rules, the chemical shifts of amino acids reported, and those observed for thiostreptine and a quinaldic acid derivative. Their ^<13>C spectra quite similar to each other revealed the numbers of carbon atoms and dehydroalanine (Deala) residues. It was found that (1) the signals of the Val-Deala residues in SIM's are changed to those of the Ile-Ala residue in TST, that (2) SIM-B lacks of the terminal Deala-Deala residue in the long side-chain, and that (3) SIM-C has an unknown amino-acid residue instead of the terminal Deala. On the basis of the above spectral and other chemical studies, and a tentative structure (Ia) proposed for TST by an X-ray crystallographic analysis, the structures Ib, II, and III were concluded to be assigned to TST, and SIM-A and -B, respectively.

著者

秋元 隆史 篠原 涼子 岩本 理 山下 まり 山岡 薫 長澤 和夫

出版者

天然有機化合物討論会実行委員会

雑誌

天然有機化合物討論会講演要旨集

巻号頁・発行日

vol.53, pp.517-522, 2011

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Voltage-gated sodium channels (Na_vCh) are transmembrane proteins that provide inward current carried by sodium ions, and they contribute to the control of membrane excitability, as well as the propagation of action potentials along axons. To date, nine subtypes of sodium channels (NaChs) have been identified, which are closely related to life activity such as a sense of pain, a heartbeat, the muscle expansion and contraction. Since each of these subtypes has unique properties, subtype selective ligand is required for controlling and elucidation of these functions. Saxitoxin (STX) is a naturally occurring NavCh inhibitor, which is believed to bind to the P-loop region of the ion-selective filter in NavCh, and blocks ion influx of Na_vChs in a similar manner to tetrdotoxin (TTX). Recently, a binding model of STX with P-loop domain was proposed based on molecular docking studies by Zhorov. From this model, domain I and STX in C13 and N7 is crucial for the interaction. In this paper, we described the structure-activity relationship studies on STX derivatives with focusing on the C13 and N7 positions. New STX derivatives of 14, 16-18, 23 and 24 modified at C13 and N7 were synthesized from fully protected form of STX of 8 efficiently. Inhibitory activity of these new derivatives against Na_vChs, i.e., Na_v1.2, Na_v1.4 (these are TTX-sensitive) and Na_v1.5 (TTX-resistant), were evaluated by the who'e-cell patch clamp method. As shown in Table 1, these derivatives show moderate inhibitory activities against Na_v1.2, Na_v1.4, but no inhibitory activity was observed to Na_v1.5. Further SAR studies are in progress.

著者

岩本 理 篠原 涼子 此木 敬一 山下 まり 長澤 和夫

出版者

天然有機化合物討論会

雑誌

天然有機化合物討論会講演要旨集

巻号頁・発行日

no.51, pp.181-186, 2009-09-01

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Saxitoxin (STX) (2) and its analogues known as causative agents of paralytic shellfish poisoning, so called PSP, are potent neurotoxins produced by harmful dinoflagellates. This fatal intoxication is attributed to STXs' potent affinity against the voltage gated sodium channels (NaChs), thus the toxins strongly block the influx of sodium ion and inhibit the depolarization process of neuronal cells. We have recently accomplished total synthesis of (-) and (+)-doSTX (ent-2 and 2) and (+)-STX (1) by the use of 1,3-dipolar cycloaddition reaction and unique IBX oxidation reaction. In this paper, we described the NaCh inhibitory activity of novel synthetic STX derivatives 19-22. We also succeeded in developing the new synthetic methodology for constructing the cyclic guanidine skeleton under the extremely mild conditions, which successfully allow us to the total synthesis of (+)-dcSTX (3) and (+)-GTX3 (7) from "protected" saxitoxinol 34.

著者

野川 俊彦 ジャン ジュンピル 本郷 やよい 清水 猛 岡野 亜紀子 二村 友史 高橋 俊二 アン ジョンセオ 長田 裕之

出版者

天然有機化合物討論会実行委員会

雑誌

天然有機化合物討論会講演要旨集

巻号頁・発行日

vol.56, 2014

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<p>放線菌や糸状菌をはじめとする微生物は、多様な構造と活性を有する二次代謝産物を生産することで知られている。それら二次代謝産物は、医薬品や農薬またはそのリード化合物として利用されているものが多い。さらにケミカルバイオロジー研究における生命現象解明のための有用なツール、すなわちバイオプローブとして利用されているものもある。¹これら代謝産物を効率よく探索・単離するために、我々の研究室ではフラクションライブラリーとスペクトルデータベースを用いる方法を構築し利用している。²フラクションライブラリーは、微生物培養液をHPLCや中圧液体クロマトグラフィー(MPLC)により系統的に分画することで作製し、得られたフラクションをPDA-LC/MSにより分析することでデータベースを構築している。データベースは、代謝産物の物性を二次元上の分布として表現したNPPlot(Natural Products Plot)を作成し利用している。今までに、このNPPlotを活用することで特徴的な構造を有する新規化合物を発見・単離してきた。³さらに昨年度の本大会において、複数の菌株より作成したNPPlotの分布パターンの比較による新規化合物の探索と単離について報告した。⁴今回、放線菌Streptomyces sp. RK85-270のフラクションライブラリーより作成したNPPlotの分布パターンから菌株特有の化合物群の探索を行い、2種の新規環状デプシペプチド1および2(図1)を見出すことができたので、それらの単離・構造決定について報告する。</p><p>図1.新規環状デプシペプチド1および2の構造</p><p>【微生物代謝産物フラクションライブラリーの作製】</p><p>放線菌Streptomyces. sp. RK85-270の30 L培養液に等量のアセトンを加え撹拌抽出後、吸引ろ過により菌体を除去し含水アセトン抽出液を得た。減圧下でアセトンを留去し、残った水懸濁液を酢酸エチルにより分配することで有機溶媒可溶性画分と水溶性画分を調製した。有機溶媒画分を減圧濃縮することで抽出物37.2 gを得た。このうち28.7 gをシリカゲル順相MPLCにより、クロロホルム/メタノールのステップワイズ溶出を用いて8分画とした。それぞれを逆相HPLCにより移動相にアセトニトリル/0.05%ギ酸水のグラジエント溶出を用いて一定時間で分画することでフラクションを作製した。水溶性画分は、DIAION HP-20によりメタノールに可溶なものを抽出後、得られたメタノール可溶性画分を逆相MPLCによりメタノール/水を移動相として分画することでフラクションを作製した。以上の方法で約400フラクションを作製した。各フラクションをPDA-LC/MSにより分析し、含有成分のUV吸収およびマススペクトルの収集を行い、成分情報の付加したフラクションライブラリーとした。</p><p>図2.放線菌RK85-270のNPPlotと特徴的分布を示した領域の拡大および</p><p>それら化合物のUV吸収スペクトル</p><p>【スペクトルデータベースNPPlot(Natural Products Plot)の作成】</p><p>PDA-LC/MS分析より得られたUV吸収およびマススペクトルデータをもとに化合物探索に利用するためのスペクトルデータベースを作成した。一般的なスペクトルデータベースに加え、研究室オリジナルのデータベースNPPlot</p><p>(View PDFfor the rest of the abstract.)</p>

著者

村上 悌一 芝上 基成

出版者

天然有機化合物討論会

雑誌

天然有機化合物討論会講演要旨集

巻号頁・発行日

no.50, pp.617-622, 2008-09-01

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Sphingofungins (A-F) are a family of antifungal metabolites produced by microorganisms, and have been shown to be potent and specific inhibitors of serine palmitoyl transferase, an essential enzyme for the biosynthesis of sphingolipids. These compounds have a lipid tail and a polyhydroxy-amino acid head moiety with four contiguous chiral centers and a trans-olefinic function. Due to their biological activity and structural complexity, the sphingofungins have inspired a number of synthetic efforts. We report here a novel synthetic approach to sphingofungins using D-gluconolactone as a chiral source of the head moiety. Gluconolactone 1 was converted to 2-azido-mannonate derivative 3, from which C5-aldehyde derivative 4 was readily prepared. The hydrophobic portion containing (R)-hydroxy group was prepared via asymmetric transfer hydrogenation of pentadec-8-yn-7-one 13. The resulting pentadec-1-yn-9(R)-ol derivative 15 was converted to pentadec-1(E)-enyl-zinc derivative 17, which was reacted with the C5-aldehyde 4 to give separable diastereomeric adducts (7:1). The major adduct was deduced to be natural C5-(S)-alcohol 18, a key intermediate for the synthesis of sphingofungins A-D. Acidic hydrolysis of 18 gave the azide-lactone 19, and the azide was reduced with zinc in acetic acid to give the amine 20. When the reduction was carried out in the presence of acetic anhydride, the acetamide 21 was obtained. Mild basic hydrolysis of 20 and 21 afforded sphingofungins B and D, respectively.

著者

錦部 健人 鴇田 百栄 滝 直人 西川 慶祐 森本 善樹

出版者

天然有機化合物討論会実行委員会

雑誌

天然有機化合物討論会講演要旨集

巻号頁・発行日

vol.59, pp.195-200, 2017

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In the past, through enantioselective total synthesis, our laboratory has found that isodehydrothyrsiferol (5), a marine squalene-derived triterpene polyether isolated from the red alga <I>Laurencia viridis</I>, shows partial enantiodivergency in that six asymmetric centers in the ABC ring system (a dioxabicyclo[4.4.0]decane ring system with an attached bromine-containing tetrahydropyranyl ring that forms the core structure of the triterpene polyethers produced from the genus <I>Laurencia</I>) are enantiomeric to those of other members of the thyrsiferol family.<SUP>1)</SUP> In this presentation, our laboratory performed the total syntheis of aplysiol B and 22-hydroxy-15(28)-dehydrovenustatriol whose absolute configurations have never been determined to research the partial enantiodivergency in the thyrsiferol family in depth.Aplysiol B, a member of the thyrsiferol family isolated from the sea hare <I>Aplysia dactylomela</I>, possesses feeding-deterrent and ichthyotoxic properties. However, the proposed structures 6a<SUP>2)</SUP> and 6b<SUP>3)</SUP> were in contradiction to the biogenetic hypothesis. Therefore, we reconsidered the biogenetic pathway of aplysiol B and synthesized the reasonable structure 6c through a key Shi epoxidation<SUP>12)</SUP> followed by a 5-<I>exo</I> cyclization and a subsequent 6-<I>endo</I> bromoetherification using BDSB.<SUP>13)</SUP> The spectral data and the optical rotation of synthetic 6c were in agreement with those reported for the natural sample.<SUP>2)</SUP> As a result, the first total synthesis of aplysiol B was accomplished, and the reported structures 6a and 6b were revised to 6c.The planar structure of 22-hydroxy-15(28)-dehydrovenuatatriol was determined by NMR analysis.<SUP>6)</SUP> The stereostructure of the ABC ring system was elucidated by comparing the NMR data with those of dehydrothyrsiferol (4), whose absolute structure was known. However, the stereochemical relationship between the ABC ring system and D ring due to the intervening methylene chain and the absolute configuration has not been determined to date. Our laboratory synthesized the proposed structure 8a <I>via</I> a key Suzuki-Miyaura cross-coupling between the BC ring system 19 and D ring 20. However, the NMR spectra of synthetic 8a did not match with those of the reported data.<SUP>6)</SUP> We also synthesized 8b, a possible diastereomer of 8a, and the proposed structure 8a was revised to 8b. Moreover, we observed that the ABC ring system of 8b has the same absolute configuration as that of isodehydrothyrsiferol (5).Considering an enantiodivergent phenomenon in the common skeleton of the thyrsiferol family, based on the biogenesis of the squalene-derived thyrsiferol family suggested by the Fernández group,<SUP>4)</SUP> we propose the biogenesis of 6c and 8b <I>via</I> the bromocation-initiated epoxide-opening cascade reaction of squalene pentaepoxide 37.

著者

中村 仁美 ショルツ エリカ バルスカス エミリー

出版者

天然有機化合物討論会実行委員会

雑誌

天然有機化合物討論会講演要旨集

巻号頁・発行日

vol.58, 2016

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<p>Nature constructs structurally diverse, bioactive molecules using enzymes. Many enzymes catalyze synthetically challenging reactions under mild, physiological conditions. Consequently, they have long been a source of inspiration for developing biomimetic organic syntheses and methods. In addition, enzymes are increasingly being used as biocatalysts in industry. Therefore, the discovery of enzymes that catalyze chemically intriguing transformations can positively impact synthesis in multiple ways. With the recent advances in next-generation DNA sequencing technologies, we are now able to access enormous amount of genomic sequencing data, which encodes a treasure chest of new enzymatic chemistry. The challenge now is to devise a method to efficiently identify chemically interesting enzymes from this vast pool of information.</p><p>One possible solution to this problem is to study the biosynthetic pathways of structurally unique natural products, which are predicted to involve novel enzymatic reactions. We aimed to discover new enzymes that catalyze intriguing chemical reactions through biosynthetic investigation guided by our knowledge in organic chemistry. The cylindrocyclophanes are a family of natural products that contain an unusual [7.7]paracyclophane core scaffold.¹ Based on the results of the previous feeding studies, cylindrocyclophane biosynthesis is predicted to involve an unusual C–C bond formation (Figure 1).² To discover the enzymes responsible for this chemistry, we studied the biosynthesis of the cylindrocyclophanes.</p><p>Figure 1. The structures of the cylindrocyclophanes. The predicted biosynthetic disconnection suggests that an unusual C–C bond formation is involved in their biosynthesis.</p><p>First, the candidate cylindrocyclophane biosynthetic (cyl) gene cluster was identified from the genomic sequence of the cylindrocyclophane producer, Cylindrospermum licheniforme ATCC 29412. We next formulated a biosynthetic hypothesis based on the cyl gene cluster annotation (Figure 2). In our original biosynthetic hypothesis, we predicted that cylindrocyclophane biosynthesis initiates with the activation of decanoic acid by the fatty acid activating enzymes, CylA and CylB, to form decanoyl-CylB. The activated decanoyl-CylB is then processed by the type I polyketide synthase (PKS) machinery, CylD-H. The nascent polyketide is released from the type I PKS assembly line by the type III PKS CylI to form the alkylresorcinol, which is the predicted monomeric unit of the cylindrocyclophanes.</p><p>Figure 2. The initial biosynthetic hypothesis for cylindrocyclophane assembly.</p><p>Based on our initial biosynthetic hypothesis, we biochemically characterized the functions of the fatty acid activating enzymes CylA/CylB and the type III PKS CylI. The in vitro activities of these three enzymes were consistent with our biosynthetic hypothesis, which validated the involvement of the cyl gene cluster in cylindrocyclophane production.³ In addition, we conducted feeding experiments using deuterium-labeled decanoic acid in the native producer to confirm that decanoic acid is a precursor to the cylindrocyclophanes. The incorporation of deuterium-labeled decanoic acid into the final cylindrocyclophane scaffold also indicated that cylindrocyclophane biosynthesis involves functionalization of the unactivated carbon center.³</p><p>Following our discovery and validation of the cyl gene cluster, we next focused on the investigation of the key C–C bond formation that results in the construction of the [7.7]paracyclophane scaffold. Through bioinformatics and biochemical characterizations of the enzymes encoded in the cyl gene cluster, we determined that cylindrocyclophane biosynthesis involv</p><p>(View PDFfor the rest of the abstract.)</p>

著者

工藤 雄大 山下 瑶子 此木 敬一 長 由扶子 安元 健 山下 まり

出版者

天然有機化合物討論会実行委員会

雑誌

天然有機化合物討論会講演要旨集

巻号頁・発行日

vol.55, 2013

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<p>テトロドトキシン (TTX, 1)は電位依存性ナトリウムチャネルを特異的に阻害する強力な神経毒である。TTXはフグから単離されたが、その後、カニや巻貝、ヒョウモンダコ、ヒラムシなどの多様な海洋生物、更には陸棲のイモリ、カエルからも同定された。高度に架橋した構造と強力な生理活性、広範な生物種に分布する特徴から、極めて興味深い化合物である。TTX生産細菌を報告し ¹⁾、その後も数多くの報告があるが、TTXの生合成に関わる出発物質、遺伝子は未だに同定できていない。我々はTTX天然類縁体が生合成経路解明の手がかりになると考え、フグやイモリから種々のTTX類縁体を単離・構造決定してきた ^2-4)。今回HILIC (Hydrophilic interaction liquid chromatography: 親水性相互作用) -LC-MSを用い ⁵⁾、新規TTX類縁体を探索したところ、オキナワシリケンイモリ (Cynops ensicauda popei) 及びヒガンフグ (Takifugu pardalis)から新規TTX類縁体と推測される化合物が数種検出され、これらの単離・構造決定を行った。さらに、各種TTX含有生物における分布を調査し、TTXの生合成経路の推定を試みた。</p><p>1. イモリから得られた新規TTX類縁体の構造と分布</p><p>TTXの生合成中間体は生理活性を持たない可能性が高く、生理活性を指標としたスクリーニングは適切ではなかった。そこで、TTX類縁体の一斉分析が可能なHILIC-LC-MSを用い、既知のTTX類縁体のフラグメントイオンを指標として新規TTX類縁体を探索した。C. e. popeiを希酢酸加熱抽出し、活性炭カラムで粗精製した後、HILIC-LC-MSに供し、新規TTX類縁体を探索した。2種の新規TTX類縁体 (2, 3) (Fig. 1)が検出されたため、これらを弱酸性陽イオン交換カラムBio-Rex70 (Bio-Rad)、HITACHI GEL #3011-C、HITACHI GEL #3013-Cを用いて精製した。3は更なる精製が必要であったため、TSK-gel Amide-80 (Tosoh)を用いて精製した。2はC. e. popeiの全組織170 gから約250 μg得られた。3は内臓組織を除いた身体組織65 gから約300 μg、4,9-anhydroTTXとの混合物 (約1:1)として得られ、そのまま解析に用いた。2, 3の分子式はそれぞれESI-Q-TOF-MSを用いてC₁₁H₁₅N₃O₄及びC₁₁H₁₅N₃O₆と決定した。2: [M+H]⁺ m/z254.1136 (calcd. for C₁₁H₁₆N₃O₄254.1135, error: 0.4 ppm), 3: [M+H]⁺ m/z 286.1036 (calcd. for C₁₁H₁₆N₃O₆286.1034, error: 0.7 ppm)。</p><p>2の分子式は、4,9-anhydro-5,6,11-trideoxyTTX (4)と一致した。また、2を各種NMR (600 MHz, CD₃COOD-D₂O 4:96, v/v)に供したところ、そのシグナルは4 ⁶⁾に類似していたが、2ではH5のシグナルが一つしか示されず、かつH9の大きな高磁場シフト (-0.73 ppm)が観測された。C5、C10のケミカルシフト (50.7, 107.6 ppm)、及び、C5/H9, C10/H4a, C10/H6のHMBC相関が観測されたことから、2はこれまで報告例のない、C5とC10が直接結合した10-hemiketal構造を持つと考えられた。2のNOESY 1DではH4a/H6のNOEが観測されたが、H4a/H8, H6/H8のNOEは観測されなかった。このことからC6の立体化学はTTXと同じであり、C8位はイモリに特異的な8-epi体であると考えられた ⁴⁾。以上より、2の構造を4,9-anhydro-10-hemiketal-8-epi- 5,6,11-trideoxyTTXと推定した (Fig. 1)。</p><p>(View PDFfor the rest of the abstract.)</p>

著者

村岡 修 田邉 元三 森川 敏生 二宮 清文 松田 久司 吉川 雅之

出版者

天然有機化合物討論会

雑誌

天然有機化合物討論会講演要旨集

巻号頁・発行日

no.51, pp.1-6, 2009-09-01

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Salacinol and kotalanol are new class of potent glycosidase inhibitors, isolated by presenters from Ayruvedic traditional medicine Salacia reticulata, having the unique zwitter-ionic structure comprising of 1-deoxy-4-thio-D-arabinofranosyl cation and the sulfate anion in the alditol side chain. Elucidation of the stereostructure of kotalanol, which has long been unknown and very recently approved by Pinto and co-workers by the synthesis, by the independent manner involving the degradation of natural kotalanol is presented. In the detradation of 2, characteristic deprotective cyclization of heptitols to anhydroheptitols was found to occur to a large extent. Structural elucidation of salalprinol, one of the sulfonium analogs recently isolated from the same species, by the synthesis is also presented. Revisions of the structures of new constituents from Salacia species, neosalacinol and 13-membered cyclic sulfoxide, recently reported as constituents responsible for the α-glucosidase inhibitory activity by Minami and Osaki and co-workers, respectively, are presented. In relation to this study, synthetic route of de-O-sufonated salacinol, which was proved as potent as 1, has been developed. Finally, conditions for the quantitative analysis of 1, 2, and their de-O-sulfonates (3 and 4) by LC-MS for the qualitative evaluation of Salacia extracts is discussed.

著者

田邉 元三 松田 侑也 松本 裕朗 筒井 望 村岡 修

出版者

天然有機化合物討論会実行委員会

雑誌

天然有機化合物討論会講演要旨集

巻号頁・発行日

vol.56, 2018-07-19

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<p>インドやスリランカの伝統医学であるアーユルヴェーダでは, 糖尿病の初期の治療薬としてサラキア属植物の抽出物が用いられている. これまでに, その活性寄与成分として, 特異なチオ糖スルホニウム硫酸分子内塩構造をもつ新規化合物 salacinol (1), kotalanol (2), ponkoranol (3) およびその脱硫酸エステル体, neosalacinol (4), neokotalanol (5), neoponkoranol (6) を単離した.^1,2,3).また, その作用機序が消化管表層に存在する糖質加水分解酵素 (a-glucosidase) の阻害に基づくことを明らかにするとともに, その阻害強度の程度は, いずれも市販糖尿病治療薬のアカルボースやボグリボースに匹敵するほど強いことも明らかにしている.¹⁾ スルホニウム塩という天然有機化合物として極めて特異な構造であること, また, その a-glucosidase 阻害活性が極めて強いことから活発な構造活性相関研究が国内外において活発に行われている.最近我々は, in silico 計算化学を用いて salacinol (1) の約10~40倍強い活性を示す化合物群 (7) の合成にも成功している (Fig.1).⁴⁾ </p><p>Fig.1</p><p>一方、これまでのスルホニウム塩の合成には Scheme 1 に示すように, もっぱら, チオ糖8と側鎖部となる求電子剤 (9, 10, 11 など) とのS-アルキル化が鍵反応として用いられている. しかし, 本鍵反応では反応時間が著しく長いものが多く (< 7 days), また, 側鎖部に用いる求電子剤あるいは生成物が, 反応中に徐々に分解することも報告されている. さらに, 反応が環状チオ糖のS-アルキル化のため, 生成物のジアステレオ選択性が低くとどまる欠点 (dr, a/b = < 9/1) も有している. このような反応性のために, 目的のαアルキル化体 a-12の収率が中程度にとどまるものがほとんどであり, 本鍵反応は"Salacia"由来スルホニウム塩の簡便大量供給法としていまだ多くの問題を残している.⁵⁾ </p><p>Scheme 1</p><p>そこで, "Salacia" 由来スルホニウム塩の簡便かつ効率的な新規スルホニウム塩骨格構法の開発研究の一環として, 今回, スルフィド (13) の閉環反応によるneosalacinol (4) の合成を検討した. その結果, 13 の環化反応が高いジアステレオ選択性 (dr, a/b = ca. 30/1) で効率よく進み, 短時間で 4 の合成中間体 (a-14) が高収率で得られることを見出した. さらに, a-13 を脱保護に付し, 目的の 4 の全合成を達成したので, その詳細について報告する.</p><p> </p><p>Scheme 2</p><p>1.スルフィド 13 の合成</p><p>鍵化合物となるスルフィド 13 は, neosalacinol (4) の側鎖部となる erythritol 誘導体 (15) と チオ糖部となるxylose誘導体 (16) のカップリング反応により合成した. </p><p> </p><p>Scheme 3</p><p>Erythritol 誘導体 15 は, 文献⁶⁾の方法に改良を加え, 極めて高い収率で合成した. すなわち, D-isoascorbic acid (18) を, アセトン中, PTSA の存在下に, 2,2-DMP との処理により調製した化合物 (19) のエンジオール部を過酸化水素で酸化的に解裂後, 生成するカルボン酸塩を単離することなくヨウ化エチルとのエステル化に付し, 18より 93% の収率でエステル (20) に導いた. 次に, 20 のLAH 還元により得たジオール (21) を水素化ナトリウムの存在下で臭</p><p>(View PDFfor the rest of the abstract.)</p>

著者

大村 智 中川 彰 鈴木 数広 秦 藤樹 Jakubowski Ann Tishler Max

出版者

天然有機化合物討論会実行委員会

雑誌

天然有機化合物討論会講演要旨集

巻号頁・発行日

vol.17, pp.229-236, 1973

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We have been studied the relationship between the structures and the biological activities on 16-membered lactone ring macrolide antibiotics. The aglycone moiety from 16-membered macrolides has not been reported, but in the present series of work, we have chemically obtained the aglycone from leucomycin A_3 (LM A_3) (I). Treatment of (I) with m-chloroperbenzoic acid in CHCl_3 gave the N-oxide (II), which was refluxed with Ac_2O in CHCl_3 to obtaine aglycone, leuconolide-A_3 5,18-hemiacetal (III). In the above reaction, a neutral macrolide, 2'-acetyl 3'-desdimethylamino 3'-oxo LM A_3 (X) which 3'-dimethylamino group on mycaminose moiety was converted to ketone carbonyl was isolated from the same reaction product. Furthermore, (I) was reacted with Al-isopropoxide to give 9-dehydro 18-dihydro leucomycin A_3 (V). (V) was oxidized with m-chloroperbenzoic acid to N-oxide (VII), and(VII)was then treated with Ac_2O in CHCl_3 to obtain 9-dehydro 18-dihydro leuconolide-A_3 (VIII). In order to clarify the correlation between the structure and biological activity of mycaminose moiety, various derivatives were synthesized. The antimicrobial activities of the both glycone, (III) and (VIII) completly disappeared, and it was found that the decreasing of electro-density on dimethylamino group on mycaminose moiety resulted in the decrease of the activity.

著者

大村 智 中川 彰 竹嶋 秀雄 宮沢 淳 渥美 清夫 Piriou F. Lukacs G.

出版者

天然有機化合物討論会実行委員会

雑誌

天然有機化合物討論会講演要旨集

巻号頁・発行日

vol.19, pp.434-441, 1975

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According to previous reports, the aglycone carbons of the 16-membered macrolide antibiotic, magnamycin A, 1 are derived from nine acetates, one propionate and one methionine as shown in Fig. 1. As an application of a recent systematic ^<13>C-NMR study of 16-membered macrolide antibiotic, the validity of these investigation was reexamined on leucomycin A_3 2 which is structurally similar to magnamycin A. It was found that carbons-5, -6, -17 and -18 of leucomycin A_3, 2 were derived from butyrate and carbons-3 and -4 on the aglycone arose from outside of acetate contrary to the proposal in the study on magnamycin biosynthesis. Although the origin of the carbons-3 and -4 is not yet known at present time, this finding let us to investigate the origin for the carbons-3 and -4 of the aglycone of tylosin which has different carbon skeleton from leucomycin or magnamycin (Fig. 3). Consequently, the metabolic origin, acetate, propionate and butyrate was proposed as shown in Fig. 5. The addition of [1-^<13>C]butyrate to a fermentation medium of tylosin showed the enrichment for carbons-3, -7, -11, -13 and -15 of aglycone as like as carbon-5 which is predicted to be enriched by the precursor. On the other hand, carbons-4, -8, -12, -14 and -16 were enriched as like as carbon-19 by [4-^<13>C]2-ethylmalonate. The metabolic pathway is not yet clear, however these precursors are thought to be partially incorporated to the aglycone of tylosin via propionate.

著者

船山 信次 中川 彰 大村 智

出版者

天然有機化合物討論会実行委員会

雑誌

天然有機化合物討論会講演要旨集

巻号頁・発行日

vol.28, pp.73-80, 1986

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During the cource of our screening program for new antibiotics, herbimycin C (1), trienomycins A (6), B (7) and C (8). awamycin (9) and hitachimycin (stubomycin) (10) were isolated and characterized. Each antibiotic except for 10 possesses macrocyclic lactam structure containing benzenoid or naphthalenoid moiety as a chromophore. Structures 1 and 6-9 were elucidated mainly through the comparative NMR analysis with the known ansamycin antibiotics and the structure of 10 was established by the chemical degradations. Further, "Celmer's model" which was applied to the stereochemistry and biogenecis of macrolide antibiotics was applied to those of ansamycin antibiotics such as macbecin I (14). naphthomycin A (15). rifamycin B (16) and streptovaricin C (17) in which the absolute configurartions have been established. Consequently, the absolute configurations of herbimycin A (2) and 9 except for C-6 and C-7 were proposed as shown in Fig. 2. through the model.

著者

今村 信孝 今井 美光 三浦 聡美 中川 彰 大村 智

出版者

天然有機化合物討論会実行委員会

雑誌

天然有機化合物討論会講演要旨集

巻号頁・発行日

vol.30, pp.308-315, 1988

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A new antibiotic, phthoramycin (1; C_<40>H_<68>O_<12>) which exhibits antimicrobial activities against fungi such as the plant pathogen Phytophthora parasitica was isolated from the cultured broth of a strain of Streptomyces sp. The structure and biosynthetic origin of 1 were elucidated by the 2-D NMR spectral experiments of pentaacetylphthoramycin (2) in combination with biosynthetic means using [1-^<13>C]- and [1,2-^<13>C_2]acetate and [1-^<13>C]propionate. From the results of ^<13>C-NMR analysis of labeled compounds (2), it was revealed that the antibiotic contained nine intact acetate and six propionate units as shown in Fig. 2. The biosynthesis of okilactomycin (3), produced by a strain of Streptomyces sp., was also investigated by the feeding experiments of [1-^<13>C]- and [2-^<13>C]acetate, [1-^<13>C]propionate, [U-^<13>C_6]glucose, and L-[Me-^<13>C]methionine. The incorporation of seven intact acetate and four propionate units, a glycerol moiety from glucose, and a methyl group of methionine were observed by the ^<13>C-NMR analysis. The biosynthetic pathway may be unique as shown in Fig. 4 in light of the methyl of methionine incorporated into a methyl group of the antibiotic produced by an actinomycete.

著者

高橋 宣治 内田 健一 中川 彰 松崎 桂一 大村 智 中村 朝朗 三宅 洋子 武 佳和 甲斐荘 正恒

出版者

天然有機化合物討論会実行委員会

雑誌

天然有機化合物討論会講演要旨集

巻号頁・発行日

vol.35, pp.762-768, 1993

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The biosynthesis of lactacystin, a new microbial metabolite which induces differentiation of neuroblastoma cells, was studied by ^<13>C NMR spectroscopy using various ^<13>C labeled precursors. The feeding experiment of L-[2-^<13>C ] leucine showed a strong enrichement at C-5 of Lactacystin. Incorporation of [1-^<13>C] isobutyrate labeled C-1, C-4, C-8, and C-14. These ^<13>C labeling patterns indicate that lactacystin consists of three biosynthetic units, namely isobutyrate (or L-valine), L-leucine, and L-cysteine. The C_<10> unit containing γ-lactam moiety arises by a condensation between methylmalonate semialdehyde and C-5 of the C_6 unit derived biosynthetically from L-leucine, followed by intramolecular cyclization. The stereochemistry of two diastereotopic methyl carbons of lactacystin which appeard at δc 19.85 and δc 21.37 was investigated by incorporation of a new type of chiral ^<13>C L-leucine (or L-valine), designated as the ^<13>C block labeled leucine (or valine), which was obtained from the fermentation of leucine producing organism using a mixture of 99% [U-^<13>C_6] glucose and natural glucose as a carbon source.

著者

大村 智 田中 晴雄 小山 泰昭 長井 敏明 丸茂 博大

出版者

天然有機化合物討論会実行委員会

雑誌

天然有機化合物討論会講演要旨集

巻号頁・発行日

vol.20, pp.9-15, 1976

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In the course of our research for new antibiotics produced by actinomycetes, new antibiotics, nanaomycins A, B, C and D, effective against mycoplasma, fungi and Gram-positive bacteria were obtained from the cultured broth of a strain which had been isolated from a soil sample collected at Nanao-shi, Ishikawa prefecture and designated Streptomyces rosa var. notoensis. Evidence is put forward which describes the structure and stereochemistry of nanaomycins A, B, C and D, as I, V, IV and VI, respectively. In order to study biosynthesis and to determine the position of the hydroxyl group in the naphthoquinone moiety, a feeding experiment with [1-^<13>C] acetate was effectively carried out. Nanaomycins are synthesized from 8 acetate units via a "polyketide" in S. rosa var. notoensis. Since the carbon atom adjacent to the phenolic hydroxyl group was enriched with [1-^<13>C] acetate, the hydroxyl group is not at C-6 position but must be at C-9 position. The absolute configuration was determined by ORD comparisons. The results indicated that nanaomycin D is an enantiomer of kalafungin produced by S. tanashiensis. The production of each enantiomer by two different species belonging to the genus Streptomyces is of interest in the biosynthesis of a series of these antibiotics.

著者

木梨 陽康 染野 衣美 坂口 健二 東島 勉 宮沢 辰雄

出版者

天然有機化合物討論会実行委員会

雑誌

天然有機化合物討論会講演要旨集

巻号頁・発行日

vol.24, pp.183-190, 1981

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Concanamycins A (1a), B (1b), and C (1c) were found as inhibitors of the proliferation of the mouse splenic lymphocytes stimulated by concanavalin A. For the structure determination of the main component, concanamycin A (1a), several chemical transformations were performed. Treatment of (1a) with 0.03N NaOH in methanol afforded an anhydroagly-cone P1 (2a) and a sugar S1 (3a), and their structures were determined by 270MHz PMR analysis. In order to elucidate the mode of binding of these components, ozonolysis of (1a) was performed. Of the three degradation products, Oz3 (5) proved to be the key compound containing S1 and a fragment of P1. Extensive PMR analysis of (5) and (1a) itself revealed the full structure of (1a). Thus, concanamycin A (1a) is a novel 18-membered macrolide antibiotic consisting of an α,β,γ,δ-unsaturated lactone ring, a long side chain which forms an intramolecular hemiketal ring, and 4-O-carbamyl-2-deoxy-D-rhamnose. The structures of concanamycin B (1b) and C (1c) were also determined by chemical trans-formations and spectroscopic methods.

著者

上江田 捷博 上村 大輔 平田 義正 高野 敏

出版者

天然有機化合物討論会

雑誌

天然有機化合物討論会講演要旨集

巻号頁・発行日

no.21, pp.245-252, 1978-08-22

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The isolation and structure elucidation of palytoxin, a potent coelenterate toxin, have been studied. Though palytoxin was not obtained as a crystalline form, the structures of λ233 and λ263 chromophores in palytoxin were determined. Oxidation of toxin with NaIO_4 was suitable for elucidation of these chromophores and the positive part to ninhydrin in palytoxin. On the other hand, in the course of our studies on toxin of Palythoa tuberculosa we have isolated four compounds (3), (4), (5), and (6) characterized by their absorption maxima at 310nm, 320nm, 332nm, and 360nm, respectively. Structures of these compounds and a 334nm UV-absorbing substance (7) isolated from Porphyra species were established.