著者

磯部 稔 Uyakul D. 高橋 宏幸 後藤 俊夫

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.31, pp.396-403, 1989-09-17

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Lampteroflavin (1), a riboflavin α-D-riboside was isolated in extraordinary small amount from the luminous mushroom, Lampteromyces japonicus (Fig 1), which was available only two weeks in a year. Extraction method was improved to utilize only alive gills under aeration instead of using the whole body (Fig 3), and the method was established as Scheme 1. It's structure has been elucidated by chromatographic and spectroscopic analyses(1). It's fluorescence spectrum was identical to the bioluminescence spectrum of the mushroom, having maximum at 524nm (Fig 2). We concluded that 1 was responsible to the bioluminescence mechanism as the light emitter, since 1 was only the fluorescent constituent in fresh gills. Previous report that illudin S (lampterol) or ergosta-4,6,8(14),22-tetraen-3-one(2) could be the emitter is thus unlikely judging from the weak fluorescent intensity and the different maximum wavelength from that of mush-room bioluminescence. Lampteroflavin (Table 1) was hydrolyzed with dil. mineral acid to give riboflavin and D-ribose. Riboflavin was identified by HPLC, ^1H NMR, UV, Fluorescence and FAB mass spectrometry. D-ribose was acetylated and then confirmed by ^1H NMR, CD and tandem mass spectrometry. Riboflavin and D-ribose was connected together with α-glycosidic linkage which was determined by ^<13>C NMR of the anomeric carbon (δ=103.2ppm)(3), NOSEY spectrum (H-1" being close to H-3" and H-5') and ^1H NMR pattern of anomeric proton. The total structure of lampteroflavin was confirmed through its chemical synthesis.

著者

福山 圭 大類 洋 桑原 重文

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.57, 2015

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<p>【緒言】</p><p> 後天性免疫不全症候群 (AIDS) は世界的に問題となっているHIV(レトロウイルス)感染症である。現在,作用機序の異なる薬剤を併用する多剤併用療法(HAART) が行われており飛躍的な予後の改善が図られている。しかし生涯にわたる多剤併用療法は予期せぬ副作用の発現と多剤耐性ウイルスの出現という新たな問題に直面しており,新薬の創出と供給は創薬化学およびプロセス化学上,喫緊の研究課題である。</p><p> 近年4'-C-置換ヌクレオシドの特異な生物活性に注目が集まっている。4′-ethynyl-2-fluoro-2′-deoxyadeno- sine (EFdA, 1)は大類,満屋,ヤマサ醤油(株)の共同研究により創出された逆転写酵素阻害剤である (Figure 1)¹⁾。近年,ヤマサ醤油(株)からメルク社(米国)へのライセンス供与が行われ,抗エイズ薬としての実用化研究が進められている。同様の作用機序を持つ代表的処方薬であるアジドチミジン(AZT, ジドブジン, EC₅₀ = 22 nM, HIV-1_NL4-3)等に比べ数百倍から数万倍という桁違いに強力なHIV複製阻害作用(EC₅₀= 50 pM)を有することに加え,急性毒性を示さない(LD₅₀>100 mg/kg,マウス,p.o.),様々な耐性ウイルスに対しても有効である,長い血中半減期 (t_1/2= 17.2 h) を持つ等の優れた特性から,極めて有望な抗エイズ薬候補と考えられている²⁾(Proc. Jpn. Acad., Ser. B 2011, 87, 53)。</p><p> 一方,本化合物の臨床開発における最大のネックは1の供給体制が十分でない点にある。既存の2つの合成法(大類法¹⁾,桑原法³⁾)が知られているものの(Figure 2),原料価格,収率,立体選択性の点で問題を残していた。この様な背景の下,我々は真に実用的なEFdA合成法の開発に着手した。</p><p>【フラノース4位の新規増炭法の開発】</p><p> フラノース誘導体の4位を増炭する方法としては,安価で大量に入手可能なdiacetone-D-glucose (2)から5工程で得られるアルデヒド3をaldol/ Cannizzaro反応により4-ヒドロキシメチル化して4を得るMoffattらの方法⁴⁾が唯一の報告例であるが,生成する2つの水酸基の選択的保護に問題があった(Scheme 1)。</p><p> 我々は,3-ケトフラノース誘導体6とホルムアルデヒドとのアルドール反応について検討した結果,K₂CO₃やEt₃Nを塩基として用いると4位の立体化学の反転を伴って,アルドール反応生成物 7とそれがホルムアルデヒドと過剰反応を起こした8の混合物が定量的に得られることを見出した(Scheme 2, Table 1)。</p><p></p><p> 8は報告例の少ないアセタール/ヘミアセタール連続構造を持つ新規糖誘導体であり,還元処理により7とともにアルコール9へ立体選択的に変換できた(アルドール反応完結後,濾過により塩基を除去し,濾液に水とNaBH₄を加えることで簡便に四置換の4位炭素を持つ9を得る手法を確立した;白色結晶,100 g スケール,2から3工程,通算収率93%)。9の3位,5位および5'/6'位は選択的な修飾が可能であり,自由度の高い新規な四置換炭素含有合成ユニットになり得るものと考えている。</p><p>【水酸基</p><p>(View PDFfor the rest of the abstract.)</p>

著者

小菅 卓夫 横田 正実

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.211-217, 1974

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As a cardiac principle of aconite root, Yokonoside had been reported by us in previous meeting, but synthesized Yokonoside did not have any biological activities. Then, separating procedure had been reinvestigated to obtain the true cardiac principle. In order to remove the inactive glycoside, the fractn. III was subjected to counter current distribution of n-buthanol-0.1N-HCl solvent system. And a crystalline matter (mp.260°), was obtained as colorless plate from the active fractn. IV as HCl-salt. The principle stimulates flog's heart even in ten billionth dilution, thus it was designated as Higenamine. Higenamine was identified as dl-demethyl coclaurine [V] from the spectral data and in comparison with synthesized authentic sample.

著者

岡 希太郎 池 祥雅 木下 仁 原 昭二

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.15, pp.169-176, 1971-10-01

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The results of the synthetic studies on several steroidal alkaloids of salamander and frog venoms were presented. (1) Cycloneosamandione (VIII) and Cycloneosamandaridine (IX) Recently, the early proposed structure of cycloneosamandione (VI), which had been determined by G. Habermehl with the X-ray diffraction method, has been revised to be VIII on the basis of his own synthetic work. In order to reconfirm this structure, the compound VIII was synthesized by the sequre synthetic sequence. As a result, the physical data of the synthetic specimen were consistent with those of the natural product. Cycloneosamandaridine has been known as one of the minor constituents of the salamander alkaloids. Since this alkaloid has been recognized to have the identical skeleton with cycloneosamandione, the structure, we suppose, should be also revised to be IX from VII. Consequently, we have synthesized the compound IX via the same intermediate 16 as the synthesis of cycloneosamandione (VIII). The identification of our synthetic product with the natural one is now in progress. (2) Batrachotoxin (XI) The synthesis of batrachotoxin has been attempted. The treatment of the hemiacetal 27 with aminoethanol followed by reduction afforded a mixture of 18-hydroxyethylamino steroids (28a and 28b). Then the mixture was converted into the enone 36, which might serve as an useful intermediate for our purpose.

著者

小原 平太郎 小野寺 準一 阿部 敏

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.380-385, 1975

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In the previous papers, we have reported that the conventional structures of carthamin, presented by Kuroda and Seshadri, should be reexamined from the comparison of its properties with those of their synthetic analogs. The IR, UV, PMR, and ^<13>C-NMR spectral data and the chemical evidences suggested that carthamin is humulone-like C-glycosyl compound, having two p-hydroxycinnamoyl groups and one unsaturated methine group. On the bases of these results and the comparison of the spectral data with those of some synthetic analogs, we will propose a new structure (11) for carthamin.

著者

犀川 陽子 岡本 博樹 乾 泰地 橋本 貴美子 中田 雅也 真壁 みどり 奥野 智旦 須田 隆

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.43, pp.443-448, 2001

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A poisonous mushroom Podostoma cormu-damae caused two lethal poisoning in Japan in 1999 and 2000. Some of the following symptoms are observed in these poisonings: gastrointestinal disorder, erroneous perception, decrease in the number of leukocytes and thrombocytes, deciduous skin of face, loss of hair, and atrophy of the cerebellum which brings about a speech impediment and voluntary movement problems. We studied the toxic constituents of its culture broth and the fruit bodies using lethal effect on mice as an index. The extracts from the culture filtrate and the fruit bodies were injected into the abdominal cavity of a mouse. The lethal effect was observed in both extracts from the culture filtrate and the fruit bodies. The organic extracts of the culture filtrate were chromatographed on silica gel to give the major compounds 1, 2, and 3. The ^1H and ^<13>C NMR spectroscopic analyses revealed that these compounds 1〜3 are members of the macrocyclic trichothecene group. Comparison of the spectral data of 1〜3 with those in the literature revealed that 1 is roridin E, 2 is verrucarin J (muconomycin B), and 3 is satratoxin H. On the other hand, the fruit bodies were extracted with water and methanol. The water extracts were chromatographed on ODS to give satratoxin H (3), and the methanol extracts were chromatographed on silica gel to give 4〜6. The NMR and MS analyses showed that 4, 5, and 6 is the 12',13'-diacetate, 12'-acetate, and 13'-acetate of satratoxin H (3), respectively. The 4〜6 are new compounds that occur in nature. All these macrocyclic trichothecenes except for 2 had a lethal effect on mice by at least 0.5 mg per capita.

著者

野副 重男 小池 隆 辻 恵美 草野 源次郎 瀬戸 治男 青柳 富貴子 松本 春樹 松本 毅 奥野 智旦

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.25, pp.282-289, 1982-09-10

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In the course of our continuing investigation of the constituents of a hallucinogenic mushroom, Gymnopilus spectabilis (Japanese name, O-waraitake) collected at Oguni, Yamagata, we have isolated novel type of polyisoprenepolyols designated as gymnopilins -A, -B, and gymnoprenols -A, -B, -C, and -D etc. These substances occured as a mixture of some homologues were separated and throughly purified by means of preparative HPLC and their chemical structures were determined on the basis of the results of oxidative degradation as well as their spectroscopic properties. These polyisoprenepolyols were shown to contain same repeated unit corresponding to hydrated form of usual isoprenoid chain, two or three double bonds and a terminal vicinal diol moiety or the corresponding ester with 3-hydroxy-3-methyl-glutaric acid. The location of double bond was confirmed by the degradation studies. The structures of polyisoprenepolyols such as 1a and 2a have never been encountered in natural products obtained so far. The stereochemistry and biological activities are under investigation.

著者

目 武雄 藤野 明 村井 不二男 鈴井 明男 仏願 保男 西沢 麦夫

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.50, pp.19-24, 2008-09-01

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Matatabi (Actinidia polygamy Miq., Actinidiaceae) is widely distributed in this country. It is well known from early times that the leaf, the fruit, and the root of this plant show special biological activity in Felidae animals. Although significant chemical studies were carried out, the isolation and structure elucidation of the active principles were not reported until 1959. We isolated two active principles from the methanol extract of the leaf and the fruit of matatabi, a lactone C_<10>H_<16>O_2 named matatabilactone (1), and a base C_<10>H_<13>N named actinidine (2), in 0.0035 and 0.12% yield, respectively. Herein the structure study and the synthesis of 1 and 2 will be discussed.

著者

露木 孝彦 塩見 賢吾 緒方 行治 北村 節子 山本 出

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.7, pp.12-17, 1963

著者

濱田 季之 松永 茂樹 伏谷 伸宏 藤原 正子 藤田 憲一

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.37, pp.695-700, 1995-09-01

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A highly cytotoxic polypeptide, polytheonamide B (1), has been isolated from the marine sponge Theonella swinhoei. The structure of polytheonamide B was determined, to be a linear 48-residues polypeptide with the N-terminus blocked by a carbamoyl group, by extensive 2D NMR experiments in DMSO-d_6. The absolute configuration of each amino acid residue was determined by chiral chromatographies of fragment peptides obtained by partial acid hydrolysis of polytheonamide B. Amino acid residues in polytheonamide B have alternating D- and L-configuration. The NMR spectra in CD_3OH/CDCl_3 (1:1) indicated that polytheonamide B adopted certain secondary structure. Conformation analysis was carried out by distance geometry calculations, by DADAS90 program, using NMR parameters obtained in CD_3OH/CDCl_3 (1:1), i.e., a total of 378 distance constraints (160 intra-residue, 96 sequential, 80 long-range NOEs, and 42 hydrogen bonds) and 48 dihedral angle constraints. The calculated structure fit a right-handed parallel β-helix structure, which was proposed for the structure of a pore-forming peptide, gramicidin A.

著者

清田 洋正 五十嵐 渉 齋藤 亜紀 古川 博之 星川 浩輝 桑原 重文

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.57, 2015

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<p> Enacyloxin (ENX)類(Fig. 1)は、赤パンカビNeurospora crassaの培養上清で培養した酢酸菌の一種Frateuria sp. W-315株の生産する、珍しい鎖状ポリエン-ポリオール型の抗生物質である[1]。そのポリエン構造のため光に不安定であり、渡邉敏彦博士による発見報告以来、当研究室での全立体構造決定まで25年を要した[2]。中でもENX IIa (2) は抗グラム陽性・陰性細菌活性を示し、その作用機構はリボソームelongation factor-Tuに作用するタンパク質合成阻害によることが知られている[3]。酵母やカビには抗菌活性を示さないことからも選択的な抗菌剤としての開発が期待される。ENX IIaの他、ENX oxidaseによる酸化の前駆体であるENX IVa (1) やdecarbamoyl ENX IIa など様々な類縁体が単離されている。</p><p>Fig. 1. エナシロキシン (ENX) 類の構造と逆合成解析</p><p> 我々はENX類の創薬への展開を目指して全合成研究を行っている[4]。ENX IIa (2) の逆合成解析をFig. 1に示す。全体をポリオールC16'-C23'部A、C9'-C15'部B、 ポリエンC1'-C8'部C及びシクロヘキサンカルボン酸部Dに分けた。Aの3箇所の不斉点についてはd-アラビノースを利用し、Bはd-グリセルアルデヒド=アセトニドからクロチルホウ素化で導くことにした。ポリエン部C はWittig反応で調製し、シクロヘキサンカルボン酸部Dについては、d-キナ酸の立体化学と位置選択的なアシル化反応を利用する。AとBの連結では、ジアニオン型求核試薬と酸クロリドとのカップリング反応を計画した。BCD間についてはHorner-Wadsworth-Emmons反応を用いることにした。</p><p>1)ポリオールC16'-C23'部の合成(Scheme 1)</p><p> d-アラビノースをラクトン誘導体3に導き、Wittig-Horner反応により4を経てE-アルケニル部分を増炭した5を得た。4のカルボニル基の還元は非選択的であったが、塩基処理で生じたオレフィンはE-体のみであった。トシラート6を経てエポキシド7を調製後、C16'-C23'部となるスルホンA1を合成した[4b]。また、相当するブロミドA2、ホスホニウム塩A3も調製した。</p><p>Scheme 1. C16'-C23'部の合成</p><p>2)ポリオールC9'-C15'部の合成(Scheme 2)</p><p> d-グリセルアルデヒド=アセトニド9からクロチルホウ素により4炭素増炭してアルコール10を得、酸触媒を用いて1,2-アセトニド部分を2,3-位に掛け替えて11とした[5]。11から相当する酸クロリドB1を調製した。一方、11の二重結合をオゾン分解した後、LiCHCl₂を用いて増炭[6]、アルキノール12及び酸クロリドB2に導いた。また、12のアルキン部分をRed-Al/NCSを用いて塩素化し、酸クロリドB3を得た。</p><p>Scheme 2. C9'-C15'部の合成</p><p>3)C9'-C15'部とC16'-C23'部のカップリング反応(Scheme 3)</p><p> 予備実験において、相当するスルホン(O-EE-A1)由来のモノアニオンでは、アルデヒド、酸クロリド何れともカップリング体は得られなかった。そこで求核性の向上を狙い、ヒドロキシスルホンA1からジアニオンを調製、酸クロリドB2を加えたところ、目的物A1-B2が10%の収率で得られた。一方、ホスホニウム塩A3を用いても目的物は得られなかった。更に求核性を向上させるため、共鳴安定化していないヒドロキシアルキ</p><p>(View PDFfor the rest of the abstract.)</p>

著者

紺野 勝弘 Picolo Gisele Gutierrez Vanessa Brigatte Patricia Zambelli Vanessa Camargo Antonio C.M. Cury Yara

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.409-413, 2008-09-01

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Snakebite accidents by the South American rattlesnake Crotalus durissus terrificus account for 10% of those occurred in Brazil. It induces severe neurological symptoms, but does not induce pain or severe tissue destruction at the site of inoculation, which is in contrast to the most other snakebites. Due to these properties, the crude venom of this snake used to be employed for controlling pain, for example, of cancer. Recent studies using the crude venom experimentally demonstrated that this venom shows antinociceptive effect more potent than morphine. This effect is orally active and long-lasting for 3-5 days, and despite mediated by opioid receptors, it dose not develop peripheral tolerance nor induce physical dependence unlike morphine. These remarkable properties prompted us to purify and chemically characterize the substance responsible for the analgesic effect. Bioassay-guided fractionation led to the isolation of a novel peptide, designated crotalphine, with a sequence of 14 amino acid residues having a single disulfide bond. We report herein the isolation, sequence determination and synthesis of crotalphine. Pharmacological evaluation using synthetic peptide will also be reported.

著者

広野 巌 大場 茂 斉藤 喜彦 丹羽 治樹 小鹿 一 若松 一雅 山田 静之 松下 和弘

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.26, pp.9-15, 1983-09-15

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We have examined the constituents of bracken fern, Pteridium aquilinum var. latiusculum and performed fractionation of the boiling water extracts by means of the assay based on carcinogenicity to rats. From the fraction exhibiting carcinogenicity, we have isolated an unstable norsesquiterpene glucoside of illudane type named ptaquiloside (1). The planar structure of (1) has been established on the basis of spectral and chemical means. The carcinogenicity of (1) to rats is currently under investigation.

著者

安元 健 伊藤 志保美 浮穴 学宗 ツインゴーネ アドリアーナ ロッシ ラケーレ ソプラノ ビットリオ

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>腔腸動物スナギンチャク(Palythoa spp.)から発見されたパリトキシン(palytoxin,PLTx)と同族体は複雑な構造と強力な毒性を持つ¹。演者ら(TY,TU))は底生渦鞭毛藻Ostreopsis siamensisから42-hydroxy-3,26-didemethyl-19,44-dideoxypalytoxinを単離決定し,最近,LC-QTOF を使用して伊計島産O. cf. ovata 中のovatoxin-a,-d,-e(IK2) の新規構造を推定した^2,3。一方,Ciminielloらは地中海産Ostreopsis cf. ovata から単離したovatoxin-aの構造を42-hydroxy-17,44,64-trideoxypalytoxinと決定した⁴。本研究はLC-MSを用いてPLTx類縁体の高感度・迅速構造解析法を開発して化学構造と分布の多様性,生合成解明,安全性監視への端緒とすることを目的とした。</p><p>[方法] スペクトル測定はLC(ESI)-TOFMS(Agilent Technology)を用いて正・負両モードで行い,質量100~3000の範囲のイオンを抽出した。本文中のm/zは小数点以下を省略してある。LCは移動相に0.1%ギ酸/MeCNによる勾配法を用いた。PLTxは市販品を使用し,混在するpalytoxin carboxylic acid(PLTxCOOH)とpalytoxin amide (PLTx-NH₂)も対象とした。渦鞭毛試料はナポリ湾産O. cf. ovata (AZ株)の培養藻体をMeOHで抽出して使用した。誤差の許容値は10ppmとした。</p><p>[パリトキシンの正イオンスペクトル] フラグメントイオンは生成機構に基づいて3型に分類された。第一は115-NH₂に電荷を有し,チャージリモートフラグメンテーションで生じる(Fig.1)。C79-C81-triol周辺の開裂と脱水で生じるイオン(m/z744,726,708,804,798,768)はPLTx同族体に特徴的である²。m/z916とその脱水イオンは73-OHの存在を示し,天然同族体73-deoxypalytoxinとの区別に役立つ。F環の開裂で生じるイオン群は,70-deoxy の推定構造を持つovatoxin-a-IK2との区別に役立つ。その他の主要なC-C結合の開裂位置も図中に示す。結合が切断されて生じる最初のモノエンのイオンは観測されず,共役が進行してトリエン以上になって観測される。水酸基の位置が適切でなければ脱水による共役は進行せず,イオンの確実な同定を可能とする。第二のグループはC1に結合した末端構造(A1+A2)中のアミド窒素が正電荷を担うと推定され,C8'からC11に至る部分構造の情報を与える(Fig.2)。末端の3-aminopropanol(A1)が脱落したm/z740のイオンは,dioxabicyclononane環の存在と位置を示す唯一のイオンである。開裂箇所のC28-C29結合の近傍に水酸基が存在しないので,脱水による共役化が進行せず,イオン強度が低い。第三のグループは炭素結合が2か所で同時に開裂し,その後の脱水によって生じた共役ポリエンである(Fig.3, 4)。A環とD環周辺の開裂の組み合わせによって多様なイオンが生成し,水酸基の情報を与える。例えば炭素数39の共役ポリエンでは水酸基5個の脱離で生成する。C41-C46間の水酸基は4個だけなので脱水は13-OHから20-OHに向けて進行している。</p><p>[パリトキシンの負イオンスペクトル] 第一のグループはD環周辺の開裂によって生じ,C1に結合した末端アミド構造は保持されている。第二グループは115-NH₂を有し,鎖長が長くて水酸基(酸素原子)の数が増加すると観測される。第三グループのフラグメントm/z947ではC1-アミドが開裂してアルドヒドを生成したと推定さ</p><p>(View PDFfor the rest of the abstract.)</p>

著者

四津 まり 村田 道雄 安元 健 直木 秀夫

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.29, pp.240-247, 1987-07-25

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The newt Cynops ensicauda collected in Okinawa, Japan, contained tetrodotoxin (TTX)(1) and its new analogs. Two analogs, compound A and B, were isolated by successive treatment of AcOH extracts on columns of charcoal, BioGel P-2, BioRex70, and Hitachigel 3011C gel. From 3.5kg of the newts 120mg of TTX, 18mg of compound A, and 30mg of compound B were obtained. High resolution FAB mass spectra taken on a JEOL JMS-DX-303HF indicated A to have the same molecular formula as TTX(C_<11>H_<17>O_8N_3) and B to be deoxyTTX (C_<11>H_<17>O_7N_3). ^1H NMR spectra of A showed a high field shift of 11-CH_2 suggested the CH_2OH at C-6 to be axial, 6-epiTTX(2) The axial configuration was further confirmed by NOE measurments. Configuration at C-9 was proved to be the same as TTX. Likewise B was assigned to 11-deoxyTTX(3), and its 11-CH_3 was suggested equatorial as same as TTX. Both 2 and I were in a tautomeric equilibrium between hemilactal (2a,3a) and lactone (2b,3b) forms that were confirmed by NOESY measurments which indicated the saturation transfer between two froms.

著者

田口 貴章 小澤 誠 Kimberley Meriel R. Booker-Milburn Kevin I. Stephenson G. Richard 海老塚 豊 市瀬 浩志

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.44, pp.235-240, 2002-09-01

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A class of Streptomyces aromatic polyketide antibiotics, the benzoisochromanequinone (BIQs) antibiotics all show trans stereochemistry at C-3 and C-15 in the pyran ring. The opposite stereochemical control is found in actinorhodin (3S, 15R, ACT) from S. coelicolor A3(2) and dihydrogranaticin (3R, 15S, DHGRA) from S. violaceoruber Tu22. A common bicyclic intermediate, which is produced by the early biosynthetic genes encoding a type II minimal polyketide synthase, C-9 ketoreductase (KR), aromatase, and cyclase, was postulated to undergo stereospecific reduction to provide either (S)-DNPA or (R)-DNPA. In the ACT biosynthesis, RED1 encoded by act VI-ORF 1 was proved to reduce C-3 of bicyclic intermediate to determine the 3-(S)-configuration of DNPA. Although the homolog of act VI-ORF 1 was not found in the gra cluster, RED2 was suggested to reduce bicyclic intermediate. An explored RED-2 coding gene, gra-6, was subjected to updated BLAST analysis. The gra-6 product, a putative short-chain alcohol dehydrogenase, has virtually no sequence similarity with RED1. Functional analysis of RED1/2 was made from the following points. 1) Introduction of gra-ORF 6 and gra-ORF 5 under translational coupling (gra-5+6) into the act VI-ORF 1 mutant, S. coelicolor B22, led to ACT-like pigmentation, demonstrating gra-ORF 6 to complement the function of act VI-ORF 1 possibly under unnatural stereochemical control. 2) Combinations of the ketoreductase genes were co-expressed with the early biosynthetic genes required for the bicyclic intermediate formation. gra-ORF6 was essential to produce (R)-DNPA in DHGRA biosynthesis. gra-5+6 led to the most efficient production of (R)-DNPA, implying a possible unique cooperative function as RED2. 3) A series of synthetic analogues was applied to the biotransformations based on ketosynthase-deficient recombinants of S. coelicolor carrying either RED1 or RED2. In all cases for RED1, the β-keto ester substrates were reduced with good to excellent enantioselectivity. However, the simpler substrates were not accepted by RED2, indicating the significant difference in substrate specificity between the two reductases. 4) 3D structures of RED1 and RED2 were predicted based on homology modeling (FAMS) using the templates, L-3-hydroxyacyl-CoA dehydrogenase from human heart (for RED1) and tropinone reductase II (for RED2). Catalytically key amino acid residues were revealed for the both enzymes. 5) RED1 and RED2 were overexpressed in E. coli, and in vitro assay system were successfully established. Optimization of the system, purification of both enzymes and site directed mutagenesis to the suggested key residues are in progress.

著者

柳屋 光俊 続木 一夫 渡辺 隆啓 中島 康之 松田 冬彦 長谷川 和夫 松本 毅

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.22, pp.635-641, 1979-09-20

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Pederin, a potent insect poison isolated from paedrus fuscipes, exhibits various interesting physiological activities, such as inhibition of mitosis in HeLa cell and blocking of protein synthesis at concentrations of 1-10 ng/me. We describe here the first total synthesis of pederin. Asymmetric Synthesis of Pedaldehyde Derivatives. Asymmetric reduction of ketone 14 was examined under various conditions. The desired alcohol 13R was obtained by reduction with LiAlH_4 in ether-toluene (54: 46) at -123°in 74% e.e. The alcohol 13R was converted stereoselectively to pedamide 28 (Fig. 4,5). Synthesis of N-acyl aminoacetals. A new general method for the synthesis of N-acyl aminoacetals was developed and the method was applied to the synthesis of pederin, starting from (+)-pederic acid and (+)-pedamide.

著者

丸田 聡 山岡 薫 大越 夏実 山下 まり

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.49, pp.443-448, 2007-08-24

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Tetrodotoxin (TTX) and saxitoxin (STX) bind to a single site in the outer pore of the voltage-gated sodium channels (Na_vs), formed by the amino-acid residues in the outer-pore loops (p-loops) located between the S5 and S6 segments of each of the homologous domain (I-IV) of the a-subunit. Since puffer fish and newts accumulate TTX at high concentration in their tissues, they are thought to have special defense systems against their own TTX. We previously obtained a cDNA encoding Na_v from Fugu pardalis skeletal muscle (fMNa1=fNav1.4a). In fNav1.4a protein, the aromatic amino acid in p-loop region of Domain I in TTX-sensitive Nays was replaced by Asn. Also, Kaneko et al. reported that similar mutation was found in Na_v of retinal neuron of the newt, Cynops pyrrhogaster. In this study, we confirmed that these mutations are responsible to TTX-resistance of puffer fish and newts by evaluation of IC_<50>-TTX values of the corresponding mutants of rNav1.2a transiently expressed in HEK293 cells by electrophysiological study.

著者

竹本 常松 中島 正 横部 哲朗

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.8, pp.47-52, 1964-10-20

著者

亀谷 哲治 鈴木 幸夫 伴 千恵子 三沢 薫 高田 信子 叶田 清 本多 利雄

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.29, pp.63-70, 1987

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Chiral cyclopentane derivatives have widely been employed as important starting materials in the syntheses of naturally occurring compounds. Development of an efficient preparation of a chiral cyclopentane derivative from readly available substances with both (+)- and (-)-forms is therefore desirable. We have established an efficient procedure for the preparation of chiral 2-isopropeny1-5-methyl-4-oxocyclo-pentane-1-carboxylate(1) and (2), whose substituents would be transformed into variety of functional groups, from readily avairable (-)- and (+)-carvone. First, the (-)-isomer(1) was employed in the synthesis of (+)-tecomanine (7), an antipodal form of hypoglycemic monoterpene alkaloid, where the aminylium ion-induced cyclization played an important role. Whereas, N-acetyl-L-acosamine (32), found as a structural component of glycosidic antibiotic, was also derived from the (+)-isomer (2) by utilizing the Beckmann rearrangement and Baeyer-Villiger oxidation as key reactions. Finally, Melillo's lactone(34), a key intermediate for the synthesis of carbapenem antibiotic (+)-thienamycin, was prepared from (-)-isomer(1) by manipulation of its substituents in reasonably high-yield.