JPWO2013031239A1 - 新規マングロマイシン化合物及びその製造方法 - Google Patents
新規マングロマイシン化合物及びその製造方法 Download PDFInfo
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- JPWO2013031239A1 JPWO2013031239A1 JP2013531108A JP2013531108A JPWO2013031239A1 JP WO2013031239 A1 JPWO2013031239 A1 JP WO2013031239A1 JP 2013531108 A JP2013531108 A JP 2013531108A JP 2013531108 A JP2013531108 A JP 2013531108A JP WO2013031239 A1 JPWO2013031239 A1 JP WO2013031239A1
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- Prior art keywords
- mangromicins
- compound
- methanol
- mangromicin
- trypanosoma
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- KCXFHTAICRTXLI-UHFFFAOYSA-N propane-1-sulfonic acid Chemical compound CCCS(O)(=O)=O KCXFHTAICRTXLI-UHFFFAOYSA-N 0.000 description 1
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- 230000005180 public health Effects 0.000 description 1
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Classifications
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- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
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- C07D493/16—Peri-condensed systems
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Abstract
Description
(1)性状:白色粉末または淡黄色粉末
(2)分子量:410
(3)分子式:C22H34O7
(4)高分解能質量分析による[M+H]+ 理論値(m/z)411.2383、実測値(m/z)411.2377
(5)比旋光度:[α]D 25.3=−13.56°(c=0.1、メタノール)
(6)紫外部吸収極大(メタノール中)λmax(ε):251(2747)
(7)赤外部吸収極大νmax(KBr錠):3440,1637cm−1に極大吸収を有する
(8)1H NMR(重メタノール中)δ ppm:4.73(1H,d),2.10(1H,dd),2.05(1H,ddd),2.88(1H,ddd),1.25(1H,ddd),2.43(1H,ddd),1.62(1H),1.85(1H,dd),2.55(1H,m),3.20(1H,d,br),4.30(1H,d),3.32(1H,d),2.75(1H,q),2.50(1H,d),4.55(1H,dd),1.60(2H),1.40(1H,m),1.52(1H,m),0.95(3H,t),1.35(3H,s),1.06(3H,d),1.03(3H,d)
(9)13C NMR(重メタノール中)δ ppm:73.8,44.4,167.9,103.4,19.3,37.4,85.0,48.9,37.3,80.2,73.0,72.3,52.7,223.3,44.4,169.3,34.6,21.3,14.4,24.8,13.7,8.5
(10)溶解性:クロロホルム、ジクロロメタン、エタノール、及びメタノールに易溶、水に難溶。
(1)性状:白色粉末または淡黄色粉末
(2)分子量:392
(3)分子式:C22H32O6
(4)高分解能質量分析による[M+H]+ 理論値(m/z)393.2277、 実測値(m/z)393.2271
(5)比旋光度:[α]D 25.3=−24.08°(C=0.1、メタノール)
(6)紫外部吸収極大(メタノール中)λmax(ε):236(8036)
(7)赤外部吸収極大νmax(KBr錠):3450,1672cm−1に極大吸収を有する
(8)1H NMR(重メタノール中)δ ppm:4.61(1H,d),2.28(1H,dd),2.05(1H,ddd),2.91(1H,ddd),1.27(1H,m),2.59(1H,m),1.41(1H,dd),1.97(1H,dd),2.53(1H,m),3.68(1H,dd),4.54(1H,dd),6.74(1H,d),2.18(1H,dd),4.03(1H,dd),1.56(1H,m),1.59(1H,m),1.36(1H,m),1.43(1H,d),0.94(3H,t),1.37(3H,s),1.22(3H,d)
(9)13C NMR(重メタノール中)δ ppm:78.3,43.5,167.4,104.0,20.1,33.8,82.3,50.4,37.3,84.8,69.9,150.7,134.8,205.2,43.3,168.3,36.4,20.7,14.3,24.9,16.5
(10)溶解性:クロロホルム、ジクロロメタン、エタノール、メタノールに易溶、水に難溶。
(1)性状:白色粉末または淡黄色粉末
(2)分子量:394
(3)分子式:C22H34O6
(4)高分解能質量分析による[M+H]+理論値(m/z)395.2434、実測値(m/z)395.2413
(5)比旋光度:[α]D 25.3=23.24°(c=0.1、メタノール)
(6)紫外部吸収極大(メタノール中)λmax(ε):251(5595)
(7)赤外部吸収極大νmax(KBr錠):3430,1657cm−1に極大吸収を有する
(8)1H NMR(重メタノール中)δ ppm:4.78(1H,d),2.14(1H),2.02(1H,dd),2.85(1H,dddd),1.25(1H,ddd),2.46(1H),1.68(2H,m),2.74(1H,m),1.72(1H,ddd),2.43(1H),3.56(1H,ddd),3.39(1H),2.43(1H),2.38(1H),4.46(1H),1.61(2H,m),1.38(1H),1.52(1H),0.96(3H,t),1.34(3H,s),1.06(3H,d),1.04(3H,d)
(9)13C NMR(重メタノール中)δ ppm:74.0,43.9,167.3,103.7,19.5,36.5,83.7,49.9,44.4,37.6,69.5,81.9,37.0,212.6,44.2,169.2,35.0,21.2,14.4,25.2,15.4
(10)溶解性:クロロホルム、ジクロロメタン、エタノール、メタノールに易溶、水に難溶。
本発明者等によって沖縄県西表島マングローブ土壌より新たに、レシェバリエリア・エスピー(Lechevalieria sp.)K10−0216株を分離した。レシェバリエリア・エスピー(Lechevalieria sp.)K10−0216株の菌学的性状は以下の通りであった。
(I)形態的性質
栄養菌糸は各種寒天培地上でよく発達し、分断は観察されない。気菌糸はスターチ無機塩寒天でわずかに着生し、ホワイトの色調を呈する。約0.3〜0.4μmの気菌糸は織り交ざり凝集塊を形成する。胞子のう及び遊走子は見出されない。
(II)各種培地上での性状
イー・ビー・シャーリング(E.B.Shirling)とデー・ゴットリーブ(D.Gottlieb)の方法(インターナショナル・ジャーナル・オブ・システィマティック・バクテリオロジー、16巻、313頁、1966年)によって調べた本菌株の培養性状を表1に示す。色調は標準色として、カラー・ハーモニー・マニュアル第4版(コンテナー・コーポレーション・オブ・アメリカ・シカゴ、1958年)を用いて決定することができ、色票名は括弧内のコードと併せて記されている。以下は特記しない限り、27℃、2週間目の各培地における観察の結果である。
(1)メラニン色素の生成
(イ)チロシン寒天 :陰性
(ロ)ペプトン・イースト・鉄寒天:陰性
(ハ)トリプトン・イースト液 :陰性
(2)ゼラチンの液化(単純ゼラチン培地)(20℃):陰性
(3)スターチの加水分解:陽性
(4)脱脂乳の凝固(37℃):陽性
(5)脱脂乳のペプトン化(37℃):陽性
(6)生育温度範囲:12〜40℃
(7)炭素源の利用性(プリドハム・ゴトリーブ寒天培地)
利用する:D−グルコース、L−アラビノース、D−キシロース、メリビオース、D−マンニトール、D−フラクトース、myo−イノシトール、シュークロース
やや利用する:ラフィノース、L−ラムノース、
(8)セルロースの分解:陰性
細胞壁のジアミノピメリン酸はメソ型である。主要メナキノンはMK−9(H4)でMK−8(H4)およびMK−10(H4)を少量有する。
(V)16S rRNA遺伝子解析
16S rRNA遺伝子のうち約1400塩基配列を決定した(配列番号1)。DNAデータベースに登録され公開されているレシェバリエリア属に属する菌株およびその他の放線菌のデータを用いた近隣結合法による系統解析の結果から、本菌株はレシェバリエリア属に分類することが妥当であり、レシェバリエリア アエロコロニゲネス(Lechevalieria aerocolonigenes)に最も近縁である。
以上、本菌の菌学的性状を要約すると次のとおりである。細胞壁中のジアミノピメリン酸はメソ型、主要メナキノンはMK−9(H4)である。わずかに着生する気菌糸は織り交ざり凝集塊を形成する。コロニーは淡黄色を呈し、メラニン色素は産生しない。これらの結果および16S rRNA遺伝子の解析結果から、本菌株は2001年にインターナショナル・ジャーナル・オブ・システマティック・アンド・エボリューショナリー・ミクロバイオロジー(International Journal of Systematic and Evolutionary Microbiology)に発表されたレシェバリエリア属に属する1菌種であると判断された。本菌株はレシェバリエリア・エスピー(Lechevalieria sp.)K10−0216として、2011年7月21日付にて独立行政法人製品評価技術基盤機構 特許生物寄託センター(千葉県木更津市かずさ鎌足2−5−8)に寄託した(受託番号 NITE BP−1114)。
スターチ2.4%、グルコース0.1%、ペプトン(極東製薬工業株式会社製)0.3%、カツオエキス(極東製薬工業株式会社製)0.3%、酵母エキス(オリエンタル酵母工業株式会社製)0.5%、炭酸水素カルシウム0.4%からなる液体培地(pH 7.0)100mLを含む500mL容三角フラスコに60本に、液体培地で培養したレシェバリエリア・エスピー(Lechevalieria sp.)K10−0216(受託番号 NITE BP−1114)を各1mlずつ植菌し、27℃で3日間振盪培養した。得られた種培養液を、スターチ2.0%、グリセロール0.5%、脱脂小麦胚芽(日清ファルマ株式会社製)1.0%、カツオ肉エキス(極東製薬工業株式会社製)0.3%、ドライ酵母(JTフーズ株式会社製)0.3%、炭酸水素カルシウム0.4%からなる液体培地(pH7.0)100mLを含む500mL容三角フラスコに60本に、各1mLずつ植菌し、27℃で7日間振盪培養した。
Mangromicin A
(1)性状:白色粉末または淡黄色
(2)分子量:410
(3)分子式:C22H34O7
高分解能質量分析による[M+H]+理論値(m/z)411.2383、実測値(m/z)411.2377
(4)比旋光度:[α]D 25.3=−13.56°(c=0.1、メタノール)
(5)紫外部吸収極大λmax(メタノール中):251(2747)(括弧内はε)
(6)赤外部吸収極大νmax(KBr錠):3440,1637cm−1に極大吸収を有する。
(7)プロトン核磁気共鳴スペクトル:重メタノール中の化学シフト(ppm)を表2に示す。(表中、sは一重線、dは二重線、mは多重線、Hはプロトンの数を示す。)
(8)カーボン核磁気共鳴スペクトル:重メタノール中の化学シフト(ppm)を表2に示す。
(9)溶剤に対する溶解性:クロロホルム、ジクロロメタン、エタノール、メタノールに易溶。水に難溶。
(1)性状:白色粉末または淡黄色
(2)分子量:392
(3)分子式:C22H32O6
高分解能質量分析による[M+H]+理論値(m/z)393.2277、実測値(m/z)393.2271
(4)比旋光度:[α]D 25.3=−24.08°(c=0.1、メタノール)
(5)紫外部吸収極大λmax(メタノール中):236(8036)(括弧内はε)
(6)赤外部吸収極大νmax(KBr錠):3450,1672cm−1に極大吸収を有する。
(7)プロトン核磁気共鳴スペクトル:重メタノール中の化学シフト(ppm)を表3に示す。(表中、sは一重線、dは二重線、mは多重線、Hはプロトンの数を示す。)
(8)カーボン核磁気共鳴スペクトル:重メタノール中の化学シフト(ppm)を表3に示す。
(9)溶剤に対する溶解性:クロロホルム、ジクロロメタン、エタノール、メタノールに易溶。水に難溶。
(1)性状:白色粉末または淡黄色
(2)分子量:394
(3)分子式:C22H34O6
高分解能質量分析による[M+H]+理論値(m/z)395.2434、実測値(m/z)395.2413
(4)比旋光度:[α]D 25.3=23.24°(c=0.1、メタノール)
(5)紫外部吸収極大λmax(メタノール中):251(5595)(括弧内はε)
(6)赤外部吸収極大νmax(KBr錠):3430,1657cm−1に極大吸収を有する。
(7)プロトン核磁気共鳴スペクトル:重メタノール中の化学シフト(ppm)を表4に示す。(表中、sは一重線、dは二重線、mは多重線、Hはプロトンの数を示す。)
(8)カーボン核磁気共鳴スペクトル:重メタノール中の化学シフト(ppm)を表4に示す。
(9)溶剤に対する溶解性:クロロホルム、ジクロロメタン、エタノール、メタノールに易溶。水に難溶。
本発明のMangromicin A,B及びCのin vitroでのトリパノソーマ原虫の増殖を阻害する活性を以下の通り調べた。
試験原虫として、トリパノソーマ原虫のナガナ病の起因原虫Trypanosoma brucei brucei GUTat 3.1株(名古屋市立大学医学部藪義貞講師より分与可能)を用いた。原虫の維持継代は藪らの方法[Yabu Y, Koide T, Ohota N, Nose M, Ogihara Y. Continuous growth of bloodstream forms of Trypanosoma brucei brucei in axenic culture system containing a low concentration of serum. Southeast Asian J. Trop. Med. Public Health,29:591−595(1998)]を若干改変して行った。すなわち、24 well plateの各well内で、10%非動化牛胎児血清(FBS)、抗生物質及び種々の補給剤添加イスコフ改変ダルベッコ(IMDM)培地を用い、37℃、5%CO2−95% air下で培養を行い、1〜3日毎に培地交換して連続培養を行った。
本発明のMangromicins A,B及びCの細胞毒性試験は乙黒らの方法[Otoguro K, Kohana A, Manabe C, Ishiyama A, Ui H, Shiomi K, Yamada H, Omura S. Potent antimalarial activities of polyether antibiotic, X−206. J. Antibiotics,54:658−663,(2001)]に準じて行った。すなわち、宿主細胞のモデルとしてヒト胎児肺由来正常繊維芽細胞MRC−5細胞[Dr. L. Maes(Tibotec NV,Mechelen,ベルギー国)より分与可能]を10%牛胎児血清(FCS)及び抗生物質添加MEM培地にて維持、継代培養を行ったものを用いた。
本発明のMangromicins A,B及びCの抗菌活性は以下の方法で測定した。濾紙円板(アドバンテック社製、直径6mm)にMangromicins A,B及びCの1mg/mLのメタノール溶液をそれぞれ10μL浸漬し、一定時間風乾して溶媒を除去後、表7に記載の試験菌含菌寒天平板に張り付け、35℃で24時間培養後、濾紙円板の周りにできた生育阻止円の直径測定した。
Claims (8)
- 請求項1〜3のいずれか1項に記載の化合物を生産する能力を有する放線菌に属する微生物を培地で培養し、培養物中請求項1〜3のいずれか1項に記載の化合物を蓄積せしめ、該培養物から請求項1〜3のいずれか1項に記載の化合物を採取することを特徴とする、請求項1〜3のいずれか1項に記載の化合物の製造方法。
- 請求項1〜3のいずれか1項に記載の化合物を生産する能力を有する放線菌に属する微生物が、レシェバリエリア・エスピー(Lechevalieria sp.)K10−0216(受託番号 NITE BP−1114)である請求項4に記載の製造方法。
- レシェバリエリア・エスピー(Lechevalieria sp.)K10−0216(受託番号 NITE BP−1114)。
- 請求項1〜3のいずれか1項に記載の化合物を有効成分とするトリパノソーマ原虫の増殖阻害活性物質。
- 請求項1〜3のいずれか1項に記載の化合物を有効成分とする抗トリパノソーマ原虫薬。
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