JP2011505877A - 環状ペンタデプシペプチドおよびそれを生産するフザリウム属微生物 - Google Patents
環状ペンタデプシペプチドおよびそれを生産するフザリウム属微生物 Download PDFInfo
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- JP2011505877A JP2011505877A JP2010544880A JP2010544880A JP2011505877A JP 2011505877 A JP2011505877 A JP 2011505877A JP 2010544880 A JP2010544880 A JP 2010544880A JP 2010544880 A JP2010544880 A JP 2010544880A JP 2011505877 A JP2011505877 A JP 2011505877A
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- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K11/00—Depsipeptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K11/02—Depsipeptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof cyclic, e.g. valinomycins ; Derivatives thereof
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- A61P35/00—Antineoplastic agents
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- C12N1/00—Microorganisms, e.g. protozoa; Compositions thereof; Processes of propagating, maintaining or preserving microorganisms or compositions thereof; Processes of preparing or isolating a composition containing a microorganism; Culture media therefor
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- A—HUMAN NECESSITIES
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- C12R2001/00—Microorganisms ; Processes using microorganisms
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- C12R2001/77—Fusarium
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Abstract
【解決手段】本発明のフザリウム属微生物が生産する環状ペンタデプシペプチドは、薬剤耐性抑制活性および癌細胞増殖抑制活性に優れるので、抗生剤耐性菌の治療および癌治療用医薬として利用できる。
【選択図】図17
Description
サンサルバミドAは、プロテアーゼ耐性および細胞膜透過性を有する親脂性の環状デプシペプチドであって、他の薬剤に比べて経口投与が容易であり且つ4つのアミノ酸および1つのヒドロキシ酸が結合しているコア構造は、結合の回転が制限されてさらに硬い配列を形成するので、生体内における親和性に優れるうえ、半減期が長いという利点がある。
(1)分離および形態学的同定
韓国ムンキョウのジャガイモから、環状デプシペプチドを生産するフザリウム属菌株を分離した。分離された菌株はSamson等およびNelson等の方法で同定した[Samson RA, Hoekstra ES, Oorschot V, Connie AN.(1981) Introdution to food−borne fungi. Published and distributed by Centraalbureau voor Schimmelcultures; Nelson PE, Toussoun TA, Marasas WF.(1983) Fusarium species: An illustrated manual for identification. The Pennsylvania State University. Press]。
このような形態学的特性によって分離されたフザリウム属菌株はフザリウムソラニと同定された。
A.DNA抽出
本発明の分離されたフザリウムソラニ菌株の全体ゲノムDNAをポテトデキストロースアガ培地で育てた菌糸体からCorrell等の方法で抽出した[Correll JC, Klittich CJR, Leslie JF.(1987) Nitrate nonutilizing mutants of Fusarium oxysporum and their use in vegetative compatibility tests. Phytopathology, 77, 1640−1646]。
Hue等により提案されたフザリウム特異プライマーである、配列番号1のP28SL(5’−ACA AAT TAC AAC TCG GGC CCG AGA−3’)と配列番号2のP58SL(5’−AGT ATT CTG GCG GGC ATG CCT GT−3’)を用いた対照群PCR分析が利用された[Hue, F.X., M.Huerre, M.A. Rouffault, and C.D. Bievre. Specified detection of Fusarium species in blood and tissues by a PCR technique. Journal of Clinical Microbiology, 37: 2434−2438. 1999]。前記フザリウム特異プライマー対は、PCRによってフザリウム属菌株のrDNAをコードする遺伝子の断片を増幅させる。前記P28SLおよびP58SLプライマー対の結合部位はrDNAのITS2および5.8Sと28S部分であって、フザリウム菌株で保存される部分である。
本発明のフザリウム菌株のPCR増幅産物を精製した後、マクロジェン(韓国)でその配列を分析し、GenBankデータベースのBLAST検索によって相同性を調査した。本発明のフザリウム菌株のITS−5.8rDNA配列は配列番号3に示した。本発明のフザリウム菌株のITS−5.8rDNA配列はフザリウムソラニのものと98%以上の相同性を示した(図6)。
(1)フザリウム制限培地ブロスにおける培養
1×105spore/mLのフザリウムソラニ(Fusarium solani)KCCM90040をフザリウム制限培地ブロス(FDM broth;リットル当り25gのスクロース、4.25gのNaNO3、5gのNaCl、2.5gのMgSO47H2O、1.36gのKH2PO4、0.01gのFeSO47H2O、および0.0029gのZnSO47H2O)100mLに接種して25℃で7日間培養した。
1×105spore/mLのフザリウムソラニ(Fusarium solani)KCCM90040を、50gの米を滅菌蒸留水で40重量%の水分含量に調整した米培地に接種して25℃で7日間培養した。
前記(1)の菌糸体を含んでいる培養液に、培養液の2倍に相当するクロロホルムを入れて激烈に振とうした後、下層のクロロホルム層を取り、これを乾燥させた後、メタノールでさらに溶解させた。
前記(2)のフザリウムが培養された穀類培地は12時間常温で乾燥させる。乾燥した菌糸体は、均質にした後、アセトニトリル:メタノール:水を16:3:1の体積比で混合した溶媒75mLで一晩抽出し、しかる後に、滅菌濾過紙で濾過した。濾液は25mLのn−ヘプタンで2回脂肪を除去し、下層を乾燥させた後、さらにメタノール:水を55:45の体積比で混合した溶媒50mLに溶解させ、45mLの二塩化メタンで2回抽出した。二塩化メタン層を乾燥させた後、メタノールでさらに溶解させた。
前記(1)および(2)の培養物から製造された(3)の抽出物それぞれを、シセイドパックC18カラム(0.46×25cm)[資生党、日本]を用いて、アセトニトリル:水を70:30の体積比で混合した溶液とともに分当り1mLの流速で40分間溶出させた。ピークは210nmで検出された。
前記(4)の化合物AおよびBはエレクトロスプレイイオン化質量分析器(electrospray ionization mass spectrometry、ESI−MS)を用いて分子量を測定した結果、その分子量はそれぞれ586.36および600.36m/zであることを確認することができた(図9および図10)。
化合物AおよびBは、既存に報告された環状デプシペプチドの分子量と非常に類似であった。報告された化合物の由来、分子量および文献をまとめて表1に示した。
Belofsky等(1999):Belofsky GN, Jensen PR, Fenical W. (1999) Sansalvamide: A new cytotoxic cyclic depsipeptide produced by a marine fungus of the genus Fusarium. Tetrahedron Lett. 40, 2913−2916
Cueto等(2000): Cueto M, Jensen PR, Fenical W. (2000) N−Methylsansalvamide, a cytotoxic cyclic depsipeptide from a marine fungus of the genus Fusarium. Phytochemistry. 55, 223−226
Oh等(2006):Oh DC, Jensen PR, Fenical W. (2006) Zygosporamide, a cytotoxic cyclic depsipeptide from the marine−derived fungus Zygosporium masonii. Tetrahedron Lett. 47, 8625−8628
(A)化合物A
化合物Aの機能基確認のためにFT IR−8400S赤外線分光器(SHIMADZU、日本)を用いた。化合物AはIR分析の結果、アミド結合(1654.42cm−1)およびエステル結合(1745.52cm−1)を持っていた(図11)。最大UVスペクトルはメタノールで287nmであり、融解点測定器(Thermo fisher scientific Inc.Waltham、米国)で測定した融解点は82℃であった。
ID−NMR(1H NMR、13C NMRおよびDEPT)測定は、Bruker DMX 600スペクトロメーターシステムを用い、2D−NMR(COSY、HMQCおよびHMBC)はBruker AVANCE800スペクトロメーターシステムを用いてメタノール(CD3OD)で測定した。
1H NMRおよび13C NMRスペクトル結果は、化合物Aが典型的な環状デプシペプチドであることを示した(表2)。
化合物Bは、IR分析の結果、アミド結合(1653.24cm−1)およびエステル結合(1742.65cm−1)を持っていた(図13)。最大UVスペクトルはメタノールで213nmであり、融解点は82℃であった。
1D−NMR(1H NMR、13C NMR、およびDEPT)測定は、Bruker DMX 600スペクトロメーターシステムを用い、2D−NMR(COSY、HMQCおよびHMBC)はBruker DMX 600 スペクトロメーターシステムを用いてCDCl3で測定した。
1H NMRおよび13C NMRスペクトル結果は、化合物Bが典型的な環状デプシペプチドであることを示した(表3)。
化合物AおよびBに含まれたアミノ酸の立体化学構造を確認するために酸加水分解した後、Marfey試薬によって各アミノ酸を誘導体化させた後、対照群と共にHPLCで分析し、その分析結果を図15(化合物A)および図16(化合物B)にそれぞれ示した。化合物AびBに含まれた全てのアミノ酸はL型であることを確認することができた。
公知の環状ヘキサデプシペプチド(ビューベリシン、エンニアチンH、IおよびMK1688)と化学式1および2の化合物の多薬剤耐性がない癌細胞株および多薬剤耐性を持つ癌細胞株を対象としてSRB方法で細胞毒性を測定した。
化学式1および2の環状ペンタデプシペプチドの多薬剤耐性抑制活性を多薬剤耐性のない癌細胞株(MES−SAおよびHCT15)と比較して多薬剤耐性を持つ癌細胞、すなわちMES−SA/DX5およびHCT15/CL02で確認した。多薬剤耐性癌細胞株に対するパクリタキセル(TAX)の細胞毒性に対する化学式1および2の環状ペンタデプシペプチドの多薬剤耐性の逆転効果を測定した(表6)。対照群としてP−糖タンパク質阻害活性を有し、多薬剤耐性抑制剤として用いられているベラパミル(VER)を用いた。
(1)抗バクテリア活性
3種のグラム陽性菌(L. monocytogenes ATCC 14028;S. aureus ATCC 35556;B. cereus ATCC 13061 )、3種のグラム陰性菌(E. coli ATCC8739;P. aeruginosa ATCC9026;S. typhimurium ATCC14028)に対する抗バクテリア活性を測定した。化学式1および化学式2の化合物をそれぞれ0.1、0.5、1および2mMの濃度でDMSOに溶解させた後、滅菌ペーパーディスク(直径5mm)に滴下し、DMSOは蒸発させた。TSA(Tryptic Soy Agar)に1×107CFU/mL濃度のバクテリアを接種し、前記ペーパーディスクをのせて37℃で24時間培養した後、クリアゾーンおよびその直径を観察した。
4種のカビ菌株(Mucor rouxii、Penicillium citrinum、Fusarium oxysporum、およびAspergillus oryzae)に対する抗カビ活性を測定した。
1×105spore/mLのフザリウムソラニ(Fusarium solani)KCCM90040を、50gの穀類を滅菌させた後で蒸留水で40重量%の水分含量に調整した穀類培地に接種し、25℃で培養しながら一日に一回攪拌して培養した。6種の異なる固体穀類培地で培養したとき、培養期間によって生産される化学式1および2の化合物の生産量をそれぞれ図27および図28に示した。
本発明のフザリウムソラニKCCM90040菌株において、化学式1および2の化合物を生産するための培養条件の実験結果は表7に示した。
成分含量
化学式1または化学式2の環状ペンタデプシペプチド 100mg
コーンスターチ 68mg
ラクトース 90mg
微細結晶質セルロース 40mg
ステアリン酸マグネシウム 2mg
成分含量
化学式1または化学式2の環状ペンタデプシペプチド 50mg
メタ重亜硫酸ナトリウム 1.5mg
メチルパラベン 1.0mg
プロピルパラベン 0.1mg
注射用精製水 適量
成分含量
化学式1または化学式2の環状ペンタデプシペプチド 200mg
濃縮果汁 2g
スクロース 5g
クエン酸ナトリウム 100mg
香料 70mg
水 適量
Claims (12)
- 下記化学式1または下記化学式2の環状ペンタデプシペプチドを生産するフザリウム属菌株。
- フザリウムソラニであることを特徴とする、請求項1に記載の菌株。
- 前記フザリウムソラニがフザリウムソラニ(Fusarium solani)KCCM90040[寄託番号KCCM10881P]であることを特徴とする、請求項2に記載の菌株。
- 請求項1〜3のいずれか1項の菌株を培養して請求項1の化学式1または化学式2の環状ペンタデプシペプチドを生産する方法。
- 前記培養は穀類を用いた固体培養であることを特徴とする、請求項4に記載の環状ペンタデプシペプチドを生産する方法。
- 前記穀類が米であることを特徴とする、請求項5に記載の環状ペンタデプシペプチドを生産する方法。
- 前記培養条件は温度20〜30℃、湿度20〜50%、培養期間10〜20日であることを特徴とする、請求項5に記載の環状ペンタデプシペプチドを生産する方法。
- 下記化学式1の環状ペンタデプシペプチド。
- 下記化学式2の環状ペンタデプシペプチド。
- 下記化学式1の環状ペンタデプシペプチド、下記化学式2の環状ペンタデプシペプチドおよびこれらの薬学的に許容される塩よりなる群から選ばれる少なくとも一つを有効成分として含有する、薬剤耐性抑制用薬学組成物。
- 腫瘍細胞の薬剤耐性抑制用であることを特徴とする、請求項10に記載の薬剤耐性抑制用薬学組成物。
- 下記化学式1の環状ペンタデプシペプチド、下記化学式2の環状ペンタデプシペプチドおよびこれらの薬学的に許容される塩よりなる群から選ばれる少なくとも一つを有効成分として含有する、腫瘍細胞増殖抑制活性を有する癌治療用薬学組成物。
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