JP6249415B2 - 新規光線過敏症抑制剤トレハンジェリン物質及びその製造法 - Google Patents
新規光線過敏症抑制剤トレハンジェリン物質及びその製造法 Download PDFInfo
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- JP6249415B2 JP6249415B2 JP2014532813A JP2014532813A JP6249415B2 JP 6249415 B2 JP6249415 B2 JP 6249415B2 JP 2014532813 A JP2014532813 A JP 2014532813A JP 2014532813 A JP2014532813 A JP 2014532813A JP 6249415 B2 JP6249415 B2 JP 6249415B2
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Description
本発明は、かかる知見に基づいて完成されたものであって、下記一般式
で表されるトレハンジェリンに関する。
(1)性状:透明あるいは白色粉末
(2)分子量:506
(3)分子式:C22H34O13
(4)高分解能質量分析による[M+H]+ 理論値(m/z)507.2078、実測値(m/z)507.2087
(5)比旋光度:[α]D 25.3=+167.12°(c=0.1、メタノール)
(6)紫外部吸収極大 λmax(メタノール中):216nm
(7)赤外部吸収極大 νmax(KBr錠):=2919cm−1,1033cm−1に極大吸収を有する。
(8)1H NMR(重メタノール中)δ ppm:6.11(1H,m),5.475(1H,dd),5.21(1H,d),3.92(1H,m),3.80(1H,dd),3.714(1H,dd),3.713(1H,dd),3.56(1H,dd),2.00(3H,m),1.95(3H,m)
(9)13C NMR(重メタノール中)δ ppm:169.6,138.2,129.6,95.1,76.5,73.9,71.6,70.0,62.2,20.8,16.0
(10)溶剤に対する溶解性:エタノール、メタノール及び水に易溶。クロロホルムに難溶。
(2)分子量:506
(3)分子式:C22H34O13
(4)高分解能質量分析による[M+H]+ 理論値(m/z)507.2078、実測値(m/z)507.2074
(5)比旋光度:[α]D 25.3=+13.5°(c=0.1、メタノール)
(6)紫外部吸収極大 λmax(メタノール中):218nm
(7)赤外部吸収極大 νmax(KBr錠):=2942cm−1,1147cm−1に極大吸収を有する。
(8)1H NMR(重メタノール中)δ ppm:6.22(1H,m),6.12(1H,m),5.37(1H,d),5.30(1H,dd),5.15(1H,d),4.76(1H,dd),4.13(1H,dd),3.91(1H,ddd),3.82(1H,dd),3.72(1H,dd),3.68(1H,dd),3.67(1H,dd),3.61(1H,dd),3.60(1H,dd),3.59(1H,ddd),3.44(1H,dd),2.08(3H,dd),2.00(3H,dd),1.96(3H,dd),1.94(3H,dd)
(9)13C NMR(重メタノール中)δ ppm:169.6,168.8,141.1,138.4,129.5,128.4,95.6,92.7,76.3,74.3,74.0,73.9,72.1,72.0,71.4,68.9,62.4,61.5,20.9,20.7,16.5,16.0
(10)溶剤に対する溶解性:エタノール、メタノール及び水に易溶。クロロホルムに難溶。
(2)分子量:506
(3)分子式:C22H34O13
(4)高分解能質量分析による[M+H]+ 理論値(m/z)507.2078、実測値(m/z)507.2074
(5)比旋光度:[α]D 25.3=+11.4°(c=0.1、メタノール)
(6)紫外部吸収極大 λmax(メタノール中):218nm
(7)赤外部吸収極大 νmax(KBr錠):=2927cm−1,1149cm−1に極大吸収を有する。
(8)1H NMR(重メタノール中)δ ppm:6.15(1H,m),5.20(1H,d),4.91(1H,dd),4.07(1H,ddd),4.02(1H,dd),3.59(1H,dd),3.58(1H,dd)3.51(1H,dd),2.00(3H,m),1.91(3H,m)
(9)13C NMR(重メタノール中)δ ppm:168.8,139.5,129.0,95.1,73.4,72.4,72.3,72.0,62.3,20.7,16.1
(10)溶剤に対する溶解性:エタノール、メタノール及び水に易溶。クロロホルムに難溶。
本発明者等によって沖縄県西表島に生息している植物より新たに、ポリモーフォスポラ ルブラ(Polymorphospora rubra)K07−0510株を分離した。ポリモーフォスポラ ルブラ(Polymorphospora rubra)K07−0510株の菌学的性状は以下の通りであった。
栄養菌糸は各種寒天培地上でよく発達し、分断が観察される。気菌糸はグルコース・肉エキス・ペプトン寒天でわずかに着生する。顕微鏡下の観察では、気菌糸上に短い胞子鎖を着生し、胞子の大きさは約0.7〜1.1×0.5〜1.0μmの円筒状で、その表面は平滑である。胞子のう及び遊走子は見出されない。
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)によって調べた本生産菌の培養性状を次表に示す。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)を用いて決定し、色票名とともに括弧内にそのコードを併せて記した。以下は特記しない限り、27℃、3週間目の各培地における観察の結果である。
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−10(H6)、MK−9(H6)、MK−10(H8)及びMK−10(H4)でMK−9(H8)及びMK−9(H4)を少量有する。
16S rRNA遺伝子のうち約1200塩基配列を決定し、DNAデータベースに登録され公開されている細菌と比較した結果、その配列はポリモーフォスポラ ルブラ (Polymorphospora rubra)TT97−42と100%一致したことから、本菌株はポリモーフォスポラ ルブラ(Polymorphospora rubra)に分類することが妥当である。
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−10(H6)、MK−9(H6)、MK−10 (H8)及びMK−10(H4)である。全菌体糖としてガラクトースを含むアラビノースは含まない。気菌糸はほとんどの培地で着生しないがグルコース・肉エキス・ペプトン培地でわずかに着生し短い胞子鎖を形成する。コロニーは赤橙色を呈し、メラニン色素は産生しない。
これらの結果及び16S rRNA遺伝子の解析結果から、本菌株は2006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)に発表されたポリモーフォスポラ ルブラに分類される1菌種であると判断された。なお、本菌株はポリモーフォスポラ ルブラ(Polymorphospora rubra)K07−0510として、独立行政法人製品評価技術基盤機構 特許微生物寄託センターに寄託が受領されている(受領日2012年8月28日、受託番号 NITE BP−1411)。
スターチ2.4%、グルコース0.1%、ペプトン〔極東製薬工業(株)製〕0.3%、カツオエキス〔極東製薬工業(株)製〕0.3%、酵母エキス〔オリエンタル酵母工業(株)製〕0.5%、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、液体培地で培養したポリモーフォスポラ ルブラ (Polymorphospora rubra) K07−0510(受託番号 NITE BP−1411)を1本に1mL植菌し、27℃で7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〕1.0%、カツオ肉エキス〔極東製薬工業(株)製]0.3%、ドライ酵母〔JTフーズ(株)製〕0.3%、炭酸水素カルシウム0.4%からなる液体培地(pH7.0)が100mL入った500mL容三角フラスコに18本に各1mLずつ植菌し、27℃で9日間振盪培養した。
本発明のトレハンジェリンA及びトレハンジェリンBのin vitroでの抗光線過敏症活性を以下の通り調べた。
フェオフォルバイドA(フロンティア・サイエンティフィック社製)は,400μg/mLとなるようにジメチルスルホキシドに溶解し,さらにリン酸緩衝液生理食塩水(PBS,pH=7.4)で希釈し,5μg/mLのフェオフォルバイドa溶液を調製した。トレハンジェリンA又はトレハンジェリンBは、10mg/mLとなるようにPBSに溶解し、さらにPBSで適宜希釈し、サンプル溶液として使用した。赤血球はウサギ赤血球(日本生体材料センター社製)を用いた。赤血球懸濁液の調製は赤血球層に5倍量のPBSを加え、1,500rpm、4℃で10分間遠心分離し、2回洗浄した。上清を除去し,赤血球層にPBSを加えて5%(v/v)赤血球懸濁(RBC)を調製した。光酸化的溶血試験は96穴平底マイクロプレートに、5%RBC 100μL+PBS 100μL(バックグラウンド),5%RBC 100μL+フェオフォルバイドa 20μL+PBS 80μL、5%RBC 100μL+フェオフォルバイドa 20μL+トレハンジェリンA又はトレハンジェリンB溶液20μL(終濃度0.025%〜0.2%)を各3穴(n=3)ずつ準備し、シェイカー上で撹拌しながら光照射した。光源には500Wのアイランプ(岩崎電気)を用いた。光照射後、反応液を直ちに1,500rpm、4℃で5分間遠心分離し、上清100μLを別の96穴マイクロプレートに移し、570nmにおける吸光度をマイクロプレートリーダー(BIO−RAD社製)で測定した。さらに、5%RBC 100μLを遠心分離して得られた赤血球に,200μLの蒸留水を加えて完全に溶血させ,上清100μLの吸光度を測定して100%溶血の指標とした。溶血率は下式で算出した。
溶血率(%)=[吸光度(サンプル)−吸光度(バックグラウンド)]/[吸光度(フェオフォルバイドa)−吸光度(バックグラウンド)]×100
トレハンジェリンA及びトレハンジェリンBの細胞毒性を以下の方法により測定した。本試験では、ヒト胎児腎由来HEK−293細胞、ヒト膵臓腺癌由来Panc−1細胞、ヒト肺非小細胞癌由来H1299細胞及びヒト結腸癌由来HT−29細胞を用い、並びに、Cell Counting Kit−8(同人化学)を用いた。80%コンフルエントの細胞を血球計算盤で計数して細胞浮遊液を調製した。マルチピペットを用い100μLずつ、96穴マイクロプレートの各ウェルに細胞浮遊液を分注した。ブランク(バックグランド値)用のウェルには培地のみを100μL加えた。炭酸ガスインキュベーター内で72時間培養したのち、培地を吸引により除いた。新たに培地100μLを各ウェルに加え、培地交換を行った。培地で種々濃度に調製したトレハンジェリンA及びトレハンジェリンBを10μLずつ添加した。37℃の炭酸ガスインキュベーター内で24時間培養した。プレートを取り出し、Cell Counting Kit溶液を各ウェルに10μLずつ添加した。プレートを炭酸ガスインキュベーター内に戻し、2時間呈色反応を行った。マイクロプレートリーダーで450nmの吸光度を測定した。下記の式により細胞生存率を算出した。
細胞生存率(%)=[(As−Ab)/(Ac−Ab)]×100
As:検体の吸光度(細胞、トレハンジェリンA又はトレハンジェリンB、及び、Cell Counting Kit溶液の入ったウェル)
Ac:陰性対照の吸光度(細胞、及び、Cell Counting Kit溶液の入ったウェル:トレハンジェリン無し)
Ab:ブランク吸光度(培地、及び、Cell Counting Kit溶液の入ったウェル:細胞無し)
トレハンジェリンA及びトレハンジェリンBの抗菌活性は以下のとおりである。濾紙円板(アドバンテック社製、直径6mm)にトレハンジェリンAの5mg/mLのメタノール溶液をそれぞれ20μL浸漬し、一定時間風乾して溶媒を除去後、バチルス・サブチリス(Bacillus subtilis)ATCC 6633、ミクロコッカス・ルテウス(Micrococcus luteus)ATCC 9341、エシエリヒア・コリ(Escherichia coli)NIHJ KB 213、キサントモナス・カンペストリスpv.オリゼ(Xanthomonas campestris pv. oryzae)KB 88、カンジダ・アルビカンス(Candida albicans)KF1、ムコール・ラセモサス(Mucor racemosus)IFO 4581の試験菌含菌寒天平板に張り付け、バチルス・サブチリス(Bacillus subtilis)ATCC 6633、ミクロコッカス・ルテウス(Micrococcus luteus)ATCC 9341、エシエリヒア・コリ(Escherichia coli)NIHJ KB 213は37℃で24時間培養、キサントモナス・カンペストリスpv.オリゼ(Xanthomonas campestris pv. oryzae)KB 88、カンジダ・アルビカンス(Candida albicans)KF1、ムコール・ラセモサス(Mucor racemosus)IFO 4581は27℃で48時間培養後、濾紙円板の周りにできた生育阻止円の直径を測定した。
Claims (12)
- 請求項1〜4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ポリモーフォスポラ属に属する放線菌に属する微生物を培地で培養し、培養物中に請求項1〜4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1〜4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1〜4のいずれか1項に記載の化合物の製造方法。
- 請求項1〜4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、ポリモーフォスポラ ルブラ(Polymorphospora rubra)K07−0510(NITE BP−1411)株である請求項5記載の製造方法。
- ポリモーフォスポラ ルブラ(Polymorphospora rubra)K07−0510(NITE BP−1411)株。
- 請求項1〜4のいずれか1項に記載の化合物を有効成分とする膜脂質障害抑制剤。
- 請求項1〜4のいずれか1項に記載の化合物を有効成分とする酸化防止剤。
- 請求項1〜4のいずれか1項に記載の化合物を有効成分とする医薬組成物。
- 光線過敏症の治療薬又は予防薬である、請求項10に記載の医薬組成物。
- 請求項1〜4のいずれか1項に記載の化合物を有効成分とする光線過敏症の予防及び/又は改善のための化粧品組成物。
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