JP5933748B2 - ジテルペン化合物、美白剤およびジテルペン化合物の製造方法 - Google Patents
ジテルペン化合物、美白剤およびジテルペン化合物の製造方法 Download PDFInfo
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- JP5933748B2 JP5933748B2 JP2014548476A JP2014548476A JP5933748B2 JP 5933748 B2 JP5933748 B2 JP 5933748B2 JP 2014548476 A JP2014548476 A JP 2014548476A JP 2014548476 A JP2014548476 A JP 2014548476A JP 5933748 B2 JP5933748 B2 JP 5933748B2
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- stevia
- diterpene compound
- yeast
- solvent
- compound
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- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
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- 239000011734 sodium Substances 0.000 description 1
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- 125000001424 substituent group Chemical group 0.000 description 1
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- 150000003460 sulfonic acids Chemical class 0.000 description 1
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- 239000000516 sunscreening agent Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 229960000278 theophylline Drugs 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
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- 239000011732 tocopherol Substances 0.000 description 1
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 1
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- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
- C12P17/02—Oxygen as only ring hetero atoms
- C12P17/04—Oxygen as only ring hetero atoms containing a five-membered hetero ring, e.g. griseofulvin, vitamin C
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
- A61K8/4973—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with oxygen as the only hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/96—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution
- A61K8/97—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution from algae, fungi, lichens or plants; from derivatives thereof
- A61K8/9728—Fungi, e.g. yeasts
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/96—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution
- A61K8/97—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution from algae, fungi, lichens or plants; from derivatives thereof
- A61K8/9783—Angiosperms [Magnoliophyta]
- A61K8/9789—Magnoliopsida [dicotyledons]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
- A61Q19/02—Preparations for care of the skin for chemically bleaching or whitening the skin
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/92—Naphthofurans; Hydrogenated naphthofurans
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P5/00—Preparation of hydrocarbons or halogenated hydrocarbons
- C12P5/007—Preparation of hydrocarbons or halogenated hydrocarbons containing one or more isoprene units, i.e. terpenes
Landscapes
- Life Sciences & Earth Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Microbiology (AREA)
- Biotechnology (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Wood Science & Technology (AREA)
- Mycology (AREA)
- Zoology (AREA)
- Epidemiology (AREA)
- Birds (AREA)
- Botany (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Biochemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Engineering & Computer Science (AREA)
- Genetics & Genomics (AREA)
- Dermatology (AREA)
- Cosmetics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Furan Compounds (AREA)
Description
当該ジテルペン化合物の抽出溶剤としては、極性溶剤、非極性溶剤のいずれを使用することもでき、これらを混合して使用することもできる。抽出溶剤としては、水のほか、メタノール、エタノール、プロパノール、ブタノールなどの炭素数1〜12の分岐を有していても良いアルコール類、エチレングリコール、プロピレングリコール、ブチレングリコールなどの多価アルコール類、アセトン、メチルエチルケトンなどのケトン類、酢酸メチル、酢酸エチルなどのエステル類、テトラヒドロフラン、ジエチルエーテルなどのエーテル類、ポリエチレングリコールなどのポリエーテル類、ジクロロメタン、クロロホルム、四塩化炭素などのハロゲン化炭素類、ヘキサン、シクロヘキサン、石油エーテルなどの炭化水素類、ベンゼン、トルエンなどの芳香族炭化水素類、ピリジン類、超臨界二酸化炭素、油脂、ワックスその他のオイル類がある。これらは単独でも組み合わせて用いてもよい。
本発明では、アルコールを使用することが好ましい。アルコールとしては、炭素数1〜5の一価アルコールが好適である。この中でも、特に好ましくはエタノールである。アルコールは、水を含む含水アルコールであってもよい。含水アルコールを使用する場合のアルコール濃度は、30〜99(v/v)%であることが好ましく、より好ましくは50〜90(v/v)%である。アルコールまたは含水アルコールによる抽出は、上記ステビア酵母発酵物1質量部(乾燥重量)に対して0.1〜100質量部、好ましくは1〜50質量部の溶剤を添加し、温度5〜35℃で3〜30日間の浸漬が好適である。
(1)ステビア酵母発酵物の調製
日本国北海道産のステビア植物(学名:Stevia rebaudiana)の茎と葉とを乾燥させた乾燥ステビア植物を約1cm以下に粉砕した。粉砕ステビア植物2,000gに酵母菌(Saccharomyces)45g、水4,500gを加えて温度25〜35℃の条件下に撹拌すると、発酵が開始した。これを温度25〜35℃にて14日間静置、発酵させた。発酵物から甘味が消失しており、これを発酵終期とした。上記の発酵物を温度25〜35℃にて10日間乾燥させ、酵母発酵を停止した。
10質量倍量の28.5(v/v)%エタノールに前記乾燥発酵物の全量を加え、穏やかに攪拌しながら数日、常温にて浸潤させた。浸潤後、140メッシュ程度の大きさでろ過した。得られたろ液を60℃ほどで減圧濃縮(60mmHg)し、ダイヤイオンHP20カラムに吸着させた後に85.5%含水エタノール液で溶出し、これを含水エタノール抽出液とした。
上記含水エタノール抽出液の溶媒を留去した抽出物(40g)をステビア発酵エキスとし、これにクロロホルム1000mL加え、温度23〜28℃(室温)で抽出した。残渣をろ過により除き、クロロホルム層を分取し、溶媒を留去したものをクロロホルム抽出液(12.1g)とした。
上記(3)で得たクロロホルム抽出液(12.1g)を、下記分離条件(1)に示すシリカゲルカラムクロマトグラフィーより10の画分に分離した。
分離条件(1):
カラム:内径7cm、高さ22cm
充填物:シリカゲル(KANTO CHEMICAL社製、Silica Gel 60N(球状,中性)、粒子径63〜210μm)、320g
溶出溶媒:クロロホルム:メタノール=100:1→50:1→30:1→15:1→7:1→5:1→0:1の混合溶液を溶離液とし、順次カラムに各溶媒1000mLずつ流し、200mLずつ分取した。
分取物:分取した各フラスコ内容物についてTLC(MERCK Silica Gel 60 F254)を行った。TLCは、クロロホルム:メタノール=10:1の溶媒で展開した後、50%硫酸を噴霧し、110℃で加熱して検出した。検出結果に基づき、スポットの近似するa〜jの10の画分に分画した。各画分の収量を図1に示す。
分離条件(2):
カラム:内径5.2cm、高さ20cm
充填物:シリカゲル(KANTO CHEMICAL社製、Silica Gel 60N(球状,中性)、粒子径63〜210μm)、160g
溶出溶媒:n−ヘキサン:アセトン=7:1→4:1→2:1→1:1→0:1の混合溶液を溶離液とし、順次カラムに各溶媒700mLずつ流し、150mLずつ分取した。
分取物:分取した各フラスコ内容物についてTLC(MERCK Silica Gel 60 F254)を行った。TLCは、クロロホルム:メタノール=10:1の溶媒で展開した後、50%硫酸を噴霧し、110℃で加熱して検出した。検出結果に基づき、スポットの近似するd−1〜d−6の6つの画分に分画した。d−4画分は沈殿が発生したためこれを濾取した。d−4画分のろ液(d−4−fil.)とd−5画分とには、TLCのRF値が近似するスポットが確認されたためd−4−fil.とd−5とを合一した。この画分をd−(4,5)と称する。d−(4,5)の収量は、380.9mgであった。)とし、主スポットを単離するために以下の分離3を行った。
分離条件(3):
カラム:内径1.0cm、高さ21cm
充填物:シリカゲル(YMC GEL ODS−A、12nm、S−75μm、AA12S75)、16g
溶出溶媒:水:メタノール=5:5(100 mL)→4:6(100 mL)→3:7(100 mL)→2:8(100 mL)→0:1(100 mL)の混合溶液を溶離液とし、順次カラムに各溶媒700mLずつ流し、20mLずつ分取した。
分取物:分取した各フラスコ内容物についてTLC(MERCK Silica Gel 60 F254)を行った。TLCは、水:メタノール=2:8の溶媒で展開した後、50%硫酸を噴霧し、110℃で加熱して検出した。検出結果に基づき、スポットの近似するd−(4,5)−1からd−(4,5)−7の7つの画分に分画した。d−(4,5)−3に単一スポットが認められ、この画分の溶媒を留去すると白色粉末が得られた(29.1mg)。この化合物をCompound VIIとした。
前記白色粉末について、1H−NMRおよび13C−NMRを測定した。結果を表1に示す。1H−NMRおよび13C−NMRのシグナルパターンより、炭素数16であり、すでにステビアより単離報告のあるステレビンAとA環、B環は同じ構造を有すると推定されるが、C環以降の構造が異なっていると推定された。そこで、HMQCとHMBCの相関を詳細に検討したところ、表1に示すHMBC相関が認められ、最終的に、下記式(VII)に示されるジテルペン化合物と決定した。なお、表1の下部に当該化合物の基本骨格と位置番号とを示す。
実施例1で得た化合物について、下記測定方法に従って、細胞数当たりのメラニン産生量および対照に対するメラニン産生率の算出方法に従って、B16メラノーマ細胞生存数を計測し、溶液当たりのメラニン産生量を測定し、これにより生細胞当たりのメラニン産生量(ng/104cells)を算出した。また、対照の生細胞当たりのメラニン産生量(ng/104cells)に対する式(VII)の化合物によるメラニン濃度を算出した。結果を表2に示す。なお、化合物の濃度は100μMとし、比較のため1000μMのコウジ酸も同様に処理した。
細胞数当たりのメラニン産生量および対照に対するメラニン産生率の算出方法は、以下に従った。
6ウェルプレートで一晩培養を行ったB16マウスメラノーマ細胞の培地を除去し、各ウェルにテオフィリン(最終濃度として10mM)、目的濃度のサンプルを加えた10%−FBS−DMEM培地(サンプル溶解のためのDMSOの最終濃度は0.1%)を2mLずつ加えた。
37℃、5%CO2存在下で72時間培養した後、培地を除去し、pH7.4等張リン酸緩衝液(PBS)で細胞を2回リンスした。各ウェルに0.25%トリプシン−EDTA溶液を200μlずつ加えてトリプシン処理をし、培地を1mlずつ添加して全量を15ml遠沈管に回収した。細胞液を1000rpm、5分間遠心分離し、上清を除去した細胞にPBSを2ml加えて再懸濁させ、このうち200μlをマイクロチューブに移し、セルカウンター(ミリポアコーポレーション製、Sceptor(登録商標))を用いて細胞数を計測した。残りの細胞液を再び同条件で遠心分離し上清を取り除き、1MのNaOHを1ml添加して80℃の水浴で1時間処理した。細胞融解液の濃度の吸光度をImmuno Mini NJ−2300(コスモバイオコーポレーション製)を用いて波長475nmにて測定し、細胞数あたりのメラニン産生量を算出した。検量線には1M NaOHに融解した合成メラニン(シグマアルドリッチコーポレーション製)を用いた。データは対照(1mMテオフィリン添加培地適用)群の値を100%とした細胞数あたりのメラニン産生率及び生細胞数率で表し、それぞれn=3の平均値±標準偏差にて表した。また、統計学的解析には分散分析(ANOVA)及び多重比較検定(Dunnet法)を用いた。
本発明は2012年11月26日に出願された日本国特許出願2012−257994号に基づく。本明細書中に日本国特許出願2012−257994号の明細書、特許請求の範囲、図面全体を参照として取り込むものとする。
Claims (3)
- 下記式(VII)で示されるジテルペン化合物、またはそれらの医学的に許容可能な塩。
- 下記式(VII)で示されるジテルペン化合物、またはそれらの医学的に許容可能な塩からなる美白剤。
- ステビア植物またはステビア植物抽出物を酵母菌発酵してステビア酵母菌発酵物を調製し、
前記ステビア酵母菌発酵物から下記式(VII)で示されるジテルペン化合物を回収することを特徴とする、前記ジテルペン化合物の製造方法。
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WO2008126638A1 (ja) * | 2007-04-06 | 2008-10-23 | Shalom Co., Ltd. | 抗ヒスタミン物質およびその製造方法 |
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JPH0977636A (ja) * | 1995-09-14 | 1997-03-25 | Mikimoto Pharmaceut Co Ltd | 美白化粧品 |
JPH11335233A (ja) * | 1998-05-22 | 1999-12-07 | Ichimaru Pharcos Co Ltd | メラニン生成抑制剤及び化粧料組成物 |
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