JP5943833B2 - 新規化合物、美白剤および前記化合物の製造方法 - Google Patents
新規化合物、美白剤および前記化合物の製造方法 Download PDFInfo
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- JP5943833B2 JP5943833B2 JP2012288811A JP2012288811A JP5943833B2 JP 5943833 B2 JP5943833 B2 JP 5943833B2 JP 2012288811 A JP2012288811 A JP 2012288811A JP 2012288811 A JP2012288811 A JP 2012288811A JP 5943833 B2 JP5943833 B2 JP 5943833B2
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- compound
- stevia
- lactic acid
- acid
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Images
Landscapes
- Cosmetics (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
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Description
当該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、含水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。含水アルコールとしては、アルコール濃度が20〜99(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。含水アルコールによる抽出は、上記ステビア乳酸産生菌発酵物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)ステビア乳酸産生菌発酵物の調製
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2kgに乳酸産生菌(Bacillus coagulans)45g、水4,500gを加えて温度25〜30℃の条件下に撹拌すると、発酵が開始した。これを温度25〜30℃、14日間放置した。発酵物から甘味が消失しており、これを発酵終期とした。上記した発酵物を室温で2週間乾燥させ、乳酸菌発酵を停止した。
乾燥発酵物の全量に対し、10質量倍量の28.5(v/v)%エタノールを添加し、2週間、常温で浸潤し、ついで150〜200メッシュのステンレス篩でろ過した。ろ液を60℃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66.5%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除去し、この抽出物にクロロホルムを3質量倍添加し、温度23〜28℃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、溶媒を除去したものをクロロホルム抽出物とした。
上記(3)で得たクロロホルム抽出物の1.2g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8つの画分に分離した。
分離条件(1):
カラム:内径2.5cm、高さ15cm
充填物:シリカゲル(KANTO CHEMICAL社製、Silica Gel 60N(球状,中性)、粒子径63〜210μm)、45g、
溶出溶媒:クロロホルム:メタノール=100:1(500mL)→50:1(500mL)→20:1(300mL)→7:1(300mL)→0:1(300mL)の混合溶液を溶離液とし、250mLずつ分取した。
分取物:上記溶出溶媒毎に第1〜8の8つの画分に分画した。各画分の収量を図1に示す。
分離条件(2):
カラム:内径1cm、高さ15.5cm
充填物:逆相シリカゲル(YMC GEL ODS−A、12nm、S−75μm、AA12S75)、12g、
溶出溶媒:水:メタノール=4:6(100mL)→3:7(100mL)→0:1(100mL)の混合溶液を溶離液とし、順次カラムに流し、20mLずつ分取した。溶出した各画分についてTLC(MERCK Silica Gel 60 RP−18)を行った。TLCは、水:メタノール=3:7の溶媒で展開後、50%硫酸を噴霧し、110℃で加熱して検出した。TLCの結果に基づき、第5−1から5−4の4つに分画した。
分離条件(3):
HPLC用カラム:Senshu Pak PEGASIL Silica SP−100,内径1cm、長さ25cm
検出:254nm
流速:1mL/min
溶出溶媒:クロロホルム:メタノール=40:1の混合溶液を溶離液とし、一定量ごとに溶出画分を得た。得られた各画分についてTLC(MERCK Silica Gel 60 F254)を行った。TLCは、クロロホルム:メタノール=5:1の溶媒で展開後、50%硫酸を噴霧し、110℃で加熱して検出した。その結果、リテンションタイム約42分に溶出した画分がTLC上単一スポットであり、本化合物とした。本化合物の収量は0.7mgであった。
本化合物は、pos. HRFABMS m/z 295.2276 ([M+H]+,calcd for 295.2195)より分子式をC18H30O3と決定した。
次いで、本化合物について、1H−NMRおよび13C−NMRを測定したところ、これらのシグナルからもC18H30が支持された。1H−NMRおよび13C−NMRのシグナルパターンから、ステビアより単離報告のあるステレビンAと類似する構造が推定された。
そこで、異核間多量子コヒーレンス相関分光法(HMQC)、異核間多結合相関分光法(HMBC)の相関を測定した。結果を表1に示す。これらの結果に基づいて、本化合物を、(E)−4−((2,4,8a)−2,4−dihydroxy−2,5,5,8a−tetramethyldecahydronaphthalen−1−yl)but−3−en−2−oneと決定した。1H−NMRの詳細な検討により、本化合物の相対立体配置を決定した。表1の下部に当該化合物の相対立体配置と位置番号とを示す。本化合物の構造を下記式(I)に示す。
実施例1で得た式(I)で示される化合物について、下記測定方法に従って、メラニン産生量、生細胞数、生細胞数当たりのメラニン産生、および対照に対するメラニン産生率を算出した。これらの結果を表2に示す。なお、式(I)で示される化合物の濃度は、0.001%とした。
メラニン産生量、生細胞数、生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したB16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の濃度が1mM、式(I)の化合物の濃度が0.001%、DMSOの濃度が0.5%となるように調製した培養培地を全量が2ml/ウェルとなるように添加した。
37℃、5%CO2存在下で72時間培養した後に培地を除去し、pH7.4のリン酸緩衝液(PBS)で2回、細胞をリンスした。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、上記培地を1mlずつ添加して細胞液全量を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(BIO−RAD社製、TC10)を用いて生細胞数を計測した。
残りの細胞液を再び同条件で遠心分離し上清を除き、1MのNaOHを500μl添加して80℃の水浴で30分間処理した。NaOHによる細胞融解液の波長475nmの吸光度を蛍光マイクロプレートリーダー(TECAN社製、infiniteM1000)を用いて測定し、溶液当たりのメラニン産生量を測定した。検量線には1M NaOHに溶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。上記した溶液当たりのメラニン産生量と前記生細胞数とから、生細胞数当たりのメラニン産生量を算出した。これらはいずれも、n=2の平均値にて表した。
式(I)の化合物を添加せず、1mMのテオフィリンと0.5%のDMSOとからなる培地を対照培地として上記と同様に操作して対照群とした。また、対照群の生細胞当りのメラニン産生量を100%とし、生細胞数あたりのメラニン産生率を算出しして、対照に対するメラニン濃度(%)を評価した。
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