JP2011173803A - コラーゲン産生促進剤 - Google Patents
コラーゲン産生促進剤 Download PDFInfo
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- JP2011173803A JP2011173803A JP2010037089A JP2010037089A JP2011173803A JP 2011173803 A JP2011173803 A JP 2011173803A JP 2010037089 A JP2010037089 A JP 2010037089A JP 2010037089 A JP2010037089 A JP 2010037089A JP 2011173803 A JP2011173803 A JP 2011173803A
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Abstract
Description
項2:項1に記載のコラーゲン産生促進剤を含有する化粧用組成物。
項3:項1に記載のコラーゲン産生促進剤を含有する細胞培養液用組成物。
項4:項1に記載のコラーゲン産生促進剤を含有する創傷治癒用医薬組成物。
本発明のコラーゲン産生促進剤は、下記一般式(1)で表される化合物を有効成分とする:
一般式(1)
4-((E)-3-ヒドロキシ-1-プロペニル)フェニルアセテート(4-((E)-3-Hydroxyprop-1-enyl)phenyl
acetateもしくはp-acetoxy cinnamic alcohol、以下、HPAとも称する)、
2-アセトキシ-4-((E)-3-ヒドロキシ-1-プロペニル)フェニルアセテート(2-Acetoxy-4-((E)-3-hydroxyprop-1-enyl)phenyl
acetate、以下、2,4-HPAとも称する)、
2-ヒドロキシ-4-((E)-3-ヒドロキシ-1-プロペニル)フェニルアセテート(2-Hydroxy-4-((E)-3-hydroxyprop-1-enyl)phenyl
acetate、以下、2H,4-HPAとも称する)、
2-アセトキシ-4-((E)-3-ヒドロキシ-1-プロペニル)フェノール(2-Acetoxy -4-((E)-3-hydroxyprop-1-enyl)phenol、以下、2,4H-HPAとも称する)、
4-((E)-3-ヒドロキシ-1-プロペニル)-2-メチルフェニルアセテート(4-((E)-3-hydroxyprop-1-enyl)-2-methylphenyl
acetate、以下、2M,4-HPAとも称する)、
3-アセトキシ-4-((E)-3-ヒドロキシ-1-プロペニル)フェニルアセテート(3-Acetoxy-4-((E)-3-hydroxyprop-1-enyl)phenyl
acetate、以下、3,4-HPAとも称する)
3-ヒドロキシ-4-((E)-3-ヒドロキシ-1-プロペニル)フェニルアセテート(3-Hydroxy-4-((E)-3-hydroxyprop-1-enyl)phenyl
acetate、以下、3H,4-HPAとも称する)、
3-アセトキシ-4-((E)-3-ヒドロキシ-1-プロペニル)フェノール(3-Acetoxy -4-((E)-3-hydroxyprop-1-enyl)phenol、以下、3,4H-HPAとも称する)、
4-((E)-3-ヒドロキシ-1-プロペニル)-3-メチルフェニルアセテート(4-((E)-3-hydroxyprop-1-enyl)-3-methylphenyl
acetate、以下、3M,4-HPAとも称する)、などが含まれる。
本発明の化粧用組成物は、上記コラーゲン産生促進剤を含有することを特徴とする。
以下、「TPEN」とも称する)及びACAなどのコラーゲン産生能を向上させ得る化合物、或いはビタミンC又はその誘導体などのコラーゲン産生を増強させる化合物を配合することもできる。これらの他の成分の種類及び量は、本発明の効果を阻害しない範囲で適宜設定することができる。
本発明の細胞培養用組成物は、上記コラーゲン産生促進剤を含有することを特徴とする。
本発明の創傷治癒用医薬組成物は、上記これー現産生促進剤を含有することを特徴とする。本発明の医薬組成物は、皮膚表面などにおける創傷の治癒を促進するために利用される。
HPAを以下に示す方法に従って調製した。なお、同様の方法で出発原料に4-Iodo-3-methylphenol又は4-Iodo-2-methylphenolを用いることにより、2M,4-HPA又は3M,4-HPAを合成することが可能である。
(Wako,3 g, 13.6 mmol) を乾燥CH2Cl2に溶解し、Et3N (Wako, 2.75 g, 2 equiv)、4-dimethylaminopyridine
(Wako, 83 mg, 0.05 equiv)、Ac2O (Wako, 0.93 g, 2 equiv) を加え、室温で一晩撹拌した。溶媒を減圧留去し、クロロホルムに溶解した後、1 M HCl水溶液で洗浄した。有機層を無水硫酸ナトリウムで乾燥後、濃縮し、シリカゲルカラムクロマトグラフィー(展開溶媒:Hexane : EtOAc = 10 : 1)にて精製を行い、4-Iodophenyl acetateを得た (3.3 g, 92.5%)。
acetate (500 mg, 1.91 mmol) をDMF(脱水,Wako)4 mLに溶解し、allyl alcohol (Wako, 260 mL, 3 equiv), AgOAc (Wako, 318 mg, 1 equiv), Ph3P
(Wako, 50 mg, 0.1 equiv), Pd(OAc)2 (Wako, 21.4 mg, 0.05 equiv) を加え、N2下、70℃で一晩撹拌した。セライトで沈殿物を除去し、EtOAcを加え、1 M HCl、続いて飽和NaHCO3水溶液で洗浄した。有機層を 無水硫酸ナトリウムで乾燥後、濃縮し、シリカゲルカラムクロマトグラフィー(展開溶媒:Hexane : EtOAc = 2 : 1)にて精製を行い、得られた粗結晶をHexane-EtOAc (5 : 1) より再結晶して4-((E)-3-hydroxyprop-1-enyl)phenyl acetate(HPA)を得た (150 mg,
41%)。
mmol) を20%エタノール含有水溶液80 mLに溶解し、80℃で2日間撹拌した。溶媒を濃縮後、凍結乾燥を行い、残留物をシリカゲルカラムクロマトグラフィー(展開溶媒:Hexane : EtOAc = 2 : 1)にて分離精製を行った。わずかに赤みがかった結晶をHexane-EtOAc (5 : 1) より再結晶して無色の結晶を得た(収量 87 mg)。
(JEOL)
HRMS (CI, direct) calcd for C11H13O3,
[M+H]+ 193.0865; found, 193.0873.
NMR: AVANCE 300N
(BRUKER)
1H NMR (300 MHz, MeOD); d 2.26 (s, 3 H, a), 4.22 (dd, 2 H, J
= 1.5, 5.4 Hz, b), 6.34 (dt, 1 H, J = 15.9, 5.4 Hz, c), 6.61
(dd, 1 H, J = 1.5, 15.9 Hz, d), 7.04 (d, 2 H, J = 8.7 Hz, e),
7.43 (d, 2 H, J = 8.7 Hz, f).
2,4-ACA (240 mg, 0.82 mmol) を20%エタノール含有水溶液80 mLに溶解し、80℃で2日間撹拌した。溶媒を濃縮後、凍結乾燥を行い、残留物をシリカゲルカラムクロマトグラフィー(展開溶媒:CHCl3 : MeOH = 10 : 1)にて分離精製を行い、2,4-HPA(収量50 mg)及び2H,4-HPA,
2,4H-HPA混合物(存在比6 : 4, 収量25 mg)を得た。この概要を式3に示す
1H NMR (300 MHz, CDCl3); d 2.29 (s, 3 H), 2.33 (s, 3
H), 2.45 (brs, 1 H), 4.29 (dd, 2 H, J = 1.5, 5.4 Hz), 6.32 (dt, 1 H, J
= 15.9, 5.4 Hz), 6.59 (dt, 1 H, J = 15.9, 1.5 Hz), 6.88 (d, 1 H, J
= 2.1 Hz), 6.98 (dd, 1 H, J = 8.7, 2.1 Hz), 7.54 (d, 1 H, J = 8.7 Hz).
以下の手法で、化合物のコラーゲン産生促進作用を評価した。
ヒト正常皮膚由来線維芽細胞(CCD-1059SK、大日本製薬株式会社)を、10% FBS(fetal bovine serum)を含むEMEM培地で3〜6回継代培養した。次いで、細胞数が1 x 106個になるようにカルチャースライド(Culture slide: Falcon社製)に調製し、10% FBSを含むEMEM培地で24時間培養して、細胞をスライドに固定させ、更に、細胞周期を合わせるためにEMEM培地のみで24時間培養した。その後、10% FBSを含むEMEM培地に交換し、同時に上記の被験化合物を添加、24時間培養して、以下に示す各サンプル群を調製した。被験化合物としては、上述の方法で調製したHPAおよび2,4−HPAを用いた。また比較のために、類似化合物であるラセミACA(図6参照)を用いた。また、コントロールとして被験化合物を添加しない群を調製した。
サンプル1)コントロール(化合物無添加)
サンプル2)HPA0.1μM添加
サンプル3)HPA1.0μM添加
サンプル4)2,4−HPA0.1μM添加
サンプル5)2,4−HPA1.0μM添加
サンプル6)ラセミACA 0.1μM添加(比較例1)
サンプル7)ラセミACA 1.0μM添加(比較例2)
(1)で調製したサンプル群について、次の手順により、コラーゲンの産生量を免疫組織化学的に解析した。
peroxidase-labelled streptavidine-biotine complex(DAKO社製)400倍希釈液)による反応を30分間行った。PBS溶液で5分間、3回洗浄した後、DAB(3,3-diaminobenzidin
tetra-hydrocheloride)溶液を5分間反応させ、peroxidase発色反応を行った。PBS溶液で5分間、3回洗浄した後、水溶性封入剤で封入して、標本を作製した。得られた標本における陽性反応(I型コラーゲンの発現)箇所における染色強度について画像解析を行った。
HPAの水溶液中での安定性について、分解前の前駆体であるACAを用いて評価を行った。まず、ACAの水溶液中での安定性を調べるため、加熱前の (S)-もしくは (R)-ACAのストック溶液を4日間、室温保存し、下記の条件で逆相HPLC分析を行った。
カラム:
SHODEX シリカ5C8 4E(粒径5 mm, 4.6 mmφ´ 250 mm)
カラム温度:40℃
移動相:10 mM KH2PO4/アセトニトリル=30/70
流速: 1 mL/min
測定波長:210 nm
逆相HPLC分析の結果を図3に示す。その結果、室温でもACAは水溶液中では4日間で完全に分解されていることが確認された。
ACAはアポトーシスの誘導能やNF-kBの活性化抑制など様々な生理活性をもつことが知られている。コラーゲン産生亢進効果と同様、HPAもこれらの生理活性を有するかどうかを評価した。
各種ACAは5, 10, 20 mM、HPAは5, 10, 20, 40 mM DMSOもしくはエタノール溶液となるように調製し、ストック溶液とした。使用時は培養液に対して1,000倍希釈となるように添加した。
ヒト子宮頚癌由来HeLa細胞(0.5 x 105 cells/mL、10% FBS含有RPMI1640)を96穴プレートに100 mLずつ播種し、24時間培養した後、所定濃度のACAもしくはHPAを含む培養液に交換し、37℃で22時間インキュベートした。WST試薬(Cell Counting Kit-8, DOJINDO製)を10 mLずつ添加した後、96穴マイクロプレートリーダーで620 nm及び450 nmの吸光度差を測定し、未処理の細胞を生存率100%として細胞生存率を評価した。
NF-kBが活性化される際、その阻害タンパクであるIkBaが速やかに分解されることが知られている。よってIkBa 分解を指標にNF-kBの活性化抑制を評価した。マウスマクロファージ様RAW262.7細胞(0.5 x 106 cells/mL、10% FBS含有RPMI1640)を30 mm dishに1 mLずつ播種し、24時間培養した。
produced in rabbit, Sigma製, 1,000倍希釈)を用いて一次抗体反応を60分間行った。0.1% Tween 20 TBS溶液(pH 7.5)で10分間、2回洗浄した後、アルカリホスファターゼ標識抗ラビットIgG抗体(Anti-rabbit IgG antibody, alkaline phosphatase conjugated, Sigma製, 5,000倍希釈)を用いて二次抗体反応を60分間行った。0.1% Tween 20
TBS溶液(pH
7.5)溶液で10分間、2回洗浄した後、NBT-BCIP溶液(Sigma製)を加えて発色反応を行い、IkBaの分解を確認した。
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