JP2020519622A - イソトレチノインとペプチドの結合体 - Google Patents
イソトレチノインとペプチドの結合体 Download PDFInfo
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- JP2020519622A JP2020519622A JP2019561984A JP2019561984A JP2020519622A JP 2020519622 A JP2020519622 A JP 2020519622A JP 2019561984 A JP2019561984 A JP 2019561984A JP 2019561984 A JP2019561984 A JP 2019561984A JP 2020519622 A JP2020519622 A JP 2020519622A
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- isotretinoin
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Abstract
Description
但し、下記実施例は本発明を例示するためのものに過ぎず、本発明の内容が下記実施例によって限定されるものではない。
<1−1>配列番号1のペプチドの合成
700mgのクロロトリチルクロリド樹脂(Chloro trityl chloride resin;CTL resin,Nova biochem[0064]CatNo.01−64−0021)を反応容器に入れ、メチレンクロリド(MC)10mlを加えて3分間撹拌した。溶液を除去し、ジメチルホルムアミド(DMF)10mlを入れて3分間の間撹拌した後、再び溶媒を除去した。反応器に10mlのジクロロメタン溶液を入れ、Fmoc−Cys(trt)−OH(Bachem、Swiss)200mmole及びジイソプロピルエチルアミン(DIEA)400mmoleを入れた後、撹拌してよく溶かし、1時間の間撹拌しながら反応させた。反応後、洗浄してメタノールとDIEA(2:1)をDCM(dichloromethane)に溶かし、10分間反応させて過量のDCM/DMF(1:1)で洗浄した。溶液を除去し、ジメチルホルムアミド(DMF)を10ml入れて3分間撹拌した後、再び溶媒を除去した。脱保護溶液(20%のピペリジン/DMF)10mlを反応容器に入れ、10分間常温で撹拌した後、溶液を除去した。同量の脱保護溶液を入れて再び10分間反応を維持した後、溶液を除去してそれぞれ3分ずつDMFで2回、MCで1回、DMFで1回洗浄してMet−CTL樹脂を製造した。
ペブタイト反応器に脱保護されたペプチド(1mmol)とジメチルホルムアミド(DMF)10mlを入れ、1−ヒドロキシベンゾトリアゾール(HOBt)270mg(2.0equiv.)とヘキサフルオロリン酸(ベンゾトリアゾール−1−イルオキシ)トリピロリジノホスホニウム(PyBOP)1.04g(2.0equiv.)とイソトレチノイン277mg(2.0equiv.)を添加して30分間反応させた。N,N−ジイソプロピルエチルアミン(DIEA)388mg(3equiv.)を添加し、常温で2〜4時間の間反応させ、ジエチルエーテル10ml(10mmol)を用いて再結晶をして濾過後、ハイブリッドペプチドを収得した。
前記実施例<1−2>で製造されたイソトレチノイン−ペプチド化合物とイソトレチノインをそれぞれ10mg/mlの濃度で蒸溜水に溶解させた。
その結果、イソトレチノイン自体は水に殆ど溶解されないのと対照的に、本発明のイソトレチノイン−ペプチド化合物は、いずれも水に完全に溶解されることを確認した(図1)。
実施例<1−2>で合成された本発明のイソトレチノイン−ペプチド化合物が皮脂形成に連関された信号伝達遺伝子の発現に及ぶ影響を確認するため、RT−PCR分析を行った。具体的に、セボサイトに刺激源として100μMのアラキドン酸を処理して刺激させた後、1又は10μMの本発明のイソトレチノイン−ペプチド化合物又はイソトレチノインを処理し、24時間培養した後、培養された細胞から下記のような方法でRNAを分離した後、下記表2に記載されたプライマーを用いて前記化合物が皮脂の形成に関与する信号伝達分子であるcEBPα、PPARγ及びSREBP1cの発現に及ぶ影響を確認した。RNA抽出キット(Qiagen RNeasy kit)を用いて細胞の全体RNAを抽出し、RNAから単一本DNAを合成するために3μgRNA、ランダムヘキサマー2μgとDEPCを処理した水を加え、65℃で5分間反応させた。5×ファーストストランドバッファ5×ファーストストランドバッファー、0.1 M DTT、10mM dNTP、逆転写酵素を入れて総20mlとなるようにし、42℃で1時間の間反応させた。再び95℃で5分間加熱した後、蒸溜水20mlを加えて最終40mlのcDNAを作った。ポリメラーゼ連鎖反応(PCR)は、3μl cDNA、cEBPα、PPARγ、SREBP1c及びGAPDHの各遺伝子に特異的な、下記表2に示した10pmoleのプライマー、10×Tagバッファ、10mM dNTP及びi−Tag DNA重合酵素を混合して行った。PCR条件は94℃で30秒、55〜56℃で30秒、72℃で30秒で反応させた。サイクル数の遺伝子は、PCR結果が指数的に増幅し得る条件で分析した。5mlのPCR産物を得て1%のアガローズゲルに電気泳動し、臭化エチジウム(ethidium bromide)で染色して皮脂形成信号伝達遺伝子であるcEBPα、PPARγ、SREBP1cのmRNAレベルを確認した。
実施例<1−2>で合成された本発明のイソトレチノイン−ペプチド化合物が脂肪形成に連関された遺伝子の発現に及ぶ影響を確認するため、RT−PCR分析を行った。具体的に、3T3 L1脂肪前駆細胞を2×104細胞/ウェルで24ウェルプレートに接種して培養した後、0.5mM IBMX、0.25μMデキサメタゾン、1μg/mlインシュリンが含まれた分化培地に交換し、10μMの本発明のイソトレチノイン−ペプチド化合物又はイソトレチノイン10μMとともに10日間培養した後、前記化合物が脂肪形成に関与する遺伝子であるPPARγ、ACC及びaP2の発現に及ぶ影響を確認した。このため、PPARγ、ACC及びaP2に特異的なプライマーとして下記表3で示したプライマーを用いたことを除いては、前記実験例2と同一の方式でRT−PCRを行った。
実施例<1−2>で合成された本発明のイソトレチノイン−ペプチド化合物がニキビ菌によって誘導される炎症に及ぶ影響を確認するため、RT−PCR分析を行った。具体的に、6ウェルプレートの各ウェルにHaCaT角質細胞を300,000細胞ずつ接種した後、10%FBSを含むDMEM培養液(Gibco、米国)で24時間の間、37℃、5%CO2条件下で培養した。新鮮な培地に交換した後、50μg/mlのニキビ菌(P.acnes)、50μMのサリチル酸及び10μM又は50μMのCG−Dinflaを処理し、処理されたニキビ菌に本発明のイソトレチノイン−ペプチド化合物と良性対照群として用いられたイソトレチノインを1又は10μMの濃度で処理した後、前記と同一の条件で24時間の間培養した後、前記化合物が炎症形成に関与する遺伝子であるIFN−γ、IL−1β、IL−6、IL−17A及びTNF−αの発現に及ぶ影響を確認した。このため、IFN−γ、IL−1β、IL−6、IL−17A及びTNF−αに特異的なプライマーとして下記表4に示したプライマーを用いたことを除いては、前記実験例2と同一の方式でRT−PCRを行った。
実施例<1−2>で合成された本発明のイソトレチノイン−ペプチド化合物がニキビ菌によって誘導されるMMPの活性に及ぶ影響を確認した。具体的に、HaCaT角質細胞を培養後、1又は10μMの本発明のイソトレチノイン−ペプチド化合物又はイソトレチノインを細胞に前処理し、30分後に刺激剤であるニキビ菌(P.acnes)を処理した。48時間培養した後、培養液を収去し、前記培養液とザイモグラフィー(zymography)バッファ(シグマアルドリッチ)を1:1で反応させた後、20μlの反応液を8%SDS−PAGE(sodium dodecylsulfate−polyacrylamide gel electrophoresis)(10% gelatin)で電気泳動した。その後、ゲルを0.1%Triton X−100バッファ(シグマアルドリッチ)で10分間3回洗浄し、TNCBバッファ(シグマアルドリッチ)で活性化させ、クマシブルー染色した後、バンドの強度を測定した。
実施例<1−2>で合成された本発明のイソトレチノイン−ペプチド化合物がニキビ菌によって誘導される細胞内の活性酸素種(reactive oxygen species、ROS)の形成に及ぶ影響を確認した。具体的に、セボサイトを1×106細胞/ウェルで6ウェルプレートに接種し、一晩の間培養した。本発明のイソトレチノイン−ペプチド化合物又はイソトレチノインを細胞に前処理して30分後に刺激剤であるニキビ菌(P.acnes)を100ug/mlの濃度で処理し、48時間の間培養した。DCF−DHを処理して30分後、FACSを用いて蛍光の程度に酸化活性を測定した。
脂肪細胞は、余分のエネルギーを脂肪滴(lipid droplet)中に中性脂肪の形態で貯蔵するが、エネルギーが必要となると、脂肪トリグリセリドリパーゼ(adipose triglyceride lipase)とHSL、モノグリセリドリパーゼ(monoglyceride lipase)のような酵素により脂肪酸とグリセロールに分解され、エネルギーを生産したり細胞信号の伝達又は脂肪合成に用いる。よって、本発明者は、実施例<1−2>で合成された本発明のイソトレチノイン−ペプチド化合物が脂肪分解(lipolysis)に及ぶ影響を確認するため、ガラスグリセロールの放出及び細胞内のトリグリセロール含量分析を行った。具体的に、3T3−L1細胞を2×104細胞/ウェルで24ウェルプレートに接種した後(DMEM、10%BCS)、2日間培養した。10%FBSを含むDMEM培地に交換した後、2日間培養し、0.5mM IBMX、0.25μMデキサメタゾン及び10μg/mlインシュリンを含むDMEM(10%FBS)で2日間さらに培養した。以後、1μg/mlインシュリンを含むDMEM(10%FBS)で2日間培養した後、再び1μg/mlインシュリンを含むDMEM(10%FBS)で3日間培養した。FBS培地に交替するとき、本発明のイソトレチノイン−ペプチド化合物又はイソトレチノインを細胞に処理し、分化8日目の培養液を収去してグリセロール比色分析キット(Cayman)を用いてグリセロール分析を行った。
実施例<1−2>で合成された本発明のイソトレチノイン−ペプチド化合物が脂肪分解に連関された遺伝子の発現に及ぶ影響を確認するため、前記実験例3に開示されたものと同一の方法でRT−PCR分析及びオイルレッドO染色を行った。このとき、脂肪分解に関与する遺伝子としては、CPT1a、Acox、HSL及びATGLを用いて、前記遺伝子に特異的なプライマーとして下記表5に示したプライマーを用いた。対照群として用いられたTNF−αの場合、一般的に脂肪分解の効果が知られており、脂肪分解因子であるHSLのリン酸化及びATGLの発現増加の機能を有しており、これを対照群として用いることにより本発明の化合物の効果を比べた。
前記実施例<1−2>で製造された本発明の化合物を含み、下記組成からなる柔軟化粧水を一般的な化粧水の製造方法により製造した。
前記実施例<1−2>で製造された本発明の化合物を含み、下記組成からなる栄養クリームを一般的な栄養クリームの製造方法により製造した。
前記実施例<1−2>で製造された本発明の化合物を含み、下記組成からなる栄養化粧水を一般的な化粧水の製造方法により製造した。
前記実施例<1−2>で製造された本発明の化合物を含み、下記組成からなるエッセンスを一般的なエッセンスの製造方法により製造した。
Claims (15)
- イソトレチノインとペプチドが共有結合で連結された構造を有する化合物。
- 前記ペプチドは、2から30個のアミノ酸配列からなる、請求項1に記載の化合物。
- 前記ペプチドは、8から15個のアミノ酸配列からなる、請求項2に記載の化合物。
- 前記ペプチドは、水溶性ペプチドである、請求項1に記載の化合物。
- 前記水溶性ペプチドは、親水性測鎖(side chain)を有するアミノ酸の比率が50%以上である、請求項4に記載の化合物。
- 前記水溶性ペプチドは、親水性測鎖を有するアミノ酸の比率が70%以上である、請求項5に記載の化合物。
- 前記水溶性ペプチドは、親水性測鎖を有するアミノ酸の比率が90%以上である、請求項6に記載の化合物。
- 前記親水性測鎖を有するアミノ酸は、アルギニン(Arg)、ヒスチジン(His)、リシン(Lys)、アスパラギン酸(Asp)、グルタミン酸(Glu)、セリン(Ser)、スレオニン(Thr)、アスパラギン(Asn)、グルタミン(Gln)、システイン(Cys)、セレノシステイン(Sec)、グリシン(Gly)及びプロリン(Pro)からなる群より選択される、請求項5に記載の化合物。
- 前記水溶性ペプチドは、疎水性測鎖を有するアミノ酸が5個以下である、請求項4に記載の化合物。
- 前記水溶性ペプチドは、疎水性測鎖を有するアミノ酸が3個以下である、請求項9に記載の化合物。
- 前記疎水性測鎖を有するアミノ酸は、アラニン(Ala)、バリン(Val)、イソロイシン(Ile)、ロイシン(Leu)、メチオニン(Met)、フェニルアラニン(Phe)、チロシン(Tyr)及びトリプトファン(Trp)からなる群より選択される、請求項9に記載の化合物。
- 前記ペプチドは、配列番号1から構成されるアミノ酸配列を有するペプチドである、請求項1に記載の化合物。
- 請求項1から請求項12のいずれか1項に記載の化合物を含有する抗菌、抗炎症又は抗酸化用の薬学的組成物。
- 請求項1から請求項12のいずれか1項に記載の化合物を含有する抗菌、抗炎症又は抗酸化用の化粧料組成物。
- 柔軟化粧水、栄養化粧水、栄養クリーム、マッサージクリーム、エッセンス、アイクリーム、クレンジングクリーム、クレンジングフォーム、クレンジングウォーター、パック、スプレー、パウダー、ヘアトニック、ヘアクリーム、ヘアローション、ヘアシャンプー、ヘアリンス、ヘアコンディショナー、ヘアスプレー、ヘアエアロゾル、ポマード、ゾルゲル、エマルジョン、オイル、ワックス及びエアロゾルからなる群より選択される剤形を有する、請求項14に記載の化粧料組成物。
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KR1020170058866A KR102093209B1 (ko) | 2017-05-11 | 2017-05-11 | 이소트레티노인과 펩타이드의 결합체 |
PCT/KR2018/005447 WO2018208124A2 (ko) | 2017-05-11 | 2018-05-11 | 이소트레티노인과 펩타이드의 결합체 |
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US11351266B2 (en) | 2022-06-07 |
US12005123B2 (en) | 2024-06-11 |
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US20220265840A1 (en) | 2022-08-25 |
EA201992544A1 (ru) | 2020-03-13 |
BR112019023568A2 (pt) | 2020-06-02 |
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MX2019013467A (es) | 2020-02-12 |
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