JPH04221395A - Peptide lipid - Google Patents

Peptide lipid

Info

Publication number
JPH04221395A
JPH04221395A JP2333336A JP33333690A JPH04221395A JP H04221395 A JPH04221395 A JP H04221395A JP 2333336 A JP2333336 A JP 2333336A JP 33333690 A JP33333690 A JP 33333690A JP H04221395 A JPH04221395 A JP H04221395A
Authority
JP
Japan
Prior art keywords
gly
asp
arg
peptide
amino acid
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
JP2333336A
Other languages
Japanese (ja)
Inventor
Naoyuki Nishikawa
尚之 西川
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Fujifilm Holdings Corp
Original Assignee
Fuji Photo Film Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Fuji Photo Film Co Ltd filed Critical Fuji Photo Film Co Ltd
Priority to JP2333336A priority Critical patent/JPH04221395A/en
Publication of JPH04221395A publication Critical patent/JPH04221395A/en
Pending legal-status Critical Current

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Classifications

    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02PCLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00Technologies relating to chemical industry
    • Y02P20/50Improvements relating to the production of bulk chemicals
    • Y02P20/55Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Landscapes

  • Peptides Or Proteins (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)
  • Medicinal Preparation (AREA)

Abstract

PURPOSE:To provide a new peptide lipid containing a tripeptide unit of Arg- Gly-Asp and having terminal acyl group, suitable for forming a molecular aggregate such as liposome and micelle and useful as a cell migration suppressing agent, cell adhesion membrane and cell culture medium. CONSTITUTION:The objective new synthetic peptide lipid (salt) expressed by formula {[X] and [Y] are amino acid residue, peptide residue or none; n is 1-5; R<1> is 8-24C acyl} can be produced by reacting a compound of formula Boc-Ser(Bzl)OH (Boc is t-butyloxycarbonyl; Bzl is benzyl) with a compound of formula R<1>ZH (R<1> is 8-24C alkyl; Z is O or NH) in the presence of a carbodiimide, successively bonding amino acids containing aspartic acid, glycine and arginine having protected alpha-amino group and side-chain functional group while removing the terminal amino-protecting group to obtain a synthesized peptide chain, acylating the peptide by reacting with a 8-24C straight-chain or branched chain aliphatic carboxylic acid and finally removing all protecting groups from the product.

Description

【発明の詳細な説明】 〔産業上の利用分野〕 本発明は、Arg−Gly−Aspのトリペプチド単位
を有する、リボソームあるいはミセル等の分子集合体を
形成するのに最適なペプチド脂質に関する。 〔従来の技術〕 フィブロネクチンは細胞−細胞外基質の接着に関与する
タンパク質であり、血小板凝集やガン転移にも関与して
いると考えられている。これらの相互作用は一連の細胞
表面のレセプターにより仲介されること、これらのレセ
プターが、分子量約25万の巨大分子であるフィブロネ
クチンのアルギニン−グリシン−アスパラギン酸(Ar
g−Gly−AspまたはRGD)配列を特異的に認識
することが明らかにされ、レセプターとの相互作用に重
要なものであることが報告されている(ネイチャー(N
ature)、第309巻、30頁、1984年)。 以来、Arg−Gly−Asp配列を有するオリゴある
いはポリペプチドを用いる研究が進められている。 例えば、Arg−Gly−Asp配列を有する種々の鎖
状および環状のオリゴペプチドを用いて血小板凝集を阻
害する方法(高分子学会予稿集(PolymerPre
prints,Japan)、第38巻、3149頁、
1989年、特開平2−174797号)、Arg−G
ly−Asp配列を有するペプチドを細胞移動抑制剤と
して用いる方法(特開平2−4716号)、Arg−G
ly−Aspを固定化したPMMA膜を細胞接着膜とし
て用いる方法(高分子学会予稿集(Polymer P
reprints,Japan)、第37巻、705頁
、1988年)が報告されている。さらに、ポリマーに
Arg−Gly−Aspを必須構成単位とするペプチド
を共有結合させ動物細胞培養基体、生体複合人工臓器用
基体として用いる方法(特開平1−309682号、特
開平1−305960号)、Arg−Gly−Asp−
Ser配列を有するポリペプチドを体外血液用血小板保
護剤として用いる方法が開示されている(特開昭64−
6217号)。 また、Arg−Gly−Asp配列を有するオリゴペプ
チドあるいはその繰り返し構造を有するポリペプチドを
用いて、ガン転移を抑制する方法が知られている(イン
ターナショナル・ジャーナル・オブ・バイオロジカル・
マクロモレキュルズ(Int.J.Biol.Macr
omol.)、第11巻、23頁、1989年、同誌、
第11巻、226頁、1989年、ジャパン・ジャーナ
ル・オブ・キャンサー・リサーチ(Jpn.J.Can
cer Res.)第60巻、722頁、1989年)
。 一方、リボソームやミセル等の分子集合体をドラッグキ
ャリアーとして用いる方法が多数検討されている(例え
ば、リボソーム、245頁〜271頁、南江堂、198
8年、キャンサー・リサーチ(Cancer Res.
)第43巻、5328頁、1983年、ジャーナル・オ
ブ・コントロールド.リリース(J.Controll
ed Release)269頁、1990年)。 しかし、リボソーム等の分子集合体形成脂質にArg−
Gly−Asp配列を有するペプチド脂質を用いた例は
知られていない。 〔発明が解決しようとする課題〕 本発明の目的は、Arg−Gly−Aspのトリペプチ
ド単位を有する、リボソームあるいはミセル等の分子集
合体を形成するのに最適なペプチド脂質誘導体及びその
合成法を提供することである。 〔課題を解決するための手段〕  本発明の化合物は下記、一般式〔I〕で示される合成ペ
プチド脂質またはその塩である。 R1−(〔X〕−Arg−Gly−Asp−〔Y〕)n
−Z−R2…〔I〕式中、Arg、Gly、Aspはそ
れぞれアルギニン、グリシン、アスパラギン酸残基を示
す。 〔X〕、〔Y〕は、存在するかあるいは存在しないアミ
ノ酸残基または、二つあるいは三つのアミノ酸残基から
なるペプチド残基を示す。存在する場合には〔X〕〔Y
〕は、Ser、Gly、Val、Asn、Pro、Cy
s、Thrから選択されるアミノ酸残基または、これら
のアミノ酸残基の組み合わせにより構成されるペプチド
残基が好ましい。特に〔Y〕はSerであることが好ま
しい。また、〔X〕、〔Y〕が共に存在しない場合も特
に好ましい。さらに、〔X〕はGly、〔Y〕はSer
−Proであることも特に好ましい。Ser、Val、
Asn、Pro、Cys、Thrはそれぞれセリン、バ
リン、アスパラギン、プロリン、システイン、トレオニ
ン残基を示す。 nは1〜5の整数を示し、特に1〜3が好ましい。 Zは−O−または−NH−を示す。 本発明において、アミノ酸はL−、D−、ラセミ体いず
れでもよいが、L−アミノ酸が好ましい。 R1は炭素数8〜24の直鎖または分岐のアシル基であ
り、置換基、不飽和基を有していてもよい。好ましくは
炭素数12〜18である。例えばミリストイル基、パル
ミトイル基、ステアロイル基、3,7,11,15−テ
トラメチルヘキサデカノイル基、3,7,11−トリメ
チルドデカノイル基が好ましい例として示される。 R2は炭素数8〜24の直鎖または分岐のアルキル基で
あり、置換基、不飽和基を有していてもよい。好ましく
は炭素数12〜18である。例えばミリスチル基、パル
ミチル基、ステアリル基、フィチル基3,7,11,1
5−テトラメチルヘキサデシル基、3,7,11−トリ
メチルドデシル基が好ましい例として示される。 好ましい塩の例として、トリフルオロ酢酸塩、塩酸塩、
酢酸塩、硫酸塩、乳酸塩があげられる。 以下に本発明の好ましい具体例を物性値とともに示すが
、本発明はこれらに限定されるものではない。 ペプチド脂質−1 C13H27CO−Arg−Gly−Asp−O−C1
4H29FAB−MS(Pos.)(M+Na)+77
5(M+H)+753FAB−MS(Neg.)(M+
Na)−775(M−H)−751アミノ酸分析:Ar
g 0.96,Gly 0.97,Asp 0.96,
ペプチド脂質−2 C15H31CO−Arg−Gly−Asp−Ser−
O−C16H33FAB−MS(Pos.)(M+Na
)+918(M+H)+896FAB−MS(Neg.
)(M+Na)−918(M−H)−894アミノ酸分
析:Arg 0.99,Gly 1.01,Asp 0
.95,Ser 0.79 ペプチド脂質−3 C8H17CO−Gly−Arg−Gly−Asp−S
er−O−C10H21FAB−MS(Pos.)(M
+Na)+793(M+H)+771FAB−MS(N
eg.)(M+Na)−793(M−H)−769アミ
ノ酸分析:Arg 0.98,Gly 2.17,As
p 0.92,Ser 0.76 ペプチド脂質−4 C17H35CO−Cys−Arg−Gly−Asp−
Cys−O−C18H37FAB−MS(Pos.)(
M+Na)+1093(M+H)+1071FAB−M
S(Neg.)(M+Na)−1093(M−H)−1
069アミノ酸分析:Arg 0.97,Gly 0.
92,Asp 0.82,Cys 1.71 ペプチド脂質−5 C8H17CO−Gly−Arg−Gly−Asp−T
hr−O−C20H41FAB−MS(Pos.)(M
+Na)+947(M+H)+925FAB−MS(N
eg.)(M+Na)−947(M−H)−923アミ
ノ酸分析:Arg 0.93,Gly 1.94,As
p 0.97,Thr 0.74 ペプチド脂質−6 C13H27CO−Arg−Gly−Asp−NH−C
14H29FAB−MS(Pos.)(M+Na)+7
74(M+H)+752FAB−MS(Neg.)(M
+Na)−774(M−H)−750アミノ酸分析:A
rg 0.99,Gly 0.95,Asp 0.91
,ペプチド脂質−7 C15H31CO−Arg−Gly−Asp−Ser−
NH−C16H33FAB−MS(Pos.)(M+N
a)+917(M+H)+895FAB−MS(Neg
.)(M+Na)−917(M−H)−893アミノ酸
分析:Arg 0.97,Gly 0.98,Asp 
0.88,Ser 0.75 ペプチド脂質−8 C17H35CO−Gly−Arg−Gly−Asp−
Thr−NH−C18H37FAB−MS(Pos.)
(M+Na)+1043(M+H)+1022FAB−
MS(Neg.)(M+Na)−1043(M−H)−
1020アミノ酸分析:Arg 0.94,Gly 1
.84,Asp 0.92,Thr 0.72 ペプチド脂質−9 FAB−MS(Pos.)(M+Na)+943(M+
H)+921FAB−MS(Neg.)(M+Na)−
943(M−H)−919アミノ酸分析:Arg 0.
99,Gly 0.95,Asp 0.96,ペプチド
脂質−10 C17H35CO(Arg−Gly−Asp)2−O−
C18H37FAB−MS(Pos.)(M+Na)+
1215(M+H)+1193FAB−MS(Neg.
)(M+Na)−1215(M−H)−1191アミノ
酸分析:Arg 1.99,Gly 1.94,Asp
 1.92,ペプチド脂質−11 C13H27CO−(Arg−Gly−Asp−Ser
)2−NH−C14H29FAB−MS(Pos.)(
M+Na)+1276(M+H)+1254FAB−M
S(Neg.)(M+Na)−1276(M−H)−1
252アミノ酸分析:Arg 1.92,Gly 1.
95,Asp 1.79,Ser 1.53 ペプチド脂質−12 C15H31CO−(Arg−Gly−Asp)3−O
−C16H33FAB−MS(Pos.)(M+Na)
+1487(M+H)+1465FAB−MS(Neg
.)(M+Na)−1487(M−H)−1463アミ
ノ酸分析:Arg 3.03,Gly 2.81,As
p 3.01,ペプチド脂質−13 C9H19CO−Arg−Gly−Asp−Ser−P
ro−NH−C10H21FAB−MS(Pos.)(
M+H)+825FAB−MS(Neg.)(M+H)
−823ペプチド脂質−14 FAB−MS(Pos.)(M+H)+1022FAB
−MS(Neg.)(M+H)−1020本発明の化合
物は、たとえば次の4段階の工程により合成することが
できる。 ■保護アミノ酸と、R2−Z−Hとの縮合(R2は相当
するアルキル基、Zは−O−または−NH−を示す、) ■保護アミノ酸の逐次延伸 ■R1−Wとの縮合 (R1は相当するアシル基を示す。Wは水酸基またはハ
ロゲン原子を示す。) ■脱保護、精製 以下、各段階の工程について詳細に説明する。 ■一般式〔I〕で示される化合物の場合、Yで示される
アミノ酸の保護体またはYが存在しない場合はAspの
保護体と相当するR2−Z−Hとを縮合し、エステルあ
るいはアミドとする。 縮合に関しては、DCC法、DCC−additive
法、CDI法等一般の手法が採用される。 ■保護アミノ酸を逐次伸長する方法としては、既知の方
法、すなわら泉屋ら編「ペプチド合成の基礎と実験」(
丸善)やBodanszky著“PRINCIPLES
 OF PEPTIDE SYNTHESIS“THE
PRACTICE OF PEPTIDE SYNTH
SIS”(SpringerVerlag,New Y
ork)に記載されている方法がいずれも有効である。 縮合反応の段階では、DCC法、DCC−additi
ve法、アジド法、CDI法、混合酸無水物法、活性化
エステル法のいずれを採用してもよいが、1−ヒドロキ
シベンゾトリアゾール(HOBt)とDCCを併用する
DCC−HOBt法が好ましい。 ■相当するR1−OHと(〔X〕−Arg−Gly−A
sp−〔Y〕)n−Z−R2とを縮合する方法としては
、DCC法、DCC−additive法、CDI法、
いずれを採用してもよい。 また、R1−OHをR1−Cl等の酸クロライドに変え
てアミド化を行ってもよい。 尚、アミノ酸残基の多いペプチド脂質に関しては、R1
−、R2−Z−両端からペプチド逐次伸長を行い、フラ
グメント縮合を行うのが好ましい。この縮合法は、上記
■の方法に従う。 ■保護基を脱保護するのに用いられる条件は、用いた保
護基の種類に大きく依存する。通常使用される脱保護方
法は、加水素分解、トリフルオロ酢酸、無水フッ化水素
、トリフルオロメタンスルホン酸−チオアニソール混合
系、トリフルオロ酢酸−チオアニソール混合系等である
が、保護基の種類によってはさらに多様な手段が可能で
ある。 以下に、本発明のペプチド脂質−2、ペプチド脂質−6
及びペプチド脂質−10の合成例を示すが、本発明の合
成法はこれらに限定されるものではない。 また、本発明の化合物の好ましい具体例で示したペプチ
ド脂質(1) ̄(12)は、アミノ酸側鎖をベンジルエ
ーテル、ベンジルチオエーテルあるいはベンジルエステ
ルで保護した相当するBoc−アミノ酸と相当するR1
−OHおよび相当するR2−OHあるいはR2−NH2
を用いて、以下に示す合成例と同様にして合成できる。 実施例1 ペプチド脂質−2の合成 Boc−セリンベンジルエーテル5.9g、ヘキサデシ
ルアルコール(カテコール60、花王品)4.8g、ジ
シクロヘキシルカルボジイミド4.6g、ジメチルアミ
ノピリジン0.24g、をジクロロメタンに溶解し10
℃で一昼夜撹拌した。反応液をろ過し、ろ液を減圧濃縮
してシリカゲルクロマトグラフィーにて精製(溶離液ク
ロロホルム)し、Boc−Ser(Bzl)−OC16
H33 10.3gを得た。 次に、Boc−Ser(Bzl)−OC16H33 1
0.3gをジクロロメタン、トリフルオロ酢酸混合液(
20ml/20ml)に溶解し30分間撹拌した。 溶媒を減圧留去した後、クロロホルムに溶解し、飽和炭
酸水素ナトリウム水溶液で処理して有機層をボウ硝乾燥
した後、クロロホルムを減圧留去してSer(Bzl)
−OC16H33 9.3gを得た。 Boc−アスパラギン酸−β−ベンジルエステル7.1
g、Ser(Bzl)−OC16H33 9.3g、1
−ヒドロキシベンゾトリアゾール3.7gのジクロロメ
タン、ジメチルホルムアミド混合液60mlにジシクロ
ヘキシルカルボジイミド4.9gを加え一昼夜攪拌した
。 反応液をろ過し、ろ液を減圧留去した後、クロロホルム
に溶解した。飽和炭酸水素ナトリウム−水溶液で有機層
を洗いボウ硝乾燥した後、クロロホルムを減圧留去し、
残留物をシリカゲルクロマトグラフィーにて精製(溶離
液ヘキサン/酢酸エチル=6/4)してBoc−Asp
(OBzl)−Ser(Bzl)−OC16H33 1
4.2gを得た。 次に、Boc−Asp(OBzl)−Ser(Bzl)
−OC16H33 14.2gをジクロロメタン、トリ
フルオロ酢酸混合液(20ml/20ml)に溶解し3
0分間撹拌した。 溶媒を減圧留去した後、クロロホルムに溶解し飽和炭酸
水素ナトリウム水溶液で処理して有機層をボウ硝乾燥し
た後、クロロホルムを減圧留去してAsp(OBzl)
−Ser(Bzl)−OC16H33 13.5gを得
た。 Asp(OBzl)−Ser(Bzl)−OC16H3
3 13.5gをジクロロメタン50mlに溶解し、B
oc−グリシン無水物8.7gを加え一昼夜攪拌した、
反応液を飽和炭酸水素ナトリウム水溶液で洗い、ボウ硝
乾燥した後、ジクロロメタンを減圧留去し、残留物をシ
リカゲルクロマトグラフィーにて精製(溶離液ジクロロ
メタン/酢酸エチル=6/4)して Boc−Gly−Asp(OBzl)−Ser(Bzl
)−OC16H33 11.8gを得た。 次に、Boc−Gly−Asp(OBzl)−Ser(
Bzl)−OC16H3311.8gをジクロロメタン
、トリフルオロ酢酸混合液(20ml/20ml)に溶
解し30分間撹拌した。 溶媒を減圧留去した後、クロロホルムに溶解し飽和炭酸
水素ナトリウム水溶液で処理して有機層をボウ硝乾燥し
た後、クロロホルムを減圧留去してGly−Asp(O
Bzl)−Ser(Bzl)−OC16H33 10.
2gを得た。 Boc−Arg(Z)2 8.4g、1−ヒドロキシベ
ンゾトリアゾール2.4g,Gly−Asp(OBzl
)−Ser(Bzl)−OC16H33 10.2gの
ジクロロメタン、ジメチルホルムアミド混合液60ml
にジシクロヘキシルカルボジイミド3.2gのジクロロ
メタン溶液20mlを加え、一昼夜撹拌した。 反応液をろ過し、ろ液を減圧留去した後、クロロホルム
に溶解した。飽和炭酸水素ナトリウム水溶液で有機層を
洗いボウ硝乾燥した後、クロロホルムを減圧留去し、残
留物をシリカゲルクロマトグラフィーにて精製(溶離液
ジクロロメタン/酢酸エチル=6/4)した後、酢酸エ
チルで再結晶しBoc−Arg(Z)2−Gly−As
p(OBzl)−Ser(Bzl)−OC16H336
.6gを得た。 Boc−Arg(Z)2−Gly−Asp(OBzl)
−Ser(Bzl)−OC16H332.0gジクロロ
メタン、トリフルオロ酢酸混合液(20ml/20ml
)に溶解し30分間撹拌した。 溶媒を減圧留去した後、クロロホルムに溶解し飽和炭酸
水素ナトリウム水溶液で処理して有機層をボウ硝乾燥し
た後、クロロホルムを減圧留去してArg(Z)2−G
ly−Asp(OBzl)−Ser(Bzl)−OC1
6H33 1.5gを得た。 パルミチン酸0.56g、ジシクロヘキシルカルボジイ
ミド0.23gをジクロロメタン50mlに溶解し、室
温で一時間攪拌した後に、Arg(Z)2−Gly−A
sp(OBzl)−Ser(Bzl)OC16H33 
1.1gのジクロロメタン溶液30mlを加え、一昼夜
攪拌した。 反応液をろ過し、ろ液を飽和炭酸水素ナトリウム水溶液
で洗いボウ硝乾燥した後、ジクロロメタンを減圧留去し
た。残留物をシリカゲルクロマトグラフィーにて精製(
溶離液クロロホルム/酢酸エチル=5/5)した後、ク
ロロホルム、酢酸エチルで再結晶し、C15H31CO
−Arg(Z)2−Gly−Asp(OBzl)−Se
r(Bzl)−OC16H33 1.3gを得た。 C15H31Co−Arg(Z)2−Gly−Asp(
OBzl)−Ser(Bzl)−OC16H33 50
0mgを酢酸70mlに溶解し二酸化白金150mgを
加え加水素分解を50℃で行った。 反応液をセライトにてろ過し、ろ液を減圧濃縮した。残
留物を酢酸、酢酸エチルにて再結晶し、C15H31C
O−Arg−Gly−Asp−Ser−OC16H33
 260mgを得た。 実施例2 ペプチド脂質−6の合成 Boc−アスパラギン酸−β−ベンジルエステル6.5
g、1−テトラデシルアミン4.3g、1−ヒドロキシ
ベンゾトリアゾール3.1g、ジシクロヘキシルカルボ
ジイミド4.6g、ジメチルアミノピリジン0.24g
、をジクロロメタンに溶解し10℃で一昼夜撹拌した。 反応液をろ過し、ろ液を減圧濃縮してシリカゲルクロマ
トグラフィーにて精製(溶離液クロロホルム)し、Bo
c−Asp(OBzl)−NH−C14H29 9.7
gを得た。 次に、Boc−Asp(OBzl)−NH−C14H2
9 9.7gをジクロロメタン、トリフルオロ酢酸混合
液(20ml/20ml)に溶解し30分間攪拌した。 溶媒を減圧留去した後、クロロホルムに溶解し、飽和炭
酸水素ナトリウム水溶液で処理して有機層をボウ硝乾燥
した後、クロロホルムを減圧留去してAsp(OBzl
)−NH−C14H29 9.3gを得た。 Asp(OBzl)−NH−C14H29 9.3gを
ジクロロメタン40mlに溶解し、Boc−グリシン無
水物10.0gを加え一昼夜撹拌した。反応液を飽和炭
酸水素ナトリウム水溶液で洗いボウ硝乾燥した後、ジク
ロロメタンを減圧留去し、残留物をシリカゲルクロマト
グラフィーにて精製(溶離液ジクロロメタン/酢酸エチ
ル=6/4)してBoc−Gly−Asp(OBzl)
−NH−C14H29 9.1gを得た。 次に、Boc−Gly−Asp(OBzl)−NH−C
14H29 9.1gをジクロロメタン、トリフルオロ
酢酸混合液(20ml/20ml)に溶解し30分間攪
拌した。 溶媒を減圧留去した後、クロロホルムに溶解し飽和炭酸
水素ナトリウム水溶液で処理して有機層をボウ硝乾燥し
た後、クロロホルムを減圧留去してGly−Asp(O
Bzl)−NH−C14H29 8.8gを得た。 Boc−Arg(Z)2 9.5g、1−ヒドロキシベ
ンゾトリアゾール2.8g、Gly−Asp(OBzl
)−NH−C14H298.8gのジクロロメタン、ジ
メチルホルムアミド混合液60mlにジシクロヘキシル
カルボジイミド3.7gのジクロロメタン溶液20ml
を加え、一昼夜攪拌した。 反応液をろ過し、ろ液を減圧留去した後、クロロホルム
に溶解した。飽和炭酸水素ナトリウム水溶液で有機層を
洗いボウ硝乾燥した後、クロロホルムを減圧留去し、残
留物をシリカゲルクロマトグラフィーにて精製(溶離液
ジクロロメタン/酢酸エチル=7/3)した後、酢酸エ
チルで再結晶しBoc−Arg(Z)2−Gly−As
p(OBzl)−NH−C14H29 12.4gを得
た。 Boc−Arg(Z)2−Gly−Asp(OBzl)
−NH−C14H29 2.0gをジクロロメタン、ト
リフルオロ酢酸混合液(20ml/20ml)に溶解し
30分間攪拌した。 溶媒を減圧留去した後、クロロホルムに溶解し飽和炭酸
水素ナトリウム水溶液で処理して有機層をボウ硝乾燥し
た後、クロロホルムを減圧留去してArg(Z)2−G
ly−Asp(OBzl)−NH−C14H29 1.
8gを得た。 ミリスチン酸0.45g、ジシクロヘキシルカルボジイ
ミド0.23gをジクロロメタン50mlに溶解し、室
温で一時間撹拌した後にArg(Z)2−Gly−As
p(OBzl)−NH−C14H29 1.4gのジク
ロロメタン溶液30mlを加え、一昼夜攪拌した。 反応液をろ過し、ろ液を飽和炭酸水素ナトリウム水溶液
で洗いボウ硝乾燥した後、ジクロロメタンを減圧留去し
た。残留物をシリカゲルクロマトグラフィーにて精製(
溶離液ジクロロメタン/酢酸エチル=6/4)した後、
クロロホルム、酢酸エチルで再結晶しC13H27CO
−Arg(Z)2−Gly−Asp(OBzl)−NH
−C14H29 1.7gを得た。 C13H27CO−Arg(Z)2−Gly−Asp(
OBzl)−NH−C14H29500mgを酢酸70
mlに溶解し二酸化白金150mgを加え加水素分解を
50℃で行った。反応液をセライトにてろ過し、ろ液を
減圧濃縮した。残留物を酢酸、酢酸エチルにて再結晶し
、C13H27CO−Arg−Gly−Asp−NH−
C14H29 220mgを得た。 実施例3 ペプチド脂質−10の合成 (Asp(OBzl)−Arg(Z)2−Gly−As
p(OBzl)−O−C18H37の合成) Boc−アスパラギン酸−β−ベンジルエステル6.5
g、オクタデシルアルコール5.4g、ジシクロヘキシ
ルカルボジイミド4.6g、ジメチルアミノピリジン0
.24g、をジクロロメタンに溶解し10℃で一昼夜攪
拌した。反応液をろ過し、ろ液を減圧濃縮してシリカゲ
ルクロマトグラフィーにて精製(溶離液クロロホルム)
し、Boc−Asp(OBzl)−O−C18H37 
10.3gを得た。 次に、Boc−Asp(OBzl)−O−C18H37
 10.3gをジクロロメタン、トリフルオロ酢酸混合
液(20ml/20ml)に溶解し30分間撹拌した。 溶媒を減圧留去した後、クロロホルムに溶解し、飽和炭
酸水素ナトリウム水溶液で処理して有機層をボウ硝乾燥
した後、クロロホルムを減圧留去してAsp(OBzl
)−O−C18H37 8.2gを得た。 Asp(OBzl)−O−C18H37 8.2gジク
ロロメタン40mlに溶解し、Boc−グリシン無水物
12.0gを加え一昼夜攪拌した。反応液を飽和炭酸水
素ナトリウム水溶液で洗いボウ硝乾燥した後、ジクロロ
メタンを減圧留去し、残留物をシリカゲルクロマトグラ
フィーにて精製(溶離液ジクロロメタン/酢酸エチル=
6/4)してBoc−Gly−Asp(OBzl)−O
−C18H37 10.7gを得た。 次に、Boc−Gly−Asp(OBzl)−O−C1
8H37 10.7gをジクロロメタン、トリフルオロ
酢酸混合液(20ml/20ml)に溶解し30分間撹
拌した、。 溶媒を減圧留去した後、クロロホルムに溶解し飽和炭酸
水素ナトリウム水溶液で処理して有機層をボウ硝乾燥し
た後、クロロホルムを減圧留去してGly−Asp(O
Bzl)−O−C18H37 9.1gを得た。 Boc−Arg(Z)2 9.1g、1−ヒドロキシベ
ンゾトリアゾール2.5g、Gly−Asp(OBzl
)−O−C18H37 8.8gのジクロロメタン、ジ
メチルホルムアミド混合液60mlにジシクロヘキシル
カルボジイミド3.4gのジクロロメタン溶液20ml
を加え、一昼夜攪拌した。 反応液をろ過し、ろ液を減圧濃縮した後、クロロホルム
に溶解した。飽和炭酸水素ナトリウム水溶液で有機層を
洗いボウ硝乾燥した後、クロロホルムを減圧留去し、残
留物をシリカゲルクロマトグラフィーにて精製(溶離液
ジクロロメタン/酢酸エチル=7/3)した後、酢酸エ
チルで再結晶し、Boc−Arg(Z)2−Gly−A
sp(OBzl)−O−C18H37 13.7gを得
た。 Boc−Arg(Z)2−Gly−Asp(OBzl)
−O−C18H37 13.7gをジクロロメタン、ト
リフルオロ酢酸混合液(20ml/20ml)に溶解し
30分間攪拌した。 溶媒を減圧留去した後、クロロホルムに溶解し、飽和炭
酸水素ナトリウム水溶液で処理して有機層をボウ硝乾燥
した後、クロロホルムを減圧留去してArg(Z)2−
Gly−Asp(OBzl)−O−C18H3712.
4gを得た。 Boc−アスパラギン酸−β−ベンジルエステル4.2
g、Arg(Z)2−Gly−Asp(OBzl)−O
−C18H3712.4g、1−ヒドロキシベンゾトリ
アゾール2.9gをジクロロメタン50mlに溶解した
後に、ジシクロヘキシルカルボジイミド3.9gを加え
、一昼夜攪拌した。 反応液をろ過し、ろ液を飽和炭酸水素ナトリウム水溶液
で洗いボウ硝乾燥した後、ジクロロメタンを減圧留去し
た。残留物をシリカゲルクロマトグラフィーにて精製(
溶離液クロロホルム/酢酸エチル=6/4)してBoc
−Asp−(OBzl)−Arg(Z)2−Gly−A
sp(OBzl)−O−C18H3713.9gを得た
。 Boc−Asp(OBzl)−Arg(Z)2−Gly
−Asp(OBzl)−O−C18H3713.9gを
ジクロロメタン、トリフルオロ酢酸混合液(20ml/
20ml)に溶解し30分間攪拌した。 溶媒を減圧留去した後、クロロホルムに溶解し、飽和炭
酸水素ナトリウム水溶液で処理して有機層をボウ硝乾燥
した後、クロロホルムを減圧留去してAsp(OBzl
)−Arg(Z)2−Gly−Asp(OBzl)−O
−C18H37を12.2g得た。 (C17H35−CO−Arg(Z)2−Gly−の合
成)ステアリン酸5.6g、ジシクロロヘキシルカルボ
ジイミド4.2g、をジクロロメタン100mlに溶解
し室温で攪拌した、N−ヒドロキシスクシンイミド2.
3gを加え一昼夜攪拌した。反応液をろ過し、ろ液を水
で洗い、ボウ硝乾燥した後、ジクロロメタンを減圧留去
した。残留物をシリカゲルクロマトグラフィーにて精製
(溶離液ヘキサン/酢酸エチル8/2)した。続いて、
酢酸エチル/ヘキサン系にて分別結晶を行ない縮合剤転
移生成物を除き、ステアリン酸−N−ヒドロキシスクシ
ンイミドエステルを2.7g得た。 ステアリン酸−N−ヒドロキシスクシンイミドエステル
2.7g、Arg(Z)2−Gly3.5g、ジメチル
アミノピリジン0.2gをジクロロメタンに溶解して一
昼夜攪拌した。反応液を飽和炭酸水素ナトリウム水溶液
、クエン酸水溶液で洗った後、ボウ硝乾燥した。残留物
をジクロロメタン/酢酸エチル系で再結晶してC17H
35CO−Arg(Z)2−Gly5.8gを得た。 (C17H35CO−(Arg−Gly−Asp)2−
O−C18H37の合成)上記で得たC17H35CO
−Arg(Z)2−Gly0.75gAsp(OBzl
)−Arg(Z)2−Gly−Asp(OBzl)−O
−C18H371.16g、シンクロヘキシルカルボジ
イミド2.1g、1−ヒドロキシベンゾトリアゾール1
.53g、ジメチルアミノピリジン0.3gをジクロロ
メタン−DMF混合液100mlに溶解して一昼夜攪拌
した、反応液を減圧留去して、残留物にジクロロメタン
を加え有機層を飽和炭酸水素ナトリウム水溶液、クエン
酸水溶液で洗いボウ硝乾燥した。ジクロロメタンを減圧
留去して残留物をシリカゲルクロマトグラフィーにて精
製(溶離液クロロホルム/酢酸エチル−4/6)した後
、ジクロロメタン−酢酸エチル系で再結晶し、 C17H35CO−(Arg(Z)2−Gly−Asp
(OBzl))2−O′−C18H37を0.85g得
た。 C17H35CO−(Arg(Z)2−Gly−ASP
(OBzl))2−O−C18H370.5gを酢酸4
0mlに溶解し5%パラジウム炭素200mg、二酸化
白金200mgを加え、加水素分解(65℃)を行ない
、C17H35CO−(Arg−Gly−Asp)2−
O−C18H37を0.08g得た。 実施例4ペプチド脂質−14の合成 ファルネソール50gをエタノール350mlに溶解し
、二酸化白金500mgを加えて12時間加水素分解を
行った。反応液をセライトを用いてろ過し、ろ液を減圧
濃縮して定量的に3,7,11−トリメチルドデシルア
ルコールを得た。 3,7,11−トリメチルドデシルアルコール10gを
アセトンに溶解し、室温攪拌下Jones試薬(オーガ
ニック.シンセシス(Org.Syntheses)、
Col.第4巻310頁)を滴下した。反応液に酢酸エ
チルを加え、有機層を飽和食塩水で洗い、ホウ硝乾燥し
て減圧濃縮した。残留物をシリカゲルカラムクロマトに
より精製し(溶出液ヘキサン/酢酸エチル9/1)、3
,7,11−トリメチルドデカン酸8.6gを得た。 Boc−Pro 21.5g、ジシクロヘキシルカルボ
ジイミド(DCC)20.6g、3,7,11−トリメ
チルドデシルアルコール22.8g、トリエチルアミン
10.1gを用いて実施例1と同様にDCC縮合を行っ
た。反応液をろ過し、ろ液を減圧濃縮した。残留物をジ
クロロメタン50mlに溶解し、トリフルオロ酢酸50
mlを加えて30分間攪拌した。 反応液を減圧濃縮した。 続いて実施例1と同様にして、DCC−additiv
e法、対称酸無水物法によりBoc−Ser(Bzl)
、Boc−Asp(OBzl)、Boc−グリシン無水
物、Boc−Arg(Z)2、Boc−グリシン無水物
を用いてペプチドを伸長し、3,7,11−トリメチル
ドデカン酸と縮合し、5%−パラジウム炭素を用いて脱
保護を行った。 精製も実施例1と同様に再結晶法、イオン交換を行いペ
プチド脂質−14を得た。 〔有用性〕 不発明の化合物は細胞移動抑制剤、細胞接着膜、細胞培
養基体として有用である。
DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to a peptide lipid having a tripeptide unit of Arg-Gly-Asp, which is optimal for forming molecular aggregates such as ribosomes or micelles. [Prior Art] Fibronectin is a protein involved in cell-extracellular matrix adhesion, and is also thought to be involved in platelet aggregation and cancer metastasis. These interactions are mediated by a series of cell surface receptors, and these receptors are linked to arginine-glycine-aspartate (Ar) of fibronectin, a macromolecule with a molecular weight of approximately 250,000.
g-Gly-Asp or RGD) sequence, and has been reported to be important for interaction with the receptor (Nature (N
ature), Vol. 309, p. 30, 1984). Since then, research using oligos or polypeptides having the Arg-Gly-Asp sequence has been progressing. For example, a method of inhibiting platelet aggregation using various linear and cyclic oligopeptides having an Arg-Gly-Asp sequence (Proceedings of the Society of Polymer Science and Technology (PolymerPre
prints, Japan), Volume 38, Page 3149,
1989, JP-A-2-174797), Arg-G
Method of using a peptide having a ly-Asp sequence as a cell migration inhibitor (Japanese Patent Application Laid-Open No. 2-4716), Arg-G
Method of using PMMA membrane with immobilized ly-Asp as a cell adhesion membrane (Proceedings of the Society of Polymer Science and Technology (Polymer P
(Reprints, Japan), Vol. 37, p. 705, 1988). Furthermore, a method of covalently bonding a peptide having Arg-Gly-Asp as an essential constituent unit to a polymer and using it as an animal cell culture substrate or a biocomposite artificial organ substrate (Japanese Patent Application Laid-open Nos. 1-309682 and 1-305960); Arg-Gly-Asp-
A method of using a polypeptide having a Ser sequence as a platelet protective agent for extracorporeal blood has been disclosed (Japanese Patent Application Laid-Open No. 1986-1999).
No. 6217). In addition, a method of suppressing cancer metastasis using an oligopeptide having an Arg-Gly-Asp sequence or a polypeptide having a repeating structure thereof is known (International Journal of Biological Sciences).
Macromolecules (Int.J.Biol.Macr)
omol. ), vol. 11, p. 23, 1989, same magazine.
Volume 11, page 226, 1989, Japan Journal of Cancer Research (Jpn.J.Can
cerRes. ) Vol. 60, p. 722, 1989)
. On the other hand, many methods using molecular aggregates such as ribosomes and micelles as drug carriers have been investigated (e.g., Ribosomes, pp. 245-271, Nankodo, 198
8 years, Cancer Research (Cancer Res.
) Volume 43, page 5328, 1983, Journal of Controlled. Release (J.Control
ed Release) p. 269, 1990). However, Arg-
There are no known examples using a peptide lipid having a Gly-Asp sequence. [Problems to be Solved by the Invention] The purpose of the present invention is to provide a peptide-lipid derivative having a tripeptide unit of Arg-Gly-Asp, which is optimal for forming molecular aggregates such as ribosomes or micelles, and a method for synthesizing the same. It is to provide. [Means for Solving the Problems] The compound of the present invention is a synthetic peptide lipid represented by the following general formula [I] or a salt thereof. R1-([X]-Arg-Gly-Asp-[Y])n
-Z-R2...[I] In the formula, Arg, Gly, and Asp represent arginine, glycine, and aspartic acid residues, respectively. [X] and [Y] represent an amino acid residue that is present or absent, or a peptide residue consisting of two or three amino acid residues. If it exists, [X] [Y
] is Ser, Gly, Val, Asn, Pro, Cy
Preferred are amino acid residues selected from s and Thr, or peptide residues composed of a combination of these amino acid residues. In particular, [Y] is preferably Ser. Furthermore, it is particularly preferable that both [X] and [Y] are absent. Furthermore, [X] is Gly, [Y] is Ser
-Pro is also particularly preferred. Ser, Val,
Asn, Pro, Cys, and Thr represent serine, valine, asparagine, proline, cysteine, and threonine residues, respectively. n represents an integer of 1 to 5, particularly preferably 1 to 3. Z represents -O- or -NH-. In the present invention, the amino acid may be L-, D-, or racemic, but L-amino acids are preferred. R1 is a linear or branched acyl group having 8 to 24 carbon atoms, and may have a substituent or an unsaturated group. Preferably it has 12 to 18 carbon atoms. For example, preferred examples include myristoyl group, palmitoyl group, stearoyl group, 3,7,11,15-tetramethylhexadecanoyl group, and 3,7,11-trimethyldodecanoyl group. R2 is a straight chain or branched alkyl group having 8 to 24 carbon atoms, and may have a substituent or an unsaturated group. Preferably it has 12 to 18 carbon atoms. For example, myristyl group, palmityl group, stearyl group, phytyl group 3,7,11,1
Preferred examples include 5-tetramethylhexadecyl group and 3,7,11-trimethyldodecyl group. Examples of preferred salts include trifluoroacetate, hydrochloride,
Examples include acetate, sulfate, and lactate. Preferred specific examples of the present invention are shown below along with physical property values, but the present invention is not limited thereto. Peptide lipid-1 C13H27CO-Arg-Gly-Asp-O-C1
4H29FAB-MS (Pos.) (M+Na)+77
5(M+H)+753FAB-MS(Neg.)(M+
Na)-775(MH)-751 amino acid analysis: Ar
g 0.96, Gly 0.97, Asp 0.96,
Peptide lipid-2 C15H31CO-Arg-Gly-Asp-Ser-
O-C16H33FAB-MS (Pos.) (M+Na
)+918(M+H)+896FAB-MS(Neg.
)(M+Na)-918(MH)-894 Amino acid analysis: Arg 0.99, Gly 1.01, Asp 0
.. 95, Ser 0.79 Peptide lipid-3 C8H17CO-Gly-Arg-Gly-Asp-S
er-O-C10H21FAB-MS (Pos.) (M
+Na)+793(M+H)+771FAB-MS(N
eg. )(M+Na)-793(MH)-769 Amino acid analysis: Arg 0.98, Gly 2.17, As
p 0.92, Ser 0.76 Peptide lipid-4 C17H35CO-Cys-Arg-Gly-Asp-
Cys-O-C18H37FAB-MS (Pos.) (
M+Na)+1093(M+H)+1071FAB-M
S(Neg.)(M+Na)-1093(MH)-1
069 amino acid analysis: Arg 0.97, Gly 0.
92, Asp 0.82, Cys 1.71 Peptide lipid-5 C8H17CO-Gly-Arg-Gly-Asp-T
hr-O-C20H41FAB-MS (Pos.) (M
+Na)+947(M+H)+925FAB-MS(N
eg. )(M+Na)-947(MH)-923 Amino acid analysis: Arg 0.93, Gly 1.94, As
p 0.97, Thr 0.74 Peptide lipid-6 C13H27CO-Arg-Gly-Asp-NH-C
14H29FAB-MS (Pos.) (M+Na)+7
74(M+H)+752FAB-MS(Neg.)(M
+Na)-774(MH)-750 amino acid analysis: A
rg 0.99, Gly 0.95, Asp 0.91
, peptide lipid-7 C15H31CO-Arg-Gly-Asp-Ser-
NH-C16H33FAB-MS (Pos.) (M+N
a)+917(M+H)+895FAB-MS(Neg
.. )(M+Na)-917(MH)-893 Amino acid analysis: Arg 0.97, Gly 0.98, Asp
0.88, Ser 0.75 Peptide lipid-8 C17H35CO-Gly-Arg-Gly-Asp-
Thr-NH-C18H37FAB-MS (Pos.)
(M+Na)+1043(M+H)+1022FAB-
MS(Neg.)(M+Na)-1043(MH)-
1020 amino acid analysis: Arg 0.94, Gly 1
.. 84, Asp 0.92, Thr 0.72 Peptide lipid-9 FAB-MS (Pos.) (M+Na)+943 (M+
H)+921FAB-MS(Neg.)(M+Na)-
943(MH)-919 amino acid analysis: Arg 0.
99, Gly 0.95, Asp 0.96, Peptide lipid-10 C17H35CO(Arg-Gly-Asp)2-O-
C18H37FAB-MS (Pos.) (M+Na)+
1215(M+H)+1193FAB-MS(Neg.
)(M+Na)-1215(MH)-1191 Amino acid analysis: Arg 1.99, Gly 1.94, Asp
1.92, peptide lipid-11 C13H27CO-(Arg-Gly-Asp-Ser
) 2-NH-C14H29FAB-MS (Pos.) (
M+Na)+1276(M+H)+1254FAB-M
S(Neg.)(M+Na)-1276(MH)-1
252 amino acid analysis: Arg 1.92, Gly 1.
95, Asp 1.79, Ser 1.53 Peptide lipid-12 C15H31CO-(Arg-Gly-Asp)3-O
-C16H33FAB-MS (Pos.) (M+Na)
+1487(M+H)+1465FAB-MS(Neg
.. )(M+Na)-1487(MH)-1463 Amino acid analysis: Arg 3.03, Gly 2.81, As
p 3.01, peptide lipid-13 C9H19CO-Arg-Gly-Asp-Ser-P
ro-NH-C10H21FAB-MS (Pos.) (
M+H)+825FAB-MS(Neg.)(M+H)
-823 Peptide Lipid-14 FAB-MS (Pos.) (M+H)+1022FAB
-MS(Neg.)(M+H)-1020 The compound of the present invention can be synthesized, for example, by the following four-step process. ■ Condensation of a protected amino acid with R2-Z-H (R2 is a corresponding alkyl group, Z represents -O- or -NH-) ■ Sequential stretching of a protected amino acid ■ Condensation with R1-W (R1 is This represents a corresponding acyl group. W represents a hydroxyl group or a halogen atom.) (1) Deprotection and purification Each step of the process will be explained in detail below. ■In the case of the compound represented by the general formula [I], the protected form of the amino acid represented by Y or, if Y does not exist, the protected form of Asp and the corresponding R2-Z-H are condensed to form an ester or amide. . Regarding condensation, DCC method, DCC-additive
General methods such as the method and CDI method are adopted. ■There are known methods for sequentially elongating protected amino acids, such as "Basics and Experiments of Peptide Synthesis" edited by Izumiya et al.
Maruzen) and “PRINCIPLES” by Bodanszky.
OF PEPTIDE SYNTHESIS“THE
PRACTICE OF PEPTIDE SYNTH
SIS” (Springer Verlag, New Y
All of the methods described in (ork) are effective. At the stage of condensation reaction, DCC method, DCC-additi
Any of the ve method, azide method, CDI method, mixed acid anhydride method, and activated ester method may be employed, but the DCC-HOBt method using 1-hydroxybenzotriazole (HOBt) and DCC in combination is preferred. ■ Corresponding R1-OH and ([X]-Arg-Gly-A
The methods for condensing with sp-[Y])n-Z-R2 include DCC method, DCC-additive method, CDI method,
Either one may be adopted. Further, amidation may be performed by changing R1-OH to an acid chloride such as R1-Cl. Regarding peptide lipids with many amino acid residues, R1
-, R2-Z- It is preferable to perform sequential peptide elongation from both ends and perform fragment condensation. This condensation method follows method (2) above. ■The conditions used to deprotect a protecting group are highly dependent on the type of protecting group used. Commonly used deprotection methods include hydrolysis, trifluoroacetic acid, anhydrous hydrogen fluoride, trifluoromethanesulfonic acid-thioanisole mixed system, trifluoroacetic acid-thioanisole mixed system, etc., but depending on the type of protecting group. Even more diverse methods are possible. Below, peptide lipid-2 and peptide lipid-6 of the present invention
and peptide lipid-10, but the synthesis method of the present invention is not limited thereto. In addition, the peptide lipids (1) - (12) shown as preferred specific examples of the compounds of the present invention are R1 corresponding to the corresponding Boc-amino acids in which the amino acid side chain is protected with benzyl ether, benzyl thioether or benzyl ester.
-OH and the corresponding R2-OH or R2-NH2
can be synthesized in the same manner as in the synthesis example shown below. Example 1 Synthesis of Peptide Lipid-2 5.9 g of Boc-serine benzyl ether, 4.8 g of hexadecyl alcohol (Catechol 60, Kao product), 4.6 g of dicyclohexylcarbodiimide, and 0.24 g of dimethylaminopyridine were dissolved in dichloromethane. 10
The mixture was stirred at ℃ overnight. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and purified by silica gel chromatography (eluent: chloroform) to obtain Boc-Ser(Bzl)-OC16.
10.3 g of H33 was obtained. Next, Boc-Ser(Bzl)-OC16H33 1
0.3g of dichloromethane and trifluoroacetic acid mixture (
20ml/20ml) and stirred for 30 minutes. After the solvent was distilled off under reduced pressure, it was dissolved in chloroform, treated with a saturated aqueous sodium bicarbonate solution, and the organic layer was dried with sulfur salt.The chloroform was distilled off under reduced pressure to obtain Ser(Bzl).
-OC16H33 9.3g was obtained. Boc-aspartic acid-β-benzyl ester 7.1
g, Ser(Bzl)-OC16H33 9.3g, 1
4.9 g of dicyclohexylcarbodiimide was added to 60 ml of a mixed solution of 3.7 g of -hydroxybenzotriazole in dichloromethane and dimethylformamide, and the mixture was stirred all day and night. The reaction solution was filtered, the filtrate was distilled off under reduced pressure, and then dissolved in chloroform. After washing the organic layer with a saturated aqueous sodium bicarbonate solution and drying it over salt water, chloroform was distilled off under reduced pressure.
The residue was purified by silica gel chromatography (eluent: hexane/ethyl acetate = 6/4) to obtain Boc-Asp.
(OBzl)-Ser(Bzl)-OC16H33 1
4.2g was obtained. Then Boc-Asp(OBzl)-Ser(Bzl)
-Dissolve 14.2 g of OC16H33 in dichloromethane and trifluoroacetic acid mixture (20 ml/20 ml) and
Stirred for 0 minutes. After distilling off the solvent under reduced pressure, it was dissolved in chloroform and treated with a saturated aqueous solution of sodium bicarbonate, and the organic layer was dried over sulfur salt.The chloroform was distilled off under reduced pressure to obtain Asp(OBzl).
-Ser(Bzl)-OC16H33 13.5g was obtained. Asp(OBzl)-Ser(Bzl)-OC16H3
3 Dissolve 13.5g in dichloromethane 50ml,
8.7 g of oc-glycine anhydride was added and stirred overnight.
The reaction solution was washed with a saturated aqueous solution of sodium hydrogen carbonate and dried with Boc-Gly. Dichloromethane was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (eluent dichloromethane/ethyl acetate = 6/4) to obtain Boc-Gly. -Asp(OBzl)-Ser(Bzl
)-OC16H33 11.8g was obtained. Next, Boc-Gly-Asp(OBzl)-Ser(
Bzl)-OC16H3311.8g was dissolved in a dichloromethane/trifluoroacetic acid mixture (20ml/20ml) and stirred for 30 minutes. After distilling off the solvent under reduced pressure, it was dissolved in chloroform and treated with a saturated aqueous solution of sodium bicarbonate, and the organic layer was dried with sulfur salt. The chloroform was distilled off under reduced pressure to give Gly-Asp(O
Bzl)-Ser(Bzl)-OC16H33 10.
2g was obtained. Boc-Arg(Z)2 8.4g, 1-hydroxybenzotriazole 2.4g, Gly-Asp(OBzl
)-Ser(Bzl)-OC16H33 10.2g dichloromethane, dimethylformamide mixture 60ml
20 ml of a dichloromethane solution containing 3.2 g of dicyclohexylcarbodiimide was added to the mixture, and the mixture was stirred all day and night. The reaction solution was filtered, the filtrate was distilled off under reduced pressure, and then dissolved in chloroform. After washing the organic layer with a saturated aqueous solution of sodium hydrogen carbonate and drying with sulfur salt, chloroform was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (eluent dichloromethane/ethyl acetate = 6/4), and then purified with ethyl acetate. Recrystallized Boc-Arg(Z)2-Gly-As
p(OBzl)-Ser(Bzl)-OC16H336
.. 6g was obtained. Boc-Arg(Z)2-Gly-Asp(OBzl)
-Ser(Bzl)-OC16H332.0g Dichloromethane, trifluoroacetic acid mixture (20ml/20ml
) and stirred for 30 minutes. After distilling off the solvent under reduced pressure, it was dissolved in chloroform and treated with a saturated aqueous solution of sodium bicarbonate, and the organic layer was dried with sulfur salt.The chloroform was distilled off under reduced pressure to obtain Arg(Z)2-G.
ly-Asp(OBzl)-Ser(Bzl)-OC1
1.5 g of 6H33 was obtained. After dissolving 0.56 g of palmitic acid and 0.23 g of dicyclohexylcarbodiimide in 50 ml of dichloromethane and stirring at room temperature for 1 hour, Arg(Z)2-Gly-A
sp(OBzl)-Ser(Bzl)OC16H33
30 ml of a dichloromethane solution containing 1.1 g was added, and the mixture was stirred all day and night. The reaction solution was filtered, the filtrate was washed with a saturated aqueous sodium bicarbonate solution and dried over salt water, and then dichloromethane was distilled off under reduced pressure. The residue was purified by silica gel chromatography (
Eluent chloroform/ethyl acetate = 5/5), then recrystallized from chloroform and ethyl acetate to obtain C15H31CO
-Arg(Z)2-Gly-Asp(OBzl)-Se
1.3 g of r(Bzl)-OC16H33 was obtained. C15H31Co-Arg(Z)2-Gly-Asp(
OBzl)-Ser(Bzl)-OC16H33 50
0 mg was dissolved in 70 ml of acetic acid, 150 mg of platinum dioxide was added, and hydrolysis was performed at 50°C. The reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was recrystallized from acetic acid and ethyl acetate to give C15H31C
O-Arg-Gly-Asp-Ser-OC16H33
260 mg was obtained. Example 2 Synthesis of Peptide Lipid-6 Boc-aspartic acid-β-benzyl ester 6.5
g, 1-tetradecylamine 4.3g, 1-hydroxybenzotriazole 3.1g, dicyclohexylcarbodiimide 4.6g, dimethylaminopyridine 0.24g
was dissolved in dichloromethane and stirred at 10°C overnight. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and purified by silica gel chromatography (eluent: chloroform).
c-Asp(OBzl)-NH-C14H29 9.7
I got g. Next, Boc-Asp(OBzl)-NH-C14H2
9.7 g was dissolved in dichloromethane and trifluoroacetic acid mixture (20 ml/20 ml) and stirred for 30 minutes. After distilling off the solvent under reduced pressure, it was dissolved in chloroform, treated with a saturated aqueous solution of sodium bicarbonate, and the organic layer was dried with salt water.
)-NH-C14H29 9.3g was obtained. 9.3 g of Asp(OBzl)-NH-C14H29 was dissolved in 40 ml of dichloromethane, 10.0 g of Boc-glycine anhydride was added, and the mixture was stirred all day and night. After washing the reaction solution with a saturated aqueous solution of sodium hydrogen carbonate and drying the dichloromethane under reduced pressure, the residue was purified by silica gel chromatography (eluent dichloromethane/ethyl acetate = 6/4) to obtain Boc-Gly- Asp(OBzl)
-NH-C14H29 9.1g was obtained. Next, Boc-Gly-Asp(OBzl)-NH-C
9.1 g of 14H29 was dissolved in a mixture of dichloromethane and trifluoroacetic acid (20 ml/20 ml) and stirred for 30 minutes. After distilling off the solvent under reduced pressure, it was dissolved in chloroform and treated with a saturated aqueous solution of sodium bicarbonate, and the organic layer was dried with sulfur salt. The chloroform was distilled off under reduced pressure to give Gly-Asp(O
8.8 g of Bzl)-NH-C14H29 was obtained. Boc-Arg(Z)2 9.5g, 1-hydroxybenzotriazole 2.8g, Gly-Asp(OBzl
)-NH-C14H 298.8 g of dichloromethane and 60 ml of dimethylformamide mixture to 20 ml of dichloromethane solution of 3.7 g of dicyclohexylcarbodiimide
was added and stirred overnight. The reaction solution was filtered, the filtrate was distilled off under reduced pressure, and then dissolved in chloroform. After washing the organic layer with a saturated aqueous solution of sodium hydrogen carbonate and drying with sulfur salt, chloroform was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent dichloromethane/ethyl acetate = 7/3), and then purified with ethyl acetate. Recrystallized Boc-Arg(Z)2-Gly-As
12.4 g of p(OBzl)-NH-C14H29 was obtained. Boc-Arg(Z)2-Gly-Asp(OBzl)
-NH-C14H29 2.0g was dissolved in dichloromethane and trifluoroacetic acid mixture (20ml/20ml) and stirred for 30 minutes. After distilling off the solvent under reduced pressure, it was dissolved in chloroform and treated with a saturated aqueous solution of sodium bicarbonate, and the organic layer was dried with sulfur salt.The chloroform was distilled off under reduced pressure to obtain Arg(Z)2-G.
ly-Asp(OBzl)-NH-C14H29 1.
8g was obtained. 0.45 g of myristic acid and 0.23 g of dicyclohexylcarbodiimide were dissolved in 50 ml of dichloromethane, and after stirring at room temperature for 1 hour, Arg(Z)2-Gly-As
A solution of 1.4 g of p(OBzl)-NH-C14H29 in 30 ml of dichloromethane was added, and the mixture was stirred all day and night. The reaction solution was filtered, the filtrate was washed with a saturated aqueous sodium bicarbonate solution and dried over salt water, and then dichloromethane was distilled off under reduced pressure. The residue was purified by silica gel chromatography (
After eluent dichloromethane/ethyl acetate = 6/4),
Recrystallize from chloroform and ethyl acetate to obtain C13H27CO
-Arg(Z)2-Gly-Asp(OBzl)-NH
-C14H29 1.7g was obtained. C13H27CO-Arg(Z)2-Gly-Asp(
OBzl)-NH-C14H29500mg to acetic acid 70
ml, and 150 mg of platinum dioxide was added thereto, followed by hydrogenolysis at 50°C. The reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was recrystallized from acetic acid and ethyl acetate to give C13H27CO-Arg-Gly-Asp-NH-
220 mg of C14H29 was obtained. Example 3 Synthesis of peptide lipid-10 (Asp(OBzl)-Arg(Z)2-Gly-As
Synthesis of p(OBzl)-O-C18H37) Boc-aspartic acid-β-benzyl ester 6.5
g, octadecyl alcohol 5.4 g, dicyclohexylcarbodiimide 4.6 g, dimethylaminopyridine 0
.. 24g was dissolved in dichloromethane and stirred at 10°C all day and night. Filter the reaction solution, concentrate the filtrate under reduced pressure, and purify with silica gel chromatography (eluent: chloroform).
Boc-Asp(OBzl)-O-C18H37
10.3g was obtained. Next, Boc-Asp(OBzl)-O-C18H37
10.3 g was dissolved in a dichloromethane/trifluoroacetic acid mixture (20 ml/20 ml) and stirred for 30 minutes. After distilling off the solvent under reduced pressure, it was dissolved in chloroform, treated with a saturated aqueous solution of sodium bicarbonate, and the organic layer was dried with salt water.
)-O-C18H37 8.2g was obtained. 8.2 g of Asp(OBzl)-O-C18H37 was dissolved in 40 ml of dichloromethane, 12.0 g of Boc-glycine anhydride was added, and the mixture was stirred all day and night. After washing the reaction solution with a saturated aqueous sodium hydrogen carbonate solution and drying it with salt water, dichloromethane was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (eluent dichloromethane/ethyl acetate=
6/4) and Boc-Gly-Asp(OBzl)-O
-C18H37 10.7g was obtained. Next, Boc-Gly-Asp(OBzl)-O-C1
10.7 g of 8H37 was dissolved in a dichloromethane/trifluoroacetic acid mixture (20 ml/20 ml) and stirred for 30 minutes. After distilling off the solvent under reduced pressure, it was dissolved in chloroform and treated with a saturated aqueous solution of sodium bicarbonate, and the organic layer was dried with sulfur salt. The chloroform was distilled off under reduced pressure to give Gly-Asp(O
9.1 g of Bzl)-O-C18H37 was obtained. Boc-Arg(Z)2 9.1g, 1-hydroxybenzotriazole 2.5g, Gly-Asp(OBzl
)-O-C18H37 A solution of 3.4 g of dicyclohexylcarbodiimide in 20 ml of dichloromethane in 60 ml of a mixture of 8.8 g of dichloromethane and dimethylformamide.
was added and stirred overnight. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and then dissolved in chloroform. After washing the organic layer with a saturated aqueous solution of sodium hydrogen carbonate and drying with sulfur salt, chloroform was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent dichloromethane/ethyl acetate = 7/3), and then purified with ethyl acetate. Recrystallize to form Boc-Arg(Z)2-Gly-A
13.7 g of sp(OBzl)-O-C18H37 was obtained. Boc-Arg(Z)2-Gly-Asp(OBzl)
13.7 g of -O-C18H37 was dissolved in a dichloromethane/trifluoroacetic acid mixture (20 ml/20 ml) and stirred for 30 minutes. After distilling off the solvent under reduced pressure, it was dissolved in chloroform, treated with a saturated aqueous solution of sodium bicarbonate, and the organic layer was dried with sulfur salt.The chloroform was distilled off under reduced pressure to obtain Arg(Z)2-
Gly-Asp(OBzl)-O-C18H3712.
4g was obtained. Boc-aspartic acid-β-benzyl ester 4.2
g, Arg(Z)2-Gly-Asp(OBzl)-O
After dissolving 12.4 g of -C18H3 and 2.9 g of 1-hydroxybenzotriazole in 50 ml of dichloromethane, 3.9 g of dicyclohexylcarbodiimide was added and stirred all day and night. The reaction solution was filtered, the filtrate was washed with a saturated aqueous sodium bicarbonate solution and dried over salt water, and then dichloromethane was distilled off under reduced pressure. The residue was purified by silica gel chromatography (
Eluent chloroform/ethyl acetate = 6/4) and Boc
-Asp-(OBzl)-Arg(Z)2-Gly-A
713.9 g of sp(OBzl)-O-C18H3 was obtained. Boc-Asp(OBzl)-Arg(Z)2-Gly
-Asp(OBzl)-O-C18H3713.9g was mixed with dichloromethane and trifluoroacetic acid mixture (20ml/
20 ml) and stirred for 30 minutes. After distilling off the solvent under reduced pressure, it was dissolved in chloroform, treated with a saturated aqueous solution of sodium bicarbonate, and the organic layer was dried with salt water.
)-Arg(Z)2-Gly-Asp(OBzl)-O
12.2g of -C18H37 was obtained. (Synthesis of C17H35-CO-Arg(Z)2-Gly-) N-hydroxysuccinimide 2.5.6 g of stearic acid and 4.2 g of dicyclohexylcarbodiimide were dissolved in 100 ml of dichloromethane and stirred at room temperature.
3 g was added and stirred all day and night. The reaction solution was filtered, and the filtrate was washed with water and dried over salt water, and then dichloromethane was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent hexane/ethyl acetate 8/2). continue,
Fractional crystallization was performed in an ethyl acetate/hexane system to remove the condensing agent transfer product to obtain 2.7 g of stearic acid-N-hydroxysuccinimide ester. 2.7 g of stearic acid-N-hydroxysuccinimide ester, 3.5 g of Arg(Z)2-Gly, and 0.2 g of dimethylaminopyridine were dissolved in dichloromethane and stirred overnight. The reaction solution was washed with a saturated aqueous sodium hydrogen carbonate solution and an aqueous citric acid solution, and then dried over sulfate. The residue was recrystallized from dichloromethane/ethyl acetate system to obtain C17H.
5.8 g of 35CO-Arg(Z)2-Gly was obtained. (C17H35CO-(Arg-Gly-Asp)2-
Synthesis of O-C18H37) C17H35CO obtained above
-Arg(Z)2-Gly0.75gAsp(OBzl
)-Arg(Z)2-Gly-Asp(OBzl)-O
-C18H371.16g, synchhexylcarbodiimide 2.1g, 1-hydroxybenzotriazole 1
.. 53 g of dimethylaminopyridine and 0.3 g of dimethylaminopyridine were dissolved in 100 ml of dichloromethane-DMF mixture and stirred overnight. The reaction solution was distilled off under reduced pressure, dichloromethane was added to the residue, and the organic layer was dissolved in a saturated aqueous sodium bicarbonate solution and a citric acid aqueous solution. Washed with salt and dried. Dichloromethane was distilled off under reduced pressure and the residue was purified by silica gel chromatography (eluent chloroform/ethyl acetate - 4/6), then recrystallized from dichloromethane-ethyl acetate system to obtain C17H35CO-(Arg(Z)2- Gly-Asp
(OBzl)) 0.85 g of 2-O'-C18H37 was obtained. C17H35CO-(Arg(Z)2-Gly-ASP
(OBzl)) 370.5g of 2-O-C18H was dissolved in acetic acid 4
0 ml, add 200 mg of 5% palladium on carbon and 200 mg of platinum dioxide, and perform hydrolysis (65°C) to obtain C17H35CO-(Arg-Gly-Asp)2-
0.08g of O-C18H37 was obtained. Example 4 Synthesis of Peptide Lipid-14 50 g of farnesol was dissolved in 350 ml of ethanol, 500 mg of platinum dioxide was added, and hydrolysis was carried out for 12 hours. The reaction solution was filtered using Celite, and the filtrate was concentrated under reduced pressure to quantitatively obtain 3,7,11-trimethyldodecyl alcohol. 10 g of 3,7,11-trimethyldodecyl alcohol was dissolved in acetone, and Jones reagent (Org.Syntheses) was added under stirring at room temperature.
Col. Volume 4, page 310) was added dropwise. Ethyl acetate was added to the reaction solution, and the organic layer was washed with saturated brine, dried over borax, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent hexane/ethyl acetate 9/1),
, 8.6 g of 7,11-trimethyldodecanoic acid was obtained. DCC condensation was performed in the same manner as in Example 1 using 21.5 g of Boc-Pro, 20.6 g of dicyclohexylcarbodiimide (DCC), 22.8 g of 3,7,11-trimethyldodecyl alcohol, and 10.1 g of triethylamine. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. Dissolve the residue in 50 ml of dichloromethane and add 50 ml of trifluoroacetic acid.
ml was added and stirred for 30 minutes. The reaction solution was concentrated under reduced pressure. Subsequently, in the same manner as in Example 1, DCC-additive
Boc-Ser (Bzl) by e method, symmetric acid anhydride method
, Boc-Asp(OBzl), Boc-glycine anhydride, Boc-Arg(Z)2, Boc-glycine anhydride and condensation with 3,7,11-trimethyldodecanoic acid, 5% -Deprotection was performed using palladium on carbon. Purification was carried out in the same manner as in Example 1 by recrystallization and ion exchange to obtain peptide lipid-14. [Utility] The uninvented compound is useful as a cell migration inhibitor, a cell adhesion membrane, and a cell culture substrate.

Claims (4)

【特許請求の範囲】[Claims] 【請求項1】下記、一般式〔I〕で示される合成ペプチ
ド 脂質またはその塩。 R1−(〔X〕−Arg−Gly−Asp−〔Y〕)n
−Z−R2…〔I〕式中、Arg、Gly、Aspはそ
れぞれアルギニン、グリシン、アスパラギン酸残基を示
す。 〔X〕、〔Y〕は、存在するかあるいは存在しないアミ
ノ酸残基または、二つあるいは三つのアミノ酸残基から
なるペプチド残基を示す。 nは1〜5の整数を示す。Zは−O−または−NH−を
示す。 R1は炭素数8〜24の直鎖または分岐のアシル基であ
り、置換基、不飽和基を有していてもよい。R2は炭素
数8〜24の直鎖または分岐のアルキル基であり、置換
基、不飽和基を有していてもよい。
Claims 1: A synthetic peptide lipid represented by the following general formula [I] or a salt thereof. R1-([X]-Arg-Gly-Asp-[Y])n
-Z-R2...[I] In the formula, Arg, Gly, and Asp represent arginine, glycine, and aspartic acid residues, respectively. [X] and [Y] represent an amino acid residue that is present or absent, or a peptide residue consisting of two or three amino acid residues. n represents an integer of 1 to 5. Z represents -O- or -NH-. R1 is a linear or branched acyl group having 8 to 24 carbon atoms, and may have a substituent or an unsaturated group. R2 is a straight chain or branched alkyl group having 8 to 24 carbon atoms, and may have a substituent or an unsaturated group.
【請求項2】〔X〕、〔Y〕が、存在するアミノ酸残基
または、二つあるいは三つのアミノ酸残基からなるペプ
チド残基を示し、〔X〕、〔Y〕は、Ser、Gly、
Val、Asn、Pro、Cys、Thrから選択され
るアミノ酸で残基または、これらのアミノ酸残基の組み
合わせにより構成されるペプチド残基である請求項(1
)記載の合成ペプチド脂質。Ser、Val、Asn、
Pro、Cys、Thrはそれぞれセリン、バリン、ア
スパラギン、プロリン、システイン、トレオニン残基を
示す。
[Claim 2] [X] and [Y] represent existing amino acid residues or peptide residues consisting of two or three amino acid residues, and [X] and [Y] represent Ser, Gly,
Claim (1) is a peptide residue composed of an amino acid residue selected from Val, Asn, Pro, Cys, and Thr or a combination of these amino acid residues.
) Synthetic peptide lipids described in ). Ser, Val, Asn,
Pro, Cys, and Thr represent serine, valine, asparagine, proline, cysteine, and threonine residues, respectively.
【請求項3】下記式〔II〕で示される請求項(1)記
載の合成ペプチド脂質。 R1−(Arg−Gly−Asp−Ser)n−Z−R
2…〔II〕式中、nは1〜5の整数を示し、Zは−O
−または−NH−を示す。 R1は炭素数8〜24の直鎖または分岐のアシル基であ
り、置換基、不飽和基を有していてもよい。R2は炭素
数8〜24の直鎖または分岐のアルキル基であり、置換
基、不飽和基を有していてもよい。
3. The synthetic peptide lipid according to claim 1, which is represented by the following formula [II]. R1-(Arg-Gly-Asp-Ser)n-Z-R
2... [II] In the formula, n represents an integer of 1 to 5, and Z is -O
- or -NH-. R1 is a linear or branched acyl group having 8 to 24 carbon atoms, and may have a substituent or an unsaturated group. R2 is a straight chain or branched alkyl group having 8 to 24 carbon atoms, and may have a substituent or an unsaturated group.
【請求項4】下記式〔III〕で示される請求項(1)
記載の合成ペプチド脂質。 R1−(Arg−Gly−Asp)n−Z−R2….〔
III〕式中、nは1〜5の整数を示し、Zは−O−ま
たは−NH−を示す。 R1は炭素数8〜24の直鎖または分岐のアシル基であ
り、置換基、不飽和基を有していてもよい。R2は炭素
数8〜24の直鎖または分岐のアルキル基であり、置換
基、不飽和基を有していてもよい。
Claim 4: Claim (1) represented by the following formula [III]
The synthetic peptide lipids described. R1-(Arg-Gly-Asp)n-Z-R2.... [
III] In the formula, n represents an integer of 1 to 5, and Z represents -O- or -NH-. R1 is a linear or branched acyl group having 8 to 24 carbon atoms, and may have a substituent or an unsaturated group. R2 is a straight chain or branched alkyl group having 8 to 24 carbon atoms, and may have a substituent or an unsaturated group.
JP2333336A 1990-10-26 1990-11-29 Peptide lipid Pending JPH04221395A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP2333336A JPH04221395A (en) 1990-10-26 1990-11-29 Peptide lipid

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
JP28949490 1990-10-26
JP2-289494 1990-10-26
JP2333336A JPH04221395A (en) 1990-10-26 1990-11-29 Peptide lipid

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5670483A (en) * 1992-12-28 1997-09-23 Massachusetts Insititute Of Technology Stable macroscopic membranes formed by self-assembly of amphiphilic peptides and uses therefor
WO2004087106A1 (en) * 2003-03-31 2004-10-14 Fujirebio Inc. Method of controlling release speed of subject to be transported from liposome
WO2017217855A1 (en) * 2016-06-17 2017-12-21 Erasmus University Medical Center Rotterdam Geminoid lipopeptide compounds and their uses

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5670483A (en) * 1992-12-28 1997-09-23 Massachusetts Insititute Of Technology Stable macroscopic membranes formed by self-assembly of amphiphilic peptides and uses therefor
WO2004087106A1 (en) * 2003-03-31 2004-10-14 Fujirebio Inc. Method of controlling release speed of subject to be transported from liposome
WO2017217855A1 (en) * 2016-06-17 2017-12-21 Erasmus University Medical Center Rotterdam Geminoid lipopeptide compounds and their uses

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