JPH0415224A - Poly(amino acid) and its preparation - Google Patents
Poly(amino acid) and its preparationInfo
- Publication number
- JPH0415224A JPH0415224A JP11819690A JP11819690A JPH0415224A JP H0415224 A JPH0415224 A JP H0415224A JP 11819690 A JP11819690 A JP 11819690A JP 11819690 A JP11819690 A JP 11819690A JP H0415224 A JPH0415224 A JP H0415224A
- Authority
- JP
- Japan
- Prior art keywords
- group
- formula
- water
- poly
- side chain
- 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
Links
- 229920001308 poly(aminoacid) Polymers 0.000 title claims abstract description 12
- -1 Poly(amino acid) Polymers 0.000 title abstract description 13
- 125000003368 amide group Chemical group 0.000 claims abstract description 34
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 25
- 125000003277 amino group Chemical group 0.000 claims abstract description 20
- 239000000126 substance Substances 0.000 claims abstract description 9
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 7
- 125000003710 aryl alkyl group Chemical group 0.000 claims abstract description 6
- 239000002253 acid Substances 0.000 claims description 35
- 238000006116 polymerization reaction Methods 0.000 claims description 9
- 238000004519 manufacturing process Methods 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 239000001257 hydrogen Substances 0.000 claims description 7
- 125000000962 organic group Chemical group 0.000 claims description 7
- 239000012670 alkaline solution Substances 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 2
- 239000003513 alkali Substances 0.000 abstract description 5
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- 239000012528 membrane Substances 0.000 description 10
- 150000001413 amino acids Chemical class 0.000 description 8
- 238000010586 diagram Methods 0.000 description 8
- 238000000034 method Methods 0.000 description 8
- 229920000642 polymer Polymers 0.000 description 7
- 238000006460 hydrolysis reaction Methods 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- 108091006146 Channels Proteins 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 239000004472 Lysine Substances 0.000 description 4
- 239000008346 aqueous phase Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000003012 bilayer membrane Substances 0.000 description 3
- 150000002431 hydrogen Chemical group 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 235000018977 lysine Nutrition 0.000 description 3
- 239000002356 single layer Substances 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 108010052285 Membrane Proteins Proteins 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 235000001014 amino acid Nutrition 0.000 description 2
- 229940024606 amino acid Drugs 0.000 description 2
- 229960001230 asparagine Drugs 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000000084 colloidal system Substances 0.000 description 2
- 239000000470 constituent Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 2
- 238000005192 partition Methods 0.000 description 2
- 230000000379 polymerizing effect Effects 0.000 description 2
- 238000013268 sustained release Methods 0.000 description 2
- 239000012730 sustained-release form Substances 0.000 description 2
- JITSWUFGPFIMFG-UHFFFAOYSA-N 1,1,2,2,4-pentachlorobutane Chemical compound ClCCC(Cl)(Cl)C(Cl)Cl JITSWUFGPFIMFG-UHFFFAOYSA-N 0.000 description 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- IGHBXJSNZCFXNK-UHFFFAOYSA-N 4-chloro-7-nitrobenzofurazan Chemical compound [O-][N+](=O)C1=CC=C(Cl)C2=NON=C12 IGHBXJSNZCFXNK-UHFFFAOYSA-N 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 108090000862 Ion Channels Proteins 0.000 description 1
- 102000004310 Ion Channels Human genes 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 238000005904 alkaline hydrolysis reaction Methods 0.000 description 1
- 125000002947 alkylene group Chemical group 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 238000002189 fluorescence spectrum Methods 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000012456 homogeneous solution Substances 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 125000001165 hydrophobic group Chemical group 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- TYZROVQLWOKYKF-ZDUSSCGKSA-N linezolid Chemical group O=C1O[C@@H](CNC(=O)C)CN1C(C=C1F)=CC=C1N1CCOCC1 TYZROVQLWOKYKF-ZDUSSCGKSA-N 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000002120 nanofilm Substances 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 229920001281 polyalkylene Polymers 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- WPLOVIFNBMNBPD-ATHMIXSHSA-N subtilin Chemical compound CC1SCC(NC2=O)C(=O)NC(CC(N)=O)C(=O)NC(C(=O)NC(CCCCN)C(=O)NC(C(C)CC)C(=O)NC(=C)C(=O)NC(CCCCN)C(O)=O)CSC(C)C2NC(=O)C(CC(C)C)NC(=O)C1NC(=O)C(CCC(N)=O)NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C1NC(=O)C(=C/C)/NC(=O)C(CCC(N)=O)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)CNC(=O)C(NC(=O)C(NC(=O)C2NC(=O)CNC(=O)C3CCCN3C(=O)C(NC(=O)C3NC(=O)C(CC(C)C)NC(=O)C(=C)NC(=O)C(CCC(O)=O)NC(=O)C(NC(=O)C(CCCCN)NC(=O)C(N)CC=4C5=CC=CC=C5NC=4)CSC3)C(C)SC2)C(C)C)C(C)SC1)CC1=CC=CC=C1 WPLOVIFNBMNBPD-ATHMIXSHSA-N 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
Landscapes
- Polyamides (AREA)
Abstract
Description
【発明の詳細な説明】
〔産業上の利用分野〕
本発明は規則性の良い一次構造を有するポリアミノ酸お
よびその製造方法に関するものである。DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to a polyamino acid having a highly regular primary structure and a method for producing the same.
生体膜の持っている、特定の物質に対する選択透過性、
情報伝達、細胞間の相互認識といった機能は、膜タンパ
ク譬とリン脂質二分子膜との相互作用に依存していると
考えられている。The selective permeability of biological membranes to specific substances,
Functions such as information transmission and mutual recognition between cells are thought to depend on interactions between membrane proteins and phospholipid bilayer membranes.
チャネルを形成するような膜タンパク質の一次構造は、
親・疎水性アミノ酸の周期的配列から成り、これがα−
ヘリックスを形成して二分子膜内で会合することにより
、チャネル内部に親水性残基が、脂質側に疎水性残基が
配向した安定なチャネル構造が形成されると言われてい
る。The primary structure of membrane proteins that form channels is
It consists of a periodic sequence of parent and hydrophobic amino acids, which is α-
It is said that by forming a helix and associating within a bilayer membrane, a stable channel structure is formed in which hydrophilic residues are oriented inside the channel and hydrophobic residues are oriented on the lipid side.
一方、側鎖にアミド基を有するポリマーを、ケン化する
ことにより、アミノ基を有するポリマーに変換すること
は一般に知られている。On the other hand, it is generally known that a polymer having an amide group in its side chain can be converted into a polymer having an amino group by saponifying it.
また、アミド基とアミノ基とを一分子中に有するポリマ
ーは、これら側鎖を有する七ツマ−の重合により得られ
ることも一般に知られている。It is also generally known that a polymer having an amide group and an amino group in one molecule can be obtained by polymerizing heptads having these side chains.
膜タンパク賞様物質として、規則性の良い一次構造を有
するポリアミノ酸を製造するために、前者の方法を用い
ると、側鎖アミド基を有するポリアミノ酸を均−溶液系
で加水分解することにより、アミド基を一定量のアミノ
基に変換することは可能であるが、−次構造はランダム
になってしまう。When the former method is used to produce a polyamino acid with a well-ordered primary structure as a membrane protein-like substance, the polyamino acid having a side chain amide group is hydrolyzed in a homogeneous solution system. Although it is possible to convert an amide group into a certain amount of amino groups, the secondary structure becomes random.
又、後者の方法では、アミド基とアミノ基の量比を一定
の割合に調整することは出来るが、この二つの基を規則
正しく配列させること、即ち、分子の一次構造を制御す
ることは出来ず、ランダムな一次構造をもつものしか製
造することはできなかった。In addition, in the latter method, although it is possible to adjust the ratio of amide groups to amino groups to a certain ratio, it is not possible to arrange these two groups regularly, that is, to control the primary structure of the molecule. , only those with random primary structures could be produced.
本発明は、アミド基側鎖を有するアミノ酸単位とアミノ
基側鎖を有するアミノ酸単位とが規則正しく配列した規
則性の良い一次構造を有するポリアミノ酸およびその製
造方法を提供することを目的とする。An object of the present invention is to provide a polyamino acid having a highly regular primary structure in which amino acid units having an amide group side chain and amino acid units having an amino group side chain are regularly arranged, and a method for producing the same.
すなわち、本発明は下記一般式（１）で示されるアミド
基側鎖を有する構成単位と下記一般式（Ｉｆ）で示され
るアミノ基側鎖を有する構成単位とからなる、α−へリ
ックス構造を有するポリアミノ酸であって、該α−へリ
ンクス構造による棒状分子の軸方向特定の部分側面が、
実質的に一般式（ＩＩ）で示されるアミノ基側鎖の構成
単位であることを特徴とする平均重合度１０以上のポリ
アミノ酸
＋ＨＮ−ＣＨ−Ｃｏ−← ・ ・ ・ ・ （Ｉ）（式
中、Ｘは２価の有機基を表わし、Ｒは水素、アルキル基
またはアラルキル基を表わし、Ｒ′は一価の有機基を表
わす。）
−（−ＨＮ −ＣＨ−ＣＯ−＋−・ ・ ・ ・ （Ｉ
ｌ）（式中、ＸおよびＲは前記式（Ｉ）に同じ）および
、α−へリンクス構造を有し側鎖にアミド基を含有する
ポリアミノ酸の単分子膜を水面上に形成した後、水相に
アルカリ溶液を添加して水中に存在するアミド基を選択
的に加水分解することを特徴とする上記ポリアミノ酸の
製造方法を要旨とするものである。That is, the present invention has an α-helical structure consisting of a constitutional unit having an amide group side chain represented by the following general formula (1) and a constitutional unit having an amino group side chain represented by the following general formula (If). A polyamino acid having a specific partial side surface in the axial direction of the rod-shaped molecule due to the α-helix structure,
A polyamino acid with an average degree of polymerization of 10 or more, which is substantially a constituent unit of the amino group side chain represented by the general formula (II)+HN-CH-Co-← ・ ・ ・ ・ (I) (in the formula , X represents a divalent organic group, R represents hydrogen, an alkyl group or an aralkyl group, and R' represents a monovalent organic group.) -(-HN -CH-CO-+-. . . . (I
l) (wherein X and R are the same as in formula (I) above) and after forming a monomolecular film of a polyamino acid having an α-helix structure and containing an amide group in the side chain on the water surface, The gist of the present invention is the method for producing the polyamino acid described above, which is characterized in that an alkaline solution is added to the aqueous phase to selectively hydrolyze the amide groups present in the water.
本発明に用いるα−へリソクス構造を有し、側鎖にアミ
ド基を含有するポリアミノ酸としては、前記一般式（１
）で示される繰返し単位からなるポリアミノ酸を挙げる
ことができる。The polyamino acid having an α-helical structure and containing an amide group in the side chain used in the present invention has the general formula (1
) is a polyamino acid consisting of a repeating unit represented by:
一般式（１）において、Ｘは２価の有機基、Ｒは水素、
アルキル基またはアラルキル基を表わすが、Ｒのアルキ
ル基としては、メチル、エチル、プロピル、ヘキシル、
オクチル等及び炭素数１８程度までの長鎖アルキル基が
好ましく挙げられ、またアラルキル基としてはベンジル
基、フェネチル基等が好ましく挙げられる。これらのう
ち、特に好ましいのは水素である。またＸとしてはアル
キレン基、又はポリアルキレンアミド基が好ましく挙げ
られる。In general formula (1), X is a divalent organic group, R is hydrogen,
It represents an alkyl group or an aralkyl group, and examples of the alkyl group for R include methyl, ethyl, propyl, hexyl,
Preferred examples include octyl and the like and long-chain alkyl groups having up to about 18 carbon atoms, and preferred aralkyl groups include benzyl and phenethyl groups. Among these, hydrogen is particularly preferred. Moreover, as X, an alkylene group or a polyalkylene amide group is preferably mentioned.
一般式（１）を与えるモノアミノ酸としては、Ｌ−リジ
ン、グルタミン酸、アスパラギン酸が挙げられ、一般式
（１）の単位からなるポリアミノ酸としては、ポリ（Ｎ
−トリフルオロアセチルし一リジン）、ポリ［Ｎ−１
−リフルオロアセチル−し−グルタミン］、ポリ 〔Ｎ
−（β−トリクロロアセチルアミノエチル）−Ｌ−グ
ルタミン〕、ポリ （Ｎ−）リフルオロアセチル−しア
スパラギン〕、ポリ〔Ｎ −（β−トリフルオロアミノ
エチル）−Ｌ−アスパラギン］等が挙げられる。Examples of monoamino acids giving general formula (1) include L-lysine, glutamic acid, and aspartic acid, and examples of polyamino acids consisting of units of general formula (1) include poly(N
-trifluoroacetyl-lysine), poly[N-1
-Lifluoroacetyl-glutamine], poly[N
-(β-trichloroacetylaminoethyl)-L-glutamine], poly(N-)lifluoroacetyl-asparagine], poly[N-(β-trifluoroaminoethyl)-L-asparagine], and the like.
これらポリアミノ酸は、α−アミノ酸−Ｎ−無水物（い
わゆるＮＣＡ）の重合により得られる。These polyamino acids are obtained by polymerization of α-amino acid-N-anhydride (so-called NCA).
例えば、ポリ（Ｎ −トリフルオロアセチル−し−リジ
ン）は、Ｎ −トリフルオロアセチル−しリジン無水物
を、有機アミン、アルコラード、水、アルカリ等の触媒
を用いて公知の方法で重合することにより得られる。For example, poly(N-trifluoroacetyl-lysine) is produced by polymerizing N-trifluoroacetyl-lysine anhydride using a known method using a catalyst such as an organic amine, an alcoholade, water, or an alkali. can get.
単分子膜の製造は、常法（例えば、新実験化学講座１８
巻「界面とコロイド」 （丸善、昭和５２年１０月）ｐ
、４３９〜４９７）によることができる。例えば、前記
ポリアミノ酸を、非水系でかつポリアミノ酸と非会合で
ある溶媒（好ましくは、テトラヒドロフラン、クロロホ
ルム、トリクロロエチレン、エチレンジクロライド、ヘ
ンセン等）に、溶解して０．０１〜１重量％溶液を調製
し、これを水面上に展開し、膜が固体状態になる（即ち
、膜を構成するポリマーの棒状分子が回転等を起こさな
い固定化された状態となる）表面圧で調整し、α−へリ
ノクス構造を有するポリアミノ酸の単分子膜が、形成さ
れる。Monomolecular films can be manufactured using conventional methods (for example, New Experimental Chemistry Course 18).
Volume “Interfaces and Colloids” (Maruzen, October 1978) p.
, 439-497). For example, the polyamino acid is dissolved in a non-aqueous solvent that is non-associated with the polyamino acid (preferably tetrahydrofuran, chloroform, trichloroethylene, ethylene dichloride, Hensen, etc.) to prepare a 0.01 to 1% by weight solution. Then, spread it on the water surface, adjust the surface pressure so that the membrane becomes a solid state (that is, the rod-shaped molecules of the polymer that make up the membrane are in a fixed state that does not cause rotation, etc.), and transfer it to α-. A monolayer of polyamino acids having a linox structure is formed.
次に、図面に従って、本発明の詳細な説明すると、第１
図は本発明の製造方法の各工程を示す図である。水槽１
に水を入れ、仕切り板２を移動させて清浄な水面３とす
る。次にポリアミノ酸の上記溶液をマイクロシリンジ４
を用いて一定量を水面３にゆっくり滴下し、ポリアミノ
酸単分子（α−へリソクス構造を有する棒状分子）５の
膜を展開し仕切り板２を移動させて単分子膜６を作成す
る（１−ａ図）。Next, a detailed explanation of the present invention will be given according to the drawings.
The figure is a diagram showing each step of the manufacturing method of the present invention. Aquarium 1
Fill with water and move the partition plate 2 to create a clean water surface 3. Next, pour the above polyamino acid solution into the microsyringe 4.
A certain amount is slowly dropped onto the water surface 3 using -a figure).
この単分子膜を形成するポリアミノ酸単分子５は、α−
ヘリックス構造を有するので、側鎖アミド基はα−ヘリ
ックス構造を有する棒状分子の表面に、該棒状分子の断
面から見て１００°の間隔をおいて存在する。即ち、ア
ミド基の配列は、その棒状分子の断面に対する投影図（
第２図）の如く、アミド基１８個で５回転（３，６個／
回転）が単位周期である。ただし第２図中の番号は分子
鎖末端アミノ酸の側鎖アミド基を１として示した。The polyamino acid monomolecule 5 forming this monolayer is α-
Since it has a helical structure, the side chain amide groups are present on the surface of a rod-like molecule having an α-helical structure at intervals of 100° when viewed from the cross section of the rod-like molecule. In other words, the arrangement of amide groups can be determined by the projection of the cross section of the rod-shaped molecule (
As shown in Figure 2), 18 amide groups make 5 turns (3,6/
rotation) is the unit period. However, the numbers in FIG. 2 indicate the side chain amide group of the terminal amino acid of the molecular chain as 1.
中分子膜形成時においてアミド基が水側に存在するか非
水（空気）側に在るかは棒状分子の断面に対する水のぬ
れ角度に依存するが、これを１２０゜に採ると、該棒状
分子表面のアミド基は概略÷水側のアミド基−空気側の
アミド基−空気側のアミド基→−のくり返しで形成され
る。Whether the amide group is present on the water side or on the non-water (air) side during the formation of a middle molecular film depends on the wetting angle of water with respect to the cross section of the rod-shaped molecule. The amide group on the surface of the molecule is approximately formed by repeating ÷ amide group on the water side - amide group on the air side - amide group on the air side ->-.
次いでアミド基の５モル以上の量のアルカリを含む水溶
液を、１−ｂ図の如くマイクロシリンジ４等で添加し、
単分子膜６の水相側を加水分解させる。本発明において
は、ポリアミノ酸の棒状分子の回転運動が生しないほど
棒状分子間の相互作用が大きくなる状態、即ち、２層目
の膜形成がはじまる直前の２次元固体状態において、加
水分解を行なうのが好ましい。Next, an aqueous solution containing an alkali in an amount of 5 moles or more of the amide group is added using a microsyringe 4 or the like as shown in Figure 1-b,
The aqueous phase side of the monomolecular film 6 is hydrolyzed. In the present invention, hydrolysis is carried out in a state where the interaction between the rod-shaped molecules of the polyamino acid is so strong that no rotational movement occurs, that is, in a two-dimensional solid state immediately before the formation of the second layer film begins. is preferable.
加水分解時間は、アルカリ溶液が均−分散後５〜１０分
間で十分である。加水分解反応後、アルカリと等モル量
の酸を添加し、反応を停止させる（１−０図）。酸とし
ては、塩酸、リン酸、酢酸等を挙げることができる。A sufficient hydrolysis time is 5 to 10 minutes after the alkaline solution is uniformly dispersed. After the hydrolysis reaction, an equimolar amount of acid to the alkali is added to stop the reaction (Figure 1-0). Examples of acids include hydrochloric acid, phosphoric acid, and acetic acid.
単分子膜製造から中和に至る工程においての水温として
は、５〜３０°Ｃを挙げれることができる。The water temperature in the steps from monomolecular film production to neutralization can be 5 to 30°C.
かくして、水中に存在するアミド基のみ、即ち、単分子
膜の片側のみが加水分解され、概略アミノ基１ケにアミ
ド基２ケのくり返しからなる、規則性のよい一次構造を
有するポリアミノ酸が得られる。In this way, only the amide groups present in water, that is, only one side of the monomolecular film, are hydrolyzed, resulting in a polyamino acid having a highly regular primary structure consisting roughly of one amino group and two amide groups. It will be done.
１−ｄ図は、本発明のポリアミノ酸の構造を示す模式図
であり、５はα−へリソクス構造による棒状体として表
わされるポリアミノ酸分子を示し、６はケン化されてい
ないアミド基側鎖部であり、斜線部７はケン化されたア
ミン基側鎖部であり、アミノ基側鎖部がα−へリンクス
構造による棒状分子の軸方向部分側面に存在することを
示す。Figure 1-d is a schematic diagram showing the structure of the polyamino acid of the present invention, where 5 represents a polyamino acid molecule expressed as a rod with an α-helisox structure, and 6 represents an unsaponified amide group side chain. The shaded part 7 is a saponified amine group side chain part, indicating that the amino group side chain part is present on the side surface of the rod-shaped molecule in the axial direction due to the α-helix structure.
アミド基の加水分解可能な範囲がへリソクス断面に対し
１２０°の範囲であると仮定すると、次の１８個のアミ
ノ酸配列をくり返し単位とする規則性のよい一次構造を
有するポリアミノ酸が得られる。Assuming that the hydrolyzable range of the amide group is 120° with respect to the helisox cross section, a polyamino acid having a highly regular primary structure with the following 18 amino acid sequences as repeating units can be obtained.
−＋−Ｅ Ａ Ｅ Ｅ Ａ Ａ Ｅ Ｅ Ａ Ｅ Ｅ
Ｅ Ａ Ｅ Ｅ Ａ、 Ａ Ｅ −＋−１−（ここでＥ
およびＡは、各々前記一般式（１）のアミド基、一般式
（ＩＩ）のアミノ基を有するアミノ酸単位を示す。）こ
の場合、重合度５７のポリアミノ酸に対するアミノ基の
含率は３６．７モル％となる。同様に加水分解可能な範
囲をｉｏｏ’１４０° １６０°に仮定した時のアミ
ノ基含率ハ、各々３０モル％、４０モル％、４６．７モ
ル％となる。-+-E A E E A A E E A E E
E A E E A, A E −+−1− (here E
and A each represent an amino acid unit having an amide group represented by the general formula (1) and an amino group represented by the general formula (II). ) In this case, the content of amino groups with respect to the polyamino acid with a degree of polymerization of 57 is 36.7 mol%. Similarly, assuming that the hydrolyzable range is ioo'140° to 160°, the amino group contents C are 30 mol%, 40 mol%, and 46.7 mol%, respectively.
本発明のポリアミノ酸は、平均重合度が１０以上、好ま
しくは１５〜１０００のものであり、また、数平均分子
量が１４００〜５００，０００、好ましくは２０００−
１．５０，０００のものである。The polyamino acid of the present invention has an average degree of polymerization of 10 or more, preferably 15-1000, and a number average molecular weight of 1400-500,000, preferably 2000-
1.50,000.
本発明で得られるポリアミノ酸は、両親媒性であり、二
分子膜形成物質に膜チャネルを形成することが出来る。The polyamino acid obtained in the present invention is amphipathic and can form a membrane channel in a bilayer membrane forming substance.
従って、徐放薬剤等への応用が考えられる。Therefore, application to sustained release drugs and the like is possible.
（実施例］
以下、実施例により本発明を更に詳細に説明するが、本
発明は以下の実施例に限定されるものではない。(Examples) Hereinafter, the present invention will be explained in more detail with reference to Examples, but the present invention is not limited to the following Examples.
尚、本実施例におけるポリマーの重合度の測定方法は以
下の通りである。The method for measuring the degree of polymerization of the polymer in this example is as follows.
１）皮遥Ｚ法・・・分光蛍光測定により行った。1) Haruka Z method: Performed by spectrofluorescence measurement.
末端アミノ基をＮＢＤでラヘルして、蛍光スペクトルを
測定し、ポリアミノ酸の仕込み量からアミン当量を出し
てこれを分子量とし、Ｎ −）リフルオロアセチル−
し−リジン等の重合度を算出した。The terminal amino group was treated with NBD, the fluorescence spectrum was measured, the amine equivalent was calculated from the amount of polyamino acid charged, this was taken as the molecular weight, and N-)lifluoroacetyl-
The degree of polymerization of lysine, etc. was calculated.
励起波長：４７５ｒ＋ｍ
発光波長＋５４０ｎｍ
＊ＮＢＤ ７−クロロ−４−ニトロベンゾ−２−オキ
サ−１，３−ジアゾル
実施例１
〈ポリアミノ酸溶液の調製〉
Ｎ −トリフルオロアセチル−し−リジン無水物をテ
トラヒドロフランに７容解してｌ Ｏ％ ？客演とし、
これにトリエチルアミンを加え室温で重合したところ、
重合度５７（分子量（Ｍｎ）、１２８００）のポリ（Ｎ
−トリフルオロアセチル−し−リジン）を得た。これ
を、テトラヒドロフラン（ＴＨＦ）で希釈し、０．１％
濃度に調製した。Excitation wavelength: 475r+m Emission wavelength +540nm *NBD 7-chloro-4-nitrobenzo-2-oxa-1,3-diazole Example 1 <Preparation of polyamino acid solution> N-trifluoroacetyl-cys-lysine anhydride in tetrahydrofuran 7 Do you understand l O%? As a guest performer,
When triethylamine was added to this and polymerized at room temperature,
Poly(N) with a polymerization degree of 57 (molecular weight (Mn), 12800)
-trifluoroacetyl-lysine) was obtained. This was diluted with tetrahydrofuran (THF) and 0.1%
The concentration was adjusted to
く単分子膜の製造〉
前記ポリ（Ｎ−）リフルオロアセチル−し−リジン）
（Ｐｌｙｓ（Ｔｆａ） と略称することがある。）の
０．２％ＴＨＦ溶液を、室温下水面上に展開し、膜が固
体状態となる表面圧状態となる表面圧（即ち、膜を構成
するポリマー分子が固定化された状態となる表面圧）（
第３図）で調整し、α−へリンクス構造を有するポリア
ミノ酸の単分子膜を製造した。（第３図中、矢印のとこ
ろで後述する水酸化カリウム添加を行なった。）
尚、第３図における単分子膜を構成するポリマーの構成
単位の占有面積と表面圧は、前記新実験化学講座第１８
巻「界面とコロイド」に記載の方法に準じて求めた。Production of a monomolecular film>
A 0.2% THF solution of (sometimes abbreviated as Plys (Tfa)) is spread on the water surface at room temperature, and the surface pressure is such that the membrane becomes a solid state. surface pressure at which polymer molecules become immobilized) (
(Fig. 3) to produce a monomolecular film of polyamino acid having an α-helix structure. (Potassium hydroxide, which will be described later, was added at the arrow in Fig. 3.) The occupied area and surface pressure of the polymer constituent units constituting the monomolecular film in Fig. 3 are determined from the above-mentioned New Experimental Chemistry Course. 18
It was determined according to the method described in Vol. ``Interfaces and Colloids''.
〈単分子膜の片側面の加水分解方法〉
室温下で、水相の水酸化カリウム濃度が０４モル（Ｎ−
１−リフルオロアセチル−し−リシン総残基の１０Ｓ倍
モル）となるように、水酸化カリウム溶液を添加し、１
０分間加水分解反応を行なった。その後等量の塩酸で反
応を停止し、目的の片側加水分解の膜を得た。<Hydrolysis method for one side of monomolecular film> At room temperature, the concentration of potassium hydroxide in the aqueous phase is 0.4 mol (N-
Potassium hydroxide solution was added so that the amount was 10S times the total mole of 1-lifluoroacetyl-lysine, and 1
The hydrolysis reaction was carried out for 0 minutes. Thereafter, the reaction was stopped with an equal amount of hydrochloric acid to obtain the desired one-sided hydrolyzed membrane.
第４図にはアルカリ加水分解反応に伴う表面圧の経時変
化を示す。（図中、矢印はＫＯＨを添加した時点を示す
。）ＫＯＨの添加により表面圧は若干低下し約７分で定
常値に達した。このことがら固体状態のＰＬｙｓ （Ｔ
ｆａ）単分子膜中では、ＰＬｙｓ（Ｔｆａ）分子の回転
は起こらず、水相側に配向したトリフルオロアセチル側
鎖のみが選択的に加水分解されたことを確認した。FIG. 4 shows the change in surface pressure over time accompanying the alkaline hydrolysis reaction. (In the figure, the arrow indicates the point at which KOH was added.) The surface pressure decreased slightly due to the addition of KOH, and reached a steady value in about 7 minutes. This means that PLys (T
fa) It was confirmed that rotation of PLys(Tfa) molecules did not occur in the monolayer, and only the trifluoroacetyl side chains oriented toward the aqueous phase were selectively hydrolyzed.
〈加水分解膜の評価〉
第５図にこの片側加水分解膜のＮＭＲを測定した結果を
示す。<Evaluation of Hydrolyzed Membrane> Figure 5 shows the results of NMR measurements of this one-sided hydrolyzed membrane.
得られた片側加水分解膜のトリフルオロ酢酸系での高分
解能ＮＭＲスペクトル（第５図）の主鎖アミド基水素（
７，７ｐｐｍ付近■）と側鎖水素（８、Ｏｐｐｍ付近■
）のピークの面積の比より、し−リジンコンテントは大
過剰のＫＯＨ添加にもかかわらず３４モル％であった。The high-resolution NMR spectrum (Figure 5) using trifluoroacetic acid of the obtained one-side hydrolyzed membrane shows that the main chain amide group hydrogen (
Around 7,7 ppm■) and side chain hydrogen (around 8, Oppm■
), the lysine content was 34 mol % despite the addition of a large excess of KOH.
またこの値はへリックス断面に対するケン化可能な範囲
を１２０°として得たし一リジンコンテントの計算値３
６．７モル％と良好に一致した。This value was obtained assuming that the saponifiable range for the helix cross section was 120°, and the calculated value of the lysine content was 3.
It was in good agreement with 6.7 mol%.
［発明の効果〕
本発明方法によれば、アミド基側鎖を有するアミノ酸単
位とアミノ基側鎖を有するアミノ酸単位とが規則正しく
配列した規則性の良い一次構造を有するポリアミノ酸を
得ることができる。[Effects of the Invention] According to the method of the present invention, a polyamino acid having a highly regular primary structure in which amino acid units having an amide group side chain and amino acid units having an amino group side chain are regularly arranged can be obtained.
本発明のポリアミノ酸は、物質の選択透過等に有用であ
り、例えば、徐放薬剤等に応用可能である。又ヘシクル
に埋め込むと、チャネルを形成することができる。The polyamino acid of the present invention is useful for selective permeation of substances, and can be applied, for example, to sustained release drugs. Also, when embedded in a hesicle, a channel can be formed.
第１図は本発明のポリアミノ酸の製造工程を示す図、第
２図は側鎖エステル基の配列を示す模式図、第３図はポ
リ（Ｎ −トリフルオロアセチル−Ｌ−リジン）の単分
子膜が固体状態となる表面圧を示す図、第４図は表面圧
の経時変化を示す図、第５図は本発明のポリアミノ酸の
ＮＭＲスペクトルを示す図である。
尚、第１図中１は水槽、２は仕切り板、３は清浄な水面
、４はマイクロシリンジ、５は棒状分子、６は単分子膜
をそれぞれ示す。
纂 ）図Figure 1 is a diagram showing the manufacturing process of the polyamino acid of the present invention, Figure 2 is a schematic diagram showing the arrangement of side chain ester groups, and Figure 3 is a monomolecule of poly(N-trifluoroacetyl-L-lysine). FIG. 4 is a diagram showing the surface pressure at which the membrane becomes a solid state, FIG. 4 is a diagram showing the change in surface pressure over time, and FIG. 5 is a diagram showing the NMR spectrum of the polyamino acid of the present invention. In FIG. 1, 1 is a water tank, 2 is a partition plate, 3 is a clean water surface, 4 is a microsyringe, 5 is a rod-shaped molecule, and 6 is a monomolecular film. ) diagram
Claims (2)
する構成単位と下記一般式（II）で示されるアミノ基側
鎖を有する構成単位とからなる、α−ヘリックス構造を
有するポリアミノ酸であって、該α−ヘリックス構造に
よる棒状分子の軸方向特定の部分側面が、実質的に一般
式（II）で示されるアミノ基側鎖を有する構成単位であ
ることを特徴とする平均重合度１０以上のポリアミノ酸
。 ▲数式、化学式、表等があります▼・・・・（ I ） （式中、Ｘは２価の有機基を表わし、Ｒは水素、アルキ
ル基またはアラルキル基を表わし、Ｒ′は一価の有機基
を表わす。） ▲数式、化学式、表等があります▼・・・・（II） （式中、ＸおよびＲは前記（ I ）式と同じ。）(1) A polyamino acid having an α-helical structure consisting of a constitutional unit having an amide group side chain represented by the following general formula (I) and a constitutional unit having an amino group side chain represented by the following general formula (II) The average degree of polymerization is characterized in that a specific partial side surface in the axial direction of the rod-like molecule with the α-helical structure is substantially a constitutional unit having an amino group side chain represented by the general formula (II). 10 or more polyamino acids. ▲There are mathematical formulas, chemical formulas, tables, etc.▼...(I) (In the formula, X represents a divalent organic group, R represents hydrogen, an alkyl group, or an aralkyl group, and R' represents a monovalent organic group. (Represents a group.) ▲There are mathematical formulas, chemical formulas, tables, etc.▼...(II) (In the formula, X and R are the same as in formula (I) above.)
するポリアミノ酸の単分子膜を水面上に形成した後、水
相にアルカリ溶液を添加して水中に存在するアミド基を
選択的に加水分解することを特徴とする、下記一般式（
I ）で示されるアミド基側鎖を有する構成単位と下記
一般式（II）で示されるアミノ基側鎖を有する構成単位
とからなる、α−ヘリックス構造を有するポリアミノ酸
であって、該α−ヘリックス構造による棒状分子の軸方
向特定の部分側面が、実質的に一般式（II）で示される
アミノ基側鎖の構成単位である平均重合度１０以上のポ
リアミノ酸の製造方法。 ▲数式、化学式、表等があります▼・・・・（ I ） （式中、Ｘは２価の有機基を表わし、Ｒは水素、アルキ
ル基またはアラルキル基を表わし、Ｒ′は一価の有機基
を表わす。） ▲数式、化学式、表等があります▼・・・・（II） （式中、ＸおよびＲは前記（ I ）式と同じ。）(2) After forming a monomolecular film of polyamino acids having an α-helical structure and containing amide groups in the side chains on the water surface, an alkaline solution is added to the water phase to selectively remove the amide groups present in the water. The following general formula (
A polyamino acid having an α-helical structure consisting of a constitutional unit having an amide group side chain represented by I) and a constitutional unit having an amino group side chain represented by the following general formula (II), wherein the α- A method for producing a polyamino acid having an average degree of polymerization of 10 or more, in which a specific partial side surface in the axial direction of a rod-like molecule with a helical structure is substantially a constitutional unit of an amino group side chain represented by general formula (II). ▲There are mathematical formulas, chemical formulas, tables, etc.▼...(I) (In the formula, X represents a divalent organic group, R represents hydrogen, an alkyl group, or an aralkyl group, and R' represents a monovalent organic group. (Represents a group.) ▲There are mathematical formulas, chemical formulas, tables, etc.▼...(II) (In the formula, X and R are the same as in formula (I) above.)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP11819690A JPH0415224A (en) | 1990-05-08 | 1990-05-08 | Poly(amino acid) and its preparation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP11819690A JPH0415224A (en) | 1990-05-08 | 1990-05-08 | Poly(amino acid) and its preparation |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH0415224A true JPH0415224A (en) | 1992-01-20 |
Family
ID=14730550
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP11819690A Pending JPH0415224A (en) | 1990-05-08 | 1990-05-08 | Poly(amino acid) and its preparation |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH0415224A (en) |
-
1990
- 1990-05-08 JP JP11819690A patent/JPH0415224A/en active Pending
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