KR101141243B1 - Oligoethylene glycol based gelator comprising cyclic peptides and its preparation method - Google Patents
Oligoethylene glycol based gelator comprising cyclic peptides and its preparation method Download PDFInfo
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- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 title claims abstract description 29
- 102000001189 Cyclic Peptides Human genes 0.000 title claims abstract description 5
- 108010069514 Cyclic Peptides Proteins 0.000 title claims abstract description 5
- 238000002360 preparation method Methods 0.000 title description 3
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 title 1
- 239000003349 gelling agent Substances 0.000 claims abstract description 28
- 238000000034 method Methods 0.000 claims abstract description 7
- 150000001875 compounds Chemical class 0.000 claims description 46
- 239000000126 substance Substances 0.000 claims description 12
- 239000012620 biological material Substances 0.000 claims description 8
- 238000004519 manufacturing process Methods 0.000 claims description 7
- 125000006239 protecting group Chemical group 0.000 claims description 6
- 230000008878 coupling Effects 0.000 claims description 5
- 238000010168 coupling process Methods 0.000 claims description 5
- 238000005859 coupling reaction Methods 0.000 claims description 5
- 239000002537 cosmetic Substances 0.000 claims description 4
- 125000000539 amino acid group Chemical group 0.000 claims description 3
- 239000006143 cell culture medium Substances 0.000 claims description 3
- 238000012377 drug delivery Methods 0.000 claims description 3
- 239000000945 filler Substances 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 238000001879 gelation Methods 0.000 abstract description 26
- 230000000694 effects Effects 0.000 abstract description 6
- 239000002904 solvent Substances 0.000 abstract description 4
- 230000036571 hydration Effects 0.000 abstract description 3
- 238000006703 hydration reaction Methods 0.000 abstract description 3
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 8
- 239000000017 hydrogel Substances 0.000 description 8
- 229940126062 Compound A Drugs 0.000 description 6
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 6
- 235000001014 amino acid Nutrition 0.000 description 5
- 150000001413 amino acids Chemical class 0.000 description 5
- 239000003960 organic solvent Substances 0.000 description 5
- 230000000052 comparative effect Effects 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- NIPNSKYNPDTRPC-UHFFFAOYSA-N N-[2-oxo-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 NIPNSKYNPDTRPC-UHFFFAOYSA-N 0.000 description 3
- AFCARXCZXQIEQB-UHFFFAOYSA-N N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CCNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 AFCARXCZXQIEQB-UHFFFAOYSA-N 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 description 2
- 235000004279 alanine Nutrition 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- ZSIAUFGUXNUGDI-UHFFFAOYSA-N hexan-1-ol Chemical compound CCCCCCO ZSIAUFGUXNUGDI-UHFFFAOYSA-N 0.000 description 2
- 230000002209 hydrophobic effect Effects 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 238000004949 mass spectrometry Methods 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 231100000956 nontoxicity Toxicity 0.000 description 2
- JLFNLZLINWHATN-UHFFFAOYSA-N pentaethylene glycol Chemical compound OCCOCCOCCOCCOCCO JLFNLZLINWHATN-UHFFFAOYSA-N 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 description 1
- NTIGNJOEVBTPJJ-UHFFFAOYSA-N 3,3-dibromopentane Chemical compound CCC(Br)(Br)CC NTIGNJOEVBTPJJ-UHFFFAOYSA-N 0.000 description 1
- 0 CC(C)(C)OC(NC(Cc(cc1)ccc1OCCCCCOc(cc1)ccc1-c(cc1)ccc1OCCCCCOc1ccc(CC(*)C(NC(*)C(OC)=O)=O)cc1)C(NC(*)C(OC)=O)=O)=O Chemical compound CC(C)(C)OC(NC(Cc(cc1)ccc1OCCCCCOc(cc1)ccc1-c(cc1)ccc1OCCCCCOc1ccc(CC(*)C(NC(*)C(OC)=O)=O)cc1)C(NC(*)C(OC)=O)=O)=O 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- 108010016626 Dipeptides Proteins 0.000 description 1
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- -1 biosensors Substances 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000004772 dichloromethyl group Chemical group [H]C(Cl)(Cl)* 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 230000000887 hydrating effect Effects 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 125000002524 organometallic group Chemical group 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- UWHCKJMYHZGTIT-UHFFFAOYSA-N tetraethylene glycol Chemical compound OCCOCCOCCOCCO UWHCKJMYHZGTIT-UHFFFAOYSA-N 0.000 description 1
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
- 231100000820 toxicity test Toxicity 0.000 description 1
- ZIBGPFATKBEMQZ-UHFFFAOYSA-N triethylene glycol Chemical compound OCCOCCOCCO ZIBGPFATKBEMQZ-UHFFFAOYSA-N 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K19/00—Hybrid peptides, i.e. peptides covalently bound to nucleic acids, or non-covalently bound protein-protein complexes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/06—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members
- C07D241/08—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms
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- C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
- C12N5/0018—Culture media for cell or tissue culture
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- Engineering & Computer Science (AREA)
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- Biochemistry (AREA)
- Genetics & Genomics (AREA)
- Biotechnology (AREA)
- Medicinal Chemistry (AREA)
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- Chemical Kinetics & Catalysis (AREA)
- General Engineering & Computer Science (AREA)
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Abstract
본 발명은 고리형 펩티드를 포함하는 올리고(에틸렌 글리콜) 계열 젤화제 및 이의 제조방법에 관한 것이며, 본 발명에 따른 젤화제는 생체 적합성, 다양한 용매에 적용 가능성 및 낮은 농도에서의 젤화 가능성 측면에서 우수한 효과를 달성함과 동시에 젤화 시간, 젤화의 균일성 및 수화젤화 후 수분 보유력 등의 측면에서도 현저한 효과를 보임을 확인하였다.The present invention relates to an oligo (ethylene glycol) -based gelling agent comprising a cyclic peptide and a process for producing the same, and the gelling agent according to the present invention is excellent in biocompatibility, applicability to various solvents, And it is confirmed that the effect is remarkable in terms of gelation time, homogeneity of gelation, and water retention after hydration gelation.
Description
본 발명은 고리형 펩티드를 포함하는 올리고(에틸렌 글리콜) 계열 젤화제 및 이의 제조방법에 관한 것이다.The present invention relates to an oligo (ethylene glycol) -based gelling agent comprising a cyclic peptide and a process for producing the same.
하이드로젤은 초창기 주로 고흡수성을 기반으로 하는 위생용품에 많이 응용되다가, 현재에는 다양한 부가적인 기능성을 도입하여 생체 물질, 조직공학용 지지체, 바이오 센서, 화학적 밸브, 화장품 충진제, 세포 배양용 배지, 약물전달체 등 산업적 응용에서 의약학적 응용에 이르기까지 매우 다양한 용도로 이용되고 있다.Hydrogels are widely used in hygienic products based on high absorption in the earliest days and nowadays, various functionalities have been introduced to provide biomaterials, tissue engineering supports, biosensors, chemical valves, cosmetics fillers, cell culture media, From industrial applications to medicinal applications.
이러한 하이드로젤을 제조하기 위한 젤화제(gelator)로서 종래 사용되어 오던 화합물에는 지방산 및 이의 염, 스테로이드, 시클로헥산, 당(sugar), 오르가노메탈(organometallics), 다성분 시스템, 아미노산 등을 들 수 있다. 이 중에서도 아미노산, 특히 고리형 디펩티드는 아래와 같이 4개의 수소결합 부위를 가지고 있어 분자 응집을 쉽게 이룰 수 있는 특징이 있다.Compounds that have been conventionally used as a gelator for preparing such hydrogels include fatty acids and their salts, steroids, cyclohexane, sugars, organometallics, multicomponent systems, amino acids, and the like. have. Among them, amino acids, especially cyclic dipeptides, have four hydrogen bonding sites as shown below, which makes it easy to achieve molecular aggregation.
그러나, 종래의 젤화제는 생체 비적합성 또는 체내 독성을 보이거나, 소수성 유기 용매에서만 젤화를 보이는 등의 문제가 있었으며, 생체 적합성 및 체내 비독성을 보이고 양성자성 유기 용매에서 젤화를 나타내는 경우에도 젤화가 가능한 최저 농도가 만족스러울 정도로 낮지 않아 젤화를 위해서는 상대적으로 많은 양의 젤화제가 필요한 문제가 있었다. 또한, 상기의 요건이 충족되더라도 젤화 시간, 젤화의 균일성 및 수화젤화 후 수분 보유력 등의 측면에서 만족스럽지 못한 결과를 보였다.However, conventional gelling agents have problems such as biocompatibility or toxicity in the body, gelation in hydrophobic organic solvents, and the like, and they show biocompatibility and non-toxicity in the body. Even when they exhibit gelation in a protic organic solvent, The lowest possible concentration was not satisfactorily low and there was a problem in that a relatively large amount of gelling agent was required for gelation. In addition, even when the above requirements are met, the results are unsatisfactory in terms of gelation time, homogeneity of gelation, and moisture retention after hydrating gelation.
본 발명은 상기 언급된 종래 젤화제의 문제점, 즉 생체 비적합성, 체내 독성, 양성자성 유기 용매에서 비젤화성, 충분히 낮지 않은 젤화 가능 최저 농도, 낮은 젤화 시간, 젤화 균일성, 수분 보유력 등의 문제점을 극복하고자 한다.Disclosure of the Invention Problems to be solved by the conventional gelling agents mentioned above, namely, non-bioequivalence, toxicity in the body, non-gellability in a protonic organic solvent, minimum gelling potential which is not sufficiently low, low gelling time, uniformity of gelation, I want to overcome.
상기 과제를 달성하기 위하여 본 발명에서는 고리형 펩티드를 포함하는 올리고(에틸렌 글리콜) 계열 젤화제 및 이의 제조방법을 개시한다.In order to achieve the above object, the present invention discloses an oligo (ethylene glycol) -based gelling agent comprising a cyclic peptide and a method for producing the same.
일 측면에 있어서, 본 발명은 에틸렌글리콜과 양 말단에 고리형 펩티드가 결합된 젤화제로서, 하기 화학식 1 또는 화학식 2의 구조를 갖는 것을 특징으로 하는 젤화제를 개시한다.In one aspect, the present invention provides a gelling agent having a structure represented by the following general formula (1) or (2), wherein a gelling agent having an annular peptide bonded to ethylene glycol at both ends thereof.
상기 n은 1-10의 정수이고, 상기 R은 아미노산 잔기이다.N is an integer of 1-10, and R is an amino acid residue.
본 발명에서 아미노산 잔기는 하기의 구조를 갖는 아미노산에서 R의 부분을 의미하고, 본 발명에서 바람직한 아미노산은 21개의 천연 L-타입 아미노산이고, 가장 바람직하게는 알라닌이다.In the present invention, an amino acid residue means a portion of R in an amino acid having the following structure, and the preferred amino acid in the present invention is 21 natural L-type amino acids, and most preferably alanine.
바람직한 구현예에 있어서, 상기 젤화제는 화학식 1의 구조를 가지는 것이 생체 적합성, 다양한 용매에 적용 가능성 및 낮은 농도에서의 젤화 가능성 등 본 발명이 목적하는 효과를 달성함에 있어 바람직하며, 특히 상기 n은 3-5의 정수인 경우에는 위 우수한 효과를 달성함과 동시에 젤화 시간, 젤화의 균일성 및 수화젤화 후 수분 보유력 등의 측면에서도 현저한 효과를 보임을 확인하였다.In a preferred embodiment, the gelling agent having the structure of formula (1) is preferable in achieving the desired effects of the present invention such as biocompatibility, applicability to various solvents and gelation potential at low concentration, It was confirmed that the above-mentioned excellent effect is achieved when the water is an integer of 3-5, and also the effect is remarkable in terms of gelation time, uniformity of gelation, and water retention after hydration gelation.
다른 측면에 있어서, 본 발명은 본 발명에 따른 젤화제를 포함하는 바이오 물질을 개시하며, 상기 바이오 물질은 약물 전달체, 바이오 센서, 화장품 충진제, 세포 배양용 배지, 조직공학용 지지체, 화학적 밸브, 생체 물질 등을 들 수 있다.In another aspect, the present invention discloses a biomaterial comprising a gelling agent according to the present invention, wherein the biomaterial is selected from the group consisting of a drug delivery vehicle, a biosensor, a cosmetic filler, a cell culture medium, a tissue engineering support, And the like.
또 다른 측면에 있어서, 본 발명은 하기 화학식 1의 구조를 갖는 젤화제를 제조하는 방법으로서, 상기 제조방법은 하기 단계를 포함하는 것을 특징으로 하는 하기 화학식 1의 젤화제의 제조방법을 개시한다.In another aspect, the present invention provides a process for preparing a gelling agent having a structure of the following formula (1), wherein the process comprises the following steps:
[화학식 1][Chemical Formula 1]
(a) 하기 화학식 3의 화합물과 하기 화학식 4의 화합물을 커플링시켜 하기 화학식 5의 화합물을 얻는 단계:(a) coupling a compound of formula (3) and a compound of formula (4) to obtain a compound of formula (5): < EMI ID =
(b) 상기 화학식 5의 화합물과 하기 화학식 6의 화합물을 반응시켜 하기 화학식 7의 화합물을 얻는 단계:(b) reacting the compound of Formula 5 with a compound of Formula 6 to obtain a compound of Formula 7:
(c) 상기 화학식 7의 화합물에서 Boc 보호기를 탈보호하여 하기 화학식 8의 화합물을 얻는 단계:(c) deprotecting the Boc protecting group in the compound of Formula 7 to obtain a compound of Formula 8:
(d) 상기 화학식 8의 화합물의 양 말단기를 고리화하여 상기 화학식 1의 화합물을 얻는 단계:(d) cyclizing both end groups of the compound of formula (8) to obtain the compound of formula (1)
상기 n은 1-10의 정수이다.Wherein n is an integer of 1-10.
상기에서 n은 3-5의 정수인 것이 본 발명이 목적하는 효과를 달성함에 있어 바람직하다.It is preferable that n is an integer of 3-5 in order to achieve the desired effect of the present invention.
또 다른 측면에 있어서, 본 발명은 하기 화학식 2의 구조를 갖는 젤화제를 제조하는 방법으로서, 상기 제조방법은 하기 단계를 포함하는 것을 특징으로 하는 하기 화학식 2의 젤화제의 제조방법을 개시한다.In still another aspect, the present invention provides a process for preparing a gelling agent having a structure of the following formula (2), wherein the process comprises the following steps:
[화학식 2](2)
(a) 디할로펜탄과 비페놀을 커플링시켜 하기 화학식 9의 화합물을 얻는 단계:(a) coupling dihalopentane with biphenol to obtain a compound of the formula 9:
(b) 상기 화학식 9의 화합물과 하기 화학식 10의 화합물을 반응시켜 하기 화학식 11의 화합물을 얻는 단계:(b) reacting the compound of Formula 9 with a compound of Formula 10 to obtain a compound of Formula 11:
(c) 상기 화학식 11의 화합물의 Boc 보호기를 탈보호하여 하기 화학식 12의 화합물을 얻는 단계:(c) deprotecting the Boc protecting group of the compound of Formula 11 to obtain a compound of Formula 12:
(d) 상기 화학식 12의 화합물의 양 말단기를 고리화하여 상기 화학식 2의 화합물을 얻는 단계:(d) cyclizing both end groups of the compound of formula (12) to obtain the compound of formula (2)
상기 X는 할로겐 원소이다.X is a halogen element.
본 발명의 젤화제는 에틸렌 글리콜 및 시클로디펩티드와 같은 생체 적합한 단위로 구성되어 있을 뿐만 아니라, 실제에도 생체 적합성이 뛰어나, 특히 생체 적합성이 크게 요구되는 생체물질, 바이오 센서, 약물전달체, 세포 배양용 배지 등으로 사용될 수 있다.The gelling agent of the present invention is not only composed of biocompatible units such as ethylene glycol and cyclodipeptide, but also has excellent biocompatibility in actual use, and is useful for biomaterials, biosensors, drug delivery vehicles, Medium or the like.
본 발명의 젤화제는 디클로로메틸, 에틸아세테이트과 같은 소수성 유기 용매뿐만 아니라 메탄올, 에탄올, 프로판올, 부탄올, 펜탄올, 헥산올과 같은 양성자성 유기 용매에서도 젤화를 보이고, 그중에서도 물에 대해서도 수화젤을 형성하여 특히 기능성 화장품이나, 생체물질, 바이오 센서, 약물전달체 세포 배양용 배지 등에 사용되기에 적합하다.The gelling agent of the present invention exhibits gelation not only in hydrophobic organic solvents such as dichloromethyl and ethyl acetate but also in protic organic solvents such as methanol, ethanol, propanol, butanol, pentanol and hexanol. Among them, hydrated gel is formed And is particularly suitable for use in functional cosmetics, biomaterials, biosensors, medium for drug cell culture, and the like.
젤화(gelation)가 가능한 최저 농도는 낮으면 낮을수록 유리하다고 할 수 있는데, 본 발명의 젤화제의 경우에 통상 논문으로 보고되는 수준의 1/10 수준으로(0.22~0.88 중량%) 매우 낮은 젤화 가능 최저 농도를 보인다.The lower the concentration that can be gelated, the better. The gelling agent of the present invention can be gelled at a level of 1/10 of that reported in the literature (0.22-0.88 wt.%) It shows the lowest concentration.
또한, 위 우수한 효과를 달성함과 동시에 젤화 시간, 젤화의 균일성 및 수화젤화 후 수분 보유력 등의 측면에서도 현저한 효과를 보임을 확인하였다.In addition, it was confirmed that the above effect is remarkably exerted in terms of gelling time, homogeneity of gelation, and water retention after hydration gelation.
도 1은 화학식 1에 속하는 목적 화합물 A의 질량 분석 결과이며, 도 2는 이 화합물의 NMR 데이터이다.
도 3은 본 발명의 일 구현예에 따라 본 발명의 젤화제를 이용하여 수화젤을 제조하는 과정에 대한 개략도이며, 도 4는 이와 같이 제조된 수화젤의 사진이다.
도 5와 도 6은 화학식 1에 속하는 목적 화합물 A를 이용하여 제조된 수화젤을 자연 건조하여 촬영한 SEM 사진이며(각각 10,000 배율과 70,000 배율), 섬유 구조가 서로 엉켜있음을 확인할 수 있다.Fig. 1 shows the results of mass spectrometry of the target compound A belonging to the formula (1), and Fig. 2 shows NMR data of the compound.
FIG. 3 is a schematic view of a process for preparing a hydrogel using the gelling agent of the present invention according to an embodiment of the present invention, and FIG. 4 is a photograph of the hydrogel prepared as described above.
FIGS. 5 and 6 are SEM photographs (at a magnification of 10,000 and a magnification of 70,000, respectively) photographed by naturally drying the hydrogel prepared using the target compound A belonging to the formula 1, and it can be confirmed that the fiber structures are entangled with each other.
이하 실시예는 본 발명을 더욱 구체적으로 설명하기 위한 목적으로 제시되며, 이에 의해서 결코 본 발명의 범위가 축소되거나 한정되어 해석될 수 없다.The following examples are presented for the purpose of further illustrating the present invention and are not to be construed as limiting or limiting the scope of the present invention in any way.
실시예Example 1-1: 목적 화합물 A의 제조 1-1: Preparation of desired compound A
(1) 하기 반응식에 나타낸 바와 같이 Boc으로 보호한 타이로신과 알라닌을 EDC와 HOBT을 이용하여 아미드 커플링시켰다(수율 89%). 또한 양 말단이 Tosyl로 치환된 펜타에틸렌 글리콜을 염기성 조건에서 반응을 수행하였다(수율 64%).(1) As shown in the following reaction formula, tyrosine and alanine protected with Boc were amide coupled with EDC and HOBT (yield: 89%). The reaction was carried out under basic conditions (yield 64%) of pentaethylene glycol in which both terminals were substituted with Tosyl.
[반응식 1][Reaction Scheme 1]
(2) 하기 반응식에 나타낸 바와 같이, 위에서 얻은 화합물에서 Boc 보호기를 탈보호시키고 양 말단기를 고리화하여, 화학식 1에 속하는 목적 화합물 A를 제조하였다. 이에 대한 질량 분석 결과 및 NMR 데이터를 각각 도 1과 도 2에 제시하였다.(2) As shown in the following reaction formula, the Boc protecting group was deprotected from the compound obtained above, and the both end groups were cyclized to prepare the target compound A belonging to the formula (1). Mass spectrometry results and NMR data are shown in FIGS. 1 and 2, respectively.
[반응식 2][Reaction Scheme 2]
(3) 또한, 위에서 n=5인 펜타에틸렌 글리콜을 사용하는 대신에 n=3인 트리에틸렌 글리콜 및 n=4인 테트라에틸렌 글리콜을 사용하여 상기 실험 조건에 준하여 실험을 진행하였다.(3) In place of using pentaethylene glycol having n = 5 above, triethyleneglycol having n = 3 and tetraethylene glycol having n = 4 were used to conduct experiments according to the above experimental conditions.
실시예Example 1-2 및 1-2 and 실시예Example 1-3: 목적 화합물 1-3: Target compound A'A ' 또는 A''의 제조 Or A "
상기 실시예 1-1에서 n=3-5인 화합물을 사용하는 대신에 n=2인 올리고(에틸렌 글리콜)을 사용하거나(실시예 1-2) 또는 n=6인 올리고(에틸렌 글리콜)을 사용하는(실시예 1-3) 것을 제외하고는, 상기 실시예 1-1의 실험 조건에 준하여 실험을 진행하였다.(Ethylene glycol) having n = 2 (Example 1-2) or oligo (ethylene glycol) having n = 6 was used instead of the compound having n = 3-5 in Example 1-1 (Example 1-3), the experiment was carried out in accordance with the experimental conditions of Example 1-1.
비교예Comparative Example 1: 화합물 1: Compound A'''A '' ' 의 제조Manufacturing
상기 실시예 1-1에서 n=3-5인 화합물을 사용하는 대신에 n=11인 올리고(에틸렌 글리콜)을 사용하는 것을 제외하고는, 상기 실시예 1-1의 실험 조건에 준하여 실험을 진행하였다.Experiments were conducted according to the experimental conditions of Example 1-1 except that oligo (ethylene glycol) having n = 11 was used instead of the compound having n = 3-5 in Example 1-1 Respectively.
실시예Example 2: 목적 화합물 B의 제조 2: Preparation of desired compound B
(1) 하기 반응식에 나타낸 바와 같이, 디브로모펜탄과 비페놀을 커플링시키고 나서(수율 82%), Boc-Tyr-Ala-OMe을 브릿징시켰다. 그리고, Boc 보호기를 탈보호시키고 양 말단기를 고리화하여 화학식 2에 속하는 목적 화합물 B를 제조하였다.(1) As shown in the following reaction formula, Boc-Tyr-Ala-OMe was bridged after coupling of dibromopentane with biphenol (yield: 82%). Then, the Boc protecting group was deprotected and both terminal groups were cyclized to produce the desired compound B belonging to the formula (2).
[반응식 3][Reaction Scheme 3]
[반응식 4][Reaction Scheme 4]
시험예Test Example 1-1 1-1
상기 실시예 1-1에서 제조된 화합물을 이용하여 다양한 용매에서 도 3에 도식적으로 나타낸 바와 같이 젤화를 수행하였다. 이 중에서 특히 물에서 젤화를 수행하여 얻는 수화젤의 사진을 도 4에 나타내었으며, 이 수화젤을 자연 건조하여 촬영한 SEM 사진을 도 5와 도 6에 제시하였다(각각 10,000 배율과 70,000 배율).Using the compounds prepared in Example 1-1, gelation was carried out as shown schematically in FIG. 3 in various solvents. Among them, a photograph of a hydrogel obtained by performing gelation in water is shown in FIG. 4, and SEM photographs taken by natural drying of the hydrogel are shown in FIGS. 5 and 6 (10,000 magnifications and 70,000 magnifications, respectively).
또한, n=3-5인 화합물에 대해 여러 용매에서의 젤화 가능 최저 농도를 하기 표에 나타내었으며, 상기 화합물에 대한 생체 적합성 및 독성 시험 결과 생체 적합성을 지니고 있고 체내 독성이 없음을 확인하였다.In addition, for the compounds of n = 3-5, the lowest possible gellation concentrations in various solvents are shown in the table below. Biocompatibility and toxicity tests on the compounds show that they have biocompatibility and no toxicity in the body.
시험예Test Example 1-2 및 1-2 and 시험예Test Example 1-3 1-3
상기 비교예 1에서 제조한 젤화제를 이용하여 젤화를 수행한 결과, 생체 적합성, 물에서의 수화젤 형성 능력, 젤화 가능 최저 농도 측면에서는 상기 실시예 1-1의 젤화제와 거의 대등하거나 다소 떨어지는 반면, 젤화 시간, 젤화의 균일성, 수화젤에 있어서의 수분 보유력 측면에서는 실시예 1-1의 젤화제과 대비해서 크게 떨어지는 것을 확인하였다.As a result of carrying out gelation using the gelling agent prepared in Comparative Example 1, it was found that the gelling agent obtained in Comparative Example 1 was almost equal to or slightly different from the gelling agent of Example 1-1 in terms of biocompatibility, ability to form hydrated gel in water, On the other hand, it was confirmed that the gelation time, the homogeneity of the gelation, and the moisture retention in the hydrogel were significantly lower than those of the gelation agent of Example 1-1.
비교 compare 시험예Test Example 1 One
상기 비교예 1에서 제조한 젤화제를 이용하여 젤화를 수행한 결과, 물에서의 수화젤 형성 능력, 젤화 가능 최저 농도, 젤화 시간, 젤화의 균일성, 수화젤에 있어서의 수분 보유력 측면에서 실시예 1-1뿐만 아니라 실시예 1-2 및 1-3의 젤화제과 대비해서도 크게 떨어지는 것을 확인하였다.As a result of carrying out gelation using the gelling agent prepared in Comparative Example 1, it was found that the water-soluble gel-forming ability in water, the lowest possible gelling degree, the gelling time, the uniformity of gelation, 1-1, as well as the gelation agents of Examples 1-2 and 1-3.
Claims (6)
하기 화학식 1 또는 화학식 2의 구조를 갖는 것을 특징으로 하는 젤화제:
[화학식 1]
[화학식 2]
상기 n은 1-10의 정수이고, 상기 R은 아미노산 잔기이다.As a gelling agent in which ethylene glycol and cyclic peptides are bonded at both ends,
A gelling agent having a structure represented by the following formula (1) or (2):
[Chemical Formula 1]
(2)
N is an integer of 1-10, and R is an amino acid residue.
[화학식 1]
(a) 하기 화학식 3의 화합물과 하기 화학식 4의 화합물을 커플링시켜 하기 화학식 5의 화합물을 얻는 단계:
[화학식 3]
[화학식 4]
[화학식 5]
(b) 상기 화학식 5의 화합물과 하기 화학식 6의 화합물을 반응시켜 하기 화학식 7의 화합물을 얻는 단계:
[화학식 6]
[화학식 7]
(c) 상기 화학식 7의 화합물에서 Boc 보호기를 탈보호하여 하기 화학식 8의 화합물을 얻는 단계:
[화학식 8]
(d) 상기 화학식 8의 화합물의 양 말단기를 고리화하여 상기 화학식 1의 화합물을 얻는 단계:
상기 n은 1-10의 정수이다.A process for preparing a gelling agent having a structure of the following formula (1), wherein the process comprises the following steps:
[Chemical Formula 1]
(a) coupling a compound of formula (3) and a compound of formula (4) to obtain a compound of formula (5): < EMI ID =
(3)
[Chemical Formula 4]
[Chemical Formula 5]
(b) reacting the compound of Formula 5 with a compound of Formula 6 to obtain a compound of Formula 7:
[Chemical Formula 6]
(7)
(c) deprotecting the Boc protecting group in the compound of Formula 7 to obtain a compound of Formula 8:
[Chemical Formula 8]
(d) cyclizing both end groups of the compound of formula (8) to obtain the compound of formula (1)
Wherein n is an integer of 1-10.
[화학식 2]
(a) 디할로펜탄과 비페놀을 커플링시켜 하기 화학식 9의 화합물을 얻는 단계:
[화학식 9]
(b) 상기 화학식 9의 화합물과 하기 화학식 10의 화합물을 반응시켜 하기 화학식 11의 화합물을 얻는 단계:
[화학식 10]
[화학식 11]
(c) 상기 화학식 11의 화합물의 Boc 보호기를 탈보호하여 하기 화학식 12의 화합물을 얻는 단계:
[화학식 12]
(d) 상기 화학식 12의 화합물의 양 말단기를 고리화하여 상기 화학식 2의 화합물을 얻는 단계:
상기 X는 할로겐 원소이다.A process for preparing a gelling agent having a structure of the following formula (2), wherein the process comprises the following steps:
(2)
(a) coupling dihalopentane with biphenol to obtain a compound of the formula 9:
[Chemical Formula 9]
(b) reacting the compound of Formula 9 with a compound of Formula 10 to obtain a compound of Formula 11:
[Chemical formula 10]
(11)
(c) deprotecting the Boc protecting group of the compound of Formula 11 to obtain a compound of Formula 12:
[Chemical Formula 12]
(d) cyclizing both end groups of the compound of formula (12) to obtain the compound of formula (2)
X is a halogen element.
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