CN108479649A - A kind of preparation method of organogel and application - Google Patents
A kind of preparation method of organogel and application Download PDFInfo
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- CN108479649A CN108479649A CN201810445125.3A CN201810445125A CN108479649A CN 108479649 A CN108479649 A CN 108479649A CN 201810445125 A CN201810445125 A CN 201810445125A CN 108479649 A CN108479649 A CN 108479649A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- 238000000034 method Methods 0.000 claims abstract description 37
- 230000008569 process Effects 0.000 claims abstract description 12
- 239000000499 gel Substances 0.000 claims description 92
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 39
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 18
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 18
- 125000004836 hexamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 claims description 16
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 14
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 14
- 239000003349 gelling agent Substances 0.000 claims description 13
- 239000000843 powder Substances 0.000 claims description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- 239000003960 organic solvent Substances 0.000 claims description 12
- 150000003384 small molecules Chemical class 0.000 claims description 12
- KZJWDPNRJALLNS-VJSFXXLFSA-N sitosterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CC[C@@H](CC)C(C)C)[C@@]1(C)CC2 KZJWDPNRJALLNS-VJSFXXLFSA-N 0.000 claims description 10
- 239000000203 mixture Substances 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 8
- 150000001875 compounds Chemical class 0.000 claims description 8
- 239000000741 silica gel Substances 0.000 claims description 8
- 229910002027 silica gel Inorganic materials 0.000 claims description 8
- 239000000287 crude extract Substances 0.000 claims description 6
- 238000010828 elution Methods 0.000 claims description 6
- 238000000605 extraction Methods 0.000 claims description 6
- 239000003208 petroleum Substances 0.000 claims description 6
- 239000002026 chloroform extract Substances 0.000 claims description 5
- 238000010438 heat treatment Methods 0.000 claims description 4
- 239000008236 heating water Substances 0.000 claims description 4
- XELZGAJCZANUQH-UHFFFAOYSA-N methyl 1-acetylthieno[3,2-c]pyrazole-5-carboxylate Chemical compound CC(=O)N1N=CC2=C1C=C(C(=O)OC)S2 XELZGAJCZANUQH-UHFFFAOYSA-N 0.000 claims description 4
- 239000007787 solid Substances 0.000 claims description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 239000003480 eluent Substances 0.000 claims description 3
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 claims description 3
- 238000011068 loading method Methods 0.000 claims description 3
- 238000010898 silica gel chromatography Methods 0.000 claims description 3
- 239000000725 suspension Substances 0.000 claims description 3
- 238000009835 boiling Methods 0.000 claims description 2
- 238000010992 reflux Methods 0.000 claims description 2
- 150000003431 steroids Chemical class 0.000 claims description 2
- 229940076810 beta sitosterol Drugs 0.000 claims 1
- LGJMUZUPVCAVPU-UHFFFAOYSA-N beta-Sitostanol Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(C)CCC(CC)C(C)C)C1(C)CC2 LGJMUZUPVCAVPU-UHFFFAOYSA-N 0.000 claims 1
- NJKOMDUNNDKEAI-UHFFFAOYSA-N beta-sitosterol Natural products CCC(CCC(C)C1CCC2(C)C3CC=C4CC(O)CCC4C3CCC12C)C(C)C NJKOMDUNNDKEAI-UHFFFAOYSA-N 0.000 claims 1
- 150000002576 ketones Chemical class 0.000 claims 1
- 239000007788 liquid Substances 0.000 claims 1
- 229950005143 sitosterol Drugs 0.000 claims 1
- 229910052739 hydrogen Inorganic materials 0.000 abstract description 20
- 239000001257 hydrogen Substances 0.000 abstract description 20
- 238000012360 testing method Methods 0.000 abstract description 17
- 239000002904 solvent Substances 0.000 abstract description 16
- 238000001338 self-assembly Methods 0.000 abstract description 12
- 238000001879 gelation Methods 0.000 abstract description 9
- 238000011160 research Methods 0.000 abstract description 8
- 206010028980 Neoplasm Diseases 0.000 abstract description 6
- 238000004458 analytical method Methods 0.000 abstract description 6
- 201000011510 cancer Diseases 0.000 abstract description 6
- 238000001816 cooling Methods 0.000 abstract description 6
- 230000000694 effects Effects 0.000 abstract description 6
- 238000000338 in vitro Methods 0.000 abstract description 5
- 238000012856 packing Methods 0.000 abstract description 5
- 230000001093 anti-cancer Effects 0.000 abstract description 4
- 241000196324 Embryophyta Species 0.000 abstract description 3
- 239000002121 nanofiber Substances 0.000 abstract description 3
- 230000005764 inhibitory process Effects 0.000 abstract description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 48
- 229940125904 compound 1 Drugs 0.000 description 10
- 239000000835 fiber Substances 0.000 description 8
- 238000001988 small-angle X-ray diffraction Methods 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- 229930014626 natural product Natural products 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 239000000243 solution Substances 0.000 description 5
- 230000007704 transition Effects 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- 238000010521 absorption reaction Methods 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 239000000539 dimer Substances 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 238000002329 infrared spectrum Methods 0.000 description 4
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 3
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- 238000001878 scanning electron micrograph Methods 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 238000000862 absorption spectrum Methods 0.000 description 2
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 2
- 230000003833 cell viability Effects 0.000 description 2
- 238000005094 computer simulation Methods 0.000 description 2
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- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 2
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 2
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- 238000004736 wide-angle X-ray diffraction Methods 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 238000004566 IR spectroscopy Methods 0.000 description 1
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- 229930182558 Sterol Natural products 0.000 description 1
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- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 1
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- 238000012377 drug delivery Methods 0.000 description 1
- 238000002451 electron ionisation mass spectrometry Methods 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
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- 238000004108 freeze drying Methods 0.000 description 1
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000003292 glue Substances 0.000 description 1
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- 150000002431 hydrogen Chemical group 0.000 description 1
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- 238000002347 injection Methods 0.000 description 1
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- 238000004806 packaging method and process Methods 0.000 description 1
- 235000002378 plant sterols Nutrition 0.000 description 1
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Classifications
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J13/00—Colloid chemistry, e.g. the production of colloidal materials or their solutions, not otherwise provided for; Making microcapsules or microballoons
- B01J13/0091—Preparation of aerogels, e.g. xerogels
-
- 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
- A61K47/28—Steroids, e.g. cholesterol, bile acids or glycyrrhetinic acid
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- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Medicinal Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Engineering & Computer Science (AREA)
- Dispersion Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a kind of preparation method of organogel, effective method isolated Sito from plant rhizoma arisaematis using a kind of general, and carry out the preparation of Sito organogels.Gel shows that Sito not only can be by hot cooling method gelation, but also can pass through supersound process gelation；Senile Mouse discloses the network structure inside gel and the nanofiber of entanglement, and different structures is formd with supersound process by the way that heat is cold.Simultaneously, it is proposed that influence of the solvent polarity to gel pattern.The research of driving force and packing of molecules model analysis to Sito and its gel confirms important function of the hydrogen bond in self assembly, and proposes possible packing of molecules model.In addition, testing the Anticancer Activity in vitro of Sito nanoscale xerogel, Sito nanoscale xerogel shows even preferably inhibition of cancer cell effect identical as non-nano grade Sito.
Description
Technical field
The invention belongs to small molecule self assembly field, it is related to a kind of natural small molecule gelling agent cupreol organogel
Preparation method and application.
Background technology
The peculiar property and structure of low molecular weight gel (LMWG) have caused the extensive concern of many decades.Non-covalent phase
The gelling agent combination of interaction gives the specific characteristics of LMWG, such as invertibity, outside stimulus reactivity, self-healing property.Low point
" dynamic growth " self assembly behavior of son amount gelling agent (LMWGs) also results in the interest of researcher.Wherein, it is based on natural production
The LMWG of object is used for the fields such as medicine, agricultural and environment due to its excellent biocompatibility and biodegradable, but
Virtually all it is synthesis.In recent years, it has been found that some natural products (i.e. natural products gelling agent, NPGs), which have, to be passed through
It is self-assembly of the new ability of gel (i.e. natural products gel, NPG).It provides the natural products of new possibility for research
With low molecular weight gel (LMWG).
NPG usually has multiple biological activities and good biodegradable, and exploitation can be supported with the biology of enhancing
Active drug delivery system.Simultaneously NPG be renewable resource, therefore its application and development can efficiently reduce or eliminate it is harmful
The use or generation of substance.
Until 2011, Bag and his colleagues reported a kind of unmodified LMWGs of organism, it to hide
Natural LMWG (i.e. natural products gelling agent, NPG) in natural prodcuts is found.The application and development and self assembly of NPG is studied
Natural products research field will be extended to the fields such as supramolecular chemistry, material science, bioscience and Chinese medicine.
Cupreol is a plant sterols, has effects that be substantially reduced serum cholesterol, study it in the past
It is very extensive, but do not have also research mention cupreol as single gel agent in organic solvent gelling ability test and its
The preparation of organogel.
Invention content
The purpose of the present invention is use a kind of general and effective method separating natural small molecule from plant rhizoma arisaematis solidifying
Jelly (NPGs)-cupreol (Sito), and carry out the preparation of Sito organogels.
The purpose of the present invention is what is be achieved through the following technical solutions：
A kind of preparation method of organogel, includes the following steps：
The first step：5~25mg natural small molecule gelling agent cupreols are mixed with 0.5~1mL organic solvents；
Second step：By mixture heating water bath obtained by the first step or it is ultrasonically treated until solid dissolving or evenly dispersed, control
Water bath heating temperature processed is in organic solvent boiling point hereinafter, being no more than 80 DEG C；The frequency of supersound process is 30~50KHz, and temperature is
20~40 DEG C；
Third walks：Mixture obtained by second step is placed at 25 DEG C to 20~30 hours to get cupreol organogel,
It can be used as pharmaceutical carrier.
In the present invention, the extracting method of the cupreol is as follows：
The first step：Air-dried rhizoma arisaematis rhizome is crushed, it is spare；
Second step：It weighs 5~15kg rhizoma arisaematis rhizomes and air-dries powder, be placed in the ethanol water of 95% volume ratio and flow back
Extraction obtains crude extract after extraction concentration, crude extract is suspended in water, then suspension is extracted with chloroform, obtains chlorine
Imitative extract；
Third walks：Wet method dress post is carried out by petroleum ether is added in silica gel, by chloroform extract wet method loading, using oil
Ether/acetone carries out gradient elution as eluent, obtains five fractions of Fr.1-Fr.5；
4th step：Fr.2 is further chromatographed on a silica gel column according to the method for step 3, is made using hexane/ethyl acetate
Gradient elution is carried out for eluent, obtains tri- fractions of Fr.2a-Fr.2c；
5th step：By Fr.2a components by silica gel column chromatography, sephadex lh-20 column obtains gel active chemical combination
Object cupreol.
The invention has the advantages that：
1, Sito not only can be by hot-cold method gelation in the present invention, but also can pass through supersound process gelation.
2, Sito nanoscale xerogel shows even preferably cancer cell suppression identical as non-nano grade Sito in the present invention
It makes and uses.
Description of the drawings
Fig. 1 is the extraction process flow chart of natural small molecule gelling agent cupreol of the present invention；
Fig. 2 is that the EIMS of compound 1 schemes；
Fig. 3 is compound 11H-NMR schemes；
Fig. 4 is compound 113C-NMR schemes；
Fig. 5 is gel process flow chart；
Fig. 6 is the picture of gel, and a be that (number on bottle is corresponding to table 3 for the pictures of the T gels formed by heating-cooling
In solvent)；B is to be ultrasonically treated the S gel images (left figure one and two) formed and the partial gel by being cooled into (right figure)；
Fig. 7 is the phase transition temperature of T- gels and S- gels in hexamethylene；
Fig. 8 is the SEM image of Sito gel-forming processes in hexamethylene, (a) 10min；(b)20min；(c)30min；
Fig. 9 is the SEM image of the T gels in methanol (a), acetonitrile (b), DMSO (c), hexamethylene (d)；
It in concentration range is 0.2-1.8 (mg mL that Figure 10, which is Sito,-1) when ultra-violet absorption spectrum；
Figure 11 is the infrared spectrum of Sito in different solvents；
Figure 12 is the water contact angle measured value of the non-gels (i) of Sito and T gels (ii) powder that are obtained in hexamethylene；
Figure 13 is that the small angle x-ray diffraction (SAXD) of Sito dry gel powders is tested；
Figure 14 is that the small angle x-ray diffraction (SAXD) of Sito dry gel powders is tested；
Figure 15 is Sito unimolecule computer mould quasi-lengths；
Figure 16 is the dimer computer mould quasi-length that Sito is formed by hydrogen bond；
Figure 17 simulates for Sito self assembling processes；
Figure 18 is Anticancer Activity in vitro tests of the nanoscale Sito and non-nano grade Sito in two kinds of different cancer cells, (a)
MCF-7；(b)HT-29.
Specific implementation mode
Technical scheme of the present invention is further described below in conjunction with the accompanying drawings, however, it is not limited to this, every to this
Inventive technique scheme is modified or replaced equivalently, and without departing from the spirit of the technical scheme of the invention and range, should all be covered
In protection scope of the present invention.
Using a kind of general, effective method detaches a kind of gel active substance i.e. day to the present invention from plant rhizoma arisaematis
Right small molecule gelling agent (NPGs)-cupreol (Sito), and carry out the preparation of Sito organogels.In 47 kinds of organic solvents
In test the gelling performance of Sito, and explain Sito gels using UV-vis, FT-IR, CAT, XRD and calculating and simulation
Property, form, driving force and molecule packaging model.Gel shows that Sito can not only pass through hot-cold method gelation, Er Qieke
With by being ultrasonically treated gelation；Senile Mouse discloses the network structure inside gel and the nanofiber of entanglement, passes through
Hot-cold and supersound process form different structures.Simultaneously, it is proposed that influence of the solvent polarity to gel pattern.To Sito and
The driving force of its gel and the research of packing of molecules model analysis confirm important function of the hydrogen bond in self assembly, and propose
Possible packing of molecules model.In addition, in order to provide reference for the application of these newfound NPG, we test Sito and receive
The Anticancer Activity in vitro of meter level xerogel.As it is anticipated that as, Sito nanoscale xerogel is shown and non-nano grade
The identical even preferably inhibition of cancer cell effects of Sito.
Specific technical solution is as follows：
One, the extraction of NPGs
Silica gel, sephadex lh-20：For column chromatography；TLC is carried out on GF254 silica gel plates；With UV light (254nm)
Observation.
As shown in Figure 1, the specific extracting method of natural small molecule gelling agent cupreol is as follows：
The first step：Air-dried rhizoma arisaematis rhizome is crushed using crusher, it is spare to weigh 10kg.
Second step：Reflux extraction method extracts the wind of 10kg rhizoma arisaematis rhizomes in the ethanol water of 95% volume ratio
Dry powder obtains crude extract after concentration, crude extract is suspended in water.Then suspension is extracted with chloroform, obtains chloroform
Extract.
Third walks：Petroleum ether progress wet method dress post will be added in silica gel, chloroform extract wet method loading is used into petroleum ether：
Acetone (100:0→0:100, v/v, petroleum ether volumn concentration successively decreases according to 10% gradient) gradient elution, obtain five grades
Divide (Fr.1-Fr.5).
4th step：Select the solvent of the opposed polarities such as methanol, acetonitrile, DMSO, ethyl acetate, n-hexane, hexamethylene, chloroform
Carry out gel active test.Gel active test confirms that gel section is present in Fr.2.
5th step：Fr.2 on a silica gel column further chromatography (method with third walk, use hexane：Ethyl acetate (100:0→
0:100, v/v, hexane volumn concentration successively decreases according to 10% gradient) gradient elution, obtain three fraction (Fr.2a-
Fr.2c)。
6th step：Three obtained fraction is subjected to gel active test (method is with the 4th step).Gel test shows
Fr.2a components have gel active.
7th step：Fr.2a components are passed through into silica gel column chromatography (hexane：Acetone, 100：0→0：100, v/v, hexane body
Product percentage composition successively decreases according to 10% gradient), sephadex lh-20 column obtains compound 1.HPLC system：Using being connected to
UV detectors 1260 high performance liquid chromatography of Agilent Technology (HPLC) and Agilent-C18 columns (4.6 ×
250mm, i.e., 5.0 μm).Column temperature is maintained at 30 DEG C, and injection ring body product is 10.0 μ L.Mobile phase is methanol and aqueous systems (95：5；v/
V) mixture, flow velocity are 1.0mL min-1.Detection monitoring wavelength selection is in 210nm.It is pure that high performance liquid chromatography measures compound
Spend (chloroform：Methanol, 1：1, v/v)：Compound 1 is colourless acicular crystal (purity 99.10%).
Two, the Structural Identification and characterization of NPGs
Using the structure of mass spectrum, nuclear magnetic resonance authenticating compound 1.Research is enterprising in Agilent 6890N GC-MS (EI)
Row.NMR experiments carry out on the BrukerDRX-400 of 400MHz.
Molecular ion peak 414 is shown in mass spectrogram shown in Fig. 2 first, and obtaining molecular formula with isotope abundance method later is
C29H50O, then to the characteristic peak of spectrogram overall the characteristics of browsing, finding spectrogram or substance.There are sterol chemical combination in spectrogram
The essential characteristic peak (m/z) of object：273[M-R]+、231[M-(R+42)]+、399[M-15]+、396[M-18]+、141[R]+, also have
The base peak of Sitosterolum composes 399 [M-15]+、396[M-H2O]+, 381,329,303,255,145,97,57,43 plasma peaks.
Mass spectrum main feature fragment source is as follows：1The analysis of H-NMR spectrum first looks for the position of cutting edge of a knife or a sword, determines that chemical shift, ownership are each
A peak belongs to the hydrogen in that group.Pass through1H-NMR spectrum analysis shows that result：1H-NMR(CDCl3, 600MHz) and δ 5.35
(1H, t, H-6), 3.52 (1H, q, H-3) show that compound contains alkene hydrogen, and even miscellaneous tertiary hydrogen, has complexity between δ (ppm) 0.5-2.5
SP3 hydbridized carbon atoms on hydrogen signal, the comparison of chemical displacement value therein and document is consistent.The hydrogen nuclear magnetic resonance of compound 1
Modal data and data in literature comparison are as shown in table 1.
1 compound 1 of table1H-NMR is compareed with data in literature
The carbon-13 nmr spectra data of compound 1 compare as follows with document：
Shown in Fig. 413C-NMR spectrum analysis shows that result：13C-NMR (CDCl3,150MHz) δ 140.7 (C-5),
71.8 (C-3), 56.7 (C-14), 56.0 (C-17), 50.1 (C-9), 45.8 (C-4), 42.3 (C-13), 39.7 (C-12),
37.2 (C-24), 36.2 (C-1), 36.1 (C-20), 36.1 (C-10), 33.9 (C-22), 31.9 (C-8), 31.6 (C-7),
29.7 (C-2) 29.1 (C-16), 28.2 (C-11), 26.0 (C-15), 24.3 (C-23), 23.0 (C-27), 21.1 (C-28),
19.8 (C-19), 19.4 (C-21), 19.0 (C-25), 18.8 (C-29), 12.0 (C-26), 11.8 (C-18).
2 compound 1 of table13C-NMR is compareed with data in literature
After the nuclear magnetic resonance data of compound 1 is compared with the result of document report, compound 1 is accredited as β-paddy steroid
Alcohol (Sito).Structure chart is as follows：
Three, the preparation of Sito gels
It is put into the mixture of 20mg samples and 0.5mL solvents in the bottle that volume is 1.5mL, a diameter of 10mm, will mix
Conjunction object heating water bath (>75 DEG C) or (40KHz, 25 DEG C) is ultrasonically treated until solid dissolving or evenly dispersed.Gained mixture exists
25 DEG C are placed 24 hours.When bottle can be inverted and when the shape invariance of content, it is accredited as gel (G).Work as test tube
When inversion, if it is observed that the variation of its partial content object shape, partial gel (PG) is appointed as by sample.Only liquid
Solution (S) is marked as in the presence of body.When gelling agent does not dissolve, sediment is named as (P).All samples concentration is with mg
mL-1It indicates, i.e. the ratio of gel weight (mg) and solvent volume (mL).When preparing sample in the above described manner, critical gel is dense
Degree (CGC) is defined as generating the minimum gelling agent concentration of gel.
We test gel behaviors of the Sito in 47 kinds of organic solvents.Sito can not only pass through heating-cooling shape
At gel (this method is used for most of gels), gel can also be formed by ultrasonic stimulation.For heating-cooling, in water
Heating makes Sito be dissolved completely in organic solvent (close to gel solvent volatilization temperature) in bath, then cools to room temperature, and finds
Gel (being denoted as T gels) is formed in methanol, acetonitrile, dimethyl sulfoxide (DMSO) and hexamethylene.For ultrasound stimulation, Sito is dissolved in
It in organic solvent, is being stored at room temperature after being then ultrasonically treated 2 minutes, it is found that forming gel in hexamethylene and n-hexane (is denoted as
S- gels).Thus it was found that Sito is in hexamethylene can form T gels but also form S gels.In n-hexane solvent
S gels are can be only formed, and what is formed after being handled with heating means is partial gel, can form three-dimensional network organization, but not
(Fig. 5) can be tested by inversion.
Phase transition temperature (Tg) is a testing index of small molecule gel strength.We are to invert bottle method result judgement
It is phase transition temperature to lead to the temperature that the gel state changes.The Sito of 5mg, 10mg, 15mg, 20mg, 25mg are taken respectively successively
It is placed in five identical bottles, and the hexamethylene of 1mL is added thereto respectively, by heating-cooling cycle and ultrasound two
Kind of method completes the preparation of small molecule gel.By small molecule gel made of gradient concentration press from low concentration to high concentration, from
Low temperature to high temperature sequence heating water bath successively, until phase transition state as defined in reaching.The results are shown in Figure 7, and Sito is in phase
Tg with the S gels formed in solvent is higher than T gels.That is, the gel being ultrasonically formed has better thermal stability, i.e.,
Ultrasonic wave contributes to the stability of gel.And measuring in concentration range, compound sol-gel transition temperature is all with dense
The increase of degree and increase, this indicates that the raising of concentration can improve the stability and robustness of gel, this may be with fiber in gel
The dense degree of network is related.
Gelling properties test results and critical gelation concentration result such as Fig. 6 and table 3 institute of the Sito in 47 kinds of organic solvents
Show：
Gelling results of the table 3Sito in 47 kinds of organic solvents
* G=gels；S=solution；P=sediments；PG=partial gels；"-" indicates no content.
Four, gel pattern is studied
Fig. 9 is the different micro-structures of gel in the different solvents that SEM results are shown.It is observed in methanol and acetonitrile band-like
Form, width is about 3 μm, and length is about 100 μm (Fig. 9 a-b).Presence (the figure of lamellar structure is observed in DMSO
9c).And the gel shows the poly- behavior of lamination.In hexamethylene, gel is strongly depend on outside stimulus.It is found in T gels
Width is the fibre structure (Fig. 9 d) of about 10 μm of 100-200nm and length.
In order to disclose gel-forming process, SEM images (Fig. 8) of the Sito in different time hexamethylene is tested.Herein
In measurement, 10 during being prepared for gel-forming, 20,30 minutes samples investigate the growth of gel.For being prepared at 10 minutes
Sample, observe form wind, distribution it is sparse, width be 100~200nm fiber.As time increases, fiber becomes
It is thicker, more, and arrange more crypto set.At 30 minutes, observe that three-dimensional network has preliminarily formed.It is seen in methanol and acetonitrile
Observe similar phenomenon.
Therefore we assume that a dimensional tissue of the gel in different solvents is identical fibre structure.And solvent effect
The further orientation of fiber, so that the generation of different gel forms.
Five, self assembly driving force research
(1) uv-vis spectra
We have prepared 0.2,0.4,0.6,0.8,1.0,1.2,1.4,1.6,1.8mg mL-1A series of Sito methanol
Solution as a contrast with blank methanol solvate tests their ultraviolet-visible absorption spectroscopy respectively.Sito is low dense in methyl alcohol
The ultra-violet absorption spectrum concentration range for spending solution is 0.2-1.8 (mg ml-1) the results show that working as a concentration of 0.2mg mL of Sito-1
When, occurring maximum absorption band at 209nm, this peak coating is accredited as compound molecule internal double bond absorption peak, it is observed that with
The continuous increase of Sito concentration, maximum absorption band peak height become larger and occur red shift (spectrum moves a distance towards red end,
I.e. wavelength is elongated, and frequency reduces), red shift 5nm (Figure 10) is total within the scope of experimental concentration.
For this explanation with the increase of compound concentration, the energy of system has the tendency that reduction, system with Sito concentration
Increase and more stablizes.
(2) infrared spectrum
It is logical in n-hexane that we are prepared for xerogel, Sito under the critical gelation concentration of the methanol of Sito, hexamethylene
The non-gel powder crossed the partial gel of heating-cooling formation and obtained after chloroform dissolving freeze-drying, by grinding, adding
After potassium bromide carries out tabletting, tested on infrared spectrometer.
Measure the infrared spectrum of the Sito formed in different solvents.Infrared spectrum shown in Figure 11 shows Sito T gels
The stretching vibration variation of-OH in (methanol, hexamethylene), partial gel (n-hexane) and non-gel (chloroform).- OH is in methanol, ring
Stretching vibration in hexane, n-hexane and chloroform is respectively 3419.75cm-1、3224.13cm-1、3427.60cm-1With
3434.63cm-1.As can be seen that the stretching vibrations of-OH in methanol and hexamethylene is transferred to lower frequency (red shift) and adjoint
The bandwidth for absorption peak increases.
This is because free-OH is associated with hydrogen bond ,-the OH that dissociates, which absorbs, to be weakened, and bandwidth increase is due in whole system
The increase of polarity and Charge scaling.This fully demonstrates the formation of hydrogen bond in nanostructure.However, partial gel (n-hexane)
In the stretching vibration of-OH be also transferred to lower frequency, but its mobility is less than T gels.This proves solidifying in T gels and part
The interaction of hydrogen bond of varying strength is produced in glue, and the hydrogen bond in partial gel (n-hexane) may be weakened, and be caused
Gel cannot ultimately form.
The IR data for the Sito solid samples that table 4 is prepared with different solvents
It can be seen that the formation of hydrogen bond and HYDROGEN BOND INTENSITY determine ultimately forming for gel in Sito self assemblies.
(3) Contact-angle measurement
Water contact angle is tested, we are prepared for respectively in T gels xerogel and chloroform of the Sito in hexamethylene
Non- gel powder is applied on the glass slide of covering double faced adhesive tape, and after so that it is uniformly distributed, two samples are measured on instrument
Water contact angle.Keep drop size self-consistent when test.
In order to further confirm that driving force of the hydrogen bond as gel-forming, we are also tested for obtains under non-gel and gel
The contact angle of the powder obtained.The result shows that, Sito nanoscale xerogel has larger contact angle, that is, forms gel shown in Figure 12
(hydrogen bond gradually increases) consumes hydrophily-OH, to enhance the hydrophobicity of Sito nanoscale xerogel.In view of the foregoing,
We judge that hydrogen bond is the main drive that gelling is formed.
Six, self assembly simulation and molecular computing
We are prepared for the dried powder of the Sito of different solvents under critical gelation concentration, for measuring wide-angle and small
Angle x-ray diffraction is tested.As a result, it has been found that the dried powder appearance situation of gel and partial gel is roughly the same, so we are right
Xerogel in methanol carries out interpretation of result.This helps to study packing of molecules structure of the compound under gel state, we
Observe the compound wide-angle of dry gel powder and small angle x-ray diffraction (SAXD) experimental result, wherein low-angle XRD in methyl alcohol
As a result two 2 θ=2.34 ° of diffraction maximums correspondence of (Figure 13) display appearance, 4.70 °, by bragg's formula:2dsinx=n λ are calculated
Go out the corresponding interplanar distance d values of angle, respectively 3.77nm, 1.88nm, it is observed that the ratio of two d values is 2:1, this says
It is in layer structure that intermolecular accumulation, which is illustrated, and macrocyclic length is 3.77nm.
Coincidentally, the length of the Sito molecules by Computer Simulation Software optimization is(Figure 15), withThe d values at place are sufficiently close to, and the molecule of dimer made of the Sito Hydrogenbonds Jing Guo computer Simulation calculation is long
Degree is(Figure 16), withD values be sufficiently close to.Therefore it is concluded that Sito is to first pass through in self assembly
Hydrogen bond links together two molecules, this has corresponded to macrocyclic distance in XRD spectra.In addition, by these results with it is infrared
After analysis result combines, we again demonstrate the main drive that hydrogen bond is self assembly.
Shown in wide-angle X-ray diffraction spectrum 2 θ angles be respectively 14.336 °, 17.658 °, 18.821 °,
19.322 ° a series of peaks, correspond to 6.144,4.934,4.776,D- spacing (Figure 14), this indicates Sito point
Son accumulation is that closer stacked direction occurred.
Accumulated by computer simulation, it has been found that the width of these data and Sito molecules is 5.854,5.260,
4.888、Corresponding, numerical value is sufficiently close to.This illustrates that the distance in banking process between hydrophobic grouping is very tight
It is close, form the accumulation mode mutually bordered on, this also illustrates when steroidal rigid structure is accumulated Van der Waals force play it is certain
Effect.
Therefore, according to XRD, FT-IR and CAT as a result, it is presumed that, in Sito self assembling processes, the first step is from group
Dress is to form dimer by hydrogen bond by Sito is intermolecular, and as the unit further accumulated, further self assembly is by model
The strength driving of moral China, dimer vertical and horizontal arrangement form secondary structure, finally, secondary structure continue to wind or accumulate
To generate fibrous web-like aggregation (Figure 17).
Seven, experiment in vitro
From research before it was found that the self-assembled nanometer fibre diameter of Sito is uniform and stable, surface area is big and surface
There is no defect uniformly, while fiber aspect ratio is big and continuity is good.This nanofiber can be a kind of load medicinal material well
Material.We test the Anticancer Activity in vitro of Sito nanoscales xerogel and non-nano grade Sito.As a result it is shown in incubation time
After 48 hours, in 0.1,1.0,10,30 and 50 μm of olL-1Under dosage, it is exposed to Sito non-nano grade powder and Sito nanoscales is dry
The viability (Figure 18) of the HT-29 and MCF-7 cells of gel.It was found that two kinds of Sito is aobvious to HT-29 and MCF-7 cells
Show effective antiproliferative effect (p<0.05).However, under the same conditions, the vigor of MCF-7 cells is less than HT-29 cells, table
Bright Sito has better inhibiting effect to MCF-7 cells.In 50 μm of olL-1 non-nano grade Sito and Sito nanoscale xerogel
Under processing, 55.01% and 66.34% (p of MCF-7 cell survival rates reduction more significant than control group<0.05).HT-29 cell viabilities
It is significant to be less than control group (p<0.05), respectively 52.91% and 60.47%.The life of the cancer cell of two kinds of Sito processing
Power is deposited with Sito dosage 0.1,1.0,10,30 and 50 μm of olL-1The increase of concentration and reduce.As expecting we,
It tests and finds from cell viability, compared with non-nano grade Sito, two kinds of cancer cells of Sito nanoscales xerogel pair show phase
Etc. even higher cytotoxicity.This result illustrates that Sito is suitable as pharmaceutical carrier and carries out carrying medicine experiment, and carrier has good
Good biocompatibility, and pharmaceutical activity can be enhanced to a certain extent.
Claims (6)
1. a kind of preparation method of organogel, it is characterised in that steps are as follows for the method：
The first step：5~25mg natural small molecule gelling agent cupreols are mixed with 0.5~1mL organic solvents；
Second step：By mixture heating water bath obtained by the first step or it is ultrasonically treated until solid dissolving or evenly dispersed；
Third walks：Mixture obtained by second step is placed 20~30 hours to get natural small molecule gelling agent β-paddy steroid at 25 DEG C
Alcohol organogel.
2. the preparation method of organogel according to claim 1, it is characterised in that the extracting method of the cupreol
It is as follows：
The first step：Air-dried rhizoma arisaematis rhizome is crushed, it is spare；
Second step：It weighs 5~15kg rhizoma arisaematis rhizomes and air-dries powder, be placed in reflux in the ethanol water of 95% volume ratio and carry
It takes, obtains crude extract after extraction concentration, crude extract is suspended in water, suspension is extracted with chloroform then, obtains chloroform
Extract；
Third walks：Wet method dress post is carried out by petroleum ether is added in silica gel, by chloroform extract wet method loading, using petroleum ether/the third
Ketone carries out gradient elution as eluent, obtains five fractions of Fr.1-Fr.5；
4th step：Fr.2 is further chromatographed on a silica gel column according to the method for step 3, is used as and is washed using hexane/ethyl acetate
De- liquid carries out gradient elution, obtains tri- fractions of Fr.2a-Fr.2c；
5th step：By Fr.2a components by silica gel column chromatography, sephadex lh-20 column obtains gel active compound β-
Sitosterol.
3. the preparation method of organogel according to claim 1, it is characterised in that the water bath heating temperature is organic
Solvent boiling point is hereinafter, be no more than 80 DEG C.
4. the preparation method of organogel according to claim 1, it is characterised in that the frequency of the supersound process is 30
~50KHz, temperature are 20~40 DEG C.
5. the preparation method of organogel according to claim 1, it is characterised in that the organic solvent is hexamethylene, first
Alcohol, n-hexane, acetonitrile or dimethyl sulfoxide (DMSO).
6. a kind of application of organogel prepared by claim 1 the method in pharmaceutical carrier.
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