JP2005239632A - Polymerizable bicephalic glycolipid, tube-shaped aggregate thereof and its polymer - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a new glycolipid capable of forming a tube-shaped aggregate stabilizable by polymerization; and to provide a fine fiber or tube-shaped aggregate thereof. <P>SOLUTION: The tube-shaped fiber stable over a long period is obtained by forming autoaggregate by using an asymmetrical polymerizable bicephalic glycolipid, and polymerizing the product. The polymerizable bicephalic glycolipid is represented by the general formula (wherein, G is a residue obtained by removing a reduced terminal hydroxy group of aldopyranose; X is a hydrogen atom, a hydroxy group, a carboxy group or an amino group; (a) and b are the same or different and each an integer of 0-20). The aggregate, and the hollow tube-shaped polymer obtained by polymerizing the aggregate are also provided. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

  The present invention relates to a novel polymerizable double-headed glycolipid, a hollow tubular aggregate formed from the lipid, and a hollow tubular polymer obtained by polymerizing the aggregate. This hollow tubular aggregate or tubular polymer is useful as a functional material in the pharmaceutical / cosmetic field, electronic information field, food industry, agriculture / forestry industry, textile industry, and the like.

  It has long been known that lipids self-assemble in water to form stable molecular aggregates. As a method for producing a molecular assembly formed from such lipids, conventionally, a spherical molecular assembly (called a liposome) formed from a naturally-derived phospholipid is converted into a thin film method, a thermal dispersion method, a solution injection method, A method of producing by a cholic acid method, a reverse layer evaporation method or the like is known (Non-Patent Document 1). However, these methods require complicated and skilled techniques, and the formed molecular aggregates are spherical single membrane liposomes or spherical multilamellar liposomes, which are nanometer-scale ultrafine fibers, Or fine tube-shaped aggregates are not formed.

  In recent years, many phospholipids and glycolipid-based compounds containing diacetylene groups have been reported for the purpose of constructing nanometer-scale ultrafine fibrous or fine tube-like aggregates (Non-patent Documents 2 and 3). . These give a tubular structure having an outer diameter of 20 nm to several tens of μm. The molecules that give such a structure are either “one-headed single-chain type” with one hydrophilic part (head) and one hydrophobic part (chain), or “one-headed two-chain type” with one hydrophilic part and two hydrophobic parts. Most are lipids. On the other hand, only a few examples of such tube-shaped aggregates are formed in the world using double-headed and double-chain lipids (Patent Document 1, Non-Patent Documents 4 and 5), Gives a two-dimensional sheet-like structure.

  These tubular aggregates are generally stable only in dispersed solvents, and the specific structure collapses when subjected to physical vibration or impact, or a solvent that dissolves lipids well or is heated. . In order to stabilize and insolubilize the structure of the aggregate, an amphiphilic molecule containing a polymerizable functional group is synthesized, and the obtained aggregate is also polymerized using a radical initiator or ultraviolet rays. (Non-patent document 6). However, when a polymerizable functional group is introduced into the double-headed lipid described above, only a fine fibrous aggregate (Patent Documents 2 and 3 and Non-Patent Document 7) or a tape-like aggregate can be obtained (Non-Patent Document). Reference 8), tubular aggregates are not obtained.

JP 2002-322190 A Japanese Patent No. 2876044 Japanese Patent No. 2905875 Inoue Shinzo “Biological membrane experiment method (bottom)”, page 185, Akamatsu et al., Kyoritsu Shuppan (1974) Journal of The American Chemical Society, vol.107, 509-510, 1985 Chemistry and Physics of Lipids, vol.47, 135-148, 1987 New Journal of Chemistry, vol.24, 1043-1048, 2000 Langmuir, vol. 17, 3162-3167, 2001 Polymer for Advanced Technologies, vol.5, 358-393, 1994 Journal of the American Chemical Society, vol.123, 3205-3213, 2001 Advanced Materials, vol.12, 871-874, 2000

  The tubular aggregate (Patent Document 1) composed of double-headed lipids already developed by the present inventors has not been able to withstand stable use. On the other hand, the fine fibrous aggregates of the double-headed lipids already developed by the present inventors (Patent Documents 2 and 3) are fibrous, and a hollow tubular aggregate has not been obtained. Accordingly, an object of the present invention is to provide a novel glycolipid capable of forming a tube-shaped aggregate that can be stabilized, the tube-shaped aggregate, and the tube-shaped polymer, which have not been obtained conventionally.

  As a result of intensive studies, the present inventors have found that the above problem can be solved by making the polymerizable double-headed glycolipid asymmetric as shown in the following formula (Formula 1), and the present invention has been completed. I came to let you. That is, the present inventors synthesize an asymmetric polymerizable double-headed glycolipid, use it to form a self-aggregate, and polymerize it to obtain a long-term stable hollow tubular fiber. I was able to.

That is, the present invention has the following general formula (Formula 1)
(In the formula, G represents a residue excluding the reducing terminal hydroxyl group of aldopyranose, X represents a hydrogen atom, a hydroxyl group, a carboxyl group or an amino group, and a and b each represents an integer of 0 to 20). It is a polymerizable double-headed glycolipid represented.
The present invention further relates to a hollow tubular polymer produced by irradiating the tubular aggregate with radiation.

The present invention also includes the following general formula:
(In the formula, G represents a residue excluding the reducing terminal hydroxyl group of aldopyranose, X represents a hydrogen atom, a hydroxyl group, a carboxyl group or an amino group, a and b each represents an integer of 0 to 20, n represents It represents an integer depending on the degree of polymerization.) And is a hollow tubular polymer having an average outer diameter of about 80 to 5100 nm and an average inner diameter of about 50 to 2900 nm.

  The hollow tubular polymer of the present invention is stable over a long period of time. For example, in the fine chemical industry, medicine, cosmetics field, etc., a material for inclusion and separation of drugs and useful biomolecules, a drug delivery material, or a nanotube It is useful in the electronic / information field as a microelectronic component by coating a conductive material or metal on the surface. Furthermore, it is useful as a gas storage material in the energy industry field, and as an artificial blood vessel, a nanotube capillary, and a nanoreactor using a minute tube structure in the medical field, analysis, chemical product manufacturing field, etc., and has high industrial utility value.

The polymerizable double-headed glycolipid of the present invention has the following general formula (Formula 1)
It is represented by
G in this general formula (Formula 1) is a sugar residue excluding the hemiacetal hydroxyl group bonded to the anomeric carbon atom of the sugar. Examples of the sugar include glucopyranose, galactopyranose, galactopyranose, maltose, Examples include lactose, cellobiose, and chitobiose, and glucopyranose is preferable. The sugar is a monosaccharide or oligosaccharide, preferably a monosaccharide. The sugar residue may be D, L, or racemic, but naturally derived is usually D. Furthermore, in the aldopyranosyl group, since the anomeric carbon atom is an asymmetric carbon atom, there are α-anomers and β-anomers, but any of α-anomers, β-anomers and mixtures thereof may be used. In particular, those in which G is a D-glucopyranosyl group, a D-galactopyranosyl group, particularly a D-glucopyranosyl group are preferable because they are easy to produce and easy to produce.
Moreover, as G, a part or all of the hydroxyl group may be protected with a protecting group such as an acetyl group, a benzyl group, or an isopropylidene group.

The hydrocarbon groups represented by — (CH ₂ ) _a — and — (CH ₂ ) _b — in the general formula (Chemical Formula 1) are each a hydrocarbon group having 0 to 20 carbon atoms, and preferably a straight chain. It is. The hydrocarbon group represented by — (CH ₂ ) _a — preferably has 4 to 16 carbon atoms, more preferably 4 to 10 carbon atoms. The hydrocarbon group represented by — (CH ₂ ) _b — preferably has 0 to 8 carbon atoms, more preferably 8. Such hydrocarbon groups include methylene, dimethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, octamethylene, nonamethylene, decyl, undecyl, dodecyl, Examples include tridecyl group, tetradecyl group, pentadecyl group, hexadecyl group, heptadecyl group, octadecyl group, nonadecyl group, and eicosyl group.

The polymerizable double-headed glycolipid represented by the general formula (Chemical Formula 1) may be synthesized by any method, but can be produced, for example, by the following method.
First, the general formula (Formula 3)
Acetyl GN ₃
(In the formula, acetyl G represents a residue other than the reducing terminal hydroxyl group of D- or L-glucopyranose or D- or L-galactopyranose in which all hydroxyl groups are protected with acetyl groups). After one or two of these are subjected to catalytic reduction using platinum oxide or the like, D- or L-glucopyranosylamine or D- or L-galactopyranosylamine in which all hydroxyl groups are protected with acetyl groups And general formula (Chemical Formula 4)
(Wherein a and b are as described above) An excess amount of the dicarboxylic acid represented by the formula (2) is added and condensed. This condensation reaction uses oxalyl dichloride to convert the dicarboxylic acid component to the corresponding dicarboxylic acid chloride, which is converted to D- or L-glucopyranosylamine, D- or L, in which all hydroxyl groups are protected with acetyl groups. -A polymerizable double-headed glycolipid containing a diacetylene group, which is coupled with galactopyranosylamine and has an acetylated protector of a sugar residue at both ends, is obtained. After isolation and purification of this, a sodium methoxide / methanol solution is allowed to act to deprotect the acetyl group of the sugar residue to obtain a polymerizable asymmetric bihead lipid containing diacetylene.

  On the other hand, examples of the dicarboxylic acid represented by the general formula (Chemical Formula 4) include 3,5-octadiindioic acid, 4,6-decadiindioic acid, 5,7-dodecadiindioic acid, and 6,8-tetradecadiyne. Dionic acid, 7,9-hexadecadiindioic acid, 8,10-octadecadiindioic acid, 9,11-icosadiindioic acid, 10,12-docosadiindicarboxylic acid, 11,13-tetracosadiindicarboxylic acid An acid, 12,14-hexacosadiyne dicarboxylic acid, etc. can be used.

Next, a desirable embodiment for producing a carboxylic acid type lipid of the above general formula (in the case where X is a carboxylic acid group) according to the present invention will be described. First, the catalytic reduction of the azido sugar represented by the general formula (Chemical Formula 3) is performed by, for example, dissolving the azido sugar in methanol and bringing it into contact with hydrogen using platinum oxide as a catalyst. At this time, although the reaction proceeds in the same manner even when a palladium catalyst is used, platinum oxide is more preferable because some side reaction occurs.
Next, it was confirmed by thin layer chromatography that the azide group was completely reduced and converted to an amino group, and the produced amino sugar was isolated and purified without any purification. The dicarboxylic acid represented by is condensed. This condensation reaction is obtained by mixing and reacting both in an equimolar amount. At this time, for example, N, N-dimethylformamide, chloroform, methyl alcohol, ethyl alcohol and the like can be used as a reaction solvent. Among these, N, N- Dimethylformamide is preferred. Examples of the condensing agent include 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, 1-hydroxybenzotriazole, diethylphosphorusanidate, 1-ethoxycarbonyl-2-ethoxy- 1,2-dihydroquinoline, isobutyl chloroformate, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, 1-hydroxybenzotriazole, diethyl phosphorocyanidate, 1-ethoxycarbonyl-2-ethoxy- 1,2-dihydroquinoline, isobutyl chloroformate, benzotriazol-1-yl-oxy-tris (dimethylamino) -phosphonium hexafluorophosphate (below) BOP "), 1-hydroxybenzotriazole (hereinafter referred to as" HOBt "), benzotriazol-1-yl-oxy-tripyrrolidinophosphonium hexafluorophosphate (benzotriazol-1-yl-oxy-) tripyrrolidinophosphonium hexafluorophosphate; hereinafter referred to as “PyBOP”), O- (benzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate (O- (benzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate; hereinafter referred to as “HBTU”) and diphenyl (2,3-dihydro-2-thioxo-3-benzoxazolyl) phosphonate (diphenyl (2,3-dihydro-2) -thioxo-3-benzoxazolyl) phosphonate; hereinafter referred to as "DBP"). Among these, an acid halide is used, or a combination of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, 1-hydroxybenzotriazole and HOBt as a condensing agent is preferable because it reacts in a high yield.
The reaction temperature is selected in the range of -30 ° C to 30 ° C, and the reaction time is usually 30 minutes to 10 hours.

The composition obtained in this way can be made highly pure by purifying it using, for example, silica gel column chromatography (developing solvent: chloroform / methanol 20/1). Carboxylic acid-type lipids obtained by such a method can be confirmed by ¹ H-NMR spectrum.
Furthermore, it melt | dissolves in methanol and a sodium methoxide / methanol solution is made to act, The target object from which the sugar residue part was deacetylated is obtained in the form of a sodium salt. Further, a strongly acidic ion exchange resin can be added to neutralize the sodium salt to obtain the target product in the carboxylic acid form. Since the above deacetylation reaction proceeds quantitatively, it is not necessary to purify it in particular. However, if necessary, it can be purified to a high purity by, for example, silica gel column chromatography. .

The obtained carboxylic acid type lipids are those in which the anomeric carbon of the sugar residue is 100% β. This indicates that the ¹ H-NMR spectrum (in heavy dimethyl sulfoxide, 60 ° C.) of the carboxylic acid type lipid shows a double line signal (spin-spin coupling constant 8.8 Hz) at a δ value of 4.9 ppm. This can be confirmed.
This compound was in agreement with the calculated values within a range error elemental analysis of the actual measurement example, also, the infrared absorption characteristic absorption derived from a sugar carboxyl group 1696 cm ^-1 in the ^spectrum, 1634 cm -1, amide carbonyl group 1549Cm ^-1 The characteristic absorption derived from is shown. Further, in the ¹ H-NMR spectrum (in heavy dimethyl sulfoxide, room temperature), the δ value is 1.2 to 1.4 ppm (methylene hydrogen of a long-chain alkylene chain), 1.5 to 1.7 ppm (adjacent to the amide group). Methylene group hydrogen next to methylene group), 2.3-2.4 ppm (hydrogen methylene group adjacent to amide group), 1.5-1.7 ppm (methylene group next to methylene group adjacent to carboxyl group) Hydrogen), 2.3-2.4 ppm (hydrogen of methylene group adjacent to carboxyl group), 2.0-2.1 ppm (hydrogen of sugar acetyl group), 6.3-6.4 ppm (position 1 of glucopyranosyl group) Methine hydrogen) signal can be observed. From this, the compound can be identified as the target carboxylic acid type lipid.

Next, another method for producing the polymerizable double-headed glycolipid represented by the above general formula (Formula 1) will be described.
Although there is no particular limitation on the production method of the N-glycoside type glycolipid, this N-glycoside type glycolipid has, for example, the general formula G-COOH (wherein G has the same meaning as G in the general formula (Formula 1)). )) Or an unsaturated long-chain carboxylic acid chloride represented by the general formula G-COCl is reacted with a sugar amine having an amino group at the anomeric position to form an N-glycosidic bond. Can be produced.

Although there is no restriction | limiting in particular also about the manufacturing method of this sugar amine, This sugar amine can be manufactured as follows, for example.
A specific sugar (aldopyranose or its oligosaccharide) and ammonium hydrogen carbonate are dissolved in water. At this time, the temperature of the aqueous solution is preferably 37 ° C. As a result, this ammonium hydrogen carbonate selectively reacts with the hemiacetal hydroxyl group bonded to the anomeric carbon atom of the sugar to obtain an aminated product having an amino group at the anomeric carbon atom (position 1) of the sugar, a so-called amino sugar. In this reaction, β-form is selectively obtained.

  As diacetylene monocarboxylic acid, 10-12 heptadecadiynoic acid, 2-4 pentadecadiynoic acid, 2-12 pentadecadiynoic acid, 10-12 tricosadiinoic acid ( 10-12 tricosadiynoic acid), 2-4 heptadecadiynoic acid, 10-12 pentacosadiynoic acid, 2-4 nonadecadinoic acid (2-4 nonadecadiynoic acid), 10-12 heptacosadiynoic acid, 10-4 heneacosadiynoic acid, 2-4 heneicosadiynoic acid, and 10-12 nonakosadinoic acid And acid (10-12 nonacosadiynoic acid). Among these, 10-12 heptadecadiynoic acid and 10-12 tricosadiynoic acid are the amphiphilic balance of the resulting glycolipid and the melting point in water. This is desirable.

  In the reaction of unsaturated long-chain carboxylic acid and sugar amine, a condensing agent may be used as a reaction accelerator. Examples of the condensing agent include benzotriazol-1-yl-oxy-tris (dimethylamino) -phosphonium hexafluorophosphate (hereinafter referred to as “BOP”). ), 1-hydroxybenzotriazole (hereinafter referred to as “HOBt”), benzotriazol-1-yl-oxy-tripyrrolidinophosphonium hexafluorophosphate; Hereinafter referred to as “PyBOP”), O- (benzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate (O- (benzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate; hereinafter referred to as “HBTU”) and diphenyl (2,3 Dihydro-2-thioxo-3-benzoxazolyl) Hosuhoneito (diphenyl (2,3-dihydro-2-thioxo-3-benzoxazolyl) phosphonate;. Hereinafter referred to as "DBP"), and the like. Among these, the combination of BOP and HOBt is preferable because it reacts in a high yield.

The reaction for forming an N-glycoside bond from the sugar amine and the unsaturated long-chain carboxylic acid can be performed, for example, as follows.
Using HOBt and BOP as condensing agents, magnetic stirring is performed for 5 hours or more at room temperature using dimethyl sulfoxide as a solvent. In order to increase the yield, the reaction may be carried out at a molar ratio of sugar amine: fatty acid: HOBt: BOP = 1: 1 to 100: 1 to 100: 1 to 100, particularly 1: 2 or more: 3: 1. preferable. That is, it is preferable to add an excess of fatty acid or condensing agent to the sugar amine.
The range as a condensing agent other than the combination of HOBt and BOP includes the use of DBP alone, the combination of HOBt and HBTU, the combination of HOBt and PyBOP, the combination of DBP and triethylamine (TEA), HOBt, HBTU, and N , N-diisopropylethylamine (DIEA) and the like.
In order to activate the carboxylic acid of the fatty acid before the reaction, it is desirable to add the sugar amine after first mixing the fatty acid and the condensing agent in a solvent for about 10 minutes. After completion of the reaction, the crude product can be made to have a high purity by a separation and purification operation by silica gel column and reprecipitation.

The reaction for forming an N-glycoside bond from the sugar amine and the unsaturated long-chain carboxylic acid chloride can be performed, for example, as follows.
In the presence of a basic substance, magnetic stirring is performed for 5 hours or more at a reaction temperature of 0 ° C. Examples of the solvent include methanol, water, and tetrahydrofuran. In order to activate the amino group of the sugar amine before the reaction, the sugar amine and the basic substance are first mixed in a solvent at 0 ° C. for about 2 hours, and then the unsaturated long-chain carboxylic acid chloride is added. It is desirable to add.

As a result of such a reaction, the N-glycoside type glycolipid of the present invention in which an unsaturated hydrocarbon group is bonded to the anomeric carbon atom (position 1) of the sugar via an amide bond is produced. The structure of the produced N-glycoside type glycolipid can be confirmed by ¹ H-NMR spectrum or ¹³ C-NMR spectrum.

Next, a method for producing hollow fiber organic nanotubes using the polymerizable double-headed glycolipid synthesized as described above will be described.
First, a solution such as water is added to a raw material polymerizable double-headed glycolipid and heated to prepare a solution. The higher the concentration of the polymerizable double-headed glycolipid in this solution is, the more preferable it is, and it is most preferable that it is saturated.
As a solvent for preparing this aqueous solution, water is usually used alone, but a mixed solvent of water and an organic solvent may be used. Examples of the organic solvent include hydrophilic solvents such as dimethyl sulfoxide, acetone, methyl alcohol, ethyl alcohol, and propyl alcohol.
At this time, if the amount of the solvent in the solution is too small, an insoluble portion remains, and if the amount of the solvent is too large, the saturated concentration is not reached. Therefore, the amount of the solvent to be added is 10,000 to It is selected within the range of 40,000 times the weight.
The heating temperature at this time is preferably as high as possible in order to increase the amount of the polymerizable double-headed glycolipid dissolved, and is preferably raised to the boiling point of the solution, but a lower temperature may be used. This temperature is specifically 80 ° C. to boiling point, preferably 90 ° C. to boiling point, most preferably boiling point.

  The solution of the polymerizable double-headed glycolipid thus prepared is slowly cooled and allowed to stand at room temperature to produce hollow fiber-like organic nanotubes. This “slow cooling” has two meanings, in particular, that the temperature is lowered without performing heating and cooling operations and that the temperature is slowly lowered while performing heating and cooling operations. Therefore, the temperature at the time of slow cooling may vary depending on the ambient temperature, the heat capacity of the apparatus, or the like, and may depend on the setting of the apparatus that controls the temperature. Further, “room temperature” means a temperature at which excessive heating and cooling are not performed, and specifically refers to a temperature of 0 to 40 ° C., preferably around 20 ° C. In this way, fibrous materials precipitate from the solution after slow cooling for a few dozen hours to several days.

By collecting the fibrous material and air-drying or vacuum-drying, a hollow tubular aggregate stable in the air can be obtained. The size of the hollow tubular aggregate varies depending on the structure of the N-glycoside type glycolipid, but the average outer diameter is about 80-5100 nm, the average inner diameter (hollow average diameter) is about 50-2900 nm, Is several hundred nm to several hundred μm. In particular, when the terminal (X) is an alkyl group (or a hydrogen atom), the average outer diameter is about 170-5100 nm, the average inner diameter (hollow average diameter) is about 90-2900 nm, and the length is several hundred nm. When the terminal (X) is a carboxyl group, the average outer diameter is about 80 to 160 nm, the inner diameter is about 50 to 100 nm, and the length is about 0.5 to 100 μm.
The form of the obtained hollow fiber-like organic nanotube can be easily observed using a normal optical microscope. The tube structure can be confirmed in more detail by using a laser microscope, an atomic force microscope, or an electron microscope.

Polymerization is carried out by irradiating the hollow tubular aggregate thus obtained with radiation to produce a hollow tubular polymer. The ultraviolet rays used at this time include active rays such as ultraviolet rays, electron beams, X-rays, laser beams, alpha rays, beta rays, and gamma rays, and ultraviolet rays and gamma rays are particularly advantageous. In the case of this ultraviolet irradiation, a 5 to 300 W low-pressure mercury lamp is used, and ultraviolet rays having a wavelength of 230 to 300 nm are irradiated for about 5 to 40 minutes. In the case of gamma ray irradiation, irradiation is performed with a dose of 1.0 × 10 ^{5 to} 1.0 × 10 ⁶ R. When irradiated in this way, the hollow tubular aggregate changes its color from the initial white color to finally red to purple while retaining its shape, fiber diameter, and fiber length. Since this discoloration is known to originate from the polymerization reaction of diacetylene groups, it can be seen that this resulted in the conversion of the hollow tubular aggregate into a polymer. Its size is almost the same as the aggregate.

The following examples illustrate the invention but are not intended to limit the invention.
The Rf value of thin layer chromatography is a value obtained when a mixed solvent of chloroform / methanol (volume ratio 20/1) is used as a developing solvent, and is a mixture of Rf1, chloroform / methanol / water (volume ratio 64/31/5). The value when the solvent was the developing solvent was Rf2.

While dissolving 5.0 g (12.2 mmol) of 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide in 120 ml of DMF, 15.8 g (243 mmol) of sodium azide was added. In addition, the mixture was stirred overnight at room temperature under light shielding. The reaction mixture was added dropwise to 1000 ml of ice water with stirring, the insoluble matter was extracted with 900 ml of methylene chloride, and the organic phase was washed with ice water and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the solvent was completely distilled off under reduced pressure, and the resulting pale yellow solid was washed with diethyl ether, dried and recrystallized from 2-propanol to give white needle crystals. There was obtained 3.30 g (yield 79%) of 2,3,4,6-tetra-O-acetyl-β-glucopyranosyl azide. The physical properties of this are as follows.
Rf value of thin layer chromatography Rf1 = 0.6
Melting point 131-132 ° C
Elemental analysis _{(as C 14 H 19 O 9 N 3} )
C H N
Calculated Value (%) 45.04 5.13 11.26
Actual value (%) 45.36 5.10 11.14

  The obtained 2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl azide 2.24 g (6.0 mmol) was dissolved in 60 ml of dehydrated methyl alcohol, and platinum oxide was added under a nitrogen atmosphere. 0.32 g (1.4 mmol) was added. Subsequently, it stirred for 2 hours, introducing hydrogen at room temperature. The reaction mixture was suction filtered using silica gel, dehydrated N, N′-dimethylformamide (30 ml) was added to the filtrate, and the mixture was concentrated under reduced pressure. To this was added 3 drops of dehydrated pyridine, and the solvent was distilled off under vacuum to obtain the desired 2,3,4,6-tetra-O-acetyl-β-D-glucopyranosylamine. The target product was confirmed by thin layer chromatography without isolation and purification (Rf = 0.8).

Next, 1.63 g (12 mmol) of 1-hydroxybenzotriazole was added at room temperature to a solution of 6.55 g (18 mmol) of 10,12-docosadiyne dicarboxylic acid in dehydrated N, N′-dimethylformamide (30 ml). After stirring for a minute, a solution of 3.45 g (18 mmol) of 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide in methylene chloride (60 ml) was added dropwise over 15 minutes. To this, 2.08 g (6.0 mmol) of 2,3,4,6-tetra-O-acetyl-β-D-glucopyranosylamine which was not purified was added and stirred at room temperature for 16.5 hours. Chloroform (150 ml) was added thereto, washed with water (100 ml), citric acid (100 ml), aqueous sodium carbonate solution (100 ml), and aqueous sodium chloride solution (100 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
The obtained crude product was purified by silica gel column chromatography [eluent: chloroform / methanol = change from 10/0 to 95/5] to give colorless oil 20-[(2,3,4,6- Tetra-O-acetyl-N-β-D-glucopyranosyl) carbamoyl] 9,11-eicosadiyne carboxylic acid was obtained (1.245 g, 30% yield).
Rf value of thin layer chromatography Rf1 = 0.3
Elemental analysis value (as C ₃₆ H ₅₃ O ₁₂ N ₁ )
C H N
Calculated value (%) 62.50 7.72 2.02
Actual value (%) 62.48 7.88 2.11.

The obtained 51.2 mg (0.074 mmol) was dissolved in dehydrated methyl alcohol (1.5 ml), and 1.63 ml (0.082 mmol) of 0.05 M sodium methoxide was added under an argon atmosphere for 2 hours at room temperature. After stirring, 0.3 ml (0.015 mmol) of 0.05M sodium methoxide was added. This was stirred for 2.5 hours, and further 0.3 ml (0.015 mmol) of 0.05M sodium methoxide was added and stirred for 1 hour. An acidic resin was added thereto to adjust the pH to 6 to 7, and then the supernatant was taken out and concentrated under reduced pressure. This was dried to obtain the desired product (hereinafter referred to as “polymerizable double-headed glycolipid I”) (36.8 mg, 95%). A ¹ H-NMR spectrum chart of this compound (in heavy dimethyl sulfoxide, 25 ° C.) is shown in FIG.
Rf value of thin layer chromatography Rf2 = 0.3
Elemental analysis value (as C ₂₈ H ₄₅ O ₈ N ₁ )
C H N
Calculated value (%) 64.22 8.66 2.67
Actual value (%) 64.09 8.79 2.62

  The polymerizable double-headed glycolipid I (2.5 mg, 0.0048 mmol) obtained in Example 1 is placed in a flask, 5 ml of distilled water is added thereto, dispersed by shaking, heated to 100 ° C. using an incubator and dissolved. And gradually cooled to room temperature (0.1 ° C. per minute). As a result, a tubular assembly having an outer diameter of 100 to 140 nm, an inner diameter of 60 to 100 nm, and a length of 0.5 to 100 μm was obtained. Its form could be easily confirmed from a scanning electron microscope. The obtained observation image is shown in FIG.

  The polymerizable double-headed glycolipid I (2.47 mg, 0.0047 mmol) obtained in Example 1 was placed in a flask, and 5 ml of distilled water was added thereto. To this was added 28.2 μl of 0.01M NaOH (0.06 equivalent to lipid), dispersed by shaking, dissolved by heating using an incubator, and gradually cooled to room temperature (20 ° C.) (0.1 ° C. per minute) And left at room temperature for 1 day. At this time, the pH of the solution changed from 7.0 to 6.9. As a result, a tubular assembly having an outer diameter of 70 to 130 nm, an inner diameter of 50 to 90 nm, and a length of 0.5 to 50 μm was obtained. The form could be easily confirmed from a scanning transmission electron microscope. The obtained observation image is shown in FIG.

  The polymerizable double-headed glycolipid I (5 mg, 0.0096 mmol) obtained in Example 1 is placed in a flask, 5 ml of a phosphate buffered water solution (0.2 M) having a pH of 5.2 is added thereto, and dispersed by shaking. The solution was heated and dissolved, and gradually cooled to room temperature (0.1 ° C. per minute). As a result, a tubular assembly having an outer diameter of 110 to 170 nm, an inner diameter of 50 to 90 nm, and a length of 0.5 to 50 μm was obtained. The form could be easily confirmed from a scanning transmission electron microscope. The obtained observation image is shown in FIG.

  The polymerizable double-headed glycolipid I (5 mg, 0.0096 mmol) obtained in Example 1 was placed in a flask, and 5 ml of distilled water was added thereto. To this was added 0.01M NaOH, 955 μl (1 equivalent with respect to lipid), and the mixture was dispersed by shaking. 1 ml of this solution was placed in a glass sample bottle (for 3 ml) and stoppered with a hole having a diameter of about 1 mm. Further, this was placed in a glass sample bottle (for 50 ml) containing 3 ml of 0.1% acetic acid aqueous solution and left at room temperature for 2 weeks. As a result, a tubular assembly having an outer diameter of 70 to 130 nm, an inner diameter of 50 to 90 nm, and a length of 0.5 to 50 μm was obtained. The form could be easily confirmed from a scanning transmission electron microscope. The obtained observation image is shown in FIG.

  The aqueous solution (concentration: 1 mM) containing the hollow fiber tube aggregate obtained in Example 2 was taken in a quartz glass cell, and irradiated with UV light (deuterium lamp, output 4 W, 254 nm) for 24 hours in an argon atmosphere at room temperature. . As a result, it was found that the color changed from transparent to reddish purple and changed to polydiacetylene in the form of polymerized diacetylene. When the polymer of the obtained hollow fiber tube was observed using a UV spectrum, peaks that were not present before UV irradiation were observed at 542 nm and 498 nm. When the polymer of the obtained hollow fiber tube is observed using a scanning electron microscope, a hollow fiber tube structure having an outer diameter of 100 to 140 nm, an inner diameter of 50 to 100 nm, and a length of 0.5 to 50 μm can be confirmed. It was. FIG. 6 shows a change in absorbance of the polymer of the hollow fiber tube under ultraviolet irradiation, and FIG. 7 shows an electron micrograph.

  The aqueous solution (concentration 1 mM) containing the aggregates of the hollow fiber tube obtained in Example 2 was taken in a quartz glass cell and irradiated with gamma rays (1.03 × 106 R) at room temperature in an argon atmosphere. As a result, it was found that the color changed from transparent to reddish purple and changed to polydiacetylene in the form of polymerized diacetylene. When the polymer of the obtained hollow fiber tube is observed using a scanning electron microscope, a hollow fiber tube structure having an outer diameter of 100 to 140 nm, an inner diameter of 50 to 100 nm, and a length of 0.5 to 50 μm can be confirmed. It was. An electron micrograph of the polymer of this hollow fiber tube is shown in FIG.

  Into the flask, D-(+)-glucopyranose (Fluka, 1.0 g, 5.55 mmol) was taken and dissolved by adding 50 mL of water. To this, 10 g of ammonium hydrogen carbonate (manufactured by Wako) was added until crystals were deposited at the bottom of the flask. This was magnetically stirred in a 37 ° C. oil bath for 3-5 days. To maintain saturation during the reaction, ammonium bicarbonate was sometimes added. The total amount of ammonium bicarbonate was 40-50 g. The reaction was monitored by thin layer chromatography (Rf value = 0.40, developing solvent: ethyl acetate / acetic acid / methanol / water (volume ratio 4/3/3/1)). In order to remove unreacted ammonium hydrogen carbonate from the reaction system as a post-treatment, the reaction mixture was cooled to precipitate ammonium hydrogen carbonate as crystals. In addition to this method, the reaction system may be vaporized by adding an appropriate amount of water and concentrated, or unreacted ammonium hydrogen carbonate may be removed using a desalting apparatus. In this way, β-D-glucopyranosylamine was obtained.

A flask in which 10,12-heptadecadinoic acid (Tokyo Chemical Industry Co., Ltd., 200 mg, 0.76 mmol) was dissolved in 3 mL of dimethyl sulfoxide was placed in a flask covered with aluminum foil and shielded from light to prepare a reaction system. . A solution prepared by dissolving HOBt (manufactured by WAKO, 117 mg, 0.76 mmol) and BOP (manufactured by WAKO, 1.01 g, 2.29 mmol) in 1.0 mL of dimethyl sulfoxide was added to the reaction system at 37 ° C. Magnetically stirred for minutes.
Next, β-D-glucopyranosylamine (410 mg, 2.29 mmol) obtained above was added to the reaction system, and the mixture was reacted with magnetic stirring at 37 ° C. for 18 hours. This reaction was followed by thin layer chromatography (Rf value = 0.51, developing solvent: chloroform / methanol (volume ratio 4/1)).
The obtained crude product is subjected to silica gel column chromatography using an ethyl acetate / methanol (volume ratio 4/1) mixed solvent as an eluent, and then re-reacted using an ethyl acetate / methanol (volume ratio 3/1) mixed solvent as a solvent. Precipitation was carried out to obtain N- (10,12-heptadecadinoinoyl) -β-D-glucopyranosylamine (49 mg, 15% yield) as a white solid.

The physical properties of this product are as follows:
Melting point: 168 ° C
The ¹ H-NMR spectrum of this product (in heavy dimethyl sulfoxide, 25 ° C.) is shown in FIG.
^{In the 1} H-NMR spectrum (FIG. 9), the δ value is 0.87 ppm (hydrogen of hydrocarbon group methyl group), 1.24-1.44 ppm (hydrogen of hydrocarbon group methylene group), 2.09 ppm. (Hydrocarbon of the first methylene group counted from the amide bond part in the hydrocarbon group), 2.28 ppm (Hydrogen of the first methylene group counted from the diacetylene group part of the hydrocarbon group), 3.04-3.62 ppm (hydrogen linked to carbons C2, C3, C4, C5, and C6 of the sugar chain), 4.45-4.93 ppm (carbons C2, C3, C4, and C6 of the sugar chain) Hydroxyl linked to C1 of the sugar chain, dd, J1,2 9.2 Hz), and 8.23 ppm (hydrogen linked to nitrogen of the amide group, d, J1, NH) 8.8 Hz).
The analytical values for the N-glycoside glycolipids obtained in these Examples agreed with the structural formula (Chemical Formula 1) within an error range.

Next, 1 mg of N- (10,12-heptadecadinoino) -β-D-glucopyranosylamine obtained in Example 8 was weighed into a flask, 10 mL of water was added to the flask, and an oil bath was used. The mixture was heated and refluxed at 95 ° C. for 30 minutes to disperse, and then allowed to stand at room temperature for a dozen hours.
When the obtained aqueous solution is observed using a scanning electron microscope, a hollow fiber organic nanotube material having an inner diameter of 0.2 to 2.9 μm and an outer diameter of 1.7 to 5.1 μm can be confirmed. It was. Furthermore, when observed with an optical microscope, a needle-like structure having a length of several tens of μm was confirmed. Scanning electron micrographs of the organic nanotubes are shown in FIGS. 10 and 11, and optical micrographs are shown in FIGS.

  An aqueous solution containing the organic nanotubes obtained in Example 9 was taken in a petri dish and allowed to air dry at room temperature. The white organic nanotubes were colored pink, red, or die-dyed when dried. This was irradiated with UV (254 nm) for 5 minutes in an argon atmosphere. When the obtained organic nanotube polymer was observed using an optical microscope, a needle-like structure having a length of several tens of μm could be confirmed. Optical micrographs of this organic nanotube polymer are shown in FIGS.

In a flask covered with aluminum foil and shielded from light, 10,12-tricosadiinoic acid (Tokyo Chemical Industry Co., Ltd., 200 mg, 0.58 mmol) dissolved in 3 mL of dimethyl sulfoxide was added to prepare a reaction system. A solution prepared by dissolving HOBt (WAKO, 89 mg, 0.58 mmol) and BOP (WAKO, 765 mg, 1.73 mmol) in 1.0 mL of dimethyl sulfoxide was added to the reaction system and magnetically added at 37 ° C. for 10 minutes. Stir.
Next, β-D-glucopyranosylamine (310 mg, 1.73 mmol) obtained in Example 8 was added to the reaction system, and the mixture was reacted with magnetic stirring at 37 ° C. for 21 hours. This reaction was followed by thin layer chromatography (Rf value = 0.50, developing solvent: chloroform / methanol (volume ratio 4/1)).
The obtained crude product is subjected to silica gel column chromatography using an ethyl acetate / methanol (volume ratio 4/1) mixed solvent as an eluent, and then re-reacted using an ethyl acetate / methanol (volume ratio 3/1) mixed solvent as a solvent. Precipitation was carried out to obtain N- (10,12-tricosadiinoyl) -β-D-glucopyranosylamine (49 mg, 17% yield) as a white solid.
The physical properties of this product are as follows:
Melting point: 150 ° C

Next, 1 mg of N- (10,12-heptadecadinoino) -β-D-glucopyranosylamine obtained in Example 11 was weighed into a flask, 15 mL of water was added thereto, and an oil bath was used. The mixture was heated and refluxed at 95 ° C. for 30 minutes to disperse, and then allowed to stand at room temperature for a dozen hours.
When the obtained aqueous solution was observed using a scanning electron microscope, a hollow fiber organic nanotube material having an inner diameter of 90 to 550 nm and an outer diameter of 170 to 890 nm could be confirmed. Furthermore, when observed with an optical microscope, a needle-like structure having a length of several to several tens of μm was confirmed.

  The aqueous solution containing the organic nanotube obtained in Example 11 was taken in a quartz glass cell, and this was irradiated with UV (254 nm) in an argon atmosphere. White organic nanotubes were colored pink, red, or die-dyed. When the obtained organic nanotube polymer was observed using a UV spectrum, peaks that were not present before UV irradiation were observed at 542 nm and 498 nm. In the CD spectrum, peaks that were not present before UV irradiation were observed as negative cotton effects at 529 nm and 497 nm.

It is a diagram showing ¹ H-NMR spectrum of the compound obtained in Example 1 (concentration of 4 mg / 0.6 ml, in deuterochloroform, 25 ℃, 600MHz). 6 is a view showing a scanning electron microscope image of a tube-like aggregate obtained in Example 2. FIG. 4 is a view showing a scanning transmission electron microscope image of a tube-like aggregate obtained in Example 3. FIG. 6 is a view showing a scanning transmission electron microscope image of a tube-shaped aggregate obtained in Example 4. FIG. 6 is a view showing a scanning transmission electron microscope image of a tube-like aggregate obtained in Example 5. FIG. It is a figure which shows the light absorbency change of the hollow fiber tube by superposition | polymerization under ultraviolet irradiation of Example 6. FIG. 6 is a view showing a scanning electron micrograph of an aggregate of hollow fiber tubes obtained in Example 6. FIG. 6 is a view showing a scanning electron micrograph of an aggregate of hollow fiber tubes obtained in Example 7. FIG. Is a diagram showing ¹ H-NMR spectrum of the produced N- glycoside type glycolipid (N- (10,12-heptadecafluoro diisopropyl butanoyl)-beta-D-glucopyranosyl amine) in Example 8. 6 is a view showing a scanning electron micrograph of an organic nanotube obtained in Example 8. FIG. The size of the photograph is 24.3 μm long × 8.7 μm wide. 6 is a view showing an optical micrograph of organic nanotubes obtained in Example 8. FIG. The size of the photograph is 26 μm long × 49 μm wide. 6 is a view showing an optical micrograph of an organic nanotube polymer obtained in Example 10. FIG. The size of the photograph is 13 μm long × 56 μm wide.

Claims (6)

The following general formula (Formula 1)
(In the formula, G represents a residue excluding the reducing terminal hydroxyl group of aldopyranose, X represents a hydrogen atom, a hydroxyl group, a carboxyl group or an amino group, and a and b each represents an integer of 0 to 20). A polymerizable double-headed glycolipid represented. The polymerizable double-headed glycolipid according to claim 1, wherein G is a D-glucopyranosyl group or an L-glucopyranosyl group. A hollow tubular aggregate comprising the polymerizable double-headed glycolipid according to claim 1 or 2 and having an average outer diameter of about 80 to 5100 nm and an average inner diameter of about 50 to 2900 nm. A hollow tubular polymer produced by irradiating the tubular aggregate according to claim 3 with radiation. The hollow tubular polymer according to claim 4, wherein the radiation is ultraviolet rays or gamma rays. The following general formula
(In the formula, G represents a residue excluding the reducing terminal hydroxyl group of aldopyranose, X represents a hydrogen atom, a hydroxyl group, a carboxyl group or an amino group, a and b each represents an integer of 0 to 20, n represents A hollow tubular polymer having an average outer diameter of about 80 to 5100 nm and an average inner diameter of about 50 to 2900 nm.