Photosensitive amphiphilic compound containing coumarin unit as well as preparation method and application of photosensitive amphiphilic compound

Abstract

The invention provides a photosensitive amphiphilic compound containing a coumarin unit as well as a preparation method and application of the photosensitive amphiphilic compound. The photosensitive amphiphilic compound can be used for precise and controllable release of loaded drugs, and has a structure shown in the formula I: # imgabs0 #, and the structure shown in the formula I is shown in the specification.

Description

Technical Field

[0001] The present application relates to the field of biomedicine, and in particular, to a photosensitive amphiphilic compound containing a coumarin unit, a preparation method and a use thereof. Background Art

[0002] Micelles, vesicles, emulsions and assemblies of various forms formed by amphiphilic molecules play an important role in drug encapsulation and controlled release. Developing drug carriers that can accurately and controllably release drugs in time and space is an important method for developing new drug delivery systems. Coumarin compounds are a class of compounds with good chemical stability and photoresponsiveness with high photochemical activity. By introducing different numbers and different structures of modifying groups on coumarin, the absorption wavelength and intensity of coumarin can be adjusted to obtain coumarin units that can undergo photochemical reactions in different light bands, that is, coumarin units with light responses in different bands.

[0003] However, the photosensitive materials based on coumarin compounds that can be used as drug sustained-release assemblies and their preparation methods still need to be improved. Summary of the invention

[0004] The present application aims to provide a photosensitive amphiphilic compound containing a coumarin unit, a preparation method and a use thereof. The photosensitive amphiphilic compound can be controllably photodegraded under light of different wavelengths such as 365nm, 395nm and 405nm, and the photodegradation rate under each light is quite different, and can be used for precise and controllable release of drug delivery.

[0005] In one aspect of the present application, the present application provides a photosensitive amphiphilic compound containing a coumarin unit. The photosensitive amphiphilic compound has a structure shown in the following formula I:

[0006]

[0007] Among them, A is a hydrophilic unit and B is a hydrophobic unit.

[0008] The A comprises a nucleotide, the B comprises a fat chain, the nucleotide is connected to the coumarin structure via a phosphodiester bond, and the fat chain is connected to the coumarin structure via an ester group. The photosensitive amphiphilic compound can be controllably photodegraded in different wavelengths, and the degradation speed varies greatly, and can be used to form a drug assembly for precise and controllable release of the drug.

[0009] According to an embodiment of the present application, the nucleotide is a natural and / or non-natural nucleotide, and the nucleotide includes a modified or unmodified nucleotide unit, and the modification group is located on the sugar ring and / or the base.

[0010] According to an embodiment of the present application, in the hydrophilic unit, the sugar ring of the nucleotide includes at least one selected from the following structures: natural deoxyribose, natural ribose, 2'-methoxy substituted deoxyribose, 2'-fluoro substituted deoxyribose, 2'-methoxyethyl substituted deoxyribose, 2'-methylamino-2-oxyethyl substituted deoxyribose, 2'-propargyloxy substituted deoxyribose, 2'-butoxy substituted deoxyribose, 2'-hexyloxy substituted deoxyribose, 2'-octyloxy substituted deoxyribose, 2'-decyloxy substituted deoxyribose, 2'-dodecyloxy substituted deoxyribose, 2'-tetradecyloxy substituted deoxyribose, 2'-hexadecyloxy substituted deoxyribose, 2'-octadecyloxy substituted deoxyribose, 2'-eicosyloxy substituted deoxyribose, 2'-oxy-4' carbonyl methylene lock configuration deoxyribose, 2'-oxy-4' carbonyl vinyl lock configuration deoxyribose, 2'-oxy-4' carbonyl-S-configuration ethyl lock configuration deoxyribose, 2'-oxy-4' carbonyl-R-configuration ethyl lock configuration deoxyribose, 2'-fluoro substituted arabinose, 2'-methoxy substituted arabinose, L-configuration deoxyribose, L-configuration ribose, 3' and 5' end inverted deoxyribose, 3' and 5' end inverted ribose; and / or

[0011] The base of the nucleotide includes at least one selected from the following structures: uracil, thymine, cytosine, adenine, guanine, hypoxanthine, 5-methylcytosine, 5-hydroxymethylcytosine, 6-methyladenine, 2,6-diaminopurine, 2-thiouracil, 4-thiouracil, dihydrouracil, tetrahydrouracil, pseudouridine, and N-methylpseudouridine.

[0012] According to an embodiment of the present application, the fatty chain includes at least one selected from the following: a C6-C22 normal alkyl group, a C6-C22 normal alkenyl group, wherein the normal alkenyl group contains one C=C, or contains two non-conjugated double bonds, or contains three non-conjugated double bonds.

[0013] According to an embodiment of the present application, the photosensitive amphiphilic compound has a structure shown in the following formula II:

[0014]

[0015] Wherein, Q is a base group, and M is H or a substituent group.

[0016] According to an embodiment of the present application, the photosensitive amphiphilic compound includes at least one selected from the following:

[0017]

[0018] In another aspect of the present application, the present application proposes a method for preparing the aforementioned photosensitive amphiphilic compound containing a coumarin unit. The method comprises: passivating one of the hydroxyl groups in 7-diethylamino-4-(1,2-dihydroxyethyl) coumarin to obtain a coumarin compound with a single hydroxyl group protected; subjecting a fatty acid to an esterification reaction with another hydroxyl group in the coumarin compound to obtain a coumarin compound containing a fatty chain; subjecting the coumarin compound containing a fatty chain to a deprotection treatment to obtain a coumarin compound containing a hydroxyl group and connected to a fatty chain; and connecting a nucleotide pass and a coumarin compound containing a hydroxyl group and connected to a fatty chain through an esterification reaction to form a phosphodiester bond, and obtaining the photosensitive amphiphilic compound. Thus, the aforementioned photosensitive amphiphilic compound can be easily obtained.

[0019] According to an embodiment of the present application, the passivation treatment comprises: reacting 4,4-dimethoxytriphenylmethane and 7-diethylamino-4-(1,2-dihydroxyethyl)coumarin in pyridine; and / or

[0020] The purification treatment comprises: adding dodecanoic acid, dicyclohexylcarbodiimide and N-hydroxysuccinimide into tetrahydrofuran, adding the coumarin compound under stirring conditions and reacting; and / or

[0021] The esterification reaction comprises: adding the coumarin compound containing hydroxyl group and connected with a fatty chain, nucleotide structure and 4,5-dicyanoimidazole diethylamine salt into a reactor, injecting dichloromethane in an anhydrous and oxygen-free environment, and reacting.

[0022] According to an embodiment of the present application, the nucleotide structure includes at least one selected from the following:

[0023] 5'-4,4-dimethoxy-3-'-O-cyanoethyl-N,N-diisopropylaminophosphoramidite-deoxythymidine;

[0024] 5'-4,4-dimethoxy-3-'-O-cyanoethyl-N,N-diisopropylaminophosphoramidite-2'-methoxy substituted uridine;

[0025] 5'-4,4-dimethoxy-3-'-O-cyanoethyl-N,N-diisopropylaminophosphoramidite-2'-fluorouridine.

[0026] In another aspect of the present application, the present application proposes the use of the aforementioned photosensitive amphiphilic compound containing a coumarin unit in the preparation of a sustained-release drug assembly.

[0027] The above summary is for the purpose of description only and is not intended to be limiting in any way. In addition to the illustrative aspects, embodiments and features described above, further aspects, embodiments and features of the present application will be readily apparent through the following detailed description. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Figure 1 This is the H NMR spectrum of compound 4 synthesized in the examples of the present application;

[0029] Figure 2 The mass spectrum of compound 4 synthesized in the examples of the present application;

[0030] Figure 3 is the UV absorption spectrum of the acetonitrile solution containing compound 4;

[0031] Figure 4 This is the H NMR spectrum of compound 5 synthesized in the examples of the present application;

[0032] Figure 5 The mass spectrum of compound 5 synthesized in the examples of the present application;

[0033] Figure 6 This is the H NMR spectrum of compound 6 synthesized in the examples of the present application;

[0034] Figure 7 The mass spectrum of compound 6 synthesized in the examples of the present application;

[0035] Figure 8 This is the H NMR spectrum of compound 7 synthesized in the examples of the present application;

[0036] Fig. 9 The mass spectrum of compound 6 synthesized in the examples of the present application;

[0037] Fig.10 This is the light-controlled release curve of compound 5 synthesized in the example of the present application under 365nm ultraviolet light;

[0038] Fig.11 This is the light-controlled release curve of compound 5 synthesized in the example of the present application under 385nm blue-violet light;

[0039] Fig.12 This is the light-controlled release curve of compound 5 synthesized in the examples of the present application under 405nm blue light. DETAILED DESCRIPTION

[0040] The following embodiments of the technical solution of the present application are described in detail in conjunction with the accompanying drawings. The following embodiments are only used to more clearly illustrate the technical solution of the present application, and are therefore only used as examples, and cannot be used to limit the scope of protection of the present application.

[0041] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by technicians in the technical field to which this application belongs; the terms used herein are only for the purpose of describing specific embodiments and are not intended to limit this application; the terms "including" and "having" in the specification and claims of this application and the above-mentioned figure descriptions and any variations thereof are intended to cover non-exclusive inclusions.

[0042] Reference to "embodiments" herein means that a particular feature, structure, or characteristic described in conjunction with the embodiments may be included in at least one embodiment of the present application. The appearance of the phrase in various locations in the specification does not necessarily refer to the same embodiment, nor is it an independent or alternative embodiment that is mutually exclusive with other embodiments. It is explicitly and implicitly understood by those skilled in the art that the embodiments described herein may be combined with other embodiments.

[0043] In the description of the embodiments of the present application, the term "and / or" is only a description of the association relationship of associated objects, indicating that three relationships may exist. For example, A and / or B can represent: A exists, A and B exist at the same time, and B exists. In addition, the character " / " in this article generally indicates that the associated objects before and after are in an "or" relationship.

[0044] In one aspect of the present application, the present application provides a photosensitive amphiphilic compound containing a coumarin unit. The photosensitive amphiphilic compound has a structure shown in the following formula I:

[0045]

[0046] Among them, A is a hydrophilic unit and B is a hydrophobic unit.

[0047] The A comprises a nucleotide, the B comprises a fat chain, the nucleotide is connected to the coumarin structure via a phosphodiester bond, and the fat chain is connected to the coumarin structure via an ester group. The photosensitive amphiphilic compound can be controllably photodegraded in different wavelengths, and the degradation speed varies greatly, and can be used to form a drug assembly for precise and controllable release of the drug.

[0048] As mentioned above, micelles, vesicles, emulsions and various forms of assemblies formed by amphiphilic molecules play an important role in the packaging and controlled release of drugs. The degradation of amphiphilic molecules / compounds is particularly important for the precise and controlled release of drugs in time and space. The present application introduces specific modifying groups on coumarin, which can adjust the absorption wavelength and intensity of coumarin, and obtain coumarin units that can undergo photochemical reactions in different light bands, that is, coumarin units with different band light responses. With the hydrophilic unit A and the hydrophobic unit B connected to the coumarin unit, the obtained amphiphilic compound has a good potential for application in drug controlled release assemblies.

[0049] According to an embodiment of the present application, the hydrophilic unit A includes nucleotides. Specifically, the nucleotides are natural and / or non-natural nucleotides, and the nucleotides include modified or non-modified nucleotide units, and the modification groups are located on the sugar ring and / or the base. Using nucleotides as hydrophilic units has good biocompatibility and a variety of choices, so that the obtained compounds can be applied to a variety of drug systems.

[0050] This application uses 7-diethylamino-4-(1,2-dihydroxyethyl) coumarin as the starting material, and connects the hydrophilic unit A and the hydrophobic unit B to coumarin through the two hydroxyl groups of 1,2-dihydroxyethyl to form the aforementioned amphiphilic compound. The amphiphilic compound undergoes controllable photodegradation under light of different wavelengths such as 365nm, 395nm and 405nm, and the photodegradation rate under each light is quite different, so the drug assembly prepared by the compound having this chain segment can have a better sustained release and precise release effect.

[0051] According to an embodiment of the present application, in the hydrophilic unit, the sugar ring of the nucleotide includes at least one selected from the following structures: natural deoxyribose, natural ribose, 2'-methoxy substituted deoxyribose, 2'-fluoro substituted deoxyribose, 2'-methoxyethyl substituted deoxyribose, 2'-methylamino-2-oxyethyl substituted deoxyribose, 2'-propargyloxy substituted deoxyribose, 2'-butoxy substituted deoxyribose, 2'-hexyloxy substituted deoxyribose, 2'-octyloxy substituted deoxyribose, 2'-decyloxy substituted deoxyribose, 2'-dodecyloxy substituted deoxyribose, 2'-tetradecyloxy substituted deoxyribose. , 2'-hexadecyloxy substituted deoxyribose, 2'-octadecyloxy substituted deoxyribose, 2'-eicosyloxy substituted deoxyribose, 2'-oxy-4' carbonyl methylene lock configuration deoxyribose, 2'-oxy-4' carbonyl vinyl lock configuration deoxyribose, 2'-oxy-4' carbonyl-S-configuration ethyl lock configuration deoxyribose, 2'-oxy-4' carbonyl-R-configuration ethyl lock configuration deoxyribose, 2'-fluoro substituted arabinose, 2'-methoxy substituted arabinose, L-configuration deoxyribose, L-configuration ribose, 3' and 5' end flipped deoxyribose, 3' and 5' end flipped ribose.

[0052] In some embodiments, the base of the nucleotide includes at least one selected from the following structures: uracil, thymine, cytosine, adenine, guanine, hypoxanthine, 5-methylcytosine, 5-hydroxymethylcytosine, 6-methyladenine, 2,6-diaminopurine, 2-thiouracil, 4-thiouracil, dihydrouracil, tetrahydrouracil, pseudouridine, N-methylpseudouridine.

[0053] According to an embodiment of the present application, the hydrophobic unit B may be a normal fatty chain. For example, in some embodiments, the fatty chain in the hydrophobic unit includes at least one selected from the following: a C6-C22 normal alkyl group, a C6-C22 normal alkenyl group, wherein the normal alkenyl group contains one C=C, or contains two non-conjugated double bonds, or contains three non-conjugated double bonds.

[0054] For example, specifically, the fatty chain can be a saturated or unsaturated fatty chain with 6-16 carbon atoms, for example, a fatty chain containing 10, 12, 14 or 16 carbon atoms. The fatty chain has a moderate length, has a good hydrophobic effect and is suitable for forming a drug assembly. The fatty chain raw material with a carbon number within the above range is also relatively easy to obtain.

[0055] According to an embodiment of the present application, the photosensitive amphiphilic compound has a structure shown in the following formula II:

[0056]

[0057] Wherein, Q is a base group, and M is H or a substituent group. In some embodiments, the nucleotide portion of the photosensitive amphiphilic compound can be functionalized to improve stability. Specifically, M can be a substituent group capable of forming the aforementioned sugar ring structure, or M can be hydrogen.

[0058] According to an embodiment of the present application, the photosensitive amphiphilic compound includes at least one selected from the following:

[0059]

[0060] On the one hand, the above compounds can be modified on the two hydroxyl groups of 1,2-dihydroxyethyl in coumarin by a simple method; on the other hand, the above compounds all have appropriate hydrophilic and hydrophobic properties and are suitable for forming drug assemblies.

[0061] In another aspect of the present application, the present application proposes a method for preparing the aforementioned photosensitive amphiphilic compound containing a coumarin unit. The method comprises: passivating one of the hydroxyl groups in 7-diethylamino-4-(1,2-dihydroxyethyl) coumarin to obtain a coumarin compound with a single hydroxyl group protected; subjecting a fatty acid to an esterification reaction with another hydroxyl group in the coumarin compound to obtain a coumarin compound containing a fatty chain; subjecting the coumarin compound containing a fatty chain to a deprotection treatment to obtain a coumarin compound containing a hydroxyl group and connected to a fatty chain; and connecting a nucleotide pass and a coumarin compound containing a hydroxyl group and connected to a fatty chain through an esterification reaction to form a phosphodiester bond, and obtaining the photosensitive amphiphilic compound. Thus, the aforementioned photosensitive amphiphilic compound can be easily obtained.

[0062] In general, the method uses 7-diethylamino-4-(1,2-dihydroxyethyl)coumarin (compound 1) as the starting material, and prepares the aforementioned photosensitive amphiphilic compound through multi-step etherification, esterification, deprotection and oxidation reactions.

[0063] According to an embodiment of the present application, the passivation treatment includes: reacting 4,4-dimethoxytriphenylmethane and 7-diethylamino-4-(1,2-dihydroxyethyl)coumarin in pyridine.

[0064] According to an embodiment of the present application, the purification process comprises: adding dodecanoic acid, dicyclohexylcarbodiimide and N-hydroxysuccinimide into tetrahydrofuran, and adding the coumarin compound under stirring conditions and reacting.

[0065] According to an embodiment of the present application, the esterification reaction includes: adding the coumarin compound containing a hydroxyl group and connected to a fatty chain, a nucleotide structure, and 4,5-dicyanoimidazole diethylamine salt to a reactor, injecting dichloromethane in an anhydrous and oxygen-free environment, and reacting.

[0066] According to an embodiment of the present application, the nucleotide structure includes at least one selected from the following:

[0067] 5'-4,4-dimethoxy-3-'-O-cyanoethyl-N,N-diisopropylaminophosphoramidite-deoxythymidine;

[0068] 5'-4,4-dimethoxy-3-'-O-cyanoethyl-N,N-diisopropylaminophosphoramidite-2'-methoxy substituted uridine;

[0069] 5'-4,4-dimethoxy-3-'-O-cyanoethyl-N,N-diisopropylaminophosphoramidite-2'-fluorouridine.

[0070] It is understood by those skilled in the art that, in order to improve the yield and the purity of the obtained amphiphilic compound, a pre-treatment and a post-treatment for purification, solvent removal, etc. may be included before and after each step. For example, the method may include one or more steps of extraction, filtration, precipitation, filtration, drying, rotary evaporation to remove the organic solvent, purification using a chromatography column, etc.

[0071] In another aspect of the present application, the present application proposes the use of the aforementioned photosensitive amphiphilic compound containing a coumarin unit in the preparation of a sustained-release drug assembly.

[0072] The method proposed in this application is described below by means of specific examples. The methods used in the following examples are conventional methods unless otherwise specified, and the reagents used are commercially available reagents unless otherwise specified.

[0073] Example 1

[0074] The schematic diagram of the synthesis route is shown below:

[0075]

[0076] Among them, a) the added reagents include 4,4-dimethoxytriphenylmethane and pyridine; b) the added reagents include dodecanoic acid, dicyclohexylcarbodiimide, N-hydroxysuccinimide, and tetrahydrofuran; c) the added reagents include 80% acetic acid aqueous solution. The specific operation is as follows:

[0077] (1) Synthesis of Compound 2:

[0078] Compound 1 (27.7 g) was dissolved in 300 ml of anhydrous pyridine, and a solution of 4,4-dimethoxytriphenylmethane (37.2 g) in 200 ml of anhydrous pyridine was added, and the reaction was allowed to proceed overnight at room temperature. After the reaction was complete, 3 ml of methanol was added to quench the reaction. After the solvent was dried, 400 ml of ethyl acetate and 600 ml of saturated sodium bicarbonate aqueous solution were added for washing, and the organic phase was dried over anhydrous sodium sulfate. After filtering out the desiccant, the product was concentrated to obtain a viscous yellow oily liquid, which was dissolved in 70 ml of ethyl acetate and added to 400 ml of n-heptane under stirring to obtain a yellow solid. The solid was filtered to obtain a solid, which was redissolved in 60 ml of ethyl acetate, added to 600 ml of n-heptane under stirring, and filtered to obtain a solid.

[0079] (2) Synthesis of compound 3:

[0080] Dodecanoic acid (2.0 g), dicyclohexylcarbodiimide (2.3 g) and N-hydroxysuccinimide (1.2 g) were added to 40 ml of tetrahydrofuran, stirred at room temperature for 1 hour, compound 2 (5.8 g) was added, and stirred at room temperature for 48 hours. After the reaction was completed, 160 ml of saturated sodium bicarbonate aqueous solution and 200 ml of ethyl acetate were added for extraction, the organic phase was washed with 150 ml of saturated sodium chloride aqueous solution, and the organic phase was dried over anhydrous sodium sulfate to obtain a light yellow waxy solid.

[0081] (3) Synthesis of compound 4:

[0082] The crude product from the previous step was dissolved in 60 ml of 80% acetic acid aqueous solution, refluxed under nitrogen for 6 hours, and the solvent was concentrated to obtain 5.0 g of crude product. The product was dissolved in 20 ml of ethyl acetate, added to 120 ml of n-heptane, and the precipitate was collected. The precipitate was redissolved in 15 ml of ethyl acetate and added to 120 ml of 0°C n-heptane to obtain 3.27 g of light yellow solid, with a yield of 71%.

[0083] The obtained product was subjected to NMR 1 H spectrum detection and mass spectrometry test, test spectrum reference Figure 1 as well as Figure 2 , the test results are as follows:

[0084] 1 H NMR (CDCl 3 ,400MHz), δ(ppm):0.85-0.90(t,CH 3 ,3H); 1.17-1.23(t,NCH 2 CH 3 ,6H); 1.26-1.34(m,CH 2 ,18H);1.61-1.70(m,CH 2 ,2H); 2.35-2.48 (m,CH 2,2H); 3.36-3.46(q,NCH 2 ,4H);3.86-3.98(m,OH,1H);6.08-6.10(m,CH,1H);6.49-6.52(t,ArH,1H);6.57-6.62(m,ArH,1H);7.43-7.48(d,ArH,1H);

[0085] Molecular formula C 27 H 41 NO 5 , ESIMS calculated molecular weight 459.2985 measured molecular weight 460.3015 [M+H + ].

[0086] The ultraviolet absorption spectrum of compound 4 is detected. The ultraviolet absorption spectrum of the acetonitrile solution containing compound 4 is as follows: Figure 3 As shown. This proves that the compound has photosensitivity.

[0087] (4) Synthesis of Compound 5:

[0088] 5'-4,4-dimethoxy-3-'-O-cyanoethyl-N,N-diisopropylaminophosphoramidite deoxythymidine (1.6 g), compound 4 (0.92 g) and 4,5-dicyanoimidazole diethylamine salt (0.22 g) were added to a dried reaction bottle, and the nitrogen was replaced by vacuum. 20 ml of anhydrous dichloromethane was injected into the reaction bottle, and the reaction was carried out at room temperature for 10 hours, and the solution became turbid.

[0089] Add 0.6 ml of 30% hydrogen peroxide solution to the above system, and the solution changes from turbid to clear, and continue stirring for 30 minutes. Then add 30 ml of 5% sodium bisulfite aqueous solution to quench the excess hydrogen peroxide, remove tetrahydrofuran by rotary evaporation, and add 70 ml of ethyl acetate for extraction. The collected organic phase is repeatedly washed twice with 200 ml of saturated sodium bicarbonate aqueous solution, and dried over anhydrous sodium sulfate. The next day, the system is filtered and the organic solvent is removed by rotary evaporation.

[0090] The residual oil from the previous step was dissolved in 20 ml of dichloromethane. 10 mL of 10% trichloroacetic acid dichloromethane solution was added to the above solution, and the solution turned bright red and stirred at room temperature for 1 hour. 150 ml of saturated sodium bicarbonate aqueous solution was added dropwise thereto to quench the excess trichloroacetic acid, and the solution turned white. 50 ml of saturated brine was added to the above organic phase and extracted again, and then anhydrous sodium sulfate was added and dried for 1 hour. The system was then filtered and rotary evaporated, and the concentrated oily product was purified by column chromatography. 200-300 mesh silica gel was used, and the eluent was dichloromethane: methanol = 40:1 (volume ratio) to obtain a light yellow solid. It was directly used for the next step of synthesis.

[0091] The purified product was dissolved in 5 ml of tetrahydrofuran, and 2 ml of diisopropylamine was added, and the mixture was reacted for 4 hours at room temperature. The solvent was dried by spin drying to obtain a light yellow powder, 0.95 g, with a yield of 55%.

[0092] The obtained product was subjected to NMR 1 H spectrum detection and mass spectrometry test, test spectrum reference Figure 4 as well as Figure 5 , the test results are as follows:

[0093] 1 H NMR (CDCl 3 ,400MHz), δ(ppm):0.84-0.90(m,CH 3 ,12H); 1.22-1.26(m,CH 2 ,22H);1.27-1.30(m,CH 3 ,9H); 1.31-1.36(m,ArCH 3 ,3H); 1.56-1.66(m,CH 2 ,2H); 1.85-1.95(m,CH 2 ,2H)2.22-2.43(m,CH 2 ,2H);3.18-3.30(m,CH,1H);3.33-3.47(m,CH,1H);3.74-3.90(m,CH,1H);3.99-4.17(m,CHOPO 3 ,1H); 6.08-6.20(m,CONH,1H); 6.45-6.50(m,ArH,1H); 6.57-6.63(m,ArH,1H); 7.47-7.63(m,ArH,1H).

[0094] Molecular formula C 43 H 69 N 4 O 12 P, ESIMS calculated molecular weight 864.4650 measured molecular weight 764.3511 [M-(C 3 H 7 ) 2 NH 2 + +2H + ]

[0095] Example 2

[0096] The schematic diagram of the synthesis route is shown below:

[0097]

[0098] The specific operations are as follows:

[0099] 5'-4,4-dimethoxy-3-'-O-cyanoethyl-N,N-diisopropylaminophosphoramidite-2'-fluorouridine (1.7 g), compound 4 (0.92 g) and 4,5-dicyanoimidazole diethylamine salt (0.22 g) were added to a dried reaction bottle, and the nitrogen was replaced by vacuum. 20 ml of anhydrous dichloromethane was injected into the reaction bottle, and the reaction was carried out at room temperature for 10 hours, and the solution became turbid.

[0100] Add 0.6 ml of 30% hydrogen peroxide solution to the above system, and the solution changes from turbid to clear, and continue stirring for 30 minutes. Then add 30 ml of 5% sodium bisulfite aqueous solution to quench the excess hydrogen peroxide, remove tetrahydrofuran by rotary evaporation, and add 70 ml of ethyl acetate for extraction. The collected organic phase is repeatedly washed twice with 200 ml of saturated sodium bicarbonate aqueous solution, and dried over anhydrous sodium sulfate. The next day, the system is filtered and the organic solvent is removed by rotary evaporation.

[0101] The residual oil from the previous step was dissolved in 20 ml of dichloromethane. 10 mL of 10% trichloroacetic acid dichloromethane solution was added to the above solution, and the solution turned bright red and stirred at room temperature for 1 hour. 150 ml of saturated sodium bicarbonate aqueous solution was added dropwise thereto to quench the excess trichloroacetic acid, and the solution turned white. 50 ml of saturated brine was added to the above organic phase and extracted again, and then anhydrous sodium sulfate was added and dried for 1 hour. The system was then filtered and rotary evaporated, and the concentrated oily product was purified by column chromatography. 200-300 mesh silica gel was used, and the eluent was dichloromethane: methanol = 40:1 (volume ratio) to obtain a light yellow solid. It was directly used for the next step of synthesis.

[0102] The purified product was dissolved in 5 ml of tetrahydrofuran, and 2 ml of diisopropylamine was added, and the mixture was reacted for 4 hours at room temperature. The solvent was dried by spin drying to obtain a light yellow powder, 0.88 g, with a yield of 47%.

[0103] The obtained product was subjected to NMR 1 H spectrum detection and mass spectrometry test, test spectrum reference Figure 6 as well as Figure 7 , the test results are as follows:

[0104] 1 H NMR (CDCl 3 ,400MHz), δ(ppm):0.84-0.90(t,CH 3 ,3H); 1.16-1.22(t,CH 3 ,6H); 1.20-1.27(m,CH 2 ,20H); 1.28-1.33(m,CH 3,12H);1.57-1.65(m,CH 2 ,2H); 2.35-2.43(t,CH 2 ,2H); 3.17-3.31(m,CH 2 ,2H); 3.35-3.45(q,CH 2 ,4H);3.84-4.01(m,CH,2H);4.02-4.22(m,CH,2H);4.23-4.34(m,CHOPO 3 ,1H);4.67-4.81(m,CHF,1H);5.63-5.71(d,CH,1H);5.80-5.92(dd,CH,1H);6.11(s,ArH,1H);6.21-6.30(m ,CONH,1H);6.46-6.51(d,ArH,1H);6.57-6.63(d,ArH,1H);7.50-7.63(m,ArH,1H);7.90-8.00(m,ArH,1H).

[0105] Molecular formula C 42 H 66 FN 4 O 12 P, ESIMS calculated molecular weight 868.4399 measured molecular weight 768.3263 [M-(C 3 H 7 ) 2 NH 2 + +2H + ].

[0106] Example 3

[0107] The schematic diagram of the synthesis route is shown below:

[0108]

[0109] The specific operations are as follows:

[0110] 5'-4,4-dimethoxy-3-'-O-cyanoethyl-N,N-diisopropylaminophosphoramidite-2'-methoxy substituted uridine (1.7 g), compound 4 (0.92 g) and 4,5-dicyanoimidazole diethylamine salt (0.22 g) were added to a dried reaction bottle, and the nitrogen was replaced by vacuum. 20 ml of anhydrous dichloromethane was injected into the reaction bottle, and the reaction was carried out at room temperature for 10 hours, and the solution became turbid.

[0111] Add 0.6 ml of 30% hydrogen peroxide solution to the above system, and the solution changes from turbid to clear, and continue stirring for 30 minutes. Then add 30 ml of 5% sodium bisulfite aqueous solution to quench the excess hydrogen peroxide, remove tetrahydrofuran by rotary evaporation, and add 70 ml of ethyl acetate for extraction. The collected organic phase is repeatedly washed twice with 200 ml of saturated sodium bicarbonate aqueous solution, and dried over anhydrous sodium sulfate. The next day, the system is filtered and the organic solvent is removed by rotary evaporation.

[0112] The residual oil from the previous step was dissolved in 20 ml of dichloromethane. 10 mL of 10% trichloroacetic acid dichloromethane solution was added to the above solution, and the solution turned bright red and stirred at room temperature for 1 hour. 150 ml of saturated sodium bicarbonate aqueous solution was added dropwise thereto to quench the excess trichloroacetic acid, and the solution turned white. 50 ml of saturated brine was added to the above organic phase and extracted again, and then anhydrous sodium sulfate was added and dried for 1 hour. The system was then filtered and rotary evaporated, and the concentrated oily product was purified by column chromatography. 200-300 mesh silica gel was used, and the eluent was dichloromethane: methanol = 40:1 (volume ratio) to obtain a light yellow solid. It was directly used for the next step of synthesis.

[0113] The purified product was dissolved in 5 ml of tetrahydrofuran, and 2 ml of diisopropylamine was added, and the mixture was reacted for 4 hours at room temperature. The solvent was dried by spin drying to obtain a light yellow powder, 0.92 g, with a yield of 53%.

[0114] The obtained product was subjected to NMR 1 H spectrum detection and mass spectrometry test, test spectrum reference Figure 8 as well as Fig. 9 , the test results are as follows:

[0115] 1 H NMR (CDCl 3 ,400MHz), δ(ppm):0.84-0.90(t,CH 3 ,3H); 1.17-1.20(m,CH 3 ,6H); 1.20-1.27(m,CH 2 ,20H); 1.28-1.44(m,CH 3 ,12H);1.66-1.72(m,CH 2 ,2H); 2.20-2.43 (m,CH 2 ,2H);3.21-3.26(m,CH,1H);3.38-3.45(m,OCH 3 ,3H);3.50-3.56(m,CH,1H);3.83-4.01(m,CH,2H);4.10-4.21(m,CHOPO 3,1H);4.46-4.62(m,CH,1H);5.56-5.78(m,CH 2 ,2H);6.21-6.31(m,CONH,1H);6.47-6.63(m,ArH,1H);6.55-6.63(m,ArH,1H);7.52-7.61(m,ArH,1H);7.88-8.05(m,ArH,1H);8.82(s,NH 2 ,2H).

[0116] Molecular formula C 43 H 69 N 4 O 13 P, ESIMS calculated molecular weight 880.4599 measured molecular weight 780.3456 [M-(C 3 H 7 ) 2 NH 2 + +2H + ].

[0117] Performance Testing

[0118] Nile red dye was selected as a model of hydrophobic drugs to verify the encapsulation effect of the micelles formed by the synthesized compound 5 on hydrophobic drugs and its photodegradation kinetics under light of different wavelengths. Fluorescence spectroscopy confirmed that this type of amphiphilic molecules can release drugs in a highly time-controlled manner at different wavelengths.

[0119] The photolysis conditions are as follows:

[0120] The test environment temperature was 25±1° C. and the humidity was 10% to 30%. A photosensitive amphiphilic molecule solution (20 mM) containing Nile Red was placed in a quartz cuvette with an optical path of 1 mm, and sealed after nitrogen purging.

[0121] When irradiated with a 365nm light source, the optical power density was 80 and 160mW / cm 2 , the light source model is JAXMAN 365nm.

[0122] When irradiated with a 385nm light source, the optical power density was 80 and 140mW / cm 2 , the light source model is JAXMAN 385nm.

[0123] When irradiated with a 405nm light source, the light power density is 280mW / cm 2 , the light source model is OXLasers 405nm.

[0124] Fluorescence test conditions

[0125] The fluorescence spectrum model is Hitachi F2500, the excitation wavelength is set to 550nm, the emission wavelength is set to 630nm, the excitation wavelength scanning interval is 10nm, the emission wavelength scanning interval is 2nm, the optical path is 10mm, and the release rate calculation method is:

[0126]

[0127] Among them I t is the excitation light intensity at 630nm before illumination, I 0 is the excitation light intensity at 630 nm after illumination.

[0128] The light-controlled release curve of compound 5 under 365nm ultraviolet light is shown in Fig.10 As shown, the light-controlled release curve under 385nm blue-violet light is as follows Fig.11 As shown in Figure 2, the light-controlled release curve under 405nm blue light is as follows: Fig.12 shown.

[0129] Depend on Figure 10-12 It can be seen that there are significant differences in the slopes of the release curves under light irradiation of different wavelengths, so the amphiphilic compound has a good controlled sustained release effect as a drug assembly.

[0130] The above application provides many different embodiments or examples to realize the different structures of the present application. In order to simplify the present application, the parts and settings of specific examples are described above. Of course, they are only examples, and the purpose is not to limit the present application. In addition, the present application can repeat reference numbers and / or reference letters in different examples, and this repetition is for the purpose of simplification and clarity, which itself does not indicate the relationship between the various embodiments and / or settings discussed.

[0131] The above are only specific implementations of the present application, but the protection scope of the present application is not limited thereto. Any technician familiar with the technical field can easily think of various changes or substitutions within the technical scope disclosed in the present application, which should be included in the protection scope of the present application. Therefore, the protection scope of the present application should be based on the protection scope of the claims.

Claims

1. A photosensitive amphiphilic compound containing a coumarin unit, characterized in that: The photosensitive amphiphilic compound has a structure shown in the following formula I: Among them, A is a hydrophilic unit and B is a hydrophobic unit. The A comprises nucleotides, and the B comprises a fat chain. The nucleotides are connected to the coumarin structure via a phosphodiester bond, and the fat chain is connected to the coumarin structure via an ester group.

2. The photosensitive amphiphilic compound according to claim 1, characterized in that The nucleotides are natural and / or non-natural nucleotides, and the nucleotides include modified or non-modified nucleotide units, and the modification groups are located on the sugar ring and / or the base.

3. The photosensitive amphiphilic compound according to claim 2, characterized in that: In the hydrophilic unit, The sugar ring of the nucleotide includes at least one of the following structures: natural deoxyribose, natural ribose, 2'-methoxy substituted deoxyribose, 2'-fluoro substituted deoxyribose, 2'-methoxyethyl substituted deoxyribose, 2'-methylamino-2-oxyethyl substituted deoxyribose, 2'-propargyloxy substituted deoxyribose, 2'-butoxy substituted deoxyribose, 2'-hexyloxy substituted deoxyribose, 2'-octyloxy substituted deoxyribose, 2'-decyloxy substituted deoxyribose, 2'-dodecyloxy substituted deoxyribose, 2'-tetradecyloxy substituted deoxyribose, 2'-hexa ... Substituted deoxyribose, 2'-octadecyloxy substituted deoxyribose, 2'-eicosyloxy substituted deoxyribose, 2'-oxy-4' carbonyl methylene lock configuration deoxyribose, 2'-oxy-4' carbonyl vinyl lock configuration deoxyribose, 2'-oxy-4' carbonyl-S-configuration ethyl lock configuration deoxyribose, 2'-oxy-4' carbonyl-R-configuration ethyl lock configuration deoxyribose, 2'-fluoro substituted arabinose, 2'-methoxy substituted arabinose, L-configuration deoxyribose, L-configuration ribose, 3' and 5' end inverted deoxyribose, 3' and 5' end inverted ribose; and / or The base of the nucleotide includes at least one selected from the following structures: uracil, thymine, cytosine, adenine, guanine, hypoxanthine, 5-methylcytosine, 5-hydroxymethylcytosine, 6-methyladenine, 2,6-diaminopurine, 2-thiouracil, 4-thiouracil, dihydrouracil, tetrahydrouracil, pseudouridine, and N-methylpseudouridine.

4. The photosensitive amphiphilic compound according to claim 2, characterized in that: The fatty chain comprises at least one selected from the following: C6-C22 normal alkyl, C6-C22 normal alkenyl, The normal alkenyl group contains one C=C, or two non-conjugated double bonds, or three non-conjugated double bonds.

5. The photosensitive amphiphilic compound according to any one of claims 1 to 4, characterized in that: The photosensitive amphiphilic compound has a structure shown in the following formula II: Wherein, Q is a base group, and M is H or a substituent group.

6. The photosensitive amphiphilic compound according to claim 1, characterized in that: The photosensitive amphiphilic compound comprises at least one selected from the following:

7. A method for preparing the photosensitive amphiphilic compound containing coumarin units according to any one of claims 1 to 6, characterized in that: include: Passivating one of the hydroxyl groups in 7-diethylamino-4-(1,2-dihydroxyethyl) coumarin to obtain a coumarin compound in which a single hydroxyl group is protected; Allowing a fatty acid to undergo an esterification reaction with another hydroxyl group in the coumarin compound to obtain a coumarin compound containing a fatty chain; Deprotecting the aliphatic chain-containing coumarin compound to obtain a hydroxyl-containing coumarin compound connected to aliphatic chains; The nucleotides and the coumarin compound containing a hydroxyl group and connected with a fatty chain are connected through an esterification reaction to form a phosphodiester bond, thereby obtaining the photosensitive amphiphilic compound.

8. The method according to claim 7, characterized in that The passivation treatment comprises: reacting 4,4-dimethoxytriphenylmethane and 7-diethylamino-4-(1,2-dihydroxyethyl)coumarin in pyridine; and / or The purification treatment comprises: adding dodecanoic acid, dicyclohexylcarbodiimide and N-hydroxysuccinimide into tetrahydrofuran, adding the coumarin compound under stirring conditions and reacting; and / or The esterification reaction comprises: adding the coumarin compound containing hydroxyl group and connected with a fatty chain, nucleotide structure and 4,5-dicyanoimidazole diethylamine salt into a reactor, injecting dichloromethane in an anhydrous and oxygen-free environment, and reacting.

9. The method according to claim 8, characterized in that The nucleotide structure comprises at least one selected from the following: 5'-4,4-dimethoxy-3-'-O-cyanoethyl-N,N-diisopropylaminophosphoramidite-deoxythymidine; 5'-4,4-dimethoxy-3-'-O-cyanoethyl-N,N-diisopropylaminophosphoramidite-2'-methoxy substituted uridine; 5'-4,4-dimethoxy-3-'-O-cyanoethyl-N,N-diisopropylaminophosphoramidite-2'-fluorouridine.

10. Use of the photosensitive amphiphilic compound containing coumarin units according to any one of claims 1 to 6 in the preparation of a sustained-release drug assembly.

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