CN116970027A - Dumbbell amphiphilic peptide dendrimer, synthesis and application thereof as drug delivery system - Google Patents

Dumbbell amphiphilic peptide dendrimer, synthesis and application thereof as drug delivery system Download PDF

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CN116970027A
CN116970027A CN202310947846.5A CN202310947846A CN116970027A CN 116970027 A CN116970027 A CN 116970027A CN 202310947846 A CN202310947846 A CN 202310947846A CN 116970027 A CN116970027 A CN 116970027A
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arbe
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刘潇璇
黄元政
李运
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China Pharmaceutical University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06086—Dipeptides with the first amino acid being basic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • 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
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/0205—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-(X)3-C(=0)-, e.g. statine or derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms

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Abstract

The application discloses a dumbbell type amphiphilic peptide dendrimer, synthesis and application thereof as a drug delivery system, wherein the molecule has a compound with a structure shown in the following general formula (IV) or pharmaceutically acceptable salt thereof; the compound of the application can be used as a nano delivery system based on tumor microenvironment specific response, has good solubility in aqueous solution, can form a relatively stable nano complex with the self-assembly of the drug in the aqueous solution, can effectively deliver the loaded drug to a tumor site, and can be subjected to response grouping under corresponding stimulationThe nano-delivery carrier can be used for effectively loading genes and medicines, and has potential clinical application prospect.

Description

Dumbbell amphiphilic peptide dendrimer, synthesis and application thereof as drug delivery system
The application relates to a dumbbell type amphiphilic peptide dendrimer, synthesis and application thereof as a drug delivery system, and a divisional application of a patent application with the application number of 2021112991202.
Technical Field
The application belongs to the technical field of medicine, and particularly relates to a dumbbell (Bola) amphiphilic dendrimer with pathological response and application of the amphiphilic dendrimer serving as a nano delivery system in pharmacy.
Background
In recent years, pathology-responsive drug delivery systems have received widespread attention in the biomedical field. Such delivery systems may trigger the release of therapeutic agents therein by local chemical and biological molecule levels, including acidic, oxidative or reductive molecules, hydrolytic enzymes, and the like. Compared to conventional delivery systems, the responsive system has the following advantages: 1) Selectively releasing the medicine at the focus part; 2) Improving the curative effect; 3) Reducing toxic and side effects; 4) The drug administration dosage is reduced by increasing the drug concentration at the focus part. Therefore, research and development of a stimulus-responsive drug controlled release system have been the focus of multi-disciplinary cross-research in chemistry, materials science, pharmacy, biology, basic medicine, and the like.
Studies have shown that appropriate concentrations of Reactive Oxygen Species (ROS) help to maintain normal cell function such as growth, migration, secretion, and apoptosis; however, excessive ROS are closely related to the occurrence and development of tumors, aging, diabetes, inflammation, cardiovascular diseases, neurodegenerative diseases, etc. For example, under pathological conditions such as inflammation, colitis, colon cancer, breast cancer and the like, the concentration of local ROS on the mucosa of a patient is 10-100 times higher than that of normal people, and the level of ROS is positively correlated with the disease development process. Therefore, the ROS responsive drug delivery system has great significance for treating the diseases, and materials with specific responsiveness can be designed, so that the ROS responsive drug delivery system can be constructed and can be used for treating some ROS related diseases. However, current research efforts have only made limited progress and materials with good safety and ideal ROS responsiveness remain lacking, which is a major bottleneck limiting the successful development of ROS-responsive drug delivery systems.
Dendrimers can be an ideal drug delivery material. Dendrimers have a regular structure, an accurate molecular weight, a large number of internal cavities and a large number of surface groups, and currently have a wide range of applications in various fields, such as biological medicine, biological sensors, catalysts, tissue engineering, etc. The peptide dendrimer is taken as one of dendrimers, is formed by connecting natural amino acid or unnatural amino acid through peptide bonds, has the characteristics of protein analogues, and has good biocompatibility, degradability and water solubility. In addition, the dumbbell (Bola) amphiphilic molecule is formed by connecting two hydrophilic head groups through a hydrophobic chain, and the special structure enables the Bola molecule to have unique properties and form a more stable supermolecule assembly structure. The Bola type amphiphilic molecule can be used as an ideal drug delivery carrier to construct a pathology responsive nano delivery system. The inventor constructs a series of Bola amphiphilic peptide dendrimers by using Bola molecules and peptide dendrimers, so that the stability of a drug delivery system can be enhanced, and meanwhile, the pathological response performance can have the performance of specific quick drug release.
Disclosure of Invention
The application aims to provide a series of dumbbell (Bola) shaped amphiphilic dendrimers and a method for forming nano particles by self-assembly based on the prior art.
The application also provides a method for synthesizing the Bola amphiphilic dendrimer.
The application also aims to provide an application of the Bola amphiphilic dendrimer as a nano delivery system in medicine.
In order to achieve the above purpose, the present application provides the following technical solutions:
a compound having a structure represented by the following general formula (IV), or a pharmaceutically acceptable salt thereof;
in the method, in the process of the application,
R 1 methyl, methoxy or halogen groups;
n＝4～12；
x is independently represented by the following two structures (I), (II) and (III)
Wherein,,
R 2 、R 4 or R is 6 Each independently is C 1-5 An alkylene group;
R 3 、R 5 or R is 7 Are each independently a covalent bond, C 1-4 Alkylene groups or C 1-4 An alkylene group;
r is amino, carboxyl or-NHR 8 ；
R 8 Is tert-butyloxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyl, trifluoroacetyl,
In a preferred embodiment, R 1 Methyl, methoxy, fluoro, chloro or bromo, and each group is independently a different substitution position on the phenyl ring;
in a preferred embodiment, R 1 Methyl, methoxy, fluoro, chloro or bromo.
In another preferred embodiment, R 1 Methyl, methoxy or fluoro;
in a preferred embodiment, R 1 Para to the M group on the benzene ring.
In a preferred embodiment, n is an integer from 4 to 12.
In a preferred embodiment, n is an integer from 5 to 12.
In another preferred embodiment, n is 4,6, 8, 9, 10, 11.
In a preferred embodiment, R 2 、R 4 Or R is 6 Each independently is C 3-5 An alkylene group.
In another preferred embodiment, R 3 、R 5 Or R is 7 Each independently a covalent bond.
In a preferred embodiment, R is-NHR 8 ；
In a preferred embodiment, R 8 Is tert-butyloxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyl, trifluoroacetyl,
In another preferred embodiment, R 8 Is tert-butyloxycarbonyl, benzyloxycarbonyl, benzyl, trifluoroacetyl or
In a preferred embodiment, R 8 Is tert-butyloxycarbonyl or
In a preferred embodiment, the compounds according to the application may in particular be selected from
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The preparation method of the compound comprises the steps (1) (2) and (3), the steps (1) (2) and (4) or the steps (1) (2) and (5).
Step (1):
in a preferred embodiment, the reaction process of step (1) is as follows:
step 1): sequentially adding the compound 1, the azido trimethylsilane, the cesium fluoride and the dimethylformamide into a reaction bottle, and stirring at 30-70 ℃ until the reaction is complete. Ethyl acetate was added to extract, the organic phases were combined and dried over anhydrous sodium sulfate, filtered, the solvent was removed by distillation under the reduced pressure, and the residue was separated by silica gel column chromatography to give compound 2.
Step 2): sequentially adding the compound 2, triethylamine and dichloromethane into a reaction bottle, dropwise adding dichloromethane solution of methanesulfonyl chloride at 0-30 ℃, and stirring at 30-50 ℃ until the reaction is complete after the dropwise addition. After that, extraction was performed with methylene chloride, and the organic phases were combined and dried over anhydrous sodium sulfate, filtered, the solvent was removed by distillation under the reduced pressure, and the residue was separated by silica gel column chromatography to give compound 3.
Step 3): adding the compound 3 and the dimethylformamide into a reaction bottle, adding the potassium thioacetate in batches at the temperature of 30-50 ℃, and stirring at the temperature of 30-50 ℃ until the reaction is complete. After dilution with water, extraction with ethyl acetate was carried out, and the organic phases were combined, dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and the residue was separated by silica gel column chromatography to give compound 4.
Step 4): the reaction flask was charged with compound 4 and methanol. Stirring at 30-50deg.C, and slowly adding sodium hydroxide solution. After stirring at 30-50 ℃ until the reaction is complete, the solvent is removed. Extraction with dichloromethane, combining the organic phases and drying over anhydrous sodium sulfate, filtration, and distillation of the solvent under reduced pressure gave compound 5.
Step 5): adding compound 6 and methanol into a reaction bottle, dropwise adding sodium hydroxide solution at 0-20 ℃, then reacting for 1-5h at 50-80 ℃, adding formaldehyde solution, stirring at 30-50 ℃ until the reaction is complete, removing the methanol by reduced pressure distillation, and adding acetic acid solution to adjust the pH to 3-5. Extraction with ethyl acetate, combining the organic phases and drying over anhydrous sodium sulfate, filtration, distillation under reduced pressure to remove the solvent, and separation of the residue by silica gel column chromatography gave compound 7.
Step 6): the reaction flask was charged with a solution of compound 7, imidazole and dimethylformamide and tert-butyldimethylsilyl chloride, followed by stirring at 30-50 ℃ until the reaction was complete. The solution was dried by spinning, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered, the solvent was removed by distillation under the reduced pressure, and the residue was separated by silica gel column chromatography to give compound 8.
Step 7): adding the compound 8, potassium carbonate, dimethylformamide and 4-bromomethylbenzoic acid pinacol ester into a reaction bottle, stirring at 30-50 ℃ until the reaction is complete, removing the solvent, adding water, extracting with ethyl acetate, combining the organic phases, drying with anhydrous sodium sulfate, filtering, distilling under reduced pressure to remove the solvent, and separating the residues by silica gel column chromatography to obtain the compound 9.
Step 8): the compound 9, p-toluenesulfonic acid monohydrate and methanol were added to a reaction flask, followed by stirring at 30-50 ℃ until the reaction was complete, the solvent was removed, and the residue was separated by silica gel column chromatography to give the compound 10.
Step 9): adding the compound 10, dimethylaminopyridine, triethylamine and methylene chloride into a reaction bottle, dropwise adding a solution of methacrylic anhydride at 0-20 ℃, stirring at 30-50 ℃ until the reaction is complete, adding water, extracting with methylene chloride, combining organic phases, drying with anhydrous sodium sulfate, filtering, distilling under reduced pressure to remove the solvent, and separating the residues by silica gel column chromatography to obtain the compound 11.
Step 10): the reaction flask was charged with 11 and dimethyl phenyl phosphorus and dimethyl sulfoxide, followed by a solution of 5, followed by stirring at 30-50 ℃ until the reaction was completed, dilution with ethyl acetate, washing with saturated brine, drying the organic phase with anhydrous sodium sulfate, filtering, distilling off the solvent under reduced pressure, and separating the residue by silica gel column chromatography to give 12.
Step (2):
in a preferred embodiment, the reaction process of each step of step (2) is as follows:
step 1): sequentially adding Boc-Lys (Boc) -OH, 1-hydroxybenzotriazole and O-benzotriazole-tetramethylurea hexafluorophosphate into a reaction bottle, adding N, N-dimethylformamide for dissolving, then adding propargylamine, and stirring at 30-50 ℃ until the reaction is complete. Spin-drying the solvent, adding ethyl acetate for extraction, then washing with saturated sodium bicarbonate, dilute hydrochloric acid and saturated brine, respectively, combining the organic phases and drying over anhydrous sodium sulfate, filtering, distilling off the solvent under reduced pressure, and separating the residue by silica gel column chromatography to obtain compound 14.
Step 2): adding the compound 13 into a reaction bottle, adding dichloromethane for dissolution, then adding trifluoroacetic acid, stirring at 30-50 ℃ until the reaction is complete, spin-drying the reaction liquid, adding diethyl ether for washing three times, and obtaining the compound 15.
Step 3): compound 14 and amino acid derivatives containing protecting groups (including but not limited to Boc-L-glutamic acid-1-tert-butyl ester, boc-Arg (Pbf) -OH), 1-hydroxybenzotriazole, O-benzotriazole-tetramethylurea hexafluorophosphate were added into a reaction flask, dissolved in N, N-dimethylformamide, and stirred at 30-50 ℃ until reaction was complete. The solvent was removed, ethyl acetate was added to the mixture to extract, and then the mixture was washed with saturated sodium hydrogencarbonate, diluted hydrochloric acid and saturated brine, and the organic phases were combined and dried over anhydrous sodium sulfate, filtered, distilled off under reduced pressure to remove the solvent, and the residue was separated by silica gel column chromatography to give compound 16.
Step 4): adding a compound 14, boc-Lys (Boc) -OH, 1-hydroxybenzotriazole and O-benzotriazole-tetramethylurea hexafluorophosphate into a reaction bottle, adding N, N-dimethylformamide for dissolution, and stirring at 30-50 ℃ until the reaction is complete. The solvent was removed, ethyl acetate was added to the mixture to extract, and then the mixture was washed with saturated sodium hydrogencarbonate, diluted hydrochloric acid and saturated brine, and the organic phases were combined and dried over anhydrous sodium sulfate, filtered, distilled off under reduced pressure to remove the solvent, and the residue was separated by silica gel column chromatography to give compound 17.
Step 5): adding the compound 17 into a reaction bottle, adding dichloromethane for dissolution, then adding trifluoroacetic acid, stirring at 30-50 ℃ until the reaction is complete, spin-drying the reaction liquid, adding diethyl ether for washing three times, and obtaining the compound 18.
Step 6): compound 18 and amino acid derivatives containing protecting groups (including but not limited to Boc-L-glutamic acid-1-tert-butyl ester, boc-Arg (Pbf) -OH) are added into a reaction flask, dissolved by adding N, N-dimethylformamide, and stirred at 30-50 ℃ until the reaction is complete. The solvent was removed, ethyl acetate was then added for extraction, and then, the organic phases were combined and dried over anhydrous sodium sulfate, filtered, the solvent was removed by distillation under the reduced pressure, and the residue was separated by silica gel column chromatography, respectively, to give compound 19.
The synthesis of the Bola amphiphilic dendrimer comprises the steps (3), the step (4) or the step (5).
Step (3):
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step (4):
step (5):
in a preferred embodiment, the reaction process of step (3), step (4) or step (5) is as follows:
step 1): a hydrophobic end compound 12 containing two azide groups, a hydrophilic end (compound 16, compound 17 or compound 19) containing alkynyl, cuprous iodide, 1, 8-diazabicyclo undec-7-ene and dimethylformamide are sequentially added into a reaction bottle. The system was stirred at 40-70 ℃ until the reaction was complete. The solvent was removed, and after addition of a saturated ammonium chloride solution, extraction was performed with methylene chloride, the organic phases were combined and washed with a saturated ammonium chloride solution, then with anhydrous sodium sulfate, filtration, distillation under reduced pressure, and separation of the residue by silica gel column chromatography gave an amino acid terminal compound (compound 14, compound 17 or compound 20) containing a protecting group.
In another preferred embodiment, the reaction procedure of step 1) is as follows:
a hydrophobic end compound 12 containing two azide groups, a hydrophilic end containing alkynyl groups (compound 16, compound 17 or compound 19), copper sulfate pentahydrate, sodium ascorbate, tetrahydrofuran and water are sequentially added into a reaction bottle. The system is stirred at 40-70 ℃ in the dark until the reaction is complete. The solvent was removed, and after addition of a saturated ammonium chloride solution, extraction was performed with methylene chloride, the organic phases were combined and washed with a saturated ammonium chloride solution, then with anhydrous sodium sulfate, filtration, distillation under reduced pressure, and separation of the residue by silica gel column chromatography gave an amino acid terminal compound (compound 14, compound 17 or compound 20) containing a protecting group.
Step 2) amino acid terminal compound (compound 20, compound 22 or compound 24) containing a protecting group is subjected to a protecting group removal reaction to obtain different amino acid terminals; wherein the removal of the protecting group is performed in the presence or absence of a catalyst; the catalyst is a catalyst for removing protecting groups commonly used in the art, and comprises, but is not limited to, sodium hydroxide, potassium hydroxide, ethyl hydrogen chloride acetate solution, trifluoroacetic acid, piperidine, hydrogen palladium carbon and the like;
the compounds of the application may be used in drug nano-delivery systems based on pathological microenvironment specific responses. The medicament herein includes a chemical medicament. The chemical is a hydrophobic drug including, but not limited to, imatinib and its derivatives and analogs, doxorubicin and its derivatives and analogs, camptothecin and its derivatives and analogs, paclitaxel and its derivatives and analogs, and the like. It can be formulated into preparations for oral administration or external use, including, but not limited to, powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, suppositories, sterile injectable solutions, etc., according to conventional methods suitable for each preparation.
The application also includes a pharmaceutical composition comprising each of the above compounds of the application.
Unless otherwise indicated, the groups referred to in the present application have the following meanings, respectively.
"halogen" means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
"methoxy" refers to a methoxyalkoxy group.
“-NH 2 ", refers to amino groups.
“-N 3 ", refers to an azide group.
"alkynyl" means an unsaturated hydrocarbon group having at least one carbon-carbon triple bond and includes both straight and branched chain groups (the numerical ranges mentioned herein, e.g., "2-5", means that the group, in this case alkynyl, may contain 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, etc., up to and including 5 carbon atoms). Alkynyl groups in the present application may be C 2-8 Alkynyl, C 2-6 Alkynyl, C 2-5 Alkynyl, C 2-4 Alkynyl, C 2-3 Alkynyl groups, and the like, specific alkenyl groups include, but are not limited to, ethynyl, propynyl, and butynyl.
"alkylene" means an-alkyl-group, alkyl including straight and branched chain groups. Specific alkyl groups include, but are not limited to, isopropyl, isobutyl, 2-propyl, tert-butyl, and the like.
"alkyl" refers to saturated aliphatic groups of 1 to 30 carbon atoms, including straight and branched chain groups. Specific alkyl groups include, but are not limited to, methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl, and the like. Alkyl groups may be substituted or unsubstituted.
"Boc" refers to a t-butoxycarbonyl group of the structure
"Pbf" means (2, 4,6, 7-pentamethyl-2, 3-dihydrobenzo [ b ]]Furan) -5-sulfonyl group of the structure
"pharmaceutically acceptable salts" are salts comprising the compound of formula (IV) with an organic or inorganic acid, meaning those salts which retain the biological effectiveness and properties of the parent compound. Such salts include:
(1) Salified with acids, obtained by reaction of the free base of the parent compound with an inorganic acid such as, but not limited to, hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, metaphosphoric acid, sulfuric acid, sulfurous acid, perchloric acid, and the like, or an organic acid such as, but not limited to, acetic acid, propionic acid, acrylic acid, oxalic acid, (D) or (L) malic acid, fumaric acid, maleic acid, hydroxybenzoic acid, gamma-hydroxybutyric acid, methoxybenzoic acid, phthalic acid, methanesulfonic acid, ethanesulfonic acid, naphthalene-1-sulfonic acid, naphthalene-2-sulfonic acid, p-toluenesulfonic acid, salicylic acid, tartaric acid, citric acid, lactic acid, mandelic acid, succinic acid, malonic acid, and the like.
(2) The acidic protons present in the parent compound are replaced by metal ions, such as alkali metal ions, alkaline earth metal ions or aluminum ions, or salts formed by complexation with organic bases, such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like.
"pharmaceutical compositions" refers to mixtures of one or more of the compounds described herein or their pharmaceutically acceptable salts and prodrugs with other chemical components, such as pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate the administration of the compound to the organism.
The compound can be used as a nano delivery system based on pathological microenvironment specific response, has good solubility in aqueous solution, can form a stable nano composite with the drug in the aqueous solution in a self-assembly way, can effectively deliver the loaded drug to a disease part, can realize the aim of accurately releasing the drug by responsive disassembly and assembly under corresponding pathological stimulation, can release the drug to the focus part to a large extent, and is a novel nano delivery carrier with potential clinical application prospect.
Drawings
FIG. 1H-NMR spectrum of the Bola amphiphilic dendrimer ROS response;
FIG. 2 is a graph of critical aggregation concentration of Bola amphiphilic dendrimers;
FIG. 3 shows a particle size diagram of a Bola amphiphilic dendrimer nanoparticle;
FIG. 4 is a chart of ROS response tests of the Bola amphiphilic dendrimer drug delivery system;
FIG. 5 shows in vitro antitumor activity graph of Bola amphiphilic dendrimer drug-loading system
Detailed Description
The detection method of the present application is further illustrated by the following examples, which are not intended to limit the present application in any way.
A. Molecular synthesis part examples:
example 1: compound ArBE C 6 KK 2 Is prepared from
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1.1 HO-C 6 -N 3 Is prepared from
Taking 6-chlorohexanol in a reaction bottle, adding azido trimethylsilane and cesium fluoride, adding dimethylformamide for dissolution, reacting at 60-80 ℃, and monitoring the end of the reaction by thin layer chromatography. The solvent was removed, washed with water, and the organic phase was dried over anhydrous sodium sulfate, and filtered and dried to give a crude product as a pale yellow oil. Separating by column chromatography, and spin-drying to obtain colorless oily liquid HO-C 6 -N 3 (1270mg，89％)。
1 H NMR(300MHz,CDCl 3 )δ3.59(t,J＝6.5Hz,2H),3.24(t,J＝6.9Hz,2H),2.11(s,1H),1.69-1.46(m,4H),1.44-1.27(m,4H).
1.2 MsO-C 6 -N 3 Is prepared from
Taking HO-C 6 -N 3 Dissolving in dichloromethane, adding triethylamine, adding methanesulfonyl chloride, and continuing reaction at 30-50deg.C, and monitoring the end of reaction by thin layer chromatography. The reaction mixture was diluted with water, extracted with dichloromethane, and the organic phase was washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered and dried to give a pure product (1106 mg, 100%).
1 H NMR(300MHz,CDCl 3 )δ4.22(t,J＝6.4Hz,2H),3.28(t,J＝6.8Hz,2H),3.01(s,3H),1.83-1.69(m,2H),1.66-1.55(m,2H),1.51-1.35(m,4H).
1.3 AcS-C 6 -N 3 Is prepared from
Taking MsO-C 6 -N 3 And (3) adding dimethylformamide into a reaction bottle to dissolve, adding potassium thioacetate to react at 30-50 ℃, and monitoring the reaction completion by thin layer chromatography. Water was added thereto, extraction was performed with methylene chloride, and the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and filtered to dryness. Separating by column chromatography, and spin-drying to obtain pure product (332 mg, 88.7%).
1 H NMR(300MHz,CDCl 3 )δ3.26(t,J＝6.8Hz,2H),2.86(t,J＝7.3Hz,2H),2.32(s,3H),1.63-1.57(m,4H),1.38(dd,J＝8.9,5.3Hz,4H).
1.4 HS-C 6 -N 3 Is prepared from
Taking AcS-C 6 -N 3 Adding methanol into a reaction bottle, uniformly mixing, dropwise adding sodium hydroxide solution, reacting at 30-50 ℃, and monitoring the reaction by thin layer chromatography. The methanol was dried by spinning, extracted three times with ethyl acetate, and the organic phases were combined, dried over anhydrous magnesium sulfate, and filtered to give a pale yellow oily liquid which was directly subjected to the next reaction.
1 H NMR(300MHz,CDCl 3 )δ3.25(t,J＝6.8Hz,2H),2.69-2.61(m,1H),2.51(q,J＝7.3Hz,2H),1.70-1.51(m,4H),1.46-1.28(m,4H).
1.5 Preparation of ArBE 1-1
Dissolving 4-fluorophenol in methanol, adding sodium hydroxide and formaldehyde, and reacting at 30-50deg.C. After the completion of the reaction, the pH of the reaction mixture was adjusted to 3-5 with an acetic acid solution, the reaction mixture was dried by spin-drying, diluted with water, extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and dried by spin-drying, and purified by column chromatography to give ArBE 1-1 (240 mg, 70%) as a pure product.
1 H NMR(300MHz,d 6 -DMSO)δ8.39(s,1H),6.95(d,J＝9.4Hz,2H),5.27(t,J＝5.4Hz,2H),4.52(d,J＝5.3Hz,4H).
1.6 Preparation of ArBE 1-2
And (3) taking ArBE 1-1 and imidazole in a reaction bottle, adding dimethylformamide for dissolving, and dropwise adding a dimethylformamide solution of tert-butyl dimethyl silicon chloride. Then the reaction is carried out at 30-50 ℃, and the reaction is finished after monitoring by thin layer chromatography. The reaction mixture was washed with diethyl ether and water. The organic phase was dried over anhydrous sodium sulfate, filtered and spun-dried to give crude product, which was separated by column chromatography to give pure ArBE 1-2 (258 mg, 81%).
1 H NMR(300MHz,CDCl 3 )δ8.06(s,1H),6.82(d,J＝8.9Hz,2H),4.81(s,4H),1.57(s,4H),0.97-0.92(m,18H),0.15-0.10(m,12H).
1.7 Preparation of ArBE 1-3
Taking potassium carbonate and ArBE 1-2 in a reaction bottle, and dropwise adding a dimethylformamide solution of 4-bromomethylbenzoic acid pinacol ester. The reaction is carried out at 30-50 ℃, and the reaction is finished after monitoring by thin layer chromatography. The reaction mixture was diluted with ethyl acetate, and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered and dried to give crude product. Column chromatography separation gave pure ArBE 1-3 (470 mg, 77%).
1 H NMR(300MHz,CDCl 3 )δ7.84(d,J＝8.0Hz,2H),7.39(d,J＝8.0Hz,2H),7.08(d,J＝9.2Hz,2H),4.83(s,2H),4.67(s,4H),1.36(s,12H),0.91(s,18H),0.06(s,12H).
1.8 Preparation of ArBE 1-4
ArBE 1-3 was taken in a reaction flask, dissolved in methanol, and then added with a methanol solution of p-toluenesulfonic acid monohydrate. The reaction is carried out at 30-50 ℃, and the reaction is finished after monitoring by thin layer chromatography. Spin-drying the reaction mixture, and separating by column chromatography to obtain pure ArBE 1-4 (140 mg, 78%).
1 H NMR(300MHz,CDCl 3 )δ7.83(d,J＝8.0Hz,2H),7.39(d,J＝7.9Hz,2H),7.07(d,J＝8.6Hz,2H),4.89(s,2H),4.65(s,4H),1.35(s,12H).
1.9 Preparation of ArBE 1-5
And taking ArBE-1-4 and dimethylaminopyridine in a reaction bottle, adding dichloromethane for dissolution, adding triethylamine for uniform mixing, dropwise adding a dichloromethane solution of methacrylic anhydride, then reacting at 30-50 ℃, and monitoring the end of the reaction by thin-layer chromatography. Extraction with dichloromethane followed by one wash with saturated brine, and the combined organic phases were dried over anhydrous sodium sulfate, filtered and spun-dried to give the crude product. Column chromatography gave ArBE 1-5 (435 mg, 83%) as pure product.
1 H NMR(300MHz,CDCl 3 )δ7.84(d,J＝7.9Hz,2H),7.43(d,J＝7.9Hz,2H),7.11(d,J＝8.6Hz,2H),6.15(s,2H),5.67-5.56(m,2H),5.23(s,4H),4.98(s,2H),1.35(s,12H).
1.10 ArBE C 6 Preparation of-1
Taking ArBE-2-4 in a reaction bottle, pumping air three times, adding solvent for dissolving, then adding dimethylphenylphosphine, and then adding HS-C 6 -N 3 And (3) reacting at room temperature, and monitoring the end of the reaction by thin layer chromatography. The reaction solution was diluted with dichloromethane, washed with saturated brine, and the organic phase was dried over anhydrous sodium sulfate, filtered and dried to give a crude product. Separating by column chromatography to obtain pureArBE product C 6 -1(328mg，78％)。
1 H NMR(300MHz,CDCl 3 )δ7.83(d,J＝8.0Hz,2H),7.43(d,J＝7.9Hz,2H),7.10(d,J＝8.6Hz,2H),5.18(s,4H),4.94(s,2H),3.24(t,J＝6.9Hz,4H),2.77(d,J＝7.1Hz,4H),2.58(d,J＝6.2Hz,2H),2.49(t,J＝7.3Hz,4H),1.65-1.49(m,8H),1.44-1.29(m,20H),1.25(d,J＝4.9Hz,6H).
1.11 Preparation of AlkylK-0
Sequentially adding Boc-Lys (Boc) -OH, 1-hydroxybenzotriazole and O-benzotriazole-tetramethylurea hexafluorophosphate into a reaction bottle, adding N, N-dimethylformamide, uniformly mixing, then adding propargylamine, and stirring at room temperature until the reaction is complete. The reaction solution was dried by rotation, extracted with ethyl acetate, then washed with saturated sodium hydrogencarbonate, diluted hydrochloric acid and saturated brine, respectively, and the organic phases were combined and dried over anhydrous sodium sulfate, filtered, the solvent was removed by distillation under the reduced pressure, and the residue was separated by silica gel column chromatography to give a white solid (79mg, 85%).
1 H NMR(300MHz,CDCl 3 )δ6.54(br,1H),5.14(br,1H),4.62(br,1H),4.20-3.94(m,3H),3.13(q,J＝5.9Hz,2H),2.24(t,J＝2.4Hz,1H),1.95-1.75(m,1H),1.66-1.30(m,22H).
1.12 Preparation of AlkylK
And taking the Alkyl K-0 in a reaction bottle, adding dichloromethane, uniformly mixing, then adding trifluoroacetic acid, stirring at room temperature until the reaction is complete, spin-drying the reaction liquid, and adding diethyl ether for washing to obtain a pure product of the Alkyl K (660 mg, 100%).
1 H NMR(300MHz,D 2 O)δ4.11-3.80(m,3H),2.92(t,J＝7.7Hz,2H),2.57(t,J＝2.5Hz,1H),1.90-1.77(m,2H),1.68-1.53(m,2H),1.44-1.31(m,2H).
1.13 Alkyl KK 2 Preparation of-0
The preparation method of 1.11 in reference example 1 gives pure AlkylKK 2 -0(750mg，81％)。
1 H NMR(300MHz,d 6 -DMSO)δ8.35(t,J＝5.4Hz,1H),7.74(q,J＝6.1,5.6Hz,2H),6.88(d,J＝7.9Hz,1H),6.82-6.32(m,3H),4.21(d,J＝6.2Hz,1H),3.95-3.72(m,4H),3.10(t,J＝2.5Hz,1H),3.06-2.77(m,6H),1.64-1.10(m,54H).
1.14 ArBE C 6 KK 2 Preparation of-0
ArBE C is taken 6 Adding sodium ascorbate and copper sulfate pentahydrate into a reaction bottle, adding tetrahydrofuran, uniformly mixing, and then adding Alkyl KK 2 -0, adding water, stirring at 30-60 ℃ for reaction, and monitoring the end of the reaction by thin layer chromatography. Spin-drying the reaction solution, adding saturated ammonium chloride solution, extracting with dichloromethane, mixing the organic phases, washing with saturated saline solution, drying the organic phase with anhydrous sodium sulfate, filtering, spin-drying to obtain crude product, and purifying by column chromatography to obtain pure ArBE C 6 KK 2 -0(80mg，66％)。
1 H NMR(300MHz,d 6 -DMSO)7.83(s,2H),7.79-7.65(d,2H),7.44(d,J＝16.9,8.1Hz,2H),7.26(d,J＝9.0Hz,2H),5.15(s,4H),4.93(s,2H),4.25(d,J＝19.8Hz,10H),3.83(m,4H),3.09-2.55(m,18H),2.43(t,J＝7.0Hz,4H),1.84-1.04(m,142H).
1.15 ArBE C 6 KK 2 Is prepared from
ArBE C is taken 6 KK 2 -0 in a reaction flask, ethyl acetate was added for dissolution, followed by ethyl hydrogen chloride acetate solution, reaction at room temperature, and thin layer chromatography monitoring of the reaction end. Spin-drying the reaction solution, adding diethyl ether for washing, and repeating for three times to obtain a crude product. Dialyzing, lyophilizing to obtain ArBE C as white solid 6 KK 2 (55mg，85％)。
1 H NMR(300MHz,CDCl 3 /CD 3 OD＝1/1)δ7.79(s,2H),7.67(d,J＝7.6Hz,2H),7.47(d,J＝7.8Hz,2H),7.15(d,J＝8.6Hz,2H),5.20(s,4H),4.97(s,2H),4.51-4.28(m,12H),4.12(t,J＝6.6Hz,2H),4.02(t,J＝6.7Hz,2H),3.33-3.15(m,4H),3.06-2.93(m,8H),2.85-2.71(m,4H),2.62(h,J＝6.4Hz,2H),2.50(t,J＝7.1Hz,4H),2.02-1.17(m,60H).
Example 2: compound ArBE C 6 KE 2 Is prepared from
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1.1 HO-C 6 -N 3 Is prepared from
The same as in 1.1 of example 1.
1.2 MsO-C 6 -N 3 Is prepared from
The same as in 1.2 of example 1.
1.3 AcS-C 6 -N 3 Is prepared from
The same as in 1.3 of example 1.
1.4 HS-C 6 -N 3 Is prepared from
The same as in 1.4 of example 1.
1.5 Preparation of ArBE 1-1
The same as in 1.5 of example 1.
1.6 Preparation of ArBE 1-2
The same as in 1.6 of example 1.
1.7 Preparation of ArBE 1-3
The same as in 1.7 of example 1.
1.8 Preparation of ArBE 1-4
The same as in 1.8 of example 1.
1.9 Preparation of ArBE 1-5
The same as 1.9 in example 1.
1.10 ArBE C 6 Preparation of-1
The same as 1.10 in example 1.
1.11 Preparation of AlkylK-0
The same as 1.11 in example 1.
1.12 Preparation of AlkylK
The same as in 1.12 of example 1.
1.13 Alkyl KE 2 Preparation of-0
The preparation method of 1.11 in reference example 1 gives pure AlkylKE 2 -0(750mg，81％)。
1 H NMR(300MHz,CD 3 OD)δ4.35-4.25(m,1H),4.07-3.88(m,4H),3.27-3.13(m,2H),2.60(t,J＝2.6Hz,1H),2.43-2.23(m,4H),2.18-2.05(m,2H),1.96-1.61(m,4H),1.59-1.33(m,42H).
1.14ArBE C 6 KE 2 Preparation of-0
Reference example 1, 1.14, gives ArBE C as pure product 6 KE 2 -0(90mg，82％)。
1 H NMR(300MHz,CD 3 OD)δ7.83(s,2H),7.71(d,J＝7.9Hz,2H),7.47(d,J＝8.0Hz,2H),7.20(d,J＝8.8Hz,2H),5.26-5.10(m,4H),5.00(d,J＝5.3Hz,2H),4.44(s,4H),4.34(t,J＝7.1Hz,4H),4.24(dd,J＝8.5,5.5Hz,2H),3.94(d,J＝6.8Hz,4H),3.21-3.08(m,4H),2.83-2.58(m,6H),2.45(t,J＝7.1Hz,4H),2.35(t,J＝7.5Hz,4H),2.26(t,J＝7.6Hz,4H),2.13-1.99(m,4H),1.91-1.60(m,8H),1.56-1.16(m,110H).
1.15ArBE C 6 KE 2 Is prepared from
ArBE C is taken 6 KE 2 -0 in a reaction flask, adding dichloromethane for dissolution, then adding trifluoroacetic acid, and completely reacting at room temperature. The reaction solution was dried by spinning to obtain a pale yellow solid, which was washed with diethyl ether to obtain a crude product. Dialyzing, lyophilizing to obtain pure ArBE C 6 KE 2 (42mg，92％)。
1 H NMR(300MHz,D 2 O)δ7.85-7.58(m,4H),7.47-7.12(m,2H),6.96(br,2H),5.66(br,2H),5.19(br,4H),4.67-4.03(m,10H),3.76-3.60(m,4H),3.47-2.92(m,8H),2.76-2.52(m,4H),2.50-2.20(m,10H),2.15-1.91(m,8H),1.86-0.84(m,46H).
Example 3: compound ArBE C 6 KR 2 Is prepared from
1.1 HO-C 6 -N 3 Is prepared from
The same as in 1.1 of example 1.
1.2 MsO-C 6 -N 3 Is prepared from
The same as in 1.2 of example 1.
1.3 AcS-C 6 -N 3 Is prepared from
The same as in 1.3 of example 1.
1.4 HS-C 6 -N 3 Is prepared from
The same as in 1.4 of example 1.
1.5 Preparation of ArBE 1-1
The same as in 1.5 of example 1.
1.6 Preparation of ArBE 1-2
The same as in 1.6 of example 1.
1.7 Preparation of ArBE 1-3
The same as in 1.7 of example 1.
1.8 Preparation of ArBE 1-4
The same as in 1.8 of example 1.
1.9 Preparation of ArBE 1-5
The same as 1.9 in example 1.
1.10 ArBE C 6 Preparation of-1
The same as 1.10 in example 1.
1.11 Preparation of AlkylK-0
The same as 1.11 in example 1.
1.12 Preparation of AlkylK
The same as in 1.12 of example 1.
1.13 Alkyl KR 2 Preparation of-0
The preparation method of 1.11 in reference example 1 gives pure AlkylKR 2 -0(670mg，83％)。
1 H NMR(400MHz,DMSO-d 6 )δ4.26-4.16(m,1H),3.92-3.77(m,4H),3.10(t,J＝2.5Hz,1H),3.06-2.89(m,8H),2.54-2.45(m,16H),2.01(s,6H),1.65-1.09(m,44H).
1.14 ArBE C 6 KR 2 Preparation of-0
Reference example 1, 1.14, gives ArBE C as pure product 6 KR 2 -0(76mg，80％)。
1 H NMR(300MHz,CD 3 OD/CDCl 3 ＝2/1)δ7.95(s,1H),7.81(d,J＝7.9Hz,3H),7.67(d,J＝13.3Hz,4H),7.43(d,J＝7.9Hz,2H),7.12(d,J＝8.6Hz,2H),5.17(d,J＝2.9Hz,4H),4.95(s,2H),4.30(t,J＝7.3Hz,6H),4.05(s,5H),3.61(d,J＝2.7Hz,1H),3.37(s,78H),3.28-3.06(m,12H),3.01-2.86(m,12H),2.85-2.67(m,4H),2.64-2.42(m,28H),2.07(s,12H),1.93-1.14(m,122H).
1.15 ArBE C 6 KR 2 Is prepared from
The preparation method of 1.15 in reference example 1 gave ArBE C as a pure product 6 KR 2 (48mg，86％)。
1 H NMR(400MHz,D 2 O)δ8.00-6.77(m,8H),5.22-4.94(m,5H),4.59-4.07(m,13H),4.02-3.79(m,6H),3.29-2.94(m,22H),2.85-2.11(m,13H),1.98-0.85(m,87H).
Example 4: compound ArBE C 6 K(AE) 2 Is prepared from
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1.1HO-C 6 -N 3 Is prepared from
The same as in 1.1 of example 1.
1.2MsO-C 6 -N 3 Is prepared from
The same as in 1.2 of example 1.
1.3AcS-C 6 -N 3 Is prepared from
The same as in 1.3 of example 1.
1.4HS-C 6 -N 3 Is prepared from
The same as in 1.4 of example 1.
1.5 preparation of ArBE 1-1
The same as in 1.5 of example 1.
1.6 preparation of ArBE 1-2
The same as in 1.6 of example 1.
1.7 preparation of ArBE 1-3
The same as in 1.7 of example 1.
1.8 preparation of ArBE 1-4
The same as in 1.8 of example 1.
1.9 preparation of ArBE 1-5
The same as 1.9 in example 1.
1.10ArBE C 6 Preparation of-1
The same as 1.10 in example 1.
1.11 preparation of AlkylK-0
The same as 1.11 in example 1.
1.12 preparation of AlkylK
The same as in 1.12 of example 1.
1.13Alkyl K(AE) 2 Preparation of-0
Reference example 1, 1.11, gives pure AlkylK (AE) 2 -0(480mg，75％)。
1 H NMR(300MHz,CD 3 OD)δ4.35-4.13(m,3H),4.05-3.81(m,4H),3.20(d,J＝8.5Hz,2H),2.61-2.56(m,1H),2.35(t,J＝7.4Hz,3H),2.19-1.98(m,2H),1.96-1.59(m,8H),1.59-1.21(m,36H),1.01-0.90(m,6H).
1.14ArBE C 6 K(AE) 2 Preparation of-0
Reference example 1, 1.14, gives ArBE C as pure product 6 K(AE) 2 -0(95mg，80％)。
1 H NMR(300MHz,CD 3 OD)δ7.82(d,J＝3.8Hz,2H),7.71(d,J＝7.8Hz,2H),7.47(d,J＝8.0Hz,2H),7.20(d,J＝8.7Hz,2H),5.26-5.12(m,4H),5.00(d,J＝5.2Hz,2H),4.43(s,4H),4.39-4.10(m,10H),3.96(dd,J＝9.4,4.8Hz,4H),3.17(br,4H),2.81-2.70(m,4H),2.66-2.56(m,2H),2.49-2.31(m,10H),2.06(br,4H),1.95-1.57(m,20H),1.59-1.13(m,102H),1.05-0.85(m,12H).
1.15ArBE C 6 K(AE) 2 Is prepared from
Reference example 2, 1.15, gives ArBE C as pure product 6 K(AE) 2 (44mg，92％)。
1 H NMR(300MHz,D 2 O)δ7.95-7.65(m,4H),7.58-7.20(m,2H),7.16-6.87(m,2H),5.75(br,2H),5.12(br,4H),4.76-3.89(m,18H),3.63-2.95(m,8H),2.90-2.05(m,22H),1.97-1.02(m,54H),1.01-0.74(m,12H).
Example 5: compound ArBE C 6 KK 2 K 4 Is prepared from
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1.1HO-C 6 -N 3 Is prepared in the same way as 1.1 in example 1. 1.2MsO-C 6 -N 3 Is prepared in the same way as 1.2 in example 1. 1.3AcS-C 6 -N 3 Is prepared in the same manner as 1.3 in example 1. 1.4HS-C 6 -N 3 Is prepared in the same manner as 1.4 in example 1. 1.5ArBE 1-1 was prepared in the same manner as 1.5 in example 1. 1.6ArBE 1-2 was prepared in the same manner as 1.6 in example 1. 1.7ArBE 1-3 was prepared in the same manner as 1.7 in example 1. 1.8ArBE 1-4 was prepared in the same manner as 1.8 in example 1. 1.9ArBE 1-5 was prepared in the same manner as 1.9 in example 1.
1.10 ArBE C 6 Preparation of-1
The same as 1.10 in example 1.
1.11 Preparation of AlkylK-0
The same as 1.11 in example 1.
1.12 Preparation of AlkylK
The same as in 1.12 of example 1.
1.13 Alkyl KK 2 Preparation of-0
The same as in 1.13 of example 1.
1.14 Alkyl KK 2 Is prepared from
The preparation method of 1.12 in example 1 was referred to as a white solid (280 mg, 100%).
1 H NMR(300MHz,D 2 O)δ4.13(t,J＝7.3Hz,1H),3.95-3.74(m,4H),3.10(t,J＝7.2Hz,2H),2.95-2.79(m,4H),2.49(t,J＝2.5Hz,1H),1.86-1.71(m,4H),1.71-1.49(m,6H),1.49-1.12(m,8H).
1.15 Alkyl KK 2 K 4 Preparation of-0
The preparation method of 1.11 in reference example 1 gave a white solid (480 mg, 77%).
1 H NMR(300MHz,d 6 -DMSO)δ8.34(br,1H),7.98-7.85(m,2H),7.81-7.61(m,4H),6.97-6.86(m,2H),6.83-6.67(m,5H),4.28-4.11(m,3H),3.95-3.70(m,6H),3.09(t,J＝2.5Hz,1H),3.07-2.75(m,14H),1.69-0.99(m,114H).
1.16 ArBE C 6 KK 2 K 4 Preparation of-0
ArBE C is taken 6 Adding cuprous iodide into a reaction bottle, adding dimethylformamide, uniformly mixing, and then adding Alkyl-KK 2 K 4 -0, adding 1, 8-diazabicyclo undec-7-ene, stirring at 30-70 ℃ for reaction, and monitoring the end of the reaction by thin layer chromatography. The reaction solution was dried by spinning, a saturated ammonium chloride solution was added, extraction was performed with methylene chloride, the organic phases were combined, washed with saturated ammonium chloride and saturated brine, and the organic phase was dried over anhydrous sodium sulfate, and filtered and dried by spinning to obtain a crude product. Separating by column chromatography to obtain pure ArBE C 6 KK 2 K 4 -0(150mg，73％)。
1 H NMR(300MHz,d 6 -DMSO)δ7.85(s,2H),7.66(d,J＝7.8Hz,2H),7.46(d,J＝7.8Hz,2H),7.26(d,J＝8.9Hz,2H),5.15(s,4H),4.93(s,2H),4.37-4.12(m,14H),3.94-3.61(m,8H),3.10-2.79(m,28H),2.79-2.37(m,10H),1.74-1.09(m,262H).
1.17 ArBE C 6 KK 2 K 4 Is prepared from
ArBE C is taken 6 KK 2 K 4 And (0) adding dichloromethane into a reaction bottle to dissolve, then adding ethyl hydrogen chloride acetate solution, and completely reacting. The reaction solution was dried by spinning to obtain a pale yellow solid, which was washed with diethyl ether to obtain a pale yellow solid. Dialysis and freeze-drying to obtain pureArBE product C 6 KK 2 K 4 (60mg，89％)。
1 H NMR(300MHz,CDCl 3 /CD 3 OD＝1/1)δ7.86(s,2H),7.45(d,J＝7.6Hz,2H),7.15(d,J＝8.6Hz,2H),5.20(s,4H),4.97(s,2H),4.50-4.26(m,14H),3.85-3.73(m,8H),3.31-3.09(m,12H),3.09-2.89(m,16H),2.89-2.56(m,8H),2.50(t,J＝7.1Hz,4H),2.13-0.96(m,118H).
Example 6: compound ArBE C 6 KK 2 E 4 Is prepared from
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1.1HO-C 6 -N 3 Is prepared in the same way as 1.1 in example 1. 1.2MsO-C 6 -N 3 Is prepared in the same way as 1.2 in example 1. 1.3AcS-C 6 -N 3 Is prepared in the same manner as 1.3 in example 1. 1.4HS-C 6 -N 3 Is prepared in the same manner as 1.4 in example 1. 1.5ArBE 1-1 was prepared in the same manner as 1.5 in example 1. 1.6ArBE 1-2 was prepared in the same manner as 1.6 in example 1. 1.7ArBE 1-3 was prepared in the same manner as 1.7 in example 1. 1.8 preparation of ArBE 1-4
The same as in 1.8 of example 1.
1.9 Preparation of ArBE 1-5
The same as 1.9 in example 1.
1.10 ArBE C 6 Preparation of-1
The same as 1.10 in example 1.
1.11 Preparation of AlkylK-0
The same as 1.11 in example 1.
1.12 Preparation of AlkylK
The same as in 1.12 of example 1.
1.13 Alkyl KK 2 Preparation of-0
The same as in 1.13 of example 1.
1.14 Alkyl KK 2 Is prepared from
The same as in 1.14 of example 4.
1.15 Alkyl KK 2 E 4 Preparation of-0
The preparation method of 1.15 in reference example 4 gave a white solid (480 mg, 77%).
1H NMR(300MHz,d 6 -DMSO)δ8.40-8.20(m,1H),8.00-7.81(m,4H),7.76(s,2H),7.81-7.68(m,3H),4.33-4.04(s,3H),3.91-3.62(m,6H),3.12-2.87(m,7H),2.28-2.04(m,8H),1.96-1.07(m,100H)..
1.16 ArBE C 6 KK 2 E 4 Preparation of-0
The preparation method of 1.16 in reference example 4 gave ArBE C as a pure product 6 KK 2 E 4 -0(120mg，61％)。
1 H NMR(300MHz,d 6 -DMSO)δ7.86(s,2H),7.71(d,J＝7.7Hz,2H),7.43(d,J＝7.6Hz,2H),7.26(d,J＝8.9Hz,2H),5.16(s,4H),4.93(s,2H),4.32-4.12(m,18H),3.80-3.69(m,8H),3.04-2.90(m,12H),2.78-2.35(m,10H),2.24-2.05(m,16H),1.94-1.10(m,224H).
1.17 ArBE C 6 KK 2 E 4 Is prepared from
Reference example 2, 1.15, gives ArBE C as pure product 6 KK 2 E 4 (60mg，89％)。
1 1H NMR(300MHz,D 2 O)δ7.92-7.66(m,4H),7.50(d,J＝7.9Hz,1H),7.05(d,J＝7.9Hz,2H),5.74(s,2H),5.23-5.01(m,4H),4.54-4.07(m,16H),3.75-3.71(m,8H),3.37-2.28(m,12H),2.13-2.03(m,26H),1.95-0.76(m,80H).
Example 7: compound ArBE C 8 KE 2 Is prepared from
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1.1HO-C 8 -N 3 Is prepared from
With reference to the preparation method of 1.1 in example 1, pure product (650 mg, 92%) was obtained.
1 H NMR(300MHz,CDCl 3 )δ3.64(t,J＝6.6Hz,2H),3.25(t,J＝6.9Hz,2H),1.73-1.46(m,4H),1.46-1.17(m,8H).
1.2MsO-C 8 -N 3 Is prepared from
With reference to the preparation method of 1.2 in example 1, pure product (580 mg, 98%) was obtained.
1 H NMR(300MHz,CDCl 3 )δ4.32(t,J＝6.3Hz,2H),3.31(t,J＝6.7Hz,2H),3.15(s,3H),1.81-1.71(m,2H),1.67-1.57(m,2H),1.58-1.32(m,8H).
1.3AcS-C 8 -N 3 Is prepared from
With reference to the preparation method of 1.3 in example 1, pure product (780 mg, 88%) was obtained.
1 H NMR(300MHz,CDCl 3 )δ3.27(t,J＝6.9Hz,2H),2.88(t,J＝6Hz,2H),2.34(s,3H),1.70-1.52(m,4H),1.52(d,J＝9.7Hz,8H).
1.4HS-C 8 -N 3 Is prepared from
With reference to the preparation method of 1.4 in example 1, pure product (320 mg, 96%) was obtained.
1 H NMR(300MHz,CDCl 3 )δ3.27(t,J＝6.9Hz,2H),2.55(t,J＝7.4Hz,2H),1.68-1.60(m,4H),1.51-1.26(m,8H).
1.5 preparation of ArBE 1-1
The same as in 1.5 of example 1.
1.6 preparation of ArBE 1-2
The same as in 1.6 of example 1.
1.7 Preparation of ArBE 1-3
The same as in 1.7 of example 1.
1.8 Preparation of ArBE 1-4
The same as in 1.8 of example 1.
1.9 Preparation of ArBE 1-5
The same as 1.9 in example 1.
1.10 ArBE C 8 Preparation of-1
With reference to the preparation method of 1.10 in example 1, a pure product was obtained.
1 H NMR(300MHz,CDCl 3 )δ7.87-7.80(m,2H),7.47-7.40(m,2H),7.10(d,J＝8.6Hz,2H),5.18(s,4H),4.94(s,2H),3.25(t,J＝6.9Hz,4H),2.88-2.66(m,4H),2.58(m,2H),2.52-2.43(m,4H),1.68-1.46(m,8H),1.41-1.21(m,34H).
1.11 Preparation of AlkylK-0
The same as 1.11 in example 1.
1.12 Preparation of AlkylK
The same as in 1.12 of example 1.
1.13 Alkyl KE 2 Preparation of-0
The same as 1.13 in example 2.
1.14 ArBE C 8 KE 2 Preparation of-0
Reference example 1, 1.14, gives ArBE C as pure product 8 KE 2 -0(79mg，84％)。
1 H NMR(300MHz,CD 3 OD)δ7.84(s,2H),7.69(d,J＝7.9Hz,2H),7.44(d,J＝8.0Hz,2H),7.16(d,J＝8.8Hz,2H),5.23-5.02(m,4H),5.01(d,J＝5.3Hz,2H),4.34(s,4H),4.24(t,J＝7.1Hz,4H),4.25(dd,J＝8.5,5.5Hz,2H),3.91(d,J＝6.8Hz,4H),3.19-3.06(m,4H),2.82-2.57(m,6H),2.47(t,J＝7.1Hz,4H),2.36(t,J＝7.5Hz,4H),2.25(t,J＝7.6Hz,4H),2.14-1.93(m,4H),1.97-1.58(m,16H),1.71-1.14(m,110H).
1.15 ArBE C 8 KE 2 Is prepared from
Reference example 2, 1.15, gives ArBE C as pure product 8 KE 2 (82mg，82％)。
1 H NMR(300MHz,D 2 O)δ7.82-7.57(m,4H),7.51-7.11(m,2H),6.99(br,2H),5.58(br,2H),5.21(br,4H),4.61-4.04(m,10H),3.87-3.54(m,4H),3.45-2.87(m,8H),2.69-2.47(m,4H),2.49-2.180(m,10H),2.12-1.90(m,16H),1.84-0.83(m,46H).
Example 8: compound ArBE C 11 KK 2 Is prepared from
1.1HO-C 11 -N 3 Is prepared from
With reference to the preparation method of 1.1 in example 1, pure product (580 mg, 95%) was obtained.
1 H NMR(300MHz,CDCl3)δ3.69(t,J＝6.7Hz,2H),3.29(t,J＝6.9Hz,2H),1.76-1.43(m,4H),1.41-1.17(m,14H).
1.2MsO-C 11 -N 3 Is prepared from
With reference to the preparation method of 1.2 in example 1, pure product (670 mg, 100%) was obtained.
H NMR(300MHz,CDCl 3 )δ4.36(t,J＝6.5Hz,2H),3.36(t,J＝6.8Hz,2H),3.17(s,3H),1.85-1.75(m,
2H),1.69-1.57(m,2H),1.60-1.34(m,14H).
1.3AcS-C 11 -N 3 Is prepared from
With reference to the preparation method of 1.3 in example 1, a pure product AcS-C was obtained 11 -N 3 (211mg,76％)。
1 H NMR(300MHz,CDCl 3 )δ3.25(t,J＝7.0Hz,2H),2.93-2.77(m,2H),2.32(s,3H),1.69-1.44(m,4H),1.42-1.13(m,14H).
1.4HS-C 11 -N 3 Is prepared from
Referring to the preparation method of 1.4 in the example 1, the pure HS-C is obtained by spin drying 11 -N 3 (130mg，93％)。
1 H NMR(300MHz,CDCl 3 )δ3.29(t,J＝6.8Hz,2H),2.68-2.42(m,2H),2.59(q,J＝7.3Hz,2H),1.64-1.57(m,4H),1.69-1.25(m,14H).
1.5 Preparation of ArBE 1-1
The same as in 1.5 of example 1.
1.6 Preparation of ArBE 1-2
The same as in 1.6 of example 1.
1.7 Preparation of ArBE 1-3
The same as in 1.7 of example 1.
1.8 Preparation of ArBE 1-4
The same as in 1.8 of example 1.
1.9 Preparation of ArBE 1-5
The same as 1.9 in example 1.
1.10 ArBE C 11 Preparation of-1
With reference to the preparation method of 1.14 in example 1, pure ArBE C was obtained 11 -1(132mg，74％)。
1 H NMR(300MHz,CDCl 3 )δ7.91-7.81(m,2H),7.51-7.41(m,2H),7.17-7.08(m,2H),5.20(s,4H),4.97(d,J＝5.3Hz,2H),3.27(t,J＝6.9Hz,4H),2.91-2.68(m,4H),2.65-2.55(m,2H),2.55-2.45(m,4H),1.67-1.48(m,8H),1.46-1.16(m,46H).
1.11 Preparation of AlkylK-0
The same as 1.11 in example 1.
1.12 Preparation of AlkylK
The same as in 1.12 of example 1.
1.13 Alkyl KK 2 Preparation of-0
The same as in 1.13 of example 1.
1.14 ArBE C 11 KK 2 Preparation of-0
With reference to the preparation method of 1.11 in example 1, pure ArBE C was obtained 11 -KK 2 -0(135mg，81％)。
1 H NMR(300MHz,CDCl 3 )7.83(s,2H),7.79-7.65(m,2H),7.43(d,J＝16.9,8.1Hz,2H),7.24(d,J＝9.0Hz,2H),5.23(s,4H),4.96(s,2H),4.68-4.37(m,10H),3.92-3.83(m,4H),3.09-2.55(m,18H),2.43(t,J＝7.0Hz,28H),1.84-1.04(m,142H).
1.15 ArBE C 11 KK 2 Is prepared from
With reference to the preparation method of 1.12 in example 1, pure ArBE C was obtained 11 -KK 2 (89mg，76％)。
1 H NMR(300MHz,CD 3 OD/CDCl 3 ＝1/1)δ7.80(s,2H),7.65(d,J＝7.3Hz,1H),7.45(d,JJ＝8.6Hz,2H),5.24-5.13(m,4H),4.96(s,2H),4.44(s,4H),4.41-3.28(m,6H),4.08-3.92(m,4H),3.30-3.15(m,4H),3.04-2.91(m,8H),2.77(m,7.2Hz,4H),2.66-2.55(m,2H),2.54-2.42(m,4H),1.98-1.67(m,26H),1.63-1.43(m,22H),1.39-1.14(m,36H).
B. Physical and chemical property characterization part:
example 9 Nuclear magnetic Hydrogen Spectrometry characterization of Reactive Oxygen Species (ROS) response Properties of Bola amphiphilic dendrimers
The ROS response performance of amphiphilic dendrimers is characterized by nuclear magnetic hydrogen spectroscopy. Firstly, preparing a solution with the compound concentration of 500-2000 mu M, placing a sample into a nuclear magnetic tube, and detecting by using nuclear magnetism. H is then added to the sample 2 O 2 And (3) carrying out nuclear magnetic resonance detection again after incubation.
The results indicate that H was added 2 O 2 After the solution, the compound ArBE C 6 KK 2 The H signal on the aromatic ring of (C) is changed, and finally complete conversion occurs, which shows that the compound can be subjected to responsive fracture under the condition of ROS (figure 1).
Example 10 Mass Spectrometry characterization of Reactive Oxygen Species (ROS) response Properties of Bola amphiphilic dendrimers
The ROS response properties of amphiphilic dendrimers are characterized by mass spectrometry. First, two solutions having a compound concentration of 500 to 2000. Mu.M were prepared. One part of direct mass spectrum detection; another portion of the sample was added to the vial with H 2 O 2 The solution was again detected using mass spectrometry after incubation.
Example 11 determination of Critical aggregation concentration of Bola amphiphilic dendrimers
The critical aggregation concentration of the amphiphilic dendrimer is determined by pyrene fluorescent probe spectrometry. Firstly, preparing aqueous solutions of amphiphilic dendrimers with different concentrations, adding acetone solution of pyrene, and standing after ultrasonic treatment. By fluorescence light-splittingThe fluorescence emission spectrum was measured by a densitometer, and the fluorescence intensity contrast values (I 373 /I 384 ) And drawing a curve of the critical aggregation concentration, and calculating the critical aggregation concentration of the amphiphilic dendrimer.
The result shows that the amphiphilic dendrimers have certain critical aggregation concentration values, which indicates that the amphiphilic dendrimers can self-assemble in aqueous solution to form nanoparticles and have potential for drug delivery (figure 2).
EXAMPLE 12 particle size and morphology studies of the formation of nanoparticles from Bola amphiphilic dendrimers
Preparation of ArBE C using film dispersion method 6 KK 2 、ArBE C 6 KK 2 K 4 、ArBE C 6 KK 2 E 4 Is a blank nano-formulation of (2). 2.0 to 5.0mg of the material was dissolved in 1.0 to 3.0mL of a mixed solvent (chloroform: methanol), and the solvent was removed by rotary evaporation under vacuum to form a dry film. Then adding 1.0-3.0mL of ultrapure water, and hydrating for 30-60 minutes at 30-50 ℃ under ultrasonic. Filtration through a polycarbonate membrane. ArBE C 6 KK 2 、ArBE C 6 KK 2 K 4 、ArBE C 6 KK 2 E 4 The particle size and distribution of the nano-formulations of (a) were determined by dynamic light scattering particle size measurement (figure 3). The zeta potential of the nanofabricated was also determined using a potentiometric instrument. Further characterization of ArBE C using Transmission Electron Microscopy (TEM) 6 KK 2 、ArBE C 6 KK 2 K 4 、ArBE C 6 KK 2 E 4 The morphology and size of the nano-preparation. 2.0 to 6.0 mu L of the nano preparation is dripped on a copper mesh and air-dried, 2.0 to 6.0 mu L of 30% uranyl acetate is dripped for dyeing, and then TEM observation is carried out.
C. As an example of drug carrier Activity test
The experiment adopts amphiphilic dendrimers to construct a nano drug-carrying system, wherein the drug carried by the experiment is a hydrophobic drug, and the hydrophobic drug can be doxorubicin and derivatives thereof, imatinib and derivatives thereof, camptothecine and derivatives thereof and the like. The model drug adopted in the experiment is hydrophobic drug imatinib.
Example 13 preparation of imatinib-loaded assembled nanoparticles
The film dispersion method is adopted to prepare the imatinib-loaded nano-particles. The imatinib and the material were dissolved in a mixed solvent (chloroform: methanol), and the solvent was evaporated by a vacuum rotameter to form a dry film, which was then hydrated with PBS or ultrapure water, and left to stand at 4℃for 4 hours. Unencapsulated imatinib was removed by filtration through a 0.45 μm microporous membrane.
The drug loading and drug encapsulation rate were calculated as follows:
drug loading (%) =wt/ws×100%
Encapsulation efficiency (%) =wt/wo×100%:
wt represents the amount of imatinib loaded into the nanoparticle; wo represents an initial amount of imatinib added; ws represents the amount of nanoparticles after lyophilization.
The result shows that the drug loading rate of the Bola amphiphilic dendrimer drug loading system is more than 30%, and the amphiphilic dendrimer has better drug loading capacity and can be effectively used for drug delivery (shown in the attached table 1).
TABLE 1 encapsulation efficiency and drug loading capacity of Bola amphiphilic dendrimer drug loading nanoparticles
EXAMPLE 14 Reactive Oxygen Species (ROS) responsive drug Release
The ROS responsiveness of the vehicle was studied using nile red as a model drug. To 0.5-2.0mL of the ArBE compound PBS solution (50-300. Mu.M) was added 3.5-6.0. Mu.L of nile red ethanol solution (1.5-3.5 mM), sonicated at room temperature for 10-30 min, and allowed to stand overnight. Adding 100-300 mu L of ArBE compound-nile red solution into each hole of the ELISA plate, and adding 50-100 mu L of H with different concentrations into the solution 2 O 2 Is a solution of PBS. The response of the vector was studied by measuring the changes in nile red fluorescence at different time points (0 min, 1min, 15min, 30min, 1h, 2h, 4h, 6h, 8h, 12h, 24 h) using a multimode microplate reader (cytotion 5, bioTek, vermont, US).
The results show that: the Bola amphiphilic drug-carrying system can responsively release drugs under the condition of ROS and can release drugs under H 2 O 2 Drug release can occur at a concentration of 1mM, which indicates that the Bola amphiphilic dendrimer has ROS responsiveness, can specifically respond and release drugs under the high ROS level of tumor microenvironment, and is a shortage of research in the field at present (figure 4).
Example 15 in vitro anticancer Activity assay of Imatinib-loaded nanocomposites
The antiproliferative activity of free drug Imatinib and ArBE/Imatinib drug-loaded particles on human chronic myelogenous leukemia cells (K562) and human acute myelogenous leukemia cells (KG 1) was evaluated using the CCK-8 method. Wherein, arBE C is selected for the experiment 6 KK 2 And ArBE C 6 KK 2 K 4 As nano-carriers. The concentration of the cell suspension is adjusted to 2X 10 by using the chronic granulocytic leukemia cell K562 5 Per mL, the concentration of the acute myelogenous leukemia cell KG1 in the cell suspension is adjusted to be 4 multiplied by 10 5 /mL. A series of solutions of imatinib and formulation at concentrations from 0.001 to 50. Mu.M were prepared with complete medium. 150. Mu.L of the cell suspension was mixed with 150. Mu.L of the drug-containing medium, 100. Mu.L was added to a 96-well plate, and 3 sub-wells were set. After incubation for 24h in an incubator at 37℃10. Mu.L of CCK-8 reagent was added to each well and incubated for 4h at 37℃the absorbance at 490nm was measured using a microplate reader.
The results show that: arBE C compared with free Imatinib 6 KK 2 /Imatinib、ArBE C 6 KK 2 K 4 The Imatinib drug delivery system can effectively inhibit proliferation of K562 cells. For KG1 cells, arBE C 6 KK 2 K 4 Imatinib can effectively improve the sensitivity of KG1 to Imatinib. The series of ArBE Bola amphiphilic dendrimer carriers can effectively deliver drugs to tumor cells to achieve an anti-tumor effect, and the ArBE Bola amphiphilic dendrimer carrier has a good application prospect in drug delivery (shown in figure 5).
Example 16 preparation of Bola amphiphilic dendrimers for chemical drug delivery
Step 1), accurately weighing a hydrophobic drug and an amphiphilic dendrimer (wherein the mass ratio of the dendrimer to the drug is 1:0.2-1:2.0), and completely dissolving the two in a mixed solvent of chloroform and methanol;
step 2) removing the solvent by vacuum rotary evaporation to form a uniform film on the bottle wall;
step 3), adding 1.0-3.0mL of physiological saline, and carrying out ultrasonic hydration in an ultrasonic instrument;
step 4) filtering to remove the unsupported medicine through a 0.22 mu m polycarbonate membrane to obtain a clear and transparent sterile injection;
step 5) freeze-drying the solution in the step 4 to obtain a freeze-dried powder form.

Claims (9)

1. A compound having a structure represented by the following general formula (IV), or a pharmaceutically acceptable salt thereof;
in the method, in the process of the application,
R 1 methyl, methoxy or halogen groups;
n＝4～12；
x is independently represented by the following two structures (I), (II) and (III)
Wherein,,
R 2 、R 4 or R is 6 Each independently is C 1-5 An alkylene group;
R 3 、R 5 or R is 7 Are each independently a covalent bond, C 1-4 An alkylene group;
r is amino, carboxyl or-NHR 8 ；
R 8 Is tert-butyloxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyl, trifluoroacetyl,
2. The compound of claim 1, wherein R 1 Methyl, methoxy, fluoro, chloro or bromo.
3. The compound of claim 1, wherein n is an integer from 5 to 12.
4. The compound of claim 1, wherein R 2 、R 4 Or R is 6 Each independently is C 3-5 An alkylene group.
5. The compound of claim 1, wherein R 3 、R 5 Or R is 7 Each independently a covalent bond.
6. The compound of claim 1, wherein the compound is selected from the group consisting of
/>
/>
/>
7. The method for producing a compound according to claim 1, which comprises steps (1) (2) and (3), steps (1) (2) and (4), or steps (1) (2) and (5).
Step (1):
step (2):
/>
step (3):
step (4):
/>
step (5):
8. use of a compound according to claim 1 in a drug delivery system.
9. A pharmaceutical composition comprising a compound of claim 1.
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