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CN116874515B - Amino acid-BSH targeted hybrid compound, and preparation method and application thereof - Google Patents

Amino acid-BSH targeted hybrid compound, and preparation method and application thereof Download PDF

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CN116874515B
CN116874515B CN202310521783.7A CN202310521783A CN116874515B CN 116874515 B CN116874515 B CN 116874515B CN 202310521783 A CN202310521783 A CN 202310521783A CN 116874515 B CN116874515 B CN 116874515B
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bridged
boc
bsh
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CN116874515A (en
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陈河如
蔡绍晖
杜军
王可
刘志军
曾燕聪
徐俊
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Chongqing Gaoboron Biotechnology Co ltd
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    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/02—Boron compounds
    • C07F5/05—Cyclic compounds having at least one ring containing boron but no carbon in the ring
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A61K41/009—Neutron capture therapy, e.g. using uranium or non-boron material
    • A61K41/0095—Boron neutron capture therapy, i.e. BNCT, e.g. using boronated porphyrins
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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Abstract

The invention discloses an amino acid-BSH targeted hybrid compound, a preparation method thereof and application of the targeted hybrid compound in preparing related cancer treatment medicines in the process of treating cancers by adopting a boron neutron capture method. The structure of the amino acid-BSH targeted hybrid compound is shown as a formula I. The boron uptake and the T/N ratio of the amino acid-BSH targeted hybrid compound in the corresponding tumor are superior to those of a positive control drug sodium boron carboxylate, and the permeability of the amino acid-BSH targeted hybrid compound to cells is superior to that of sodium boron carboxylate. The preparation method of the amino acid-BSH targeted hybrid compound has the characteristics of mild reaction conditions, simple experimental steps, high yield, high product purity, economy, practicability and the like.

Description

Amino acid-BSH targeted hybrid compound, and preparation method and application thereof
Technical Field
The invention relates to the fields of pharmaceutical chemistry and radiation medicine, in particular to an amino acid-BSH targeted hybrid compound, a preparation method and application thereof.
Background
Cancer is a large group of diseases characterized by abnormal proliferation and metastasis of cells. In town residents, cancer has become the leading cause of death. Although scientists in various countries of the world have conducted intensive studies from various disciplines on how to solve the world problem of cancer, various therapies have been proposed, which have a certain effect on specific subjects, but the curative effect is not as satisfactory, and there is still a considerable distance from radical cure. Therefore, research into cancer therapeutic drugs and techniques remains a hotspot and difficulty in the medical field today.
Boron neutron capture therapy (boron neutron capture therapy, BNCT) is a novel radiotherapy technique that is a binary therapy based on nuclear capture and fission reactions. Compared with the traditional radiotherapy and chemotherapy, the method has the advantages of obvious low side effect, high selectivity and high efficiency. However, the technology not only needs high-quality neutron beams, but also needs high-targeting boron-containing drugs, and the high-quality neutron beams and the high-targeting boron-containing drugs are closely matched and indispensible, so that cell-level accurate targeted killing of tumors can be realized under the condition of both aspects. At present, the development of BNCT neutron beam equipment has been greatly advanced (scientific report 2022,67 (14), 1471-1478), and the boron medicine is approved by FDA to be applied to clinic, namely only mercaptododecaboron disodium salt (BSH) and L-p-dihydroxyboranylphenylalanine (BPA), and the two have the problem of insufficient tumor targeting. For BSH, the medicine also has the problems of incapability of penetrating the blood brain barrier, low tumor uptake and retention, certain toxic and side effects and the like. Therefore, the clinical and practical high-targeting boron drug still cannot meet the requirements of BNCT treatment.
It was found that L-type amino acid transporter 1 (L-amino acid tansporter, LAT 1) can transport neutral amino acids such as leucine, isoleucine, valine, phenylalanine, tyrosine, tryptophan, methionine, histidine and the like. LAT1 is highly expressed in human tumor tissue. The accumulation and selectivity of boron-containing compounds in tumor cells can be increased by designing the boron-containing compounds as amino acid mimetic substrates, utilizing LAT 1-mediated selective delivery to target cells, while increasing the ability to penetrate the Blood Brain Barrier (BBB).
Disclosure of Invention
In order to improve tumor targeting, BBB penetration and active absorption capacity of thiododecaboron disodium salt (BSH), the technical problem solved by the invention is to provide an amino acid-BSH targeted hybrid compound.
The technical problem solved by the invention is also to provide the application of the targeted hybrid compound in preparing related cancer therapeutic drugs in the process of treating cancers by adopting a boron neutron capture method.
The technical problems solved by the invention are realized by the following technical scheme:
an amino acid-BSH targeted hybrid compound has a structure shown in a formula I,
Wherein X is any one of CHMe2、CH2CHMe2、CH(CH3)CH2CH3、CH2CH2SMe、Bn、CH2(3-Indoyl)、CH2[4-(OH)Ph]、CH2[3,4-bis(OH)Ph]、CH2(4-Imidazolyl), the configuration of the marked carbon can be R-or S-, Y can be O or NH, B is 10 B or natural boron (10B/11 B is about 1/4), and SNaB 12H11 has the following structure:
Preferably, the amino acid-BSH targeted hybrid compound comprises the following specific compounds:
The preparation method of the amino acid-BSH targeted hybrid compound comprises the following steps when Y=O:
(O-1) preparation of 2- (2- (2-hydroxyethoxy) ethoxy) ethyl active ester (TrG Es) the preparation method comprises the steps of weighing triethylene glycol, dissolving the triethylene glycol in dry and redistilled Dichloromethane (DCM), adding a stirrer, adding a proper amount of organic base under ice bath, adding an acylating reagent in batches, stirring at room temperature for reaction for about 30min, and keeping the room temperature for continuous reaction for 12 hours. Adding a proper amount of DCM, washing with water, pickling, drying, and concentrating under reduced pressure.
The synthetic route is as follows:
In the step, the feeding molar ratio of the triethylene glycol to the organic base is 1:1.1-1.5, and the feeding molar ratio of the triethylene glycol to the acylating agent is 1:1.1-1.5.
The organic base is any one of triethylamine, trimethylamine and diisopropylethylamine, and the acylating agent is any one of p-toluenesulfonyl chloride, methanesulfonyl chloride and trifluoromethanesulfonyl chloride.
(O-2) preparation of N-t-Butoxycarbonyl amino acid ester bridging active ester (N-Boc-AA-O-TrG Es) N-Boc amino acid was weighed and dissolved in a proper amount of DCM, the reaction flask was equilibrated under ice for 5 minutes, condensing agent and 4-Dimethylaminopyridine (DMAP) were sequentially added, stirring was maintained under ice for 10 minutes, trG Es were added, and after the addition was completed, the reaction was continued under ice for 30 minutes, and then kept at room temperature for 12 hours. After the reaction, a proper amount of DCM is added, the DCM layer is washed with water and 1N HCl in turn, dried and concentrated to obtain a residue, and the residue is purified by silica gel column chromatography and concentrated to obtain the target product.
The synthetic route is as follows:
in the step, the feeding molar ratio of the N-Boc amino acid to the condensing agent is 1:1.1-1.5, the feeding molar ratio of the N-Boc amino acid to the DMAP is 1:0.1-0.5, and the feeding molar ratio of the N-Boc amino acid to the TrG Es is 1:1.1-1.5.
The condensing agent is any one of 2- (7-oxybenzotriazol) -N, N, N ', N ' -tetramethylurea Hexafluorophosphate (HATU), ethyl chloroformate, 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI), N, N ' -Diisopropylcarbodiimide (DIC) and benzotriazol-1-yl-oxy-tripyrrolidinyl phosphate (PyBOP).
The preparation of (O-3) N-tertiary Ding Yangtan-amino acid ester bridged bromine (N-Boc-AA-O-TrG-Br) comprises the steps of weighing a compound N-Boc-AA-O-TrG Es, dissolving in a proper amount of acetone, adding lithium bromide, and placing a reactor in an oil bath with a proper temperature for heating reaction for 2-10 hours. After the reaction, the solvent was distilled off, and an appropriate amount of DCM was added thereto, followed by washing with water, drying, and separation and purification by column chromatography.
The synthesis steps are as follows:
In the steps, the feeding molar ratio of the N-Boc-AA-O-TrG Es to the lithium bromide is 1:1.1-1.5, and the reaction temperature is 40-100 ℃, preferably 58 ℃.
The preparation of (O-4) N-tertiary Ding Yangtan-amino acid ester bridged boron-calide (N-Boc-AA-O-TrG-BSH) comprises the steps of weighing compounds N-Boc-AA-O-TrG Br and boron-calide sodium, dissolving in a proper amount of dry acetonitrile, adding inorganic base and potassium iodide under stirring, and placing a reaction system on an oil bath for heating reflux for 5-10 hours. After the reaction, the solvent was removed by rotary evaporation, and the residue was separated and purified by flash column chromatography.
The synthetic route is as follows:
In the steps, the feeding molar ratio of N-Boc-AA-O-TrG-Br to sodium boron is 1.1-1.5:1, the feeding molar ratio of N-Boc-AA-O-TrG-Br to inorganic base is 1:2.0-5.0, and the feeding molar ratio of N-Boc-AA-O-TrG-Br to potassium iodide is 1:2.0-5.0.
The inorganic base is lithium carbonate, cesium carbonate, potassium carbonate, preferably cesium carbonate.
Preparation of (O-5) amino acid ester bridged boron card (AA-O-BSH) the compound N-Boc-AA-O-TrG-BSH was weighed out and dissolved in dry DCM, placed in ice bath for 5min, acid was added with stirring, then the reaction was continued for 1-5 h at room temperature, and TLC detection of complete reaction conversion (developing reagent: DCM/MeOH=1/1). And regulating the pH value of the reaction system to be slightly alkaline by saturated sodium bicarbonate, removing the solvent by rotary evaporation, separating residues by column chromatography, and freeze-drying to obtain a product.
The synthetic route is as follows:
In the step, the feeding molar ratio of the N-Boc-AA-O-TrG-BSH to the acid is 1.0:100-250, and the acid is any one of trifluoroacetic acid (TFA) and hydrochloric acid/DCM solution.
The preparation method of the amino acid-BSH targeted hybrid compound comprises the following steps when Y=NH:
Preparation of (N-1) N-tertiary Ding Yangtan-amino acid amide bridged alcohol (N-Boc-AA-N-TrG-OH) N-Boc amino acid was weighed and dissolved in a suitable amount of DCM, the reaction flask was equilibrated under ice for 5 minutes, condensing agent and organic base were added sequentially, stirring was maintained under ice for 10 minutes, then 2- (2- (2-aminoethoxy) ethoxy) ethanol was added, after the addition was completed, the reaction was continued under ice for 30 minutes, and then kept at room temperature for 12 hours. After the reaction, a proper amount of DCM is added, the DCM layer is washed with water and 1N HCl in turn, dried and concentrated to obtain a residue, and the residue is purified by silica gel column chromatography and concentrated to obtain the target product.
The synthetic route is as follows:
In the step, the feeding molar ratio of the N-Boc amino acid to the condensing agent is 1:1.1-1.5, the feeding molar ratio of the N-Boc amino acid to the organic base is 1:2.0-5.0, and the feeding molar ratio of the N-Boc amino acid to the 2- (2- (2-aminoethoxy) ethoxy) ethanol is 1:1.1-1.5.
The condensing agent is the same as the condensing agent in the step (O-2), and the organic base is any one of Diisopropylethylamine (DIPEA), triethylamine and 2, 6-tetramethylpiperidine.
Preparation of (N-2) N-t Ding Yangtan-yl amino acid amide bridged active ester (N-Boc-AA-N-TrG Es) Tri-ethylene glycol was replaced with N-t Ding Yangtan-yl amino acid amide bridged alcohol, prepared as described in step (O-1). The synthetic route is as follows:
Preparation of (N-3) N-tertiary Ding Yangtan-amino acid amide bridged bromo (N-Boc-AA-N-TrG-Br) N-tertiary Ding Yangtan-amino acid ester bridged active ester was replaced with N-tertiary Ding Yangtan-amino acid amide bridged active ester, prepared as described in step (O-3). The synthetic route is as follows:
Preparation of (N-4) N-t Ding Yangtan-yl amino acid amide bridged boron card (N-Boc-AA-N-TrG-BSH) N-t Ding Yangtan-yl amino acid ester bridged bromine was replaced with N-t Ding Yangtan-yl amino acid amide bridged bromine, prepared as described in step (O-4). The synthetic route is as follows:
Preparation of (N-5) amino acid amide bridged boron card (AA-N-BSH) N-tertiary Ding Yangtan-yl amino acid ester bridged boron card was replaced with N-tertiary Ding Yangtan-yl amino acid amide bridged boron card, prepared as described in step (O-5). The synthetic route is as follows:
the invention detects cytotoxicity of serial amino acid-BSH targeted hybrid compounds on Human Umbilical Vein Endothelial Cells (HUVEC), human normal liver cells (LO 2) and human liver cancer cells (HepG 2) by using an MTT method, and discovers that the compounds have no toxicity in the concentration range of 500 mu M.
The invention detects the uptake and T/N ratio (uptake of tumor cell boron/uptake of normal cell boron) of serial amino acid-BSH targeted hybrid compounds in Human Umbilical Vein Endothelial Cells (HUVEC), human liver cancer cells (HepG 2), human breast cancer cells (MDA-MB-231) and human glioma cells (U87) by utilizing an ICP-MS method. As a result, it was found that the boron uptake of the series of amino acid-BSH-targeted hybrid compounds in the cells under investigation was greater than 10 9 B/cell, and was in the range of 10 11 B/cell, and T/N >3, and that the amino acid-BSH-targeted hybrids with the corresponding structures exhibited superior boron uptake characteristics than BSH for different tumor cells as compared with BSH.
The invention utilizes a shake flask method and an HPLC technology to detect the lipophilic and hydrophilic coefficients of the series of amino acid-BSH targeted hybrid compounds. As a result, it was found that all amino acid-BSH targeted hybrid compounds exhibit a lipophilic hydrophilic character that is superior to BSH, which optimizes the disadvantage of BSH being too hydrophilic.
Compared with the prior art, the invention has the following beneficial effects:
(1) The invention relates to a compound shown in a general formula (I) and a synthesis method thereof, which are reported for the first time. The synthesis method has the characteristics of mild reaction conditions, simple experimental steps, high yield, high product purity, economy, practicability and the like;
(2) The amino acid-BSH targeted hybrid compound has the characteristic of targeting LAT 1. They have a higher T/N ratio and boron loading in tumor cells compared to BSH;
(3) Compared with BSH, the amino acid-BSH targeted hybrid compound has more excellent oleophilic and hydrophilic characteristics.
Detailed Description
The present invention is further illustrated by the following examples, which are not intended to limit the invention in any way.
EXAMPLE 1 preparation of amino acid ester-bridged boron card (AA-O-BSH)
1.1. Preparation of valine ester-bridged boron card (Val-O-BSH)
Synthesized in 5 steps.
1.1.1.2 Preparation of- (2- (2-hydroxyethoxy) ethoxy) ethyl-p-methylbenzenesulfonate 1.5g (10.0 mmol) of triethylene glycol are weighed into a 100ml round bottom flask, the magnet is placed in, and 5ml of redistilled dichloromethane are added under stirring. After the reaction flask was stirred under ice bath for 5 minutes, 1.2g (11.8 mmol) of Triethylamine (TEA) was added, followed by three additions of 2.25g (11.8 mmol) of p-toluenesulfonyl chloride (TsCl) over a period of 6 minutes. After stirring at room temperature for 30 minutes, the reaction system was warmed to room temperature and reacted for 12 hours. TLC detects complete reaction conversion (developing reagent: PE/ea=3/1, r f =0.3). 50ml of methylene chloride was added to the reaction system to dilute it, followed by washing with purified water (3X 60 ml), 1mol/L aqueous HCl (3X 60 ml), drying the organic phase over anhydrous sodium sulfate, filtering, concentrating the solution under reduced pressure (0.1 MPa) at 60℃to give 2.41g of a colorless transparent liquid, yield 79.1％.1H NMR(400MHz,CDCl3)δ7.75(d,J＝6.6Hz,2H),7.31(d,J＝7.2Hz,2H),4.14(m,2H),3.66(m,4H),3.55(m,4H),3.52(m,2H),2.97(s,1H),2.40(s,3H).
Preparation of N-Boc-valine ester-bridged p-toluenesulfonate (N-Boc-Val-O-TrG Ts) 0.65g (3.0 mmol) of N-Boc-L-valine was weighed into a 50ml round bottom flask, dried dichloromethane 20ml was added, the magnetons were placed, and the substrate was dissolved with stirring. The reaction flask was equilibrated under an ice bath for 5 minutes, EDCI (0.69 g,3.6 mmol) and DMAP (0.11 g,0.9 mmol) were sequentially added, and after maintaining the ice bath for 10 minutes, 2- (2- (2-hydroxyethoxy) ethoxy) ethyl p-methylbenzenesulfonate (1.0 g,3.0 mmol) was added, and after the addition, the reaction was continued under the ice bath for 30 minutes, and then transferred to room temperature for 12 hours. TLC detects complete reaction conversion (developing reagent: PE/ea=1/3 to 1/1). Washing the reaction solution with purified water (3×20 ml) and 1mol/L HCl solution (3×20 ml), mixing the organic phases, drying, concentrating to obtain residue, purifying with silica gel column chromatography (200-300 mesh, eluent: PE/EA=3/1 to 1/1), concentrating to obtain target 1.25g, and obtaining yield 82.8％.1H NMR(400MHz,CDCl3)δ7.79(d,J＝8.3Hz,2H),7.34(d,J＝8.1Hz,2H),5.06(d,J＝8.8Hz,1H),4.29(t,J＝4.9Hz,1H),4.25(m,2H),4.18–4.13(m,2H),3.71–3.63(m,4H),3.57(m,4H),2.44(s,3H),2.13(td,J＝12.7,6.4Hz,1H),1.44(s,9H),0.92(m,6H).
Preparation of N-Boc-Val-O-TrG Br, 1.01g (2.0 mmol) of N-Boc-Val-O-TrG Br was weighed into a 50ml round bottom flask, magnetic stirrer and acetonitrile (10 ml) were added, and 0.87g (10.0 mmol) of LiBr was added under stirring. The reaction was then stirred for 6 hours with heating in a 58 ℃ oil bath, followed by TLC until the reaction was complete. The solvent was then distilled off under reduced pressure, 20ml of methylene chloride was added to the residue, which was washed with purified water (3X 20 ml), dried over anhydrous sodium sulfate, filtered, and concentrated to give 766.9mg of a colorless liquid, yield 93.0％.1H NMR(400MHz,CDCl3)δ5.05(d,J＝8.6Hz,1H),4.46(s,1H),4.29(m,2H),3.81(t,J＝6.3Hz,2H),3.72(t,J＝4.9Hz,2H),3.66(s,4H),3.48(t,J＝6.3Hz,2H),2.15(m,1H),1.45(s,9H),0.97(d,J＝6.9Hz,3H),0.90(d,J＝6.9Hz,3H);13C NMR(101MHz,CDCl3)δ:172.26,155.84,79.75,71.20,70.54,70.33,69.10,64.01,58.51,31.37,30.20,28.32,18.97.
Preparation of valine N-Boc-Val-O-TrG BSH 102.8mg (0.25 mmol) of valine N-Boc-Val-O-TrG bridged bromine, 53.5mg (0.29 mmol) of sodium Boc (10 BSH) were weighed into a 100ml round bottom three neck flask, put in a magnet, 15ml of dry acetonitrile was added, and 244.0mg (0.75 mmol) of cesium carbonate and 50.0mg (0.3 mmol) of potassium iodide were added with stirring. The reaction system was heated under reflux for 12 hours in an oil bath, HPLC was performed to detect the conversion of the reaction substrate to half, new product was formed, heating was stopped, the reaction solution was cooled to room temperature, 5g of silica gel was directly added to mix the sample, and flash column chromatography (200-300 mesh, eluent: DCM/MeOH=20/1 to 10/1) was used to separate and purify the product to 75.3mg, yield 57.0%.
1.1.5. Preparation of valine ester-bridged sodium boron calide (Val-O-BSH) 74.3mg (0.14 mmol) of valine ester-bridged sodium boron calide of N-t-butoxycarbonyl was weighed into a 50ml round bottom flask, 10ml of dry dichloromethane was added, stirred and dissolved, the system was placed under ice bath and stirred for 5 minutes, 2.0ml of trifluoroacetic acid (TFA) was added and slowly warmed to room temperature, stirring was continued for 2 hours, and TLC detection was followed until the reaction was complete (developer: DCM/MeOH=1/1). The pH of the reaction system is regulated to be neutral by saturated sodium bicarbonate, the solvent is evaporated by concentration, the residue is separated by column chromatography, 45.0mg of a product is obtained by freeze drying, and the yield 76.1％.1H NMR(400MHz,DMSO-d6)δ8.61(s,1H),4.44-4.31(m,1H),4.24-4.11(m,2H),4.02-3.98(m,2H),3.79-3.69(m,3H),3.69-3.61(m,3H),3.58-3.45(m,4H),3.44-3.34(m,1H),3.25-3.02(m,2H),2.23-2.09(m,1H),1.83-1.02(m,5H),1.01-0.90(m,6H),0.87-0.47(m,1H);13C NMR(101MHz,DMSO-d6)δ174.54,116.12,70.06,69.78,68.46,57.54,51.56,48.85,45.38,29.85,18.52. all data prove that the compound is L-valine (2- (2- (sodium dodecyl sulfhydryl) ethyl) oxyethyl ester (Val-O-BSH) with the following structural formula:
1.2. preparation of leucine ester bridged boron card (Leu-O-BSH)
Synthesized in 5 steps.
1.2.1. The experimental procedure was the same as 1.1.1.
Preparation of N-Boc-Leu-O-TrG Ts with N-t-Butoxycarbonyl leucine ester bridge preparation according to Experimental procedure 1.1.2 substituting 0.65g (3.0 mmol) of N-Boc-L-valine with 0.69g (3.0 mmol) of N-Boc-L-leucine. After separation and purification, colorless liquid 1.31g is obtained, yield 84.4％.1HNMR(400MHz,CDCl3)δ7.80(d,J＝8.2Hz,2H),7.35(d,J＝8.2Hz,2H),4.96(d,J＝8.2Hz,1H),4.33-4.29(m,1H),4.26(dd,J＝9.0,4.4Hz,2H),4.20-4.13(m,2H),3.69(dt,J＝14.7,5.0Hz,4H),3.58(m,4H),2.45(s,3H),1.70(dt,J＝19.4,6.5Hz,1H),1.65-1.54(m,1H),1.54-1.47(m,1H),1.44(s,9H),0.93(d,J＝6.6Hz,6H).
Preparation of N-t-Butoxycarbonyl leucine ester-bridged bromo (N-Boc-Leu-O-TrG Br) 1.01g (2.0 mmol) of valine N-t-Butoxycarbonyl-bridged p-toluenesulfonate was replaced with 1.04g (2.0 mmol) of leucine N-t-Butoxycarbonyl-bridged p-toluenesulfonate, prepared according to experimental procedure 1.1.3. Separating and purifying to obtain colorless liquid 738.4mg, yield 86.6％.1H NMR(400MHz,CDCl3)δ4.95(s,1H),4.26(m,2H),3.79(s,1H),3.74-3.54(m,8H),3.45(m,2H),1.69(m,1H),1.58(m,1H),1.48(m,1H),1.42(s,9H),0.92(d,J＝4.7Hz,6H);13C NMR(101MHz,CDCl3)δ174.28,155.16,79.69,71.19,70.48,68.97,64.08,61.66,51.93,41.75,30.37,28.42,24.71,22.63.
Preparation of N-Boc-Leu-O-TrG BSH 102.8mg (0.25 mmol) of valine N-Boc-ester bridged bromine was replaced with 106.6mg (0.25 mmol) of leucine N-Boc-ester bridged bromine, prepared according to experimental procedure 1.1.4. The colorless viscous liquid obtained by separation and purification was 61mg, and the yield was 51.7%.
1.2.5. Preparation of Leu-O-BSH 74.3mg (0.14 mmol) of valine N-t-butoxycarbonyl ester-bridged sodium boron carboxylate was replaced with 75.9mg (0.14 mmol) of leucine N-t-butoxycarbonyl ester-bridged sodium boron carboxylate prepared according to experimental procedure 1.1.5. The colorless viscous liquid obtained by separation and purification was 35.0mg, and the yield was 56.5%. 1H NMR(400MHz,DMSO-d6)δ8.40(s,2H),4.49-4.11(m,2H),3.96(s,1H),3.75(s,2H),3.65(s,2H),3.59-3.36(m,6H),3.26-3.04(m,2H),1.81-1.68(m,1H),1.66-1.53(m,2H),1.50-0.32(m,15H);13C NMR(101MHz,DMSO-d6)δ170.47,72.80,70.28,68.63,66.52,65.41,60.66,51.06,42.07,24.18,22.72,22.47. All data confirm that this compound is L-leucine (2- (2- (2- (sodium dodecyl mercapto) ethyl) oxyethyl) alkoxide (Leu-O-BSH) with the following structure:
preparation of D-leucine ester bridged boron card (D-Leu-O-BSH)
Synthesized in 5 steps.
1.3.1. The experimental procedure was the same as 1.1.1.
Preparation of N-Boc-D-leucine ester-bridged p-toluenesulfonate (N-Boc-D-Leu-O-TrGTs) 0.65g (3.0 mmol) of N-Boc-L-valine was replaced by 0.69g (3.0 mmol) of N-Boc-D-leucine, prepared according to experimental procedure 1.1.2. After separation and purification, colorless liquid 1.32g is obtained, yield 84.7％.1H NMR(400MHz,CDCl3)δ7.80(d,J＝8.2Hz,2H),7.35(d,J＝8.2Hz,2H),4.96(d,J＝8.2Hz,1H),4.33-4.29(m,1H),4.26(dd,J＝9.0,4.4Hz,2H),4.20-4.13(m,2H),3.69(dt,J＝14.7,5.0Hz,4H),3.58(m,4H),2.45(s,3H),1.70(dt,J＝19.4,6.5Hz,1H),1.65-1.54(m,1H),1.54-1.47(m,1H),1.44(s,9H),0.93(d,J＝6.6Hz,6H).
Preparation of N-t-Butoxycarbonyl D-leucine ester-bridged Bromide (N-Boc-D-Leu-O-TrG Br) 1.01g (2.0 mmol) of N-t-Butoxycarbonyl valine ester-bridged p-toluenesulfonate was replaced with 1.04g (2.0 mmol) of N-t-Butoxycarbonyl D-leucine ester-bridged p-toluenesulfonate, prepared according to experimental procedure 1.1.3. Separating and purifying to obtain colorless liquid 738.6mg, yield 86.7％.1H NMR(400MHz,CDCl3)δ4.95(s,1H),4.26(m,2H),3.79(s,1H),3.74-3.54(m,8H),3.45(m,2H),1.69(m,1H),1.58(m,1H),1.48(m,1H),1.42(s,9H),0.92(d,J＝4.7Hz,6H);13C NMR(101MHz,CDCl3)δ174.28,155.16,79.69,71.19,70.48,68.97,64.08,61.66,51.93,41.75,30.37,28.42,24.71,22.63.
Preparation of N-Boc-D-leucine bridged boron carbaryl sodium (N-Boc-D-Leu-O-TrG BSH) 102.8mg (0.25 mmol) of valine N-Boc-bridged bromine was replaced with 106.6mg (0.25 mmol) of leucine N-Boc-bridged bromine according to experimental procedure 1.1.4. The colorless viscous liquid obtained by separation and purification was 61mg, and the yield was 51.7%.
Preparation of D-leucine ester bridged boron sodium carbonate (Leu-O-BSH) 74.3mg (0.14 mmol) of valine N-t-butoxycarbonyl ester bridged boron sodium carbonate was replaced with 75.9mg (0.14 mmol) of D-leucine ester bridged boron sodium carbonate, prepared according to experimental procedure 1.1.5. The colorless viscous liquid obtained by separation and purification was 35.2mg, and the yield was 56.6%. 1H NMR(400MHz,DMSO-d6)δ8.40(s,2H),4.49-4.11(m,2H),3.96(s,1H),3.75(s,2H),3.65(s,2H),3.59-3.36(m,6H),3.26-3.04(m,2H),1.81-1.68(m,1H),1.66-1.53(m,2H),1.50-0.32(m,15H);13C NMR(101MHz,DMSO-d6)δ170.47,72.80,70.28,68.63,66.52,65.41,60.66,51.06,42.07,24.18,22.72,22.47. All data confirm that this compound is D-leucine (2- (2- (2- (sodium dodecyl mercapto) ethyl) oxyethyl) alkoxide (D-Leu-O-BSH) with the following structure:
1.4. Preparation of isoleucine ester bridged boron card (Ile-O-BSH)
Synthesized in 5 steps.
1.4.1. The experimental procedure was the same as 1.1.1.
Preparation of N-t-Butoxycarbonyl isoleucine ester-bridged p-toluenesulfonate (N-Boc-Ile-O-TrG Ts) 0.65g (3.0 mmol) of N-Boc-L-valine was replaced with 0.69g (3.0 mmol) of N-Boc-L-isoleucine prepared according to experimental procedure 1.1.2. Separating and purifying to obtain colorless liquid 903.0mg, yield 85.1％.1H NMR(400MHz,CDCl3)δ7.79(d,J＝8.1Hz,1H),7.34(d,J＝8.1Hz,1H),5.08(d,J＝8.7Hz,1H),4.28(s,1H),4.24(m,2H),4.17-4.13(m,2H),3.67(m,4H),3.57(m,4H),2.44(s,3H),1.97(m,1H),1.85(m,1H),1.43(s,9H),1.23-1.08(m,1H),0.92(m,3H),0.90(d,J＝7.2Hz 3H).
Preparation of N-t-Butoxycarbonyl isoleucine ester-bridged bromo (N-Boc-Ile-O-TrG Br) 1.01g (2.0 mmol) of valine N-t-Butoxycarbonyl-bridged p-toluenesulfonate was replaced with 1.04g (2.0 mmol) of isoleucine N-t-Butoxycarbonyl-bridged p-toluenesulfonate, prepared according to experimental procedure 1.1.3. Separating and purifying to obtain colorless liquid 723.9mg, yield 84.9％.1H NMR(400MHz,CDCl3)δ5.12(d,J＝6.4Hz,1H),3.99-3.88(m,1H),3.82(t,J＝6.1Hz,2H),3.65(m,4H),3.56(m,2H),3.49(t,J＝6.1Hz,4H),2.14(m,1H),1.87(m,1H),1.44(s,9H),1.21-1.03(m,1H),0.93(d,J＝7.9Hz,3H),0.91(t,J＝8.1Hz,3H);13C NMR(101MHz,CDCl3)δ171.58,155.84,79.80,71.15,70.40,70.21,69.81,59.22,39.15,37.49,30.34,28.33,24.82,15.56,11.58.
Preparation of N-t-Butoxycarbonyl isoleucine ester bridged sodium boron carboxylate (N-Boc-Ile-O-TrG BSH) 102.8mg (0.25 mmol) of N-t-Butoxycarbonyl valine ester bridged bromine was replaced with 106.6mg (0.25 mmol) of N-t-Butoxycarbonyl isoleucine ester bridged bromine, prepared according to experimental procedure 1.1.4. The colorless viscous liquid obtained by separation and purification was 85.4mg, and the yield was 63.0%.
1.4.5. Preparation of isoleucine ester-bridged sodium boron carboxylate (Ile-O-BSH) 74.3mg (0.14 mmol) of valine N-t-butoxycarbonyl ester-bridged sodium boron carboxylate was replaced with 75.9mg (0.14 mmol) of isoleucine N-t-butoxycarbonyl ester-bridged sodium boron carboxylate, prepared according to experimental procedure 1.1.5. The colorless viscous liquid obtained by separation and purification was 50.1mg, and the yield 80.9％.1H NMR(400MHz,D2O)δ:3.95-3.88(m,2H),3.70(S,6H),3.65-3.59(m,2H),3.57-3.51(m,1H),3.39-3.23(m,2H),2.76-2.69(m,1H),1.93-0.82(m,14H);13C NMR(400MHz,D2O)δ:173.68,81.30,79.95,70.76,68.50,68.05,60.84,50.72,34.19,23.35,16.16,11.88. all data confirm that the compound was L-isoleucine (2- (2- (2- (sodium dodecyl mercapto) ethyl) oxyethyl ester (Leu-O-BSH) with the following structure:
1.5. Preparation of methionine ester bridged boron card (Met-O-BSH)
Synthesized in 5 steps.
1.5.1. The experimental procedure was the same as 1.1.1.
Preparation of N-Boc-Met-O-TrG Ts with N-t-Butoxycarbonyl methionine ester bridge preparation of p-toluenesulfonate (N-Boc-Met-O-TrG Ts) 0.65g (3.0 mmol) of N-Boc-L-valine was replaced with 0.75g (3.0 mmol) of N-Boc-L-methionine prepared according to experimental procedure 1.1.2. After separation and purification, colorless liquid 1.32g is obtained, yield 82.3％.1H NMR(400MHz,CDCl3)δ7.80(d,J＝7.8Hz,2H),7.35(d,J＝7.8Hz,2H),5.19(s,1H),4.43(s,1H),4.37-4.22(m,2H),4.20-4.14(m,2H),3.69(dd,J＝9.9,4.8Hz,4H),3.59(s,4H),2.54(t,J＝7.5Hz,2H),2.45(s,3H),2.09(s,3H),2.03-1.74(m,2H),1.45(s,9H).
Preparation of N-t-Butoxycarbonyl methionine ester bridged bromide (N-Boc-Met-O-TrG Br) 1.01g (2.0 mmol) of valine N-t-butoxycarbonyl ester bridged p-toluenesulfonate was replaced with 1.07g (2.0 mmol) of N-t-butoxycarbonyl methionine ester bridged p-toluenesulfonate, prepared according to experimental step 1.1.3. Separating and purifying to obtain colorless liquid 719.9mg, yield 81.0％.1H NMR(400MHz,CDCl3)δ5.18(d,J＝7.0Hz,1H),4.41(s,1H),4.35-4.19(m,2H),3.80(dd,J＝12.2,6.1Hz,2H),3.70(t,J＝4.5Hz,2H),3.68-3.57(m,4H),3.46(t,J＝6.2Hz,2H),2.53(t,J＝7.5Hz,2H),2.18-2.09(m,2H),2.08(s,3H),2.00-1.85(m,1H),1.42(s,9H);13C NMR(101MHz,CDCl3)δ172.17,154.93,79.94,71.18,70.59,68.85,64.31,52.73,30.59,29.83,28.26,15.37.
Preparation of N-Boc-Met-O-TrG BSH 102.8mg (0.25 mmol) of valine N-Boc-ester-bridged bromine was replaced with 111.1mg (0.25 mmol) of N-Boc-methionine ester-bridged bromine, prepared according to experimental procedure 1.1.4. The colorless viscous liquid 91.6mg was obtained by separation and purification, and the yield was 65.4%.
1.5.5. Preparation of methionine ester-bridged sodium boron carboxylate (Met-O-BSH) 74.3mg (0.14 mmol) of valine N-t-butoxycarbonyl ester-bridged sodium boron carboxylate was replaced with 78.4mg (0.14 mmol) of methionine N-t-butoxycarbonyl ester-bridged sodium boron carboxylate, prepared according to experimental procedure 1.1.5. The colorless viscous liquid obtained by separation and purification was 37.1mg, and the yield was 57.6%. 1H NMR(400MHz,DMSO-d6)δ5.18(d,J＝7.0Hz,1H),4.41(s,1H),4.35-4.19(m,2H),3.80(dd,J＝12.2,6.1Hz,2H),3.70(t,J＝4.5Hz,2H),3.68-3.57(m,4H),3.46(t,J＝6.2Hz,2H),2.53(t,J＝7.5Hz,2H),2.18-2.09(m,2H),2.08(s,3H),2.00-1.85(m,1H);13C NMR(151MHz,DMSO-d6)δ171.13,159.19,158.98,158.77,158.57,118.61,116.63,72.71,72.68,72.62,70.13,69.99,60.54,51.55,30.02,29.02,14.72. All data confirm that this compound is L-methionine (2- (2- (2- (sodium dodecyl mercapto) ethyl) oxyethyl ester (Met-O-BSH) with the following structure:
preparation of D-methionine ester bridged boron card (Met-O-BSH)
Synthesized in 5 steps.
1.6.1. The experimental procedure was the same as 1.1.1.
Preparation of N-Boc-D-methionine ester bridged p-toluenesulfonate (N-Boc-D-Met-O-TrG Ts) 0.65g (3.0 mmol) N-Boc-L-valine was replaced with 0.75g (3.0 mmol) N-Boc-D-methionine, prepared according to Experimental procedure 1.1.2. After separation and purification, colorless liquid 1.32g is obtained, yield 82.3％.1H NMR(400MHz,CDCl3)δ7.81(d,J＝7.8Hz,2H),7.34(d,J＝7.9Hz,2H),5.18(s,1H),4.42(s,1H),4.36-4.21(m,2H),4.19-4.13(m,2H),3.68(dd,J＝9.8,4.7Hz,4H),3.58(s,4H),2.55(t,J＝7.6Hz,2H),2.46(s,3H),2.11(s,3H),2.04-1.75(m,2H),1.45(s,9H).
Preparation of N-t-Butoxycarbonyl D-methionine ester bridged bromide (N-Boc-D-Met-O-TrG Br) 1.01g (2.0 mmol) of valine N-t-Butoxycarbonyl bridged p-toluenesulfonate was replaced with 1.07g (2.0 mmol) of D-methionine ester bridged p-toluenesulfonate, prepared as per experimental step 1.1.3. Separating and purifying to obtain colorless liquid 719.7mg, yield 80.9％.1H NMR(400MHz,CDCl3)δ5.19(d,J＝7.0Hz,1H),4.42(s,1H),4.34-4.18(m,2H),3.81(dd,J＝12.3,6.2Hz,2H),3.71(t,J＝4.5Hz,2H),3.67-3.56(m,4H),3.47(t,J＝6.3Hz,2H),2.54(t,J＝7.4Hz,2H),2.19-2.10(m,2H),2.09(s,3H),2.01-1.86(m,1H),1.43(s,9H);13CNMR(101MHz,CDCl3)δ172.18,154.94,79.93,71.17,70.58,68.86,64.32,52.72,30.58,29.84,28.27,15.36.
Preparation of N-Boc-D-methionine ester bridged boron sodium (N-Boc-D-Met-O-TrG BSH) 102.8mg (0.25 mmol) of valine N-Boc-ester bridged bromine was replaced with 111.1mg (0.25 mmol) of D-methionine ester bridged bromine, prepared according to experimental procedure 1.1.4. The colorless viscous liquid 91.8mg was obtained by separation and purification, and the yield was 65.5%.
1.6.5. Preparation of methionine ester-bridged sodium boron calorie (D-Met-O-BSH) 74.3mg (0.14 mmol) of valine N-t-butoxycarbonyl ester-bridged sodium boron calorie was replaced with 78.4mg (0.14 mmol) of D-methionine ester-bridged sodium boron calorie, prepared according to experimental procedure 1.1.5. The colorless viscous liquid obtained by separation and purification was 36.8mg, and the yield was 57.5%. 1H NMR(400MHz,DMSO-d6)δ5.17(d,J＝7.1Hz,1H),4.42(s,1H),4.34-4.18(m,2H),3.81(dd,J＝12.3,6.2Hz,2H),3.71(t,J＝4.6Hz,2H),3.67-3.56(m,4H),3.47(t,J＝6.1Hz,2H),2.54(t,J＝7.6Hz,2H),2.17-2.08(m,2H),2.09(s,3H),2.01-1.86(m,1H);13CNMR(151MHz,DMSO-d6)δ171.12,159.18,158.97,158.78,158.56,118.62,116.64,72.72,72.67,72.63,70.14,69.98,60.53,51.54,30.03,29.01,14.73. All data confirm that this compound is D-methionine (2- (2- (2- (sodium dodecyl mercapto) ethyl) oxyethyl) alkoxide (D-Met-O-BSH) with the following structure:
1.7. Preparation of phenylalanine ester-bridged boron-calipers (Phe-O-BSH)
Synthesized in 5 steps.
1.7.1. The experimental procedure was the same as 1.1.1.
Preparation of N-Boc-phenylalanine ester-bridged p-toluenesulfonate (N-Boc-Phe-O-TrG Ts) 0.65g (3.0 mmol) of N-Boc-L-valine was replaced with 0.80g (3.0 mmol) of N-Boc-phenylalanine according to experimental procedure 1.1.2. After separation and purification, colorless liquid 1.35g is obtained, yield 81.6％.1H NMR(400MHz,CDCl3)δ7.78(d,J＝8.2Hz,2H),7.33(d,J＝8.2Hz,2H),7.30-7.19(m,3H),7.15(d,J＝6.9Hz,2H),5.05(d,J＝8.2Hz,1H),4.59(m,1H),4.24(m,2H),4.17-4.11(m,2H),3.69-3.65(m,2H),3.63(m,2H),3.56(m,4H),3.08(m,2H),2.43(s,3H),1.41(s,9H).
Preparation of N-t-Butoxycarbonyl phenylalanine ester-bridged bromo (N-Boc-Phe-O-TrG Br) 1.01g (2.0 mmol) of valine N-t-butoxycarbonyl ester-bridged p-toluenesulfonate was replaced with 1.10g (2.0 mmol) of phenylalanine N-t-butoxycarbonyl ester-bridged p-toluenesulfonate, prepared according to experimental procedure 1.1.3. Separating and purifying to obtain colorless liquid 778.7mg, yield 84.8％.1H NMR(400MHz,CDCl3)δ5.19(d,J＝7.0Hz,1H),4.42(s,1H),4.34-4.18(m,2H),3.81(dd,J＝12.3,6.2Hz,2H),3.71(t,J＝4.5Hz,2H),3.67-3.56(m,4H),3.47(t,J＝6.3Hz,2H),2.54(t,J＝7.4Hz,2H),2.19-2.10(m,2H),2.09(s,3H),2.01-1.86(m,1H),1.43(s,9H);13C NMR(101MHz,CDCl3)δ172.18,154.94,79.93,71.17,70.58,68.86,64.32,52.72,30.58,29.84,28.27,15.36.
Preparation of N-t-Butoxycarbonyl phenylalanine ester bridged boron sodium (N-Boc-Phe-O-TrG BSH) 102.8mg (0.25 mmol) of N-t-butoxycarbonyl valine ester bridged bromine was replaced with 114.8mg (0.25 mmol) of N-t-butoxycarbonyl phenylalanine ester bridged bromine, prepared according to experimental step 1.1.4. The colorless viscous liquid obtained by separation and purification was 70.6mg, and the yield was 48.8%.
1.7.5. Preparation of phenylalanine ester-bridged sodium boron carboxylate (Phe-O-BSH) 74.3mg (0.14 mmol) of valine ester-bridged sodium boron carboxylate was replaced with 81.0mg (0.14 mmol) of phenylalanine ester-bridged sodium boron carboxylate, prepared according to experimental procedure 1.1.5. The colorless viscous liquid obtained by separation and purification was 53.6mg, and the yield was 80.1%. 1H NMR(400MHz,DMSO-d6)δ8.54(s,1H),7.31-7.23(m,5H),4.31(s,1H),4.19(s,2H),3.86-3.46(m,10H),3.26-3.02(m,4H),2.00-0.65(m,10H);13C NMR(101MHz,DMSO-d6)δ170.48,159.08,158.74,121.24,118.31,115.38,112.45,87.50,81.23,77.64,68.60,66.70,52.94,47.79,42.19,29.36. All data confirm that this compound is phenylalanine (2- (2- (2- (sodium dodecyl mercapto) ethyl) oxyethyl ester (Phe-O-BSH) with the following structure:
Preparation of D-phenylalanine ester-bridged boron card (D-Phe-O-BSH)
Synthesized in 5 steps.
1.8.1. The experimental procedure was the same as 1.1.1.
Preparation of N-Boc-D-phenylalanine ester-bridged p-toluenesulfonate (N-Boc-D-Phe-O-TrG Ts) 0.65g (3.0 mmol) of N-Boc-L-valine was replaced with 0.80g (3.0 mmol) of N-Boc-D-phenylalanine, prepared according to experimental procedure 1.1.2. After separation and purification, colorless liquid 1.37g is obtained, yield 81.7％.1H NMR(400MHz,CDCl3)δ7.79(d,J＝8.3Hz,2H),7.34(d,J＝8.2Hz,2H),7.31-7.18(m,3H),7.16(d,J＝6.8Hz,2H),5.06(d,J＝8.3Hz,1H),4.58(m,1H),4.25(m,2H),4.18-4.12(m,2H),3.68-3.64(m,2H),3.62(m,2H),3.57(m,4H),3.07(m,2H),2.42(s,3H),1.42(s,9H).
Preparation of N-t-Butoxycarbonyl D-phenylalanine ester-bridged bromo (N-Boc-D-Phe-O-TrG Br) 1.01g (2.0 mmol) of N-t-Butoxycarbonyl valine ester-bridged p-toluenesulfonate was replaced with 1.10g (2.0 mmol) of N-t-Butoxycarbonyl D-phenylalanine ester-bridged p-toluenesulfonate, prepared according to experimental procedure 1.1.3. Separating and purifying to obtain colorless liquid 778.5mg, yield 84.7％.1H NMR(400MHz,CDCl3)δ5.18(d,J＝7.1Hz,1H),4.43(s,1H),4.35-4.19(m,2H),3.82(dd,J＝12.4,6.3Hz,2H),3.72(t,J＝4.5Hz,2H),3.68-3.57(m,4H),3.46(t,J＝6.2Hz,2H),2.53(t,J＝7.3Hz,2H),2.18-2.11(m,2H),2.08(s,3H),2.02-1.87(m,1H),1.42(s,9H);13CNMR(101MHz,CDCl3)δ172.19,154.95,79.92,71.16,70.57,68.85,64.33,52.71,30.57,29.85,28.26,15.37.
Preparation of N-Boc-D-phenylalanine ester-bridged boron sodium carbonate (N-Boc-D-Phe-O-TrG BSH) 102.8mg (0.25 mmol) of valine N-Boc-ester-bridged bromine was replaced with 114.8mg (0.25 mmol) of D-phenylalanine ester-bridged bromine N-Boc-D-Phe-Boc, prepared according to experimental procedure 1.1.4. The colorless viscous liquid obtained by separation and purification was 70.8mg, and the yield was 48.9%.
Preparation of D-phenylalanine ester-bridged boron sodium carbonate (D-Phe-O-BSH) 74.3mg (0.14 mmol) of valine N-t-butoxycarbonyl ester-bridged boron sodium carbonate was replaced with 81.0mg (0.14 mmol) of D-phenylalanine ester-bridged boron sodium carbonate, prepared according to experimental procedure 1.1.5. The colorless viscous liquid obtained by separation and purification was 53.8mg, and the yield was 80.2%. 1H NMR(400MHz,DMSO-d6)δ8.55(s,1H),7.32-7.24(m,5H),4.32(s,1H),4.18(s,2H),3.87-3.45(m,10H),3.27-3.03(m,4H),2.02-0.67(m,10H);13C NMR(101MHz,DMSO-d6)δ170.47,159.06,158.75,121.23,118.32,115.39,112.46,87.51,81.24,77.65,68.62,66.71,52.93,47.78,42.17,29.54. All data confirm that this compound is D-phenylalanine (2- (2- (2- (sodium dodecyl mercapto) ethyl) oxyethyl ester (D-Phe-O-BSH) with the following structure:
1.9. Preparation of tryptophan ester bridged boron card (Trp-O-BSH)
Synthesized in 5 steps.
1.9.1. The experimental procedure was the same as 1.1.1.
Preparation of N-Boc-Trp-O-TrG T-Butoxycarbonyl tryptophan ester bridge preparation of p-toluenesulfonate (N-Boc-Trp-O-TrG Ts) 0.65g (3.0 mmol) of N-Boc-L-valine was replaced with 0.91g (3.0 mmol) of N-Boc-tryptophan prepared in accordance with experimental procedure 1.1.2. After separation and purification, colorless liquid 1.24g is obtained, yield 70.3％.1HNMR(400MHz,CDCl3)δ8.68(s,1H),7.76(d,J＝8.1Hz,2H),7.57(d,J＝7.8Hz,1H),7.35(t,J＝7.4Hz,1H),7.29(d,J＝9.5Hz,2H),7.16(t,J＝7.4Hz,1H),7.10(d,J＝7.7Hz,2H),5.19(d,J＝8.0Hz,1H),4.67(d,J＝7.4Hz,1H),4.17-4.12(m,2H),3.69-3.64(m,2H),3.64-3.53(m,6H),3.53-3.47(m,2H),3.30(d,J＝4.9Hz,2H),2.42(s,3H),1.45(s,9H).
Preparation of N-t-Butoxycarbonyl tryptophan ester bridged Bromide (N-Boc-Trp-O-TrG Br) 1.01g (2.0 mmol) of valine N-t-Butoxycarbonyl bridged p-toluenesulfonate was replaced with 1.18g (2.0 mmol) of tryptophan N-t-Butoxycarbonyl bridged p-toluenesulfonate, prepared according to experimental procedure 1.1.3. Separating and purifying to obtain colorless liquid 796.0mg, yield 79.9％.1H NMR(400MHz,CDCl3)δ8.51(s,1H),7.59(d,J＝7.9Hz,1H),7.36(d,J＝8.0Hz,1H),7.19(t,J＝7.5Hz,1H),7.13(d,J＝7.7Hz,1H),7.08(s,1H),5.17(d,J＝7.9Hz,1H),4.69(d,J＝7.1Hz,1H),4.25(m,2H),3.80(t,J＝6.0Hz,2H),3.78-3.53(m,6H),3.46(t,J＝6.1Hz,2H),3.32(d,J＝5.0Hz,2H),1.45(s,9H);13C NMR(101MHz,CDCl3)δ172.26,155.48,136.25,127.88,123.35,121.99,119.51,118.74,111.34,109.70,79.91,71.18,70.49,70.45,68.90,64.56,54.62,30.61,28.38.
Preparation of N-Boc-Trp-O-TrG BSH 102.8mg (0.25 mmol) of valine N-Boc-Trp-O-TrG bridge-bridged bromine was replaced with 124.5mg (0.25 mmol) of tryptophan N-Boc-bridged bromine as per experimental procedure 1.1.4. The colorless viscous liquid obtained by separation and purification was 75.3mg, and the yield was 48.8%.
1.9.5. Preparation of Trp-O-BSH A preparation was performed according to experimental procedure 1.1.5 substituting 74.3mg (0.14 mmol) of valine N-t-butoxycarbonyl ester bridged boron sodium carbonate with 86.4mg (0.14 mmol) of N-t-butoxycarbonyl tryptophan ester bridged boron sodium carbonate. 58.4mg of colorless viscous liquid is obtained after separation and purification, and all data of yield 80.6％.1H NMR(400MHz,D2O)δ:7.68-7.58(dd,1H),7.52(d,1H,J＝8),7.30-7.23(m,2H),7.18-7.14(m,1H),4.46-4.43(m,1H),4.36-4.31(m,1H),4.24-4.21(m,1H),3.90-3.84(m,1H),3.77-3.73(m,2H),3.70-3.68(m,3H),3.62-3.58(m,2H),3.52-3.44(m,2H),3.42-3.28(m,2H),2.07-0.85(m,3H);13CNMR(400MHz,D2O)δ:170.86,141.92,131.87,125.34,119.58,114.53,114.09,107.04,99.76,94.81,84.38,70.99,67.00,65.87,52.62,44.79,26.95. prove that the compound is tryptophan (2- (2- (2- (sodium dodecyl sulfhydryl) ethyl) oxyethyl) alcohol ester (Trp-O-BSH), and the structure is as follows:
1.10. Preparation of tyrosine ester bridged boron card (Tyr-O-BSH)
Synthesized in 5 steps.
1.10.1. The experimental procedure was the same as 1.1.1.
Preparation of N-Boc-Tyr-O-TrG Ts with N-t-Butoxycarbonyl tyrosine ester bridge preparation according to Experimental procedure 1.1.2 substituting 0.65g (3.0 mmol) of N-Boc-L-valine with 0.84g (3.0 mmol) of N-Boc-tyrosine. After separation and purification, colorless liquid 1.41g is obtained, yield 82.6％.1HNMR(400MHz,CDCl3)δ7.80(d,J＝7.7Hz,2H),7.35(d,J＝7.7Hz,2H),7.01(d,J＝7.6Hz,2H),6.76(d,J＝7.5Hz,2H),5.08(d,J＝7.9Hz,1H),4.55(d,J＝6.3Hz,1H),4.29(m,2H),4.19(m,2H),3.63(m,8H),3.03(s,2H),2.45(s,3H),1.44(s,9H).
Preparation of N-t-Butoxycarbonyl tyrosine ester-bridged Bromide (N-Boc-Tyr-O-TrG Br) 1.01g (2.0 mmol) of valine N-t-Butoxycarbonyl-bridged p-toluenesulfonate was replaced with 1.13g (2.0 mmol) of tyrosine N-t-Butoxycarbonyl-bridged p-toluenesulfonate, prepared according to experimental procedure 1.1.3. Separating and purifying to obtain colorless liquid 790.6mg, yield 83.2％.1H NMR(400MHz,CDCl3)δ7.01(d,J＝7.7Hz,2H),6.75(d,J＝7.6Hz,2H),5.06(d,J＝7.7Hz,1H),4.73(m,2H),4.57(d,J＝6.3Hz,1H),4.29(m,2H),3.82(t,J＝6.1Hz,2H),3.77-3.62(m,4H),3.48(t,J＝6.1Hz,2H),3.03(s,2H),1.44(s,9H);13C NMR(101MHz,CDCl3)δ172.07,155.23,155.04,130.60,130.22,115.68,80.08,74.78,71.41,70.60,68.95,64.29,54.65,37.64,30.35,28.23.
Preparation of N-t-Butoxycarbonyl tyrosine ester bridged sodium boron calide (N-Boc-Tyr-O-TrG BSH) 102.8mg (0.25 mmol) of valine N-t-butoxycarbonyl ester bridged bromine was replaced with 118.8mg (0.25 mmol) of tyrosine N-t-butoxycarbonyl ester bridged bromine, prepared according to experimental procedure 1.1.4. The colorless viscous liquid obtained by separation and purification was 69.1mg, and the yield was 46.5%.
1.10.5. Preparation of tyrosine ester-bridged sodium boron carboxylate (Tyr-O-BSH) 74.3mg (0.14 mmol) of valine N-t-butoxycarbonyl ester-bridged sodium boron carboxylate was replaced with 83.2mg (0.14 mmol) of tyrosine N-t-butoxycarbonyl ester-bridged sodium boron carboxylate, prepared according to experimental procedure 1.1.5. The colorless viscous liquid 60.9mg is obtained after separation and purification, and all data of the yield 88.0％.1H NMR(400MHz,DMSO-d6)δ7.01(d,J＝7.7Hz,2H),6.75(d,J＝7.6Hz,2H),3.97-3.68(m,6H),3.49-3.43(m,4H),3.26-3.17(m,3H),2.83-2.32(m,4H),2.25-0.10(m,11H);13C NMR(400MHz,DMSO-d6)δ172.87,158.65,132.50,128.42,118.72,108.71,105.40,76.59,72.74,71.20,68.76,66.75,54.19,51.32,43.42,29.24. prove that the compound is tyrosine (2- (2- (2- (sodium dodecyl sulfhydryl) ethyl) oxyethyl ester (Tyr-O-BSH) with the following structure:
1.11. preparation of dihydroxyphenylalanine ester-bridged boron card (Dpa-O-BSH)
Synthesized in 5 steps.
1.11.1. The experimental procedure was the same as 1.1.1.
Preparation of N-Boc-Dpa-O-TrG Ts with N-t-Butoxycarbonyl-dihydroxyphenylalanine ester bridge para-toluenesulfonate 0.65g (3.0 mmol) N-Boc-L-valine was replaced with 0.89g (3.0 mmol) N-Boc-dihydroxyphenylalanine prepared according to experimental procedure 1.1.2. 1.47g of colorless liquid is obtained after separation and purification, and the yield is 84.2％.1H NMR(400MHz,CDCl3)δ7.79(d,J＝7.6Hz,2H),7.36(d,J＝7.5Hz,2H),6.87(d,J＝7.5Hz,1H),6.76(s,1H),6.72(d,J＝7.5Hz,1H),5.08(d,J＝7.9Hz,1H),4.54(d,J＝6.2Hz,1H),4.28(m,2H),4.17(m,2H),3.62(m,8H),3.04(s,2H),2.43(s,3H),1.45(s,9H).
Preparation of N-t-Butoxycarbonyl-dihydroxyphenylalanine ester-bridged Bromide (N-Boc-Dpa-O-TrG Br) 1.01g (2.0 mmol) of N-t-Butoxycarbonyl valine ester-bridged p-toluenesulfonate was replaced with 1.17g (2.0 mmol) of N-t-Butoxycarbonyl-dihydroxyphenylalanine ester-bridged p-toluenesulfonate, prepared according to experimental procedure 1.1.3. Separating and purifying to obtain colorless liquid 835.9mg, yield 85.1％.1H NMR(400MHz,CDCl3)δ6.92(d,J＝7.6Hz,1H),6.75(s,1H),6.73(d,J＝7.6Hz,1H),5.07(d,J＝7.5Hz,1H),4.74(m,2H),4.56(d,J＝6.4Hz,1H),4.28(m,2H),3.83(t,J＝6.2Hz,2H),3.76-3.61(m,4H),3.47(t,J＝6.1Hz,2H),3.02(s,2H),1.45(s,9H);13C NMR(101MHz,CDCl3)δ172.08,155.24,155.05,130.61,130.21,115.69,80.07,74.79,71.42,70.61,68.96,64.28,54.64,37.65,30.34,28.25.
Preparation of N-Boc-Dpa-O-TrG BSH sodium Boc-Dpa-O-TrG BSH 102.8mg (0.25 mmol) of valine Boc-ester-bridged bromine was replaced with 118.8mg (0.25 mmol) of dihydroxyphenylalanine Boc-N-Boc-ester-bridged bromine, prepared according to experimental procedure 1.1.4. The colorless viscous liquid obtained by separation and purification was 72.6mg, and the yield was 47.6%.
1.11.5. Preparation of dihydroxyphenylalanine ester-bridged boron sodium carbonate (Tyr-O-BSH) 74.3mg (0.14 mmol) of N-t-butoxycarbonyl valine ester-bridged boron sodium carbonate was replaced with 85.4mg (0.14 mmol) of N-t-butoxycarbonyl dihydroxyphenylalanine ester-bridged boron sodium carbonate, prepared according to experimental procedure 1.1.5. The colorless viscous liquid was obtained by separation and purification, 63.4mg, and the yield 88.7％.1H NMR(400MHz,DMSO-d6)δ6.92(d,J＝7.6Hz,1H),6.75(s,1H),6.73(d,J＝7.6Hz,1H),3.97-3.68(m,6H),3.49-3.43(m,4H),3.26-3.17(m,3H),2.83-2.32(m,4H),2.25-0.10(m,11H);13C NMR(400MHz,DMSO-d6)δ172.87,158.65,132.50,128.42,118.72,108.71,105.40,76.59,72.74,71.20,68.76,66.75,54.19,51.32,43.42,29.32. all data confirm that the compound was dihydroxyphenylalanine (2- (2- (2- (sodium dodecyl mercapto) ethyl) oxyethyl) alkoxide (Dpa-O-BSH) having the following structure:
1.12. Preparation of histidine ester bridged boron card (His-O-BSH)
Synthesized in 5 steps.
1.12.1. The experimental procedure was the same as 1.1.1.
Preparation of N-t-Butoxycarbonyl histidine ester-bridged p-toluenesulfonate (N-Boc-His-O-TrG Ts) 0.65g (3.0 mmol) of N-Boc-L-valine was replaced with 0.77g (3.0 mmol) of N-Boc-histidine, prepared as in experimental step 1.1.2. After separation and purification, colorless liquid 1.35g is obtained, yield 83.2％.1HNMR(400MHz,CDCl3)δ8.76(s,1H),7.76(d,J＝7.5Hz,2H),7.65(s,1H),7.46(d,J＝7.4Hz,2H),7.41(m,1H),6.73(d,J＝7.5Hz,1H),5.06(d,J＝7.7Hz,1H),4.53(d,J＝6.1Hz,1H),4.26(m,2H),4.15(m,2H),3.63(m,8H),3.05(s,2H),2.45(s,3H),1.46(s,9H).
Preparation of N-t-Butoxycarbonyl histidine ester-bridged Bromide (N-Boc-His-O-TrG Br) 1.01g (2.0 mmol) of valine N-t-Butoxycarbonyl-bridged p-toluenesulfonate was replaced with 1.08g (2.0 mmol) of N-t-Butoxycarbonyl histidine ester-bridged p-toluenesulfonate, prepared as in experimental step 1.1.3. Separating and purifying to obtain colorless liquid 757.2mg, yield 84.3％.1H NMR(400MHz,CDCl3)δ8.76(s,1H),7.65(s,1H),5.03(d,J＝7.3Hz,1H),4.71(m,2H),4.57(d,J＝6.2Hz,1H),4.25(m,2H),3.85(t,J＝6.1Hz,2H),3.77-3.62(m,4H),3.49(t,J＝5.9Hz,2H),3.01(s,2H),1.46(s,9H);13C NMR(101MHz,CDCl3)δ171.53,155.27,136.34,124.82,118.12,80.05,74.76,71.43,70.61,68.95,64.26,54.65,37.64,30.35,28.26.
Preparation of N-t-Butoxycarbonyl histidine ester-bridged sodium boron-calide (N-Boc-His-O-TrG BSH) 102.8mg (0.25 mmol) of valine N-t-butoxycarbonyl ester-bridged bromine was replaced with 112.3mg (0.25 mmol) of histidine ester-bridged bromine, prepared as per experimental step 1.1.4. The colorless viscous liquid was obtained by separation and purification, and the yield was 51.3%.
1.12.5. Preparation of histidine ester-bridged sodium boron carboxylate (Tyr-O-BSH) 74.3mg (0.14 mmol) of valine N-t-butoxycarbonyl ester-bridged sodium boron carboxylate was replaced with 79.6mg (0.14 mmol) of histidine ester-bridged sodium boron carboxylate, prepared according to experimental procedure 1.1.5. 58.5mg of colorless viscous liquid is obtained after separation and purification, and all data of yield 89.2％.1H NMR(400MHz,DMSO-d6)δ8.77(s,1H),7.68(s,1H),3.98-3.67(m,6H),3.51-3.45(m,4H),3.27-3.18(m,3H),2.84-2.33(m,4H),2.26-0.11(m,11H);13C NMR(400MHz,DMSO-d6)δ172.83,132.50,136.42,135.72,118.12,76.54,72.73,71.21,68.75,66.74,54.18,51.31,43.41,29.34. prove that the compound is histidine (2- (2- (2- (sodium dodecyl sulfhydryl) ethyl) oxyethyl alcohol ester (His-O-BSH) and has the following structure:
EXAMPLE 2 preparation of amino-amide-bridged boron card (AA-N-BSH)
2.1. Preparation of valinamide bridged boron card (Val-N-BSH)
Synthesized in 5 steps.
Preparation of N-t-Butoxycarbonyl valinamide bridged alcohol (N-Boc-Val-N-TrG OH) 0.65g (3.0 mmol) of N-Boc-L-valine was weighed into a 50ml round bottom flask, dried dichloromethane 20ml was added, the magneton was placed, and the substrate was dissolved with stirring. The reaction flask was equilibrated under an ice bath for 5 minutes, EDCI (0.69 g,3.6 mmol) and DMAP (0.11 g,0.9 mmol) were sequentially added, and after maintaining the ice bath for 10 minutes, 2- [2- (2-aminoethoxy) ethoxy ] ethanol (0.54 g,3.6 mmol) was added, stirring under an ice bath was continued for 5 minutes and then transferred to room temperature for reaction for 12 hours. TLC detection, complete conversion (developing reagent: PE/EA=1/1). The reaction solution was washed with purified water (3X 20 ml), 1mol/L HCl (3X 20 ml), saturated NaHCO 3 (3X 20 ml), the organic phases were combined, dried, concentrated to give a residue, which was purified by silica gel column chromatography (200-300 mesh, eluent: PE/EA=1/1 to 0/1), concentrated to give the objective 845.1mg, yield 80.9％.1H NMR(400MHz,DMSO)δ7.87(s,1H),6.57(s,1H),4.59(s,1H),3.81-3.70(m,1H),3.50(m,2H),3.35(m,10H),1.88(m,1H),1.38(s,9H),0.82(d,J＝6.8Hz,6H).
Preparation of N-t-Butoxycarbonyl valinamide bridged para-toluenesulfonate (N-Boc-Val-N-TrG Ts) 0.70g (2.0 mmol) of N-t-Butoxycarbonyl valinamide bridged alcohol was weighed out and dissolved in 20ml of dry dichloromethane, and after stirring for 5 min under ice bath conditions, 0.55ml (4.0 mmol) of triethylamine followed by 417.9mg (2.0 mmol) of TsCl was slowly added and after maintaining the ice bath reaction for 30 min, the reaction was warmed to room temperature for 12 h. TLC detection of complete reaction conversion (developing reagent: PE/EA=1/1), washing with purified water (20 ml. Times.3), 1M HCl ((3X 20 ml), drying, filtering, concentrating, and purifying with silica gel column chromatography (200-300 mesh, eluent: PE/EA=1/1) to obtain colorless oily matter 927.1mg, yield 92.3％.1H NMR(400MHz,CDCl3)δ7.79(d,J＝8.2Hz,2H),7.33(d,J＝8.1Hz,2H),6.54(s,1H),5.21(d,J＝7.8Hz,1H),4.19-4.12(m,2H),3.90(s,1H),3.72-3.64(m,2H),3.60-3.52(m,4H),3.51(t,J＝5.4Hz,2H),3.43(m,2H),2.43(s,3H),2.09(m,1H),1.41(s,9H),0.92(d,J＝6.7Hz,3H),0.88(d,J＝6.8Hz,3H).
Preparation of N-t-Butoxycarbonyl valinamide bridged bromo (N-Boc-Val-N-TrG Br) 1.01g (2.0 mmol) of valine N-t-Butoxycarbonyl bridged p-toluenesulfonate was replaced with 1.00g (2.0 mmol) of valinamide N-t-Butoxycarbonyl bridged p-toluenesulfonate, prepared according to experimental procedure 1.1.3. Separating and purifying to obtain colorless liquid 755.5mg, yield 92.1％.1H NMR(400MHz,CDCl3)δ7.86(m,1H),6.51(m,1H),4.91(s,1H),4.11(s,1H),3.84(t,J＝6.1Hz,2H),3.67(m,4H),3.58(t,J＝4.9Hz,2H),3.54–3.48(m,4H),1.69(m,1H),1.46(s,9H),0.96(d,J＝5.5Hz,5H);13C NMR(101MHz,CDCl3)δ172.62,155.46,79.97,71.18,70.43,70.25,69.83,67.49,41.71,39.18,30.29,28.33,24.77.
Preparation of N-t-Butoxycarbonyl valinamide bridged boron sodium card (N-Boc-Val-N-TrG BSH) 102.8mg (0.25 mmol) of N-t-Butoxycarbonyl valinate bridged bromine was replaced with 102.5mg (0.25 mmol) of N-t-Butoxycarbonyl valinamide bridged bromine, prepared according to experimental procedure 1.1.4. The mixture was separated and purified to obtain 78.9mg of a colorless oil, and the yield was 59.6%.
2.1.5. Preparation of valinamide bridged boron sodium carbonate (Val-N-BSH) 74.3mg (0.14 mmol) of valine ester of N-t-butoxycarbonyl bridged boron sodium carbonate was replaced with 74.1mg (0.14 mmol) of valinamide bridged boron sodium carbonate, prepared according to experimental procedure 1.1.5. The colorless viscous liquid obtained by separation and purification is 54.8mg, and the yield 91.2％.1H NMR(400MHz,DMSO-d6)δ8.41(s,2H),7.95(s,1H),3.76(s,2H),3.54(s,4H),3.51(s,1H),3.16(s,2H),2.89(s,2H),2.73(s,2H),1.90(s,1H),1.23(br,11H),0.92–0.85(m,6H);13C NMR(101MHz,DMSO-d6)δ172.57,158.80,158.60,158.39,158.19,120.72,118.73,116.74,114.75,70.10,69.86,69.23,66.53,51.50,24.12,22.94,21.59. all data confirm that the compound is N- (2- (2- (2-sodium dodecyl sulfhydryl) ethoxy) ethyl L-valinamide (Val-N-BSH) with the following structure:
2.2. Preparation of leucinamide bridged boron card (Leu-N-BSH)
Synthesized in 5 steps.
Preparation of N-Boc-Leu-amide bridged alcohol (N-Boc-Leu-N-TrG OH) 0.65g (3.0 mmol) of N-Boc-L-valine was replaced with 0.69g (3.0 mmol) of N-Boc-L-leucine according to experimental procedure 2.1.1. Separating, purifying, concentrating to obtain target 1.02g, and obtaining yield 93.8％.1H NMR(400MHz,CDCl3)δ7.09(s,1H),5.28(s,1H),4.11(s,1H),3.73(m,2H),3.65-3.57(m,6H),3.54(t,J＝4.8Hz,2H),3.44(d,J＝5.1Hz,1H),3.36(m,2H),1.61(m,2H),1.46(m,1H),1.40(s,9H),0.90(d,J＝2.7Hz,6H).
Preparation of N-t-Butoxycarbonyl leunamide bridged para-toluenesulfonate (N-Boc-Leu-N-TrG Ts) 0.70g (2.0 mmol) of N-t-Butoxycarbonyl valinamide bridged alcohol was replaced with 0.72g (2.0 mmol) of N-t-Butoxycarbonyl leunamide bridged alcohol, prepared according to experimental procedure 2.1.2. Separating and purifying to obtain 931.3mg of colorless oily matter with yield 90.2％.1H NMR(400MHz,CDCl3)δ7.78(d,J＝7.8Hz,2H),7.33(d,J＝7.8Hz,2H),6.66(s,1H),5.08(s,1H),4.16(m,2H),4.10(d,J＝7.0Hz,1H),3.68(m,2H),3.52(m,6H),3.41(t,J＝4.9Hz,2H),2.43(s,3H),1.61(m,2H),1.51-1.44(m,1H),1.41(s,9H),0.90(d,J＝5.6Hz,6H).
Preparation of N-t-Butoxycarbonyl leunamide bridged bromide (N-Boc-Leu-N-TrG Br) 1.01g (2.0 mmol) of valine N-t-Butoxycarbonyl bridged p-toluenesulfonate was replaced with 1.03g (2.0 mmol) of N-t-Butoxycarbonyl leunamide bridged p-toluenesulfonate, prepared according to experimental procedure 1.1.3. Separating and purifying to obtain colorless liquid 692.2mg, yield 81.6％.1H NMR(400MHz,CDCl3)δ6.54(s,1H),4.95(s,1H),4.12(s,1H),3.83(t,J＝6.1Hz,2H),3.67(m,4H),3.58(t,J＝4.9Hz,2H),3.51(m,4H),1.68(m,2H),1.48(m,1H),1.45(s,9H),0.95(d,J＝5.6Hz,6H);13C NMR(101MHz,CDCl3)δ172.66,155.59,79.87,71.16,70.41,70.23,69.82,53.09,41.69,39.22,30.35,28.32,24.75,22.96.
Preparation of N-t-Butoxycarbonyl leucinom-bridged boron sodium carbonate (N-Boc-Leu-N-TrG BSH) 102.8mg (0.25 mmol) of valine N-t-butoxycarbonyl ester-bridged bromine was replaced with 106.0mg (0.25 mmol) of N-t-butoxycarbonyl leucinom-bridged bromine, prepared according to experimental procedure 1.1.4. The mixture was separated and purified to obtain 71.2mg of colorless oily substance, and the yield was 60.2%.
2.2.5. Preparation of leucinamide bridged boron sodium carbonate (Leu-N-BSH) 74.3mg (0.14 mmol) of valine ester of N-t-butoxycarbonyl bridged boron sodium carbonate was replaced with 76.1mg (0.14 mmol) of leucinamide bridged boron sodium carbonate, prepared according to experimental procedure 1.1.5. The colorless viscous liquid obtained by separation and purification was 46.6mg, and the yield was 77.5%. 1H NMR(400MHz,DMSO-d6)δ8.75-8.66(m,1H),8.30(s,2H),3.77-3.75(m,1H),3.55-3.47(m,5H),3.45-3.39(m,3H),3.35-3.28(m,1H),3.25-3.11(m,2H),1.97-1.89(m,1H),1.68-1.58(m,1H),1.57-1.50(m,2H),1.49-0.92(m,7H),0.86(t,J＝24Hz,6H),0.79-0.10(m,3H);13CNMR(400MHz,DMSO-d6)δ167.59,82.86,72.37,70.66,67.52,60.77,49.60,41.47,40.68,26.27,22.59,21.32. All data confirm that the compound is N- (2- (2- (2-sodium dodecyl mercapto) ethoxy) ethyl L-leunamide (Leu-N-BSH) of the structure:
Preparation of D-Leu-amid bridged boron card (D-Leu-N-BSH)
Synthesized in 5 steps.
Preparation of N-Boc-D-leunamide bridged alcohol (N-Boc-D-Leu-N-TrG OH) 0.65g (3.0 mmol) of N-Boc-L-valine was replaced with 0.69g (3.0 mmol) of N-Boc-L-leucine according to experimental procedure 2.1.1. Separating, purifying and concentrating to obtain target 1.03g, yield 93.9％.1HNMR(400MHz,CDCl3)δ7.08(s,1H),5.27(s,1H),4.12(s,1H),3.72(m,2H),3.66-3.56(m,6H),3.53(t,J＝4.8Hz,2H),3.43(d,J＝5.1Hz,1H),3.35(m,2H),1.62(m,2H),1.47(m,1H),1.41(s,9H),0.91(d,J＝2.7Hz,6H).
Preparation of N-t-Butoxycarbonyl D-leucinamide bridged p-toluenesulfonate (N-Boc-D-Leu-N-TrG Ts) 0.70g (2.0 mmol) of N-t-Butoxycarbonyl valinamide bridged alcohol was replaced with 0.72g (2.0 mmol) of N-t-Butoxycarbonyl D-leucinamide bridged alcohol, prepared according to experimental procedure 2.1.2. Separating and purifying to obtain 932.4mg of colorless oily matter with yield 90.3％.1H NMR(400MHz,CDCl3)δ7.79(d,J＝7.8Hz,2H),7.34(d,J＝7.8Hz,2H),6.67(s,1H),5.09(s,1H),4.15(m,2H),4.11(d,J＝7.0Hz,1H),3.67(m,2H),3.53(m,6H),3.42(t,J＝4.9Hz,2H),2.42(s,3H),1.63(m,2H),1.52-1.45(m,1H),1.42(s,9H),0.89(d,J＝5.6Hz,6H).
Preparation of N-t-Butoxycarbonyl D-leunamide bridged bromo (N-Boc-D-Leu-N-TrG Br): will be
1.01G (2.0 mmol) of valine N-t-butoxycarbonyl-bridged p-toluenesulfonate was replaced with 1.03g (2.0 mmol) of N-t-butoxycarbonyl-D-leunamide-bridged p-toluenesulfonate, prepared as in experimental step 1.1.3. Separating and purifying to obtain colorless liquid 664.5mg, yield 78.3％.1H NMR(400MHz,CDCl3)δ6.56(s,1H),4.97(s,1H),4.13(s,1H),3.84(t,J＝6.1Hz,2H),3.68(m,4H),3.56(t,J＝4.9Hz,2H),3.53(m,4H),1.67(m,2H),1.49(m,1H),1.43(s,9H),0.97(d,J＝5.6Hz,6H);13C NMR(101MHz,CDCl3)δ172.68,155.61,79.86,71.15,70.43,70.25,69.83,53.07,41.68,39.23,30.36,28.33,24.74,22.95.
Preparation of N-t-Butoxycarbonyl leucinom-bridged boron sodium carbonate (N-Boc-D-Leu-N-TrG BSH) 102.8mg (0.25 mmol) of N-t-Butoxycarbonyl valine ester-bridged bromine was replaced with 106.0mg (0.25 mmol) of N-t-Butoxycarbonyl D-leucinom-bridged bromine, prepared according to experimental procedure 1.1.4. The colorless oily substance was obtained by separation and purification, and the yield was 62.6%.
2.3.5. Preparation of leucinamide bridged boron sodium carbonate (D-Leu-N-BSH) 74.3mg (0.14 mmol) of valine ester of N-t-butoxycarbonyl bridged boron sodium carbonate was replaced with 76.1mg (0.14 mmol) of D-leucinamide bridged boron sodium carbonate, prepared according to experimental procedure 1.1.5. The colorless viscous liquid obtained by separation and purification was 49.4mg, and the yield was 82.2%. 1H NMR(400MHz,DMSO-d6)δ8.74-8.65(m,1H),8.28(s,2H),3.78-3.76(m,1H),3.56-3.48(m,5H),3.43-3.36(m,3H),3.36-3.29(m,1H),3.23-3.08(m,2H),1.96-1.87(m,1H),1.66-1.56(m,1H),1.56-1.51(m,2H),1.47-0.93(m,7H),0.87(t,J＝24Hz,6H),0.78-0.12(m,3H);13CNMR(400MHz,DMSO-d6)δ167.61,82.87,72.38,70.67,67.53,60.78,49.62,41.46,40.67,26.25,22.57,21.34. All data confirm that the compound is N- (2- (2- (2-sodium dodecyl mercapto) ethoxy) ethyl D-leunamide (D-Leu-N-BSH) of the structure:
2.4. preparation of isoleucyl amide bridged boron card (Ile-N-BSH)
Synthesized in 5 steps.
Preparation of N-t-Butoxycarbonyl Isoglitanamide bridged alcohol (N-Boc-Ile-N-TrG OH) 0.65g (3.0 mmol) of N-Boc-L-valine was replaced with 0.69g (3.0 mmol) of N-Boc-L-isoleucine prepared according to experimental procedure 2.1.1. Separating, purifying, concentrating to obtain target 892.2mg, and obtaining yield 82.1％.1HNMR(400MHz,DMSO)δ7.87(s,1H),6.61(d,J＝9.0Hz,1H),4.59(t,J＝5.4Hz,1H),3.78(t,J＝8.2Hz,1H),3.50(m,4H),3.41(m,4H),3.36(m,4H),1.64(m,1H),
1.42(m,1H),1.37(s,9H),1.15–0.99(m,1H),0.81(d,J=7.4Hz,3H),0.79(d,J=6.7Hz,3H)。
Preparation of N-t-Butoxycarbonyl isoleucyl amide bridged para-toluenesulfonate (N-Boc-Ile-N-TrG Ts) 0.70g (2.0 mmol) of N-t-Butoxycarbonyl valinamide bridged alcohol was replaced with 0.72g (2.0 mmol) of N-t-Butoxycarbonyl isoleucyl amide bridged alcohol prepared according to experimental procedure 2.1.2. Isolation and purification gave 935.4mg of colorless oil in yield 90.6％.1H NMR(400MHz,CDCl3)δ7.80(d,J＝8.2Hz,2H),7.34(d,J＝8.2Hz,2H),6.54(s,1H),5.17(d,J＝7.9Hz,1H),4.21-4.15(m,2H),3.99-3.88(m,1H),3.72-3.65(m,2H),3.62-3.49(m,6H),3.44(m,2H),2.44(s,3H),1.83(m,1H),1.47(m,1H),1.42(s,9H),1.19-1.03(m,1H),0.91(d,J＝4.0Hz,3H),0.89(d,J＝4.5Hz,3H).
Preparation of N-t-Butoxycarbonyl isoleucyl amide bridged bromo (N-Boc-Ile-N-TrG Br) 1.01g (2.0 mmol) of valine N-t-Butoxycarbonyl bridged p-toluenesulfonate was replaced with 1.03g (2.0 mmol) of N-t-Butoxycarbonyl isoleucyl amide bridged p-toluenesulfonate, prepared according to experimental procedure 1.1.3. Separating and purifying to obtain colorless liquid 736.3mg, yield 86.8％.1H NMR(400MHz,CDCl3)δ6.98-6.13(s,1H),5.12(d,J＝6.4Hz,1H),3.99-3.88(m,1H),3.82(t,J＝6.1Hz,2H),3.65(m,4H),3.56(m,2H),3.49(t,J＝6.0Hz,4H),2.14(m,1H),1.87(m,1H),1.44(s,9H),1.21-1.03(m,1H),0.93(d,J＝3.3Hz,3H),0.91(t,J＝8.1Hz,3H);13C NMR(101MHz,CDCl3)δ171.28,156.14,79.73,71.15,70.40,70.21,69.81,59.24,39.15,37.61,30.46,28.44,24.71,15.55,11.47.
Preparation of N-t-Butoxycarbonyl isoleucyl amide bridged boron sodium (N-Boc-Ile-N-TrG BSH) 102.8mg (0.25 mmol) of N-t-Butoxycarbonyl valine ester bridged bromine was replaced with 106.0mg (0.25 mmol) of N-t-Butoxycarbonyl isoleucyl amide bridged bromine, prepared according to experimental procedure 1.1.4. The mixture was separated and purified to obtain 83.3mg of a colorless oil, and the yield was 61.3%.
2.4.5. Preparation of Isolibanum amide bridged boron sodium carbonate (Ile-N-BSH) 74.3mg (0.14 mmol) of N-t-butoxycarbonyl valine ester bridged boron sodium carbonate was replaced with 76.1mg (0.14 mmol) of N-t-butoxycarbonyl isoleucyl amide bridged boron sodium carbonate, prepared according to experimental procedure 1.1.5. The colorless viscous liquid obtained by separation and purification is 47.0mg, and the yield 75.8％.1H NMR(400MHz,DMSO-d6)δ8.52(s,1H),8.18(s,2H),4.91-4.43(m,8H),3.74(s,2H),3.63-3.38(m,6H),3.26-3.04(m,2H),1.77-0.94(m,11H),0.90-0.58(s,6H);13C NMR(101MHz,DMSO-d6)δ168.26,118.53,115.58,70.21,70.14,69.90,69.24,56.92,42.03,36.50,24.62,14.86,11.61. all data prove that the compound is N- (2- (2- (2-sodium dodecyl sulfhydryl) ethoxy) ethyl L-isoleucyl amide (Ile-N-BSH) with the following structure:
2.5. methanoammonamide bridged boron preparation of card (Met-N-BSH)
Synthesized in 5 steps.
Preparation of N-Boc-Met-N-TrG OH, N-Boc-Met-bridged alcohol by 0.65g (3.0 mmol) of N-Boc-L-valine was replaced with 0.75g (3.0 mmol) of N-Boc-L-methionine according to Experimental procedure 2.1.1. Separating, purifying, concentrating to obtain target 947.8mg, and obtaining yield 83.1％.1H NMR(400MHz,CDCl3)δ7.11(s,1H),5.54(d,J＝7.3Hz,1H),4.24(s,1H),3.72(m,2H),3.68–3.56(m,6H),3.53(t,J＝4.6Hz,2H),3.46–3.34(m,2H),3.23(s,1H),2.48(m,2H),2.06(s,3H),2.01(m,1H),1.85(m,1H),1.40(s,9H).
Preparation of N-t-Butoxycarbonyl-methylthioamid-bridged p-toluenesulfonate (N-Boc-Met-N-TrG Ts) 0.70g (2.0 mmol) of N-t-butoxycarbonyl-valinamide bridged alcohol was replaced with 0.76g (2.0 mmol) of N-t-butoxycarbonyl-methylthioamid-bridged alcohol, prepared according to experimental procedure 2.1.2. Separating and purifying to obtain colorless oily substance 1.01g, yield 94.1％.1H NMR(400MHz,CDCl3)δ7.76(d,J＝7.7Hz,2H),7.31(d,J＝7.8Hz,2H),6.73(s,1H),5.40(d,J＝8.0Hz,1H),4.22(s,1H),4.13(m,2H),3.66(m,2H),3.52(m,6H),3.40(m,2H),2.50(m,2H),2.41(s,3H),2.05(m,1H),2.04(s,3H),1.87(m,1H),1.39(s,9H).
Preparation of N-t-Butoxycarbonyl-methionamide bridged bromo (N-Boc-Met-N-TrG Br) 1.01g (2.0 mmol) of valine N-t-butoxycarbonyl-bridged p-toluenesulfonate was replaced with 1.07g (2.0 mmol) of N-t-butoxycarbonyl-methionamide-bridged p-toluenesulfonate, prepared according to experimental procedure 1.1.3. Separating and purifying to obtain colorless liquid 733.9mg, yield 83.0％.1H NMR(400MHz,CDCl3)δ6.64(s,1H),5.27(s,1H),4.27(s,1H),3.82(t,J＝6.1Hz,2H),3.65(m,4H),3.57(t,J＝4.9Hz,2H),3.54-3.43(m,4H),2.59-2.53(m,2H),2.11(s,3H),2.07(m,1H),1.91(td,J＝14.3,7.2Hz,1H),1.44(s,9H);13C NMR(101MHz,CDCl3)δ171.28,155.47,80.03,71.14,70.49,70.22,69.67,53.44,39.28,30.45,30.14,28.38,15.35,15.28.
Preparation of N-t-Butoxycarbonyl-methylthioamid-bridged boron-calix-sodium (N-Boc-Met-N-TrG BSH) 102.8mg (0.25 mmol) of valine N-t-butoxycarbonyl ester-bridged bromine was replaced with 110.5mg (0.25 mmol) of N-t-butoxycarbonyl-methylthioamid-bridged bromine, prepared according to experimental procedure 1.1.4. The colorless oily substance was obtained by separation and purification, 103.6mg, and the yield was 73.8%.
2.5.5. Preparation of Boc sodium Met-N-BSH 74.3mg (0.14 mmol) of Boc sodium bridged with valine N-Boc ester was replaced with 78.6mg (0.14 mmol) of Boc sodium bridged with Boc, according to experimental procedure 1.1.5. The colorless viscous liquid obtained by separation and purification was 50.3mg, and the yield was 77.9%. 1H NMR(400MHz,DMSO-d6)δ8.61(s,1H),8.27(s,2H),3.87-3.68(m,2H),3.58-3.49(m,3H),3.47-3.43(m,3H),3.25-3.07(m,2H),2.52-2.44(m,2H),2.06-1.95(m,3H),1.68-0.46(m,13H);13CNMR(101MHz,DMSO-d6)δ168.55,70.17,69.85,69.19,52.05,42.05,39.23,31.38,28.61,15.02. All data confirm that the compound is N- (2- (2- (2-sodium dodecyl mercapto) ethoxy) ethyl L-methionamide (Met-N-BSH) of the structure:
Preparation of D-methionamide bridged boron card (D-Met-N-BSH)
Synthesized in 5 steps.
Preparation of N-Boc-D-methionamide bridged alcohol (N-Boc-D-Met-N-TrG OH) 0.65g (3.0 mmol) of N-Boc-L-valine was replaced with 0.75g (3.0 mmol) of N-Boc-D-methionine according to experimental procedure 2.1.1. Separating, purifying, concentrating to obtain target 948.2mg, and obtaining yield 83.2％.1H NMR(400MHz,CDCl3)δ7.12(s,1H),5.53(d,J＝7.3Hz,1H),4.23(s,1H),3.74(m,2H),3.69-3.57(m,6H),3.54(t,J＝4.6Hz,2H),3.47-3.35(m,2H),3.24(s,1H),2.47(m,2H),2.08(s,3H),2.03(m,1H),1.86(m,1H),1.41(s,9H).
Preparation of N-t-Butoxycarbonyl D-methionamide bridged p-toluenesulfonate (N-Boc-D-Met-N-TrG Ts) 0.70g (2.0 mmol) of N-t-Butoxycarbonyl valinamide bridged alcohol was replaced with 0.76g (2.0 mmol) of N-t-Butoxycarbonyl methionamide bridged alcohol, prepared according to experimental procedure 2.1.2. Separating and purifying to obtain colorless oily substance 1.03g, yield 94.3％.1H NMR(400MHz,CDCl3)δ7.75(d,J＝7.7Hz,2H),7.32(d,J＝7.8Hz,2H),6.72(s,1H),5.41(d,J＝8.0Hz,1H),4.23(s,1H),4.12(m,2H),3.67(m,2H),3.53(m,6H),3.41(m,2H),2.51(m,2H),2.42(s,3H),2.06(m,1H),2.05(s,3H),1.86(m,1H),1.38(s,9H).
Preparation of N-t-Butoxycarbonyl D-methionamide bridged bromo (N-Boc-D-Met-N-TrG Br) 1.01g (2.0 mmol) of N-t-butoxycarbonyl valine ester bridged p-toluenesulfonate was replaced with 1.07g (2.0 mmol) of N-t-butoxycarbonyl methionamide bridged p-toluenesulfonate, prepared according to experimental procedure 1.1.3. Separating and purifying to obtain colorless liquid 733.7mg, yield 82.8％.1H NMR(400MHz,CDCl3)δ6.65(s,1H),5.28(s,1H),4.26(s,1H),3.83(t,J＝6.1Hz,2H),3.64(m,4H),3.56(t,J＝4.9Hz,2H),3.55-3.42(m,4H),2.58-2.54(m,2H),2.12(s,3H),2.08(m,1H),1.92(td,J＝14.3,7.2Hz,1H),1.45(s,9H);13C NMR(101MHz,CDCl3)δ171.27,155.48,80.05,71.12,70.47,70.23,69.68,53.45,39.26,30.43,30.12,28.35,15.37,15.26.
Preparation of N-t-Butoxycarbonyl D-methionamide bridged boron sodium carbomer (N-Boc-D-Met-N-TrG BSH) 102.8mg (0.25 mmol) of valine N-t-butoxycarbonyl ester bridged bromine was replaced with 110.5mg (0.25 mmol) of N-t-butoxycarbonyl D-methionamide bridged bromine, prepared according to experimental procedure 1.1.4. The colorless oily substance was obtained by separation and purification, 103.4mg, and the yield was 73.7%.
Preparation of D-Met-N-BSH sodium Boecarboxamide bridge 74.3mg (0.14 mmol) of valine N-t-butoxycarbonyl ester bridge was replaced with 78.6mg (0.14 mmol) of sodium Boecarboxamide bridge, prepared according to experimental procedure 1.1.5. The colorless viscous liquid obtained by separation and purification was 50.6mg, and the yield was 78.0%. 1H NMR(400MHz,DMSO-d6)δ8.63(s,1H),8.25(s,2H),3.85-3.67(m,2H),3.57-3.48(m,3H),3.46-3.42(m,3H),3.24-3.05(m,2H),2.51-2.43(m,2H),2.05-1.94(m,3H),1.67-0.45(m,13H);13C NMR(101MHz,DMSO-d6)δ168.56,70.15,69.83,69.17,52.03,42.02,39.26,31.37,28.63,15.05. All data confirm that the compound is N- (2- (2- (2-sodium dodecyl mercapto) ethoxy) ethyl D-methionamide (D-Met-N-BSH) having the structure:
2.7. preparation of phenylalaninamide bridged boron calipers (Phe-N-BSH)
Synthesized in 5 steps.
Preparation of N-t-Butoxycarbonyl phenylalanyl-bridged alcohol (N-Boc-Phe-N-TrG OH) 0.65g (3.0 mmol) of N-Boc-L-valine was replaced by 0.80g (3.0 mmol) of N-Boc-L-phenylalanine, prepared according to experimental procedure 2.1.1. Separating, purifying and concentrating to obtain target 1.17g, yield 98.4％.1H NMR(400MHz,CDCl3)δ7.16(m,5H),4.32(s,1H),3.66(m,2H),3.52(m,8H),3.31(m,4H),3.00(m,1H),2.89(m,1H),1.28(s,9H).
Preparation of N-t-Butoxycarbonyl phenylalanyl-bridged para-toluenesulfonate (N-Boc-Phe-N-TrG Ts) 0.70g (2.0 mmol) of N-t-butoxycarbonyl valinamide bridged alcohol was replaced with 0.79g (2.0 mmol) of N-t-butoxycarbonyl phenylalanyl-bridged alcohol, prepared according to experimental procedure 2.1.2. Separating and purifying to obtain 939.8mg of colorless oily matter with yield 85.4％.1H NMR(400MHz,CDCl3)δ7.80(d,J＝8.3Hz,2H),7.35(d,J＝8.1Hz,2H),7.32-7.25(m,2H),7.22(dd,J＝8.0,6.4Hz,3H),6.35(s,1H),5.18(s,1H),4.32(d,J＝6.7Hz,1H),4.21-4.13(m,2H),3.71-3.66(m,2H),3.57-3.53(m,2H),3.47(m,4H),3.37(m,2H),3.04(m,2H),2.46(s,3H),1.38(s,9H).
Preparation of N-t-Butoxycarbonyl-phenylalanyl-bridged bromo (N-Boc-Phe-N-TrG Br) 1.01g (2.0 mmol) of valine N-t-butoxycarbonyl-bridged p-toluenesulfonate was replaced by 1.10g (2.0 mmol) of N-t-butoxycarbonyl-phenylalanyl-bridged p-toluenesulfonate, prepared according to experimental procedure 1.1.3. Separating and purifying to obtain colorless liquid 795.3mg, yield 86.8％.1H NMR(400MHz,CDCl3)δ7.30-7.23(m,2H),7.19(t,J＝7.8Hz,3H),6.38(s,1H),5.21(s,1H),4.32(s,1H),3.75(t,J＝6.0Hz,2H),3.57(m,2H),3.63–3.17(m,8H),3.02(d,J＝5.7Hz,2H),1.38(s,9H);13C NMR(101MHz,CDCl3)δ171.55,155.23,136.99,129.11,128.50,126.77,79.87,71.03,70.37,70.18,69.60,53.96,39.15,30.29,30.21,28.27.
Preparation of N-t-Butoxycarbonyl phenylalaninamide bridged sodium boron carbate (N-Boc-Phe-N-TrG BSH) 102.8mg (0.25 mmol) of N-t-butoxycarbonyl valine ester bridged bromine was replaced with 114.5mg (0.25 mmol) of N-t-butoxycarbonyl phenylalaninamide bridged bromine, prepared according to experimental procedure 1.1.4. The colorless oily substance was obtained by separation and purification, and the yield was 87.1%.
2.7.5. Preparation of phenylalanyl-bridged sodium boron carboxylate (Phe-N-BSH) 74.3mg (0.14 mmol) of valine ester of N-t-butoxycarbonyl bridged sodium boron carboxylate was replaced with 80.8mg (0.14 mmol) of phenylalanyl-N-t-butoxycarbonyl bridged sodium boron carboxylate, prepared according to experimental procedure 1.1.5. The colorless viscous liquid obtained by separation and purification was 48.5mg, and the yield was 72.6%. 1H NMR(400MHz,DMSO-d6)δ8.56(s,1H),7.29-7.23(m,5H),4.00(s,1H),3.34-3.20(m,8H),3.18-3.08(m,2H),2.95-3.06(m,2H),1.89(s,3H),1.5-1.20(m,2H),0.86-0.44(m,11H);13C NMR(400MHz,DMSO-d6)δ165.44,135.10,131.27,129.94,127.44,126.05,123.17,81.71,72.49,72.44,56.43,46.58,41.98,41.42,35.75. All data confirm that the compound is N- (2- (2- (2-sodium dodecyl mercapto) ethoxy) ethyl L-phenylalanyl amide (Phe-N-BSH) having the structure:
Preparation of D-phenylalaninamide bridged boron card (D-Phe-N-BSH)
Synthesized in 5 steps.
Preparation of N-t-Butoxycarbonyl D-phenylalanyl-bridged alcohol (N-Boc-D-Phe-N-TrG OH) 0.65g (3.0 mmol) of N-Boc-L-valine was replaced by 0.80g (3.0 mmol) of N-Boc-D-phenylalanine, prepared according to experimental procedure 2.1.1. Separating, purifying and concentrating to obtain target 1.15g, yield 98.1％.1H NMR(400MHz,CDCl3)δ7.18(m,5H),4.33(s,1H),3.67(m,2H),3.54(m,8H),3.32(m,4H),3.03(m,1H),2.87(m,1H),1.29(s,9H).
Preparation of N-t-Butoxycarbonyl D-phenylalanyl-bridged p-toluenesulfonate (N-Boc-D-Phe-N-TrG Ts) 0.70g (2.0 mmol) of N-t-Butoxycarbonyl valinamide bridged alcohol were replaced by 0.79g (2.0 mmol) of N-t-Butoxycarbonyl D-phenylalanyl amide bridged alcohol, prepared according to experimental procedure 2.1.2. Separating and purifying to obtain 939.5mg of colorless oily matter with yield 85.3％.1H NMR(400MHz,CDCl3)δ7.78(d,J＝8.3Hz,2H),7.36(d,J＝8.1Hz,2H),7.33-7.26(m,2H),7.24(dd,J＝8.0,6.4Hz,3H),6.36(s,1H),5.16(s,1H),4.34(d,J＝6.7Hz,1H),4.22-4.14(m,2H),3.72-3.67(m,2H),3.56-3.52(m,2H),3.46(m,4H),3.38(m,2H),3.05(m,2H),2.47(s,3H),1.39(s,9H).
Preparation of N-t-Butoxycarbonyl D-phenylalanyl-bridged Bromide (N-Boc-D-Phe-N-TrG Br) 1.01g (2.0 mmol) of N-t-butoxycarbonyl valine ester-bridged p-toluenesulfonate was replaced with 1.10g (2.0 mmol) of N-t-butoxycarbonyl D-phenylalanyl-bridged p-toluenesulfonate, prepared according to experimental procedure 1.1.3. Separating and purifying to obtain colorless liquid 796.2mg, yield 87.0％.1H NMR(400MHz,CDCl3)δ7.32-7.24(m,2H),7.18(t,J＝7.8Hz,3H),6.39(s,1H),5.22(s,1H),4.33(s,1H),3.76(t,J＝6.0Hz,2H),3.58(m,2H),3.64-3.18(m,8H),3.05(d,J＝5.7Hz,2H),
1.38(s,9H);13C NMR(101MHz,CDCl3)δ171.56,155.25,136.97,129.13,128.52,126.75,79.86,71.05,70.36,70.17,69.61,53.94,39.16,30.28,30.23,28.29.
Preparation of N-t-Butoxycarbonyl D-phenylalaninamide bridged sodium boron carboxylate (N-Boc-D-Phe-N-TrG BSH) 102.8mg (0.25 mmol) of valine N-t-butoxycarbonyl ester bridged bromine was replaced with 114.5mg (0.25 mmol) of N-t-butoxycarbonyl D-phenylalaninamide bridged bromine, prepared according to experimental procedure 1.1.4. 126.2mg of colorless oil was obtained by separation and purification, and the yield was 87.5%.
Preparation of D-phenylalanyl-bridged boron sodium carbonate (D-Phe-N-BSH) 74.3mg (0.14 mmol) of valine N-t-butoxycarbonyl ester bridged boron sodium carbonate was replaced with 80.8mg (0.14 mmol) of D-phenylalanyl-bridged boron sodium carbonate, prepared according to experimental procedure 1.1.5. The colorless viscous liquid obtained by separation and purification was 49.4mg, and the yield was 73.1%. 1H NMR(400MHz,DMSO-d6)δ8.58(s,1H),7.27-7.24(m,5H),4.01(s,1H),3.35-3.21(m,8H),3.17-3.06(m,2H),2.96-3.07(m,2H),1.87(s,3H),1.6-1.22(m,2H),0.87-0.45(m,11H);13C NMR(400MHz,DMSO-d6)δ165.46,135.12,131.28,129.95,127.43,126.06,123.15,81.73,72.46,72.45,56.44,46.57,41.96,41.43,35.76. All data confirm that the compound is N- (2- (2- (2-sodium dodecyl mercapto) ethoxy) ethyl D-phenylalanyl amide (D-Phe-N-BSH) having the structure:
2.9. Preparation of tryptophane amide bridged boron card (Trp-N-BSH)
Synthesized in 5 steps.
Preparation of N-t-Boc-L-tryptophan bridged alcohol (N-Boc-Trp-N-TrG OH) 0.65g (3.0 mmol) N-Boc-L-valine was replaced with 0.91g (3.0 mmol) N-Boc-L-tryptophan prepared according to experiment 2.1.1. Separating, purifying, concentrating to obtain target 1.19g, and obtaining yield 91.1％.1H NMR(400MHz,DMSO-d6)δ10.80(s,1H),7.92(t,J＝5.3Hz,1H),7.60(d,J＝7.8Hz,1H),7.35(d,J＝8.0Hz,1H),7.15(s,1H),7.07(t,J＝7.3Hz,1H),6.99(t,J＝7.3Hz,1H),6.71(d,J＝8.3Hz,1H),4.64(s,1H),4.14(d,J＝4.2Hz,1H),3.52(m,6H),3.48-3.40(m,2H),3.37(m,2H),3.21(m,2H),3.10(dd,J＝14.5,5.0Hz,1H),2.94(dd,J＝14.5,8.7Hz,1H),1.34(s,9H).
Preparation of N-t-Butoxycarbonyl-tryptophane amide bridged p-toluenesulfonate (N-Boc-Trp-N-TrG Ts) 0.70g (2.0 mmol) of N-t-butoxycarbonyl valinamide bridged alcohol was replaced with 0.87g (2.0 mmol) of N-t-butoxycarbonyl-tryptophane amide bridged alcohol, prepared according to experimental procedure 2.1.2. Separating and purifying to obtain colorless oily substance 1.11g, yield 94.6％.1H NMR(400MHz,CDCl3)δ8.55(s,1H),7.79(d,J＝8.2Hz,2H),7.68(d,J＝7.7Hz,1H),7.37(d,J＝8.0Hz,1H),7.33(d,J＝8.1Hz,2H),7.18(t,J＝7.4Hz,1H),7.12(d,J＝7.5Hz,1H),7.09(s,1H),6.11(s,1H),5.34(s,1H),4.41(s,1H),4.20-4.07(m,2H),3.76-3.57(m,2H),3.46(t,J＝4.0Hz,2H),3.31(m,6H),3.16(m,2H),2.45(s,3H),1.44(s,9H).
Preparation of N-t-Butoxycarbonyl-tryptophane-bridged Bromide (N-Boc-Trp-N-TrG Br) 1.01g (2.0 mmol) of valine N-t-butoxycarbonyl-bridged p-toluenesulfonate was replaced with 1.18g (2.0 mmol) of N-t-butoxycarbonyl-tryptophane-bridged p-toluenesulfonate, prepared according to experimental procedure 1.1.3. Separating and purifying to obtain colorless liquid 832.2mg, yield 83.7％.1H NMR(400MHz,CDCl3)δ8.60(s,1H),7.67(d,J＝7.7Hz,1H),7.37(d,J＝8.0Hz,1H),7.19(t,J＝7.5Hz,1H),7.12(t,J＝7.4Hz,1H),7.07(s,1H),6.25(s,1H),5.31(s,1H),4.43(s,1H),3.74(t,J＝6.0Hz,2H),3.52(m,2H),3.44(t,J＝6.1Hz,2H),3.34(m,6H),3.19(m,2H),1.44(s,9H);13CNMR(101MHz,CDCl3)δ171.57,154.86,136.31,127.56,123.44,122.12,119.77,119.01,111.26,110.56,79.97,71.01,70.32,70.07,69.47,55.33,39.23,30.40,28.81,28.35.
Preparation of N-t-butoxycarbonyl-tryptophane bridged sodium boron carboxylate (N-Boc-Trp-N-TrG BSH): prepared according to experimental procedure 1.1.4 substituting 102.8mg (0.25 mmol) of valine ester-bridged bromo of N-t-butoxycarbonyl with 124.3mg (0.25 mmol) of bridged bromo of N-t-butoxycarbonyl-tryptophanamide. 88.8mg of colorless oily substance is obtained after separation and purification, and the yield is 57.6%.
2.9.5. Preparation of tryptophane-bridged boron sodium carbonate (Trp-N-BSH) 74.3mg (0.14 mmol) of N-tert-butoxycarbonyl valine ester-bridged boron sodium carbonate was replaced with 86.3mg (0.14 mmol) of N-tert-butoxycarbonyl-tryptophane-bridged boron sodium carbonate, prepared according to experimental procedure 1.1.5. The colorless viscous liquid obtained by separation and purification was 63.3mg, and the yield 87.6％.1H NMR(400MHz,DMSO-d6)δ11.00(s,1H),8.56(s,1H),8.16(s,2H),7.61(s,1H),7.34(s,1H),7.19(s,1H),7.06-6.98(m,2H),4.01-3.91(m,1H),,3.78-3.63(m,2H),3.54-3.47(m,2H),3.37-3.32(m,1H),3.30-3.23(m,2H),3.19-3.05(m,4H),1.75-0.59(m,16H);13C NMR(101MHz,DMSO-d6)δ168.95,136.65,127.52,125.27,121.66,118.94,118.90,111.97,107.33,70.18,69.89,69.63,69.19,66.46,53.26,41.07,39.28,27.71. all data confirm that the compound was N- (2- (2- (2-sodium dodecyl mercapto) ethoxy) ethyl L-tryptophane (Trp-N-BSH) with the following structure:
2.10. preparation of tyramide bridged boron card (Tyr-N-BSH)
Synthesized in 5 steps.
Preparation of N-Boc-tyramide bridged alcohol (N-Boc-Tyr-N-TrG OH) 0.65g (3.0 mmol) of N-Boc-L-valine was replaced with 0.84g (3.0 mmol) of N-Boc-L-tyrosine, prepared according to experimental procedure 2.1.1. Separating, purifying, concentrating to obtain target 1.14g, and obtaining yield 92.2％.1H NMR(400MHz,CDCl3)δ9.03(s,1H),8.05(m,1H),7.12(d,J＝7.9Hz,2H),6.89(d,J＝7.9Hz,2H),6.81(m,1H),5.42(d,J＝7.9Hz,1H),5.01(s,2H),4.33(s,1H),3.71(m,2H),3.62-3.43(m,8H),3.38(m,2H),2.97(d,J＝23.6Hz,2H),1.39(s,9H).
Preparation of N-t-Butoxycarbonyl tyramide bridged p-toluenesulfonate (N-Boc-Tyr-N-TrG Ts) 0.70g (2.0 mmol) of N-t-Butoxycarbonyl valinamide bridged alcohol was replaced with 0.82g (2.0 mmol) of N-t-Butoxycarbonyl tyramide bridged alcohol, prepared according to experimental procedure 2.1.2. Separating and purifying to obtain colorless oily substance 1.03g, yield 90.6％.1H NMR(400MHz,CDCl3)δ7.80(d,J＝7.9Hz,2H),7.35(d,J＝7.8Hz,2H),7.03(d,J＝7.8Hz,2H),6.73(d,J＝7.9Hz,2H),6.33(s,1H),5.27(s,1H),4.27(s,1H),4.17(m,2H),3.68(m,2H),3.55(m,2H),3.42(m,6H),2.96(d,J＝14.7Hz,2H),2.45(s,3H),1.42(s,9H).
Preparation of N-t-Butoxycarbonyl tyramide bridged bromo (N-Boc-Tyr-N-TrG Br) 1.01g (2.0 mmol) of valine N-t-butoxycarbonyl bridged p-toluenesulfonate was replaced with 1.13g (2.0 mmol) of N-t-butoxycarbonyl tyramide bridged p-toluenesulfonate, prepared according to experimental procedure 1.1.3. Separating and purifying to obtain colorless liquid 800.3mg, yield 84.4％.1H NMR(400MHz,CDCl3)δ7.02(d,J＝7.7Hz,2H),6.75(d,J＝7.6Hz,2H),6.54(s,1H),5.36(s,1H),4.29(s,1H),3.79(t,J＝5.9Hz,2H),3.62(m,2H),3.55(m,2H),3.52–3.43(m,4H),3.38(m,2H),2.95(m,2H),1.42(s,9H);13C NMR(101MHz,CDCl3)δ171.83,155.51,130.64,130.15,127.72,115.77,80.25,71.08,70.29,70.07,69.56,56.10,39.36,38.04,30.32,28.32.
Preparation of N-Boc-Tyr-N-TrG BSH 102.8mg (0.25 mmol) of valine ester-bridged N-Boc-Tyr-N-Boc-TrG was replaced with 118.5mg (0.25 mmol) of tyramide-bridged N-Boc-Tyr-N-Trg BSH, prepared as per experimental procedure 1.1.4. 84.7mg of colorless oil was obtained by separation and purification, and the yield was 57.1%.
2.10.5. Preparation of tyramide bridged boron sodium carbonate (Tyr-N-BSH) 74.3mg (0.14 mmol) of valine ester of N-t-butoxycarbonyl bridged boron sodium carbonate was replaced with 83.1mg (0.14 mmol) of N-t-butoxycarbonyl primary amide bridged boron sodium carbonate, prepared according to experimental procedure 1.1.5. The colorless viscous liquid obtained by separation and purification is 53.0mg, and all data of yield 76.8％.1H NMR(400MHz,DMSO-d6)δ9.52(s,1H),8.52(s,1H),8.38-8.13(m,2H),7.0(d,J＝8Hz,1H),6.68(d,J＝8Hz,1H),4.29-4.06(m,4H),3.95-3.88(m,1H),3.74-3.69(m,1H),3.61-3.57(m,1H),3.39-3.33(m,2H),3.32-3.23(m,2H),2.97-2.84(m,2H),1.47-1.32(m,2H),1.20-0.82(m,11H);13C NMR(101MHz,DMSO-d6)δ170.38,159.19,132.95,130.88,129.69,119.19,116.20,78.06,69.93,69.64,68.97,61.53,48.98,44.05,41.49. prove that the compound is N- (2- (2- (2-sodium dodecyl sulfhydryl) ethoxy) ethyl L-tyrosinamide (Tyr-N-BSH), and the structure is as follows:
2.11. preparation of dopa amide bridged boron card (Dpa-N-BSH)
Synthesized in 5 steps.
Preparation of N-t-Butoxycarbonyl-dopa amide bridged alcohol (N-Boc-Dpa-N-TrG OH) 0.65g (3.0 mmol) of N-Boc-L-valine was replaced with 0.89g (3.0 mmol) of N-Boc-L-dopa, prepared according to experimental procedure 2.1.1. Separating, purifying, concentrating to obtain target 1.18g, and obtaining yield 91.7％.1H NMR(400MHz,CDCl3)δ9.36(s,2H),8.03(m,1H),7.27(m,1H),6.89(d,J＝7.8Hz,1H),6.76(m,1H),6.63(d,J＝7.7Hz,2H),5.43(d,J＝7.8Hz,1H),5.03(s,2H),4.32(s,1H),3.73(m,2H),3.63-3.44(m,8H),3.37(m,2H),2.96(d,J＝23.6Hz,2H),1.41(s,9H).
Preparation of N-t-Butoxycarbonyl-dopa amide bridged p-toluenesulfonate (N-Boc-Dpa-N-TrG Ts) 0.70g (2.0 mmol) of N-t-butoxycarbonyl valinamide bridged alcohol was replaced with 0.86g (2.0 mmol) of N-t-butoxycarbonyl-dopa amide bridged alcohol, prepared according to experimental procedure 2.1.2. Separating and purifying to obtain colorless oily substance 1.05g, yield 90.5％.1H NMR(400MHz,CDCl3)δ9.36(s,2H),8.03(m,1H),7.83(d,J＝7.9Hz,2H),7.46(d,J＝7.8Hz,2H),6.92(d,J＝7.6Hz,1H),6.81(s,1H),6.73(d,J＝7.8Hz,1H),5.26(s,1H),4.25(s,1H),4.18(m,2H),3.69(m,2H),3.56(m,2H),3.43(m,6H),2.95(d,J＝14.7Hz,2H),2.46(s,3H),1.43(s,9H).
Preparation of N-t-Butoxycarbonyl-dopa amide bridged bromo (N-Boc-Dpa-N-TrG Br) 1.01g (2.0 mmol) of valine N-t-butoxycarbonyl-bridged p-toluenesulfonate was replaced with 1.16g (2.0 mmol) of N-t-butoxycarbonyl-dopa amide bridged p-toluenesulfonate, prepared according to experimental procedure 1.1.3. Separating and purifying to obtain colorless liquid 836.2mg, yield 85.3％.1H NMR(400MHz,CDCl3)δ9.34(s,2H),8.04(m,1H),7.38(m,1H),7.02(d,J＝7.7Hz,1H),6.87(s,1H),6.65(d,J＝7.6Hz,2H),5.35(s,1H),4.27(s,1H),3.76(t,J＝5.9Hz,2H),3.64(m,2H),3.56(m,2H),3.54-3.45(m,4H),3.39(m,2H),2.94(m,2H),1.44(s,9H);13C NMR(101MHz,CDCl3)δ171.83,155.51,144.87,143.78,130.31,122.82,116.43,115.77,80.25,71.08,70.29,70.07,69.56,56.10,39.36,38.04,30.32,28.32.
Preparation of sodium N-t-butoxycarbonyl dopa amide bridged boron carbazide (N-Boc-Tyr-N-TrG BSH) 102.8mg (0.25 mmol) of valine N-t-butoxycarbonyl ester bridged bromine was replaced with 122.5mg (0.25 mmol) of N-t-butoxycarbonyl dopa amide bridged bromine, prepared according to experimental procedure 1.1.4. The colorless oily substance was obtained by separation and purification, and the yield was 59.4%.
2.11.5. Preparation of dopa amide bridged boron sodium carbonate (Dpa-N-BSH) 74.3mg (0.14 mmol) of valine ester bridged boron sodium carbonate of N-t-butoxycarbonyl was replaced with 85.3mg (0.14 mmol) of sodium carbonate of N-t-butoxycarbonyl primary amino amide bridged boron, prepared according to experimental procedure 1.1.5. The colorless viscous liquid 63.1mg was obtained by separation and purification, and all data of yield 88.5％.1H NMR(400MHz,DMSO-d6)δ9.54(s,2H),8.52(m,1H),8.38-8.13(m,2H),6.93(d,J＝8.1Hz,1H),6.87(s,1H),6.68(d,J＝8.2Hz,1H),4.29-4.07(m,4H),3.96-3.89(m,1H),3.75-3.68(m,1H),3.63-3.58(m,1H),3.37-3.32(m,2H),3.34-3.25(m,2H),2.96-2.83(m,2H),1.48-1.33(m,2H),1.22-0.83(m,11H);13CNMR(101MHz,DMSO-d6)δ170.38,145.36,144.63,130.88,123.11,116.19,116.20,78.05,69.94,69.62,68.95,61.54,48.96,44.07,41.46. confirm that the compound was N- (2- (2- (2-sodium dodecyl mercapto) ethoxy) ethyl L-dopa amide (Dpa-N-BSH) with the following structure:
2.12. Preparation of histidinamide bridged boron-calipers (His-N-BSH)
Synthesized in 5 steps.
Preparation of N-Boc-histidinamide bridged alcohol (N-Boc-His-N-TrG OH) 0.65g (3.0 mmol) N-Boc-L-valine was replaced with 0.77g (3.0 mmol) N-Boc-L-histidine, prepared according to experimental procedure 2.1.1. Separating, purifying, concentrating to obtain target 1.11g, and obtaining yield 95.8％.1H NMR(400MHz,CDCl3)δ12.32(m,1H),8.67(m,1H),8.03(m,1H),7.68(m,1H),7.41(m,1H),4.85(m,1H),3.68(m,2H),3.53(m,8H),3.32(m,4H),3.02(m,1H),2.87(m,1H),1.38(s,9H).
Preparation of N-t-Butoxycarbonyl histidinamide bridged para-toluenesulfonate (N-Boc-His-N-TrG Ts) 0.70g (2.0 mmol) of N-t-Butoxycarbonyl valinamide bridged alcohol was replaced with 0.77g (2.0 mmol) of N-t-Butoxycarbonyl histidinamide bridged alcohol, prepared according to experimental procedure 2.1.2. Separating and purifying to obtain 935.7mg of colorless oily matter with yield 86.6％.1H NMR(400MHz,CDCl3)δ12.35(m,1H),8.69(m,1H),8.05(m,1H),7.82(d,J＝8.2Hz,2H),7.66(m,1H),7.41(m,1H),7.37(d,J＝8.1Hz,2H),5.19(m,1H),4.31(d,J＝6.6Hz,1H),4.22-4.15(m,2H),3.73-3.65(m,2H),3.56-3.52(m,2H),3.48(m,4H),3.36(m,2H),3.05(m,2H),2.48(s,3H),1.39(s,9H).
Preparation of N-t-Butoxycarbonyl histidinamide bridged bromo (N-Boc-His-N-TrG Br) 1.01g (2.0 mmol) of valine N-t-Butoxycarbonyl bridged p-toluenesulfonate was replaced with 1.08g (2.0 mmol) of N-t-Butoxycarbonyl histidinamide bridged p-toluenesulfonate, prepared according to experimental procedure 1.1.3. Separating and purifying to obtain colorless liquid 781.5mg, yield 87.2％.1H NMR(400MHz,CDCl3)δ12.38(m,1H),8.72(m,1H),8.02(m,1H),7.68(m,1H),7.42(m,1H),5.17(m,1H),4.34(s,1H),3.78(t,J＝6.0Hz,2H),3.56(m,2H),3.65-3.18(m,8H),3.04(d,J＝5.7Hz,2H),1.39(s,9H);13C NMR(101MHz,CDCl3)δ171.58,155.36,136.42,131.35,118.02,79.84,71.02,70.35,70.16,69.62,53.95,39.12,30.26,30.22,28.28.
Preparation of N-t-Butoxycarbonyl histidinamide bridged boron sodium (N-Boc-His-N-TrG BSH) 102.8mg (0.25 mmol) of valine N-t-butoxycarbonyl ester bridged bromine was replaced with 112.0mg (0.25 mmol) of N-t-butoxycarbonyl histidinamide bridged bromine, prepared according to experimental procedure 1.1.4. 126.5mg of colorless oil was obtained by separation and purification, and the yield was 89.2%.
2.12.5. Preparation of histidinamide bridged boron sodium carbonate (His-N-BSH) 74.3mg (0.14 mmol) of valine N-t-butoxycarbonyl ester bridged boron sodium carbonate was replaced with 80.8mg (0.14 mmol) of N-t-butoxycarbonyl histidinamide bridged boron sodium carbonate, prepared according to experimental procedure 1.1.5. 58.0mg of colorless viscous liquid is obtained after separation and purification, and all data of yield 88.7％.1H NMR(400MHz,DMSO-d6)δ8.56(s,1H),12.12(m,1H),8.86(br,2H),8.63(m,1H),8.03(m,1H),7.62(m,1H),4.03(m,1H),3.36-3.22(m,8H),3.17-3.06(m,2H),2.96-3.07(m,2H),1.87(s,3H),1.45-1.23(m,2H),0.87-0.45(m,11H);13C NMR(400MHz,DMSO-d6)δ165.44,136.17,131.27,118.02,81.72,72.46,72.45,56.41,46.56,41.95,41.43,35.76. prove that the compound is N- (2- (2- (2-sodium dodecyl sulfhydryl) ethoxy) ethyl L-histidinamide (His-N-BSH) and has the following structure:
EXAMPLE 3 amino acid-BSH targeting Compound cytotoxicity
The cell culture broth containing the peptide bovine serum was incubated at 37℃for 24h. The subcultured human normal liver cells LO2 were prepared into a cell suspension of 1X 10 5 cells/mL in a tissue culture medium, and the cell suspension was inoculated into a 96-well cell culture plate (100. Mu.l/well) and cultured in a 37℃carbon dioxide incubator for 24 hours. After the equal cells are grown by adherence, removing the supernatant, adding tissue culture media of a control group (without adding drugs) and a test group (adding drugs) for incubation and culture, wherein the concentration of the drugs in the cell culture fluid is 500 mu mol/L, and placing the cell culture fluid in a 37 ℃ carbon dioxide incubator for continuous culture. After incubation for 2 days, the cells were removed. MTT solution was added for further culture for 4 hours. The cell incubation was removed, DMSO was then added, and shaking was performed for 10min, and finally the absorbance was measured with a microplate reader at a wavelength of 570nm, and the relative proliferation degree (RGR) of the cells was calculated according to the formula from the absorbance. The relative proliferation of cells was calculated as:
The results are shown in Table 1. It can be seen that the RGR of the series of amino acid-BSH-targeted compounds was nearly 100% after 2 days incubation with human normal hepatocytes LO2 cells, indicating that these compounds were not toxic or very low in human normal hepatocytes at 500. Mu. Mol/L.
Table 1 relative proliferation of cells (RGR) as measured by MTT colorimetry
Example 4 cellular boron uptake characteristics of amino acid-BSH targeting Compounds of the series
The boron uptake characteristics of the serial amino acid-BSH targeting compounds in Human Umbilical Vein Endothelial Cells (HUVEC), human liver cancer cells HepG2, human breast cancer cells MDA-MB-231 and human glioma cells U87 are determined by adopting an ICP-MS method.
The specific process includes adding proper amount of RPMI 1640 culture solution (fetal calf serum 10% and penicillin 100U/ml) into tumor cells in logarithmic growth phase, regulating cell concentration to 1X 10 5 cells/ml, inoculating to 6-well culture plate, and inoculating tumor cell suspension 100 μl in each well. After 24h incubation, the prepared test drug (control group without drug) was added to give a final drug concentration of 100. Mu.M, the mixture was placed in a 5% CO 2 incubator, after 24h incubation at 37℃the medium in the dish was removed with a pipette, washed with PBS (3X 1 mL), 0.5mL pancreatin was added to the dish, followed by incubation in a 37℃constant temperature CO 2 incubator for 3min, during which time the cells were examined under a microscope for shrinkage and rounding, and after shrinkage and rounding, 0.6mL medium was added rapidly to terminate digestion, and the adherent cells were gently blown off the bottom of the dish, and then the cell suspension was transferred to a centrifuge tube, and after dilution the cell count was counted with a hemocytometer to calculate the cell number per well. The cell suspension was centrifuged, the supernatant was removed, and PBS was added to wash (3X 1 mL). Adding 500 mu L of concentrated nitric acid into the washed cell-containing centrifuge tube for digestion, measuring the boron content in cells by adopting an ICP-MS method, and calculating the T/N ratio. The T/N ratio is defined as the boron uptake in tumor cells/the boron loading in HUVEC cells.
The results are shown in tables 2 to 4. It can be seen that in all three tumor cells examined, the boron loading of all amino acid-BSH targeting compounds is much greater than 10 9 B/cells, the T/N ratio is greater than 3.0, and the preconditions for serving as boron delivery agents are met. All ester compounds showed superior boron uptake characteristics to the corresponding amide compounds, and in specific tumor cells, specific amino acid-BSH targeting compounds showed superior boron uptake characteristics to the positive control sodium boron calidate (BSH). For example, in HepG2 cells, the boron uptake characteristics of Met-O-BSH, D-Met-O-BSH, tyr-O-BSH, dpa-O-BSH, his-O-BSH, trp-N-BSH and His-N-BSH are all superior to those of positive control drugs, especially Met-O-BSH, which has a T/N value 4 times that of BSH, in human breast cancer cells MDA-MB-231, leu-O-BSH, D-Leu-O-BSH, met-O-BSH, D-Met-O-BSH, tyr-O-BSH and Dpa-O-BSH are all superior to BSH, and in human glioma cells U87, tyr-O-BSH and Dpa-O-BSH are all superior to BSH, especially Tyr-O-BSH, which has a T/N value 5.1 times that of BSH.
Table 2 boron uptake characteristics of amino acid-BSH targeting compounds in human liver cancer HepG2 cells
a The T/N ratio is defined as the boron uptake of the human hepatoma cell HepG 2/the boron uptake of the human umbilical vein endothelial cell HUVEC
Table 3 boron uptake characteristics of amino acid-BSH targeting compounds in human breast cancer cells MDA-MB-231
a The T/N ratio is defined as the boron uptake of human breast cancer cells MDA-MB-231/the boron uptake of human umbilical vein endothelial cells HUVEC
Table 4 boron uptake characteristics of amino acid-BSH targeting compounds in human glioma cells U87
a The T/N ratio is defined as the boron uptake of human glioma cells U87/the boron uptake of human umbilical vein endothelial cells HUVEC
Example 5 lipophilic hydrophilic character of amino acid-BSH targeting Compounds
The experimental method comprises a) establishing a detection standard curve of each sample to be detected. Dissolving serial amino acid-BSH targeting compound in enzymolysis buffer solution (50 mM Tris-HCl,1.0M NaCl,pH 7.4), setting 5 concentration gradients of 0.012725, 0.006363, 0.003181, 0.001591 and 0.000795 mug/mL, drawing standard curve with peak area as ordinate and medicine concentration as abscissa, repeating the experiment for 3 times, b) preparing water solution saturated n-octanol and water solution saturated n-octanol, mixing n-octanol and water in equal proportion, stirring for 24h to saturate two phases, standing for layering, separating two phases, respectively storing for standby, c) precisely weighing 10mg of sample to be measured, adding water solution saturated n-octanol to dissolve the sample, diluting to scale, precisely sucking 8-25 mL of water solution saturated n-octanol from the sample, and adding 8mL of water solution saturated n-octanol. After shaking a 25mL volumetric flask for 3 hours, standing to separate out a water phase and an oil phase, filtering by a 0.22 mu m filter membrane, sampling 10 mu l each time, measuring the peak area by using HPLC, taking the peak area into a standard curve equation, and calculating the content of a sample to be detected in each phase. The oil-water distribution coefficient calculation formula:
The results of the experiment are shown in Table 5. It can be seen that the positive control drug BSH has a LogP value of-2.36+ -0.03, less than 1, showing high solubility of BSH in water, low passive diffusion permeation, poor absorption and brain permeability, and high renal clearance. The compound disclosed by the invention has the logP value of more than 0 except His-O-BSH and His-N-BSH, and shows that the compound has better permeability than BSH, and is combined with metabolic enzyme to be increased, so that the metabolic degree is high.
TABLE 5 lipophilicity and hydrophilicity coefficients (LogP) of amino acid-BSH targeting compounds
The above examples are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above examples, and any other changes, modifications, substitutions, combinations, and simplifications that do not depart from the spirit and principle of the present invention should be made in the equivalent manner, and the embodiments are included in the protection scope of the present invention.

Claims (9)

1.一种氨基酸-BSH靶向杂合体化合物，其结构如式I所示，1. An amino acid-BSH targeting hybrid compound, the structure of which is shown in Formula I, 其中，X为CHMe2、CH2CHMe2、CH(CH3)CH2CH3、CH2CH2SMe、Bn、CH2(3-Indoyl)、CH2[4-(OH)Ph]、CH2[3,4-bis(OH)Ph]、CH2(4-Imidazolyl)中的任一种；*标记的碳的构型为R-或S-；Y可以为O或NH；B为10B或天然硼；SNaB12H11的结构如下：Wherein, X is any one of CHMe 2 , CH 2 CHMe 2 , CH(CH 3 )CH 2 CH 3 , CH 2 CH 2 SMe, Bn, CH 2 (3-Indoyl), CH 2 [4-(OH)Ph], CH 2 [3,4-bis(OH)Ph], CH 2 (4-Imidazolyl); the configuration of the carbon marked by * is R- or S-; Y can be O or NH; B is 10 B or natural boron; the structure of SNaB 12 H 11 is as follows: 2.根据权利要求1所述的氨基酸-BSH靶向杂合体化合物，其特征在于选自以下的具体化合物：2. The amino acid-BSH targeting hybrid compound according to claim 1, characterized in that it is selected from the following specific compounds: 3.一种如权利要求1或2所述的氨基酸-BSH靶向杂合体化合物的制备方法，其特征在于，当Y＝O时，包括以下步骤：3. A method for preparing an amino acid-BSH targeting hybrid compound as claimed in claim 1 or 2, characterized in that when Y=O, the method comprises the following steps: (1)2-(2-(2-羟乙氧基)乙氧基)乙基活泼酯(TrG Es)的制备：称取二缩三乙二醇溶于干燥重蒸的二氯甲烷(DCM)中，加入搅拌子，冰浴下加入适量的有机碱，分批加入酰化试剂，室温下搅拌反应约30min，保持室温继续反应12小时，加入适量DCM，分别经水洗、酸洗、干燥后，减压浓缩，(1) Preparation of 2-(2-(2-hydroxyethoxy)ethoxy)ethyl active ester (TrG Es): Weigh triethylene glycol and dissolve it in dry redistilled dichloromethane (DCM), add a stirrer, add an appropriate amount of organic base under ice bath, add acylating agent in batches, stir and react at room temperature for about 30 minutes, keep the room temperature and continue to react for 12 hours, add an appropriate amount of DCM, wash with water, wash with acid, dry, and concentrate under reduced pressure. 合成路线如下：The synthetic route is as follows: (2)N-叔丁氧羰基氨基酸酯桥连活泼酯(N-Boc-AA-O-TrG Es)的制备：称取N-Boc氨基酸溶解于适量DCM中，将反应瓶置于冰浴下平衡5分钟，依次加入缩合剂和4-二甲氨基吡啶(DMAP)，维持冰浴搅拌10分钟之后加入TrG Es，加料完毕后继续在冰浴下反应30分钟，后保持在室温下反应12小时，反应结束后，加入适量DCM，DCM层依次用水、1N HCl洗涤，干燥，浓缩得残留物，经硅胶柱层析纯化，浓缩得目标产物，(2) Preparation of N-tert-butyloxycarbonyl amino acid ester bridged active ester (N-Boc-AA-O-TrG Es): Weigh N-Boc amino acid and dissolve it in an appropriate amount of DCM. Place the reaction bottle in an ice bath for 5 minutes, add the condensing agent and 4-dimethylaminopyridine (DMAP) in turn, keep stirring in the ice bath for 10 minutes, then add TrG Es. After the addition is completed, continue to react in the ice bath for 30 minutes, then keep the reaction at room temperature for 12 hours. After the reaction is completed, add an appropriate amount of DCM, wash the DCM layer with water and 1N HCl in turn, dry, and concentrate to obtain the residue. Purify it by silica gel column chromatography and concentrate to obtain the target product. 合成路线如下：The synthetic route is as follows: (3)N-叔丁氧碳基氨基酸酯桥连溴(N-Boc-AA-O-TrG-Br)的制备：称取化合物N-Boc-AA-O-TrG Es溶于适量丙酮，加入溴化锂，将反应器置于合适温度的油浴中加热反应2～10小时，反应结束，蒸除溶剂，加适量DCM，水洗涤，干燥，柱层析分离纯化，(3) Preparation of N-tert-butyloxycarbonyl amino acid ester bridged bromine (N-Boc-AA-O-TrG-Br): Weigh the compound N-Boc-AA-O-TrG Es and dissolve it in an appropriate amount of acetone, add lithium bromide, place the reactor in an oil bath at an appropriate temperature and heat to react for 2 to 10 hours. After the reaction is completed, evaporate the solvent, add an appropriate amount of DCM, wash with water, dry, and separate and purify by column chromatography. 合成步骤如下：The synthesis steps are as follows: (4)N-叔丁氧碳基氨基酸酯桥连硼卡(N-Boc-AA-O-TrG-BSH)的制备：称取化合物N-Boc-AA-O-TrG Br和硼卡钠(Na2SB12H11)溶于适量干燥乙腈，搅拌下加入无机碱和碘化钾，将反应体系置于油浴上加热回流5～10小时，反应结束后，旋蒸除去溶剂，残留物用快速柱层析分离纯化，(4) Preparation of N-tert-butyloxycarbonyl amino acid ester bridged borocarbyl (N-Boc-AA-O-TrG-BSH): Weigh the compound N-Boc-AA-O-TrG Br and borocarbyl sodium (Na 2 SB 12 H 11 ) and dissolve them in an appropriate amount of dry acetonitrile. Add an inorganic base and potassium iodide under stirring. Place the reaction system in an oil bath and heat under reflux for 5 to 10 hours. After the reaction is completed, remove the solvent by rotary evaporation. The residue is separated and purified by flash column chromatography. 合成路线如下：The synthetic route is as follows: (5)氨基酸酯桥连硼卡(AA-O-BSH)的制备：称取化合物N-Boc-AA-O-TrG-BSH溶于干燥DCM中，置于冰浴中冷却5分钟，搅拌下加入酸，随后升至室温继续反应1～5小时，TLC检测反应转化完全，展开剂：DCM/MeOH＝1/1，饱和碳酸氢钠调节反应体系pH至弱碱性，旋蒸除去溶剂，残留物经柱层析分离，冷冻干燥得产物，(5) Preparation of amino acid ester bridged borocard (AA-O-BSH): Weigh the compound N-Boc-AA-O-TrG-BSH and dissolve it in dry DCM. Cool it in an ice bath for 5 minutes, add acid while stirring, then warm it to room temperature and continue the reaction for 1 to 5 hours. TLC detection shows that the reaction is completely converted. The developing solvent is DCM/MeOH=1/1. Saturated sodium bicarbonate is used to adjust the pH of the reaction system to weak alkalinity. The solvent is removed by rotary evaporation. The residue is separated by column chromatography and freeze-dried to obtain the product. 合成路线如下：The synthetic route is as follows: 4.一种如权利要求1或2所述的氨基酸-BSH靶向杂合体化合物的制备方法，其特征在于，当Y＝NH时，包括以下步骤：4. A method for preparing an amino acid-BSH targeting hybrid compound as claimed in claim 1 or 2, characterized in that when Y=NH, the method comprises the following steps: (1)N-叔丁氧碳基氨基酸酰胺桥连醇(N-Boc-AA-N-TrG-OH)的制备：称取N-Boc氨基酸溶解于适量DCM中，将反应瓶置于冰浴下平衡5分钟，依次加入缩合剂和有机碱，维持冰浴搅拌10分钟之后加入2-(2-(2-氨基乙氧基)乙氧基)乙醇，加料完毕后继续在冰浴下反应30分钟，后保持在室温下反应12小时，反应结束后，加入适量DCM，DCM层依次用水、1N HCl洗涤，干燥，浓缩得残留物，经硅胶柱层析纯化，浓缩得目标产物，(1) Preparation of N-tert-butyloxycarbonylamino acid amide bridged alcohol (N-Boc-AA-N-TrG-OH): Weigh N-Boc amino acid and dissolve it in an appropriate amount of DCM. Place the reaction bottle in an ice bath for 5 minutes, add a condensing agent and an organic base in sequence, keep stirring in the ice bath for 10 minutes, then add 2-(2-(2-aminoethoxy)ethoxy)ethanol. After the addition is completed, continue to react in an ice bath for 30 minutes, then keep the reaction at room temperature for 12 hours. After the reaction is completed, add an appropriate amount of DCM. The DCM layer is washed with water and 1N HCl in sequence, dried, and concentrated to obtain a residue. Purify by silica gel column chromatography and concentrate to obtain the target product. 合成路线如下：The synthetic route is as follows: (2)N-叔丁氧碳基氨基酸酰胺桥连活泼酯(N-Boc-AA-N-TrG Es)的制备：将二缩三乙二醇替换为N-叔丁氧碳基氨基酸酰胺桥连醇，按照权利要求3步骤(1)所述方法制备，合成路线如下：(2) Preparation of N-tert-butyloxycarbonyl amino acid amide bridged active ester (N-Boc-AA-N-TrG Es): Replace triethylene glycol with N-tert-butyloxycarbonyl amino acid amide bridged alcohol and prepare according to the method described in step (1) of claim 3. The synthetic route is as follows: (3)N-叔丁氧碳基氨基酸酰胺桥连溴(N-Boc-AA-N-TrG-Br)的制备：将N-叔丁氧碳基氨基酸酯桥连活泼酯替换为N-叔丁氧碳基氨基酸酰胺桥连活泼酯，按照权利要求3步骤(3)所述方法制备，合成路线如下：(3) Preparation of N-tert-butoxycarbonyl amino acid amide bridged bromide (N-Boc-AA-N-TrG-Br): Replace the N-tert-butoxycarbonyl amino acid ester bridged active ester with N-tert-butoxycarbonyl amino acid amide bridged active ester, and prepare according to the method described in step (3) of claim 3. The synthetic route is as follows: (4)N-叔丁氧碳基氨基酸酰胺桥连硼卡(N-Boc-AA-N-TrG-BSH)的制备：将N-叔丁氧碳基氨基酸酯桥连溴替换为N-叔丁氧碳基氨基酸酰胺桥连溴，按照权利要求3步骤(4)所述方法制备，合成路线如下：(4) Preparation of N-tert-butyloxycarbonyl amino acid amide bridged borocarbyl (N-Boc-AA-N-TrG-BSH): Replace the N-tert-butyloxycarbonyl amino acid ester bridged bromine with N-tert-butyloxycarbonyl amino acid amide bridged bromine, and prepare according to the method described in step (4) of claim 3. The synthetic route is as follows: (5)氨基酸酰胺桥连硼卡(AA-N-BSH)的制备：将N-叔丁氧碳基氨基酸酯桥连硼卡替换为N-叔丁氧碳基氨基酸酰胺桥连硼卡，按照权利要求3步骤(5)所述方法制备，合成路线如下：(5) Preparation of amino acid amide bridged boron card (AA-N-BSH): replace the N-tert-butyloxycarbonyl amino acid ester bridged boron card with the N-tert-butyloxycarbonyl amino acid amide bridged boron card, and prepare it according to the method described in step (5) of claim 3. The synthetic route is as follows: 5.根据权利要求3所述的制备方法，其特征在于：5. The preparation method according to claim 3, characterized in that: 步骤(1)中，二缩三乙二醇与有机碱的投料摩尔比为1:1.1～1.5；二缩三乙二醇与酰化试剂的投料摩尔比为1:1.1～1.5；所述有机碱为三乙胺、三甲胺、二异丙基乙胺中的任一种；所述酰化试剂为对甲苯磺酰氯、甲磺酰氯、三氟甲磺酰氯中的任一种；In step (1), the molar ratio of triethylene glycol to the organic base is 1:1.1-1.5; the molar ratio of triethylene glycol to the acylating agent is 1:1.1-1.5; the organic base is any one of triethylamine, trimethylamine, and diisopropylethylamine; the acylating agent is any one of p-toluenesulfonyl chloride, methanesulfonyl chloride, and trifluoromethanesulfonyl chloride; 步骤(2)中，N-Boc氨基酸与缩合剂、DMAP、TrG Es的投料摩尔比分别为1:1.1～1.5、1:0.1～0.5、1:1.1～1.5；所述缩合剂为2-(7-氧化苯骈三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(HATU)、氯甲酸乙酯、1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(EDCI)、N,N’-二异丙基碳二亚胺(DIC)、六氟磷酸苯骈三唑-1-基-氧基三吡咯烷基磷(PyBOP)中的任一种；In step (2), the molar ratios of N-Boc amino acid to condensing agent, DMAP and TrG Es are 1:1.1-1.5, 1:0.1-0.5 and 1:1.1-1.5 respectively; the condensing agent is any one of 2-(7-oxybenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), ethyl chloroformate, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI), N,N'-diisopropylcarbodiimide (DIC) and benzotriazole-1-yl-oxytripyrrolidinophosphine hexafluorophosphate (PyBOP); 步骤(3)中，N-Boc-AA-O-TrG Es与溴化锂的投料摩尔比为1:1.1～1.5；反应温度为40～100℃；In step (3), the molar ratio of N-Boc-AA-O-TrG Es to lithium bromide is 1:1.1-1.5; the reaction temperature is 40-100°C; 步骤(4)中，N-Boc-AA-O-TrG-Br与硼卡钠、无机碱、碘化钾的投料摩尔比分别为1.1～1.5:1、1:2.0～5.0、1:2.0～5.0；所述无机碱为碳酸锂、碳酸铯、碳酸钾；In step (4), the molar ratios of N-Boc-AA-O-TrG-Br to sodium borocarbamide, inorganic base, and potassium iodide are 1.1-1.5:1, 1:2.0-5.0, and 1:2.0-5.0, respectively; the inorganic base is lithium carbonate, cesium carbonate, and potassium carbonate; 步骤(5)中，N-Boc-AA-O-TrG-BSH与酸的投料摩尔比为1.0:100～250；所述的酸为三氟醋酸(TFA)或盐酸。In step (5), the molar ratio of N-Boc-AA-O-TrG-BSH to acid is 1.0:100-250; the acid is trifluoroacetic acid (TFA) or hydrochloric acid. 6.根据权利要求4所述的制备方法，其特征在于：6. The preparation method according to claim 4, characterized in that: 步骤(1)中，N-Boc氨基酸与缩合剂、有机碱、2-(2-(2-氨基乙氧基)乙氧基)乙醇的投料摩尔比为1:1.1～1.5、1:2.0～5.0、1:1.1～1.5；所述缩合剂与权利要求3步骤(2)相同；所述有机碱为二异丙基乙胺(DIPEA)、三乙胺、2,2,6,6-四甲基哌啶中的任一种。In step (1), the molar ratio of N-Boc amino acid to condensing agent, organic base and 2-(2-(2-aminoethoxy)ethoxy)ethanol is 1:1.1-1.5, 1:2.0-5.0 and 1:1.1-1.5; the condensing agent is the same as step (2) of claim 3; the organic base is any one of diisopropylethylamine (DIPEA), triethylamine and 2,2,6,6-tetramethylpiperidine. 7.如权利要求1或2所述的氨基酸-BSH靶向杂合体化合物和它们在生理上可接受的盐在制备肿瘤硼中子俘获疗法(BNCT)中的硼递送剂中的应用。7. Use of the amino acid-BSH targeting hybrid compound as claimed in claim 1 or 2 and their physiologically acceptable salts in the preparation of a boron delivery agent for tumor boron neutron capture therapy (BNCT). 8.根据权利要求7所述的应用，其特征在于：所述肿瘤为脑瘤、头颈瘤、肝癌、乳腺癌、肺癌、结肠癌、宫颈癌或前列腺癌。8. The use according to claim 7, characterized in that the tumor is a brain tumor, head and neck tumor, liver cancer, breast cancer, lung cancer, colon cancer, cervical cancer or prostate cancer. 9.根据权利要求7所述的应用，其特征在于：所述在生理上可接受的盐为酒石酸盐、硫酸盐、盐酸盐。9. The use according to claim 7, characterized in that the physiologically acceptable salt is tartrate, sulfate, or hydrochloride.
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