CN112876503B - Borate compound for cancer boron neutron capture therapeutic medicine and preparation thereof - Google Patents
Borate compound for cancer boron neutron capture therapeutic medicine and preparation thereof Download PDFInfo
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Abstract
The invention relates to a borate compound for a boron neutron capture therapeutic drug for cancer, which has the following structural general formula:
(ii) a In the formula R1Is aryl, R2,R3,R4Are one of H, alkyl, aryl, silicon base and boron base. The invention also discloses a preparation method of the borate compound. The invention has better stability and acid resistance, and has stronger selectivity to head and neck cancer cells (CAL 27).
Description
Technical Field
The invention relates to the fields of medicinal chemistry and radiation medicine, in particular to a borate compound for a boron neutron capture therapeutic drug for cancer and a preparation method thereof.
Background
Head and neck cancer is a cancer with high incidence rate, great treatment difficulty and high mortality rate, and the eradication of the cancer is a great challenge in human medicine. In recent years, with the progress of drug development at home and abroad, people have made great progress in the development of anticancer drugs, but there is still a great need for new and more effective cancer treatment methods.
Boron Neutron Capture Therapy (BNCT) is a novel radiotherapy technology for targeting tumor cells, and BNCT is a binary method based on nuclear capture and fission reaction, and has the advantages of obvious low side effect, high selectivity and high efficiency compared with the traditional radiotherapy and chemotherapy. When non-radioactive is irradiated with low-energy thermal/epithermal neutrons10B atom, high Linear Energy Transfer (LET) alpha particle and7li recoils the nucleus. The high LET particles have a travel of 5-9 μm, close to a cell diameter, and are selective and contain only10The tumor cells of the B molecule generate strong heat action, and can kill cancer cells without causing excessive damage to surrounding normal cells.
At present, mercaptododecaborane disodium salt (BSH) and (L) -4-dihydroxyborylphenylalanine (BPA) have been clinically used for BNCT boron drugs for treating tumors [ patent publication nos. CN 111971563 a and CN 111204736 a ]; among them, BPA was approved and marketed in japan in 3 months of 2020, becoming the first BNCT boron drug approved and marketed worldwide. However, BSH and BPA are found to have the problem of insufficient tumor targeting in BNCT clinical research. Chemical structure modification of boronic acids and boranes is currently the main research strategy, but efficiency needs to be further improved. Patent application No. 201980041340.X proposes that an aggregating boron 10 agent can be used in boron neutron capture therapy, can selectively or locally target tumor tissues in a short time, and has the advantages of small side effect, low invasiveness and capability of exerting a local killing effect on the tumor tissues. Chinese patent 202011268512.8 discloses carborane-based celecoxib, a preparation method thereof and application thereof in boron neutron capture treatment medicines for head and neck cancer. Chinese patent 202010020070.9 discloses a preparation method of boron-containing carbon quantum dots and application thereof in medicines for tumor diagnosis and boron neutron capture therapy, wherein the boron-containing carbon quantum dots have good biocompatibility and excellent in-vivo fluorescence imaging effect.
The microenvironment of the tumor cells is weakly acidic (pH = 6.5-6.8), while the lysosomes of the tumor cells are more acidic (pH around 5.0). If the alkalinity of the boron-containing molecules is increased, the selectivity of the boron drug in cancer cells is expected to be further improved. The four-coordination boric acid compound has certain alkalescence, is a common intermediate in the chemical reaction of organic boric acid molecules, and has very limited research on the compound due to higher instability. In 2020, Lijihui et al reported that arylboronic acid compounds can be effectively stabilized in the presence of silane and that arylboronic acid sodium salt can be used as a catalyst in heterogeneously catalyzed reactionsGreen Chem., 2020, 22, 5317-5324]. Therefore, on the basis of improving the stability of borate, the boric acid boron drug molecules are modified to obtain the boron neutron capture treatment drug for cancer with higher efficiency.
Disclosure of Invention
The invention aims to provide a borate compound which has better stability and acid resistance and is used for boron neutron capture therapeutic drugs for cancers.
The invention also provides a preparation method of the borate compound for the boron neutron capture treatment medicine for the cancer.
In order to solve the above problems, the borate compound for boron neutron capture therapeutic drugs for cancer according to the present invention is characterized in that: the structural general formula of the borate compound is as follows:
The preparation method of the borate compound for the boron neutron capture therapeutic medicine for cancer is characterized by comprising the following steps: adding a boric acid compound, strong base and a reaction solvent into a reaction container, reacting at 25-180 ℃ for 30 s-48 h, and cooling to room temperature to obtain a reaction solution A; filtering the reaction solution A to obtain a solid A, and recrystallizing and separating the solid A to obtain a borate compound A; the molar ratio of the boronic acid compound to the strong base is 1: 0.5-1: 10.
the chemical reaction formula is as follows (formula I):
the preparation method of the borate compound for the boron neutron capture therapeutic medicine for cancer is characterized by comprising the following steps: adding a boric acid compound, strong base and a reaction solvent into a reaction container, reacting at 25-180 ℃ for 30 s-48 h, adding a stabilizing reagent, and cooling to room temperature after the reaction is finished to obtain a reaction solution B; filtering the reaction solution B to obtain a solid B, and recrystallizing and separating the solid B to obtain a borate compound B; the molar ratio of the boronic acid compound to the strong base is 1: 0.5-1: 10; the molar ratio of the boronic acid compound to the stabilizing agent is 1: 0.5 to 5.
The chemical reaction formula is as follows (formula II):
the boric acid compound refers to aryl boric acid or aliphatic boric acid.
The boric acid compound is that a benzene ring is connected with B (OH)2Of phenylalanine group, ofStructural formula is
(ii) a In the formula R1It means that various functional groups in phenyl, p-tolyl, methyl, trifluoromethyl, chain or cyclic alkyl, aryl comprising fused rings or heterocycles, siloxy and halogen are mono-substituted or multi-substituted.
The structural formula of the boric acid compound is one of the following formulas:
the strong base refers to a hydroxide or alkoxylate of a metal.
The strong base is one of NaOH, KOH, LiOH, sodium methoxide, sodium ethoxide, ethylene glycol disodium, sodium glycerol and sodium salt of sugar.
The stabilizing agent is any agent with an electron withdrawing group.
The stabilizing agent is one of reagents of sodium pentafluorophenyl, phenylsilane, diphenylsilane, triphenylsilane, 2- (trimethyl silicon) phenyl trifluoromethanesulfonic acid, hexamethyldisilane, hexaphenyldisilane, tert-butyldimethylchlorosilane, diethylsilane, triethylsilane, trimethylsilanol and triethylsilanol.
The reaction solvent refers to an organic solvent, including but not limited to one or more of dimethyl sulfoxide, N-dimethylformamide, tetrahydrofuran, acetonitrile, methanol, dioxane, N-methylpyrrolidone, toluene, xylene and mesitylene.
The reaction temperature is preferably 60-100 ℃; the reaction time is preferably 1-6 h.
Compared with the prior art, the invention has the following advantages:
1. compared with the prior research object limited to boric acid compounds, the invention discloses a preparation method of four-coordination borate based on a stabilization strategy, and the obtained borate has better stability and acid resistance, and breaks through the conventional understanding that the borate is unstable and easy to decompose.
2. According to the invention, the charge of borate anions is dispersed by utilizing metal with certain Lewis acidity, Si group, B group and other groups, so that the improvement of borate stability is effectively realized.
3. The invention is a brand new improvement to the scope of the known BNCT boron medicament, successfully enriches and expands the scope of the boron medicament, fills the defects of the existing borate preparation technology, and realizes the high-efficiency and low-cost production of various borates with different structures.
4. The borate biological activity test result provided by the invention shows that the borate derived from BPA has stronger selectivity on head and neck cancer cells (CAL27), has obvious apoptosis induction effect on the head and neck cancer cells in boron neutron capture treatment, and shows better efficiency than BPA, thereby being expected to reduce the dosage of boron drugs, and showing better application prospect compared with the traditional boric acid boron drugs.
5. The invention has simple process and high synthesis efficiency.
Detailed Description
A borate compound for a boron neutron capture therapeutic agent for cancer, the borate compound having the general structural formula:
The materials used in the following examples are commercially available unless otherwise specified.
[ one-step method ]
The preparation method of the borate compound used for the boron neutron capture therapeutic medicine of the cancer comprises the following steps:
adding a boric acid compound, strong base and a reaction solvent into a reaction container, reacting at 25-180 ℃ for 30 s-48 h, and cooling to room temperature to obtain a reaction solution A; and filtering the reaction solution A to obtain a solid A, and recrystallizing and separating the solid A to obtain the borate compound A.
[ two-step Process ]
The preparation method of the borate compound used for the boron neutron capture therapeutic medicine of the cancer comprises the following steps:
adding a boric acid compound, strong base and a reaction solvent into a reaction container, reacting at 25-180 ℃ for 30 s-48 h, adding a stabilizing reagent, and cooling to room temperature after the reaction is finished to obtain a reaction solution B; and filtering the reaction solution B to obtain a solid B, and recrystallizing and separating the solid B to obtain the borate compound B.
Wherein: the boric acid compound refers to an arylboronic acid or an aliphatic boronic acid. Such as: 4-dihydroxyborylphenylalanine (BPA), phenylboronic acid, 1-naphthylboronic acid, 2-anthracenylboronic acid, methylboronic acid, 3-acetylphenylboronic acid, 3-biphenylboronic acid, 4-n-butylbenzeneboronic acid, 4-acetylphenylboronic acid and the like.
The boric acid compound is that a benzene ring is connected with B (OH)2The structural formula of the radical phenylalanine compound is
(ii) a In the formula R1It means that various functional groups in phenyl, p-tolyl, methyl, trifluoromethyl, chain or cyclic alkyl, aryl comprising fused rings or heterocycles, siloxy and halogen are mono-substituted or multi-substituted.
The structural formula of the boric acid compound is one of the following:
strong bases refer to hydroxides or alkoxylates of metals.
The strong base is one of NaOH, KOH, LiOH, sodium methoxide, sodium ethoxide, ethylene glycol disodium, sodium glycerol and sodium salt of sugar.
Stabilizing agent refers to any agent with an electron withdrawing group.
The stabilizing agent is one of reagents of sodium pentafluorophenyl, phenylsilane, diphenylsilane, triphenylsilane, 2- (trimethylsilyl) phenyltrifluoromethanesulfonic acid, hexamethyldisilane, hexaphenyldisilane, tert-butyldimethylchlorosilane, diethylsilane, triethylsilane, trimethylsilanol and triethylsilanol.
The reaction solvent refers to an organic solvent, including but not limited to one or more of dimethyl sulfoxide, N-dimethylformamide, tetrahydrofuran, acetonitrile, methanol, dioxane, N-methylpyrrolidone, toluene, xylene, and mesitylene.
The reaction temperature is preferably 60-100 ℃; the reaction time is preferably 1-6 h.
The strong alkali is a pure product prepared in advance or purchased directly from a commercial channel; the boric acid compound can be prepared in advance and used after separation and purification, and can also be prepared in situ in the reaction process and directly used without any treatment.
The borate compound A and the borate compound B are four-coordinate borate, the chemical structural formulas of which are shown in formulas I and II, and the preferred structures are as follows:
example 1: preparation of borate compound (1) (two-step process).
(L) -4-Dihydroboranophenylalanine (0.05 mmol, 10.45 mg), sodium hydroxide (0.15 mmol, 6 mg), toluene (4 mL), and a magnetic stirrer were added to a 35 mL glass pressure tube under an air atmosphere. Triphenylsilane (0.15 mmol, 39 mg) was then added, and the reaction tube was reacted at 90 ℃ for 6 hours. After the reaction is finished, cooling the reaction system to room temperature, opening the reaction container at room temperature, and filtering; and recrystallizing the obtained solid and separating to obtain a reaction product. The pure yield of the target product is 78%.
1H NMR (300 MHz, DMSO) δ 12.89 (s, 1H), 8.71 (d, 2H), 7.75 (d, 2H), 7.46 (m, 18H), 7.39-7.35 (m, 27H), 7.2(d, 2H), 4.18(s, 1H), 3.42(d, 2H).
13C NMR (100 MHz, DMSO) δ 174.7, 138.3, 136.6, 135.7, 133.3, 132.5,130.0, 129.5, 127.7, 56.7, 37.3.
EXAMPLE 2 preparation of Borate Compound (2) (one-step method)
Phenylboronic acid (0.05 mmol, 6.1 mg), sodium triphenylsilanolate (0.025 mmol, 7.46 mg), and a magnetic stir bar were added to a 35 mL glass pressure tube under air. Toluene (4 mL) was then added and the reaction tube was allowed to react at 90 ℃ for 6 hours. After the reaction is finished, cooling the reaction system to room temperature, opening the reaction container at room temperature, and filtering; and recrystallizing the obtained solid and separating to obtain a reaction product. The pure yield of the target product is 75%.
1H NMR (300 MHz, DMSO) δ 7.75(d, 2H), 7.48 - 7.44 (m, 6H),7.37-7.39(m, 10m) 7.36(s, 1H), 7.35(s, 1H), 4.2 (d, 2H).
13C NMR (101 MHz, DMSO) δ 138.5, 138.3, 133.4, 132.5, 130.0, 129.5, 128.7.
EXAMPLE 3 preparation of Borate Compound (3) (two-step Process)
Phenylboronic acid (0.05 mmol, 6.1 mg), sodium hydroxide (0.5 mmol, 20 mg), toluene (4 mL) and a magnetic stirrer were added to a 35 mL glass pressure tube under an air atmosphere. Triphenylsilane (0.15 mmol, 39 mg) was then added, and the reaction tube was reacted at 90 ℃ for 12 hours. After the reaction is finished, cooling the reaction system to room temperature, opening the reaction container at room temperature, and filtering; and recrystallizing the obtained solid and separating to obtain a reaction product. The pure yield of the target product is 75%.
1H NMR (300 MHz, DMSO) δ 7.75 (d, 2H), 7.48- 7.44 (m, 18H), 7.34 - 7.38 (m, 30H).
13C NMR (101 MHz, DMSO) δ 138.3, 133.4, 132.5, 130.0, 129.5, 128.7.
EXAMPLE 4 preparation of Borate Compound (4) (one-step method)
F-BPA (0.05 mmol, 11.35 mg), sodium triphenylsilanolate (0.2 mmol, 59.68 mg), and a magnetic stir bar were added to a 35 mL glass pressure tube under air. The reaction tube was reacted at 90 ℃ for 6 hours. After the reaction is finished, cooling the reaction system to room temperature, opening the reaction container at room temperature, and filtering; and recrystallizing the obtained solid and separating to obtain a reaction product. The pure yield of the target product is 85%.
1H NMR (300 MHz, DMSO) δ 12.89 (s, 1H), 8.71 (d, 2H), 7.52 (s, 1H), 7.46 (m, 6H), 7.35-7.39 (m, 9H), 7.18 (s, 1H), 7.04 (s, 1H), 4.2(d, 2H), 4.18 (m, 1H), 3.42 (d, 2H).
13C NMR (101 MHz, DMSO) δ 174.7, 160.2, 138.3, 137.3, 132.5, 130.0, 129.5, 128.1, 115.6, 56.7, 32.4.
EXAMPLE 5 preparation of Borate Compound (5) (two-step Process)
BPA-Tyr (0.05 mmol, 18.61 mg), potassium hydroxide (0.2 mmol, 11.2 mg), toluene (4 mL), and a magnetic stirrer were added to a 35 mL glass pressure tube under an air atmosphere. Triphenylsilane (0.25 mmol, 65.10 mg) was then added, and the reaction tube was reacted at 100 ℃ for 10 hours. After the reaction is finished, cooling the reaction system to room temperature, opening the reaction container at room temperature, and filtering; and recrystallizing the obtained solid and separating to obtain a reaction product. The pure yield of the target product is 70%.
1H NMR (300 MHz, DMSO) δ 12.8 9 (m, 1H), 9.06 (m, 1H), 8.86 (m, 2H), 8.32 (m, 1H), 7.75 (d, 2H), 7.48-7.44 (m, 24H), 7.38-7.34 (m, 20), 7.2 (m, 2H), 6.96 (m, 2H), 6.68 (m, 2H), 4.72 (m, 1H), 3.95 (d, 1H), 3.44 (m, 2H), 3.12 (m, 2H).
13C NMR (101 MHz, DMSO) δ 174.7, 171.7, 155.7, 138.3, 136.6, 135.7, 132.5, 130.2, 130.0, 129.5, 129.2,127.7, 115.8, 59.2, 56.0, 38.7, 36.5.
EXAMPLE 6 preparation of Borate Compound (6) (one-shot method)
BPA-Tyr (0.05 mmol, 18.61 mg), sodium triphenylsilanolate (0.05 mmol, 14.92 mg), and a magnetic stir bar were added to a 35 mL glass pressure tube under air. Toluene (10 mL) was then added and the reaction tube was allowed to react at 90 ℃ for 6 hours. After the reaction is finished, cooling the reaction system to room temperature, opening the reaction container at room temperature, and filtering; and recrystallizing the obtained solid and separating to obtain a reaction product. The pure yield of the target product is 85%.
1H NMR (300 MHz, DMSO) δ 12.89 (s, 1H), 9.06 (s, 1H), 8.86 (m, 2H), 8.32 (s, 1H), 7.75 (m, 2H) 7.46(m, 6H), 7.38-7.34 (m, 9H), 7.20 (m, 2H), 6.96 (m, 2H), 6.68 (m, 2H), 4.72 (m, 1H), 4.20 (m, 2H), 3.95 (m, 1H), 3.44 (m, 2H), 3.21 (m, 2H).
13C NMR (101 MHz, DMSO) δ 174.7, 171.7, 155.7, 138.3,136.6, 135.7, 133.3, 132.5, 130.2, 130.0, 129.5, 129.2, 127.7, 115.8, 59.2, 56.0, 38.7, 36.5.
Example 7 preparation of Borate Compound (7) (two-step Process)
(L) -4-Dihydroxyborylphenylalanine (0.05 mmol, 10.45 mg), potassium hydroxide (0.2 mmol, 11.2 mg), toluene (4 mL), and a magnetic stirrer were added to a 35 mL glass pressure tube under an air atmosphere. Triphenylsilane (0.025 mmol, 6.51 mg) was then added and the reaction tube was reacted at 100 ℃ for 10 hours. After the reaction is finished, cooling the reaction system to room temperature, opening the reaction container at room temperature, and filtering; and recrystallizing the obtained solid and separating to obtain a reaction product. The pure yield of the target product is 75%.
1H NMR (500 MHz, Chloroform-d) δ 7.64–7.57 (m, 7H), 7.61–7.53 (m, 1H), 7.39–7.29 (m, 9H), 7.12 (dt, J = 9.5, 1.1 Hz, 1H), 3.05–2.91 (m, 1H).
13C NMR (125 MHz, Chloroform-d) δ 174.88, 139.48, 135.07, 134.68, 133.60, 133.39, 132.18, 129.80, 127.46, 56.92, 37.79.
EXAMPLE 8 preparation of Borate Compound (8) (one-shot method)
BPA-Tyr (0.05 mmol, 18.61 mg), sodium triphenylsiloxide (0.2 mmol, 59.68 mg), a magnetic stir bar was added to a 35 mL glass pressure tube under air. Toluene (4 mL) was then added and the reaction tube was allowed to react at 80 ℃ for 48 hours. After the reaction is finished, cooling the reaction system to room temperature, opening the reaction container at room temperature, and filtering; and recrystallizing the obtained solid and separating to obtain a reaction product. The pure yield of the target product is 78%.
1H NMR (500 MHz, Chloroform-d) δ 7.90 (d, J = 9.0 Hz, 1H), 7.64-7.57 (m, 7H), 7.59-7.52 (m, 2H), 7.39-7.29 (m, 10H), 7.14 (dt, J = 9.1, 1.1 Hz, 2H), 6.95 (dt, J = 8.6, 1.1 Hz, 2H), 6.75-6.69 (m, 2H), 6.14 (s, 1H), 5.92 (s, 2H), 4.54 (dt, J = 9.0, 6.8 Hz, 1H), 3.88 (p, J = 5.9 Hz, 1H), 3.02 (m, J = 15.4, 5.7, 1.0 Hz, 1H), 2.95 (m, J = 6.8, 2.7, 1.0 Hz, 2H), 2.88 (m, J = 15.2, 5.7, 1.0 Hz, 1H), 2.58 (dd, J = 8.0, 6.0 Hz, 1H), 2.42 (dd, J = 8.0, 5.9 Hz, 1H).
13C NMR (125 MHz, Chloroform-d) δ 176.68, 173.61, 156.46, 136.89, 135.07, 134.96, 134.52, 132.75, 130.65, 129.99, 129.80, 128.56, 127.46, 115.72, 54.89, 54.55, 38.40, 37.66.
Example 9 preparation of Borate Compound (9) (two-step Process)
Tyr-BPA (0.05 mmol, 18.61 mg), sodium hydroxide (0.2 mmol, 8 mg), toluene (4 mL) and a magnetic stirrer were added to a 35 mL glass pressure tube under an air atmosphere. Triphenylsilane (0.15 mmol, 39 mg) was then added, and the reaction tube was reacted at 90 ℃ for 12 hours. After the reaction is finished, cooling the reaction system to room temperature, opening the reaction container at room temperature, and filtering; and recrystallizing the obtained solid and separating to obtain a reaction product. The pure yield of the target product is 90%.
1H NMR (500 MHz, Chloroform-d) δ 7.64-7.57 (m, 7H), 7.61-7.53 (m, 1H), 7.39-7.29 (m, 11H), 7.07 (m, J = 19.2, 8.6, 1.1 Hz, 2H), 6.75-6.69 (m, 1H), 4.54 (dt, J = 9.0, 6.8 Hz, 0H), 3.06-2.96 (m, 1H).
13C NMR (125 MHz, Chloroform-d) δ 176.69, 173.61, 156.84, 139.48, 135.16, 135.07, 133.60, 133.11, 132.17, 130.70, 129.80, 127.46, 127.25, 115.38, 54.88, 54.55, 38.39, 37.19.
EXAMPLE 10 preparation of Borate Compound (10) (one-shot method)
(L) -4-Dihydroboranophenylalanine (0.05 mmol, 10.45 mg), sodium triphenylsilanolate (0.05 mmol, 14.92 mg) and a magnetic stirrer were added to a 35 mL glass pressure tube under an air atmosphere. DCE (4 mL) was then added and the reaction tube allowed to react at 80 ℃ for 24 hours. After the reaction is finished, cooling the reaction system to room temperature, opening the reaction container at room temperature, and filtering; and recrystallizing the obtained solid and separating to obtain a reaction product. The pure yield of the target product is 89%.
1H NMR (500 MHz, Chloroform-d) δ 7.64-7.57 (m, 3H), 7.61-7.52 (m, 1H), 7.39-7.29 (m, 4H), 7.13 (dt, J = 9.0, 1.0 Hz, 1H), 5.92 (s, 1H), 3.87 (tt, J = 6.6, 5.1 Hz, 0H), 3.05-2.91 (m, 1H).
13C NMR (125 MHz, Chloroform-d) δ 174.88, 136.89, 135.07, 134.96, 134.63, 132.84, 129.99, 129.80, 127.46, 56.92, 37.79.
EXAMPLE 11 preparation of Borate Compound (11) (two-step Process)
(L) -4-Dihydroboranophenylalanine (0.05 mmol, 10.45 mg), lithium hydroxide (0.15 mmol, 3.6 mg), DMF (4 mL) and a magnetic stirrer were added to a 35 mL glass pressure tube under air. Triphenylsilane (0.15 mmol, 39 mg) was then added, and the reaction tube was reacted at 90 ℃ for 12 hours. After the reaction is finished, cooling the reaction system to room temperature, opening the reaction container at room temperature, and filtering; and recrystallizing the obtained solid and separating to obtain a reaction product. The pure yield of the target product is 72%.
1H NMR (500 MHz, Chloroform-d) δ 7.64-7.57 (m, 7H), 7.61-7.53 (m, 1H), 7.39-7.29 (m, 9H), 7.12 (dt, J = 9.5, 1.1 Hz, 1H), 3.05-2.91 (m, 1H).
13C NMR (125 MHz, Chloroform-d) δ 174.88, 139.48, 135.07, 134.68, 133.60, 133.39, 132.18, 129.80, 127.46, 56.92, 37.79.
EXAMPLE 12 preparation of Borate Compound (12) (one-shot method)
Tyr-BPA (0.05 mmol, 18.61 mg), sodium triphenylsilanolate (0.1 mmol, 29.84 mg) and a magnetic stir bar were added to a 35 mL glass pressure tube under air. Toluene (4 mL) was then added and the reaction tube was allowed to react at 90 ℃ for 12 hours. After the reaction is finished, cooling the reaction system to room temperature, opening the reaction container at room temperature, and filtering; and recrystallizing the obtained solid and separating to obtain a reaction product. The pure yield of the target product is 90%.
1H NMR (500 MHz, Chloroform-d) δ 7.64-7.56 (m, 18H), 7.47-7.41 (m, 2H), 7.37-7.27 (m, 27H), 7.10-7.01 (m, 4H), 6.73-6.67 (m, 2H), 4.38 (dt, J = 9.1, 6.8 Hz, 1H), 3.84 (p, J = 5.9 Hz, 1H), 3.08-3.00 (m, 1H), 3.04-2.95 (m, 2H), 2.84 (m, J = 15.4, 5.8, 1.1 Hz, 1H), 2.70 (dd, J = 7.9, 6.0 Hz, 1H), 2.50 (dd, J = 8.0, 5.9 Hz, 1H).
13C NMR (125 MHz, Chloroform-d) δ 176.69, 173.61, 156.84, 139.48, 135.16, 135.07, 133.60, 133.11, 132.17, 130.70, 129.80, 127.46, 127.25, 115.38, 54.88, 54.55, 38.39, 37.19.
Example 13 preparation of Borate Compound (13) (two-step Process)
F-BPA (0.05 mmol, 11.35 mg), sodium hydroxide (0.2 mmol, 8 mg), toluene (4 mL) and a magnetic stir bar were added to a 35 mL glass pressure tube under air. Triphenylsilane (0.15 mmol, 39 mg) was then added, and the reaction tube was reacted at 80 ℃ for 24 hours. After the reaction is finished, cooling the reaction system to room temperature, opening the reaction container at room temperature, and filtering; and recrystallizing the obtained solid and separating to obtain a reaction product. The pure product yield of the target product is 55 percent.
1H NMR (500 MHz, Chloroform-d) δ 7.64-7.56 (m, 8H), 7.43 (dd, J = 10.5, 2.0 Hz, 0H), 7.39-7.23 (m, 10H), 3.89 (tt, J = 7.5, 6.6 Hz, 0H), 3.18-3.07 (m, 1H).
13C NMR (125 MHz, Chloroform-d) δ 173.42, 135.07, 133.63, 129.80, 127.46, 32.61, 32.57.
EXAMPLE 14 preparation of Borate Compound (14) (one-shot method)
Tyr-BPA (0.05 mmol, 18.61 mg), sodium triphenylsilanolate (0.2 mmol, 59.68 mg) and a magnetic stir bar were added to a 35 mL glass pressure tube under air. 1, 2-dichloroethane (4 mL) was then added and the reaction tube was allowed to react at 90 ℃ for 12 hours. After the reaction is finished, cooling the reaction system to room temperature, opening the reaction container at room temperature, and filtering; and recrystallizing the obtained solid and separating to obtain a reaction product. The pure yield of the target product is 85%.
1H NMR (500 MHz, Chloroform-d) δ 7.64-7.55 (m, 18H), 7.59-7.53 (m, 2H), 7.39-7.29 (m, 28H), 7.07 (m, J = 19.2, 8.6, 1.1 Hz, 4H), 6.75-6.69 (m, 2H), 4.53 (dt, J = 9.0, 6.7 Hz, 1H), 3.88 (p, J = 5.9 Hz, 1H), 3.06-2.98 (m, 1H), 3.00 (d, J = 1.1 Hz, 1H), 3.01-2.96 (m, 1H), 2.89 (m, J = 15.4, 5.7, 1.1 Hz, 1H), 2.58 (dd, J = 8.0, 6.0 Hz, 1H), 2.42 (dd, J = 8.0, 5.9 Hz, 1H).
13C NMR (125 MHz, Chloroform-d) δ 176.69, 173.61, 156.84, 139.48, 135.16, 135.07, 133.60, 133.11, 132.17, 130.70, 129.80, 127.46, 127.25, 115.38, 54.88, 54.55, 38.39, 37.19.
EXAMPLE 15 preparation of Borate Compound (15) (two-step Process)
F-BPA derivative (0.05 mmol, 11.35 mg), sodium hydroxide (0.2 mmol, 8 mg), toluene (4 mL) and a magnetic stirrer were added to a 35 mL glass pressure tube under an air atmosphere. Triphenylsilane (0.15 mmol, 39 mg) was then added, and the reaction tube was reacted at 90 ℃ for 12 hours. After the reaction is finished, cooling the reaction system to room temperature, opening the reaction container at room temperature, and filtering; and recrystallizing the obtained solid and separating to obtain a reaction product. The pure yield of the target product is 88%.
1H NMR (500 MHz, Chloroform-d) δ 7.61 (dq, J = 8.4, 2.4, 1.9 Hz, 26H), 7.39-7.27 (m, 34H), 4.59 (dt, J = 6.2, 3.7 Hz, 1H), 4.18-4.08 (m, 2H), 4.03-3.91 (m, 2H), 3.93-3.84 (m, 1H), 3.18-3.07 (m, 2H).
13C NMR (125 MHz, Chloroform-d) δ 174.56, 161.90, 136.15, 136.08, 135.54, 135.09, 133.91, 133.72, 133.38, 133.36, 132.29, 131.42, 129.88, 128.87, 127.42, 127.40, 122.21, 120.65, 104.54, 77.48, 76.42, 72.57, 64.44, 61.18, 54.64, 30.56.
EXAMPLE 16 preparation of Borate Compound (16) (one-shot method)
Tyr-BPA (0.05 mmol, 18.61 mg), sodium triphenylsilanolate (0.2 mmol, 59.68 mg) and a magnetic stir bar were added to a 35 mL glass pressure tube under air. N, N-dimethylformamide (4 mL) was then added, and the reaction tube was reacted at 100 ℃ for 3 hours. After the reaction is finished, cooling the reaction system to room temperature, opening the reaction container at room temperature, and filtering; and recrystallizing the obtained solid and separating to obtain a reaction product. The pure yield of the target product is 81%.
1H NMR (500 MHz, Chloroform-d) δ 7.64-7.55 (m, 18H), 7.59-7.53 (m, 2H), 7.39-7.29 (m, 28H), 7.07 (m, J = 19.2, 8.6, 1.1 Hz, 4H), 6.75-6.69 (m, 2H), 4.53 (dt, J = 9.0, 6.7 Hz, 1H), 3.88 (p, J = 5.9 Hz, 1H), 3.06-2.98 (m, 1H), 3.00 (d, J = 1.1 Hz, 1H), 3.01-2.96 (m, 1H), 2.89 (m, J = 15.4, 5.7, 1.1 Hz, 1H), 2.58 (dd, J = 8.0, 6.0 Hz, 1H), 2.42 (dd, J = 8.0, 5.9 Hz, 1H).
13C NMR (125 MHz, Chloroform-d) δ 176.69, 173.61, 156.84, 139.48, 135.16, 135.07, 133.60, 133.11, 132.17, 130.70, 129.80, 127.46, 127.25, 115.38, 54.88, 54.55, 38.39, 37.19.
EXAMPLE 17 preparation of Borate Compound (17) (two-step Process)
F-BPA derivative (0.05 mmol, 11.35 mg), lithium hydroxide (0.15 mmol, 3.6 mg), N, N-dimethylformamide (4 mL) and a magnetic stirrer were added to a 35 mL glass pressure tube under an air atmosphere. Triphenylsilane (0.15 mmol, 39 mg) was then added and the reaction tube was allowed to react at 80 ℃ for 24 hours. After the reaction is finished, cooling the reaction system to room temperature, opening the reaction container at room temperature, and filtering; and recrystallizing the obtained solid and separating to obtain a reaction product. The pure yield of the target product is 80%.
1H NMR (500 MHz, Chloroform-d) δ 7.61 (m, J = 8.4, 2.4, 1.9 Hz, 26H), 7.39-7.27 (m, 34H), 4.59 (dt, J = 6.2, 3.7 Hz, 1H), 4.18-4.08 (m, 2H), 4.03-3.91 (m, 2H), 3.93-3.84 (m, 1H), 3.18-3.07 (m, 2H).
13C NMR (125 MHz, Chloroform-d) δ 174.56, 161.90, 136.15, 136.08, 135.54, 135.09, 133.91, 133.72, 133.38, 133.36, 132.29, 131.42, 129.88, 128.87, 127.42, 127.40, 122.21, 120.65, 104.54, 77.48, 76.42, 72.57, 64.44, 61.18, 54.64, 30.56.
EXAMPLE 18 preparation of Borate Compound (18) (one-shot method)
F-BPA derivative (0.05 mmol, 11.35 mg), sodium triphenylsilanolate (0.2 mmol, 59.68 mg) and a magnetic stir bar were added to a 35 mL glass pressure tube under air. 1, 2-dichloroethane (4 mL) was then added and the reaction tube was allowed to react at 90 ℃ for 12 hours. After the reaction is finished, cooling the reaction system to room temperature, opening the reaction container at room temperature, and filtering; and recrystallizing the obtained solid and separating to obtain a reaction product. The pure yield of the target product is 78%.
1H NMR (500 MHz, Chloroform-d) δ 7.64-7.56 (m, 6H), 7.44 (dd, J = 10.6, 1.8 Hz, 1H), 7.39-7.31 (m, 5H), 7.34-7.27 (m, 4H), 7.26 (s, 1H), 7.11 (m, J = 10.5, 5.0, 1.0 Hz, 1H), 4.59-4.52 (m, 2H), 4.49 (dd, J = 7.3, 6.6 Hz, 1H), 4.27 (dd, J = 7.3, 6.6 Hz, 1H), 4.15 (t, J = 6.2 Hz, 1H), 4.06 (s, 1H), 4.01-3.94 (m, 2H), 3.97-3.84 (m, 2H), 3.78-.68 (m, 2H), 3.46 (d, J = 5.1 Hz, 1H), 3.20-3.06 (m, 2H).
13C NMR (125 MHz, Chloroform-d) δ 173.42, 161.19, 159.18, 135.07, 133.94, 133.88, 133.67, 131.79, 131.72, 129.80, 128.72, 128.70, 127.46, 123.85, 123.69, 122.75, 122.59, 98.00, 78.45, 72.97, 72.74, 62.44, 60.93, 55.32, 55.30, 32.74, 32.70.
[ measurement of Borate uptake into CAL27 cells ]
CAL27 cells in logarithmic growth phase with 60-75% cell content were seeded into 6-well plates (1X 10 per well)6Individual cells). When the cells adhered, the cells were treated with BPA or borate compounds at concentrations of 20 or 100. mu.M, respectively, for 48 h (3 replicates per group and a blank control group). After the action is finished, removing the culture solution, and washing the cells for 3 times by using PBS; subsequently 1mL pronase solution with a concentration of 2mg/mL was added per well and incubated at 4 ℃ for 4 h. Discarding the pronase-containing solution, washing the cells 3 times with PBS, lysing the cells with RIPA lysate, collecting the cell lysate, centrifuging and collecting the supernatant. Detection in supernatant by ICP-MS10And (4) B concentration.
TABLE 1 measurement of the uptake of borate compounds in CAL27 cells
(should be compared to normal cell results)
As shown in Table 1, the uptake of the borate compound prepared by the invention in CAL27 cells is directly correlated with the acting concentration, and the uptake of the borate compound in CAL27 cells is higher than that of the positive control group BPA at the same concentration.
Claims (2)
1. A borate compound for use in a boron neutron capture therapeutic for cancer, characterized by: the structural formula of the borate compound is as follows:
2. the method of preparing a borate compound for use in a boron neutron capture therapy for cancer according to claim 1, wherein: adding a boric acid compound, strong base and a reaction solvent into a reaction container, reacting at 25-180 ℃ for 30 s-48 h, adding a stabilizing reagent, and cooling to room temperature after the reaction is finished to obtain a reaction solution B; filtering the reaction solution B to obtain a solid B, and recrystallizing and separating the solid B to obtain a borate compound B; the molar ratio of the boronic acid compound to the strong base is 1: 0.5-1: 10; the molar ratio of the boronic acid compound to the stabilizing agent is 1: 0.5 to 5;
the structural formula of the boric acid compound is one of the following formulas:
the strong base is one of NaOH, KOH, LiOH, sodium methoxide, sodium ethoxide, ethylene glycol disodium, sodium glycerol and sodium salt of sugar; the stabilizing agent is one of reagents of sodium pentafluorophenyl, phenylsilane, diphenylsilane, triphenylsilane, 2- (trimethylsilyl) phenyltrifluoromethanesulfonic acid, hexamethyldisilane, hexaphenyldisilane, tert-butyldimethylchlorosilane, diethylsilane, triethylsilane, trimethylsilanol and triethylsilanol; the reaction solvent includes, but is not limited to, one or more of dimethylsulfoxide, N-dimethylformamide, tetrahydrofuran, acetonitrile, methanol, dioxane, N-methylpyrrolidone, toluene, xylene, mesitylene.
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