CN116410216B - Small molecular boron medicine, preparation method thereof, pharmaceutical composition and application thereof - Google Patents
Small molecular boron medicine, preparation method thereof, pharmaceutical composition and application thereof Download PDFInfo
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- CN116410216B CN116410216B CN202310395480.5A CN202310395480A CN116410216B CN 116410216 B CN116410216 B CN 116410216B CN 202310395480 A CN202310395480 A CN 202310395480A CN 116410216 B CN116410216 B CN 116410216B
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- 238000010276 construction Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 229930193974 gastrodin Natural products 0.000 description 1
- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 description 1
- PUQSUZTXKPLAPR-NZEXEKPDSA-N helicidol Natural products O([C@H]1[C@H](O)[C@H](O)[C@@H](O)[C@@H](CO)O1)c1ccc(CO)cc1 PUQSUZTXKPLAPR-NZEXEKPDSA-N 0.000 description 1
- 230000001678 irradiating effect Effects 0.000 description 1
- 230000002147 killing effect Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- -1 methylene-hydroxy, ethylene-hydroxy Chemical group 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- BJRNKVDFDLYUGJ-UHFFFAOYSA-N p-hydroxyphenyl beta-D-alloside Natural products OC1C(O)C(O)C(CO)OC1OC1=CC=C(O)C=C1 BJRNKVDFDLYUGJ-UHFFFAOYSA-N 0.000 description 1
- 229940055695 pancreatin Drugs 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 230000000149 penetrating effect Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- ILRCGYURZSFMEG-RQICVUQASA-N salidroside Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)OC1OCCC1=CC=C(O)C=C1 ILRCGYURZSFMEG-RQICVUQASA-N 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 229940013618 stevioside Drugs 0.000 description 1
- OHHNJQXIOPOJSC-UHFFFAOYSA-N stevioside Natural products CC1(CCCC2(C)C3(C)CCC4(CC3(CCC12C)CC4=C)OC5OC(CO)C(O)C(O)C5OC6OC(CO)C(O)C(O)C6O)C(=O)OC7OC(CO)C(O)C(O)C7O OHHNJQXIOPOJSC-UHFFFAOYSA-N 0.000 description 1
- 235000019202 steviosides Nutrition 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- 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
- C07F5/025—Boronic and borinic acid compounds
-
- A—HUMAN NECESSITIES
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/18—Acyclic radicals, substituted by carbocyclic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/20—Carbocyclic rings
- C07H15/203—Monocyclic carbocyclic rings other than cyclohexane rings; Bicyclic carbocyclic ring systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/20—Carbocyclic rings
- C07H15/24—Condensed ring systems having three or more rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
- C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
- C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
- C07H17/06—Benzopyran radicals
- C07H17/065—Benzo[b]pyrans
- C07H17/075—Benzo[b]pyran-2-ones
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
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- Biotechnology (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Oncology (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to the technical field of medicines, in particular to a small molecular boron drug, a preparation method thereof, a pharmaceutical composition and application thereof. The small molecular boron drug is selected from compounds shown in the following structural formula or pharmaceutically acceptable salts thereof: Wherein R is selected from any one of substituted aryl, substituted heteroaryl and substituted alkyl. The small molecular boron drug is easy to prepare and low in cost, has better water solubility compared with the small molecular boron drug BPA approved by FDA, and shows better treatment effect than the fructose-BPA widely used clinically at present in the application of Boron Neutron Capture Treatment (BNCT) of tumors.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a small molecular boron drug, a preparation method thereof, a pharmaceutical composition and application thereof.
Background
The principle of boron neutron capture therapy (Boron Neutron Capture Therapy, abbreviated as BNCT) is as follows: the non-radioactive 10 B is firstly gathered in tumor tissue, then the tumor tissue is subjected to thermal neutron irradiation, 4He2+ (alpha particles) and 7Li3+ particles generated by nuclear reaction have very high radiation energy and very short radiation range (9 mu m and 5 mu m respectively), and the killing effect is limited to the ingestion of 10 B cells, so that target cells are selectively killed, and the normal tissue which does not ingest 10 B is minimally damaged. Here, BNCT can be used to selectively irradiate tumors while minimizing radiation damage to non-malignant tissue.
The key to the success of BNCT is the highly selective delivery of sufficient boron drug to the interior of tumor cells, and at present BNCT has been approved by the FDA as a clinical trial boron drug, albeit with (L) -4-dihydroxyborophenylalanine (BPA) and thiododecaborane disodium salt (BSH). However, the two small molecular boron drugs have the defects of poor tumor selectivity, poor water solubility, short blood half-life, low enrichment degree of tumor tissue drugs and short residence time, and severely limit the effect of BNCT. Therefore, the development of small molecular boron drugs with better targeting effect and tumor enrichment capability is important for improving the clinical tumor BNCT curative effect.
In view of this, the present invention has been made.
Disclosure of Invention
The invention aims to provide a small molecular boron drug, a preparation method thereof, a pharmaceutical composition and application thereof. The embodiment of the invention provides a novel small molecular boron drug which is easy to prepare and low in cost, has better water solubility compared with the small molecular boron drug BPA approved by FDA, and shows better treatment effect than fructose-BPA widely used clinically at present in the application of Boron Neutron Capture Treatment (BNCT) of tumors.
The invention is realized in the following way:
In a first aspect, the present invention provides a small molecule boron drug selected from the group consisting of compounds of the following structural formula:
Wherein R is selected from any one of substituted aryl, substituted heteroaryl and substituted alkyl.
In an alternative embodiment, R is selected from any one of the groups represented by the following structural formulas:
/> Wherein R 1 and R 2 are respectively and independently selected from substituted alkyl, R 3 is selected from substituted or unsubstituted alkyl, R 4 is selected from substituted heteroaryl, R 5 is selected from any one of hydrogen, substituted heteroaryl, substituted alkyl, substituted aryl and substituted carbonyl, and R6 is selected from polyhydroxy substituted alkyl.
In an alternative embodiment, R 1 and R 2 are each independently selected from C1-C8 substituted alkyl, preferably C1-C5 substituted alkyl, preferably C2-C4 substituted alkyl;
Preferably, the substituents in the substituted alkyl groups of R 1 and R 2 are each independently selected from at least one of carboxyl, amine, halogen, hydroxyl, and ether linkages;
Preferably, R 3 is selected from C1-C10 substituted or unsubstituted alkyl, preferably C1-C5 substituted or unsubstituted alkyl;
Preferably, R 3 is selected from any one of methyl, ethyl, isopropyl, isobutyl, and tert-butyl;
Preferably, R 4 is selected from Wherein X represents halogen, and R 7 represents any one of amino, primary amino, secondary amino and tertiary amino;
Preferably, R 5 is selected from hydrogen, aryl-substituted alkylene, fused substituted heteroaryl, substituted phenyl, fused aryl-substituted carbonyl;
Preferably, R 6 is selected from C2-C10 polyhydroxy substituted alkyl, preferably C2-C8 polyhydroxy substituted alkyl.
In an alternative embodiment, the small molecule boron drug is selected from any one of the compounds represented by the following structural formulas:
In a second aspect, the present invention provides a method for preparing a small molecular boron drug according to the previous embodiment, including: the small molecule boron drug was synthesized with reference to the following synthetic pathway:
Wherein R is selected from any one of substituted aryl, substituted heteroaryl and substituted alkyl.
In an alternative embodiment, the method comprises: mixing the compound shown in the formula I with the compound shown in the formula II and a solvent, regulating the pH to 10-12, stirring for 1-24h at 20-30 ℃, and regulating the pH to 7-7.5.
In an alternative embodiment, the compound of formula I is BPA having a 10 B abundance of greater than 95%;
Preferably, the molar ratio of the compound of formula I to the compound of formula II is 1.2:1 to 5:1, preferably 1.5:1.
In a third aspect, the present invention provides a pharmaceutical composition comprising the small molecule boron drug of the previous embodiments.
In an alternative embodiment, the pharmaceutical composition further comprises a pharmaceutically acceptable adjuvant.
In a fourth aspect, the present invention provides an application of the small molecular boron drug of the previous embodiment or the pharmaceutical composition of the previous embodiment in preparing a drug for treating cancer;
Preferably, the drug is a drug used in boron neutron capture therapy;
Preferably, the cancer comprises breast cancer, central nervous system, malignant melanoma, nasopharyngeal cancer, tongue cancer, meningioma, peripheral neuroepithelial tumor, primitive neuroectodermal tumor, neuroblastoma, germ cell tumor, pituitary tumor, and brain metastasis; preferably triple negative breast cancer and glioma, more preferably glioblastoma, gliosarcoma, anaplastic astrocytoma, low grade astrocytoma, hairy cell astrocytoma, oligodendroglioma and brain stem glioma;
Preferably, the cancer comprises malignant or metastatic tumor progression, preferably melanoma, breast cancer, brain glioma.
The invention has the following beneficial effects: the embodiment of the invention provides a novel small molecular boron drug which is easy to prepare and low in cost, has better water solubility compared with the small molecular boron drug BPA approved by FDA, and shows better treatment effect than fructose-BPA widely used clinically at present in the application of Boron Neutron Capture Treatment (BNCT) of tumors. Compared with fructose-BPA, the small molecular boron drug has better capacity of penetrating through a blood brain barrier model and being taken up by tumor cells, and has potential of being applied to brain glioma BNCT treatment.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings that are needed in the embodiments will be briefly described below, it being understood that the following drawings only illustrate some embodiments of the present invention and therefore should not be considered as limiting the scope, and other related drawings may be obtained according to these drawings without inventive effort for a person skilled in the art.
FIG. 1 is a nuclear magnetic resonance spectrum of a small molecular boron drug provided in example 1 of the present invention;
FIG. 2 is a nuclear magnetic resonance spectrum of the small molecular boron drug provided in example 2 of the present invention;
FIG. 3 is a nuclear magnetic resonance spectrum of the small molecular boron drug provided in example 3 of the present invention;
FIG. 4 is a nuclear magnetic resonance spectrum of the small molecular boron drug provided in example 4 of the present invention;
FIG. 5 is a nuclear magnetic resonance spectrum of the small molecular boron drug provided in example 5 of the present invention;
FIG. 6 is a nuclear magnetic resonance spectrum of the small molecular boron drug provided in example 6 of the present invention;
FIG. 7 is a nuclear magnetic resonance spectrum of the small molecular boron drug provided in example 7 of the present invention;
FIG. 8 is a nuclear magnetic resonance spectrum of the small molecular boron drug provided in example 8 of the present invention;
FIG. 9 is a nuclear magnetic resonance spectrum of the small molecular boron drug provided in example 9 of the present invention;
FIG. 10 is a nuclear magnetic resonance spectrum of the small molecular boron drug provided in example 10 of the present invention;
FIG. 11 is a nuclear magnetic resonance spectrum of the small molecular boron drug provided in example 11 of the present invention;
FIG. 12 is a nuclear magnetic resonance spectrum of a small molecular boron drug provided in example 12 of the present invention;
FIG. 13 is a nuclear magnetic resonance spectrum of a small molecular boron drug provided in example 13 of the present invention;
FIG. 14 is a nuclear magnetic resonance spectrum of a small molecular boron drug provided in example 14 of the present invention;
FIG. 15 is a graph showing the experimental results provided in experimental example 1 of the present invention;
FIG. 16 is a graph showing the experimental results provided in Experimental example 2 of the present invention;
FIG. 17 is a graph showing the experimental results provided in Experimental example 3 of the present invention;
FIG. 18 is a graph showing the experimental results provided in Experimental example 4 of the present invention;
FIG. 19 is a graph showing the experimental results provided in Experimental example 5 of the present invention;
FIG. 20 is a graph showing the experimental results provided in Experimental example 6 of the present invention.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention more clear, the technical solutions of the embodiments of the present invention will be clearly and completely described below. The specific conditions are not noted in the examples and are carried out according to conventional conditions or conditions recommended by the manufacturer. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.
The embodiment of the invention provides a small molecular boron drug which is selected from compounds shown in the following structural formula or pharmaceutically acceptable salts thereof:
Wherein R is selected from any one of substituted aryl, substituted heteroaryl and substituted alkyl.
Specifically, R may be: R 1 is selected from substituted alkyl, e.g., C1-C8 substituted alkyl, preferably C1-C5 substituted alkyl, preferably C2-C4 substituted alkyl; and the substituent groups are respectively and independently selected from at least one of carboxyl, amino, halogen, hydroxyl and ether bond.
R may beWherein R 2 is independently selected from substituted alkyl groups, e.g., C1-C8 substituted alkyl groups, preferably C1-C5 substituted alkyl groups, preferably C2-C4 substituted alkyl groups; and the substituent groups are respectively and independently selected from at least one of carboxyl, amino, halogen, hydroxyl and ether bond.
R may beWherein R 3 is selected from substituted or unsubstituted alkyl, e.g., C1-C10 substituted or unsubstituted alkyl, preferably C1-C5 substituted or unsubstituted alkyl; specifically, the unsubstituted alkyl group may be any one of methyl, ethyl, isopropyl, isobutyl and tert-butyl, or may be other unsubstituted alkyl groups in the prior art, and the substituted alkyl group may be a hydroxy-substituted alkyl group such as methylene-hydroxy, ethylene-hydroxy or the like.
R 4 is selected from substituted heteroaryl groups, e.gWherein X represents halogen, and R 7 represents any one of amino, primary amino, secondary amino and tertiary amino;
R may also be R 5 is selected from any one of hydrogen, substituted heteroaryl, substituted alkyl, substituted aryl, and substituted carbonyl, such as H, aryl-substituted alkylene, fused substituted heteroaryl, substituted phenyl, fused aryl-substituted carbonyl.
R may also beWherein R6 is selected from polyhydroxy substituted alkyl groups, such as C2-C10 polyhydroxy substituted alkyl groups, preferably C2-C8 polyhydroxy substituted alkyl groups.
The above-mentionedRefers to the position of the O-linkage to the small molecule boron drug.
Further specifically, the small molecular boron drug is selected from any one of the compounds represented by the following structural formulas:
In a second aspect, the present invention provides a method for preparing a small molecular boron drug according to the previous embodiment, including: the small molecule boron drug was synthesized with reference to the following synthetic pathway:
Wherein R is selected from any one of substituted aryl, substituted heteroaryl and substituted alkyl.
Specifically, the compound shown in the formula I, the compound shown in the formula II and the solvent are mixed, the pH is regulated to 10-12 (preferably 10.5), then the mixture is stirred for 1-24 hours at 20-30 ℃, the pH is regulated to 7-7.5, and then the mixture is filtered and freeze-dried to form the required small molecular boron medicine.
Wherein, the compound shown in the formula I is BPA with 10 B abundance higher than 95%; the molar ratio of the compound of formula I to the compound of formula II is 1.2:1 to 5:1, preferably 1.5:1.
Specifically, the compound shown in the formula II is selected from any one of the compounds shown in the following structural formulas,
The solvent for the above reaction is not limited to deionized water, but includes alkaline buffer solution, and organic solvents such as methanol, ethanol, acetonitrile, dimethyl sulfoxide, tetrahydrofuran, dimethylformamide, etc., preferably deionized water.
The invention is a brand new improvement to the category of the known BNCT boron drug, successfully enriches and expands the types of the boron drug, and realizes the efficient and low-cost production of various small molecular boron drugs with different structures. The cell and animal experimental results of the part of small molecular boron drug provided by the invention show that the part of small molecular boron drug based on BPA has stronger selectivity to tumor cells than fructose-BPA, shows better effect in BNCT treatment of cells and animals, and shows better application prospect than fructose-BPA widely used at present.
In a third aspect, the present invention provides a pharmaceutical composition comprising the small molecule boron drug of the previous embodiments.
In alternative embodiments, the pharmaceutical composition further comprises pharmaceutically acceptable excipients, for example, a pharmaceutically acceptable carrier, diluent or adjuvant may be selected.
In a fourth aspect, the present invention provides an application of the small molecular boron drug of the previous embodiment or the pharmaceutical composition of the previous embodiment in preparing a drug for treating cancer;
Preferably, the drug is a drug used in boron neutron capture therapy;
Preferably, the cancer comprises breast cancer, central nervous system, malignant melanoma, nasopharyngeal cancer, tongue cancer, meningioma, peripheral neuroepithelial tumor, primitive neuroectodermal tumor, neuroblastoma, germ cell tumor, pituitary tumor, and brain metastasis; preferably triple negative breast cancer and glioma, more preferably glioblastoma, gliosarcoma, anaplastic astrocytoma, low grade astrocytoma, hairy cell astrocytoma, oligodendroglioma and brain stem glioma;
Preferably, the cancer comprises malignant or metastatic tumor progression, preferably melanoma, breast cancer, brain glioma.
The features and capabilities of the present invention are described in further detail below in connection with the examples.
Example 1
This example provides a method for preparing a small molecule boron drug (levodopa-BPA) (compound 15) comprising: (1) 156.75mg of BPA and 98.6mg of L-dopa were added to a reaction flask, 5mL of deionized water was added, the pH was adjusted to 10.5, stirred for 3h at room temperature, then the pH was adjusted to 7.4, and filtered through a 0.22 μm aqueous filter.
(2) And freeze-drying the filtrate to obtain a product which is the synthesized novel small molecular boron drug compound 15 (levodopa-BPA).
Example 2
This example provides a method for preparing a small molecule boron drug (ascorbic acid-BPA) (compound 16), comprising: (1) 156.75mg of BPA and 88mg of ascorbic acid were added to the reaction flask, 5mL of deionized water was added, the pH was adjusted to 10.5, stirred for 3 hours at room temperature, then the pH was adjusted to 7.4, and filtered through a 0.22 μm aqueous filter.
(2) And freeze-drying the filtrate to obtain a product, namely the synthesized novel small molecular boron drug 16 (ascorbic acid-BPA).
Example 3
The present example provides a method for preparing a small molecule boron drug (5-fluorocytosine nucleoside-BPA) (compound 17), comprising: (1) 156.75mg of BPA and 130.6mg of 5-fluorocytosine were added to the reaction flask, 5mL of deionized water was added, the pH was adjusted to 10.5, stirred for 3 hours at room temperature, then the pH was adjusted to 7.4, and filtered through a 0.22 μm aqueous filter.
(2) And freeze-drying the filtrate to obtain a product which is the synthesized novel small molecular boron drug 17 (5-fluorocytosine-BPA).
Example 4
This example provides a method for preparing a small molecule boron drug (5' -deoxy-5-fluorocytosine nucleoside-BPA) (compound 18), comprising: (1) 156.75mg of BPA and 122.6mg of 5-fluorocytosine were added to the reaction flask, 5mL of deionized water was added, the pH was adjusted to 10.5, stirred for 3 hours at room temperature, then the pH was adjusted to 7.4, and filtered through a 0.22 μm aqueous filter.
(2) And freeze-drying the filtrate to obtain a product, namely the synthesized novel small molecular boron drug 18 (5' -deoxy-5-fluorocytosine nucleoside-BPA).
Example 5
The present example provides a method for preparing a small molecule boron drug (rhodiola rosea-BPA) (compound 19), comprising: (1) 156.75mg of BPA and 150.1mg of salidroside were added to a reaction flask, 5mL of deionized water was added, the pH was adjusted to 10.5, stirred at room temperature for 3 hours, then the pH was adjusted to 7.4, and filtered through a 0.22 μm aqueous filter.
(2) And freeze-drying the filtrate to obtain a product which is the synthesized novel small molecular boron drug 19 (salidroside-BPA).
Example 6
The present example provides a method for preparing a small molecule boron drug (gardenoside-BPA) (compound 20), comprising: (1) 156.75mg of BPA and 194.1mg of jasminoidin were added to the reaction flask, 5mL of deionized water was added, the pH was adjusted to 10.5, stirred at room temperature for 3 hours, then the pH was adjusted to 7.4, and filtered through a 0.22 μm aqueous filter.
(2) And freeze-drying the filtrate to obtain a product, namely the synthesized novel small molecular boron drug 20 (geniposide-BPA).
Example 7
This example provides a method for preparing a small molecule boron drug (sialic acid-BPA) (compound 21), comprising: (1) 156.75mg of BPA and 154.6mg of sialic acid were added to the reaction flask, 5mL of deionized water was added, the pH was adjusted to 10.5, stirred at room temperature for 3h, then the pH was adjusted to 7.4, and filtered through a 0.22 μm aqueous filter.
(2) And freeze-drying the filtrate to obtain a product, namely the synthesized novel small molecular boron drug 21 (sialic acid-BPA).
Example 8
This example provides a method for preparing a small molecule boron drug (phlorizin-BPA) (compound 22), comprising: (1) 156.75mg of BPA and 218.2mg of sialic acid were added to the reaction flask, 5mL of deionized water was added, the pH was adjusted to 10.5, stirred at room temperature for 3h, then the pH was adjusted to 7.4, and filtered through a 0.22 μm aqueous filter.
(2) And freeze-drying the filtrate to obtain a product, namely the synthesized novel small molecular boron drug 22 (phlorizin-BPA).
Example 9
The present example provides a method for preparing a small molecule boron drug (polydatin-BPA) (compound 23), comprising: (1) 156.75mg of BPA and 195mg of polydatin were added to a reaction flask, 5mL of deionized water was added, the pH was adjusted to 10.5, stirred at room temperature for 3 hours, then the pH was adjusted to 7.4, and filtered through a 0.22 μm aqueous filter.
(2) And freeze-drying the filtrate to obtain a product which is the synthesized novel small molecular boron drug 23 (polygonin-BPA).
Example 10
This example provides a method for preparing a small molecule boron drug (fraxinin-BPA) (compound 24), comprising: (1) 156.75mg of BPA and 170.1mg of polydatin were added to a reaction flask, 5mL of deionized water was added, the pH was adjusted to 10.5, stirred at room temperature for 3 hours, then the pH was adjusted to 7.4, and filtered through a 0.22 μm aqueous filter.
(2) And freeze-drying the filtrate to obtain a product which is the synthesized novel micromolecular boron drug 24 (fraxinin-BPA).
Example 11
The embodiment provides a preparation method of a small molecular boron drug (gastrodin-BPA) (compound 25), which comprises the following steps: (1) 156.75mg of BPA and 143.1mg of gastrodin were added to a reaction flask, 5mL of deionized water was added, the pH was adjusted to 10.5, stirred for 3 hours at room temperature, then the pH was adjusted to 7.4, and filtered through a 0.22 μm aqueous filter.
(2) And freeze-drying the filtrate to obtain a product which is the synthesized novel small molecular boron drug 25 (gastrodin-BPA).
Example 12
The present example provides a method for preparing a small molecular boron drug (arbutin-BPA) (compound 26), comprising: (1) 156.75mg of BPA and 136.1mg of arbutin are added to a reaction flask, 5mL of deionized water is added, the pH is adjusted to 10.5, stirred for 3 hours at room temperature, then the pH is adjusted to 7.4, and filtered through a 0.22 μm aqueous filter.
(2) And freeze-drying the filtrate to obtain a product, namely the synthesized novel micromolecular boron drug 26 (arbutin-BPA).
Example 13
This example provides a process for the preparation of a small molecule boron drug (sorbitol-BPA) (a mixture of compounds 27 and 28) comprising: (1) 156.75mg of BPA and 91.2mg of sorbitol were added to a reaction flask, 5mL of deionized water was added, the pH was adjusted to 10.5, stirred for 3 hours at room temperature, then the pH was adjusted to 7.4, and filtered through a 0.22 μm aqueous filter.
(2) And freeze-drying the filtrate to obtain a product which is the synthesized novel small molecular boron drug 27 and 28 mixture (sorbitol-BPA).
Example 14
This example provides a method for preparing a small molecule boron drug (stevioside-BPA) (compound 29), comprising: (1) 156.75mg of BPA and 401.5mg of stevioside were added to a reaction flask, 5mL of deionized water was added, the pH was adjusted to 10.5, stirred for 3 hours at room temperature, then the pH was adjusted to 7.4, and filtered through a 0.22 μm aqueous filter.
(2) And freeze-drying the filtrate to obtain a product which is the synthesized novel small molecular boron drug 29 (stevioside-BPA).
Characterization of
The small molecular boron drugs obtained in example 1-example 14 were dissolved in heavy water, respectively, and then their nuclear magnetic resonance hydrogen spectra were examined, and the results are shown in fig. 1-14.
Experimental example 1
In this experimental example, 4T1 (mouse breast cancer cells) was used as a subject to study the uptake capacity of a small molecular boron drug. The method specifically comprises the following steps:
Respectively preparing small molecular boron medicine 19 (salidroside-BPA) and molecular boron medicine 20 (gardenoside-BPA) with the same boron content and fructose-BPA solution. 4T1 cells (cell density 1 x 10 6) are spread in a six-hole plate for culturing for 24h, and after fresh culture medium is replaced, small molecular boron drug 19 (salidroside-BPA), small molecular boron drug 20 (geniposide-BPA) and fructose-BPA solution are respectively added for incubation for 3h. After the incubation, the well plate solutions were blotted off and washed 3 times with PBS. After TE digestion, the cells were collected in a 1.5mL EP tube, centrifuged at 1000rpm for 3min, the medium was discarded, 600. Mu.L of HNO 3 was added to each of the cells, and the cells were digested by heating for 12 hours to obtain a membrane, and the boron concentration was measured by ICP-OES.
As a result, as shown in FIG. 15, the intake of 4T1 into small molecular boron drug 19 (rhodiola rosea-BPA) and small molecular boron drug 20 (gardenia glycoside-BPA) was higher than that into fructose-BPA.
Experimental example 2
In the experimental example, 4T1 (mouse breast cancer cells) is taken as a study object, and BNCT effects of salidroside-BPA, gardenoside-BPA, sialic acid-BPA and fructose-BPA with the same B content on a cell level are studied. The method specifically comprises the following steps:
Step 1, placing 5 x 10 4 B16 cells with good cell state into a 0.6mL centrifuge tube, respectively adding a small molecular boron drug 19 (salidroside-BPA), a small molecular boron drug 20 (geniposide-BPA), a small molecular boron drug 21 (sialic acid-BPA) and fructose-BPA with the same boron content into 400uL cell culture medium, incubating for 3 hours, and irradiating for 1 hour under neutron source equipment.
And 2, after the irradiation is finished, digesting with 0.25% pancreatin, and blowing into single cell suspension when re-suspending after centrifugation. A 6-well plate was selected as the cloning plate, and 1000 cells were added to each well.
And 3, culturing for about 5 days (when macroscopic cell colonies appear), stopping culturing, removing supernatant, and washing with PBS three times. Fixation with 4% paraformaldehyde followed by addition of crystal violet dye, incubation for 10 min followed by slow washing with PBS followed by air drying.
And 4, under the same conditions, setting a control group, replacing the boron drug with PBS, and carrying out no neutron irradiation.
Six well plates of the stained cell clones were photographed.
As shown in FIG. 16, it was found that the BNCT effect of the same B content of salidroside-BPA, gardenoside-BPA, sialic acid-BPA was better than that of fructose-BPA at the cell level.
Experimental example 3
In this experimental example, BALB/c mice in which 4T1 cells were subcutaneously planted were used as subjects, and the enrichment amounts of small molecular boron drug 19 (salidroside-BPA), molecular boron drug 20 (geniposide-BPA), molecular boron drug 21 (sialic acid-BPA) and fructose-BPA with the same B content in tumor tissues were studied. The method specifically comprises the following steps:
In the experimental example, 16 mice are selected as samples, the mice are divided into four groups, intravenous injection is carried out on each mouse, small molecular boron medicine 19 (rhodiola rosea-BPA), molecular boron medicine 20 (gardenia glycoside-BPA), molecular boron medicine 21 (sialic acid-BPA) and fructose-BPA with the same B content are respectively injected, after 3 hours, the mice are sacrificed, tumors of each mouse are taken out, and the boron content of the tumors of each mouse is respectively detected by ICP-OES.
As shown in FIG. 17, the results show that the boron concentration in the tumor of the mice reaches more than 25ppm, and the enrichment of the micromolecular boron medicine 19 (salidroside-BPA) and the micromolecular boron medicine 20 (gardenin-BPA) in tumor tissues is higher than that of fructose-BPA.
Experimental example 4
In the experimental example, BALB/c mice subcutaneously planted with 4T1 cells are taken as a study object, and BNCT treatment effects of small molecular boron drugs 19 (salidroside-BPA), molecular boron drugs 20 (geniposide-BPA), molecular boron drugs 21 (sialic acid-BPA) and fructose-BPA with the same B content on animal level are studied. The method specifically comprises the following steps:
In the experimental example, 16 mice are selected as samples, the mice are divided into four groups, intravenous injection is carried out on each mouse, small molecular boron medicine 19 (rhodioside-BPA), molecular boron medicine 20 (gardenin-BPA), molecular boron medicine 21 (sialic acid-BPA) and fructose-BPA with the same B content are respectively injected, neutron irradiation is carried out on the mice for 2 hours after 3 hours, the tumor growth condition of the mice is monitored within 14 days, the long diameter and the short diameter of the tumors of the mice are measured every day, the tumor volume of the mice is calculated, the change curve of the tumor volume of the mice along with time is obtained, the tumor inhibition curve of the mice is drawn, and the tumor inhibition curve of the mice is compared with the mice injected with PBS and the neutron irradiation group as a control group.
As shown in figure 18, the results show that the small molecular boron drug can effectively inhibit the growth of tumor in BNCT treatment and prolong the survival time of mice, and the BNCT treatment effect of the salidroside-BPA and the gardenin-BPA with the same B content on animal level is better than that of fructose-BPA.
Experimental example 5
In the experimental example, a bEnd.3 cell culture layer is used for in vitro construction of a simulated blood brain barrier, and the ability of a small molecular boron drug 18 (5' -deoxy-5-fluorocytosine-BPA), a small molecular boron drug 19 (rhodioside-BPA), a small molecular boron drug 20 (geniposide-BPA) and fructose-BPA with the same B content to pass through an in vitro blood brain barrier model is studied.
1.0X10 5 mouse brain microvascular endothelial cells (bEnd.3) were seeded into the upper chamber of the Corning Transwell plate and transendothelial resistance (TEER) was measured every 24 h. When the TEER value reaches 200Ω·cm 2, the blood brain barrier model is successfully constructed.
Culture medium was added to the lower compartment of the Conning Transwell plate, and small molecular boron drug 18 (5' -deoxy-5-fluorocytosine-BPA), small molecular boron drug 19 (rhodioside-BPA), small molecular boron drug 20 (jasminoidin-BPA) and fructose-BPA were added to the upper compartment of the Conning Transwell plate, respectively, and after 12 hours, the culture medium in the lower compartment of the Transwell plate was collected, and the boron content was measured by ICP-OES.
As a result, as shown in FIG. 19, by comparison, the small molecular boron drug 18 (5' -deoxy-5-fluorocytosine-BPA) and fructose-BPA had similar ability to cross the blood brain barrier model in vitro, while the small molecular boron drug 19 (rhodioside-BPA) and the small molecular boron drug 20 (jasminoidin-BPA) had better ability to cross the blood brain barrier model in vitro than fructose-BPA.
Experimental example 6
In this experimental example, a blood brain barrier is simulated by constructing a bEnd.3 cell culture layer in vitro, and the ability of a small molecular boron drug 18 (5' -deoxy-5-fluorocytosine-BPA), a small molecular boron drug 19 (rhodiola rosea-BPA), a small molecular boron drug 20 (gardenia glycoside-BPA) and fructose-BPA with the same B content to pass through the blood brain barrier model in vitro and be taken up by human glioma cells (U87 cells) is studied.
1.0X10 5 mouse brain microvascular endothelial cells (bEnd.3) were seeded into the upper chamber of the Corning Transwell plate and transendothelial resistance (TEER) was measured every 24 h. When the TEER value reaches 200Ω·cm 2, the blood brain barrier model is successfully constructed.
Culture medium was added to the lower compartment of the corning Transwell plate, 1.0X10 6 U87 cells were implanted, and small molecular boron drug 18 (5' -deoxy-5-fluorocytosine-BPA), small molecular boron drug 19 (rhodiola rosea-BPA), small molecular boron drug 20 (gardenia glycoside-BPA) and fructose-BPA were added to the upper compartment of the corning Transwell plate, respectively, and after 12 hours, the culture medium in the lower compartment of the Transwell plate was aspirated, and washed 3 times with PBS. After TE digestion, the digestion was stopped by adding the medium, collecting the cells, centrifuging at 1000rpm for 3min in a 1.5mL EP tube, discarding the medium, adding 600. Mu.L HNO3 each, heating for digestion for 12h, and measuring the boron concentration by ICP-OES.
As a result, as shown in FIG. 20, by comparison, the small molecular boron drug 18 (5' -deoxy-5-fluorocytosine-BPA), the small molecular boron drug 19 (rhodioside-BPA), and the small molecular boron drug 20 (jasminoidin-BPA) were better in their ability to pass through the blood-brain barrier model in vitro and to be taken up by human glioma cells (U87 cells).
The above description is only of the preferred embodiments of the present invention and is not intended to limit the present invention, but various modifications and variations can be made to the present invention by those skilled in the art. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. A small molecule boron drug, which is characterized in that the small molecule boron drug is selected from any one of compounds shown in the following structural formulas or pharmaceutically acceptable salts thereof:
。
2. a method of preparing the small molecule boron drug of claim 1, comprising: the small molecule boron drug was synthesized with reference to the following synthetic pathway:
wherein R is selected from the group corresponding to the compounds defined in claim 1.
3. The method of manufacturing according to claim 2, comprising: mixing the compound shown in the formula I with the compound shown in the formula II and a solvent, regulating the pH to 10-12, stirring for 1-24h at 20-30 ℃, and regulating the pH to 7-7.5.
4. A process according to claim 2 or 3, wherein the compound of formula I is BPA having a 10 B abundance of greater than 95%.
5. A process according to claim 2 or 3, wherein,
The molar ratio of the compound shown in the formula I to the compound shown in the formula II is 1.2:1-5:1.
6. A process according to claim 2 or 3, wherein the molar ratio of the compound of formula I to the compound of formula II is 1.5:1.
7. A pharmaceutical composition comprising the small molecule boron drug of claim 1.
8. The pharmaceutical composition of claim 7, further comprising a pharmaceutically acceptable adjuvant.
9. Use of the small molecule boron drug of claim 1 or the pharmaceutical composition of claim 7 in the manufacture of a medicament for the treatment of cancer; the cancers are breast cancer and brain glioma.
10. The use according to claim 9, wherein the medicament is a medicament for use in boron neutron capture therapy.
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CN112876503A (en) * | 2021-03-18 | 2021-06-01 | 中国科学院兰州化学物理研究所 | Borate compound for cancer boron neutron capture therapeutic medicine and preparation thereof |
CN113773337A (en) * | 2020-06-05 | 2021-12-10 | 南京中硼联康医疗科技有限公司 | Radiolabeled boron-containing compounds, methods of preparation and uses |
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JP2016037467A (en) * | 2014-08-07 | 2016-03-22 | 味の素株式会社 | Sulfonamide derivatives and pharmaceutical applications thereof |
CN113773337A (en) * | 2020-06-05 | 2021-12-10 | 南京中硼联康医疗科技有限公司 | Radiolabeled boron-containing compounds, methods of preparation and uses |
CN112876503A (en) * | 2021-03-18 | 2021-06-01 | 中国科学院兰州化学物理研究所 | Borate compound for cancer boron neutron capture therapeutic medicine and preparation thereof |
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