CN116693565A - Boron-containing hinoki biflavone, derivative and salt, synthesis process and application - Google Patents
Boron-containing hinoki biflavone, derivative and salt, synthesis process and application Download PDFInfo
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- CN116693565A CN116693565A CN202310626475.0A CN202310626475A CN116693565A CN 116693565 A CN116693565 A CN 116693565A CN 202310626475 A CN202310626475 A CN 202310626475A CN 116693565 A CN116693565 A CN 116693565A
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- boron
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- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 title claims abstract description 79
- 229910052796 boron Inorganic materials 0.000 title claims abstract description 79
- 150000003839 salts Chemical class 0.000 title claims abstract description 31
- 238000000034 method Methods 0.000 title claims abstract description 15
- 230000008569 process Effects 0.000 title claims abstract description 11
- 230000015572 biosynthetic process Effects 0.000 title claims abstract description 10
- UFJORDZSBNSRQT-UHFFFAOYSA-N 3-(4-oxo-2-phenylchromen-3-yl)-2-phenylchromen-4-one Chemical compound O1C2=CC=CC=C2C(=O)C(C=2C(C3=CC=CC=C3OC=2C=2C=CC=CC=2)=O)=C1C1=CC=CC=C1 UFJORDZSBNSRQT-UHFFFAOYSA-N 0.000 title abstract description 19
- 238000003786 synthesis reaction Methods 0.000 title abstract description 7
- FUWUEFKEXZQKKA-UHFFFAOYSA-N beta-thujaplicin Chemical compound CC(C)C=1C=CC=C(O)C(=O)C=1 FUWUEFKEXZQKKA-UHFFFAOYSA-N 0.000 claims abstract description 124
- TUFYVOCKVJOUIR-UHFFFAOYSA-N alpha-Thujaplicin Natural products CC(C)C=1C=CC=CC(=O)C=1O TUFYVOCKVJOUIR-UHFFFAOYSA-N 0.000 claims abstract description 61
- 229930007845 β-thujaplicin Natural products 0.000 claims abstract description 61
- 239000000126 substance Substances 0.000 claims abstract description 40
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 31
- ZOXJGFHDIHLPTG-BJUDXGSMSA-N Boron-10 Chemical compound [10B] ZOXJGFHDIHLPTG-BJUDXGSMSA-N 0.000 claims abstract description 19
- 201000011510 cancer Diseases 0.000 claims abstract description 9
- 239000002994 raw material Substances 0.000 claims abstract description 9
- 150000001875 compounds Chemical class 0.000 claims description 32
- 239000003795 chemical substances by application Substances 0.000 claims description 19
- 125000000217 alkyl group Chemical group 0.000 claims description 11
- 239000003814 drug Substances 0.000 claims description 11
- 125000005843 halogen group Chemical group 0.000 claims description 11
- 238000006722 reduction reaction Methods 0.000 claims description 9
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 6
- 206010017758 gastric cancer Diseases 0.000 claims description 6
- 201000011549 stomach cancer Diseases 0.000 claims description 6
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 5
- 239000003054 catalyst Substances 0.000 claims description 5
- 125000001188 haloalkyl group Chemical group 0.000 claims description 5
- 201000002314 small intestine cancer Diseases 0.000 claims description 5
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims description 4
- 230000009471 action Effects 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 239000012039 electrophile Substances 0.000 claims description 4
- OVYTZAASVAZITK-UHFFFAOYSA-M sodium;ethanol;hydroxide Chemical class [OH-].[Na+].CCO OVYTZAASVAZITK-UHFFFAOYSA-M 0.000 claims description 4
- 229940124597 therapeutic agent Drugs 0.000 claims description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 3
- 125000004122 cyclic group Chemical group 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 238000003379 elimination reaction Methods 0.000 claims description 3
- 238000005658 halogenation reaction Methods 0.000 claims description 3
- 238000007254 oxidation reaction Methods 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 239000000376 reactant Substances 0.000 claims description 2
- 230000002194 synthesizing effect Effects 0.000 claims description 2
- 238000009098 adjuvant therapy Methods 0.000 claims 3
- 241000218691 Cupressaceae Species 0.000 abstract description 8
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- 208000020816 lung neoplasm Diseases 0.000 description 8
- 239000008280 blood Substances 0.000 description 7
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- 206010006187 Breast cancer Diseases 0.000 description 6
- 208000026310 Breast neoplasm Diseases 0.000 description 6
- 229930003935 flavonoid Natural products 0.000 description 6
- 235000017173 flavonoids Nutrition 0.000 description 6
- 210000004881 tumor cell Anatomy 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 208000008839 Kidney Neoplasms Diseases 0.000 description 5
- 206010038389 Renal cancer Diseases 0.000 description 5
- -1 flavonoid compounds Chemical class 0.000 description 5
- 229910052739 hydrogen Inorganic materials 0.000 description 5
- 239000001257 hydrogen Substances 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 201000010982 kidney cancer Diseases 0.000 description 5
- 201000007270 liver cancer Diseases 0.000 description 5
- 208000014018 liver neoplasm Diseases 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 238000002560 therapeutic procedure Methods 0.000 description 5
- 241000699666 Mus <mouse, genus> Species 0.000 description 4
- 238000010521 absorption reaction Methods 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 238000009203 neutron therapy Methods 0.000 description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 4
- 230000008685 targeting Effects 0.000 description 4
- 239000002253 acid Substances 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 239000003638 chemical reducing agent Substances 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 230000032895 transmembrane transport Effects 0.000 description 3
- UXJNPHBRNOEODN-UHFFFAOYSA-N tritert-butylstannane Chemical compound CC(C)(C)[SnH](C(C)(C)C)C(C)(C)C UXJNPHBRNOEODN-UHFFFAOYSA-N 0.000 description 3
- 229910018072 Al 2 O 3 Inorganic materials 0.000 description 2
- 125000006416 CBr Chemical group BrC* 0.000 description 2
- 125000006414 CCl Chemical group ClC* 0.000 description 2
- 238000012449 Kunming mouse Methods 0.000 description 2
- 206010043515 Throat cancer Diseases 0.000 description 2
- 230000005856 abnormality Effects 0.000 description 2
- 150000001336 alkenes Chemical class 0.000 description 2
- 229940024606 amino acid Drugs 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- 229910021538 borax Inorganic materials 0.000 description 2
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 2
- 239000004327 boric acid Substances 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 210000000170 cell membrane Anatomy 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- VFLDPWHFBUODDF-FCXRPNKRSA-N curcumin Chemical compound C1=C(O)C(OC)=CC(\C=C\C(=O)CC(=O)\C=C\C=2C=C(OC)C(O)=CC=2)=C1 VFLDPWHFBUODDF-FCXRPNKRSA-N 0.000 description 2
- 150000002215 flavonoids Chemical class 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 238000005286 illumination Methods 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 229960005190 phenylalanine Drugs 0.000 description 2
- 235000013824 polyphenols Nutrition 0.000 description 2
- 210000000813 small intestine Anatomy 0.000 description 2
- 239000004328 sodium tetraborate Substances 0.000 description 2
- 235000010339 sodium tetraborate Nutrition 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 229940126585 therapeutic drug Drugs 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 231100000820 toxicity test Toxicity 0.000 description 2
- 208000003174 Brain Neoplasms Diseases 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 206010014733 Endometrial cancer Diseases 0.000 description 1
- 206010014759 Endometrial neoplasm Diseases 0.000 description 1
- 206010061968 Gastric neoplasm Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 206010026749 Mania Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 208000007101 Muscle Cramp Diseases 0.000 description 1
- 240000002924 Platycladus orientalis Species 0.000 description 1
- 208000001431 Psychomotor Agitation Diseases 0.000 description 1
- 206010038743 Restlessness Diseases 0.000 description 1
- 206010054184 Small intestine carcinoma Diseases 0.000 description 1
- 230000003187 abdominal effect Effects 0.000 description 1
- 238000007259 addition reaction Methods 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000012830 cancer therapeutic Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000022131 cell cycle Effects 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 235000012754 curcumin Nutrition 0.000 description 1
- 229940109262 curcumin Drugs 0.000 description 1
- 239000004148 curcumin Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- VFLDPWHFBUODDF-UHFFFAOYSA-N diferuloylmethane Natural products C1=C(O)C(OC)=CC(C=CC(=O)CC(=O)C=CC=2C=C(OC)C(O)=CC=2)=C1 VFLDPWHFBUODDF-UHFFFAOYSA-N 0.000 description 1
- 238000006471 dimerization reaction Methods 0.000 description 1
- YWEUIGNSBFLMFL-UHFFFAOYSA-N diphosphonate Chemical compound O=P(=O)OP(=O)=O YWEUIGNSBFLMFL-UHFFFAOYSA-N 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000003517 fume Substances 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- WTDHMFBJQJSTMH-UHFFFAOYSA-N hinokiflavone Chemical compound C1=CC(O)=CC=C1C1=CC(=O)C2=C(O)C(OC=3C=CC(=CC=3)C=3OC4=CC(O)=CC(O)=C4C(=O)C=3)=C(O)C=C2O1 WTDHMFBJQJSTMH-UHFFFAOYSA-N 0.000 description 1
- HLFVFEBKCLAGBY-UHFFFAOYSA-N hinokiflavone Natural products Oc1ccc(cc1)C2=COc3cc(O)c(Oc4ccc(cc4)C5=CC(=O)c6c(O)cc(O)cc6O5)c(O)c3C2=O HLFVFEBKCLAGBY-UHFFFAOYSA-N 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 239000002105 nanoparticle Substances 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 230000009057 passive transport Effects 0.000 description 1
- 230000011340 peptidyl-tyrosine autophosphorylation Effects 0.000 description 1
- 238000011056 performance test Methods 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 238000002626 targeted therapy Methods 0.000 description 1
- 210000000115 thoracic cavity Anatomy 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 238000005303 weighing Methods 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
- C07F5/022—Boron compounds without C-boron linkages
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
- C07B59/004—Acyclic, carbocyclic or heterocyclic compounds containing elements other than carbon, hydrogen, halogen, oxygen, nitrogen, sulfur, selenium or tellurium
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/05—Isotopically modified compounds, e.g. labelled
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- 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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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The application discloses boron-containing hinokitiol and a derivative or pharmaceutically acceptable salt thereof, and relates to boron-containing hinokitiol and a derivative or pharmaceutically acceptable salt thereof, which are obtained by adopting hinokitiol or a derivative thereof with a chemical structural formula (I) as a raw material and introducing boron-10 into the structure of the raw material to obtain the boron-containing hinokitiol and a derivative or pharmaceutically acceptable salt thereof with a chemical structural formula (II). The application also provides a synthesis process and application of the boron-containing hinokitiol biflavone and the derivative or the pharmaceutically acceptable salt thereof. The novel boron carrying agent is obtained by introducing boron-10 into the cypress biflavone structure, is applied to BNCT, and aims to enable cancer cells to be conveniently killed by neutron irradiation after being passively transported and ingested with the cypress biflavone containing the boron-10.
Description
Technical Field
The application relates to the technical field of boron carrying agents, in particular to boron-containing hinokitiol, a derivative, a salt, a synthesis process and application.
Background
Boron neutron capture therapy (boron neutron capture therapy, BNCT) is a binary targeted therapy for tumor therapy, which is based on the principle that it will have specific affinity for tumors 10 B compound (boron carrier, also called boron drug) is injected into human body, and is locally irradiated by neutron beam to accumulate in tumor tissue 10 B is subjected to nuclear reaction with thermal neutrons, and the generated 7 Li and alpha particles destroy tumor tissue reaction and release 7 Li particles have a range of about 4-5 mu m, alpha particles have a range of about 9-l 0 mu m, and tumor cells generally have a diameter of less than 10 mu m, so that the radiation killing range of the method is limited to tumor cells, and the damage to surrounding normal tissues is small.
So far, the boron carrying agent for Boron Neutron Capture Therapy (BNCT) has undergone the evolution of the third generation, and the first generation boron carrying agent adopts inorganic matters such as boric acid, borax and the like, and has undesirable BNCT curative effect and side effect because of high toxicity of the boric acid and the borax. Organic 4-dihydroxyboron-L-phenylalanine (BPA) and sodium undecahydromercapto dodecaboride (BSH) are separated from each other in a boron carrying agent due to selective targeting characteristics, so that the organic 4-dihydroxyboron-L-phenylalanine (BPA) becomes a second-generation organic boron carrying agent, and BPA can be targeted and combined with specific proteins, so that the BPA can be selectively combined with proteins related to tumor growth in the rapid proliferation process of tumor cells; in the existing clinical medicine, the selectivity of BPA to ectodermal cancers is high, and the boron enrichment degree of BSH in ectomesial and endoendodermal tumors reaches the treatment standard of BNCT, so that the selectivity of BSH is poor. With the development of boron carrying agents, the third generation boron carrying agents mainly comprise amino acids, nucleotides, boron-containing nano particles and the like; the third generation amino acid boron carrier has strong metabolic stability and higher tumor specificity, but is limited by the specificity of tumor cell combination, and is currently used for treating brain-supplementing tumors, but has limitation on the treatment of tumors of thoracic organs or abdominal organs.
Hinokitiol, an alias hinokitiol, which is present in various plants of different genus, has antibacterial, antiinflammatory and antitumor effects, and has single and remarkable effective components and low toxicity. The hinoki biflavone is one of flavonoid compounds, has good in vitro and in vivo activities on stomach, small intestine, liver, kidney, lung tissue, brain cancer and the like, and suggests medicinal potential. However, there is no report of the application of hinokitiol to boron carriers (boron drugs).
Disclosure of Invention
In order to overcome the defects of the prior art, the application aims to provide the boron-containing hinokitiol, and the novel boron carrying agent is obtained by introducing boron-10 into the hinokitiol structure, and is applied to BNCT, so that cancer cells can be killed by neutron irradiation conveniently after the cancer cells take in the boron-10-containing hinokitiol through active transportation.
In order to solve the problems, the technical scheme adopted by the application is as follows:
a boron-containing hinokitiol, its derivative or its pharmaceutically acceptable salt is prepared by introducing boron-10 into the structure of hinokitiol or its derivative having chemical structural formula (I):
as a further preferable mode, X as described in the embodiment of the application 1 Is one of H atom, halogen atom, alkyl and haloalkyl, and X is 2 Is a halogen atom.
As a further preferable scheme, the halogen atom in the embodiment of the application is Cl or Br, and the alkyl and the halogenated alkyl are straight-chain or cyclic structures with the number of carbon atoms not exceeding 6.
As a further preferable mode, X as described in the embodiment of the application 1 And X 2 Are the same or different groups.
Further, the embodiment of the application also provides a synthesis process of the boron-containing hinokitiol, the boron-containing hinokitiol derivative or the pharmaceutically acceptable salt thereof, which comprises
Reduction reaction: taking hinokitiol or its derivative with chemical structural formula (I) as raw material, introducing hydrogen gas to reduce it into compound with chemical structural formula (a),
halogenation reaction: liquid bromine is adopted as electrophile to replace hydrogen atoms on six-membered ring to obtain compound with chemical structural formula (b),
elimination reaction: adopting saturated sodium hydroxide ethanol solution as a reactant to react with the compound with the chemical structural formula (b) so as to promote the formation of conjugated double bonds and obtain the compound with the chemical structural formula (c),
oxidation reaction: introducing pure oxygen under the action of a catalyst to oxidize the compound with the chemical structural formula (c) into a compound with the chemical structural formula (d),
introducing boron-10: introducing B-10 into the compound of the chemical structural formula (d) to obtain a compound of the chemical structural formula (e),
reduction reaction: and (3) carrying out reduction reaction on the compound with the chemical structural formula (e) to obtain a product with the chemical structural formula (II).
The application also provides application of the boron-containing hinokitiol and the derivatives or the pharmaceutically acceptable salts thereof in preparing auxiliary therapeutic drugs for cancers. Specifically, the auxiliary therapeutic agent for cancers comprises auxiliary therapeutic agents for diseases such as small intestine cancer, gastric cancer, lung cancer, liver cancer, breast cancer, kidney cancer and the like.
The embodiment of the application also provides a boron carrying agent which comprises the boron-containing hinokitiol and the derivative or the pharmaceutically acceptable salt thereof. The boron carrying agent is used for treating small intestine cancer, gastric cancer, lung cancer, liver cancer, breast cancer, kidney cancer and other related diseases by boron neutron therapy.
The application also provides a pharmaceutical composition, which comprises the boron-containing hinokitiol and the derivatives or the pharmaceutically acceptable salts thereof provided by the embodiment of the application, and a pharmaceutically acceptable carrier.
Compared with the prior art, the application has the beneficial effects that:
1. the boron-containing hinokitiol, the derivative or the pharmaceutically acceptable salt thereof is a product synthesized by hinokitiol and boron-10 with strong neutron absorption capacity, can provide a high-content boron carrier, and has high affinity to tumor cells, good stability and low biotoxicity.
2. The absorption part of the boron-containing hinokitiol biflavone, the derivative or the pharmaceutically acceptable salt thereof in the body is mainly absorbed in the small intestine in a passive movement mode, and the transmembrane transport of the boron-containing hinokitiol biflavone is mainly finished by targeting an Epidermal Growth Factor Receptor (EGFR), so that the boron-containing hinokitiol biflavone has a good application prospect in boron neutron therapy.
3. The boron-containing hinokitiol biflavone, the derivative or the pharmaceutically acceptable salt thereof provided by the application is used as a boron carrying agent (boron drug), so that the selection range of the boron drug in BNCT treatment is enlarged.
4. The boron-containing hinokitiol, the derivative or the pharmaceutically acceptable salt thereof provided by the application is mainly effective on the endodermal cancer cells such as lung cancer, digestive tract cancer and throat cancer when being taken as a boron carrying agent, so that the boron-containing hinokitiol can be positioned as the boron carrying agent or the boron medicine of endodermal which is represented by lung cancer boron medicine.
The application is described in further detail below with reference to the drawings and the detailed description.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present application, the drawings required for the description of the embodiments will be briefly described below, and it is apparent that the drawings in the following description are only some embodiments of the present application, and other drawings may be obtained according to these drawings without inventive effort for a person skilled in the art.
FIG. 1 is a nuclear magnetic pattern of boron-containing hinokitiol as described in example 1 of the present application.
FIG. 2 is a graph showing the concentration of boron-10-ized hinokitiol in liver, tumor and blood of mice by high performance liquid chromatography.
Detailed Description
For the purpose of making the objects, technical solutions and advantages of the embodiments of the present application more apparent, the technical solutions of the embodiments of the present application will be clearly and completely described below with reference to the accompanying drawings in the embodiments of the present application, and it is apparent that the described embodiments are some embodiments of the present application, but not all embodiments of the present application. All other embodiments, which can be made by those skilled in the art based on the embodiments of the application without making any inventive effort, are intended to be within the scope of the application.
The terms "comprises" and "comprising" and their equivalents, when used in this specification and claims, are intended to cover a non-exclusive inclusion, such that a process or element is not described, but is inherent to the product, method, or structure, but is included in the application that is expressly described in the specification and claims.
Embodiments of the present application provide
A boron-containing hinokitiol, a derivative or a pharmaceutically acceptable salt thereof is characterized in that hinokitiol or a derivative thereof with a chemical structural formula (I) is adopted as a raw material, and boron-10 is introduced into the structure of the hinokitiol or the derivative thereof to obtain a compound with or comprising the chemical structural formula (II):
B 10 is a stable isotope of boron, and atoms with strong neutron absorption capacity need to be searched in BNCT therapy, and B 10 The thermal neutron absorption capability emitted by BNCT device is very strong, in particular, the boron medicine (such as BPA, BSH, etc.) in BNCT must contain B with high enrichment degree 10 Typically, enrichment is required to exceed 99%. In the application, boron-containing hinokitiol, a derivative or pharmaceutically acceptable salt thereof is a novel boron carrying agent obtained by introducing boron-10 into the structure of hinokitiol, and the novel boron carrying agent is activated by specifically binding the binding site (-CO-) of the structure of hinokitiol with the site of the extracellular region of an Epidermal Growth Factor Receptor (EGFR) on cells such as lung cancer and the like, and induces EGFR dimerization and tyrosine autophosphorylation to start G1/S cell cycle 1; the flavonoid compound specifically binds to EGFR, so that EGFR spans TM region and intracellular region of cell membrane to change, EGFR bound by the flavonoid compound is engulfed into cell, signal is stopped, EGFR is degraded or recycled to cell membrane surface. Flavonoid compounds complete their transmembrane transport mainly by targeting the Epidermal Growth Factor Receptor (EGFR). The boronated hinokitiol has similar transmembrane transport of flavonoids to flavonoids, can be absorbed by passive transport, and is mainly completed by targeting Epidermal Growth Factor Receptor (EGFR). Concrete embodimentsThe expression is as follows: the special protein (EGFR) of boronated hinoki biflavone into lung cancer, liver cancer, breast cancer and kidney cancer cells has a binding site, NH of ligand binding site in EGFR extracellular region 2 And finally, the-CO-on the boronized cypress biflavone is specifically combined with the boronized cypress biflavone, and the high-concentration boronized cypress biflavone outside the membrane enters the low-concentration cells due to the action of an Epidermal Growth Factor Receptor (EGFR), so that the transportation process of the boronized cypress biflavone is completed, and the cypress biflavone is mainly effective on endodermal cancer cells such as lung cancer, digestive tract cancer, throat cancer and the like.
As a further preferred embodiment, in some embodiments of the application, said X 1 Is one of H atom, halogen atom, alkyl and halogenated alkyl. The X is 2 Halogen atoms, specifically, cl or Br. Wherein X is 1 、X 2 The structures of (2) may also be interchanged, e.g., X in some embodiments 1 Is a halogen atom, which may be Cl or Br, and X 2 Is one of H atom, halogen atom, alkyl and halogenated alkyl. When X is 1 Or X 2 When selected as alkyl or haloalkyl, in some embodiments, the alkyl, haloalkyl is a straight-chain or cyclic structure having no more than 6 carbon atoms, preferably, -CH may be selected 2 Cl、-CH 2 CH 2 Cl、-CH 2 CH 2 CH 2 Cl, and the like.
As a further preferable mode, X as described in the embodiment of the application 1 And X 2 Are the same or different groups. When X is 1 And X 2 When the two groups are halogen atoms, the two groups may be the same.
Further, the embodiment of the application also provides a synthesis process of the boron-containing hinokitiol, the derivative or the pharmaceutically acceptable salt thereof, wherein in the application, the main structure of the hinokitiol is as follows: phenolic hydroxyl (5), benzene ring (4), carbonyl (2), ether bond (3), alkene (2). Wherein the phenolic hydroxyl group is easily substituted, which may be substituted with a boron-containing group; the benzene ring is a six-membered ring, the property is stable, the ring structure is not easy to change, hydrogen (-OH ortho-para) on the benzene ring can be substituted, and the benzene ring can be reduced into alkane; carbonyl is nucleophilic group, which is easy to react with electrophile; ether bond is broken by strong acid under high temperature condition; the alkene is easy to undergo addition reaction, so hinokitiol is adopted as a raw material, and the method is feasible in principle.
The synthesis process comprises the following steps of,
reduction reaction: taking hinokitiol or its derivative with chemical structural formula (I) as raw material, introducing hydrogen at a flow rate of 0.2-0.8m/s to reduce it into compound with chemical structural formula (a),
halogenation reaction: due to the existence of-OH group, -X can replace hydrogen in the adjacent para position and ether bond exists, -X can also replace hydrogen in the adjacent para position, the compound (a) is heated in water bath (heating temperature is 45-55 ℃), liquid bromine (Br) is adopted 2 ) As electrophiles, substitution reactions are carried out under the illumination condition to replace hydrogen atoms on the six-membered ring, so as to obtain the compound with the chemical structural formula (b),
elimination reaction: adopting an excessive saturated sodium hydroxide ethanol solution as a reaction reagent to react with the compound with the chemical structural formula (b) at 160-180 ℃ so as to promote the formation of conjugated double bonds and obtain the compound with the chemical structural formula (c),
oxidation reaction: introducing pure oxygen under the action of a catalyst, so that the compound with the chemical structural formula (c) is oxidized into the compound with the chemical structural formula (d), wherein the catalyst is preferably CuO-ZnO-Al 2 O 3 ；
Introducing boron-10: introducing B-10 into the compound with the chemical structural formula (d) by adopting a halogenated boron-10 acid compound to obtain a compound with the chemical structural formula (e),
reduction reaction: and (3) adding a reducing agent to perform a reduction reaction on the compound with the chemical structural formula (e) to obtain a product with the chemical structural formula (II). Preferably, in some embodiments, the reducing agent employed is LiALH 4 Mixed liquid with tri-tert-butylstannane, liALH 4 Double bonds can be reduced, but triple bonds are not reduced. Tri-t-butylstannane is capable of reducing C-Br, but not C-Cl.
The application also provides application of the boron-containing hinokitiol and the derivatives or the pharmaceutically acceptable salts thereof in preparing auxiliary therapeutic drugs for cancers. Specifically, the auxiliary cancer therapeutic agent comprises the boron carrying agent which is used for treating diseases such as small intestine cancer, gastric cancer, lung cancer, liver cancer, breast cancer, kidney cancer and the like by boron neutron therapy. Is especially suitable for treating small intestine cancer and gastric cancer.
The embodiment of the application also provides a boron carrying agent which comprises the boron-containing hinokitiol and the derivative or the pharmaceutically acceptable salt thereof. The boron carrying agent can be used for treating carcinoma of small intestine, gastric cancer, breast cancer, endometrial cancer, liver cancer, and renal cancer by boron neutron therapy
The application also provides a pharmaceutical composition, which comprises the boron-containing hinokitiol and the derivatives or the pharmaceutically acceptable salts thereof provided by the embodiment of the application, and a pharmaceutically acceptable carrier.
The following are specific examples of the present application in which raw materials, reagents, instruments and the like used are available commercially, except for the specific limitations of the present application.
Example 1
This example provides a method for synthesizing a boronated hinoki biflavone compound, comprising:
taking 1.0g of hinokitiol biflavone in a 500ml conical flask, introducing 40ml of hydrogen into the conical flask in a fume hood at a flow rate of 0.5m/s, and fully reacting to obtain the following product:
heating the above products to 50 ℃ in water bath, taking 5ml of liquid bromine, slowly dripping the liquid bromine into a 500ml conical flask, carrying out illumination, and eliminating the products after full reaction:
the conical flask was heated, rapidly warmed and stabilized at 170 ℃, then an excess of 150mL of saturated sodium hydroxide ethanol prepared was added dropwise to the flask, and the following product was obtained by filtration:
drying the product with phosphorus pentoxide and lowering the pH of the product, adding a catalyst of CuO-ZnO-Al 2 O 3 And pure oxygen was introduced at a flow rate of 0.5m/s to prepare ketone.
The 500ml Erlenmeyer flask was heated to 50℃in a water bath and then 0.83g of a haloboron-10 acid compound (B) was added 10 Cl 3 ) Adding LiALH 4 (Universal reducing agent, double bond and triple bond can not be reduced), and tri-tert-butylstannane (C-Br is reduced and C-Cl is not reduced) to reduce the product, and finally obtaining the boronated hinokitiol product.
Confirmation of the boronated hinokitiol product is shown in figure 1. The relative molecular mass of the boronated hinokitiol product: 698.
product property test
The performance test, the test item package toxicity test and the enrichment degree measurement were performed on the boronated hinokitiol product obtained in example 1 above.
1. Toxicity test
1) Injection experiment
4 Kunming mice (Kunming mouse source Guangdong biomedical animal experiment center) were prepared, and no water was allowed to feed for twelve hours prior to dosing. Weighing 19.0g, 20.0g, 22.0g and 20.0g respectively, and sequentially marking 1, 2, 3 and 4; the dosage of the mice 1-2 is 10mg/kg, the dosage of the mice 3-4 is 60mg/kg, the specific dosage of the mice 1-4 is 0.20mg, 0.22mg, 0.19mg and 0.20mg respectively, and the symptoms of the toxic reaction of the mice are observed closely and continuously for 14 days after injection by injecting the boronized hinokiflavone. The experiment can initially observe the toxic reaction and death condition of the mice.
As a result, it was found that when the injection dose was 10mg/kg, the mice were normally administered with water, and showed no abnormality in appearance such as skin congestion, no abnormality in behavior such as restlessness, dullness, and cramping, and no significant change in body weight before and after administration, and were in a harmless state. When the injection dose is 60mg/kg, the mice normally drink water, the skin is slightly red, but no obvious red swelling is seen, slight uneasy symptoms are not seen, behavior anomalies such as obvious mania, cramps and the like are not seen, the weight is not obviously changed before and after injection, and the mice are not dead.
2. Enrichment degree determination
Preparing liver, stomach tumor and blood of mice into suspension, respectively measuring liver, tumor and blood by high performance liquid chromatography, and measuring boron-10 hinokitiol concentration in liver, tumor and blood of mice by high performance liquid chromatography with the boronated hinokitiol obtained by applying force 1 as shown in figure 2.
The results show that: the concentrations of boron-10 cypress biflavone in liver, tumor and blood are 244ug/g,1115ug/g and 295ug/g respectively. Boron-10 in boron-10The content of the platycladus orientalis biflavone is 20/698=2.87%; thus, it was found that the concentrations of boron-10 in liver, tumor and blood were 7.00ug B, respectively 10 /g，32.00ug B 10 /g,8.47ug B 10 And/g. The boron-10 of liver and tumor and blood and tumor are both more than 3 and the boron concentration in tumor cells reaches 32.00ug B 10 And/g, meeting BNCT treatment requirements.
3. Anti-tumor effect experiment
The tail of the breast cancer model of the mouse is injected with 500mg/kg curcumin boride intravenously, BNCT equipment is used after administration for 0.5h, thermal neutron irradiation is carried out on the mouse for 0.5h, the tumor part of the mouse is reddish and swollen after irradiation, the state of the mouse within 2 weeks is observed, and the size of the tumor part is monitored. As a result, it was found that the physiological condition of the mice was all normal within 2 weeks, and the tumor sizes were significantly different.
The above embodiments are only preferred embodiments of the present application, and the scope of the present application is not limited thereto, but any insubstantial changes and substitutions made by those skilled in the art on the basis of the present application are intended to be within the scope of the present application as claimed.
Claims (9)
1. The boron-containing hinokitiol, a derivative or a pharmaceutically acceptable salt thereof is characterized in that the boron-containing hinokitiol, a derivative or a pharmaceutically acceptable salt thereof with the chemical structural formula (II) is obtained by introducing boron-10 into the structure of the hinokitiol or the derivative of the hinokitiol with the chemical structural formula (I) serving as a raw material:
2. the boron-containing hinokitiol, derivative or pharmaceutically acceptable salt thereof according to claim 1, wherein X is 1 Is one of H atom, halogen atom, alkyl and haloalkyl, and X is 2 Is a halogen atom.
3. The boron-containing hinokitiol, its derivatives or pharmaceutically acceptable salts thereof according to claim 2, wherein said halogen atom is Cl or Br, and said alkyl or haloalkyl group has a linear or cyclic structure having not more than 6 carbon atoms.
4. The boron-containing hinokitiol, derivative or pharmaceutically acceptable salt thereof according to claim 1, wherein X is 1 And X 2 Are the same or different groups.
5. A process for synthesizing boron-containing hinokitiol, its derivative or its pharmaceutically acceptable salt, comprises
Reduction reaction: taking hinokitiol or its derivative with chemical structural formula (I) as raw material, introducing hydrogen gas to reduce it into compound with chemical structural formula (a),
halogenation reaction: liquid bromine is adopted as electrophile to replace hydrogen atoms on six-membered ring to obtain compound with chemical structural formula (b),
elimination reaction: adopting saturated sodium hydroxide ethanol solution as a reactant to react with the compound with the chemical structural formula (b) so as to promote the formation of conjugated double bonds and obtain the compound with the chemical structural formula (c),
oxidation reaction: introducing pure oxygen under the action of a catalyst to oxidize the compound with the chemical structural formula (c) into a compound with the chemical structural formula (d),
introducing boron-10: introducing B-10 into the compound of the chemical structural formula (d) to obtain a compound of the chemical structural formula (e),
reduction reaction: and (3) carrying out reduction reaction on the compound with the chemical structural formula (e) to obtain a product with the chemical structural formula (II).
6. The use of the boron-containing hinokitiol, derivative or pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 4 for the preparation of a therapeutic agent for the adjuvant treatment of cancer.
7. The use according to claim 6, wherein the cancer adjuvant therapy comprises an adjuvant therapy for small intestine cancer or stomach cancer.
8. A boron-carrying agent comprising the boron-containing hinokitiol, derivative or pharmaceutically acceptable salt thereof of claims 1-4.
9. A pharmaceutical composition comprising the boron-containing hinokitiol, derivative or pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 4, and a pharmaceutically acceptable carrier.
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