CN114246869A - Anti-tumor activity and application of bifeprunox and derivatives thereof - Google Patents
Anti-tumor activity and application of bifeprunox and derivatives thereof Download PDFInfo
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- CN114246869A CN114246869A CN202210052189.3A CN202210052189A CN114246869A CN 114246869 A CN114246869 A CN 114246869A CN 202210052189 A CN202210052189 A CN 202210052189A CN 114246869 A CN114246869 A CN 114246869A
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- CYGODHVAJQTCBG-UHFFFAOYSA-N Bifeprunox Chemical compound C=12OC(=O)NC2=CC=CC=1N(CC1)CCN1CC(C=1)=CC=CC=1C1=CC=CC=C1 CYGODHVAJQTCBG-UHFFFAOYSA-N 0.000 title claims abstract description 33
- 229950009087 bifeprunox Drugs 0.000 title claims abstract description 31
- 230000000259 anti-tumor effect Effects 0.000 title claims abstract description 10
- 239000003814 drug Substances 0.000 claims abstract description 31
- 230000000694 effects Effects 0.000 claims abstract description 16
- 208000032612 Glial tumor Diseases 0.000 claims abstract description 14
- 206010018338 Glioma Diseases 0.000 claims abstract description 14
- 206010006187 Breast cancer Diseases 0.000 claims abstract description 13
- 208000026310 Breast neoplasm Diseases 0.000 claims abstract description 13
- 206010008342 Cervix carcinoma Diseases 0.000 claims abstract description 13
- 208000000461 Esophageal Neoplasms Diseases 0.000 claims abstract description 13
- 206010025323 Lymphomas Diseases 0.000 claims abstract description 13
- 206010061306 Nasopharyngeal cancer Diseases 0.000 claims abstract description 13
- 206010033128 Ovarian cancer Diseases 0.000 claims abstract description 13
- 206010061535 Ovarian neoplasm Diseases 0.000 claims abstract description 13
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims abstract description 13
- 208000024770 Thyroid neoplasm Diseases 0.000 claims abstract description 13
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims abstract description 13
- 201000010881 cervical cancer Diseases 0.000 claims abstract description 13
- 201000004101 esophageal cancer Diseases 0.000 claims abstract description 13
- 208000032839 leukemia Diseases 0.000 claims abstract description 13
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims abstract description 13
- 201000001441 melanoma Diseases 0.000 claims abstract description 13
- 201000002528 pancreatic cancer Diseases 0.000 claims abstract description 13
- 208000008443 pancreatic carcinoma Diseases 0.000 claims abstract description 13
- 201000002510 thyroid cancer Diseases 0.000 claims abstract description 13
- 206010060862 Prostate cancer Diseases 0.000 claims abstract description 12
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims abstract description 12
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 12
- 206010030155 Oesophageal carcinoma Diseases 0.000 claims abstract description 11
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims abstract description 10
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 10
- 201000007270 liver cancer Diseases 0.000 claims abstract description 10
- 208000014018 liver neoplasm Diseases 0.000 claims abstract description 10
- 201000005202 lung cancer Diseases 0.000 claims abstract description 10
- 208000020816 lung neoplasm Diseases 0.000 claims abstract description 10
- 208000005718 Stomach Neoplasms Diseases 0.000 claims abstract description 9
- 206010017758 gastric cancer Diseases 0.000 claims abstract description 9
- 201000011549 stomach cancer Diseases 0.000 claims abstract description 9
- 206010009944 Colon cancer Diseases 0.000 claims abstract description 8
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims abstract description 8
- 239000002246 antineoplastic agent Substances 0.000 claims abstract description 7
- 230000005764 inhibitory process Effects 0.000 claims abstract description 7
- 208000001894 Nasopharyngeal Neoplasms Diseases 0.000 claims abstract description 5
- 229940041181 antineoplastic drug Drugs 0.000 claims abstract description 5
- 230000001225 therapeutic effect Effects 0.000 claims description 56
- 230000003449 preventive effect Effects 0.000 claims description 32
- 230000000069 prophylactic effect Effects 0.000 claims description 24
- 229940079593 drug Drugs 0.000 claims description 20
- 208000002454 Nasopharyngeal Carcinoma Diseases 0.000 claims description 8
- -1 hydroxy, amino Chemical group 0.000 claims description 8
- 201000011216 nasopharynx carcinoma Diseases 0.000 claims description 8
- 125000002252 acyl group Chemical group 0.000 claims description 6
- 239000000126 substance Substances 0.000 claims description 6
- 208000005016 Intestinal Neoplasms Diseases 0.000 claims description 5
- 241001024304 Mino Species 0.000 claims description 5
- 101100481912 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) tpc-1 gene Proteins 0.000 claims description 5
- 201000002313 intestinal cancer Diseases 0.000 claims description 5
- QZBRCSFGVAKGJU-UVLRMEHCSA-N (e)-2-cyano-3-[4-[(e)-2-[4-(n-phenylanilino)phenyl]ethenyl]phenyl]prop-2-enoic acid Chemical compound C1=CC(/C=C(C(=O)O)\C#N)=CC=C1\C=C\C1=CC=C(N(C=2C=CC=CC=2)C=2C=CC=CC=2)C=C1 QZBRCSFGVAKGJU-UVLRMEHCSA-N 0.000 claims description 4
- 206010027476 Metastases Diseases 0.000 claims description 4
- 125000000623 heterocyclic group Chemical group 0.000 claims description 4
- 230000009401 metastasis Effects 0.000 claims description 4
- 230000002265 prevention Effects 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- 229940126585 therapeutic drug Drugs 0.000 claims description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 3
- 239000000243 solution Substances 0.000 claims description 3
- 230000004614 tumor growth Effects 0.000 claims description 3
- 125000006704 (C5-C6) cycloalkyl group Chemical group 0.000 claims description 2
- 125000004008 6 membered carbocyclic group Chemical group 0.000 claims description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 2
- 239000000443 aerosol Substances 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 claims description 2
- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 2
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 2
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 2
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 claims description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 2
- SXDBWCPKPHAZSM-UHFFFAOYSA-M bromate Inorganic materials [O-]Br(=O)=O SXDBWCPKPHAZSM-UHFFFAOYSA-M 0.000 claims description 2
- SXDBWCPKPHAZSM-UHFFFAOYSA-N bromic acid Chemical compound OBr(=O)=O SXDBWCPKPHAZSM-UHFFFAOYSA-N 0.000 claims description 2
- 239000002775 capsule Substances 0.000 claims description 2
- 125000002837 carbocyclic group Chemical class 0.000 claims description 2
- 238000002512 chemotherapy Methods 0.000 claims description 2
- 229940044683 chemotherapy drug Drugs 0.000 claims description 2
- 239000013078 crystal Substances 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims description 2
- 125000002541 furyl group Chemical group 0.000 claims description 2
- 239000008187 granular material Substances 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 2
- 125000002883 imidazolyl group Chemical group 0.000 claims description 2
- 230000001024 immunotherapeutic effect Effects 0.000 claims description 2
- 125000001041 indolyl group Chemical group 0.000 claims description 2
- 239000007924 injection Substances 0.000 claims description 2
- 238000002347 injection Methods 0.000 claims description 2
- 125000005956 isoquinolyl group Chemical group 0.000 claims description 2
- 125000001786 isothiazolyl group Chemical group 0.000 claims description 2
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 2
- 230000002503 metabolic effect Effects 0.000 claims description 2
- 239000002207 metabolite Substances 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- 125000001624 naphthyl group Chemical group 0.000 claims description 2
- 239000002674 ointment Substances 0.000 claims description 2
- 125000002971 oxazolyl group Chemical group 0.000 claims description 2
- 239000003973 paint Substances 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 239000006187 pill Substances 0.000 claims description 2
- 239000000843 powder Substances 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
- 229940002612 prodrug Drugs 0.000 claims description 2
- 239000000651 prodrug Substances 0.000 claims description 2
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 claims description 2
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 2
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 2
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 2
- 125000004076 pyridyl group Chemical group 0.000 claims description 2
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 2
- 125000005493 quinolyl group Chemical group 0.000 claims description 2
- 150000003254 radicals Chemical class 0.000 claims description 2
- 238000001959 radiotherapy Methods 0.000 claims description 2
- 238000002271 resection Methods 0.000 claims description 2
- 229920006395 saturated elastomer Polymers 0.000 claims description 2
- 239000012453 solvate Substances 0.000 claims description 2
- 125000003107 substituted aryl group Chemical group 0.000 claims description 2
- 239000000829 suppository Substances 0.000 claims description 2
- 239000003826 tablet Substances 0.000 claims description 2
- 125000000335 thiazolyl group Chemical group 0.000 claims description 2
- 125000001544 thienyl group Chemical group 0.000 claims description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 2
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims 1
- 201000011510 cancer Diseases 0.000 claims 1
- 150000002170 ethers Chemical class 0.000 claims 1
- 230000009036 growth inhibition Effects 0.000 abstract description 17
- 210000004881 tumor cell Anatomy 0.000 abstract description 5
- 150000001875 compounds Chemical class 0.000 abstract description 2
- 210000004027 cell Anatomy 0.000 description 84
- ONWKHSGOYGLGPO-UHFFFAOYSA-N methanesulfonic acid;7-[4-[(3-phenylphenyl)methyl]piperazin-1-yl]-3h-1,3-benzoxazol-2-one Chemical compound CS(O)(=O)=O.C=12OC(=O)NC2=CC=CC=1N(CC1)CCN1CC(C=1)=CC=CC=1C1=CC=CC=C1 ONWKHSGOYGLGPO-UHFFFAOYSA-N 0.000 description 32
- 230000035945 sensitivity Effects 0.000 description 16
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 4
- 201000006585 gastric adenocarcinoma Diseases 0.000 description 4
- 208000024891 symptom Diseases 0.000 description 4
- 208000010507 Adenocarcinoma of Lung Diseases 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 201000005249 lung adenocarcinoma Diseases 0.000 description 3
- 102400000888 Cholecystokinin-8 Human genes 0.000 description 2
- 101800005151 Cholecystokinin-8 Proteins 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 239000003693 atypical antipsychotic agent Substances 0.000 description 2
- 235000010290 biphenyl Nutrition 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000003920 cognitive function Effects 0.000 description 1
- 238000004737 colorimetric analysis Methods 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 230000002996 emotional effect Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000010899 nucleation Methods 0.000 description 1
- 230000036962 time dependent Effects 0.000 description 1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- 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
- A61P35/02—Antineoplastic agents specific for leukemia
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- Hematology (AREA)
- Oncology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides application of bifeprunox or a derivative thereof and a pharmaceutical composition containing bifeprunox or a derivative thereof in preparing a medicament for preventing and/or treating tumors. Experiments show that the compound has obvious growth inhibition effect on various human tumor cells, has broad-spectrum anti-tumor activity, and has good inhibition activity on tumors such as breast cancer, esophageal cancer, thyroid cancer, nasopharyngeal cancer, cervical cancer, glioma, prostatic cancer, ovarian cancer, lung cancer, colorectal cancer, liver cancer, gastric cancer, melanoma, pancreatic cancer, leukemia, lymphoma and the like, and experiments show that the bifeprunox and derivatives thereof can become anti-tumor drugs.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to application of bifeprunox and derivatives thereof in preparation of antitumor medicines.
Background
The English name of Bifeprunox is Bifepunox, and the chemical name is 7- [4- ([1,1' -biphenyl)]-3-ylmethyl) -1-piperazinyl]-2(3H) -benzoxazolone with the chemical name 7- [4- ([1,1' -Biphenyl)]-3-ylmethyl)-1-piperazinyl]-2(3H) -benzoxazone; the english name is Bifeprunox. The molecular formula of the compound is C24H23N3O2Molecular weight 385.46, dissolved in DMSO. Bifenapino belongs to a novel atypical antipsychotic drug, has atypical characteristics in the atypical antipsychotic drug, and has positive symptoms, negative symptoms and cognitive function on schizophreniaHas good curative effect on symptoms and emotional symptoms.
Disclosure of Invention
The invention adopts the following technical scheme:
the invention provides an application of bifeprunox or a derivative thereof or a pharmaceutical composition containing bifeprunox or a derivative thereof in preparing a medicament for preventing and/or treating tumors, wherein the bifeprunox is shown as a chemical structural formula (I):
（Ⅰ）
the bifeprunox derivative is shown as a chemical structural formula (II):
（П）
R1-R18each independently selected from hydrogen, hydroxy, amino, C1-8Alkyl radical, C1-8Alkoxy radical, C1-8Alcoxyl acyl radical, C2-8Alkenyl radical, C2-8Alkynyl, C1-8Acyl radical, C6-10Aryl radical, C5-6Cycloalkyl, tetrahydropyrroloyl, tetrahydrofuroyl, Ar-C1-4Acyl, Ar-O-C1-4Acyl, Ar-S-C1-4Any one or more of acyl; or R3And R4Or R9And R10Or R14And R15Linked to form a saturated or unsaturated 6-membered carbocyclic or heterocyclic group or an alkyl-substituted carbocyclic or heterocyclic group;
further, C1-8The acyl group is selected from the group consisting of straight or branched alkanoyl, alkenoyl and alkynoyl;
further, Ar is aryl or substituted aryl, Ar is preferably any one or more of phenyl, benzoyl, naphthyl, pyridyl, furyl, thienyl, pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, oxazolyl, thiazolyl, imidazolyl, pyridazinyl, pyrazinyl, benzofuryl, benzothienyl, indolyl, quinolyl, isoquinolyl, purinyl, benzoxazolyl and benzothiazolyl;
further, the bifeprunox or its derivative includes, but is not limited to, its tautomer, mesomer, racemate, enantiomer, diastereomer or mixture form;
further, the bifeprunox or its derivative includes, but is not limited to, a pharmaceutically acceptable salt, an ether, an ester thereof, a prodrug thereof, a metabolite thereof, a solvate thereof, or a crystal thereof;
further, the bifeprunox or its derivative includes its pharmaceutically acceptable salts including but not limited to hydrochloride, bromate, fumarate, acetate, citrate, sulfate or methanesulfonate;
further, the pharmaceutical composition of bifeprunox or its derivative includes, but is not limited to, tablets, injections, capsules, oral solutions, pills, granules, powders, aerosols, patches, ointments, paints, or suppositories;
further, the pharmaceutical composition of bifeprunox or the derivative thereof also comprises a conventional antitumor drug; further, the conventional antitumor drugs include, but are not limited to, chemotherapeutic drugs, biological targeted therapeutic drugs, metabolic therapeutic drugs, or immunotherapeutic drugs;
further, the effects of the pharmaceutical composition of bifeprunox or its derivatives include, but are not limited to, inhibiting tumor growth and/or metastasis;
further, the pharmaceutical composition of bifeprunox or a derivative thereof is used for treatment including, but not limited to, surgical resection, chemotherapy, or radiation therapy;
further, the bifeprunox, the derivative or the pharmaceutical composition thereof is used for preventing and/or treating breast cancer, esophagus cancer, thyroid cancer, nasopharyngeal cancer, cervical cancer, glioma, prostate cancer, ovarian cancer, lung cancer, colorectal cancer, liver cancer, gastric cancer, melanoma, pancreatic cancer, leukemia and lymphoma;
furthermore, the prevention and/or treatment effect on the breast cancer includes but is not limited to the prevention and/or treatment effect on the breast cancer cell MDA-MB-231 LM 2;
further, the preventive and/or therapeutic effects on esophageal cancer include, but are not limited to, preventive and/or therapeutic effects on esophageal cancer cell EC 109;
further, the preventive and/or therapeutic effect on thyroid cancer includes, but is not limited to, preventive and/or therapeutic effect on thyroid cancer cell TPC-1;
further, the preventive and/or therapeutic effect on nasopharyngeal carcinoma includes, but is not limited to, preventive and/or therapeutic effect on nasopharyngeal carcinoma cells 5-8F;
further, the preventive and/or therapeutic effect on cervical cancer includes, but is not limited to, preventive and/or therapeutic effect on cervical cancer cell SiHa;
further, the prophylactic and/or therapeutic effects on glioma include, but are not limited to, the prophylactic and/or therapeutic effects on glioma cell U251;
further, the preventive and/or therapeutic effect on prostate cancer includes, but is not limited to, preventive and/or therapeutic effect on glioma cell PC-3;
further, prophylactic and/or therapeutic effects on ovarian cancer include, but are not limited to, prophylactic and/or therapeutic effects on ovarian cancer cell a 2780;
further, the preventive and/or therapeutic effect on lung cancer includes, but is not limited to, preventive and/or therapeutic effect on lung cancer cell a 549;
further, the preventive and/or therapeutic effect on intestinal cancer includes, but is not limited to, preventive and/or therapeutic effect on HCT116, which is an intestinal cancer cell;
furthermore, the effect of preventing and/or treating liver cancer includes but is not limited to the effect of preventing and/or treating liver cancer cell SMMC-7721;
further, the preventive and/or therapeutic effect on gastric cancer includes, but is not limited to, preventive and/or therapeutic effect on gastric cancer cell SGC-7901;
further, the prophylactic and/or therapeutic effects on melanoma include, but are not limited to, the prophylactic and/or therapeutic effects on melanoma cell a 375;
further, the preventive and/or therapeutic effects on pancreatic cancer include, but are not limited to, preventive and/or therapeutic effects on pancreatic cancer cells Panc-1;
further, the preventive and/or therapeutic effect on leukemia includes, but is not limited to, preventive and/or therapeutic effect on leukemia cell HL 60;
further, the prophylactic and/or therapeutic effect on lymphoma includes, but is not limited to, the prophylactic and/or therapeutic effect on lymphoma cell MINO.
Drawings
FIG. 1 shows growth inhibition curves of different concentrations of bifeprunox mesylate treated breast cancer cells MDA-MB-231 LM 224 h and 48 h;
FIG. 2 shows growth inhibition curves of different concentrations of bifeprunox mesylate treated esophageal cancer cells EC 10924 h and 48 h;
FIG. 3 shows growth inhibition curves of different concentrations of bifeprunox mesylate-treated thyroid cancer cell lines TPC-124 h and 48 h;
FIG. 4 shows growth inhibition curves of 5- 8F 24h and 48h for nasopharyngeal carcinoma cells treated with bifeprunox mesylate at different concentrations;
FIG. 5 shows growth inhibition curves of SiHa 24h and 48h for cervical cancer cells treated with different concentrations of bifeprunox mesylate;
FIG. 6 shows growth inhibition curves of different concentrations of bifeprunox mesylate treated glioma cells U25124 h and 48 h;
FIG. 7 shows growth inhibition curves of different concentrations of bifeprunox mesylate treated prostate cancer cells PC-324 h and 48 h;
FIG. 8 shows growth inhibition curves of bifeprunox mesylate treated ovarian cancer cells A278024 h and 48h at different concentrations;
FIG. 9 shows growth inhibition curves for different concentrations of bifeprunox mesylate treated lung cancer cells A54924 h and 48 h;
FIG. 10 shows growth inhibition curves of different concentrations of bifeprunox mesylate treated intestinal cancer cells HCT 11624 h and 48 h;
FIG. 11 shows growth inhibition curves of different concentrations of bifeprunox mesylate treated hepatoma cells SMMC-772124 h and 48 h;
FIG. 12 shows growth inhibition curves for different concentrations of bifeprunox mesylate for SGC-790124 h and 48h of gastric adenocarcinoma;
FIG. 13 shows growth inhibition curves for melanoma A37524 h and 48h treated with bifeprunox mesylate at different concentrations;
FIG. 14 shows growth inhibition curves for Panc-124 h and 48h of pancreatic cancer cells treated with different concentrations of bifeprunox mesylate;
FIG. 15 shows growth inhibition curves of different concentrations of bifeprunox mesylate treated leukemia cells HL 6024 h and 48 h;
FIG. 16 shows growth inhibition curves for different concentrations of bifeprunox mesylate treated lymphoma cells MINO for 24h and 48 h.
Advantageous effects
The invention relates to the anti-tumor activity of bifeprunox and derivatives thereof and a new application thereof in preparing a medicament for treating and/or preventing cancers; bifeprunox has obvious and broad-spectrum anti-tumor activity, and has inhibiting effect on tumor cells of multiple human cultured in vitro, such as breast cancer, esophageal cancer, thyroid cancer, nasopharyngeal carcinoma, cervical cancer, glioma, prostatic cancer, ovarian cancer, lung cancer, colorectal cancer, liver cancer, gastric cancer, melanoma, pancreatic cancer, leukemia, lymphoma and other tumors; the bifeprunox and the derivative thereof can be used for preparing antitumor drugs and preventing the occurrence and the metastasis of tumors.
Detailed Description
The invention is described in further detail below with reference to the drawings and the detailed description;
example 1: bifenarimol inhibiting growth of multiple tumor cells
Comparing the cytotoxicity of the bifeprunox mesylate on a human breast cancer cell line MDA-MB-231 LM2, an esophageal cancer cell line EC109, a thyroid cancer cell line TPC-1, a nasopharyngeal cancer cell line 5-8F, a glioma cell line U251, a cervical cancer cell line SiHa, a prostate cancer cell line PC-3, a human colorectal cancer cell line HCT116, a human ovarian cancer cell line A2780, a lung adenocarcinoma cell line A549, a liver cancer cell line SMMC-7721, a stomach adenocarcinoma cell line SGC-7901, a melanoma cell line A375, a pancreatic cancer cell line Panc-1, a leukemia cell line HL60 and a lymphoma cell line MINO by adopting a CCK8 colorimetric method;
the cells were seeded in 96-well plates at 8000 cells/well, and 24h after seeding, the drug was diluted to 0, 0.001, 0.01, 0.1, 1, 10, 20, 40, 80, 160 μ M, and the medium in the original well was discarded, 100 μ L per well was added to the corresponding well, 4 replicate wells per set. After 10 microliter CCK8 is added into each well for incubation for 3 hours during 24 hours and 48 hours respectively, the OD value at A450 is detected by a multifunctional microplate reader, and the inhibition rate is calculated. The results are shown in FIGS. 1-16, and are as follows:
FIG. 1 is the drug sensitivity profiles of the MDA-MB-231 LM 224 h and 48h of the bifeprunox mesylate treated human breast cancer cells, and the IC of 48h5027.23 +/-2.80 mu M; FIG. 2 is a graph of the drug sensitivity of 24h and 48h for esophageal cancer cell EC109 cells treated with bifeprunox mesylate, and the IC of 48h5021.86. + -. 4.37. mu.M. FIG. 3 is a graph showing the drug sensitivity profiles of 24h and 48h for bifeprunox mesylate-treated TPC-1 cells from human thyroid cancer cell lines, and the IC of 48h5037.29 +/-5.01 mu M; FIG. 4 is a graph of Bifenaunox treatment of nasopharyngeal carcinoma 5-8F cells for 24h and 48h drug sensitivity with 48h IC5098.13 +/-30.33 mu M; FIG. 5 is a graph showing the drug sensitivity curve of SiHa cells of cervical cancer cells treated with bifeprunox mesylate for 24h and 48h, and the IC of 48h5036.80 +/-1.67 mu M; FIG. 6 is a graph of the drug sensitivity of bifeprunox mesylate treated glioma cells U251 cells for 24h and 48h with an IC of 48h5030.85 +/-7.6 mu M; FIG. 7 drug sensitivity profiles of Bifenaonol mesylate treated prostate cancer cells PC-324 h and 48h with 48h IC5034.84 +/-3.66 mu M; FIG. 8 drug sensitivity curves of bifeprunox mesylate treated human ovarian cancer A2780 cells for 24h and 48h, and IC of 48h5037.14 +/-1.61 mu M; FIG. 9 drug sensitivity profiles of bifeprunox mesylate-treated lung adenocarcinoma cells A54924 h and 48h, IC of 48h5050.78 +/-2.73 mu M; FIG. 10 is a graph of the drug sensitivity of bifeprunox mesylate on human colorectal cancer cells HCT 11624 h and 48h, and IC of 48h5027.75 +/-2.55 mu M; FIG. 11 is a graph of Bifenarimol-treated hepatoma cells SMMC-772124 h and 48h drug sensitivity with 48h IC5030.1 +/-0.93 mu M; FIG. 12 is bifeprunox mesylate treatmentDrug sensitivity profiles of gastric adenocarcinoma SGC-7901 cells at 24h and 48h, IC at 48h5041.62 +/-3.96 mu M; FIG. 13 is a graph of the drug sensitivity of bifeprunox mesylate on melanoma A375 cells for 24h and 48h with IC for 48h5016.83 +/-4.01 mu M; FIG. 14 is a graph of drug sensitivity of pancreatic cancer cells Panc-1 cells treated with bifeprunox mesylate for 24h and 48h and IC for 48h5045.55 +/-0.70 mu M; FIG. 15 is a graph of the drug sensitivity of the leukemia cells HL60 treated with bifeprunox mesylate at 24h and 48h and the IC at 48h5058.07 +/-1.98 mu M; FIG. 16 is a graph of the drug sensitivity of bifeprunox mesylate on lymphoma cells MINO cells for 24h and 48h with an IC of 48h5021.08. + -. 2.89. mu.M. Therefore, the bifeprunox mesylate has obvious inhibition effects on the growth of breast cancer, esophagus cancer, thyroid cancer, nasopharyngeal carcinoma, cervical cancer, glioma, prostatic cancer, ovarian cancer, lung cancer, colorectal cancer, liver cancer, stomach cancer, melanoma, pancreatic cancer, leukemia and lymphoma cells, and the inhibition effects are dose-dependent and time-dependent;
example 2: in vitro tumor growth inhibition assay
The results are shown in FIGS. 1-16: after 160 mu M of bifeprunox mesylate acts on different tumor cells for 48 hours, the inhibition rates of the tumor cells are 60.68 +/-3.59% (breast cancer cell MDA-MB-231 LM2 shown in figure 1), 75.92 +/-3.09% (esophageal cancer cell EC109 shown in figure 2), 74.20 +/-3.88% (human thyroid cancer cell line TPC-1 shown in figure 3), 41.99 +/-2.56% (nasopharyngeal cancer cell 5-8F shown in figure 4), 74.28 +/-4.02% (cervical cancer cell SiHa shown in figure 5), 69.91 +/-3.85% (glioma cell U251 shown in figure 6), 84.67 +/-0.48% (prostate cancer cell PC-3 shown in figure 7), 69.27 +/-3.50% (human ovarian cancer cell A2780 shown in figure 8), 69.39 +/-1.05% (lung adenocarcinoma cell A shown in figure 9), 73.33 +/-2.67% (human colorectal cancer cell HCT 80 shown in figure 10.84) and SM367721-7721 MC respectively, as shown in fig. 11), 78.20 ± 3.45% (gastric adenocarcinoma SGC-7901 as shown in fig. 12), 73.66 ± 2.57% (melanoma a375 as shown in fig. 13), 65.64 ± 0.68% (pancreatic cancer cell Panc-1 as shown in fig. 14), 81.45 ± 0.40% (leukemia cell HL60 as shown in fig. 15), 87.36 ± 1.48% (lymphoma cell mio as shown in fig. 16). The bifeprunox has good anti-tumor activity in various tumors, and the anti-tumor activity of the bifeprunox can be used for preparing anti-tumor medicaments and medicaments for preventing tumor occurrence and metastasis;
the foregoing detailed description of the preferred embodiments of the invention has been presented. It should be understood that numerous modifications and variations could be devised by those skilled in the art in light of the present teachings without departing from the inventive concepts. Therefore, the technical solutions available to those skilled in the art through logic analysis, reasoning and limited experiments based on the prior art according to the concept of the present invention should be within the scope of protection defined by the claims.
Claims (9)
1. Use of bifeprunox or a derivative thereof, or a pharmaceutical composition comprising bifeprunox or a derivative thereof, in the preparation of a medicament for the prevention and/or treatment of tumors, wherein the bifeprunox is represented by the chemical structural formula (I):
（Ⅰ）
the bifeprunox derivative is shown as a chemical structural formula (II):
（П）
wherein:
R1-R18each independently selected from hydrogen, hydroxy, amino, C1-8Alkyl radical, C1-8Alkoxy radical, C1-8Alcoxyl acyl radical, C2-8Alkenyl radical, C2-8Alkynyl, C1-8Acyl radical, C6-10Aryl radical, C5-6Cycloalkyl, tetrahydropyrroloyl, tetrahydrofuroyl, Ar-C1-4Acyl, Ar-O-C1-4Acyl, Ar-S-C1-4Any one or more of acyl; or R3And R4Or R9And R10Or R14And R15Linked to form a saturated or unsaturated 6-membered carbocyclic or heterocyclic group or an alkyl-substituted carbocyclic or heterocyclic group;
further, C1-8The acyl group is selected from the group consisting of straight or branched alkanoyl, alkenoyl and alkynoyl;
further, Ar is aryl or substituted aryl, and Ar is preferably any one or more of phenyl, benzoyl, naphthyl, pyridyl, furyl, thienyl, pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, oxazolyl, thiazolyl, imidazolyl, pyridazinyl, pyrazinyl, benzofuryl, benzothienyl, indolyl, quinolyl, isoquinolyl, purinyl, benzoxazolyl and benzothiazolyl.
2. The use according to claim 1, wherein said bifeprunox or its derivatives include, but are not limited to, its tautomers, meso-forms, racemates, enantiomers, diastereomers or mixtures thereof.
3. The use according to claim 1 or 2, wherein said bifeprunox or its derivative includes, but is not limited to, its pharmaceutically acceptable salts, ethers, esters, its prodrugs, its metabolites, its solvates or its crystals.
4. Use according to claim 3, wherein said bifeprunox or its derivative including its pharmaceutically acceptable salts includes but is not limited to hydrochloride, bromate, fumarate, acetate, citrate, sulfate or methanesulfonate.
5. Use according to claim 1, wherein the medicament or pharmaceutical composition comprises, but is not limited to, tablets, injections, capsules, oral solutions, pills, granules, powders, aerosols, patches, ointments, paints or suppositories.
6. Use according to claim 1 or 5, wherein the medicament or pharmaceutical composition further comprises a conventional anti-tumor medicament; further, the conventional antitumor drugs include, but are not limited to, chemotherapeutic drugs, biological targeted therapeutic drugs, metabolic therapeutic drugs, or immunotherapeutic drugs.
7. Use according to any one of claims 1 to 3 or 5, wherein the effect of the medicament includes, but is not limited to, inhibition of tumor growth and/or metastasis.
8. The use according to any one of claims 1 to 3 or 5, wherein the medicament or pharmaceutical composition is for use including, but not limited to, surgical resection, chemotherapy or radiation therapy.
9. The use according to any one of claims 1-3, 5, wherein the bifeprunox, its derivative or pharmaceutical composition is used for the prevention and/or treatment of cancer including but not limited to breast cancer, esophageal cancer, thyroid cancer, nasopharyngeal cancer, cervical cancer, glioma, prostate cancer, ovarian cancer, lung cancer, colorectal cancer, liver cancer, stomach cancer, melanoma, pancreatic cancer, leukemia, lymphoma;
still further, the prophylactic and/or therapeutic effects on breast cancer include, but are not limited to, prophylactic and/or therapeutic effects on breast cancer cells MDA-MB-231 LM 2;
still further, the prophylactic and/or therapeutic effect on esophageal cancer includes, but is not limited to, a prophylactic and/or therapeutic effect on esophageal cancer cell EC 109;
still further, the preventive and/or therapeutic effects on thyroid cancer include, but are not limited to, preventive and/or therapeutic effects on thyroid cancer cell TPC-1;
still further, the preventing and/or treating effect on nasopharyngeal carcinoma includes, but is not limited to, preventing and/or treating effect on nasopharyngeal carcinoma cells 5-8F;
still further, the preventive and/or therapeutic effect on cervical cancer includes, but is not limited to, preventive and/or therapeutic effect on cervical cancer cell SiHa;
still further, the prophylactic and/or therapeutic effect on glioma includes, but is not limited to, a prophylactic and/or therapeutic effect on glioma cell U251;
still further, the preventive and/or therapeutic effect on prostate cancer includes, but is not limited to, preventive and/or therapeutic effect on prostate cancer cell PC-3;
still further, the prophylactic and/or therapeutic effect on ovarian cancer includes, but is not limited to, a prophylactic and/or therapeutic effect on ovarian cancer cells A2780;
still further, the preventive and/or therapeutic effect on lung cancer includes, but is not limited to, preventive and/or therapeutic effect on lung cancer cell a 549;
further, the preventive and/or therapeutic effect on intestinal cancer includes, but is not limited to, preventive and/or therapeutic effect on intestinal cancer cell HCT 116;
furthermore, the effect of preventing and/or treating liver cancer includes but is not limited to the effect of preventing and/or treating liver cancer cell SMMC-7721;
further, the preventive and/or therapeutic effect on gastric cancer includes, but is not limited to, preventive and/or therapeutic effect on gastric cancer cell SGC-7901;
still further, the prophylactic and/or therapeutic effect on melanoma includes, but is not limited to, a prophylactic and/or therapeutic effect on melanoma cell a 375;
still further, the prophylactic and/or therapeutic effect on pancreatic cancer includes, but is not limited to, a prophylactic and/or therapeutic effect on pancreatic cancer cells Panc-1;
still further, the prophylactic and/or therapeutic effect on leukemia includes, but is not limited to, a prophylactic and/or therapeutic effect on leukemia cell HL 60;
still further, the prophylactic and/or therapeutic effect on lymphoma includes, but is not limited to, a prophylactic and/or therapeutic effect on lymphoma cell MINO.
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| WO1997036893A1 (en) * | 1996-03-29 | 1997-10-09 | Duphar International Research B.V. | Piperazine and piperidine compounds |
| CN101918382A (en) * | 2008-01-15 | 2010-12-15 | 雅培卫生保健产品有限责任公司 | Bifeprunox derivatives |
| WO2020210643A1 (en) * | 2019-04-11 | 2020-10-15 | Ian Basil Shine | Cell membrane permeability restoring therapy |
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2022
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1997036893A1 (en) * | 1996-03-29 | 1997-10-09 | Duphar International Research B.V. | Piperazine and piperidine compounds |
| CN101918382A (en) * | 2008-01-15 | 2010-12-15 | 雅培卫生保健产品有限责任公司 | Bifeprunox derivatives |
| WO2020210643A1 (en) * | 2019-04-11 | 2020-10-15 | Ian Basil Shine | Cell membrane permeability restoring therapy |
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| BO PAN等: "Modulation by chronic antipsychotic administration of PKA- and GSK3β-mediated pathways and the NMDA receptor in rat ventral midbrain", PSYCHOPHARMACOLOGY, vol. 236, no. 9, pages 2687 - 2697, XP036863339, DOI: 10.1007/s00213-019-05243-x * |
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