CN114874135B - Small molecular compound for resisting breast cancer and preparation method thereof - Google Patents
Small molecular compound for resisting breast cancer and preparation method thereof Download PDFInfo
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 92
- 206010006187 Breast cancer Diseases 0.000 title claims abstract description 38
- 208000026310 Breast neoplasm Diseases 0.000 title claims abstract description 38
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- 239000003814 drug Substances 0.000 claims abstract description 9
- 150000003839 salts Chemical class 0.000 claims description 6
- 239000000463 material Substances 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 3
- 239000004480 active ingredient Substances 0.000 claims description 2
- 230000005764 inhibitory process Effects 0.000 abstract description 12
- 230000000694 effects Effects 0.000 abstract description 11
- 208000003721 Triple Negative Breast Neoplasms Diseases 0.000 abstract description 10
- 208000022679 triple-negative breast carcinoma Diseases 0.000 abstract description 10
- 206010028980 Neoplasm Diseases 0.000 abstract description 9
- 201000011510 cancer Diseases 0.000 abstract description 7
- 210000000481 breast Anatomy 0.000 abstract description 5
- 230000012010 growth Effects 0.000 abstract description 5
- 125000003545 alkoxy group Chemical group 0.000 description 22
- 125000000217 alkyl group Chemical group 0.000 description 20
- 229910052736 halogen Inorganic materials 0.000 description 18
- 210000004027 cell Anatomy 0.000 description 17
- 150000002367 halogens Chemical class 0.000 description 16
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 12
- 125000004093 cyano group Chemical group *C#N 0.000 description 10
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 10
- 102000015694 estrogen receptors Human genes 0.000 description 8
- 108010038795 estrogen receptors Proteins 0.000 description 8
- 125000005843 halogen group Chemical group 0.000 description 8
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 8
- 102000003998 progesterone receptors Human genes 0.000 description 8
- 108090000468 progesterone receptors Proteins 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- AZQWKYJCGOJGHM-UHFFFAOYSA-N 1,4-benzoquinone Chemical compound O=C1C=CC(=O)C=C1 AZQWKYJCGOJGHM-UHFFFAOYSA-N 0.000 description 6
- 101001012157 Homo sapiens Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 description 6
- 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 description 6
- 230000000259 anti-tumor effect Effects 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 5
- 229940079593 drug Drugs 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 210000004881 tumor cell Anatomy 0.000 description 4
- 241000196324 Embryophyta Species 0.000 description 3
- 235000009499 Vanilla fragrans Nutrition 0.000 description 3
- 244000263375 Vanilla tahitensis Species 0.000 description 3
- 235000012036 Vanilla tahitensis Nutrition 0.000 description 3
- 208000014581 breast ductal adenocarcinoma Diseases 0.000 description 3
- 201000010983 breast ductal carcinoma Diseases 0.000 description 3
- 206010073095 invasive ductal breast carcinoma Diseases 0.000 description 3
- KEQHJBNSCLWCAE-UHFFFAOYSA-N thymoquinone Chemical compound CC(C)C1=CC(=O)C(C)=CC1=O KEQHJBNSCLWCAE-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 206010027476 Metastases Diseases 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- 230000014509 gene expression Effects 0.000 description 2
- 230000036210 malignancy Effects 0.000 description 2
- 230000009401 metastasis Effects 0.000 description 2
- 238000004393 prognosis Methods 0.000 description 2
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 2
- 239000002994 raw material Substances 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
- 125000001424 substituent group Chemical group 0.000 description 2
- 239000000341 volatile oil Substances 0.000 description 2
- 101100314454 Caenorhabditis elegans tra-1 gene Proteins 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 229940126062 Compound A Drugs 0.000 description 1
- 201000004624 Dermatitis Diseases 0.000 description 1
- 102000001301 EGF receptor Human genes 0.000 description 1
- 108060006698 EGF receptor Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 238000011460 HER2-targeted therapy Methods 0.000 description 1
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 208000008589 Obesity Diseases 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 240000002657 Thymus vulgaris Species 0.000 description 1
- 235000007303 Thymus vulgaris Nutrition 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 229940046836 anti-estrogen Drugs 0.000 description 1
- 230000001833 anti-estrogenic effect Effects 0.000 description 1
- 230000002622 anti-tumorigenesis Effects 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000022131 cell cycle Effects 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
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- 208000001848 dysentery Diseases 0.000 description 1
- 239000000328 estrogen antagonist Substances 0.000 description 1
- SRCZQMGIVIYBBJ-UHFFFAOYSA-N ethoxyethane;ethyl acetate Chemical compound CCOCC.CCOC(C)=O SRCZQMGIVIYBBJ-UHFFFAOYSA-N 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 238000012151 immunohistochemical method Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
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- 208000030603 inherited susceptibility to asthma Diseases 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 230000001394 metastastic effect Effects 0.000 description 1
- 206010061289 metastatic neoplasm Diseases 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000000583 progesterone congener Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000000979 retarding effect Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
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- 229940126585 therapeutic drug Drugs 0.000 description 1
- 239000001585 thymus vulgaris Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
- C07D213/53—Nitrogen atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
- C07C251/02—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton containing imino groups
- C07C251/24—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton containing imino groups having carbon atoms of imino groups bound to carbon atoms of six-membered aromatic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C255/50—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton to carbon atoms of non-condensed six-membered aromatic rings
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- 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)
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- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
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- General Health & Medical Sciences (AREA)
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- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a kind of small molecular compound for resisting breast cancer and a preparation method thereof, and the structure of the compound is shown as a formula I. The compound can effectively inhibit the growth of breast cancer cells, in particular the inhibition effect of the compounds TQ-3, 4, 6, 11-14, 17-18 and 23-25 on human triple negative breast cancer cells MDA-MB-231, and the inhibition effect of the compounds TQ-2, 4, 5, 7, 8, 11-15, 17-18, 21 and 25 on human breast ductal cancer cells BT549 is even better than that of the compounds of the formula III. The compound provided by the invention has good application prospect in preparing medicaments for preventing and/or treating breast cancer.
Description
Technical Field
The invention belongs to the field of chemical medicines, and particularly relates to a small molecular compound for resisting breast cancer and a preparation method thereof.
Background
Breast cancer is the most common and most fatal malignancy in women. Almost 130 tens of thousands of women get breast cancer each year worldwide, and more than 40 tens of thousands die from metastatic recurrence of breast cancer. Different types of breast cancer can have significantly different biological characteristics and clinical manifestations. Currently, immunohistochemical methods are mainly used clinically, and breast cancers are classified into 4 molecular subtypes according to the detection results of Estrogen Receptor (ER), progestogen receptor (progesterone receptor, PR) and HER-2: luminal type A (ER positive or PR positive, HER-2 negative, ki67 low expression), luminal type B (ER positive or PR positive, HER-2 positive), HER-2 over-expression type (ER, PR negative, HER-2 positive, ki67 high expression) and basal-like type (ER, PR, HER-2 negative).
One subtype of breast cancer with the highest malignancy is called triple negative breast cancer, which is characterized by Estrogen Receptor (ER) negative/Progesterone Receptor (PR) negative/epidermal growth factor receptor (HER 2) negative, of which 80-90% belong to the basal-like type. The incidence rate of the breast cancer is about 17-25% of breast cancer, and the breast cancer is the worst type of prognosis due to lack of targets of antiestrogens and anti-HER 2 targeted therapies and extremely high probability of occurrence of metastasis and recurrence. Ductal breast cancer is the most common pathological type of breast cancer, accounting for about 70% of all breast cancer patients. Once metastasis occurs in breast ductal carcinoma, the prognosis becomes significantly worse, and the median survival time is only 15 to 30 months. The development of drugs that can effectively treat breast cancer, particularly triple negative breast cancer and ductal breast cancer, has important clinical value.
The thymoquinone (2-isopropyl-5-methyl-1, 4-benzoquinone) is the main component of thyme essential oil, and the bioactive component of the black seed volatile oil is separated from the seeds of plant black vanilla. Black vanilla is a plant active medicinal material commonly used in Mediterranean and middle eastern regions, and is planted in Xinjiang, yunnan, tibet and other regions of China, and the plant has been widely applied to the treatment of bronchial asthma, dysentery, eczema, hypertension, obesity and other diseases for thousands of years. In the 60 s of the 20 th century, scientists first extracted and separated an effective biomonomer, bailquinone, from the seeds of black vanilla and applied it to various model experiments. Further research in the last 90 th century found that bairimquinone had potential anti-tumorigenic and anti-tumor effects, the mechanism that may exist being to act as an anti-tumor and anti-tumor by modulating the targeting of multiple tumor-associated factors. The anti-tumor and anti-tumor effects of the bailquinone are particularly shown in several aspects of inhibiting tumor cell proliferation, inducing tumor cell apoptosis, retarding tumor cell cycle, stimulating the generation of ROS and the like. Previous studies have shown that the baili quinone can inhibit the growth of a variety of tumor cells such as pancreatic cancer, colon cancer, prostate cancer, breast cancer and the like, suggesting that the baili quinone may be a potential tumor therapeutic drug.
However, as a candidate compound for small-molecule anti-breast cancer, the anti-tumor activity of the bailquinone is still to be further improved, and the requirement cannot be met.
Disclosure of Invention
The invention aims to provide a small molecular compound for resisting breast cancer and a preparation method thereof.
The invention provides a compound shown in a formula I, or pharmaceutically acceptable salt or stereoisomer thereof:
wherein X, Y are each independently selected from N, CH or CR 1 ；
n is an integer of 0 to 5;
R 1 each independently selected from halogen, hydroxy, nitro, cyano, substituted or unsubstituted C 1～5 Alkyl, substituted or unsubstituted C 1～5 Alkoxy, COOR 4 LCHO; the substituent is selected from halogen, hydroxy, nitro, cyano, R 4 Selected from H, halogenated or unsubstituted C 1～5 Alkyl, halogenated or unsubstituted C 1～5 Alkoxy, L is selected from 0 to 3 methylene;
R 2 selected from halogenated or unsubstituted C 1～3 Alkyl, halogenated or unsubstituted C 1～3 An alkoxy group;
R 3 selected from halogenated or unsubstituted C 1～3 Alkyl, halogenated or unsubstituted C 1～3 An alkoxy group;
and the compound of formula I is not
Further, the structure of the compound is shown as a formula II:
wherein n is an integer of 0 to 3;
R 1 each independently selected from halogen, hydroxy, nitro, cyano, halo or unsubstituted C 1～3 Alkyl, halogenated or unsubstituted C 1～3 Alkoxy, COOR 4 、LCHO；R 4 Selected from H, halogenated or unsubstituted C 1～3 Alkyl, halogenated or unsubstituted C 1～3 Alkoxy, L is selected from 0 to 3 methylene;
preferably, said R 1 Each independently selected from halogen, hydroxy, C 1～3 Alkoxy, the halogen is preferably Cl, F, br.
Further, the structure of the compound is shown in a formula III:
wherein n is an integer of 0 to 3;
R 1 each independently selected from halogen, hydroxy, nitro, cyano, halo or unsubstituted C 1～3 Alkyl, halogenated or unsubstituted C 1～3 Alkoxy, COOR4, LCHO; r is R 4 Selected from H, halogenated or unsubstituted C 1～3 Alkyl, halogenated or unsubstituted C 1～3 Alkoxy, L is selected from 0 to 3 methylene;
the halogen is preferably Cl, F, br.
Further, the structure of the compound is shown as a formula IV:
wherein n is an integer of 0 to 3;
R 1 each independently selected from halogen, hydroxy, nitro, cyano, halo or unsubstituted C 1～3 Alkyl, halogenated or unsubstituted C 1～3 Alkoxy, COOR4, LCHO; r is R 4 Selected from H, halogenated or unsubstituted C 1～3 Alkyl, halogenated or unsubstituted C 1～3 Alkoxy, L is selected from 0 to 3 methylene;
the halogen is preferably Cl, F, br.
Further, the compound is one of the following compounds:
the invention also provides a preparation method of the compound or pharmaceutically acceptable salt or stereoisomer thereof, which is characterized in that: the method comprises the following steps:
the compound A and the compound B react to obtain the compound; wherein n, R 1 、R 2 、R 3 As described above;
preferably, the molar ratio of compound a to compound B is 1:1, the solvent of the reaction is ethanol, and the reaction is carried out under acidic conditions; the reaction time was 8 hours and the temperature was 80 ℃.
The invention also provides a medicine for preventing and/or treating breast cancer, which is a preparation prepared by taking the compound, or pharmaceutically acceptable salt or stereoisomer thereof as an active ingredient and adding pharmaceutically acceptable auxiliary materials.
The invention also provides application of the compound shown in the formula I-a, or pharmaceutically acceptable salt or stereoisomer thereof in preparing medicaments for preventing and/or treating breast cancer:
wherein X, Y are each independently selected from N, CH or CR 1 ；
n is an integer of 0 to 5;
R 1 each independently selected from halogen, hydroxy, nitro, cyano, substituted or unsubstituted C 1～5 Alkyl, substituted or unsubstituted C 1～5 Alkoxy, COOR 4 LCHO; the substituent is selected from halogen, hydroxy, nitro, cyano, R 4 Selected from H, halogenated or unsubstituted C 1～5 Alkyl, halogenated or unsubstituted C 1～5 Alkoxy, L is selected from 0 to 3 methylene;
R 2 selected from halogenated or unsubstituted C 1～3 Alkyl, halogenated or unsubstituted C 1～3 An alkoxy group;
R 3 selected from halogenated or unsubstituted C 1～3 Alkyl, halogenated or unsubstituted C 1～3 An alkoxy group.
Further, the structure of the compound is shown as a formula II:
wherein n is an integer of 0 to 3;
R 1 each independently selected from halogen, hydroxy, nitro, cyano, halo or unsubstituted C 1～3 Alkyl, halogenated or unsubstituted C 1～3 Alkoxy, COOR 4 、LCHO；R 4 Selected from H, halogenated or unsubstituted C 1～3 Alkyl, halogenated or unsubstituted C 1～3 Alkoxy, L is selected from 0 to 3 methylene;
preferably, said R 1 Each independently selected from halogen, hydroxy, C 1～3 Alkoxy, the halogen is preferably Cl, F, br;
or, the structure of the compound is shown as a formula III:
wherein n is an integer of 0 to 3;
R 1 each independently selected from halogen, hydroxy, nitro, cyano, halo or unsubstituted C 1～3 Alkyl, halogenated or unsubstituted C 1～3 Alkoxy, COOR4, LCHO; r is R 4 Selected from H, halogenated or unsubstituted C 1～3 Alkyl, halogenated or unsubstituted C 1～3 Alkoxy, L is selected from 0 to 3 methylene;
the halogen is preferably Cl, F, br;
or, the structure of the compound is shown as a formula IV:
wherein n is an integer of 0 to 3;
R 1 each independently selected from halogen, hydroxy, nitro, cyano, halo or unsubstituted C 1～3 Alkyl, halogenated or unsubstituted C 1～3 Alkoxy, COOR4, LCHO; r is R 4 Selected from H, halogenated or unsubstituted C 1～3 Alkyl, halogenated or unsubstituted C 1～3 Alkoxy, L is selected from 0 to 3 methylene;
the halogen is preferably Cl, F, br.
Further, the breast cancer is a triple negative breast cancer or a breast ductal cancer;
and/or, the compound is one of the following compounds:
experimental results show that the compound provided by the invention can effectively inhibit the growth of breast cancer cells, in particular the inhibition effect of the compounds TQ-3, 4, 6, 11-14, 17-18 and 23-25 on human triple negative breast cancer cells MDA-MB-231, and the inhibition effect of the compounds TQ-2, 4, 5, 7, 8, 11-15, 17-18, 21 and 25 on human breast ductal cancer cells BT549 is even better than that of the compounds. The compound provided by the invention has good application prospect in preparing medicines for preventing and/or treating breast cancer (especially triple-negative breast cancer and breast duct cancer).
The preparation method of the compound is simple, mild in condition, easy in raw material acquisition and suitable for industrial production.
It should be apparent that, in light of the foregoing, various modifications, substitutions and alterations can be made herein without departing from the spirit and scope of the invention as defined by the appended claims.
The above-described aspects of the present invention will be described in further detail below with reference to specific embodiments in the form of examples. It should not be understood that the scope of the above subject matter of the present invention is limited to the following examples only. All techniques implemented based on the above description of the invention are within the scope of the invention.
Detailed Description
The raw materials and equipment used in the invention are all known products and are obtained by purchasing commercial products.
Example 1 preparation of Compounds TQ-2 to TQ-8
1. Preparation of Compound TQ-1
A solution of TQ (1 mmol,0.164 g) and sodium azide (1.3 mmol,0.084 g) in ethanol was refluxed for 6 hours in 3ml glacial acetic acid. The reaction solution was recovered under reduced pressure, purified by silica gel column chromatography, and eluted isocratically with petroleum ether-ethyl acetate (volume ratio 30:1) to give crude 3-amino-thymic quinone (TQ-1) in 65% yield.
Compound TQ-1: 1 H NMR(500MHz,DMSO-d 6 ):1.37(6H,d),2.31(3H,s),3.23(1H,m),6.53(1H,d),6.73(1H,s),7.34(1H,d). 13 C NMR(125MHz,DMSO-d 6 ):10.5,22.9,29.2,103.0,108.9,110.4,110.9,117.8,128.5,133.6,140.0,140.1,148.2,151.0,153.0,162.3.
2. preparation of Compounds TQ-2 to TQ-8
Wherein R in the compound C is the same as the corresponding R in the compounds TQ-2 to TQ-8.
By stirring equimolar amounts of TQ-1 (0.178 mg,1 mmol) and Compound C (1 mmol) in 20mL of absolute ethanol in the presence of 0.3mL of concentrated hydrochloric acid as catalyst for 8 hours at 80 ℃. Then the reaction system is filtered, the reaction solution is concentrated and recrystallized by ethanol (60 ℃ for 6-12 hours) to obtain the target compound, and the structure of the target product is shown in the table 1.
TABLE 1 Structure of target products TQ-2-TQ-8
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The structural characterization of the target products TQ-2 to TQ-8 is as follows:
compound TQ-2: 1 H NMR(500MHz,DMSO-d 6 ):1.334(6H,d),2.33(3H,s),3.21(1H,m),6.80(1H,s),7.51(1H,d),8.02(1H,d),9.25(1H,s)； 13 C NMR(125MHz,DMSO-d 6 ):10.5,22.8,29.5,111.9,112.2,113.8,114.0,114.1,125.1,128.8,141.6,142.0,152.90,156.9.
compound TQ-3: 1 H NMR(500MHz,DMSO-d 6 ):1.36(6H,d),2.35(3H,s),3.29(1H,m),6.82(1H,s),7.94(2H,d),8.35(2H,d),9.26(1H,s)； 13 C NMR(125MHz,DMSO-d 6 ):10.5,22.9,29.3,111.8,112.4,123.2,125.4,126.6,126.6,128.1,128.8,131.1,131.2,131.5,142.1,142.4,152.9,160.6.
compound TQ-4: 1 H NMR(500MHz,DMSO-d 6 ):1.33(6H,d),2.32(3H,2),3.22(1H,m),6.70(1H,s),6.96(2H,d),8.01(2H,d),9.08(1H,s),10.21(1H,s)； 13 C NMR(125MHz,DMSO-d 6 ):10.6,23.0,29.4,110.2,111.7,116.4,118.4,128.2,129.4,141.8,142.4,152.4,160.9,162.6.
compound TQ-5: 1 H NMR(500MHz,DMSO-d 6 ):1.34(6H,d),2.34(3H,s),3.24(1H,m),6.76(1H,s),7.40(2H,t),8.20(2H,m),9.18(1H,s)； 13 C NMR(125MHz,DMSO-d 6 ):10.6,22.9,29.3,111.0,112.1,116.7,116.9,124.0,124.1,128.6,129.9,130.0,142.1,142.2,152.7,161.2,163.1,165.6.
compound TQ-6: 1 H NMR(500MHz,DMSO-d 6 ):1.34(3H,d),2.30(3H,s),6.68(1H,s),6.91(1H,d),7.50(1H,dd),7.59(1H,d),9.08(1H,s),9.45(1H,s),9.67(1H,s)； 13 C NMR(125MHz,DMSO-d 6 ):10.6,22.9,29.4,110.2,111.6,114.5,116.6,118.6,119.7,128.2,142.4,146.1,149.4,152.4,162.6.
compound TQ-7: 1 H NMR(500MHz,DMSO-d 6 ):1.34(6H,d),2.36(3H,s),3.28(1H,m),6.82(1H,s),7.60(1H,m)，8.03(1H,m),8.30(1H,d),8.79(1H,d),9.24(1H,s)； 13 C NMR(125MHz,DMSO-d 6 ):10.6,22.9,29.1,111.8,112.4,123.7,126.2,129.0,138.0,142.0,142.4,146.2,150.6,152.8,161.2.
compound TQ-8: 1 H NMR(500MHz,DMSO-d 6 ):1.34(6H,d),2.36(3H,s),3.28(1H,m),6.82(1H,s),7.60(1H,m)，8.03(1H,m),8.30(1H,d),8.79(1H,d),9.24(1H,s)； 13 C NMR(125MHz,DMSO-d 6 ):10.6,22.9,29.1,111.8,112.4,123.7,126.2,129.0,138.0,142.0,142.4,146.2,150.6,152.8,161.2。
compound TQ-9: 1 H NMR(500MHz,DMSO-d 6 ):1.35(6H,d),2.42(3H,s),3.26(1H,m),6.76(1H,s),7.60(3H,d),8.18(2H,t),9.19(1H,s), 13 C NMR(125MHz,DMSO-d 6 ):10.6,22.9,29.3,111.1,112.1,127.4,127.5,128.7,129.7,131.8,142.1,142.2,152.7,162.0。
compound TQ-10: 1 H NMR(500MHz,DMSO-d 6 ):1.35(6H,d),2.50(3H,s),3.26(1H,m),6.86(1H,s),7.63(3H,t),8.50(1H,d),8.77(1H,d),9.32(1H,s),9.40(1H,s)； 13 C NMR(125MHz,DMSO-d 6 ):10.6,22.9,29.3,111.7,112.2,123.7,124.7,128.7,134.8,142.0,142.2,148.2,152.3,153.0,160.0.
compound TQ-11: 1 H NMR(500MHz,DMSO-d 6 ):1.32(6H,d),2.50(3H,m),3.25(1H,m),6.79(1H,s),7.44(1H,m),7.70(2H,m),9.25(1H,d)； 13 C NMR(125MHz,DMSO-d 6 ):10.5,22.9,29.1,107.3,123.7,110.4,112.0,128.8,130.5,141.9,142.2,152.9,159.7,161.8,164.3.
compound TQ-12: 1 H NMR(500MHz,DMSO-d 6 ):1.33(6H,d),2.33(3H,s),3.24(1H,m),6.77(1H,d)，7.62(2H,m),8.14(2H,m),9.22(1H,s) 13 C NMR(125MHz,DMSO-d 6 ):10.6,22.9,29.3,111.3,112.1,126.3,128.7,129.1,136.5,142.1,152.8,161.0。
compound TQ-13: 1 H NMR(500MHz,DMSO-d 6 ):1.35(6H,d),2.35(3H,s),3.20(1H,m),3.81(3H,s),3.88(3H,s),3.93(3H,s),6.74(1H,s),6.98(1H,m),7.78(1H,d),9.16(1H,s)； 13 C1NMR(125MHz,DMSO-d 6 ):10.6,22.7,29.7,56.5,61.0,61.9,109.0,110.7,111.7,114.7,125.9,128.4,142.0,142.1,143.1,152.4,153.0,156.4,160.9.
compound TQ-14: 1 H NMR(500MHz,DMSO-d 6 ):1.33(6H,d),2.35(3H,s),3.29(1H,m),3.41(3H,s),3.77(3H,s),3.89(3H,s),6.76(1H,s),7.39(2H,s),9.19(1H,s)； 13 C1NMR(125MHz,DMSO-d 6 ):10.6,23.0,29.0,56.5,60.6,104.6,110.7,112.0,122.7,128.6,140.8,142.1,142.2,152.7,153.7,161.9.
compound TQ-15: 1 H NMR(500MHz,DMSO-d 6 ):1.33(6H,d),2.33(3H,s),3.26(1H,m),3.85(3H,s),3.90(3H,s),6.73(1H,s),7.14(1H,d),7.64(2H,d),7.74(1H,m)； 13 C1NMR(125MHz,DMSO-d 6 ):10.6,23.0,29.2,56.1,110.1,110.4,111.8,112.3,119.9,120.9,128.4,141.9,142.3,149.4,152.1,152.5,162.2.
compound TQ-16: 1 H NMR(500MHz,DMSO-d 6 ):1.33(6H,d),2.30(3H,s),3.19(1H,m),6.67(1H,s),7.16(2H,s)； 13 C1NMR(125MHz,DMSO-d 6 ) 10.5,22.9,29.5,106.6,110.1,111.6,117.3,128.1,137.4,141.8,142.4,146.7,152.3,162.8 Compound TQ-17: 1 H NMR(500MHz,DMSO-d 6 ):1.34(6H,d),2.34(3H,s),3.27(1H,m),4.01(3H,s),6.77(1H,s),7.64(1H,d),7.74(1H,dd),7.78(1H,d),9.22(1H,s)； 13 C1NMR(125MHz,DMSO-d 6 ):10.6,22.9,29.1,56.7,110.8,111.3,112.1,120.4,124.9,127.4,128.7,131.1,142.0,142.1,152.7,156.3,161.1.
compound TQ-18: 1 H NMR(500MHz,DMSO-d 6 ):1.33(6H,d),2.33(3H,s),3.23(1H,m),3.85(6H,s),6.73(1H,t),6.76(1H,s),7.26(1H,d),9.22(1H,s)； 13 C1NMR(125MHz,DMSO-d 6 ):10.6,22.9,29.1,49.0,55.9,103.8,106.1,111.1,112.1,128.6,129.1,142.0,152.6,161.3,161.7.
compound TQ-19: 1 H NMR(500MHz,DMSO-d 6 ):1.32(6H,d),2.29(3H,s),3.25(1H,m),6.78(1H,s),7.79(1H,t),8.00(1H,d),9.33(1H,s)； 13 C1NMR(125MHz,DMSO-d 6 ):10.4,22.9,29.0,111.8,112.2,125.5,128.8,130.5,130.9,135.4,141.8,142.2,152.9,159.2.
compound TQ-20: 1 H NMR(500MHz,DMSO-d 6 ):1.32(6H,d),2.29(3H,s),3.25(1H,m),6.78(1H,s),7.79(1H,t),8.00(1H,d),9.33(1H,s)； 13 C1NMR(125MHz,DMSO-d 6 ):10.5,23.0,28.8,112.0,112.4,122.0,124.7,125.1,127.4,129.1,129.8,131.2,131.5,131.9,132.2,141.7,142.4,153.0,159.2.
compound TQ-21: 1 H NMR(500MHz,DMSO-d 6 ):1.33(6H,d),2.33(3H,s),3.25(1H,m),5.48(1H,s),6.76(1H,s),7.59(2H,d),8.18(2H,d),9.28(1H,s)； 13 C1NMR(125MHz,DMSO-d 6 ):10.5,22.9,29.3,53.0,102.4,111.1,112.0,127.3,127.4,127.8,28.6,141.7,142.0,142.1,152.7,161.7.
compound TQ-22: 1 H NMR(500MHz,DMSO-d 6 ):1.33(6H,d),2.32(3H,s),3.21(1H,m),6.39(1H,t),6.73(1H,s),7.06(2H,d),9.20(1H,s),9.73(1H,s)； 13 C1NMR(125MHz,DMSO-d 6 ):10.5,22.9,29.4,105.3,106.0,110.9,111.9,128.4,128.8,141.9,142.1,152.5,159.4,162.2.
compound TQ-23: 1 H NMR(500MHz,DMSO-d 6 ):1.34(6H,d),2.32(3H,s),3.25(1H,m),6.80(1H,s),8.32(4H,m),9.30(1H,s)； 13 C1NMR(125MHz,DMSO-d 6 ):10.4,22.8,29.2,112.1,112.3,124.7,128.4,128.9,132.8,142.1,142.4,140.0,152.9,159.9.
compound TQ-24: 1 H NMR(500MHz,DMSO-d 6 ):1.35(6H,d),1.36(3H,t),3.25(1H,m),2.35(3H,s),4.36(2H,q),6.80(1H,s),8.14(2H,d),8.30(2H,d),9.28(1H,s),； 13 C1NMR(125MHz,DMSO-d 6 ):10.5,14.6,22.9,29.2,61.6,111.7,112.2,127.6,128.8,130.4,131.2,132.3,142.1,142.3,152.8,161.0,165.5.
compound TQ-25: 1 H NMR(500MHz,DMSO-d 6 ):1.35(6H,d),2.32(3H,s),3.22(1H,m),6.76(1H,s),7.54(1H,d),7.60(1H,dd),7.80(1H,d),9.23(1H,s),10.72(1H,s)； 13 C1NMR(125MHz,DMSO-d 6 ):10.5,22.9,29.4,111.2,112.0,114.8,119.0,123.4,127.0,128.6,131.2,142.0,142.1,152.7,154.0,161.2.
compound TQ-26: 1 H NMR(500MHz,DMSO-d 6 ):1.36(6H,d),2.35(3H,s),2.65(2H,s),3.30(1H,m),6.81(1H,s),8.15(2H,d),8.30(2H,d),9.28(1H,s)； 13 C1NMR(125MHz,DMSO-d 6 ):10.6,22.9,27.3,29.2,111.7,112.2,127.6,128.8,129.5,131.1,138.9,142.1,142.3,152.8,161.0,197.9
compound TQ-27: 1 H NMR(500MHz,DMSO-d 6 ):1.22(6H,d),1.34(6H,d),2.35(3H,s),2.94(1H,m),3.24(1H,m),6.75(1H,s),7.42(2H,d),8.08(2H,d),9.18(1H,s)； 13 C1NMR(125MHz,DMSO-d 6 ):10.6,22.9,23.9,29.2,33.9,110.8,111.9,125.1,127.5,128.4,142.0,142.2,152.5,152.6,162.1.
compound TQ-28: 1 H NMR(500MHz,DMSO-d 6 ):1.33(6H,d),2.32(3H,s),2.94(1H,m),3.23(1H,m),6.80(1H,s),7.97(2H,d),8.23(2H,d),9.27(1H,s)； 13 C1NMR(125MHz,DMSO-d 6 ):10.5,22.8,29.2,112.0,112.3,113.7,118.7,127.8,128.8,131.2,133.4,142.0,142.3,152.9,160.2.
the following experiments prove the beneficial effects of the invention.
Experimental example 1 experiment of the Effect of the Compound of the invention on Breast cancer
1. Experimental materials
Test article: the compounds TQ-2 to TQ-28 prepared in example 1; compounds TQ-1 and briquinone were used as controls.
Cell line: mouse breast cancer cells 4T1; human triple negative breast cancer cells MDA-MB-231; human ductal breast cancer cells BT549.
2. Experimental method
A certain amount of test sample is weighed, dissolved by dimethyl sulfoxide to prepare 40mM stock solution, and stored at-20 ℃. After breast cancer cells are attached, working solution (0,5,10,20,40,80 mu M) containing test samples with different concentrations is used, and 3 compound holes are formed in each concentration. After 48 hours from the addition of the drug, the original culture medium was aspirated and 10. Mu.l of cck8 solution (10. Mu.l of cck8 reagent per 100. Mu.l of medium) was added to each well after washing with pbs, and the 96-well plate was placed in 5% CO at 37℃and saturated humidity 2 OD was measured at 450nm using an enzyme-labeled instrument after 3 hours incubation in incubator. Calculating the semi-Inhibition Concentration (IC) of each test sample on breast cancer 50 μM) value.
Cell growth inhibition = (1- (experimental group mean OD value-blank group mean OD value)/(control group mean OD value-blank group mean OD value).
3. Experimental results
Table 2 inhibition of breast cancer cells by Compounds
The experimental results show that the compound prepared by the invention can effectively inhibit the growth of breast cancer cells. The inhibition effect of the compounds TQ-3, 4, 6, 11-14, 17-18 and 23-25 on the human triple-negative breast cancer cells MDA-MB-231 is superior to that of the bailquinone, and the inhibition effect of the compounds TQ-12-14 and 25 on the human triple-negative breast cancer cells MDA-MB-231 is superior to that of the compound TQ-1; the inhibition effect of the compounds TQ-2, 4, 5, 7, 8, 11-15, 17-18, 21 and 25 on the human breast ductal carcinoma cells BT549 is superior to that of the briquinone, and the inhibition effect of the compounds TQ-11-13 and 25 on the human breast ductal carcinoma cells BT549 is superior to that of the compound TQ-1.
In summary, the invention provides a small molecular compound shown in formula I and a preparation method thereof, and the compound can effectively inhibit the growth of breast cancer cells, in particular the inhibition effect of compounds TQ-3, 4, 6, 11-14, 17-18, 23-25 on human triple negative breast cancer cells MDA-MB-231, and the inhibition effect of compounds TQ-2, 4, 5, 7, 8, 11-15, 17-18, 21, 25 on human breast ductal cancer cells BT549 is even better than that of the compounds. The compound provided by the invention has good application prospect in preparing medicaments for preventing and/or treating breast cancer.
Claims (2)
1. A compound, or a pharmaceutically acceptable salt thereof, characterized in that: the compound is one of the following compounds:
2. a medicament for preventing and/or treating breast cancer, characterized in that: a preparation prepared by adding pharmaceutically acceptable auxiliary materials into the compound or pharmaceutically acceptable salt thereof as an active ingredient in the method of claim 1.
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