CN106632000B - Application of diaryl ketone compounds in the preparation of antitumor drugs - Google Patents
Application of diaryl ketone compounds in the preparation of antitumor drugs Download PDFInfo
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- -1 diaryl ketone compounds Chemical class 0.000 title claims abstract description 33
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- 239000002246 antineoplastic agent Substances 0.000 title claims abstract description 9
- 229940041181 antineoplastic drug Drugs 0.000 title claims abstract description 9
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical group O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 claims description 20
- 206010028980 Neoplasm Diseases 0.000 claims description 18
- 206010006187 Breast cancer Diseases 0.000 claims description 8
- 208000026310 Breast neoplasm Diseases 0.000 claims description 8
- 229940009456 adriamycin Drugs 0.000 claims description 7
- 150000003839 salts Chemical class 0.000 claims description 6
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 5
- 201000005202 lung cancer Diseases 0.000 claims description 5
- 208000020816 lung neoplasm Diseases 0.000 claims description 5
- 208000032612 Glial tumor Diseases 0.000 claims description 4
- 206010018338 Glioma Diseases 0.000 claims description 4
- 206010017758 gastric cancer Diseases 0.000 claims description 4
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 3
- 201000007270 liver cancer Diseases 0.000 claims description 3
- 208000014018 liver neoplasm Diseases 0.000 claims description 3
- 201000011549 stomach cancer Diseases 0.000 claims description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical group CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 2
- 229910019142 PO4 Inorganic materials 0.000 claims description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 claims description 2
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 2
- 201000010881 cervical cancer Diseases 0.000 claims description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 2
- 239000010452 phosphate Substances 0.000 claims description 2
- 206010008342 Cervix carcinoma Diseases 0.000 claims 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 claims 1
- 210000004881 tumor cell Anatomy 0.000 abstract description 38
- 150000001875 compounds Chemical class 0.000 abstract description 26
- 230000002401 inhibitory effect Effects 0.000 abstract description 20
- 230000000694 effects Effects 0.000 abstract description 13
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- 239000013641 positive control Substances 0.000 abstract description 11
- 230000000259 anti-tumor effect Effects 0.000 abstract description 8
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- 239000002994 raw material Substances 0.000 abstract description 3
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- 239000002547 new drug Substances 0.000 abstract 1
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- 230000004614 tumor growth Effects 0.000 abstract 1
- 239000003814 drug Substances 0.000 description 30
- 210000004027 cell Anatomy 0.000 description 23
- 229940079593 drug Drugs 0.000 description 15
- YCWSUKQGVSGXJO-NTUHNPAUSA-N nifuroxazide Chemical group C1=CC(O)=CC=C1C(=O)N\N=C\C1=CC=C([N+]([O-])=O)O1 YCWSUKQGVSGXJO-NTUHNPAUSA-N 0.000 description 12
- 201000011510 cancer Diseases 0.000 description 11
- 238000000034 method Methods 0.000 description 7
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 6
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- 230000000118 anti-neoplastic effect Effects 0.000 description 3
- 208000019065 cervical carcinoma Diseases 0.000 description 3
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- 230000012010 growth Effects 0.000 description 3
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- 238000011282 treatment Methods 0.000 description 3
- ODIGIKRIUKFKHP-UHFFFAOYSA-N (n-propan-2-yloxycarbonylanilino) acetate Chemical compound CC(C)OC(=O)N(OC(C)=O)C1=CC=CC=C1 ODIGIKRIUKFKHP-UHFFFAOYSA-N 0.000 description 2
- UEXCJVNBTNXOEH-UHFFFAOYSA-N Ethynylbenzene Chemical group C#CC1=CC=CC=C1 UEXCJVNBTNXOEH-UHFFFAOYSA-N 0.000 description 2
- XPDWGBQVDMORPB-UHFFFAOYSA-N Fluoroform Chemical compound FC(F)F XPDWGBQVDMORPB-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 230000003698 anagen phase Effects 0.000 description 2
- 208000030270 breast disease Diseases 0.000 description 2
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- WSFSSNUMVMOOMR-BJUDXGSMSA-N methanone Chemical class O=[11CH2] WSFSSNUMVMOOMR-BJUDXGSMSA-N 0.000 description 2
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- 239000000243 solution Substances 0.000 description 2
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- YFGHCGITMMYXAQ-UHFFFAOYSA-N 2-[(diphenylmethyl)sulfinyl]acetamide Chemical compound C=1C=CC=CC=1C(S(=O)CC(=O)N)C1=CC=CC=C1 YFGHCGITMMYXAQ-UHFFFAOYSA-N 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
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- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- 241000220317 Rosa Species 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical class OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- GUGOEEXESWIERI-UHFFFAOYSA-N Terfenadine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 GUGOEEXESWIERI-UHFFFAOYSA-N 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 230000001464 adherent effect Effects 0.000 description 1
- 230000001387 anti-histamine Effects 0.000 description 1
- 239000000739 antihistaminic agent Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- JXLHNMVSKXFWAO-UHFFFAOYSA-N azane;7-fluoro-2,1,3-benzoxadiazole-4-sulfonic acid Chemical compound N.OS(=O)(=O)C1=CC=C(F)C2=NON=C12 JXLHNMVSKXFWAO-UHFFFAOYSA-N 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 239000012930 cell culture fluid Substances 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 230000019771 cognition Effects 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000000120 cytopathologic effect Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 239000003599 detergent Substances 0.000 description 1
- 238000013399 early diagnosis Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 239000012894 fetal calf serum Substances 0.000 description 1
- 208000010749 gastric carcinoma Diseases 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 231100000518 lethal Toxicity 0.000 description 1
- 230000001665 lethal effect Effects 0.000 description 1
- 230000031700 light absorption Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229940127554 medical product Drugs 0.000 description 1
- 229960001165 modafinil Drugs 0.000 description 1
- 238000011017 operating method Methods 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 239000002304 perfume Substances 0.000 description 1
- CYXKNKQEMFBLER-UHFFFAOYSA-N perhexiline Chemical compound C1CCCNC1CC(C1CCCCC1)C1CCCCC1 CYXKNKQEMFBLER-UHFFFAOYSA-N 0.000 description 1
- 229960000989 perhexiline Drugs 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 238000007747 plating Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 201000000498 stomach carcinoma Diseases 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- 229940124549 vasodilator Drugs 0.000 description 1
- 239000003071 vasodilator agent Substances 0.000 description 1
Classifications
-
- 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
- C07D213/46—Oxygen atoms
- C07D213/50—Ketonic radicals
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及抗肿瘤药物领域。提供了二芳基甲酮类化合物在制备抗肿瘤药物中的应用。所述二芳基甲酮类化合物为式M11、M13、M14、M15、M‑126、M128、M130、M131、M132、M149所示的化合物。通过抗肿瘤活性研究实验，这些化合物都显示出一定程度的抗肿瘤细胞增殖的活性，大多数化合物呈现出很强的抑制效应；可以强效抑制肿瘤细胞生长，在很低浓度即可促发凋亡，相对于阳性对照化合物显示出更强的抑制效果。该类化合物的制备过程简单易行，原料价格低廉，易于获取；可以通过构效关系研究来寻求其抗肿瘤作用靶点，为进一步药物开发提供有价值的导向作用。本发明所述的二芳基甲酮类化合物为新药筛选提供了基础。
The present invention relates to the field of antitumor drugs. The application of diaryl ketone compounds in the preparation of antitumor drugs is provided. The diaryl ketone compounds are compounds represented by formulas M11, M13, M14, M15, M-126, M128, M130, M131, M132, and M149. Through the anti-tumor activity research experiments, these compounds all show a certain degree of anti-tumor cell proliferation activity, and most compounds show a strong inhibitory effect; they can potently inhibit the growth of tumor cells, and can induce apoptosis at very low concentrations Compared with the positive control compound, it showed a stronger inhibitory effect. The preparation process of such compounds is simple and feasible, and the raw materials are cheap and easy to obtain; their anti-tumor effect targets can be sought through structure-activity relationship research, which provides valuable guidance for further drug development. The diaryl ketone compounds of the present invention provide a basis for new drug screening.
Description
Technical field
The invention belongs to field of antineoplastic medicaments, and in particular to diaryl ketone compound is in the preparation of antitumor drugs
Using.
Background technique
Malignant tumour is a kind of common disease and frequently-occurring disease for seriously threatening human health, and the mankind are because of caused by malignant tumour
Death rate shelter has the second of mortality, becomes No. second " killer " for being only second to cardiovascular disease.At the beginning of 2013, entirely
One edition " 2012 China's tumour registration annual report " of tumour Register, state publication shows Chinese annual new cancer cases about 312
Ten thousand, because number of cancer deaths is more than 2,000,000, it means that there are 6 people to be diagnosed as cancer within every 1 minute.Nattonal Cancer is sent out at present
Sick trend is severe, and incidence and mortality is in continue ascendant trend.Cancer, which has become, to be seriously threatened human life's safety and influences
One of significant problem of human life quality, the problem of initiation, also increasingly becomes the burden of socio-economic development therefrom.
Currently, the treatment method of tumour mainly has operative treatment, radiotherapy and drug therapy (chemotherapy), but very big
It is still based on drug therapy in degree.Most common solid tumors such as lung cancer, liver cancer, colon cancer and cancer of pancreas etc. still lack effectively
Drug, many anti-tumor drugs generate drug resistance in process of clinical application.With the scientific and technological progress of society, the mankind are to cancer
Cognition is gradually clear, also reaches its maturity to the method for prevention and the early diagnosis of certain cancers, technology and theory, but still cannot
Cancer is cured completely, can only extend the time-to-live of cancer patient very limitedly.Therefore, the research and development gesture of new type antineoplastic medicine
It must go, continually develop the new type antineoplastic medicine of high-efficiency low-toxicity, become the research work when previous item is of great significance.
Diaryl ketone compound is a kind of important additive and chemical intermediate.Early in the 1950s.Two virtues
Base methanone compounds are widely used in the flourishing industrialized country such as America and Europe.Be mainly used in plastics, medicine, fragrance and
The fields such as electronics industry.In terms of medical product, diaryl ketone compound is that antihistamine perhexiline, hypnolepsy are controlled
Treat the intermediate of medicine modafinil and novel potent cerebral vasodilator fiunarizine etc..In terms of fragrance, because it has
The fragrance of rose is often used as fragrance fixastive, while the raw material also as many perfume and fragrance for detergents.China is to diaryl
The development and application of methanone compounds are started late.Just there is diaryl ketone device to be constructed and put into operation successively until the 1990s.
Project team where the applicant has independently synthesized serial diaryl ketone compound, and in 2016 in periodical Tetrahedron
Letters discloses the preparation method of these compounds.Its biological activity is not evaluated.
Summary of the invention
The purpose of the present invention is being directed to above-mentioned status, serial diaryl first ketone compounds and its pharmaceutically acceptable are provided
Salt application in preparation of anti-tumor drugs, the diaryl first ketone compounds are one of following formula:
Further, diaryl first ketone compounds pharmaceutically acceptable salt provided by the invention is hydrochloride, sulfuric acid
Salt, phosphate and acylate, such as mesylate, fluoroform sulphonate, acetate, trifluoroacetate, benzoate.
Further, the diaryl first ketone compounds are preferably formula M11, M13, M15, M126, M131, M132,
The drug is the medicine for treating liver cancer, lung cancer, breast cancer, the breast cancer of adriamycin-resistant, gastric cancer, cervical carcinoma, glioma
Object.
Further, the drug is the drug for treating cervical carcinoma.
Further, the diaryl first ketone compounds are preferably formula M131, M132, and the drug is treatment liver
The drug of cancer, lung cancer, breast cancer, the breast cancer of adriamycin-resistant, gastric cancer, cervical carcinoma, glioma.
Further, the diaryl first ketone compounds are preferably M131, M132, the drug be treat resistance to Ah
The drug of the breast cancer of mycin.
Diaryl first ketone compounds and its pharmaceutically acceptable salt of the invention are medicinal as active constituent and routine
Pharmaceutical composition is made in carrier.
Diaryl first ketone compounds of the invention and its pharmaceutically acceptable salt can be prepared by a conventional method into each
The practical medicament of kind, such as the drug of granule, tablet, pill, capsule, injection, suspending agent or emulsion.
The present invention passes through to the diaryl ketone class Compound ira vitro antitumor activity evaluation, caused tumour cell
Pathological effect and caused apoptosis of tumor cells activity rating, it was demonstrated that the diaryl first ketone compounds have suppression well
The effect for making tumor cell proliferation not of the same race, for the MCF-7/ADR tumour of showing resistance property of positive control medicine 5-Fu and DOX
Cell equally presents strong inhibitory effect.
The preparation of diaryl first ketone compounds according to the present invention, reference literature Tetrahedron Letters
2016,57,90-94 method, specifically using transition metal palladium as catalyst, using phenylacetylene as acylating reagent, at the ortho position of pyridine
Under inducing action, aroylation is carried out at the ortho position of aromatic ring, obtains final acylate.
Simple and easy in view of the preparation process of such compound, low in raw material price is easily obtained；Series compound can be with
Seek its antitumor action target spot by structure activity study, provides valuable guiding role for further drug development.
Therefore, diaryl first ketone compounds of the present invention provide the foundation for new medicament screen.
Detailed description of the invention
Fig. 1 series diaryl ketone compound (40 μ g/mL) is for the inhibitory activity of different tumour cells.
Tumour cell HepG2, Hela, C6, MCF-7, MCF- caused by Fig. 2 M131 (20 μ g/mL), M15 (40 μ g/mL)
The pathological effect of 7/ADR.
The activity of inhibition tumour cell HepG2, Hela, C6 of Fig. 3 compound M131, M15,5-Fu concentration dependant.
Tumour cell Hela caused by Fig. 4 compound 5-Fu (100 μ g/mL), M131 (10 μ g/mL), M15 (20 μ g/mL)
Apoptosis detection figure.
Specific embodiment
By following detailed description combination attached drawing it will be further appreciated that the features and advantages of the invention.Provided implementation
Example is only the explanation to the method for the present invention, remaining content without limiting the invention in any way announcement.
Hereinafter, if not specified, material therefor of the present invention and operating method are well known in the art.[implement
Example 1] compound anti tumor activity in vitro evaluation
For try tumour cell: human hepatocarcinoma cells HepG2, Human Lung Cancer cell A549, mankind mastopathy cell MCF-7,
The mankind mastopathy cell (MCF-7/ADR) of adriamycin-resistant, Human Gastric carcinoma's cell SGC-7901, human cervix cancer cells Hela,
Human glioma cells C6.
Cell culture: GIBCO DMEM culture medium, 10% fetal calf serum and 0.01%L- glutamine are configured to culture solution.
The cell strain of culture is placed in 37 DEG C, 5%CO2Routine culture passes under saturated humidity, and experiment is with thin in logarithmic growth phase
Born of the same parents.
Anti tumor activity in vitro evaluates (mtt assay):
The above tumour cell is distinguished into 96 orifice plate of bed board, at 37 DEG C, after single layer is covered in 5%CO2 incubator culture, is discarded thin
Born of the same parents' culture solution, respectively plus the cell maintenance medium of the test compound containing various concentration continues to cultivate, without pharmaceutically-active cell
As blank control, with anti-tumor drug 5 FU 5 fluorouracil (5-Fu) and adriamycin (DOX) for positive control, every group sets 8 again
Hole continues culture 48h and obtains 72h.Microscopic visual measurement simultaneously records cell situation respectively, and every hole adds 30 μ l of MTT (5mg/mL) to continue to train
4h is supported, abandons supernatant, every hole adds 30 μ lDMSO, 37 DEG C of incubations 10min, the light absorption value at microplate reader detection 492nm wavelength
(A492).Average inhibition is calculated as follows:
Inhibiting rate=(cell controls group be averaged OD492 value-medicine group be averaged OD492 value)/cell controls group is averaged OD492
Value) × 100%.
Test result show above-mentioned all diaryl ketone compounds for Hela, C6, HepG2, SGC-7901, A549,
MCF-7, MCF-7/ADR tumor cell proliferation have stronger inhibitory activity, and half-inhibitory concentration IC50 is as shown in table 1 below.
Wherein compound M11, M13, M15, M-126, M131, M132 has strongest inhibitory effect, for seven kinds of test tumour cells
The μ of average IC50≤20 g/mL.
For MCF-7/ADR tumour cell, not only control drug DOX shows drug resistance, another control drug 5-
It is super for the half-inhibitory concentration (IC50) of MCF-7/ADR tumour cell that Fu also shows drug resistance, adriamycin and 5-Fu
100 μ g/mL are crossed.And the serial diaryl ketone compound that we synthesize still has very well MCF-7/ADR tumour cell
Inhibitory effect, wherein active best compound M131, M132, IC50 is respectively 3.9 μ g/mL and 2 μ g/mL.Except this with
Outside, DOX has superpower inhibitory effect for other six kinds of tumour cells, and average IC50 is 2.5 μ g/mL, (right with M131, M132
In the average IC50 of seven kinds of tumour cells be 5.7 μ g/mL and 5.2 μ g/mL) fairly horizontal, be better than other compounds.And 5-Fu
IC50 is averaged as 31.1 μ g/mL for other six kinds of tumour cells, and (be averaged the compound M-128 μ g/mL synthesized with us IC50
For 31.1 μ g/mL), M130 (average IC50 is 39.9 μ g/mL), M149 (average IC50 is 34.5 μ g/mL), M14 (average IC50
It is 25.6 μ g/mL) in same suppression level, other compounds that in addition to this we synthesize have than 5-Fu to various tumours
The stronger inhibitory effect of cell.
Inhibitory activity of the serial diaryl ketone compound of table 1 for kinds of tumor cells
In table 1: a IC50: half-inhibitory concentration.The μ of IC50 < 20 g/mL is denoted as +++, the μ of IC5020~50 g/mL is denoted as ++,
The μ of IC50 > 50 g/mL is denoted as+.b Dox, adriamycin, positive control；C 5-Fu, 5 FU 5 fluorouracil, positive control.
40 μ g/mL series diaryl ketone compounds are as shown in Figure 1 for the inhibitory activity of different tumour cells.In 40 μ
Extremely strong inhibitory effect is all shown for all tumour cells when g/mL, wherein for A549 cell depression effect relatively
Difference.In all compounds, M131, M132 show strongest anti-tumor activity.Positive control medicine 5-Fu is for various swollen
The inhibiting rate of oncocyte is relatively low, and another positive control medicine DOX is then in addition to inhibiting MCF-7/ADR without apparent
Outside effect, to other all tumour cell inhibitory activity with super strength.
The work of the different tumour cells of the inhibition of representation compound M131, M15 and positive control medicine 5-Fu concentration dependant
Property is as shown in Figure 2.The inhibitory activity of concentration dependant is presented to all tumour cells by M131, M15, can in sufficient concentrations of situation
To achieve the effect that make the complete apoptosis of tumour cell lethal.Control drug 5-Fu presentation concentration dependent is not strong, whole 5 to 40
It is unobvious for the increase of inhibiting tumour cells activity when μ g/mL, it presents than more uniform inhibitory effect.
Tumour cell pathological effect caused by [embodiment 2] compound
Hela, C6 caused by we have further photographed to record representation compound M131, M15 with microscope, HepG2,
The cytopathic effect of MCF-7, MCF-7/ADR tumour cell.Specific implementation method is as follows:
Hela, C6, HepG2, MCF-7, MCF-7/ADR tumour cell of logarithmic growth phase are distinguished into 24 orifice plate of bed board,
37 DEG C, after single layer is covered in 5%CO2 incubator culture, cell culture fluid is discarded, respectively plus containing 20 μ g/mL M131,40 μ g/mL
M15 test Compound cellular maintaining liquid continues to cultivate, microscopic visual measurement and cytopathy situation of taking pictures when 48h.
Tumour cell pathological effect caused by compound is as shown in Figure 3.The growth of tumour cell not processed under microscope
Well, adherent secured, form is full, and edge boundary is clear.20 μ g/mL M131,40 μ g/mL M15 processing 48h cause to own
Apoptosis of tumor cells, cell is rounded in different forms, falls off from culture plate.It can be seen that M131, M15 are strong for kinds of tumor cells
Inhibition growth effects.
Apoptosis of tumor cells activity rating caused by [embodiment 3] compound
The applicant further implements the test of compound inducing apoptosis of tumour cell, and test situation is as follows: logarithmic growth
24 orifice plate of Hela plating cells of phase is added after covering with single layer containing 10 μ g/mL M131,20 μ g/mLM15, and the 100 μ g/mL positives are right
It is incubated for according to the cell maintenance medium of drug 5-Fu, setting is not added the cell controls of drug-treated, after about 48h, collects cell, uses
Annexin V-FITC/PI apoptosis detection kit carries out the detection of Apoptosis on flow cytometer.
Experimental result shows that 10 μ g/mL M131,20 μ g/mL M15 more than potent induction can be detected as shown in Figure 4
The apoptosis of tumour cell.In Hela cell, the positive control cell apoptosis rate not processed is 3.2%, M131, M15 processing
48h promotes 98.2% and 88.8% apoptosis respectively, and the Hela cell of positive control medicine 5-Fu processing withers
The rate of dying is only 71.3%.
In conclusion serial diaryl ketone compound has the increasing for inhibiting tumour cell not of the same race well in the present invention
The effect of growing equally presents strong suppression for the MCF-7/ADR tumour cell of showing resistance property of positive control medicine 5-Fu and DOX
Effect processed, it is shown that big application potential.If further clinically studied, it is hopeful preparation and effectively antagonizes tumour disease
The drug of disease.
Claims (4)
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