CN106632000A - Application of diaryl ketone compounds in preparation of antitumor drug - Google Patents
Application of diaryl ketone compounds in preparation of antitumor drug Download PDFInfo
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- CN106632000A CN106632000A CN201611176431.9A CN201611176431A CN106632000A CN 106632000 A CN106632000 A CN 106632000A CN 201611176431 A CN201611176431 A CN 201611176431A CN 106632000 A CN106632000 A CN 106632000A
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- compounds
- ketone compounds
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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
- C07D213/46—Oxygen atoms
- C07D213/50—Ketonic radicals
Abstract
The invention relates to the field of antitumor drugs and provides application of diaryl ketone compounds in preparation of the antitumor drug. The diaryl ketone compounds are compounds shown as formulas M11, M13, M14, M15, M-126, M128, M130, M131, M132 and M149. By antitumor activity research experiments, the compounds show anti-tumor cell proliferation activity with a certain degree, and most compounds show strong inhibition effect; the compounds can strongly inhibit the growth of tumor cells, can promote apoptosis at relatively-low concentration and show stronger inhibition effect compared with positive contrast compounds. The preparation process of the compounds is simple and feasible; raw materials are low in price and easy to obtain; an antitumor effect target of the compounds can be found by researching a structure-function relationship, and a valuable guiding function is provided for further research and development of the drugs. The diaryl ketone compounds disclosed by the invention provide a basis for screening new drugs.
Description
Technical field
The invention belongs to field of antineoplastic medicaments, and in particular to diaryl ketone compound is in antineoplastic is prepared
Using.
Background technology
Malignant tumour is a kind of common disease and frequently-occurring disease of serious threat human health, what the mankind caused because of malignant tumour
Death rate shelter has the second of mortality, becomes No. second " killer " for being only second to angiocardiopathy.At the beginning of 2013, entirely
One edition of tumour Register of state issue《2012 China's tumour registration annual reports》Show, the annual new cancer cases about 312 of China
Ten thousand, because number of cancer deaths is more than 2,000,000, it means that there is 6 people to be diagnosed as cancer per 1 minute.At present Nattonal Cancer is sent out
Sick trend is severe, and incidence and mortality is in lasting ascendant trend.Cancer has become serious and has threatened human life's safety and affect
One of significant problem of human life quality, the problem for causing therefrom also increasingly becomes the burden of socio-economic development.
At present, 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
Medicine, many antineoplastics produce drug resistance in process of clinical application.With the scientific and technological progress of society, the mankind are to cancer
Cognitive gradually clear, the method, technology and theory to prevention and the early diagnosis of some cancers also reaches its maturity, but still can not
Cure cancer completely, can only very limitedly extend the time-to-live of cancer patient.Therefore, the research and development gesture of new type antineoplastic medicine
Must go, continually develop the new type antineoplastic medicine of high-efficiency low-toxicity, become when the significant research work of previous item.
Diaryl ketone compound is the important additive of a class and chemical intermediate.Early in the 1950's.Two is fragrant
Base methanone compounds are widely used in the prosperity such as America and Europe industrialized country.Be mainly used in plastics, medicine, spices 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 spices, because it has
The fragrance of rose, is often used as spices fixastive, while also as many perfume and the raw material of 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 nineties in 20th century.
The applicant place project team has independently synthesized serial diaryl ketone compound, and in 2016 in periodical Tetrahedron
Letters discloses the preparation method of these compounds.Its BA is not evaluated.
The content of the invention
The purpose of the present invention is for above-mentioned present situation, there is provided serial diaryl first ketone compounds and its pharmaceutically acceptable
Application of the salt in antineoplastic is prepared, the diaryl first ketone compounds are one of following formula：
Further, the diaryl first ketone compounds pharmaceutically acceptable salt that the present invention is provided is hydrochloride, sulfuric acid
Salt, phosphate and acylate, such as mesylate, fluoroform sulphonate, acetate, trifluoroacetate, benzoate.
Further, described diaryl first ketone compounds are preferably formula M11, M13, M15, M126, M131, M132,
Described medicine is treatment liver cancer, lung cancer, breast cancer, the breast cancer of adriamycin-resistant, cancer of the stomach, cervical carcinoma, gliomatous medicine
Thing.
Further, described medicine is the medicine for treating cervical carcinoma.
Further, described diaryl first ketone compounds are preferably formula M131, M132, and described medicine is treatment liver
Cancer, lung cancer, breast cancer, the breast cancer of adriamycin-resistant, cancer of the stomach, cervical carcinoma, gliomatous medicine.
Further, described diaryl first ketone compounds are preferably M131, M132, described medicine for treatment resistance to Ah
The medicine of the breast cancer of mycin.
The diaryl first ketone compounds and its pharmaceutically acceptable salt of the present invention are medicinal with conventional as active component
Carrier makes pharmaceutical composition.
The diaryl first ketone compounds and its pharmaceutically acceptable salt of the present invention can be prepared by a conventional method into each
Plant practical medicament, the such as medicine of granule, tablet, pill, capsule, injection, suspending agent or emulsion.
The present invention is by described diaryl ketone class Compound ira vitro antitumor activity evaluation, the tumour cell for causing
Pathology effect and the apoptosis of tumor cells activity rating for causing, it was demonstrated that described diaryl first ketone compounds have suppression well
The effect of system tumor cell proliferation not of the same race, for the MCF-7/ADR tumours that positive control medicine 5-Fu and DOX are presented drug resistance
Cell equally presents strong inhibition.
The preparation of diaryl first ketone compounds involved in the present invention, reference literature Tetrahedron Letters
2016,57,90-94 method, specifically with transition metal palladium as catalyst, with phenylacetylene as acylating reagent, at the ortho position of pyridine
Under inducing action, aroylation is carried out at the ortho position of aromatic ring, obtain final acylate.
In view of the preparation process of such compound is simple, low in raw material price, it is easy to obtain；Series compound can be with
Seek its antitumor action target spot by structure activity study, for further drug development valuable guide effect is provided.
Therefore, diaryl first ketone compounds of the present invention provide the foundation for new medicament screen.
Description of the drawings
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- that Fig. 2 M131 (20 μ g/mL), M15 (40 μ g/mL) cause
The pathology effect of 7/ADR.
The activity of suppression tumour cell HepG2, Hela, C6 of Fig. 3 compound M131, M15,5-Fu concentration dependants.
The tumour cell Hela that Fig. 4 compound 5-Fu (100 μ g/mL), M131 (10 μ g/mL), M15 (20 μ g/mL) cause
Apoptosis detection figure.
Specific embodiment
By combination accompanying drawing described further below it will be further appreciated that the features and advantages of the invention.The enforcement for being provided
Example is only the explanation to the inventive method, and limits remaining content of present invention announcement never in any form.
Hereinafter, if not specified, material therefor of the present invention and method of operating are well known in the art.【Implement
Example 1】The anti tumor activity in vitro evaluation of compound
For trying 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 cell SGC-7901, human cervix cancer cells Hela,
Human glioma cells C6.
Cell culture：GIBCO DMEM culture mediums, 10% hyclone and 0.01%L- glutamine are configured to nutrient solution.
The cell line of culture is placed in 37 DEG C, 5%CO2Cellar culture is passed under saturated humidity, and experiment is with the thin of exponential phase
Born of the same parents.
Anti tumor activity in vitro evaluates (mtt assay)：
Above tumour cell is distinguished into the orifice plate of bed board 96, at 37 DEG C, 5%CO2 incubator cultures are covered with after individual layer, discarded thin
Born of the same parents' nutrient solution, adds respectively the cell maintenance medium containing variable concentrations test compound to continue to cultivate, with without pharmaceutically-active cell
As blank, with antineoplastic 5 FU 5 fluorouracil (5-Fu) and adriamycin (DOX) as positive control, 8 are set per group again
Hole, continues culture 48h and obtains 72h.Microscopic visual measurement simultaneously records respectively cell situation, adds the μ l of MTT (5mg/mL) 30 to continue to train per hole
Foster 4h, abandons supernatant, and 30 μ lDMSO, 37 DEG C of incubation 10min, the light absorption value at ELIASA detection 492nm wavelength are added per hole
(A492).Average inhibition is calculated as follows：
Inhibiting rate=(the average OD492 values of the average OD492 values-medicine group of cell controls group)/average OD492 of cell controls group
Value) × 100%.
Test result shows, above-mentioned all diaryl ketone compounds for Hela, C6, HepG2, SGC-7901, A549,
MCF-7, MCF-7/ADR tumor cell proliferation has stronger inhibitory activity, and IC50 is as shown in table 1 below for its half-inhibition concentration.
Wherein compound M11, M13, M15, M-126, M131, M132 has most strong inhibition, for seven kinds of test tumour cells
Average IC50≤20 μ g/mL.
For MCF-7/ADR tumour cells, not only control drug DOX shows drug resistance, another kind of control drug 5-
Fu also shows drug resistance, and adriamycin and 5-Fu surpass for the half-inhibition concentration (IC50) of MCF-7/ADR tumour cells
100 μ g/mL are crossed.And the serial diaryl ketone compound that we synthesize is for MCF-7/ADR tumour cells still have very well
Inhibition, wherein active best compound M131, M132, its IC50 is respectively 3.9 μ g/mL and 2 μ g/mL.Except this with
Outward, DOX has a superpower inhibition 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, better than other compounds.And 5-Fu
For the average IC50 of other six kinds of tumour cells is 31.1 μ g/mL, compound M-128 μ g/mL (the average IC50 synthesized with us
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
For 25.6 μ g/mL) in same suppression level, other compounds that in addition we synthesize have to various tumours than 5-Fu
The higher inhibition of cell.
The serial diaryl ketone compound of table 1 is for the inhibitory activity of kinds of tumor cells
In table 1：a IC50：Half-inhibition concentration.IC50<20 μ g/mL are designated as +++, IC5020～50 μ g/mL are designated as ++,
IC50>50 μ g/mL are designated 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
For all tumour cells all show extremely strong inhibition during g/mL, wherein for A549 cells depression effect relatively
Difference.In all compounds, M131, M132 show most strong antitumor activity.Positive control medicine 5-Fu is swollen for various
The inhibiting rate of oncocyte is relatively low, and another kind of positive control medicine DOX is then except for MCF-7/ADR is without significantly suppression
Outside effect, there is superpower inhibitory activity to other all tumour cells.
The work of the different tumour cells of suppression of representation compound M131, M15 and positive control medicine 5-Fu concentration dependant
Property is as shown in Figure 2.M131, M15 are presented the inhibitory activity of concentration dependant to all tumour cells, can in the case of sufficient concentrations of
To reach the effect for making the complete apoptosis of tumour cell lethal.Control drug 5-Fu presentation concentration dependent is not strong, overall 5 to 40
During μ g/mL, for inhibiting tumour cells activity increases not substantially, present than more uniform inhibition.
【Embodiment 2】The tumour cell pathology effect that compound causes
Our Hela that further representation compound M131, M15 with microscope Taking Pictures recording cause, C6, 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 exponential phase is distinguished into the orifice plate of bed board 24,
37 DEG C, 5%CO2 incubator cultures are covered with after individual layer, discard cell culture fluid, respectively plus containing 20 μ g/mL M131,40 μ g/mL
M15 test compounds cell maintenance medium continues to cultivate, microscopic visual measurement and cytopathy situation of taking pictures during 48h.
The tumour cell pathology effect that compound causes is as shown in Figure 3.The growth of tumour cell not processed under microscope
Well, adherent firm, form is full, and edge boundary is clear.20 μ g/mL M131,40 μ g/mL M15 process 48h to be caused to own
Apoptosis of tumor cells, cell is rounded in different forms, comes off from culture plate.It can be seen that M131, M15 are strong for kinds of tumor cells
Developing restraint effect.
【Embodiment 3】The apoptosis of tumor cells activity rating that compound causes
The applicant further implements the test of compound inducing apoptosis of tumour cell, and test situation is as follows：Logarithmic growth
The orifice plate of Hela plating cells 24 of phase, covers with and add after individual layer containing 10 μ g/mL M131,20 μ g/mLM15, and the 100 μ g/mL positives are right
It is incubated according to the cell maintenance medium of medicine 5-Fu, setting is not added with the cell controls of drug-treated, after about 48h, collects cell, uses
Annexin V-FITC/PI apoptosis detection kits carry out apoptotic detection on flow cytometer.
Experimental result shows that as shown in Figure 4 10 μ g/mL M131,20 μ g/mL M15 can be with more than potent induction detected
The apoptosis of tumour cell.In Hela cells, the positive control cell apoptosis rate not processed is 3.2%, M131, M15 process
48h promotes respectively 98.2% and 88.8% apoptosis, and the Hela cells that positive control medicine 5-Fu is processed wither
The rate of dying is only 71.3%.
In sum, serial diaryl ketone compound has the increasing for suppressing tumour cell not of the same race well in the present invention
The effect of growing, for the MCF-7/ADR tumour cells that positive control medicine 5-Fu and DOX are presented drug resistance equally present strong suppression
Effect processed, it is shown that big application potential.If further clinically studied, it is hopeful preparation and is effective against tumour disease
The medicine of disease.
Claims (9)
1. the application of diaryl first ketone compounds and its pharmaceutically acceptable salt in antineoplastic is prepared, described two is fragrant
Base first ketone compounds are one of following formula：
2. application according to claim 1, it is characterised in that described diaryl first ketone compounds are pharmaceutically acceptable
Salt be hydrochloride, sulfate, phosphate and acylate, such as mesylate, fluoroform sulphonate, acetate, trifluoroacetic acid
Salt, benzoate.
3. application according to claim 1, it is characterised in that described tumour is liver cancer, lung cancer, breast cancer, resistance to Ah mould
Breast cancer, cancer of the stomach, cervical carcinoma, the gliomatous medicine of element.
4. application according to claim 3, it is characterised in that described tumour is cervical carcinoma.
5. application according to claim 1, it is characterised in that described diaryl first ketone compounds be formula M11, M13,
In M15, M126, M131, M132 any one.
6. application according to claim 1, it is characterised in that described diaryl first ketone compounds be formula M131 or
M132。
7. application according to claim 6, it is characterised in that described medicine is the medicine of the breast cancer for treating adriamycin-resistant
Thing.
8. a kind of pharmaceutical composition, it is characterised in that by diaryl first ketone compounds and its pharmacy listed in claim 1
Upper acceptable salt is made as active component with conventional pharmaceutical carrier.
9. pharmaceutical composition according to claim 8, it is characterised in that can be prepared by a conventional method into various practical
Medicament, such as granule, tablet, pill, capsule, injection, the medicine of suspending agent or emulsion.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108283641A (en) * | 2017-12-27 | 2018-07-17 | 湖北工业大学 | Diaryl ketone series compound is used to prepare antitumor drug |
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2016
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| WO2004080979A1 (en) * | 2003-03-14 | 2004-09-23 | Lg Life Sciences Ltd. | Novel 3-(2-amino-4-pyrimidinyl)-4-hydroxyphenyl ketone derivatives |
| WO2008038955A1 (en) * | 2006-09-27 | 2008-04-03 | Chong Kun Dang Pharmaceutical Corp. | Benzophenone derivatives useful for inhibiting formation of microtubule |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN108283641A (en) * | 2017-12-27 | 2018-07-17 | 湖北工业大学 | Diaryl ketone series compound is used to prepare antitumor drug |
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