CN104138369B - Cancer therapy drug - Google Patents
Cancer therapy drug Download PDFInfo
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- CN104138369B CN104138369B CN201310298008.6A CN201310298008A CN104138369B CN 104138369 B CN104138369 B CN 104138369B CN 201310298008 A CN201310298008 A CN 201310298008A CN 104138369 B CN104138369 B CN 104138369B
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Abstract
The present invention proposes compound shown in formula I or its pharmaceutically acceptable salt purposes in preparing medicine, and this medicine is for suppressing malignant cell and the propagation of drug resistance malignant cell and treatment cancer.Thus there is the effect treating cancer significantly with this medicine for active component.
Description
Technical field
The present invention relates to biomedicine field, be specifically related to the J1-001 compound purposes as cancer therapy drug.
At present, cancer has become as the one of the main reasons causing human death.Clinic uses the methods such as chemotherapy, X-ray therapy and biological immune treatment to kill tumor cell more, but cannot fundamentally cure tumor, majority is because the drug resistance of tumor cell and has a strong impact on clinical chemotherapy effect (estimating according to American Cancer Society, the tumor patient of more than 90% dies from tumor cell drug resistance in various degree).Therefore, medicine that search out a kind of high-efficiency low-toxicity, that cells of resistant tumors is sensitive, the treatment to cancer has the most positive effect.
It is contemplated that solve one of above-mentioned technical problem the most to a certain extent or provide at a kind of useful business selection.
To this end, it is an object of the invention to propose J1-001 compound purposes in preparing medicine, described J1-001 compound is used for suppressing tumor cell proliferation and then may be used for treating cancer.
The present invention is following discovery based on inventor and completes: compound shown in formula I
Or its pharmaceutically acceptable salt (in this article by compound shown in formula I and pharmaceutically acceptable salt be referred to as J1-001 compound) can be individually used for suppressing malignant cell and the propagation of drug resistance malignant cell.
In a first aspect of the present invention, according to embodiments of the invention, compound shown in formula I or its pharmaceutically acceptable salt purposes in preparing medicine, described medicine is for suppressing the propagation of tumor cell
According to embodiments of the invention, inventor finds, compound shown in formula I or its pharmaceutically acceptable salt can be individually used for suppressing malignant cell and the propagation of drug resistance malignant cell.Inventors be surprised to learn that, by being mixed with malignant cell, drug resistance malignant cell by J1-001 compound, J1-001 compound can effectively suppress malignant cell, drug resistance malignant cell propagation.Thus, compound shown in formula I or its pharmaceutically acceptable salt can be used for treating malignant cell, drug resistance malignant cell, thus provide a kind of new medicine for treating this kind of disease.
Term used herein above " pharmaceutically acceptable salt " means the salt form that medicinal chemistry art is conventional, the most nontoxic and be provided that required pharmacokinetic properties, orally available, absorb, be distributed, metabolism or the salt form of Excretion.According to embodiments of the invention, should " pharmaceutically acceptable salt " can be common acid-addition salts or base addition salts, such as potassium salt or sodium salt.
According to the above embodiment of the present invention, the present invention can also have a following additional technical characteristic:
According to embodiments of the invention, described tumor cell is malignant cell and drug resistance malignant cell.According to embodiments of the invention, described malignant cell be selected from breast cancer cell, hepatoma carcinoma cell, lung carcinoma cell, stomach cancer cell and ovarian cancer cell at least one.Inventor is by studying the purposes of J1-001 compound, have been surprisingly found that it has the propagation of suppression malignant cell, therefore further study show that it, it is respectively provided with inhibitory action to the propagation of breast cancer cell, hepatoma carcinoma cell, lung carcinoma cell, stomach cancer cell and ovarian cancer cell.According to a particular embodiment of the invention, inventor is by MCF-7 (human breast cancer cell), Bel-7402(human liver cancer cell), HepG2(human liver cancer cell), NCI-H460(human lung carcinoma cell), SGC-7901(gastric carcinoma cells) and HO-8910(Proliferation of Human Ovarian Cell) be mixed in vitro with J1-001 compound especially its sodium salt respectively.Utilize MTT colorimetry, calculate suppression ratio and the IC of J1-001 compound on tumor cell proliferation50(half suppression ratio), inventor finds, J1-001 compound has inhibitory action in various degree to MCF-7, Bel-7402, HepG2, NCI-H460, SGC-7901 and HO-8910, therefore deduces that J1-001 compound all has good inhibiting effect to above tumor cell.Inventor by embodiment interpretation of result it was also surprising that the inhibited proliferation of J1-001 compounds on ovarian cancerous cell is significantly stronger than paclitaxel, thus, further illustrate J1-001 compound with this understanding for treating the superiority of malignant tumor medicine.
According to embodiments of the invention, described drug resistance malignant cell is selected from Bel-7402 hepatocarcinoma mdr cell.Inventor, by studying the purposes of J1-001 compound, has been surprisingly found that it has the propagation of suppression drug resistance malignant cell.According to a particular embodiment of the invention, inventor is by Bel-7402/5-Fu(human liver cancer cell) it is mixed in vitro with J1-001 compound especially J1-001 sodium salt.Utilize MTT colorimetry, calculate J1-001 sodium salt to the suppression ratio of tumor cell proliferation and IC50(half suppression ratio), inventor finds, J1-001 sodium salt has inhibitory action to human liver cancer cell.Thus, it is possible to show that J1-001 sodium salt has good inhibiting effect to drug resistance malignant cell with this understanding.
Thus, in a second aspect of the present invention, the present invention proposes compound shown in formula I or its pharmaceutically acceptable salt purposes in preparing medicine, and described medicine is used for treating cancer
According to embodiments of the invention, described pharmaceutically acceptable salt is sodium salt or potassium salt.
According to embodiments of the invention, described cancer be selected from breast carcinoma, hepatocarcinoma, pulmonary carcinoma, gastric cancer and ovarian cancer at least one.
Formula I or its pharmaceutically acceptable salt purposes in preparing cancer therapy drug worldwide have no that document is reported at present.According to a particular embodiment of the invention, inventor is surprised to find that formula I or its pharmaceutically acceptable salt have the effect of the propagation of suppression malignant cell and drug resistance malignant cell, further, inventor finds, it is used for formula I or its pharmaceutically acceptable salt preparing cancer therapy drug as the active component in treatment cancer therapy drug, finds that its anticancer effect is notable.Thus explanation formula I or its pharmaceutically acceptable salt can be as the active component for the treatment of cancer drug.According to one embodiment of present invention, the above-mentioned cancer therapy drug including formula I or its pharmaceutically acceptable salt may be used for treatment or Breast Cancer Prevention, hepatocarcinoma, pulmonary carcinoma, gastric cancer and ovarian cancer.Thus the invention provides the new application of formula I or its pharmaceutically acceptable salt, thus provide, for treatment cancer aspect, the cancer therapy drug that a class is new.According to a particular embodiment of the invention, formula I or its pharmaceutically acceptable salt especially can have, to the propagation of resistant tumors cell, the effect of significantly inhibiting as the active component in cancer therapy drug, it is thus possible to fundamentally reach prevention and the purpose for the treatment of cancer.
Further, in a third aspect of the present invention, according to embodiments of the invention, the present invention proposes a kind of pharmaceutical composition, comprising: compound shown in formula I or its pharmaceutically acceptable salt (being referred to as J1-001 compound)；And pharmaceutically acceptable excipient,
As it was previously stated, utilize this pharmaceutical composition can effectively suppress the propagation of tumor cell, and it is used for treating cancer.It addition, according to embodiments of the invention, compound shown in this formula I can be such as to be prepared by the method for fermentable by chemosynthesis or biosynthesis.According to embodiments of the invention, described pharmaceutically acceptable salt is sodium salt or potassium salt.
The term " pharmaceutically acceptable excipient " here used can include any common excipients that pharmaceutically can use, such as, include but not limited to binding agent, filler, film-coating polymer, plasticizer, fluidizer, disintegrating agent, lubricant etc..
According to a particular embodiment of the invention, this pharmaceutical composition can comprise a small amount of auxiliary substance, such as wetting agent or emulsifying agent, preservative or buffer further, and described auxiliary substance can strengthen pot-life or the effect of pharmaceutical composition.Pass through embodiments of the invention, the mode delivering this pharmaceutical composition is unrestricted, known various delivery systems can be used, as long as the combination of J1-001 compound or J1-001 compound and other drug can be used effectively, for preventing, manage, treat or improve disease or one or more symptom, such as cancer.
According to embodiments of the invention, described pharmaceutical composition can be in through gastrointestinal administration dosage form and parenteral administration dosage form.According to embodiments of the invention, described entrance gastrointestinal tract after gastrointestinal administration dosage form is described pharmaceutical composition oral administration, plays local action at medicine-feeding part or plays the preparation of effect through absorption.According to embodiments of the invention, described non-through gastrointestinal administration dosage form be described pharmaceutical composition except oral administration route with in addition to play local action at medicine-feeding part or played the preparation of effect after absorbing.Thus, it is possible to be further ensured that J1-001 compound or its pharmaceutically acceptable salt act on malignant cell, drug resistance malignant cell in a variety of forms, improve treatment malignant cell, the effect of drug resistance malignant cell with number of ways.
According to embodiments of the invention, described J1-001 compound is a kind of acid ester dissolubility polyether antibiotics, and Gram-positive, negative bacteria are all had inhibitory action；Having the strongest coccidiostat activity, existing being used for prevents and treats laying hen and the coccidiosis of broiler；Meanwhile, through toxicity and three cause result of the tests show this antibiotic safely, have no side effect.According to embodiments of the invention, the mode obtaining J1-001 compound is not particularly restricted, according to a particular embodiment of the invention, J1-001 compound can be produced by the fermentable of the gene cluster synthesizing this compound containing coding, it is also possible to is produced by the mode of chemosynthesis or molecular design and obtains.Therefore, J1-001 compound preparation treatment malignant cell and drug resistance malignant cell is utilized to have fine industrial applicibility.On the other hand, J1-001 compound as antibiotic prolonged application in Eimeria species prevent and treat, meanwhile, this antibiotics toxic and three cause result of the tests show its safely, have no side effect.Therefore, J1-001 compound has operability, the suitability preparing on medicinal usage.From the above mentioned, J1-001 compound is used for preparing treatment malignant tumor medicine and has very big market development prospect.
It addition, according to embodiments of the invention, inventors be surprised to learn that, described J1-001 compound is significantly stronger than paclitaxel to the Inhibit proliferaton effect of resistant tumors cell.In modern medical service technical field, the treatment to cancer over a period to come of existing cancer therapy drug has good therapeutic effect, but owing to the treatment cancer cycle is the longest, so life-time service a certain kind cancer therapy drug easily produces drug resistance.Thus, it is desirable to develop the medicine of more treatment cancer, especially the tumor cell having produced drug resistance is had the medicine of obvious inhibiting effect.It is surprisingly found by the inventors that, J1-001 compound can effectively suppress multiple human malignancies cell, particularly resistant tumors cell, and its effect is better than existing Treated with Chemotherapeutic Drugs thing.Thus, the J1-001 compound superiority as treatment malignant tumor medicine is further increased.
It addition, according to embodiments of the invention, the means using prepared medicine are also not particularly limited, such as parenteral administration (such as, Intradermal, intramuscular, intraperitoneal, intravenous and subcutaneous), epidural is used, use in tumor and mucosal administration (such as, intranasal and peroral route).In a particular embodiment, the medicine of the present invention can pass through intramuscular, intravenous, in tumor, per os, intranasal, lung or subcutaneous administration.J1-001 compound can be used by any convenient approach, such as by infusion or bolus injection, by via epithelium or mucocutaneous lining (such as, oral mucosa, rectum and intestinal mucosa etc.) absorb, by antibody protein specific treatment etc., and can use together with other biological activating agent.According to embodiments of the invention, using of J1-001 compound can be using of whole body or local.
In a particular embodiment, it may be necessary to make the therapeutic agent of the present invention be topically applied to need the region for the treatment of；This can be by such as but not limited to local infusion, injection or completing by implant, and described implant is porous or pore-free material, and including film and substrate, such as silicone rubber membrane, polymer, fibre substrate are (such as,) or collagen stroma.
The additional aspect of the present invention and advantage will part be given in the following description, and part will become apparent from the description below, or is recognized by the practice of the present invention.
Accompanying drawing explanation
Above-mentioned and/or the additional aspect of the present invention and advantage will be apparent from easy to understand, wherein from combining the accompanying drawings below description to embodiment:
Fig. 1 shows various cell strain IC under J1-001 sodium salt effect50Testing result.
Fig. 2 shows the J1-001 sodium salt result to mouse interior tumor effect.
Detailed description of the invention
Below with reference to specific embodiment, present invention is described, it should be noted that these embodiments are the most illustrative, and limits the present invention never in any form.And the J1-001 sodium salt employed in following embodiment has following structural
Embodiment 1:J1-001 sodium salt and the paclitaxel inhibitory action to HO-8910 cell proliferation
Take the logarithm respectively the HO-8910(ovarian cancer cell of trophophase), making concentration after using 0.25%-EDTA trypsinization is 5 × 104The cell suspension of individual/mL.By this cell suspension inoculation in 96 porocyte culture plates, every hole 200 μ L；Blank group is the group that every hole adds the 200 the most celliferous culture medium of μ L.The above-mentioned 96 porocyte culture plates being vaccinated with cell are put into overnight incubation in cell culture incubator, makes cell attachment.Sample J1-001 sodium salt and existing anti-cancer medicine paclitaxel dissolve with DMSO respectively, are formulated as the storage liquid of 100mmol/L, are diluted to the sample solution of variable concentrations (DMSO final concentration is less than 0.1%) before then using by corresponding culture medium.Sample solution (0.05,0.1,0.2,0.5,1.0,2.0,4.0,8.0 μm ol/L) or the paclitaxel solution (0.05,0.1,0.2,0.5,1.0,2.0,4.0,8.0 μm ol/L) of 200 μ L variable concentrations it is separately added in different experimental grouies；Matched group is the group adding 200 μ L culture medium in attached cell；Blank group is acellular the group adding 200 μ L culture medium.Then this was added after 96 porocyte culture plates of variable concentrations drug solution (0.05,0.1,0.2,0.5,1.0,2.0,4.0,8.0 μm ol/L sample solution or paclitaxel solution) cultivate 48 hours in cell culture incubator, in each hole of the above-mentioned 96 porocyte culture plates taken out, add the tetrazolium bromide (MTT) of 20 μ L0.5mg/mL, then proceed to put in cell culture incubator and cultivate.After 2 hours, the 96 porocyte culture plates jointly hatched with MTT are centrifuged 10 minutes with 2000rpm in high speed centrifuge.After Li Xin, removing supernatant in 96 porocyte culture plates, the first blueness then generated bottom 96 orifice plates by adding 200 μ L dimethyl sulfoxide (DMSO) to be dissolved in every hole crystallizes.After these 96 porocyte culture plates adding DMSO vibrate 5 minutes on oscillator plate, utilize enzyme-linked immunosorbent assay instrument, under 570nm wavelength, detect OD value (reference wavelength is 490nm), calculate suppression ratio and IC50(half suppression ratio).
Suppression ratio %=(A-A0)/(A-A1) × 100%
In formula: A represents the OD value of matched group；A0The OD value of representative sample group；A1Represent the OD value of blank group.
Table 1.J1-001 sodium salt and the IC of paclitaxel HO-891050Value
| Tested material | IC to HO-891050(μm ol/L) |
| J1-001 sodium salt | 1.43 |
| Paclitaxel | 7.41 |
Result as shown in Table 1 understands, and compared with paclitaxel, J1-001 sodium salt all has more significant inhibitory action to HO-8910 cell proliferation in vitro, its IC to HO-8910 cell strain50It is worth relatively paclitaxel and reduces 5.18 times.Illustrating that J1-001 sodium salt has stronger inhibitory action to HO-8910 tumor cell proliferation, its inhibitory action is significantly stronger than the inhibitory action of paclitaxel.
The inhibitory action that external various cell strains are bred by embodiment 2:J1-001 sodium salt
Experimental technique is with embodiment 1, except that, selected cell strain is MCF-7 (human breast cancer cell), Bel-7402(human liver cancer cell), HepG2(human liver cancer cell), NCI-H460(human lung carcinoma cell), SGC-7901(gastric carcinoma cells) and HO-8910(Proliferation of Human Ovarian Cell).
Result as shown in Figure 1 understands, and J1-001 sodium salt has inhibitory action in various degree to MCF-8, Bel-7402, HepG2, NCI-H460, SGC-7901 and HO-8910 cell proliferation in vitro, and wherein, MCF-7 is most sensitive to J1-001 sodium salt, shows as minimum IC50Value.It follows that J1-001 sodium salt all has good inhibiting effect to the propagation of above tumor cell.
The inhibitory action that external cells of resistant tumors is bred by embodiment 3:J1-001 sodium salt
Experimental technique with embodiment 1, except that, selected cell is Bel-7402(human liver cancer cell)；Bel-7402/5-Fu(human liver cancer cell).
Table 2.J1-001 sodium salt, paclitaxel and the amycin IC to Bel-7402 and Bel-7402/5-Fu50Value
Experimental result as shown in Table 2 understands, J1-001 sodium salt all has better inhibition effect to the cell proliferation of drug resistance Bel-7402/5-Fu Yu non-cells of resistant tumors strain Bel-7402, the activity that non-cells of resistant tumors strain Bel-7402 suppresses cell proliferation is close with the activity that the anticancer of paclitaxel is bred, and is better than the activity of the anticancer propagation of amycin；It is noted that J1-001 sodium salt shows as minimum IC to the tumor cell line strain of drug resistance Bel-7402/5-Fu50Value.The anti-tumor activity of the Bel-7402 hepatoma cell strain of resistance to 5-Fu is remarkably decreased by paclitaxel, amycin.Thus, more than experiment prompting J1-001 has the advantage of uniqueness in terms of antitumor drug resistance, is a potential drug having DEVELOPMENT PROSPECT.
Embodiment 4:J1-001 sodium salt Anticancer effect in vivo
The HepG2 mono-that 37 DEG C of rapid defrostings are frozen, adds RPMIl640 culture fluid 10mL, 1000r min-1Centrifuge washing 2 times, the addition RPMIl640 culture fluid containing 10% hyclone, 37 DEG C, 5%CO2Incubator in cultivate, every other day changes cell culture fluid, passes on during cell length to 70%-80% full scale, cultivates after l week, collects cell suspension, 1000r min-1Centrifugal 5min, is that every 1mL is containing 1 × 10 with serum-free medium regulation cell7Individual, standby.BABL/c nude mice about 5 week old, after 3 days, in axillary fossa subcutaneous vaccination every 0.2mL of HepG2 cell, (every 1mL contains 2 × 107Individual HepG2 cell).After tumor mass length is to a certain size, put to death tumor bearing nude mice.Take out mice with tumor tumor mass, inoculation under aseptic condition, in internal biography 3 generation, take tumor tissue and shred into 1-3mm in aseptic PBS3Fritter uses the inoculation of inserted block method, the nude mice axillary fossa subcutaneous vaccination 0.2mL in about 30 6 week old, observes inoculation situation.Gross tumor volume length is to 100mm3Filter out tumor matter homogeneous nude mice during left and right and be randomly divided into 2 groups, respectively model group, J1-001 group, often group 6, separately set blank group.21 day course for the treatment of, the diluent blank, model group gives respective volume.Within every 4 days, it is administered once, totally 5 times.Observe activity and the death condition of nude mice during administration, measure tumorous size simultaneously, with the major diameter a and minor axis b (mm) of vernier caliper measurement tumor body, take tumor after animal dead and weigh.The following is concrete to be grouped and administrations:
Blank group: intraperitoneal administration (i.p.) 0.2mL/10g dilution liquid
Model group: intraperitoneal administration (i.p.) 0.2mL/10g dilution liquid
J1-001 group: intraperitoneal administration (i.p.) 0.2mL/10g0.05mg/mL dosage is 1mg/kg
Put to death animal (taking standing separation serum after blood) after taking blood after being administered the 20th day, peel off each group of tumor mass and weigh, putting rear Taking Pictures recording.
Tumour inhibiting rate (%)=(model group gross tumor volume-experimental group gross tumor volume)/model group gross tumor volume × 100%；
Result: each dead 2 of model group, J1-001 group, simultaneously knowable to Fig. 2 result: after J1-001 treats, the tumor size in animal body is significantly less than model group tumor, and calculating its tumour inhibiting rate is about 50%.This result proves that J1-001 can suppress in-vivo tumour to increase.
In the description of this specification, the description of reference term " embodiment ", " some embodiments ", " example ", " concrete example " or " some examples " etc. means that the specific features, structure, material or the feature that combine this embodiment or example description are contained at least one embodiment or the example of the present invention.In this manual, the schematic representation to above-mentioned term is not necessarily referring to identical embodiment or example.And, the specific features of description, structure, material or feature can combine in any one or more embodiments or example in an appropriate manner.
Although above it has been shown and described that embodiments of the invention, it is understandable that, above-described embodiment is exemplary, being not considered as limiting the invention, above-described embodiment can be changed in the case of without departing from the principle of the present invention and objective, revises, replace and modification by those of ordinary skill in the art within the scope of the invention.
Claims (2)
1. compound shown in formula I or its pharmaceutically acceptable salt purposes in preparing medicine, described medicine is used for suppressing resistance to
The propagation of property of medicine malignant tumor, described malignant tumor is hepatocarcinoma,
Purposes the most according to claim 1, it is characterised in that described pharmaceutically acceptable salt is sodium salt or potassium salt.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201310298008.6A CN104138369B (en) | 2013-05-07 | 2013-07-16 | Cancer therapy drug |
| PCT/CN2014/076888 WO2014180304A1 (en) | 2013-05-07 | 2014-05-06 | Use of j1-001 compound as anti-cancer drug |
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| CN201310163640.X | 2013-05-07 | ||
| CN201310163640X | 2013-05-07 | ||
| CN201310163640 | 2013-05-07 | ||
| CN201310298008.6A CN104138369B (en) | 2013-05-07 | 2013-07-16 | Cancer therapy drug |
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| CN106913564B (en) * | 2015-12-24 | 2021-03-02 | 武汉臻智生物科技有限公司 | Use of polyether compound |
| CN107880060A (en) * | 2016-09-29 | 2018-04-06 | 武汉臻智生物科技有限公司 | Polyether compound purposes |
| CN107951879A (en) * | 2016-10-14 | 2018-04-24 | 武汉臻智生物科技有限公司 | Polyether compound purposes in medicine preparation and the method for screening cancer therapy drug |
| CN108379251A (en) * | 2017-02-03 | 2018-08-10 | 武汉臻智生物科技有限公司 | Glycosyl polyethers class compound is found as the new mechanism research of anticancer drug |
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| CN102675134A (en) * | 2012-05-29 | 2012-09-19 | 东南大学 | Nitrogen-containing substituent curcumin analogue and medical application thereof |
| CN102746360A (en) * | 2012-06-19 | 2012-10-24 | 广西民族大学 | Synthesis and application of four new conjugates of camptothecin-steroid |
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| JP2011213612A (en) * | 2010-03-31 | 2011-10-27 | Kyowa Hakko Kirin Co Ltd | Agent for reducing cancer stem cell and/or cancer precursor cell |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102675134A (en) * | 2012-05-29 | 2012-09-19 | 东南大学 | Nitrogen-containing substituent curcumin analogue and medical application thereof |
| CN102746360A (en) * | 2012-06-19 | 2012-10-24 | 广西民族大学 | Synthesis and application of four new conjugates of camptothecin-steroid |
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| Title |
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| A novel assay for discovery and characterization of pro-apoptotic drugs and for monitoring apoptosis in patient sera;K.Biven 等;《Apoptosis》;20031231;第8卷;第263-268页 * |
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