CN106420744A - Composition for treating cancers and preparations and application thereof - Google Patents
Composition for treating cancers and preparations and application thereof Download PDFInfo
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- CN106420744A CN106420744A CN201610742316.7A CN201610742316A CN106420744A CN 106420744 A CN106420744 A CN 106420744A CN 201610742316 A CN201610742316 A CN 201610742316A CN 106420744 A CN106420744 A CN 106420744A
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- qinghaosu
- chloroquine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
- A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4706—4-Aminoquinolines; 8-Aminoquinolines, e.g. chloroquine, primaquine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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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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Abstract
The invention provides a composition prepared from artemisinin antimalarials and aminoquinoline antimalarials; the composition is suitable for treating the cancers, such as lung cancer, breast cancer and melanoma, has low side effect, and is effective in improving cancer treatment effect and reducing the development and progress of a patient's complications.
Description
Technical field
The invention belongs to the pharmaceutical product field containing organic effective component, particularly to a kind of compound for the treatment of cancer
And its preparation and purposes.
Background technology
Cancer is to threaten one of most important disease of human health, and it delivers rate is in the trend rising year by year.Wherein lung cancer
It is relatively conventional malignant tumour with breast cancer.The essential therapeutic arsenals of cancer are chemotherapy at present.With the cancer therapy drug of listing relatively
Many, including alkylating agent medicine, antimetabolite, antitumor antibiotics etc., but most drug is big due to toxicity, patient intolerant to
It is subject to.With scientific and technical continuous development, the continuous change of life style, the continuous rising of cancer morbidity and the death rate, grind
The medicine studying carefully treating cancer is extremely urgent.
Qinghaosu (Artemisinin) is detached sequiterpene from Chinese herbal medicine artemisia annua (Artemisia annua L.)
Lactone, has good antimalarial active.The Antimalarial of qinghaosu is because it can be reacted shape with the ferroheme in plasmodium
Become free radical, lead to cell death.But due to qinghaosu water solubility from, its application have received restriction, again on the basis of, develop
The artemisinin-based antimalarial drugs such as Artemether, Artesunate, above drug therapy malaria effect is significant are gone out, side effect is low.Also grind
Study carefully and show, artemisinin-based antimalarial drug can be also used for treating cancer, its optionally killing tumor cell, and to normal cell
Effect weaker, there is not crossing drug resistant with other chemotherapeutic, and it can also be by suppressing the work of glutathione transferase
Property and the multidrug resistance of reversing tumor cell.
Aminoquinolines antimalarial is with amino side chain isoquinoline compound as basic structure, and the basic side chain of quinine is drawn
Enter in 4- aminoquinoline, obtain quick-acting insecticidal action derivative the most aobvious to fragmentation protozoon, wherein activity the strongest for chloroquine
(Chloroquine).After chloroquine enters plasmodium body, between its molecule insertion plasmodium DNA double coiled strand, form stable answering
Compound, thus affect DNA replication dna, the transcription of RNA and protein synthesis.When studying to 8-aminoquinoline derivatives, send out
The existing primaquine (Primaquine) that Antimalarial is strong, toxicity is low, it is changed into the quinoline having compared with strong oxidation performance in vivo
Endoerythrocytic reduced glutathione (GSH) can be changed into oxidized form of glutathione (GSSH) by quinone derivative, when the latter goes back
When former, need to consume NADPH (NADPH).Due to plasmodium Exoerythrocytic Stage develop in hepatic parenchymal cells this consumed auxiliary
Enzyme II (NADP), and the reduction process of the effect interference codehydrogenase Ⅱ of primaquine, make codehydrogenase Ⅱ reduce, and seriously destroy plasmodium
Glycometabolism and oxidizing process.
In order to improve the cure rate of cancer, prior art length adopts the method for drug combination to treat tumour, and discloses
The compound of many treating cancers, such as CN101940569 are disclosed to be derived containing Sorafenib and qinghaosu and artemisine
The pharmaceutical composition of thing, is mainly used in treating the cancers such as lung cancer, liver cancer；Artemisinin derivative disclosed in CN101380325 and length
The composition of spring Rui Bin, said composition is mainly used in treating the cancer such as breast cancer and adenocarcinoma of lung；Chen Wei by force wait (dihydroartemisinine and
Cisplatin on human Lung Adenocarcinoma A 549 Cell and its interaction in vitro of the cell line A549 of resistance to cis-platinum/CDDP, Chinese Clinical rehabilitation,
2005.43) compound of the disclosed dihydroartemisinine for treating human lung adenocarcinoma and cis-platinum composition；WO200213826 is open
The peaceful, primaquine of anti-malaria medicaments chloroquine etc. and anti-cancer agent cisplatin and to the soft composition than star, said composition is to a few cell
System can produce more preferable suppression cancer effect；And for example：The medicine of the treating cancer of Avastin disclosed in CN101920015 and chloroquine composition
Composition, etc..Prior art discloses the compound for treating cancer that many comprises antimalarial, but prior art is not
By being disclosed the compound being made up of artemisinin-based antimalarial drug and aminoquinolines antimalarial, this compound was not disclosed yet
Therapeutical uses.
Content of the invention
In order to solve the problems, such as prior art, the present invention provides one kind by artemisinin-based antimalarial drug and aminoquinolines
The compound for the treatment of cancer of antimalarial composition and its preparation and preparation method.
The present invention provides a kind of compound for the treatment of cancer, and wherein, this compound includes artemisinin-based antimalarial drug and amino
Quinolines antimalarial, described artemisinin-based antimalarial drug is 0.1-100 with the mol ratio of aminoquinolines antimalarial:0.1-100.
Further improvement, artemisinin-based antimalarial drug is 1-6 with the mol ratio of aminoquinolines antimalarial:1-15.
Preferably, artemisinin-based antimalarial drug and the mol ratio of aminoquinolines antimalarial are 5:12, or 1.25:12, or 5:
6, or 4:1.
Further improve, described artemisinin-based antimalarial drug is qinghaosu, Artesunate, Artemether, dihydroartemisinine or
Arteether.
Further improvement, described aminoquinolines antimalarial is selected from chloroquine, chloroquine diphosphate, PIPERAQUINE, primaquine or phosphoric acid
Primaquine.
Further improvement, described artemisinin-based antimalarial drug is qinghaosu, and described aminoquinolines antimalarial is chloroquine.
Another aspect of the present invention provides a kind of preparation, and said preparation selects tablet, capsule, granule etc..Further change
Enter, the preparation that the present invention provides also includes pharmaceutical carrier.
Further improve, the preparation of the present invention is preferably tablet, this tablet be by slow release layer and release layer form double
Synusia agent, described slow release layer is by parts by weight for the excipient preparation of the aminoquinolines antimalarial of 1-15 part and 15-50 part
Become；Described release layer is the artemisinin-based antimalarial drug of 1-6 part by parts by weight and the auxiliary material of 4-20 part is prepared from.
Further improvement, excipient includes lactic acid hexadecyl-glyceryl ester, styrene maleic anhydride copolymer, malt paste
Essence, microcrystalline cellulose and sodium lauroyl sarcosine；Auxiliary material include cholesteryl palmitat, pregelatinized starch, sodium starch glycol,
Colloidal silica and sodium taurocholate.
Preferably, the weight portion of each composition of described tablet is as follows：
Slow release layer：
Release layer：
Preferably, the weight portion of each composition of described tablet is as follows：
Slow release layer：
Release layer：
Further improvement, the lactic acid hexadecyl-glyceryl ester in the excipient that the present invention provides, maleic anhydride of styrene
Copolymer and maltodextrin form microballoon with aminoquinolines antimalarial, there is provided the solubility of aminoquinolines antimalarial, with
When play the effect of sustained release；Sodium lauroyl sarcosine not only plays the effect of adhesive and lubricant, goes back and microcrystalline cellulose simultaneously
Element plays the effect of disintegrant；Cholesteryl palmitat in auxiliary material and pregelatinized starch play the effect of diluent, also simultaneously
Play raising qinghaosu solubility, promote the effect that it absorbs；Sodium starch glycol and sodium taurocholate play the work of disintegrant jointly
With so that release layer disintegration time limited be less than 10s.
Another aspect of the present invention provides the preparation method of microballoon, and this preparation method comprises the steps：By aminoquinoline
Class antimalarial and styrene maleic anhydride copolymer, are dispersed in the absolute ethyl alcohol that weight portion is 20-50 part, dispersion are obtained
Liquid；By dispersion liquid magnetic stirring apparatus in 1000r min-1, stir at 5 DEG C, prepared suspension；By lactic acid hexadecyl-glyceryl
Ester and maltodextrin add in the absolute ethyl alcohol that weight portion is 10-30 part, stir, prepared oil phase；Suspension is added oil
Xiang Zhong, in 1000r min-1, stir at 5 DEG C, be spray-dried, then with petroleum ether three times, drying at room temperature, prepared grain
Footpath scope is 15-25 μm of microballoon.
Invention further provides the preparation method of tablet, the method comprises the steps：
1) prepare microballoon；
2) microballoon is mixed with microcrystalline cellulose and sodium lauroyl sarcosine, dry granulation, obtain final product particle；
3) artemisinin-based antimalarial drug is mixed with cholesteryl palmitat and pregelatinized starch, prepared mixed powder, use
Mixed powder is pulverized by ultramicro grinding method, prepared particle diameter d0.9Powder compounds for 10-25 μm；By powder compounds and starch glycolate acid
Sodium, sodium taurocholate and colloidal silica mix, dry granulation, prepared particle；
4) by step 2) be obtained particle and step 3) be obtained particle be placed in bi-layer tablet press, prepared tablet.
Another aspect of the present invention provides the application that compound is used in the medicine for the treatment of cancer in preparation.
Further improvement, cancer is lung cancer, breast cancer or melanoma etc..
Artemisinin-based antimalarial drug in compound of the present invention and aminoquinolines antimalarial can be successively using can also be with
When use.
The beneficial effects of the present invention is, the present invention provides one kind by artemisinin-based antimalarial drug and aminoquinolines antimalarial
The compound of composition, this compound can be used for treating the cancers such as lung cancer, breast cancer and melanoma, and side effect is low, Neng Gouyou
Effect ground improves the therapeutic effect to cancer, reduces generation and the development of complication for patients.
Brief description
The inhibitory action to lung adenocarcinoma cell line H460 for the compound that Fig. 1 provides for the present invention；
The inhibitory action to lung cancer cell line H1437 for the compound that Fig. 2 provides for the present invention；
The inhibitory action to breast cancer cell line mcf-7 for the compound that Fig. 3 provides for the present invention；
The inhibitory action to breast cancer T47D for the compound that Fig. 4 provides for the present invention；
The inhibitory action to melanoma cells line B16 F10 for the compound that Fig. 5 provides for the present invention；
Fig. 6 is the inhibitory action to lung adenocarcinoma cell line H460 for each compound；
Fig. 7 is the inhibitory action to breast cancer cell line mcf-7 for each compound；
Fig. 8 is the inhibitory action to melanoma cells line B16 F10 for each compound；
The Survival curves figure of two groups of mouse of Fig. 9；
Figure 10 is successive administration after 8 weeks, lung cancer in mice lung pathologies figure；
Figure 11 is successive administration after 18 weeks, lung cancer in mice lung pathologies figure；
Figure 12 is the tumour/lung ratio chart of two groups of mouse；
Figure 13 is the vitro release result of the test of the compound for the treatment of cancer of embodiment 15-17.
Specific embodiment mode
A kind of compound for the treatment of cancer of embodiment 1
This compound includes qinghaosu and chloroquine, and the mol ratio of qinghaosu and chloroquine is 0.1:100.
A kind of compound for the treatment of cancer of embodiment 2
This compound includes qinghaosu and chloroquine, and the mol ratio of qinghaosu and chloroquine is 100:0.1.
A kind of compound for the treatment of cancer of embodiment 3
This compound includes qinghaosu and chloroquine, and the mol ratio of qinghaosu and chloroquine is 1:1.
A kind of compound for the treatment of cancer of embodiment 4
This compound includes qinghaosu and chloroquine, and the mol ratio of qinghaosu and chloroquine is 5:12.
A kind of compound for the treatment of cancer of embodiment 5
This compound includes qinghaosu and chloroquine, and the mol ratio of qinghaosu and chloroquine is 1.25:12.
A kind of compound for the treatment of cancer of embodiment 6
This compound includes qinghaosu and chloroquine, and the mol ratio of qinghaosu and chloroquine is 5:6.
A kind of compound for the treatment of cancer of embodiment 7
This compound includes qinghaosu and chloroquine, and the mol ratio of qinghaosu and chloroquine is 4:1.
A kind of compound for the treatment of cancer of embodiment 8
This compound includes qinghaosu and chloroquine, and the mol ratio of qinghaosu and chloroquine is 6:15.
A kind of compound for the treatment of cancer of embodiment 9
This compound includes qinghaosu and chloroquine, the mol ratio 3.5 of qinghaosu and chloroquine:8
A kind of compound for the treatment of cancer of embodiment 10
This compound includes Artemether and chloroquine diphosphate, the mol ratio 2 of Artemether and chloroquine diphosphate:5
A kind of compound for the treatment of cancer of embodiment 11
This compound includes Artesunate and primaquine, the mol ratio 3 of Artesunate and primaquine:10.
A kind of compound for the treatment of cancer of embodiment 12
This compound includes dihydroartemisinine and chloroquine, the mol ratio 2 of dihydroartemisinine and chloroquine:15.
A kind of compound for the treatment of cancer of embodiment 13
This compound includes arteether and PIPERAQUINE, the mol ratio 5 of arteether and PIPERAQUINE:2.
A kind of compound for the treatment of cancer of embodiment 14
This compound includes qinghaosu and PIPERAQUINE, the mol ratio 5 of qinghaosu and primaquine:12.
A kind of tablet of embodiment 15
The parts by weight of each composition of this tablet are as follows：
Slow release layer：
Release layer：
A kind of tablet of embodiment 16
The parts by weight of each composition of this tablet are as follows：
Slow release layer：
Release layer：
The preparation method of this tablet is：
1) by chloroquine and styrene maleic anhydride copolymer, it is dispersed in the absolute ethyl alcohol that weight portion is 20-50 part,
Prepared dispersion liquid；By dispersion liquid magnetic stirring apparatus in 1000r min-1, stir at 5 DEG C, prepared suspension；By lactic acid 16
Alkyl glycerol ester and maltodextrin add in the absolute ethyl alcohol that weight portion is 10-30 part, stir, prepared oil phase；To be suspended
Liquid adds in oil phase, in 1000r min-1, stir at 5 DEG C, be spray-dried, then with petroleum ether three times, room temperature is dry
Dry, prepared particle size range is 15-25 μm of microballoon；
2) microballoon is mixed with microcrystalline cellulose and sodium lauroyl sarcosine, dry granulation, obtain final product particle；
3) qinghaosu is mixed with cholesteryl palmitat and pregelatinized starch, prepared mixed powder, use ultramicro grinding
Mixed powder is pulverized by method, prepared particle diameter d0.9Powder compounds for 10-25 μm；By powder compounds and sodium starch glycol, sodium taurocholate
Mix with colloidal silica, dry granulation, prepared particle；
4) by step 2) be obtained particle and step 3) be obtained particle be placed in bi-layer tablet press, prepared tablet.
A kind of tablet of embodiment 17
The parts by weight of each composition of this tablet are as follows：
Slow release layer：
Release layer：
The preparation method of this tablet is with embodiment 16.
The pharmacodynamic experiment that the compound that the present invention provides is administered alone with qinghaosu and chloroquine
1. material
1.1 instruments and consumptive material
Full-automatic CO2Incubator (Japanese Sanyo)
ELIASA (U.S. Bio-Rad 680)
Disposable Tissue Culture Flask and culture plate (U.S. Corning)
Disposable eppendorf pipe and ip head (German eppendorf).
1.2 reagent
RPMI-1640 culture medium and DMEM culture medium are purchased from U.S. Gibco, and hyclone is purchased from Sigma, and MTT is thin
Born of the same parents' propagation and citotoxicity detection kit are purchased from Invitrogen.
1.3 cell line
Lung adenocarcinoma cell line H460, lung cancer cell line H1437, breast cancer cell line mcf-7, breast cancer T47D with
And melanoma cells line B16 F10 is all purchased from U.S. ATCC.
1.4 test sample
Qinghaosu is provided by Novartis Co., Ltd of Switzerland, and chloroquine is purchased from Sigma Co., USA
2. experimental technique
2.1 cell culture
Various tumour cells are trained in the RPMI-1640 culture medium containing 10% inactivated fetal bovine serum or DMEM culture medium
Support, be placed in 37 DEG C and contain 5%CO2In cell culture incubator, pass within every 2-3 days.
2.2 CTAs (mtt assay)
Growth period cell of taking the logarithm is inoculated in 96 orifice plates, and every group sets 6 parallel holes, 8000 cells in every hole, control group
After cell is inoculated about 24 hours, give physiological saline, remaining each group cell adds the chloroquine of variable concentrations after inoculating about 24 hours,
Change culture medium after 8 hours, add the qinghaosu of variable concentrations, qinghaosu uses MTT kit detection cell after processing 24 hours
Activity, each experiment is independently repeated 3 times.The cytoactive not having any drug-treated is set to 1, then the numerical value of each administration group
It is compared with control group, thus drawing relative survival rate.
Note：Before carrying out MTT experiment, respectively titration experiments are carried out to qinghaosu and chloroquine, determine that suitable medicine is dense
Degree (i.e. this concentration range will not have significant lethal effect to tumour cell).
3. statistical procedures
Each group numerical value is all shown with mean ± SEM, and the method for inspection is unpaired t test, P<0.05 has statistics to anticipate
Justice.
4. experimental result
The compound that the present invention provides is to lung adenocarcinoma cell line H460, lung cancer cell line H1437, breast carcinoma cell strain MCF-
7th, the inhibitory action of breast cancer T47D and melanoma cells line B16 F10 is shown in Fig. 1-5 respectively.
5. conclusion
The inhibitory action to lung adenocarcinoma cell line H460 for the compound that Fig. 1 provides for the present invention, it can be seen that with
Control group is compared, P*＞ 0.05, P#＜ 0.01 it follows that, chloroquine is not notable to the inhibitory action of lung adenocarcinoma cell line H460,
The compound of qinghaosu and present invention offer has significant inhibitory action to lung adenocarcinoma cell line H460；Compared with chloroquine group,
P&＜ 0.01, compared with qinghaosu group, P&＜ 0.05 it follows that, compared with the chloroquine of matched doses or qinghaosu, different agent
The compound of the qinghaosu of amount and 60 μM of chloroquine compositions is all better than matched doses to the inhibitory action of lung adenocarcinoma cell line H460
Chloroquine or qinghaosu list product, have statistical significance.It follows that the compound of the qinghaosu of present invention offer and chloroquine is permissible
Effectively suppress the survival rate of lung adenocarcinoma cell line H460, inhibitory action is significantly better than qinghaosu or chloroquine；And with qinghaosu
The compound of the increase of concentration, qinghaosu and chloroquine strengthens to the inhibitory action of lung adenocarcinoma cell line H460.
The inhibitory action to lung cancer cell line H1437 for the compound that Fig. 2 provides for the present invention, it can be seen that with
Control group is compared, P*＞ 0.05, P#＜ 0.01 it follows that, chloroquine does not have inhibitory action, qinghaosu to lung cancer cell line H1437
And the compound that the present invention provides has significant inhibitory action to lung cancer cell line H1437；Compared with chloroquine group, P&＜
0.01, compared with qinghaosu group, P&＜ 0.05 it follows that, compared with the chloroquine of matched doses or qinghaosu, various dose
The compound of qinghaosu and 60 μM of chloroquines composition the inhibitory action of lung cancer cell line H1437 is all better than matched doses chloroquine or
Qinghaosu list product, have statistical significance；It follows that the compound of the qinghaosu of present invention offer and chloroquine can effectively press down
The survival rate of lung cancer cell line H1437 processed, inhibitory action is significantly better than qinghaosu or chloroquine；And the increasing with qinghaosu concentration
Plus, the compound of qinghaosu and chloroquine strengthens to the inhibitory action of lung cancer cell line H1437.
The inhibitory action to breast cancer cell line mcf-7 for the compound that Fig. 3 provides for the present invention, it can be seen that
Compared with control group, P*＞ 0.05, P#＜ 0.01 it follows that, the suppression to breast cancer cell line mcf-7 of the chloroquine of low dosage
Effect is not notable, and the compound of the qinghaosu of the chloroquine of high dose, not dosage and present invention offer is to breast cancer cell line mcf-7
There is significant inhibitory action；Compared with chloroquine group, P&＜ 0.01, compared with qinghaosu group, P&＜ 0.05 it follows that, and right
The chloroquine of dosage or qinghaosu is answered to compare, the compound of the qinghaosu of various dose and 60 μM of chloroquine compositions is to breast carcinoma cell strain
The inhibitory action of MCF-7 is all better than chloroquine or the qinghaosu list product of matched doses, has statistical significance.It follows that this
The compound of the qinghaosu of bright offer and chloroquine can effectively suppress the survival rate of breast cancer cell line mcf-7, and inhibitory action is bright
Show and be better than qinghaosu or chloroquine, and the increase with qinghaosu concentration, the compound of qinghaosu and chloroquine is to breast cancer cell
The inhibitory action of strain MCF-7 reduces.
The inhibitory action to breast cancer T47D for the compound that Fig. 4 provides for the present invention, it can be seen that with
Control group is compared, P*＞ 0.05, P#＜ 0.01 it follows that, qinghaosu does not have inhibitory action to breast cancer T47D, no
The compound of the chloroquine of dosage and present invention offer has significant inhibitory action to breast cancer T47D；With qinghaosu group
Compare, P&＜ 0.01, compared with chloroquine group, P&＜ 0.05 it follows that, compared with the chloroquine of matched doses or qinghaosu, different
The compound of the qinghaosu of dosage and 60 μM of chloroquine compositions is all better than matched doses to the inhibitory action of breast cancer T47D
Chloroquine or qinghaosu list product, there is statistical significance.It follows that the compound of the qinghaosu of present invention offer and chloroquine can
With effective survival rate suppressing breast cancer T47D, inhibitory action is significantly better than qinghaosu or chloroquine, and with sweet wormwood
The compound of the increase of plain concentration, qinghaosu and chloroquine reduces to the inhibitory action of breast cancer T47D.
The inhibitory action to melanoma cells line B16 F10 for the compound that Fig. 5 provides for the present invention, can from figure
Go out, compared with control group, P*＜ 0.01 it follows that, the compound that the qinghaosu of chloroquine, not dosage and the present invention provide is to black
Pigment tumor cell strain B16F10 has significant inhibitory action；Compared with qinghaosu group, P&＜ 0.01, compared with chloroquine group, P&＜
0.01 it follows that, compared with the chloroquine of matched doses or qinghaosu, the qinghaosu of various dose and answering that 30 μM of chloroquines form
Compound is all better than chloroquine or the qinghaosu list product of matched doses to the inhibitory action of melanoma cells line B16 F10, has statistics
Learn meaning.It follows that the compound of the qinghaosu of present invention offer and chloroquine can effectively suppress melanoma cell strain
The survival rate of B16F10, inhibitory action is significantly better than qinghaosu or chloroquine, and the increase with qinghaosu concentration, qinghaosu and
The compound of chloroquine strengthens to the inhibitory action of melanoma cells line B16 F10.
Compound and the pharmacodynamic experiment of prior art other compounds disclosed that the present invention provides
1. material
1.1 instruments and consumptive material
Full-automatic CO2Incubator (Japanese Sanyo)
ELIASA (U.S. Bio-Rad 680)
Disposable Tissue Culture Flask and culture plate (U.S. Corning)
Disposable eppendorf pipe and ip head (German eppendorf).
1.2 reagent
RPMI-1640 culture medium and DMEM culture medium are purchased from U.S. Gibco, and hyclone is purchased from Sigma, and MTT is thin
Born of the same parents' propagation and citotoxicity detection kit are purchased from Invitrogen.
1.3 cell line
Lung adenocarcinoma cell line H460, breast cancer cell line mcf-7 and melanoma cells line B16 F10 are all purchased from the U.S.
ATCC.
1.4 test sample
Qinghaosu, dihydroartemisinine and Artesunate are provided by Novartis Co., Ltd of Switzerland, and chloroquine, primaquine, cis-platinum, Changchun are auspicious
Shore is purchased from Sigma Co., USA.
2. experimental technique
2.1 cell culture
Various tumour cells are trained in the RPMI-1640 culture medium containing 10% inactivated fetal bovine serum or DMEM culture medium
Support, be placed in 37 DEG C and contain 5%CO2In cell culture incubator, pass within every 2-3 days.
2.2 CTAs (mtt assay)
Growth period cell of taking the logarithm is inoculated in 96 orifice plates, and every group sets 6 parallel holes, 8000 cells in every hole, and each group is thin
Born of the same parents add compound after inoculating about 24 hours, and compound is active with MTT kit detection cell after processing 24 hours, each experiment
Independently it is repeated 3 times.The cytoactive not having any drug-treated is set to 1, then the numerical value of each administration group and control group are carried out
Relatively, thus drawing relative survival rate.
Note：Before carrying out MTT experiment, respectively titration experiments are carried out to qinghaosu and chloroquine, determine that suitable medicine is dense
Degree (i.e. this concentration range will not have significant lethal effect to tumour cell).
3. it is grouped and be administered
To lung adenocarcinoma cell line H460, breast carcinoma cell strain MCF 7 and melanoma cells line B16 F10 process
The each compound machine packet situation being added is shown in Table 13 respectively.
Table 1 is processed added compound to lung adenocarcinoma cell line H460
Table 2 is processed added compound to breast carcinoma cell strain MCF 7
Table 3 is processed added compound to melanoma cells line B16 F10
4. statistical procedures
Each group numerical value is all shown with mean ± SEM, and the method for inspection is unpaired t test, P<0.05 has statistics to anticipate
Justice.
5. experimental result
The compound that the present invention provides is to lung adenocarcinoma cell line H460, lung cancer cell line H1437, breast carcinoma cell strain MCF-
7 and melanoma cells line B16 F10 inhibitory action is shown in Fig. 6-8 respectively.
6. experiment conclusion
Fig. 6 be the inhibitory action to lung adenocarcinoma cell line H460 for the different composite thing, it can be seen that with control group phase
Ratio P*＜ 0.01 it follows that, the different composite thing providing in table 1 all has obvious suppression to make to lung adenocarcinoma cell line H460
With, and its inhibitory action is all better than single product qinghaosu；Compared with being administered 1 group, P#＜ 0.05, P&＜ 0.01 it follows that, with
The compound that qinghaosu forms with chloroquine is compared, and other artemisinin-based antimalarial drugs that the present invention provides and other aminoquinolines resist
The compound of malaria medicine composition decreases to the inhibitory action of lung adenocarcinoma cell line H460, has statistical significance, and existing
Compound disclosed in technology is compared with the compound of chloroquine and qinghaosu composition, bright to the inhibitory action of lung adenocarcinoma cell line H460
Aobvious reduction, has significant difference；It follows that the compound of the qinghaosu of present invention offer and chloroquine composition can effectively press down
The survival rate of lung adenocarcinoma cell line H460 processed, curative effect is better than other compounds disclosed by the invention, and is significantly better than existing skill
The compound for the treatment of cancer disclosed in art.
Fig. 7 is the inhibitory action to breast cancer cell line mcf-7 for the different composite thing, it can be seen that and control group
Compare, P*＜ 0.01 it follows that, the different composite thing providing in table 1 all has obvious suppression to breast cancer cell line mcf-7
Effect, and its inhibitory action is all better than single product qinghaosu；Compared with being administered 1 group, P#＜ 0.05, P&＜ 0.01 it follows that,
Compared with the compound of qinghaosu and chloroquine composition, other artemisinin-based antimalarial drugs and other aminoquinolines that the present invention provides
The compound of antimalarial composition decreases to the inhibitory action of breast cancer cell line mcf-7, has statistical significance, and existing
Compared with the compound that compound disclosed in technology is formed with chloroquine and qinghaosu, the suppression to breast cancer cell line mcf-7 is made
Reduced with obvious, there is significant difference；It follows that the compound of the qinghaosu of present invention offer and chloroquine composition can have
The survival rate of effect suppression breast cancer cell line mcf-7, curative effect is better than other compounds disclosed by the invention, and significantly better than existing
There is the compound for the treatment of cancer disclosed in technology.
Fig. 8 be the inhibitory action to melanoma cells line B16 F10 for the different composite thing, it can be seen that with compare
Group is compared, P*＜ 0.01 it follows that, in table 1 provide different composite thing all melanoma cells line B16 F10 is had substantially
Inhibitory action, and its inhibitory action is all better than single product chloroquine；Compared with being administered 1 group, P#＜ 0.05, P&＜ 0.01, thus
Go out, compared with the compound of qinghaosu and chloroquine composition, other artemisinin-based antimalarial drugs and other amino quinolines that the present invention provides
The compound of quinoline class antimalarial composition decreases to the inhibitory action of melanoma cells line B16 F10, has statistics meaning
Compared with justice, and the compound of compound disclosed in prior art and chloroquine and qinghaosu composition, to melanoma cell strain
The inhibitory action of B16F10 substantially reduces, and has significant difference；It follows that the qinghaosu of present invention offer and chloroquine composition
Compound can effectively suppress the survival rate of melanoma cells line B16 F10, curative effect is better than disclosed by the invention other and is combined
Thing, and the compound significantly better than treating cancer disclosed in prior art.
Zoopery
1.1 medicines and reagent
The pure level of analysis that qinghaosu is provided by Novartis of Switzerland medicine, chloroquine is purchased from Sigma company (C6628), and corn oil is purchased
In Sigma company (C8267), Cre adenovirus is purchased from Iowa university of the U.S., and it is pure that remaining all reagent is analysis.
1.2 animal used as test
LSL-KRasG12DLung cancer in mice is purchased from jackson laboratory, and totally 60 are female, and the age is 6-8 week.
2. experimental technique
2.1 lung cancer model are set up
To be placed in after laboratory mice general anesthesia in 37 DEG C of heating plates, configure Cre adenovirus-CaCl2Mixed liquor, including
60 μ L MEME culture mediums, 2.5 μ L AdCre (1010Pfu/mL) and 0.6 μ L CaCl2(1M), after room temperature standing 20min, will
62.5 μ L mixed liquors are injected in mouse body by collunarium.
2.2 packets and administration
60 mouse are randomly divided into two groups, wherein 30 is administration group, 30 is control group.
Administration group mouse gives chloroquine (2mg/kg body weight) by lumbar injection weekly, after 4 hours, will be dissolved in corn
The qinghaosu (10mg/kg) of oil is expelled in mouse body by gavage, and Per-Hop behavior is once up to dead mouse.
Control group mice injects isopyknic PBS and corn oil in the same time respectively, but does not contain chloroquine and qinghaosu
Composition.
2.3 index determining
It is respectively compared the survival curve of two groups of mouse, result is shown in Fig. 9, and after administration the 8th week and the 18th week, every group
Arbitrarily choose 5 mouse, carry out lung pathologies experiment after execution, result is shown in Figure 10-11, compare the tumour/lung ratio of two groups of mouse
Rate, result is shown in Figure 12.
2.4 statistical method
Carry out statistics detection with Prism software, wherein survival curve is analyzed with Log RANK, pathological examination card
Side checks.P ＜ 0.05 is expressed as significant difference.
3. experimental result
It can be seen in figure 9 that compared with control group P ＜ 0.01, there is statistical significance it follows that, the present invention carries
For compound can significantly reduce the survival rate of lung cancer in mice.
From Figure 10 with Figure 11 as can be seen that compared with control group, after administration the 8th week and the 18th week, administration group can show
Write the process delaying lung cancer.
In figure 12 it can be seen that compared with control group, after being administered 8 weeks, P***＜ 0.01, after being administered 18 weeks, P**＜
0.05, there is statistical significance it follows that, the compound that the present invention provides can significantly reduce the percentage of cancerous issue.
4. conclusion
The compound that the present invention provides has significant inhibitory action to lung cancer.
Vitro release determination test
The drug release rate detection of tablet:With reference to 2010 editions versions《Chinese Pharmacopoeia》Annex XIXD vitro drug release degree is examined
Look into.
Take the tablet of above example 15-17 respectively, put in medicament dissolution instrument, in 1h, 2h, 4h, 6h, 12h, 24h respectively
Sampling, detects dissolution percentage with high performance liquid chromatography, and calculates the cumulative release percentage of medicine, and result is shown in Figure 13.
As can be seen from the figure the tablet that embodiment 15-17 provides slowly discharges in 24h；The piece that the present invention provides is described
Agent can extend its action time to cancer, extends curative effect.
Disintegration time limited effect measuring
Select to form different disintegrants by sodium starch glycol, sodium taurocholate, microcrystalline cellulose, remaining composition and enforcement
Composition in example 15 is identical；According to the regulation in Chinese Pharmacopoeia, survey the disintegration time limited of tablet, the results are shown in Table 4；
The impact to the disintegration of tablet time limit for table 4 different auxiliary material
As can be seen from the table, just may be used using the sodium starch glycol of the special parts by weight of the present invention and the mixture of sodium taurocholate
Significantly improve the disintegration time limited of release layer.
Claims (10)
1. a kind of compound for the treatment of cancer is it is characterised in that described compound includes artemisinin-based antimalarial drug and aminoquinoline
Class antimalarial, described artemisinin-based antimalarial drug is 0.1-100 with the mol ratio of aminoquinolines antimalarial:0.1-100.
2. compound as claimed in claim 1 is it is characterised in that described artemisinin-based antimalarial drug and aminoquinolines antimalarial
Mol ratio be 1-6:1-15.
3. compound as claimed in claim 1 it is characterised in that described artemisinin-based antimalarial drug be qinghaosu, Artesunate,
Artemether, dihydroartemisinine or arteether.
4. compound as claimed in claim 3 is it is characterised in that described aminoquinolines antimalarial is selected from chloroquine, p chloromethylbenzoic acid
Quinoline, PIPERAQUINE, primaquine or primaquine phosphate.
5. compound as claimed in claim 4 is it is characterised in that described artemisinin-based antimalarial drug is qinghaosu.
6. compound as claimed in claim 5 is it is characterised in that described aminoquinolines antimalarial is chloroquine.
7. a kind of preparation, including the compound described in any one of claim 1-6 it is characterised in that described preparation also includes medicine
Use carrier.
8. compound described in a kind of any one of claim 1-6 is used for the application in the medicine for the treatment of cancer in preparation.
9. application as claimed in claim 8 is it is characterised in that described cancer is lung cancer, breast cancer or melanoma.
10. application as claimed in claim 8 is it is characterised in that artemisinin-based antimalarial drug in described compound and amino quinoline
Quinoline class antimalarial can be successively using can also use simultaneously.
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| CN201910416842.8A CN110051850A (en) | 2016-08-26 | 2016-08-26 | A kind of compound is preparing the application in the drug for treating melanoma |
| CN201610742316.7A CN106420744B (en) | 2016-08-26 | 2016-08-26 | The compound and its preparation and purposes of a kind for the treatment of cancer |
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