CN106913564A - Polyether compound purposes - Google Patents
Polyether compound purposes Download PDFInfo
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- CN106913564A CN106913564A CN201511000381.4A CN201511000381A CN106913564A CN 106913564 A CN106913564 A CN 106913564A CN 201511000381 A CN201511000381 A CN 201511000381A CN 106913564 A CN106913564 A CN 106913564A
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- 0 CC(CC(C)C(C(C)=CC(C)C(CC(C1C)OC(CC2)OC(C)C2OC)OC1(CC1)OC1(C)C(CCC1C)OC1(C(C)C1)OC1C(C(C)CC1C)OC1(CO)O)=O)C(*)=O Chemical compound CC(CC(C)C(C(C)=CC(C)C(CC(C1C)OC(CC2)OC(C)C2OC)OC1(CC1)OC1(C)C(CCC1C)OC1(C(C)C1)OC1C(C(C)CC1C)OC1(CO)O)=O)C(*)=O 0.000 description 6
- SNAYCZDHAOMANG-UHFFFAOYSA-N CC(C(CC1)OC)OC1O Chemical compound CC(C(CC1)OC)OC1O SNAYCZDHAOMANG-UHFFFAOYSA-N 0.000 description 2
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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
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
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Abstract
The invention discloses a kind of purposes of the polyether compound, its chelated forms, hydrated form or its pharmaceutically acceptable salt shown in formula I in medicine is prepared, purposes of the medicine in the medicine for preparing treating cancer and prevention cancer return.Inventor has found that the polyether compound shown in formula I can suppress the propagation of malignant cell and malignant cell stem cell.
Description
Technical field
The present invention relates to pharmaceutical chemistry and pharmacotherapeutics field, and in particular to polyether compound, its preparation method, contain
The pharmaceutical composition and purposes of such compound.
Background technology
Cancer has become one of topmost disease of harm human health.At present operation is clinically generally included to control
The means such as treatment, naturopathy, radiotherapy, chemotherapy, Chinese traditional treatment.Wherein chemotherapy refers to be reached using chemotherapeutics
Kill or suppress growth of tumour cell purpose, chemotherapeutics can be divided into alkylating agent, antimetabolite, antitumor antibiotic, plant,
Steroids and miscellany etc., although wherein existing antitumor antibiotic can reach certain effect, long-term use is easily caused swollen
Oncocyte has drug resistance, and usually causes toxic and side effect.Therefore, it is necessary to expand such cancer therapy drug diversity.The present invention
It was found that ethers antibiotic has the effect for suppressing tumour growth well.
The content of the invention
It is contemplated that at least solving one of technical problem in correlation technique to a certain extent.Therefore, of the invention
One purpose be propose it is a kind of can effectively treat or pre- anti-cancer means.
According to an aspect of the present invention, the invention provides the polyether compound shown in formula I, its chelated forms,
The purposes of hydrated form or its pharmaceutically acceptable salt in medicine is prepared, the medicine is used for treating cancer and pre- anti-cancer
Recurrence,
Wherein, the R1, the R2, the R3, the R4, the R5, the R6, the R7With the R8Independently of one another
It is hydrogen ,-OH ,-NH2, halogen, optionally substituted C1~10The saturation or unsaturated alkyl of straight or branched, optionally substituted C1~10
Straight or branched oxyl, optionally substituted C1~10Acyl group, optionally substituted C6~20Aryl, optionally substituted heteroaryl,Or
Wherein, R9、R10It is each independently hydrogen ,-OH ,-NH2, halogen, C1-5The saturation or unsaturated hydrocarbons of straight or branched
Base, carboxyl, azido, oximido, amido, sulfydryl, amide groups, sulfate group, rhamanopyranosyl, phenyl or benzyl, and optionally by
One or more are selected from halogen ,-OCH3、-OH、-OCF3、-NH2, phenyl, benzyl, heteroaryl and ,-NHRXWith-NRX 2In group
Replaced, wherein, RXIt is independently of one another the aliphatic C of saturation1-4Alkyl, phenyl or benzyl, the heteroaryl are 3 yuan~6
Monocyclic or two rings the heteroaryl of unit, optionally containing 1~3 hetero atom selected from N, O or S；
N is 2~7 integer；
The halogen is-F ,-Cl ,-Br ,-I.
, wherein it is desired to illustrate, medicine of the invention can not only suppress the growth of tumour cell, can also suppress swollen
The growth of knurl stem cell, so as to thoroughly remove cancer cell, prevention cancer return, especially prevents the recurrence of breast cancer.
Embodiments in accordance with the present invention, in formula I：
The R1, the R2, the R3, the R4, the R5, the R6, the R7With the R8Be each independently hydrogen ,-
OH、-NH2, halogen, optionally substituted C1~5The saturation or unsaturated alkyl of straight or branched, optionally substituted C1~5Straight chain or branch
Chain oxyl, optionally substituted C1~5Acyl group, optionally substituted phenyl, Or
Wherein, the R9、R10It is each independently hydrogen ,-OH ,-NH2, halogen, C1~5The saturation of straight or branched or insatiable hunger
With alkyl, carboxyl, azido, oximido, amido, sulfydryl, amide groups, sulfate group, rhamanopyranosyl, phenyl or benzyl, and optionally
Ground is selected from halogen ,-OCH by one or more3、-OH、-OCF3、-NH2, phenyl, benzyl, heteroaryl ,-NHRXWith-NRX 2In base
Group is replaced, wherein, RXIt is independently of one another the aliphatic C of saturation1-4Alkyl, phenyl or benzyl, the heteroaryl are 5 yuan
~6 yuan of bicyclic heteroaryl, and optionally containing 1~3 hetero atom selected from N, O or S；
N is 2~7 integer；
The halogen is-F ,-Cl ,-Br ,-I.
Embodiments in accordance with the present invention, in formula I：
The R1, the R2, the R3, the R4, the R5, the R6, the R7, the R8With the R9It is each independent
Ground is hydrogen ,-OH ,-NH2, halogen, optionally substituted C1~3The saturation or unsaturated alkyl of straight or branched, optionally substituted C1~3
Straight or branched oxyl, optionally substituted C1~3Acyl group, optionally substituted phenyl,Or
Wherein, the R9、R10It is each independently hydrogen ,-OH ,-NH2, halogen, C1~3The saturation of straight or branched or insatiable hunger
With alkyl, carboxyl, azido, oximido, amido, sulfydryl, amide groups, sulfate group, rhamanopyranosyl, phenyl or benzyl, and optionally
Ground is selected from halogen ,-OCH by one or more3、-OH、-OCF3、-NH2, phenyl, benzyl, heteroaryl ,-NHRXWith-NRX 2In base
Group is replaced, wherein, RXIt is independently of one another the aliphatic C of saturation1-4Alkyl, phenyl or benzyl, the heteroaryl 5 yuan~6
The bicyclic heteroaryl of unit, and optionally containing 1 hetero atom selected from N, O or S；
N is 2~7 integer；
The halogen is-F ,-Cl ,-Br ,-I.
Embodiments in accordance with the present invention, in formula I：
The R1, the R2, the R3, the R4, the R5, the R6, the R7, the R8Be each independently hydrogen ,-
OH、-NH2, halogen ,-OCH3、-OCF3、C2-10Representative examples of saturated aliphatic chain hydrocarbon, acrylic, propinyl, 2- (trifluoromethyl) ethyl, 2-
Bromoethyl, 2- azidoethyls, acetyl group, 2- halogen (chlorine, bromine) acetyl group, 2- azidos acetyl group, benzoyl, phenylacetyl group,
Optionally substituted phenyl,Or
Wherein, the R9、R10It is each independently hydrogen ,-OH ,-NH2, halogen, methyl, ethyl, isopropyl, vinyl, third
Alkenyl, carboxyl, azido, oximido, amido, sulfydryl, amide groups, sulfate group, rhamanopyranosyl, phenyl or benzyl, and the benzene
Base and benzyl are optionally selected from halogen ,-OCH by one or more3、-OH、-OCF3、-NH2、-NHRXWith-NRX 2In group institute
Substitution, wherein, RXIt is independently of one another the aliphatic C of saturation1-4Alkyl, phenyl or benzyl；
N is 2~7 integer；
The halogen is-F ,-Cl ,-Br ,-I.
Embodiments in accordance with the present invention, the R1ForThe R2, the R3, the R4It is
Hydrogen, the R5It is methyl, the R7With the R8- OH is, the structural formula of the compound is as follows：
Wherein, R6It is hydrogen ,-OH ,-NH2, halogen ,-OCH3、-OCF3, methyl, ethyl, isopropyl, vinyl, acrylic,
Propinyl, 2- (trifluoromethyl) ethyl, 2- bromoethyls, 2- azidoethyls, acetyl group, 2- halogen (chlorine, bromine) acetyl group, 2- azidos
Acetyl group, benzoyl, phenylacetyl group or
Wherein, the R10It is hydrogen ,-OH ,-NH2, halogen, methyl, ethyl, isopropyl, vinyl is acrylic, carboxyl, folded
Nitrogen base, oximido, amido, sulfydryl, amide groups, sulfate group, rhamanopyranosyl, phenyl or benzyl, and the phenyl and benzyl are optional
Ground is selected from halogen ,-OCH by one or more3、-OH、-OCF3、-NH2、-NHRXWith-NRX 2In group replaced, wherein, RX
It is independently of one another the aliphatic C of saturation1-4Alkyl, phenyl or benzyl；
N is 2~7 integer；
The halogen is-F ,-Cl ,-Br ,-I.
Embodiments in accordance with the present invention, the R1ForR2、R3、R4It is hydrogen, the R5It is methyl,
The R6It is-OH, the structural formula of the compound is as follows：
Wherein, R7And R8It is each independently hydrogen ,-OH ,-NH2, halogen ,-OCH3、-OCF3, methyl, ethyl, isopropyl, second
Alkenyl, acrylic, propinyl, 2- (trifluoromethyl) ethyl, 2- bromoethyls, 2- azidoethyls, acetyl group, 2- halogen (chlorine, bromine) second
Acyl group, 2- azidos acetyl group, benzoyl, phenylacetyl group or,
Wherein, the R9It is hydrogen ,-OH ,-NH2, halogen, methyl, ethyl, isopropyl, vinyl, acrylic, carboxyl, nitrine
Base, oximido, amido, sulfydryl, amide groups, sulfate group, rhamanopyranosyl, phenyl or benzyl, and the phenyl and benzyl are optionally
Halogen ,-OCH are selected from by one or more3、-OH、-OCF3、-NH2、-NHRXWith-NRX 2In group replaced, wherein, RXRespectively
From the aliphatic C for being independently saturation1-4Alkyl, phenyl or benzyl；
N is 2~7 integer；
The halogen is-F ,-Cl ,-Br ,-I.
Embodiments in accordance with the present invention, the R2ForR1、R7And R8It is-OH, R3And R5It is
Hydrogen, R4It is methyl, the structural formula of the compound is as follows, the structural formula of the compound is as follows：
Wherein, R6It is hydrogen ,-OH ,-NH2, halogen ,-OCH3、-OCF3, methyl, ethyl, isopropyl, vinyl, acrylic,
Propinyl, 2- (trifluoromethyl) ethyl, 2- bromoethyls, 2- azidoethyls, acetyl group, 2- halogen (chlorine, bromine) acetyl group, 2- azidos
Acetyl group, benzoyl, phenylacetyl group or
Wherein, the R10It is hydrogen ,-OH ,-NH2, halogen, methyl, ethyl, isopropyl, vinyl is acrylic, carboxyl, folded
Nitrogen base, oximido, amido, sulfydryl, amide groups, sulfate group, rhamanopyranosyl, phenyl or benzyl, and the phenyl and benzyl are optional
Ground is selected from halogen ,-OCH by one or more3、-OH、-OCF3、-NH2、-NHRXWith-NRX 2In group replaced, wherein, RX
It is independently of one another the aliphatic C of saturation1-4Alkyl, phenyl or benzyl；
N is 2~7 integer；
The halogen is-F ,-Cl ,-Br ,-I.
Embodiments in accordance with the present invention, the R2ForR6It is-OH, R3、R5It is hydrogen, R4It is first
Base, the structural formula of the compound is as follows：
Wherein, R1,R7,R8It is each independently hydrogen ,-OH ,-NH2, halogen ,-OCH3、-OCF3, methyl, ethyl, isopropyl,
Vinyl, acrylic, propinyl, 2- (trifluoromethyl) ethyl, 2- bromoethyls, 2- azidoethyls, acetyl group, 2- halogen (chlorine, bromine)
Acetyl group, 2- azidos acetyl group, benzoyl, phenylacetyl group or,
Wherein, the R9It is hydrogen ,-OH ,-NH2, halogen, methyl, ethyl, isopropyl, vinyl, acrylic, carboxyl, nitrine
Base, oximido, amido, sulfydryl, amide groups, sulfate group, rhamanopyranosyl, phenyl or benzyl, and the phenyl and benzyl are optionally
Halogen ,-OCH are selected from by one or more3、-OH、-OCF3、-NH2、-NHRXWith-NRX 2In group replaced, wherein, RXRespectively
From the aliphatic C for being independently saturation1-4Alkyl, phenyl or benzyl；
N is 2~7 integer；
The halogen is-F ,-Cl ,-Br ,-I.
Embodiments in accordance with the present invention, the R3ForR1、R7And R8It is-OH, R2、R5It is
Hydrogen, R4It is methyl, the structural formula of the compound is as follows：
Wherein, R6It is hydrogen ,-OH ,-NH2, halogen ,-OCH3、-OCF3, methyl, ethyl, isopropyl, vinyl, acrylic,
Propinyl, 2- (trifluoromethyl) ethyl, 2- bromoethyls, 2- azidoethyls, acetyl group, 2- halogen (chlorine, bromine) acetyl group, 2- azidos
Acetyl group, benzoyl, phenylacetyl group or
Wherein, the R10It is hydrogen ,-OH ,-NH2, halogen, methyl, ethyl, isopropyl, vinyl is acrylic, carboxyl, folded
Nitrogen base, oximido, amido, sulfydryl, amide groups, sulfate group, rhamanopyranosyl, phenyl or benzyl, and the phenyl and benzyl are optional
Ground is selected from halogen ,-OCH by one or more3、-OH、-OCF3、-NH2、-NHRXWith-NRX 2In group replaced, wherein, RX
It is independently of one another the aliphatic C of saturation1-4Alkyl, phenyl or benzyl；
N is 2~7 integer；
The halogen is-F ,-Cl ,-Br ,-I.
Embodiments in accordance with the present invention, the R3ForR1、R7And R6It is-OH, R2、R5It is
Hydrogen, R4It is methyl, the structural formula of the compound is as follows：
Wherein, R1, R7 and R8It is each independently hydrogen ,-OH ,-NH2, halogen ,-OCH3、-OCF3, methyl, ethyl, isopropyl
Base, vinyl, acrylic, propinyl, 2- (trifluoromethyl) ethyl, 2- bromoethyls, 2- azidoethyls, acetyl group, 2- halogen (chlorine,
Bromine) acetyl group, 2- azidos acetyl group, benzoyl, phenylacetyl group or
Wherein, the R9It is hydrogen ,-OH ,-NH2, halogen, methyl, ethyl, isopropyl, vinyl, acrylic, carboxyl, nitrine
Base, oximido, amido, sulfydryl, amide groups, sulfate group, rhamanopyranosyl, phenyl or benzyl, and the phenyl and benzyl are optionally
Halogen ,-OCH are selected from by one or more3、-OH、-OCF3、-NH2、-NHRXWith-NRX 2In group replaced, wherein, RXRespectively
From the aliphatic C for being independently saturation1-4Alkyl, phenyl or benzyl；
N is 2~7 integer；
The halogen is-F ,-Cl ,-Br ,-I.
Embodiments in accordance with the present invention, the polyether compound is one of following compounds：R1 isOr-OH, R2, R3 are each independentlyOr hydrogen, R4, R5 are each independently
Methyl or hydrogen, R6, R7, R8 are-OH.
Embodiments in accordance with the present invention, the polyether compound is one of following compounds：
Embodiments in accordance with the present invention, the cancer is the cancer of the brain, cutaneum carcinoma, kidney, osteocarcinoma, sarcoma, prostate cancer, uterus
Cancer, black cancer, colon cancer, lymph cancer, leukaemia, cancer of pancreas, cell carcinoma, breast cancer, liver cancer, lung cancer, stomach cancer, ovary
Cancer and corresponding tumour cell stem cell.
Embodiments in accordance with the present invention, the medicine prevents cancer return by suppressing tumour cell stem cells hyperplasia.
First mainly as antibiotic usage, inventor chances on the compound with polyethers as parent nucleus through many experiments at present
Such compound has good antitumor activity.It is mixed with malignant cell respectively by by three compounds,
It can have different degrees of antitumor activity.Thus, the compound with polyethers as parent nucleus is in its pharmaceutically acceptable administration
Form (free form, sodium salt or potassium salt form, chelated forms, hydrated form) can be used to treat malignant cell, enrich
Treat the diversity of this kind of disease medicament.It is thin that inventor has found that the polyether compound shown in formula I can suppress malignant tumour
The propagation of born of the same parents, and compound 1, compound 2 and compound 3 these three compounds are studied, it is found that it is thin to various cancers
Born of the same parents are inhibited.Specifically, inventor demonstrates the viewpoint of inventor by following experimentation：
(1) inventor is by various cancer cells and compound 1, compound 2 and compound 3 these three compounds especially its sodium
Salt is mixed respectively in vitro.Using MTT decoration methods, by surveying its OD value, compound 1, compound 2 and compound 3 are calculated
The inhibiting rate and IC of these three compound on tumor cell propagation50(half inhibiting rate).Inventor's discovery, compound 1, compound
2 and compound 3 these three compounds have different degrees of inhibitory action to kinds of tumor cells.
(2) inventor by with anticarcinogen taxol and with the similar salinomycin for being found to have antitumaous effect
(salinomycin) contrast finds that inhibitory action of these three compounds all to various cancer cell multiplications is significantly stronger than taxol
Inhibitory action, be partly better than salinomycin.
Brief description of the drawings
Fig. 1 shows the collection of illustrative plates schematic diagram of compound according to an embodiment of the invention 1；
Fig. 2 shows the collection of illustrative plates schematic diagram of compound according to an embodiment of the invention 2；
Fig. 3 shows the collection of illustrative plates schematic diagram of compound according to an embodiment of the invention 3；
Fig. 4 shows the collection of illustrative plates schematic diagram of stem cell flow cytometer detection according to an embodiment of the invention.
Specific embodiment
Embodiment below with reference to Description of Drawings is exemplary, it is intended to for explaining the present invention, without being understood that
It is limitation of the present invention.
Embodiment 1
Compound 1, compound 2 and compound 3 be by Streptomyces hygroscopicus hypotypes streptomycetes and
What Streptomyces endus hypotypes streptomycete fermentation was obtained, specific method is as follows：
By two plants of Streptomyces hygroscopicus hypotypes and Streptomyces endus hypotypes streptomycete point
SFM flat boards are not inoculated in, are cultivated three days to four days or so.When bacterium colony is formed in SFM culture mediums, choose single bacterium and drop down onto seed culture
Cultivated three days to four days or so in base, (composition of fermentation medium forms sediment for soluble to fermentation medium to connect bacterium according to 1% amount
Powder 30g/L, soybean cake powder 10g/L, yeast extract 2.5g/L, CaCO33g/L, pH7.2) in.Condition of culture：30 degree, 220
Rotating speed, cultivates 7 to 8 days time.
When culture was by the 7th or 8 day, zymotic fluid is collected, high speed centrifugation makes supernatant be separated with mycelium, mycelium is added etc.
The broken bacterium of the acetone of amount, ultrasonic 20min rotates acetone, and supernatant is extracted using the ethyl acetate of equivalent with mycelium, is repeated once.
Concentrated by rotary evaporation uses silicagel column crude separation afterwards to dry, crude product HPLC detection products is obtained, in view of HPLC results show three plants of bacterium
Yield comparison it is high, therefore, our samples also to having concentrated have carried out TLC point plates, and are developed the color in iodine cylinder, it will be apparent that
Point is snapped out, and is dissolved with methyl alcohol, and high speed centrifugation takes supernatant and does the position that mass spectrum determines impact point, and result such as Fig. 1 of compound test-
Shown in 3, Fig. 1 shows the compound for compound 1, and Fig. 2 shows the compound for compound 2, and Fig. 3 shows that the compound is chemical combination
Thing 3.
Embodiment 2
Using the sodium salt of MTT experiment detection compound 1 and taxol to the inhibitory action of MCF-7 tumour cells, specific method
It is as follows：
Take the logarithm the MCF-7 (breast cancer cell, DSMZ of preclinical medicine institute of Wuhan University) in growth period respectively, treats
When cell covers with bottle wall 80%, cell is set to suspend using 0.25%-EDTA Trypsin Induceds (3min-5min).By the cell
Suspension inoculation in 96 porocyte culture plates (every hole cell number is at 5000 or so), per the μ L of hole 200；Control group is that every hole adds
200 μ L are not added with the group of the cell of medicine；Blank group is the group that every hole adds the not celliferous culture mediums of 200 μ L.By above-mentioned inoculation
96 porocyte culture plates of cell are put into cell containing 5% CO237 DEG C are incubated in incubator overnight, make cell attachment.Sample
The sodium salt of compound 1, salinomycin (salinomycin) and existing anti-cancer medicine paclitaxel are dissolved with DMSO respectively, are formulated as
The storing liquid of 100mg/mL, is then diluted to various concentrations using preceding with corresponding culture medium (DMSO final concentrations are less than 0.1%)
Sample solution.The sample solution (sodium salt of compound 1, salinomycin) of 200 μ L various concentrations is separately added into different experimental groups
(100 μ g/mL, 10 μ g/mL, 1 μ g/mL, 0.1 μ g/mL, 0.01 μ g/mL) or paclitaxel solution (100 μ g/mL, 10 μ g/mL, 1 μ
G/mL, 0.1 μ g/mL, 0.01 μ g/mL)；Control group is the group that 200 μ L culture mediums are added toward attached cell；Blank group is without thin
Born of the same parents only add the group of 200 μ L culture mediums.Then this was added into various concentrations drug solution (100,10,1,0.1,0.01 μ g/L samples
Solution or salinomycin or paclitaxel solution) 96 porocyte culture plates in the cell culture incubator (37 DEG C) after culture 48 hours,
The tetrazolium bromide (MTT) of 20 μ L 0.5mg/mL is added in each hole for above-mentioned 96 porocyte culture plates taken out, then proceedes to be put into
Culture in cell culture incubator (37 DEG C).After 2-4 hour, 96 porocyte culture plates being jointly incubated with MTT are in high speed centrifugation
It is centrifuged 10 minutes with 2000rpm in machine.After centrifugation, then supernatant in 96 porocyte culture plates of removal adds 100 by every hole
μ L dimethyl sulfoxide (DMSO)s (DMSO) are dissolved in the blue crystallization of generation Jia Za of 96 orifice plate bottoms.This added the 96 hole cell culture of DMSO
After plate vibrates 10 minutes on oscillator plate, using enzyme-linked immunosorbent assay instrument, OD value (reference ripples are detected under 570nm wavelength
A length of 490nm), calculate inhibiting rate and IC50(half inhibiting rate).
Inhibiting rate %=(A-A0)/(A-A1) × 100%
In formula：A represents the OD values of control group；A0The OD values of representative sample group；A1Represent the OD values of blank group.
The IC of the sodium salt of compound 1 and taxol to MCF-7 cells50Value
| Tested material | |
| The sodium salt of compound 1 | 1.63±0.04 |
| Taxol | 8.49±1.43 |
| Salinomyicn | 3.86±0.08 |
Result shown in upper table, compared with taxol, the sodium salt of compound 1 has to MCF-7 cell proliferation in vitro
More significant inhibitory action, its IC to MCF-7 cell lines50Value reduces 5.21 times compared with taxol, compared with salinomycin reductions
2.34 times.Illustrate that the sodium salt of compound 1 has stronger inhibitory action to MCF-7 tumor cell proliferations, its inhibitory action is substantially strong
In the inhibitory action of taxol.
Embodiment 3：
Using MTT experiment detection compound 3 and taxol to the inhibitory action of MCF-7 tumour cells, experimental technique and
With embodiment 2, difference is that used compound is compound 2 to detection method.The sodium salt and taxol of compound 3 are to MCF-
The IC of 7 cells50Value is as shown in the table.
The IC of the sodium salt of compound 2 and taxol to MCF-7 cells50Value
| Tested material | |
| The sodium salt of compound 2 | 2.25±0.19 |
| Taxol | 8.49±1.43 |
| Salinomyicn | 3.86±0.08 |
Result shown in upper table, compared with salinomycin, taxol, the sodium salt of compound 2 increases to MCF-7 cells in vitro
Growing has more significant inhibitory action, its IC to MCF-7 cell lines50Value reduces 3.77 times compared with taxol, with salinomycin phase
When.Illustrate that the sodium salt of compound 2 has stronger inhibitory action to MCF-7 tumor cell proliferations, its inhibitory action is significantly stronger than Japanese yew
The inhibitory action of alcohol.
Embodiment 4：
Using MTT experiment detection compound 3 and taxol to the inhibitory action of MCF-7 tumour cells, experimental technique and
With embodiment 2, difference is that used compound is compound 3 to detection method.The sodium salt and taxol of compound 3 are to MCF-
The IC of 7 cells50Value is as shown in the table.
| Tested material | |
| The sodium salt of compound 3 | 5.19±1.4 |
| Taxol | 8.49±1.43 |
| Salinomyicn | 3.86±0.08 |
Result shown in table, the sodium salt of compound 3 has more to MCF-7 cell proliferation in vitro compared with taxol
Significant inhibitory action, its IC to MCF-7 cell lines50Value reduces 1.61 times compared with taxol.Illustrate the sodium salt pair of compound 4
MCF-7 tumor cell proliferations have stronger inhibitory action, and its inhibitory action is better than the inhibitory action of taxol, but active anticancer is not
And salinomycin.
Embodiment 5：
The preparation method of the compound sodium salt derivative compound of formula of the present invention, it is specific as follows：
It is respectively that compound 1,2,3 (1.7g, 200 mMs), dicyclohexyl carbon two is sub- under the conditions of anhydrous and oxygen-free at 0 DEG C
Amine (240 mMs) and DMAP (10 mMs) are dissolved in dichloromethane (8ml), after slow drop under agitation
Plus corresponding reagent, room temperature reaction overnight is placed after completion of dropwise addition.Quenched to the HCl solution of 0.1mol/L is added in reaction system
Go out, saturated aqueous common salt washing reaction liquid is extracted with ethyl acetate, merge organic phase, anhydrous sodium sulfate drying is added in organic phase,
Revolving removes solvent and obtains concentrate, and concentrate is obtained such as the structural derivative of Formula II, IV, VI depicted by quick post of crossing.
Embodiment 6：
The preparation method of the compound sodium salt derivative compound of formula of the present invention, it is specific as follows：
At 0 DEG C, under the conditions of anhydrous and oxygen-free, arbitrarily by compound 1,2,3 (1.7g, 200 mMs) and 4- dimethylamino pyrroles
Pyridine (10 mMs) is dissolved in dichloromethane (8ml), after be slowly added dropwise triethylamine (600 mMs) under agitation, stir 10min
Afterwards, then it is added dropwise corresponding acyl chlorides, bromo compound.Room temperature stoichiometric number hour is placed after completion of dropwise addition.Added in reaction system
The HCl solution of 0.1mol/L is quenched, saturated aqueous common salt washing reaction liquid, is extracted with ethyl acetate, and merges organic phase, in organic phase
Anhydrous sodium sulfate drying, revolving is added to remove solvent and obtain concentrate, concentrate is obtained such as formula III, V, VII by quick post of crossing
The derivative of shown structure.
Embodiment 7
1,2 and 3 pairs of inhibitory action of kinds of tumor cells of detection compound, specific method is as follows：
(1) cell recovery：Before experiment, superclean bench table top ultraviolet irradiates 30min.Water-bath is preheated to 37
DEG C, the culture medium of Fresh is placed in water-bath preheating.The cell that taking-up freezes, cryopreservation tube is put into have been warmed up rapidly
Water-bath in thaw rapidly, and constantly shake, the liquid in pipe is melted rapidly.It is complete liquid in pipe to be frozen after about 1-2min
CL, takes out with the outer wall containing 70% cotton ball soaked in alcohol wiping cryopreservation tube.Cryopreservation tube inner cell is drawn, 15ml centrifuge tubes are transferred to
In, while adding 5ml preheating complete mediums.The 500g slow-speed of revolution is centrifuged 3-5min, and supernatant is abandoned in suction.Added in centrifuge tube
10ml nutrient solutions, soft piping and druming is made cell suspension.By Trypan Blue cell count and after carrying out vitality test, by cell
Suspension is added in 10cm culture dishes, the overnight incubation in containing 37 DEG C/5%CO2 incubators.
(2) cell culture：Required culture medium and the ratio of passage refer to ATCC during cell culture, and before cell experiment one
During for Secondary Culture, the culture medium of the cell is changed into without phenol red medium+10%FBS.
(3) Carbazole alkaloid experiment：Compound sample carries out 8 concentration, 5 times of gradient dilutions with DMSO, with without phenol red during detection
Complete medium be diluted, be configured to the solution of experiment concentration (5 times of ultimate densities).
Cell activity detection method:
A) inoculating cell：Logarithmic phase cell is collected, concentration of cell suspension is adjusted, 40 μ l cells is inoculated with 384 orifice plates and is hanged
Liquid, edge hole is filled with aseptic PBS.
B) cell plates are placed on 37 DEG C/5%CO2 incubator overnight incubations, add 10 μ L, 5 times of concentration to be measured within second day
Compound sample.
C) cell is in 37 DEG C/5%CO2Incubator is incubated, and is observed with inverted microscope within 72 hours.
D) read plate：10min is incubated at room temperature after 72 hours, 30 μ L is added per hole per hole CellTiter-Glo reactant mixtures,
Detection plate is vibrated 2-3 minutes, 10min is incubated at room temperature.Read RLU values in Pherastar (BMG labtech) and preserve data.
Cell Growth inhibition%=100% × [1-RLU samples/RLU is negative], wherein RLU samples are to add
Sample well or Positive control wells RLU values, the negative RLU values only to contain DMSO of RLU.Enter with the softwares of GraphPad Prism 6.0
Row data analysis, it is as a result as shown in the table, show that compound is respectively provided with significant inhibitory action to kinds of tumors.
The IC of compound 1, compound 2 and compound 3 to kinds of tumor cells50Value
Embodiment 8：
The inhibitory action that detection compound 1, compound 2 and compound 3 are bred to tumor stem cell, specific method is as follows：
(1) suspend the stem cell enriched assay cultivated：
Cell culture object：Breast cancer lines MDA-MB-231 cells.
Training method：Using suspension cell culture mode culture, 37 degree of incubator cultures.
Suspension cell culture culture medium (200ml)：B274ml；insulin 80μl；DMEM-F12194ml；hEGF:40μ
l；It is dual anti-：2ml
Blake bottle：T25(15ml)；T75(75ml)；
Inoculum density：1000/ml；
Detection kit：AldefluorTMkit；
Incubation time：10 days to 15 days or so (rocking daily more than 2 times).
Experimentation：
(1) will after cell culture dispense 15ml centrifuge tubes in, and clean one time T25 bottle, trim be centrifuged 250g, 10min；
(2) supernatant is removed, 1ml (0.05%) pancreatin is respectively added, and, is transferred in T25 blake bottles with PBS once,
Slowly gently fight each other to individual cells process 5min to 10min；
(3) it is transferred in 15ml centrifuge tubes, trim centrifugation 250g 10min；
(4) added at twice with 1ml PBS, be transferred in 1.5ml EP pipes, air exercise is uniform, take a small amount of counting；
(5) in 10 ten thousand to 20 ten thousand cells and EP pipes, PBS is removed in centrifugation to number of computations, adds kit buffer 1ml
It is resuspended；
(6) go to add the μ l of DEAB 10 in another EP pipe, the Aldfluor for having activated is added in backward cell EP pipes
The μ l of reagent 10, quickly mixing is abundant, draws 0.5ml in the EP pipes of DEAB, is well mixed, and is put into culture in 37 degree of incubators
45min；
(7) after 45min, supernatant is removed in centrifugation (250g, 10min), adds reagent buffer 0.5ml resuspended, is placed on ice
Keep in dark place.
Cell is detected using flow cytometer, experimental result as shown in figure 4, in attached cell stem cell content
Be 2.36%, by the stem cell ratio that is obtained after suspension cell culture be 25.95%, so as to improve nearly 11 times.Between data
There is significant difference.Our stem cell enriched purposes have been reached such that it is able to see.
(2) Drug inhibition experiment：
Medicine：Compound 1, compound 2 and compound 3
Cell category：The stem cell of step (1) enrichment
Cell is inoculated with：The every 120 μ L of 96 hole cell per well inoculating cell amount 12000 or so.
The diluted concentration of medicine：Diluted using PBS：Concentration is set：100μg/ML、20μg/ML、4μg/ML、0.8μg/ML、
0.16μg/ML、0.032μg/ML、0.0064μg/ML、0.00128μg/ML、0.000256μg/ML。
Plus compound：Cell plates are placed on 37 DEG C/5%CO2 incubator overnight incubations, add within second day 5 times of 10 μ L to be measured
The compound sample of concentration.
Detection time and detection mode：Administration 72h after detected using mtt assay, afterwards with three solution (10%SDS,
5% isobutanol, 0.1% concentrated hydrochloric acid) dissolve and OD values are detected at 570nm using ELIASA.
Each compound is independently repeated once.Result such as following table
| Test medicine | |
| Compound 1 | 1.176E-06±0.041 |
| Compound 2 | 2.35E-06±0.152 |
| Compound 3 | 4.251E-06±0.129 |
Result shows that compound 1, compound 2 and compound 3 have significant inhibitory action to tumor stem cell, so that
The recurrence of tumour can be suppressed.
In the description of this specification, reference term " one embodiment ", " some embodiments ", " example ", " specifically show
The description of example " or " some examples " etc. means to combine specific features, structure, material or spy that the embodiment or example are described
Point is contained at least one embodiment of the invention or example.In this manual, to the schematic representation of above-mentioned term not
Identical embodiment or example must be directed to.And, the specific features of description, structure, material or feature can be with office
Combined in an appropriate manner in one or more embodiments or example.Additionally, in the case of not conflicting, the skill of this area
Art personnel can be tied the feature of the different embodiments or example described in this specification and different embodiments or example
Close and combine.
Although embodiments of the invention have been shown and described above, it is to be understood that above-described embodiment is example
Property, it is impossible to limitation of the present invention is interpreted as, one of ordinary skill in the art within the scope of the invention can be to above-mentioned
Embodiment is changed, changes, replacing and modification.
Claims (14)
1. a kind of polyether compound shown in formula I, its chelated forms, hydrated form or its pharmaceutically acceptable salt are in system
Purposes in standby medicine, the medicine is used for treating cancer and prevention cancer return,
Wherein,
The R1, the R2, the R3, the R4, the R5, the R6, the R7With the R8Be each independently hydrogen ,-OH ,-
NH2, halogen, optionally substituted C1~10The saturation or unsaturated alkyl of straight or branched, optionally substituted C1~10Straight or branched
Oxyl, optionally substituted C1~10Acyl group, optionally substituted C6~20Aryl, optionally substituted heteroaryl,Or
Wherein, the R9With the R10It is each independently hydrogen ,-OH ,-NH2, halogen, C1-5The saturation of straight or branched or insatiable hunger
With alkyl, carboxyl, azido, oximido, amido, sulfydryl, amide groups, sulfate group, rhamanopyranosyl, phenyl or benzyl, and optionally
Ground is selected from halogen ,-OCH by one or more3、-OH、-OCF3、-NH2, phenyl, benzyl, heteroaryl ,-NHRXWith-NRX 2In base
Group is replaced, wherein, RXIt is independently of one another the aliphatic C of saturation1-4Alkyl, phenyl or benzyl, the heteroaryl are 3 yuan
~6 yuan of monocyclic or two rings heteroaryl, and optionally containing 1~3 hetero atom selected from N, O or S；
N is 2~7 integer；
The halogen is-F ,-Cl ,-Br ,-I.
2. purposes according to claim 1, it is characterised in that in formula I：
The R1, the R2, the R3, the R4, the R5, the R6, the R7With the R8Be each independently hydrogen ,-OH ,-
NH2, halogen, optionally substituted C1~5The saturation or unsaturated alkyl of straight or branched, optionally substituted C1~5Straight or branched hydrocarbon
Epoxide, optionally substituted C1~5Acyl group, optionally substituted phenyl, Or
Person
Wherein, the R9With the R10It is each independently hydrogen ,-OH ,-NH2, halogen, C1~5The saturation of straight or branched or insatiable hunger
With alkyl, carboxyl, azido, oximido, amido, sulfydryl, amide groups, sulfate group, rhamanopyranosyl, phenyl or benzyl, and optionally
Ground is selected from halogen ,-OCH by one or more3、-OH、-OCF3、-NH2, phenyl, benzyl, heteroaryl ,-NHRXWith-NRX 2In base
Group is replaced, wherein, RXIt is independently of one another the aliphatic C of saturation1-4Alkyl, phenyl or benzyl, the heteroaryl are 5 yuan
~6 yuan of bicyclic heteroaryl, and optionally containing 1~3 hetero atom selected from N, O or S；
N is 2~7 integer；
The halogen is-F ,-Cl ,-Br ,-I.
3. purposes according to claim 2, it is characterised in that in formula I：
The R1, the R2, the R3, the R4, the R5, the R6, the R7With the R8Be each independently hydrogen ,-OH ,-
NH2, halogen, optionally substituted C1~3The saturation or unsaturated alkyl of straight or branched, optionally substituted C1~3Straight or branched hydrocarbon
Epoxide, optionally substituted C1~3Acyl group, optionally substituted phenyl, Or
Person
Wherein, the R9With the R10It is each independently hydrogen ,-OH ,-NH2, halogen, C1~3The saturation of straight or branched or insatiable hunger
With alkyl, carboxyl, azido, oximido, amido, sulfydryl, amide groups, sulfate group, rhamanopyranosyl, phenyl or benzyl, and optionally
Ground ground is selected from halogen ,-OCH by one or more3、-OH、-OCF3、-NH2, phenyl, benzyl, heteroaryl ,-NHRXWith-NRX 2In
Group is replaced, wherein, RXIt is independently of one another the aliphatic C of saturation1-4Alkyl, phenyl or benzyl, the heteroaryl are 5
Unit~6 yuan of bicyclic heteroaryl, optionally contains 1 hetero atom selected from N, O or S；
N is 2~7 integer；
The halogen is-F ,-Cl ,-Br ,-I.
4. purposes according to claim 3, it is characterised in that in the formula I：
The R1, the R2, the R3, the R4, the R5, the R6, the R7, the R8Be each independently hydrogen ,-OH ,-
NH2, halogen ,-OCH3、-OCF3、C2-10Representative examples of saturated aliphatic chain hydrocarbon, acrylic, propinyl, 2- (trifluoromethyl) ethyl, 2- bromine second
Base, 2- azidoethyls, acetyl group, 2- halogen (chlorine, bromine) acetyl group, 2- azidos acetyl group, benzoyl, phenylacetyl group, optionally
Substituted phenyl,Or
Wherein, the R9With the R10It is each independently hydrogen ,-OH ,-NH2, halogen, methyl, ethyl, isopropyl, vinyl, third
Alkenyl, carboxyl, azido, oximido, amido, sulfydryl, amide groups, sulfate group, rhamanopyranosyl, phenyl or benzyl, and the benzene
Base and benzyl are optionally selected from halogen ,-OCH by one or more3、-OH、-OCF3、-NH2、-NHRXWith-NRX 2In group institute
Substitution, wherein, RXIt is independently of one another the aliphatic C of saturation1-4Alkyl, phenyl or benzyl；
N is 2~7 integer；
The halogen is-F ,-Cl ,-Br ,-I.
5. purposes according to claim 4, it is characterised in that the R1ForThe R2, it is described
R3, the R4It is hydrogen, the R5It is methyl, the R7With the R8- OH is, the structural formula of the compound is as follows：
Wherein, R6It is hydrogen ,-OH ,-NH2, halogen ,-OCH3、-OCF3, methyl, ethyl, isopropyl, vinyl, acrylic, propine
Base, 2- (trifluoromethyl) ethyl, 2- bromoethyls, 2- azidoethyls, acetyl group, 2- halogen (chlorine, bromine) acetyl group, 2- azido acetyl
Base, benzoyl, phenylacetyl group or
Wherein, the R10It is hydrogen ,-OH ,-NH2, halogen, methyl, ethyl, isopropyl, vinyl, acrylic, carboxyl, azido,
Oximido, amido, sulfydryl, amide groups, sulfate group, rhamanopyranosyl, phenyl or benzyl, and the phenyl and benzyl are optionally by one
It is individual or multiple selected from halogen ,-OCH3、-OH、-OCF3、-NH2、-NHRXWith-NRX 2In group replaced, wherein, RXEach solely
It is on the spot the aliphatic C of saturation1-4Alkyl, phenyl or benzyl；
N is 2~7 integer；
The halogen is-F ,-Cl ,-Br ,-I.
6. purposes according to claim 4, it is characterised in that the R1ForR2、R3And R4It is
Hydrogen, the R5It is methyl, the R6It is-OH, the structural formula of the compound is as follows：
Wherein, the R7With the R8It is each independently hydrogen ,-OH ,-NH2, halogen ,-OCH3、-OCF3, methyl, ethyl, isopropyl
Base, vinyl, acrylic, propinyl, 2- (trifluoromethyl) ethyl, 2- bromoethyls, 2- azidoethyls, acetyl group, 2- halogen (chlorine,
Bromine) acetyl group, 2- azidos acetyl group, benzoyl, phenylacetyl group or,
Wherein, the R9It is hydrogen ,-OH ,-NH2, halogen, methyl, ethyl, isopropyl, vinyl, acrylic, carboxyl, azido,
Oximido, amido, sulfydryl, amide groups, sulfate group, rhamanopyranosyl, phenyl or benzyl, and the phenyl and benzyl are optionally by one
It is individual or multiple selected from halogen ,-OCH3、-OH、-OCF3、-NH2、-NHRXWith-NRX 2In group replaced, wherein, RXEach solely
It is on the spot the aliphatic C of saturation1-4Alkyl, phenyl or benzyl；
N is 2~7 integer；
The halogen is-F ,-Cl ,-Br ,-I.
7. purposes according to claim 4, it is characterised in that the R2ForThe R1, the R7
With the R8It is-OH, the R3With the R5It is hydrogen, the R4It is methyl, the structural formula of the compound is as follows, described
The structural formula of compound is as follows：
Wherein, the R6It is hydrogen ,-OH ,-NH2, halogen ,-OCH3、-OCF3, methyl, ethyl, isopropyl, vinyl, acrylic, third
Alkynyl, 2- (trifluoromethyl) ethyl, 2- bromoethyls, 2- azidoethyls, acetyl group, 2- halogen (chlorine, bromine) acetyl group, 2- azido second
Acyl group, benzoyl, phenylacetyl group or
Wherein, the R10It is hydrogen ,-OH ,-NH2, halogen, methyl, ethyl, isopropyl, vinyl, acrylic, carboxyl, azido,
Oximido, amido, sulfydryl, amide groups, sulfate group, rhamanopyranosyl, phenyl or benzyl, and the phenyl and benzyl are optionally by one
It is individual or multiple selected from halogen ,-OCH3、-OH、-OCF3、-NH2、-NHRXWith-NRX 2In group replaced, wherein, RXEach solely
It is on the spot the aliphatic C of saturation1-4Alkyl, phenyl or benzyl；
N is 2~7 integer；
The halogen is-F ,-Cl ,-Br ,-I.
8. purposes according to claim 4, it is characterised in that the R2ForThe R6It is-OH,
R3With the R5It is hydrogen, R4It is methyl, the structural formula of the compound is as follows：
Wherein, the R1, the R7With the R8It is each independently hydrogen ,-OH ,-NH2, halogen ,-OCH3、-OCF3, methyl, second
Base, isopropyl, vinyl, acrylic, propinyl, 2- (trifluoromethyl) ethyl, 2- bromoethyls, 2- azidoethyls, acetyl group, 2-
Halogen (chlorine, bromine) acetyl group, 2- azidos acetyl group, benzoyl, phenylacetyl group or,
Wherein, the R9It is hydrogen ,-OH ,-NH2, halogen, methyl, ethyl, isopropyl, vinyl, acrylic, carboxyl, azido,
Oximido, amido, sulfydryl, amide groups, sulfate group, rhamanopyranosyl, phenyl or benzyl, and the phenyl and benzyl are optionally by one
It is individual or multiple selected from halogen ,-OCH3、-OH、-OCF3、-NH2、-NHRXWith-NRX 2In group replaced, wherein, RXEach solely
It is on the spot the aliphatic C of saturation1-4Alkyl, phenyl or benzyl；
N is 2~7 integer；
The halogen is-F ,-Cl ,-Br ,-I.
9. purposes according to claim 4, it is characterised in that the R3ForThe R1, the R7
With the R8It is-OH, the R2With the R5It is hydrogen, the R4It is methyl, the structural formula of the compound is as follows：
Wherein, the R6It is hydrogen ,-OH ,-NH2, halogen ,-OCH3、-OCF3, methyl, ethyl, isopropyl, vinyl, acrylic, third
Alkynyl, 2- (trifluoromethyl) ethyl, 2- bromoethyls, 2- azidoethyls, acetyl group, 2- halogen (chlorine, bromine) acetyl group, 2- azido second
Acyl group, benzoyl, phenylacetyl group or
Wherein, the R10It is hydrogen ,-OH ,-NH2, halogen, methyl, ethyl, isopropyl, vinyl, acrylic, carboxyl, azido,
Oximido, amido, sulfydryl, amide groups, sulfate group, rhamanopyranosyl, phenyl or benzyl, and the phenyl and benzyl are optionally by one
It is individual or multiple selected from halogen ,-OCH3、-OH、-OCF3、-NH2、-NHRXWith-NRX 2In group replaced, wherein, RXEach solely
It is on the spot the aliphatic C of saturation1-4Alkyl, phenyl or benzyl；
N is 2~7 integer；
The halogen is-F ,-Cl ,-Br ,-I.
10. purposes according to claim 4, it is characterised in that the R3ForThe R1, it is described
R7With the R6It is-OH, the R2With the R5It is hydrogen, the R4It is methyl, the structural formula of the compound is as follows：
Wherein, the R1, the R7With the R8It is each independently hydrogen ,-OH ,-NH2, halogen ,-OCH3、-OCF3, methyl, second
Base, isopropyl, vinyl, acrylic, propinyl, 2- (trifluoromethyl) ethyl, 2- bromoethyls, 2- azidoethyls, acetyl group, 2-
Halogen (chlorine, bromine) acetyl group, 2- azidos acetyl group, benzoyl, phenylacetyl group or
Wherein, the R9It is hydrogen ,-OH ,-NH2, halogen, methyl, ethyl, isopropyl, vinyl, acrylic, carboxyl, azido,
Oximido, amido, sulfydryl, amide groups, sulfate group, rhamanopyranosyl, phenyl or benzyl, and the phenyl and benzyl are optionally by one
It is individual or multiple selected from halogen ,-OCH3、-OH、-OCF3、-NH2、-NHRXWith-NRX 2In group replaced, wherein, RXEach solely
It is on the spot the aliphatic C of saturation1-4Alkyl, phenyl or benzyl；
N is 2~7 integer；
The halogen is-F ,-Cl ,-Br ,-I.
11. purposes according to claim 4, it is characterised in that the polyether compound is one of following compounds：Institute
State R1ForOr-OH, the R2With the R3It is each independentlyOr hydrogen, it is described
R4With the R5It is each independently methyl or hydrogen, the R6, the R7With the R8It is-OH.
12. purposes according to any one of claim 1~11, it is characterised in that the polyether compound is followingization
One of compound：
13. purposes according to claim 1, it is characterised in that the cancer is the cancer of the brain, cutaneum carcinoma, kidney, osteocarcinoma, meat
Knurl, prostate cancer, the cancer of the uterus, black cancer, colon cancer, lymph cancer, leukaemia, cancer of pancreas, cell carcinoma, breast cancer, liver
Cancer, lung cancer, stomach cancer, oophoroma.
14. purposes according to claim 1, it is characterised in that the medicine is by suppressing tumour cell stem cells hyperplasia
Prevention cancer return.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106916834A (en) * | 2015-12-24 | 2017-07-04 | 武汉臻智生物科技有限公司 | The biological synthesis gene cluster of compound and its application |
| 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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| JP2011213612A (en) * | 2010-03-31 | 2011-10-27 | Kyowa Hakko Kirin Co Ltd | Agent for reducing cancer stem cell and/or cancer precursor cell |
| CN104138369B (en) * | 2013-05-07 | 2016-11-02 | 武汉臻智生物科技有限公司 | Cancer therapy drug |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106916834A (en) * | 2015-12-24 | 2017-07-04 | 武汉臻智生物科技有限公司 | The biological synthesis gene cluster of compound and its application |
| CN106916834B (en) * | 2015-12-24 | 2022-08-05 | 武汉合生科技有限公司 | Biosynthetic gene cluster of compounds and application thereof |
| 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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