CN106279286B - A kind of camptothecine phosphonate ester compound, preparation method and application - Google Patents
A kind of camptothecine phosphonate ester compound, preparation method and application Download PDFInfo
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- CN106279286B CN106279286B CN201610658549.9A CN201610658549A CN106279286B CN 106279286 B CN106279286 B CN 106279286B CN 201610658549 A CN201610658549 A CN 201610658549A CN 106279286 B CN106279286 B CN 106279286B
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- camptothecine
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- 0 *NCC(*1=C(**C2)[C@]1C(C=C1N3Cc4cc(cccc5)c5nc14)=C2C3=O)=[U] Chemical compound *NCC(*1=C(**C2)[C@]1C(C=C1N3Cc4cc(cccc5)c5nc14)=C2C3=O)=[U] 0.000 description 2
- CMGYJDPKPZJERY-ANYOKISRSA-N CC[C@@](C(O)OC1)(C(C=C2N3Cc4c2nc(cccc2)c2c4)=C1C3=O)O Chemical compound CC[C@@](C(O)OC1)(C(C=C2N3Cc4c2nc(cccc2)c2c4)=C1C3=O)O CMGYJDPKPZJERY-ANYOKISRSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
Abstract
The invention discloses the preparation methods of a kind of camptothecine phosphonate ester compound and this compound and its purposes in the preparation of antitumor drugs.Testing through cytotoxic activity proves, such compound of the present invention has preferable cytotoxic activity, and the anti-tumor activity of all compounds is higher than clinical control drug Irinotecan, can be used for preparing anti-tumor drug.Preparation process of the present invention is simple, raw material is cheap and easy to get, and product purity is high.
Description
Technical field
The invention belongs to biomedicine fields, more particularly, to a kind of camptothecine phosphonate ester compound, its preparation side
Method and application.
Background technique
Camptothecine is that Wall is equal to 1966 first from the distinctive Nyssaceae plant camptotheca acuminata (camptotheca of China
Acuminata in) it is isolated it is a kind of with significant cytotoxic activity quinoline alkaloid (J.Nat.Prod.2004,
67,129-135) good inhibiting effect, shown to Several Kinds of Malignancy such as osteocarcinoma, liver cancer, bladder cancer and leukaemia, but
It is found when clinical use, it is more serious that camptothecine can generate bone marrow suppression, vomiting and diarrhea etc. when playing its anti-tumor activity
Side effect, at the same because in its molecular structure on quinoline ring the special alkalinity of nitrogen due to it is water-soluble poor, cannot direct human body non-bowel
Administration.Further to improve its water solubility and reducing its toxic side effect, water-soluble sodium of phase early 1970s to camptothecine
Salt has carried out I clinical trial phase, although observed certain anticancer activity and substantially increase the water solubility of such drug,
Because its serious and unpredictalbe toxic side effect interrupts further clinical test.In recent years, domestic and international researcher is to happiness
Tree bases drug has carried out system in-depth study, wherein being replaced with it for multiple reactive compounds such as Yi Li of guide's derivative synthesis
Health, topotecan, 9-aminocamptothecin, 9-nitrocamptothecin, DX-8951f, GG-211, BNP-1350, ST-1481 and CKD-
602 is equal by FDA approval listing or in clinical investigation phase (1. Bioorg. Med.Chem.2004,12,1585-1604；
②Phytochem.2004,65,2735–2749).But due to lactone with anti-tumor activity in camptothecin derivant structure
Ring (E ring) is easy hydrolysis under people's vivo physiological conditions, and anti-tumor activity is caused to reduce.And it is demonstrated experimentally that in blood plasma
Lactone ring form and open loop form, which exist, to be balanced, and there are proportional relations for the concentration and curative effect of medication of lactone ring form.And open loop shape
Formula be lead to adverse reaction reason for it, such as cause bone marrow suppression, vomiting, diarrhea and blood urine ((1) Acta Pharmaceutica Sinica .2003,
38,715–720；(2)J.Org.Chem.,2000,65, 4601-4606.).Therefore to -20, E ring structural modifications and change
It makes, improves ratio of the lactone ring form in human plasma to improve the activity of such compound and reduce toxicity, become current
Research and develop one of the Main Topics of camptothecine.
Summary of the invention
Aiming at the above defects or improvement requirements of the prior art, the present invention provides a kind of camptothecine phosphonic acid ester chemical combination
Object, preparation method and application, its object is to by with camptothecine structure activity study be guidance, by position 20 of camptothecins hydroxyl
It carries out modification and forms ester bond, improve the stability of lactonic ring, thus solve existing camptothecin derivative as anti-tumor drug
The technical problem that activity is low, toxic side effect is big.
To achieve the above object, according to one aspect of the present invention, a kind of camptothecine phosphonate ester compound is provided,
Structure with formula (I)：
Wherein, R1And R2It is each independently straight chained alkyl, branched alkyl, aryl or heteroaryl, n is 1 or 3.
Preferably, the R1And R2It is each independently C1-C12Alkyl.
Preferably, the R1And R2It is each independently C1-C7Alkyl.
Preferably, the R1For 2- propyl, isobutyl group, benzyl or 2- methyl-propyl；The R2For methyl, ethyl or phenyl.
Other side according to the invention provides the preparation method of the camptothecine phosphonate ester compound, described
Camptothecine phosphonate ester compound is to react to obtain with formaldehyde and diethyl phosphite by camptothecine amino-acid ester.
Preferably, the preparation method carries out in accordance with the following steps：Using camptothecine amino-acid ester as raw material, with tetrahydrofuran
For solvent, triethylamine is added to reaction system and anhydrous ferric trichloride is uniformly mixed, formaldehyde and Asia then is added to reaction system
Diethyl phosphate, it is 1 that the camptothecine amino-acid ester, which reacts molar ratio with formaldehyde and diethyl phosphite,:1.75:1.75,60
DEG C~100 DEG C of fully reactings after, the camptothecine phosphonate ester compound can be obtained.
Preferably, the preparation method further includes separating step, and the separating step is column chromatography for separation.
Preferably, the silica gel that the column chromatography uses is the column silica gel for chromatography of 200~300 mesh.
Other side according to the invention provides the application of camptothecine phosphonate ester compound described in one kind, answers
It is used to prepare the drug for the treatment of cancer cell.
Preferably, the cancer cell includes human liver cancer cell (Hep3B), human lung adenocarcinoma cell (A549), human breast carcinoma
Cell strain (MDA-MB-231 and MCF-7), human mouth epidermoid carcinoma cell (KB) or human mouth epidermoid carcinoma cells resistance strain
(KBvin) tumour cell.
In general, through the invention it is contemplated above technical scheme is compared with the prior art, can obtain down and show
Beneficial effect：
(1) present invention is guidance with camptothecine structure activity study, is made with the camptothecin derivative that different aminoacids replace
For raw material, position 20 of camptothecins hydroxyl is subjected to modification and forms ester bond, camptothecine phosphonic acid ester of the present invention has been prepared
Compound further prevents hydroxyl and ortho position ester carbonyl group from foring intramolecular hydrogen bond, the stability of lactonic ring is improved, to mention
The high druggability of camptothecine, anti-tumor activity simultaneously reduce its toxicity.
(2) present invention can be used as kinetophore and be connected in pharmacophore using amino acid in vivo by active transport, in favor of absorbing
With transport this principle, while using " diversity synthesis " this thought, will be common active on this drug molecule of phosphate
Functional group and camptothecine amino-acid ester by way of multi-component reaction in conjunction with and to have synthesized one kind of the present invention novel
Camptothecin derivative.
(3) show camptothecine phosphonate ester compound of the present invention to people through anti tumor activity in vitro the selection result
Lung adenocarcinoma cell (A549), Breast cancer lines (MDA-MB-231), human mouth epidermoid carcinoma cell (KB) and human mouth table
Epidermoid carcinoma cells persister (KBvin) shows stronger inhibitory activity, and some compounds are higher than current clinical medicine topology
For health, therefore the compound of the present invention can be used for preparing anti-tumor drug.
(4) camptothecine compounds structure novel of the present invention, synthesis technology is simple, product purity is high, to tumour
Cells show goes out stronger inhibiting effect, has excellent application prospect.
Detailed description of the invention
Fig. 1 is the general formula structure figure of camptothecine phosphonate ester compound provided by the invention.
Specific embodiment
In order to make the objectives, technical solutions, and advantages of the present invention clearer, with reference to the accompanying drawings and embodiments, right
The present invention is further elaborated.It should be appreciated that the specific embodiments described herein are merely illustrative of the present invention, and
It is not used in the restriction present invention.As long as in addition, technical characteristic involved in the various embodiments of the present invention described below
Not constituting a conflict with each other can be combined with each other.
Camptothecine phosphonate ester compound of the present invention has chemical structure shown in formula (I)：
Wherein, R1And R2It is each independently straight chained alkyl, branched alkyl, aryl or heteroaryl, n is 1 or 3, R1And R2
It is each independently preferably C1-C12Alkyl, further preferably C1-C7Alkyl.
Further preferably, R1For 2- propyl, isobutyl group, benzyl or 2- methyl-propyl；The R2For methyl, ethyl or
Phenyl.
Camptothecine phosphonate ester compound preparation method of the present invention is carried out by following chemical equation：
Camptothecine phosphonate ester compound (compound of formula I) preparation method of the invention is with camptothecine amino-acid ester for original
Material, suitable tetrahydrofuran make solvent, and triethylamine is added dropwise, and the anhydrous ferric trichloride of catalytic amount are added to reaction system, wait stir
It mixes after ten minutes, the formaldehyde and diethyl phosphite of reacting dose, 60~100 DEG C of 8 hours of reaction, thin layer is added to reaction system
Chromatography detection, (eluent system is chloroform to column chromatography:Methanol) separation, obtain target compound.
The best preparation method of camptothecine phosphonate ester compound of the invention is：By camptothecine amino-acid ester (2mmol) in
In round-bottomed flask, tetrahydrofuran (10mL) is added and makees solvent, triethylamine (2mmol) then is added dropwise, is added to reaction system anhydrous
Ferric trichloride (0.3mmol), it is to be mixed after ten minutes, formaldehyde (3.5mmol) and diethyl phosphite is added to reaction system
(3.5mmol), 60 degrees Celsius of 8 hours of reaction, thin layer chromatography board detect after the reaction was completed, use saturated sodium bicarbonate aqueous solution
Organic phase is washed, is concentrated under reduced pressure after anhydrous magnesium sulfate is dry, column chromatography for separation (CHCl3:MeOH it) purifies up to target product,
The silica gel that center pillar chromatography uses is the column silica gel for chromatography of 200~300 mesh.
The preparation method of starting camptothecin -20-O-L- amino ester is referring to literature method used in the present invention
(Bioorg.Med.Chem.,1998,6,551-562)。
According to the preparation method of camptothecine phosphonate ester compound of the present invention, the general formula as shown in Fig. 1 has been synthesized
Camptothecine phosphonate ester compound.Following embodiment gives the preparation that Ia-Ie has 5 kinds of camptothecine phosphonate ester compounds altogether
Synthetic method determines each compound structure using NMR, and calculates and analyze its yield.
The application of camptothecine phosphonate ester compound of the present invention, which is characterized in that be applied to preparation treatment cancer
The drug of disease cell, the cancer cell include that human liver cancer cell (Hep3B), human lung adenocarcinoma cell (A549), human breast carcinoma are thin
Born of the same parents' strain (MDA-MB-231 and MCF-7), human mouth epidermoid carcinoma cell (KB) or human mouth epidermoid carcinoma cells resistance strain
(KBvin) tumour cell.
The following are embodiments：
Embodiment 1：The synthesis of target compound Ia
The synthesis of starting camptothecin 20-O-L- glycinate：Take N-Boc- glycine (3.13mmol) in a round bottom flask,
Dry methylene chloride (200mL) is added to make it dissolve, camptothecine (3.13mmol), N, N'- are then sequentially added under ice bath
Diisopropylcarbodiimide (DIPC, 3.13mmol) and 4-dimethylaminopyridine (DMAP, 3.13mmol).Reaction is in room temperature
Lower stirring 16 hours.Thin-layer chromatography detects after the reaction was completed, filters and removes solid impurity, then organic with the salt acid elution of 0.1N
Phase, it is dry, white solid is obtained after reduced pressure, column chromatographs (chloroform-methanol) isolated intermediate camptothecine -20-O-
(N '-tertbutyloxycarbonyl)-L- glycinate.Take camptothecine -20-O- (N '-tertbutyloxycarbonyl)-L- glycinate (2mmol) in
In round-bottomed flask, CH is added2Cl2(2mL) and TFA (2mL), is removed under reduced pressure solvent after being stirred at room temperature 2 hours, uses recrystallizing methanol
Obtain the trifluoroacetate of final camptothecine -20-O-L- glycinate.Synthetic method is referring to literature method
(Bioorg.Med.Chem.,1998,6, 551-562)。
Its reaction equation is：
The synthesis of Ia：Take camptothecine L-valine ester (2mmol) in a round bottom flask, addition tetrahydrofuran (10mL) is made molten
Agent, then be added dropwise triethylamine (2mmol), backward reaction system addition anhydrous ferric trichloride (0.3mmol), 10 minutes to be mixed
Afterwards, to reaction system be added formaldehyde (3.5mmol) and diethyl phosphite (3.5mmol), 60 degrees Celsius of 8 hours of reaction,
Thin layer chromatography board detects extent of reaction, to after the reaction was completed, wash organic phase, anhydrous magnesium sulfate with saturated sodium bicarbonate aqueous solution
It is concentrated under reduced pressure after drying, column chromatography for separation (CHCl3- MeOH) it purifies up to target product.
Its reaction equation is as follows：
It is as follows to react products therefrom detection data：Yield：64%；Fusing point:275-276℃；1H-NMR (400MHz,
CDCl3)δ:8.40 (s, 1H, C7-H), 8.23 (m, 2H, C9-H, C12-H), 7.83 (t, 1H, C10-H, J=4Hz), 7.66
(t, 1H, C11-H, J=4Hz), 7.32 (s, 1H, C14-H), 5.70 (m, 1H, C17-H), 5.41 (m, 1H, C17-H), 5.31
(s,2H,C5-H),4.04-4.15(m,4H, OCH2 CH3-H),3.50-3.62(m,2H,NCH2 ), P 3.18-3.22 (m, 1H, figured silk fabrics
Propylhomoserin-H), 2.80-3.95 (m, 1H, valine-H), 2.15-2.32 (m, 2H, C18-H), 1.21-1.62 (m, 12H, figured silk fabrics ammonia
Acid-H, OCH2 CH3 - H) 0.97 (t, 3H, J=8Hz, C19-H)；MS-ESI m/z:598.2 [M+H]+, it was demonstrated that it is Ia compound.
Embodiment 2：The synthesis of target compound Ib
It is same with embodiment 1, valine is only replaced with leucine.It is as follows to react products therefrom detection data：Yield：66%；
Fusing point:261-263℃；1H-NMR(400MHz,CDCl3)δ:8.40(s,1H, C7-H),8.23(m,2H,C9-H,C12-H),
7.82 (t, 1H, C10-H, J=4Hz), 7.67 (t, 1H, C11-H, J=4Hz), 7.20 (s, 1H, C14-H), 5.70 (d, 1H,
C17-H, J=20Hz), 5.41 (d, 1H, C17-H, J=20Hz), 5.31 (s, 2H, C5-H), 4.02-4.26 (m, 5H,
OCH2 CH3- H, leucine-H), 3.41-3.63 (m, 2H, NCH2 ), P 3.11-3.19 (m, 3H, leucine-H), 2.13-2.34
(m, 2H,C18-H),1.07-1.60(m,12H,OCH2 CH3 - H, leucine-H), 0.87 (t, 3H, C19-H, J=8Hz)；MS-
ESI m/z:634.2[M+Na]+, it was demonstrated that it is Ib compound.
Embodiment 3：The synthesis of target compound Ic
It is same with embodiment 1, valine is only replaced with isoleucine.It is as follows to react products therefrom detection data：Yield：
54%；Fusing point:265-266℃；1H-NMR(400MHz,CDCl3)δ:8.40(s,1H, C7-H),8.23(m,2H,C9-H,C12-
), H 7.82 (t, 1H, C10-H, J=4Hz), 7.67 (t, 1H, C11-H, J=4Hz), 7.20 (s, 1H, C14-H), 5.71 (d,
1H, C17-H, J=20Hz), 5.41 (d, 1H, C17-H, J=20Hz), 5.30 (s, 2H, C5-H), 4.04-4.23 (m, 5H,
OCH2 CH3- H, isoleucine-H), 3.51-3.65 (m, 2H, NCH2 ), P 3.02-3.19 (m, 1H, isoleucine-H), 2.13-
2.34 (m,2H,C18-H),1.07-1.60(m,14H,OCH2 CH3 - H, isoleucine-H), 0.86 (t, 3H, C19-H, J=
8Hz)；MS-ESI m/z:634.1[M+Na]+, it was demonstrated that it is Ic compound.
Embodiment 4：The synthesis of target compound Id
It is same with embodiment 1, valine is only replaced with phenylalanine.It is as follows to react products therefrom detection data：Yield：
36%；Fusing point:268-270℃；1H-NMR(400MHz,CDCl3)δ:8.40(s,1H, C7-H),8.23(m,2H,C9-H,C12-
), H 7.82 (t, 1H, C10-H, J=4Hz), 7.67 (t, 1H, C11-H, J=4Hz), 7.21-7.36 (m, 4H, Ph-H, C14-
), H 7.00-7.03 (m, 2H, Ph-H), 5.70 (d, 1H, C17-H, J=16Hz), 5.44 (d, 1H, C17-H, J=16Hz),
5.30 (s, 2H, C5-H), 4.17-4.21 (m, 1H, phenylalanine-H), 3.86-4.08 (m, 4H, OCH2 CH3-H),2.89-
3.26(m, 4H,NCH2 P, phenylalanine-H), 2.13-2.29 (m, 2H, C18-H), 1.21-1.28 (m, 6H, OCH2 CH3 -H)
0.87 (t, 3H, J=8Hz, C19-H)；MS-ESI m/z:668.3[M+Na]+, it was demonstrated that it be Id is compound.
Embodiment 5：The synthesis of target compound Ie
It is same with embodiment 1, valine is only replaced with β-Gamma Amino Butyric Acid.It is as follows to react products therefrom detection data：Yield：
43%；Fusing point:272-276℃；1H-NMR(400MHz,CDCl3)δ:8.40(s,1H, C7-H),8.22(m,2H,C9-H,C12-
H), 7.82 (t, 1H, C10-H, J=4Hz), 7.66 (t, 1H, C11-H, J=4Hz), 7.28 (s, 1H, C14-H), 5.70 (d,
1H, C17-H, J=16Hz), 5.41 (d, 1H, C17-H, J=16Hz), 5.29 (s, 2H, C5-H), 4.08-4.14 (m, 4H,
OCH2 CH3),3.13-3.15 (m,2H,NCH2 ), P 2.55-2.63 (m, 2H, Gamma Amino Butyric Acid-H), 2.25-2.29 (m, 2H, fourth ammonia
Acid-H), 2.16-2.17 (m, 2H, C18-H), 1.83-1.86 (m, 2H, Gamma Amino Butyric Acid-H), 1.21-1.33 (m, 12H,
OCH2 CH3 ), 0.97 (t, 3H, C19-H, J=8Hz)；MS-ESI m/z:606.2[M+Na]+, it was demonstrated that it is Ie compound.
Embodiment 6
The experimental method and result of the anti-tumor activity of compound Ia-Ie
Pharmacological evaluation of the invention uses Sulforhodamine B (Sulforhodamine B, SRB) colorimetric method.Tumour cell
RPMI-1640 the or DMEM culture medium of 10% fetal calf serum (FBS) is selected in culture, by tumor cell inoculation in 96 orifice plates, each
Cultivate 3-5 × 10 in hole3The solution title compound to be tested of various concentration is added in a cell.After culture 72 hours, every hole is added
The solution of trichloroacetic acid (50%, w/v) of pre-cooling fixes cell, fixes 30 minutes in refrigerator.After 96 orifice plates dry at room temperature, often
The SRB dye liquor (1% peracetic acid formulation is purchased from Sigma Chemical company) of 0.04% (w/v) is added in hole, after dyeing 30min
Dye liquor is outwelled, is rinsed 4 times with acetic acid, removes unbonded dyestuff, room temperature is dried.It is molten with the non-buffered Tris-base lye of 100 μ L
The dyestuff in conjunction with cell protein is solved, vibrates 20min on horizontal shaker, light microplate reader (U.S. Bio-TeK is absorbed using ELx800
Company's production, operating software Gen5) measure absorbance value at 515nm.All tests set 3 parallel groups or repeat 3 times.Chemical combination
The cytotoxic activity test result of object Ia-Ie is shown in Table 1
The cytotoxic activity test result of 1 compound Ia-Ie of table：IC50(μM)
Note：(1) screening technique：Sulforhodamine B colorimetric method；(2) action time：72 hours；(3) compound number Ia-Ie
Respectively previous embodiment 1 is to 5 products therefrom of embodiment.
Six kinds of tumour cell in vitro cytotoxic effect test results are shown, compound synthesized by the present invention is shown
Good poisoning human liver cancer cell (Hep3B), human lung adenocarcinoma cell (A549), Breast cancer lines (MDA-MB-231 and
MCF-7), the activity of human mouth epidermoid carcinoma cell (KB) and human mouth the strain of epidermoid carcinoma cells resistance (KBvin) tumour cell,
Almost all of compound shows the in vitro cytotoxic effect higher than camptothecine clinical medicine Irinotecan (CPT-11), and
All compounds show good anti-tumor activity in Hep3B and MCF-7 cell.
As it will be easily appreciated by one skilled in the art that the foregoing is merely illustrative of the preferred embodiments of the present invention, not to
The limitation present invention, any modifications, equivalent substitutions and improvements made within the spirit and principles of the present invention should all include
Within protection scope of the present invention.
Claims (8)
1. a kind of camptothecine phosphonate ester compound, which is characterized in that its structure with formula (I)：
Wherein, R1And R2It is each independently C1-C12Alkyl.
2. camptothecine phosphonate ester compound as described in claim 1, which is characterized in that the R1And R2It is each independently
C1-C7Alkyl.
3. a kind of camptothecine phosphonate ester compound, which is characterized in that its structure with formula (I)：
Wherein, R1For 2- propyl, isobutyl group, benzyl or 2- methyl-propyl；R2For methyl, ethyl or phenyl.
4. the preparation method of the camptothecine phosphonate ester compound as described in claims 1 to 3 any one, which is characterized in that
It carries out in accordance with the following steps：Using camptothecine amino-acid ester as raw material, using tetrahydrofuran as solvent, triethylamine is added to reaction system
It is uniformly mixed with anhydrous ferric trichloride, formaldehyde and diethyl phosphite, the camptothecine amino acid then is added to reaction system
It is 1 that ester, which reacts molar ratio with formaldehyde and diethyl phosphite,:1.75:1.75, after 60 DEG C~100 DEG C fully reactings, it can obtain
To the camptothecine phosphonate ester compound.
5. the preparation method of camptothecine phosphonate ester compound as claimed in claim 4, which is characterized in that the preparation method
It further include separating step, the separating step is column chromatography for separation.
6. the preparation method of camptothecine phosphonate ester compound as claimed in claim 5, which is characterized in that the column chromatography is adopted
Silica gel is the column silica gel for chromatography of 200~300 mesh.
7. the application of the camptothecine phosphonate ester compound as described in claims 1 to 3 any one, which is characterized in that application
In the drug of preparation treating cancer.
8. the application of the camptothecine phosphonate ester compound as claimed in claim 7, which is characterized in that the cancer packet
Include human liver cancer, human lung adenocarcinoma, human breast carcinoma or human mouth epidermoid carcinoma.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1656101A (en) * | 2002-05-31 | 2005-08-17 | 希格马托制药工业公司 | Esters in position 20 of camptothecins |
| CN101495153A (en) * | 2006-07-28 | 2009-07-29 | 尤兰德制药有限公司 | Drug delivery system based on regioselectively amidated hyaluronic acid |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1656101A (en) * | 2002-05-31 | 2005-08-17 | 希格马托制药工业公司 | Esters in position 20 of camptothecins |
| CN101495153A (en) * | 2006-07-28 | 2009-07-29 | 尤兰德制药有限公司 | Drug delivery system based on regioselectively amidated hyaluronic acid |
Non-Patent Citations (1)
| Title |
|---|
| Synthesis of a Macromolecular Camptothecin Conjugate with Dual Phase Drug Release;Yurkovetskiy, A. V et al.;《Molecular Pharmaceutics》;20040820;第375-382页 * |
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