CN102863472B - Combretastatin A-4 analogue, preparation method of combretastatin A-4 analogue and application of combretastatin A-4 analogue in preparing anti-tumor drugs - Google Patents
Combretastatin A-4 analogue, preparation method of combretastatin A-4 analogue and application of combretastatin A-4 analogue in preparing anti-tumor drugs Download PDFInfo
- Publication number
- CN102863472B CN102863472B CN201210388825.6A CN201210388825A CN102863472B CN 102863472 B CN102863472 B CN 102863472B CN 201210388825 A CN201210388825 A CN 201210388825A CN 102863472 B CN102863472 B CN 102863472B
- Authority
- CN
- China
- Prior art keywords
- combretastatin
- analogue
- metal phosphate
- tumor
- preparation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Abstract
The invention provides a combretastatin A-4 analogue. The structure of the combretastatin A-4 analogue is represented by general formula (I), wherein R1 represents -H, OH or a metal phosphate substituent group, R2 represents -OH or the metal phosphate substituent group, and the metal phosphate substituent group is -OP(O)(ONa)2, -OP(O)(OK)2, -OP(O)(OLi)2, -OP(O) O2Zn or -OP(O) O2Ca. A pharmacology experiment shows that the combretastatin A-4 analogue can inhibit polymerization of endothelial cell tubulin, damage forming of lumens and lead to tumour organization center necrosis, and the combretastatin A-4 analogue can be applied in anti-solid tumor drugs or in tumor vessel breakers and is wide in application prospects.
Description
Technical field
The invention belongs to pharmaceutical field, particularly related to combretastatin A-4 analogue and preparation method thereof and prepared the application in antitumor drug.
Background technology
The drug main of current target tumor vascular system will be divided into two kinds: a kind of is generated by the new vessel of Tumor suppression and effectively stop the medicine of growth and metastasis of tumours, be called tumor angiogenesis inhibitor (tumor angiogenesis inhibtor, TAI), another kind is the medicine causing neoplasm necrosis by destroying inside tumor blood vessel, be called vascular damaging agents (Vascular Disrupting Agent, VDA).
Vascular damaging agents is based on solid tumor blood vessel network is chaotic, classification is not obvious, vascular endothelial cell out-of-shape, contact the feature such as loose each other and the series antineoplastic medicament developed, it can fast, optionally destroy the tumor vessel network both deposited, thus causes the necrosis of tumour.In the mechanism of action, vascular damaging agents is by suppressing solid tumor vascular endothelial cell tubulin polymerization, change cytoskeletal structure, thus cause tumor vascular endothelial cell to be out of shape, cause inside tumor thrombosis, block inside tumor oxygen and the supply of nutrition and the discharge of cellular metabolism refuse, and then cause the big area of solid tumor internal tumours cell downright bad.At present, enter in numerous vascular damaging agents of clinical study America and Europe, the sodium phosphate salt (CA4P) of combretastatin A-4 and the sodium phosphate salt (CA1P) of combretastatin A-1 demonstrate extraordinary DEVELOPMENT PROSPECT.CA4P has excellent anti-angiogenic effect, has significant curative effect, be approved as orphan's medicine for the treatment of low differentiation thyroid carcinoma by U.S. FDA to multiple noumenal tumours such as thyroid carcinoma, liver cancer, lung cancer; CA1P is that it changes the compound of structure further, enters clinical investigation phase.Therefore development of new, compare the more efficient tumor vessel disrupting agent of CA4P still tool be of great significance.
Summary of the invention
The deficiency existed for antitumor drug in prior art and defect, the invention provides combretastatin A-4 analogue and preparation method thereof and preparing the application in antitumor drug, the present invention is according to the constructional feature of combretastatin class vascular damaging agents, the analog of CA4 is provided, and be prepared into phosphoric acid salt, the good water solubility of this serial phosphate derivative, bioavailability is high, can as the antitumor drug suppressing tubulin polymerization, target tumor blood vessel.
For achieving the above object, the present invention adopts following technical proposals to be achieved:
A kind of combretastatin A-4 analogue, its structure is as shown in general formula (I):
Wherein R
1=-H, OH or metal phosphate substituting group, R
2=-OH or metal phosphate substituting group, described metal phosphate substituting group is-OP (O) (ONa)
2,-OP (O) (OK)
2,-OP (O) (OLi)
2,-OP (O) O
2zn or-OP (O) O
2ca.
Further improvement to technique scheme: described R
1and R
2in have one at least for metal phosphate substituting group.
Present invention also offers the pharmaceutical composition comprising described combretastatin A-4 analogue.
Present invention also offers the pharmaceutical composition containing the combretastatin A-4 analogue described in effective dose and pharmaceutically acceptable vehicle.
Present invention also offers the preparation method of described combretastatin A-4 analogue, it comprises the following steps:
By 4-(3 ', 4 ', 5 '-trimethoxyphenyl)-5-(2 ", 3 "-dihydroxyl-4 "-p-methoxy-phenyls)-oxazoles are dissolved in N, in the mixed solvent of dinethylformamide and acetonitrile, in protection of inert gas, under cold condition, add tetracol phenixin successively, the phosphoric acid derivatives of Dimethylamino pyridine and dibenzyl phosphite reaction Bei oxazole compounds processed, described 4-(3 ', 4 ', 5 '-trimethoxyphenyl)-5-(2 ", 3 "-dihydroxyl-4 "-p-methoxy-phenyls)-oxazoles, tetracol phenixin, Dimethylamino pyridine, the mol ratio of dibenzyl phosphite is 1:5-15:0.1-0.5:2-8 respectively,
Then bromotrimethylsilane is utilized to remove benzyl, again with in sodium methylate, potassium hydroxide, lithium hydroxide, zinc acetate and calcium hydroxide, one or more instead should obtain the phosphoric acid salt crude product of oxazole compounds, the phosphoric acid derivatives of the oxazole compounds stated and the mol ratio of bromotrimethylsilane are 1:4-8; The mol ratio of the phosphoric acid derivatives of Suo Shu oxazole compounds and sodium methylate, potassium hydroxide, lithium hydroxide is 1:1-5; The mol ratio of the phosphoric acid derivatives of Suo Shu oxazole compounds and zinc acetate, calcium hydroxide is 1:1-3;
Described phosphoric acid salt crude product is settled out in water/acetone, then in water and ethanol crystallization and the phosphoric acid salt of oxazole compounds of get ing.
Further improvement to technique scheme: by soluble in water for described crude product, adds acetone and settles out 3 times, and the volume ratio of required acetone and water is 3-5:1, the crystallization in water and ethanol of gained crude product, and the volume ratio of water and ethanol is 1:3-6.
Present invention also offers the purposes of described combretastatin A-4 analogue in preparation suppression tubulin polymerization or antitumor drug.
Present invention also offers the purposes of described pharmaceutical composition in preparation suppression tubulin polymerization or antitumor drug.
Further improvement to technique scheme: described tumour is noumenal tumour, described noumenal tumour is lung cancer, kidney, mammary cancer, cancer of the stomach, Kaposi's sarcoma, colorectal carcinoma, liver cancer, prostate cancer, thyroid carcinoma, neuroblastoma, ovarian cancer or G. cephalantha, nasopharyngeal carcinoma.
Further improvement to technique scheme: wherein antineoplastic mechanism suppresses endotheliocyte tubulin polymerization, or act on by destroying the existing blood vessel of tumour.
Compared with prior art, advantage of the present invention and positively effect are:
The invention provides combretastatin A-4 analogue, it is reacted by 4-(3 ', 4 ', 5 '-trimethoxyphenyl)-5-(2 ", 3 "-dihydroxyl-4 "-p-methoxy-phenyls)-oxazoles and dibenzyl phosphite and prepares.The good water solubility of this serial phosphate derivative, bioavailability is high, can as the antitumor drug suppressing tubulin polymerization, target tumor blood vessel.
Drug molecule and phosphate group are connected to form phosphate derivative by the present invention, contribute to drug molecule to intracellular transport, and before entering drug target, have good stability and longer transformation period; Phosphate prodrug can be hydrolyzed to female medicine by endogenic phosphoesterase in vivo and discharge, and cancer cell surfaces phosphoesterase content is higher makes hydrolysis have selectivity.Water-soluble, the selectivity of drug molecule can be improved by phosphate prodrug administration and reduce toxic side effect and the untoward reaction of medicine.
The present invention shows that the compound of similar combretastatin A4 for the preparation of suppression tubulin polymerization or antitumor drug, can have a extensive future by experiment.
After reading the specific embodiment of the present invention by reference to the accompanying drawings, the other features and advantages of the invention will become clearly.
Accompanying drawing explanation
Fig. 1 be in the present invention CA-1H to the restraining effect of tubulin polymerization.
Fig. 2 be in the present invention CA-1H on the impact of HUVEC cellular form.
Fig. 3 is that in the present invention, Immunofluorescence test medicine is to the effect diagram of HUVEC microtubule, and wherein upper left is blank, and upper right is solvent control, and bottom left is CA4, and bottom right is CA-1H.
Fig. 4 is that in the present invention, Immunofluorescence test medicine is to the effect diagram of HUVEC microfilament, and wherein upper left is blank, and upper right is solvent control, and bottom left is CA4, and bottom right is CA-1H.
Fig. 5 is that in the present invention, CA-1H schemes the destruction of the existing tube chamber of HUVEC.
Fig. 6 be in the present invention CA-1H to the destructive rate statistical graph of the existing tube chamber of HUVEC at each time point.
Fig. 7 is that in the present invention, Western blotting detects CA-1HP to the effect diagram of tubulin polymerization in HUVEC.
Fig. 8 is that in the present invention, CA-1HP causes NCI-H1975 Nude Mice organization internal necrosis figure.
Fig. 9 is that in the present invention, CA-1HP causes the downright bad statistical graph of NCI-H1975 Nude Mice organization internal.
Embodiment
Below in conjunction with the drawings and specific embodiments, technical scheme of the present invention is described in further detail.
Embodiment 1
The compound of similar combretastatin A4 of the present invention is by 4-(3 ', 4 ', 5 '-trimethoxyphenyl)-5-(2 ", 3 "-dihydroxyl-4 "-p-methoxy-phenyls)-oxazoles and dibenzyl phosphite react and be prepared, and concrete steps are as follows:
R is worked as in Chinese style of the present invention (I)
1, R
2during for-OH, name is called 4-(3 ', 4 ', 5 '-trimethoxyphenyl)-5-(2 ", 3 "-dihydroxyl-4 "-p-methoxy-phenyls) and-oxazole, referred to as CA-1H, molecular formula is C
19h
19nO
7, molecular weight is 373.36, is faint yellow solid; Its structural formula is as shown in (II):
R is worked as in formula (I)
1, R
2for-OPO
3na
2time, name is called 4-(3 ', 4 ', 5 '-trimethoxyphenyl)-5-(4 "-p-methoxy-phenyl)-oxazole-2 ", 3 "-O, O-tetra-na diphosphate salt, referred to as CA-1HP, molecular formula is C
19h
17nO
13na
4p
2, molecular weight is 621.24, is pale solid; Its structural formula is as shown in (III):
One, the preparation of sodium phosphate derivative of the present invention
By the 4-(3 ' of 0.7mmol, 4 ', 5 '-trimethoxyphenyl)-5-(2 ", 3 "-dihydroxyl-4 "-p-methoxy-phenyls)-oxazoles are dissolved in 6mL N, in the mixed solvent of dinethylformamide and 6mL acetonitrile, the low-temperature reactor of-10 DEG C is placed under argon shield, drip the tetracol phenixin of 7mmol, stir after 10 minutes, add 0.15mmol Dimethylamino pyridine, slowly drip the reaction of 4.2mmol dibenzyl phosphite after stirring for 5 min, continue reaction 2 hours, and react 2 hours again in-5 DEG C, add 10mL potassium dihydrogen phosphate (0.5mol/L) termination reaction, reaction solution is extracted with ethyl acetate (3 × 50mL), extraction liquid anhydrous sodium sulfate drying, concentrating under reduced pressure, silica gel column chromatography (petrol ether/ethyl acetate=2/1) obtains white solid bisphosphate four benzyl derivatives of 0.5mmol.Rf=0.2 (petrol ether/ethyl acetate=2/1);
1h NMR (CDCl
3, 600MHz) and δ 7.93 (s, 1H, H-2), 7.19-7.28 (m, 17H, Ph-H), 7.04-7.06 (m, 4H, Ph-H), 6.90 (d, J=8.8Hz, 1H, Ph-H), 6.8 8 (s, 2H, Ph-H), 5.14-5.19 (m, 4H, Ph-CH
2), 4.78-4.81 (m, 2H, Ph-CH
2), 4.69-4.72 (m, 2H, Ph-CH
2), 3.86 (s, 3H, OCH
3), 3.76 (s, 3H, OCH
3), 3.69 (s, 6H, OCH
3× 2);
13c NMR (D
2o, 150MHz) δ 153.8 (C-3 '), 153.2 (C-5 '), 150.2 (C-2), 141.2,137.7,136.2,135.7,135.7,135.3,135.2,128.4,128.4,128.4,128.1,127.9,127.8,116.2,109.6 (C-1 "); 103.8 (C-2 ', C-6 '), 69.8 (Ph-CH
2), 60.8 (OCH
3-4 '), 56.5 (OCH
3-4 "), 56.0 (OCH
3-3 ', OCH
3-5 ').
Described bisphosphate four benzyl derivatives of 0.5mmol is dissolved in 10mL methylene dichloride, the bromotrimethylsilane of 3.0mmol is dripped under ice bath, react 45 minutes, the white solid of underpressure distillation washs with sherwood oil (3 × 30mL), white solid is dissolved in 10mL dehydrated alcohol, add the sodium methylate (1mol/L) of the fresh preparation of 2mL, concentrating under reduced pressure, the solid of gained is dissolved in 10mL water, add 40mL acetone, precipitation solid matter filters, and is used by gains water-ethanol (volume ratio is 1:3-6) crystallization to obtain sodium phosphate derivative (CA-1HP) of the present invention again.
1H NMR(CDCl
3,600MHz)δ8.24(s,1H，H-2)，6.91(s,1H,Ph-H),6.83(d,J=8.8Hz,1H,Ph-H),6.78(s,1H,Ph-H),6.73(t,J=8.8Hz,1H,Ph-H),3.86(s,3H,OCH
3),3.72(s,3H,OCH
3),3.71(s,3H,OCH
3),3.66(d,J＝5.5Hz,3H,OCH
3)。
Two, the pharmacological evaluation of sodium phosphate derivative of the present invention
1, CA-1H vitro inhibition tubulin polymerization activity experiment
Tubulin solution is colourless transparent liquid at 0-4 DEG C, can aggregate into microtubule 37 DEG C time, and its solution raises in time in the absorbancy (OD value) of 340nm, and reaches plateau value within a certain period of time.The medicine of interference microtubule polymerization can affect the change of microtubule solution O D value.
The tubulin adopted in the present invention's experiment is extracted from pig brain.Polymerization system is: tubulin glycerine-MES solution (0.1mM MES, 1mM EGTA, 0.5mM MgCl
2, 1mM GTP now adds, 4M glycerine) and be diluted to concentration 12 μMs, the final concentration of compound is 10 μMs, 1 μM, 0.1 μM, does solvent control and positive control simultaneously.The temperature arranging microplate reader is 37 DEG C, and determined wavelength is 340nm, and per minute mixing is read once, reads 30min continuously.Experimental result as shown in Figure 1, shows that CA-1H has obvious restraining effect to tubulin polymerization.
2, CA-1H is on the impact of HUVEC form
Digestion HUVEC, with 2000 cells/well kinds in 96 orifice plates; The adherent rear dosing of 24 hour cell, drug level is 1 μM, if normal group, solvent control group (DMSO 0.1%), CA4 positive drug control group; Dosing starts to examine under a microscope cellular form after 0.5 hour, 1 hour, 2 hours and takes pictures.The results are shown in Figure 2.
As can be seen from Figure 2 normal group cell is that paving stone shape stretches, and administration 0.5 hours later cell starts to shrink and becomes circle, and after 1 hour, 2 hours later cell shrink more obvious, show that described CA-1H obviously can affect the cellular form of HUVEC.
3, the impact of CA-1H Human Umbilical Vein Endothelial Cells skeleton
Paving slide, to 24 orifice plates, wraps by 30min at 37 DEG C with serum; Digestion HUVEC, with 2 × 10
4/ hole kind is on slide; Add medicine after cell attachment, drug level is 1 μM, if blank, solvent control and positive drug CA4 contrast.After drug effect 30min, suck substratum, wash 3 times with PBS; 4% paraformaldehyde fixes 30min, sucks paraformaldehyde, and PBS washes 3 times; 0.1% Triton-100 punching 10min, suck, PBS washes 3 times; Add 1%BSA and close 30min, suck, PBS washes 3 times; Add Tubulin antibody (Sigma Products, 1:500 dilutes), 4 DEG C are spent the night; Add actin antibody (Sigma Products, 1:500 dilutes) and the anti-CY3(Sigma Products of Tubulin bis-, 1:1000 dilutes), room temperature places 30min, takes pictures with confocal laser scanning microscope.The results are shown in Figure 3, Fig. 4.
Fig. 3 is the impact of medicine on cellular microtubules, and Fig. 4 is the impact of medicine on Microfilaments In Cells.As can be seen from Figure 3, in normal cell, microtubule becomes filamentary texture, and after drug effect 30min, the microtubular network structure of cell suffers destruction in various degree, and present disperse, spot distribution, fluorescence intensity also weakens.As can be seen from Figure 4, in normal cell, microfilament is evenly distributed, and a small amount of microfilament, across whole cell, has gathering at cell periphery.After adding medicine, the distribution of microfilament is significantly different, and a large amount of microfilament forms stress fiber and is gathered in cell periphery, and the fluorescence at this position is obviously strengthened.Show that CA-1H can destroy the skeleton structure of endotheliocyte.
4, CA-1H is to the breaking test of the existing tube chamber of HUVEC
HUVEC can form tube chamber on Matrigel, in order to simulate the blood vessel of tumor tissues.Endotheliocyte is joined containing Matrigel(BD Biosciences Products) 96 orifice bores in, every hole 1.8 × 10
5individual cell, 37 DEG C of cultivations form complete tube chamber in 12 hours, and adding drug level is after 1 μM of effect, chooses the unified visual field take pictures at each time point, statistics tube chamber number, and the inhibiting rate of segment dislocation is with following formulae discovery:
Inhibiting rate (%)=(tube chamber number control wells-tube chamber number dosing holes)/tube chamber number control wells × 100%, this contrast is the control group tube chamber number of corresponding time point.
The results are shown in Figure 5, Fig. 6.Show that CA-1H can destroy the tube chamber of HUVEC formation, act on 9 hours destructive rates and reach 83.59%.
5, CA-1HP is on the impact of tubulin polymerization in HUVEC
The HUVEC taken the logarithm vegetative period, is inoculated in 6 orifice plates, after cell attachment spends the night, adds the CA-1HP that concentration is 10 μMs, 1 μM, 0.1 μM respectively, if blank, CA4P positive control.After 2 hours, every hole adds 100 μ L lysate (1mM EGTA, 1mM MgSO
4, 30% glycerine, 5%DMSO, 5mM GTP, 1% NP-40,0.1M PIPES pH 6.9), be collected in centrifuge tube with cell scraper, 37 DEG C of 180,000g centrifugal 1h, the tubulin of polymerization is precipitated to get off.Be transferred to by supernatant in corresponding centrifuge tube, often pipe adds 30 μ L 4 × SDS sample-loading buffer (200mM Tris pH 6.8,400mMDTT, 8% SDS, 0.4% tetrabromophenol sulfonphthalein, 40% glycerine), add 130 μ L 1 × SDS sample-loading buffers in precipitation, after mixing, in boiling water bath, heat 10min.Upper cleer and peaceful precipitation lysate is got respectively equivalent and carry out Western blot detection tubulin polymerization situation.The results are shown in Figure the tubulin of the polymerization in 7, P representative precipitation, S represents the tubulin of the depolymerization in supernatant liquor.
As shown in Figure 7, compared with blank group, CA-1HP can make P type microtubule obviously reduce, and S type microtubule increases, and shows that CA-1HP can dose-dependently cause the tubulin of polymerized form in cell to be depolymerized to the tubulin of free form.
6, CA-1HP causes the inner necrosis of tumor tissues
Nonsmall-cell lung cancer Iressa drug-resistant cell strain NCI-H1975 is inoculated in the right oxter of nude mouse, treats that tumor volume growth is to about 100mm
3time, random packet administration, and physiological saline blank group, CA4P positive drug group are set, after administration, after 24 hours, de-neck puts to death mouse, takes out NCI-H1975 tumor tissue; Embedded with OCT by tumor tissue ,-20 DEG C of frozen sections, HE dyes (Hematorylin is chemical reagents corporation of traditional Chinese medicines group product, and eosin W or W S is Shanghai San'aisi Reagent Co., Ltd.'s product).Basis of microscopic observation is also taken pictures.The results are shown in Figure 8, Fig. 9.
As shown in the figure, along with the increase tumor tissue necrosis area of CA-1H dosage increases, when administration concentration is 100mg/kg, tumor group tissue necrosis area accounting is 80.5%, nucleus is cracked, dissolving, and compared with CA4P, CA-1HP more can kill the border cell of tumor tissues.N=" necrosis ", V=" survival ".
Formula (I) compound can be crystallization or setting thing form.Some crystallized form of formula (I) compound can exist with the polymorphic Form be included in the scope of the present invention.The invention still further relates to the compounds of this invention containing effective dose and the pharmaceutically acceptable excipients pharmaceutical composition as carrier or thinner.
The corresponding preparations of the compounds of this invention can be used for treatment various diseases and illness, comprises tubulin polymerization and various tumour, is particularly useful for treating various noumenal tumour and suppressing endotheliocyte tubulin polymerization.Described noumenal tumour refers to lung cancer, kidney, mammary cancer, cancer of the stomach, Kaposi's sarcoma, colorectal carcinoma, liver cancer, prostate cancer, thyroid carcinoma, neuroblastoma, ovarian cancer and G. cephalantha, nasopharyngeal carcinoma, includes but not limited to noumenal tumour.
In a word, the invention provides the compound of similar combretastatin A4, and be prepared into diphosphate, the good water solubility of this serial phosphate derivative, bioavailability is high, can as the antitumor drug suppressing tubulin polymerization, target tumor blood vessel.
Above embodiment only in order to technical scheme of the present invention to be described, but not is limited; Although with reference to previous embodiment to invention has been detailed description, for the person of ordinary skill of the art, still can modify to the technical scheme described in previous embodiment, or equivalent replacement is carried out to wherein portion of techniques feature; And these amendments or replacement, do not make the essence of appropriate technical solution depart from the spirit and scope of the present invention's technical scheme required for protection.
Claims (5)
1. a combretastatin A-4 analogue, is characterized in that: its structure is as shown in general formula (I):
Wherein R
1=OH or metal phosphate substituting group, R
2=-OH or metal phosphate substituting group, described metal phosphate substituting group is-OP (O) (ONa)
2,-OP (O) (OK)
2,-OP (O) (OLi)
2,-OP (O) O
2zn or-OP (O) O
2ca;
Described R
1and R
2in have one at least for metal phosphate substituting group.
2. comprise the pharmaceutical composition of combretastatin A-4 analogue according to claim 1.
3. containing the combretastatin A-4 analogue according to claim 2 of effective dose and the pharmaceutical composition of pharmaceutically acceptable vehicle.
4. combretastatin A-4 analogue according to claim 1 suppresses the purposes in tubulin polymerization or antitumor drug in preparation.
5. pharmaceutical composition according to claim 2 suppresses the purposes in tubulin polymerization or antitumor drug in preparation.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210388825.6A CN102863472B (en) | 2012-10-15 | 2012-10-15 | Combretastatin A-4 analogue, preparation method of combretastatin A-4 analogue and application of combretastatin A-4 analogue in preparing anti-tumor drugs |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210388825.6A CN102863472B (en) | 2012-10-15 | 2012-10-15 | Combretastatin A-4 analogue, preparation method of combretastatin A-4 analogue and application of combretastatin A-4 analogue in preparing anti-tumor drugs |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102863472A CN102863472A (en) | 2013-01-09 |
| CN102863472B true CN102863472B (en) | 2015-05-13 |
Family
ID=47442630
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201210388825.6A Expired - Fee Related CN102863472B (en) | 2012-10-15 | 2012-10-15 | Combretastatin A-4 analogue, preparation method of combretastatin A-4 analogue and application of combretastatin A-4 analogue in preparing anti-tumor drugs |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102863472B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104817519B (en) * | 2015-05-11 | 2016-11-16 | 中国药科大学 | The derivant of one class CA-4, its preparation method and medical usage thereof |
| CN108088990B (en) * | 2017-12-13 | 2020-12-22 | 非因生物科技(山东)有限公司 | Pleiotropic cell protein extracting solution for protein microarray detection and preparation method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101230074A (en) * | 2008-01-29 | 2008-07-30 | 中国海洋大学 | Phosphate derivative of oxazole compounds and preparation method thereof |
| CN101230079A (en) * | 2008-01-29 | 2008-07-30 | 中国海洋大学 | 1,2-glycoside transderivative of oxazole compounds and preparation method thereof |
-
2012
- 2012-10-15 CN CN201210388825.6A patent/CN102863472B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101230074A (en) * | 2008-01-29 | 2008-07-30 | 中国海洋大学 | Phosphate derivative of oxazole compounds and preparation method thereof |
| CN101230079A (en) * | 2008-01-29 | 2008-07-30 | 中国海洋大学 | 1,2-glycoside transderivative of oxazole compounds and preparation method thereof |
Non-Patent Citations (1)
| Title |
|---|
| Small Molecule Vascular Disrupting Agents: Potential New Drugs for Cancer Treatment;Sui X. Cai;《Recent Patents on Anti-Cancer Drug Discovery》;20071231;第2卷(第1期);第82、84、85页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102863472A (en) | 2013-01-09 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN105452265B (en) | Tamoxifen derivatives for treatment of neoplastic diseases, especially with high HER2 protein level | |
| Xu et al. | Design, synthesis and biological evaluation of pyridine-chalcone derivatives as novel microtubule-destabilizing agents | |
| CN100531732C (en) | Thiomolybdate analogues | |
| KR20040095342A (en) | Angiogenesis inhibitors | |
| JP6465989B2 (en) | Isothiocyanate compounds and uses thereof | |
| CN108578412A (en) | A kind of taxol and diaza * and carbazole compound drug combination compositions | |
| EP2849743B1 (en) | Cancer cell inhibitory drug and cancer stem-cell detection probe | |
| Huang et al. | Discovery of dehydroabietic acid sulfonamide based derivatives as selective matrix metalloproteinases inactivators that inhibit cell migration and proliferation | |
| CN102863472B (en) | Combretastatin A-4 analogue, preparation method of combretastatin A-4 analogue and application of combretastatin A-4 analogue in preparing anti-tumor drugs | |
| EP1311514B1 (en) | Compositions with vascular damaging activity | |
| CN114380864A (en) | Dihydroartemisinin derivative, preparation method, pharmaceutical composition and application of dihydroartemisinin derivative in preparation of antitumor drugs | |
| CN108976187B (en) | Substituted benzofuran derivative, preparation thereof and application thereof in preparation of antitumor drugs | |
| CN101665518B (en) | Phosphoryl carboxylic acid salinomycin ester derivative and preparing method thereof | |
| CN101671369B (en) | Phosphoryl methyl salinomycin ether derivative and preparation method thereof | |
| KR101748229B1 (en) | 2,2'-bis-thiazole-based compounds, preparation method therefor and use thereof | |
| KR20060119782A (en) | Cancer treatment | |
| CN104529974B (en) | Barrenwort glycosides compounds and application thereof | |
| CN103012358A (en) | Compound extracted from antrodia camphorate, medical composition containing compound and application of compound | |
| CN101092336B (en) | Compound in cinnamic alcohol category, preparation method and usage | |
| CN105998018A (en) | Application of pirfenidone derivative to pharmacy | |
| CN1872041A (en) | Medicine use of 3 (3 nitryl 4 hydroxy)- ethyl acrylate controlled xanthine oxidase | |
| CN104940177B (en) | Medical application of vine flavone F | |
| CN101781292B (en) | E-ring substituted silybin derivative and preparation method and medical application thereof | |
| CN101648973B (en) | Water-soluble taxane and preparation method thereof | |
| CN107325031A (en) | A kind of benzophenone containing selenium and its derivative and preparation method and the application in antineoplastic is prepared |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20150513 Termination date: 20171015 |