CN102863472A - 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 PDF

Info

Publication number
CN102863472A
CN102863472A CN2012103888256A CN201210388825A CN102863472A CN 102863472 A CN102863472 A CN 102863472A CN 2012103888256 A CN2012103888256 A CN 2012103888256A CN 201210388825 A CN201210388825 A CN 201210388825A CN 102863472 A CN102863472 A CN 102863472A
Authority
CN
China
Prior art keywords
combretastatin
analogue
phosphoric acid
cancer
water
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.)
Granted
Application number
CN2012103888256A
Other languages
Chinese (zh)
Other versions
CN102863472B (en
Inventor
王鹏
李静
韩福国
戚欣
李明
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Ocean University of China
Original Assignee
Ocean University of China
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Ocean University of China filed Critical Ocean University of China
Priority to CN201210388825.6A priority Critical patent/CN102863472B/en
Publication of CN102863472A publication Critical patent/CN102863472A/en
Application granted granted Critical
Publication of CN102863472B publication Critical patent/CN102863472B/en
Expired - Fee Related legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Images

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

Combretastatin A-4 analogue and preparation method thereof and the application in the preparation antitumor drug
Technical field
The invention belongs to pharmaceutical field, related in particular to combretastatin A-4 analogue and preparation method thereof and the application in the preparation antitumor drug.
Background technology
The drug main of target tumor vascular system will be divided into two kinds at present: a kind of is the medicine that effectively stops growth and metastasis of tumours by the new vessel generation that suppresses tumour, be called tumor angiogenesis inhibitor (tumor angiogenesis inhibtor, TAI), another kind is the medicine that causes neoplasm necrosis by destroying the inside tumor blood vessel, be called vascular damaging agents (Vascular Disrupting Agent, VDA).
Vascular damaging agents is based on solid tumor blood vessel network confusion, not obvious, the vascular endothelial cell out-of-shape of classification, a series antineoplastic medicament that contacts each other the characteristics such as loose and develop, it can fast, optionally destroy the tumor vessel network of both having deposited, thereby causes the necrosis of tumour.On the mechanism of action, vascular damaging agents is by suppressing solid tumor vascular endothelial cell tubulin polymerization, change cytoskeletal structure, thereby cause the tumor vascular endothelial cell distortion, cause the inside tumor thrombosis, blocking-up inside tumor oxygen and the supply of nutrition and the discharge of cellular metabolism refuse, and then cause that the big area of solid tumor internal tumours cell is downright bad.At present, enter in numerous vascular damaging agents of clinical study the America and Europe, the sodium phosphate salt (CA1P) of the sodium phosphate salt of combretastatin A-4 (CA4P) and combretastatin A-1 demonstrates extraordinary DEVELOPMENT PROSPECT.CA4P has good anti-angiogenic activity, and the multiple noumenal tumours such as thyroid carcinoma, liver cancer, lung cancer are had significant curative effect, by the orphan medicine of drugs approved by FDA for the low differentiation for the treatment of thyroid carcinoma; CA1P is its compound that further changes structure, has entered the clinical study stage.Therefore development of new, compare the more efficient tumor vessel disrupting agent of CA4P still tool be of great significance.
Summary of the invention
Deficiency and defective for antitumor drug existence in the prior art, the invention provides combretastatin A-4 analogue and preparation method thereof and the application in the preparation antitumor drug, the present invention is according to the constructional feature of combretastatin class vascular damaging agents, the analog of CA4 is provided, and it is prepared into phosphoric acid salt, the good water solubility of this series phosphate derivative, bioavailability is high, can be as the antitumor drug that suppresses 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 shown in general formula (I):
Figure BDA00002255032500021
R wherein 1=-H, OH or metal phosphate substituting group, R 2=-OH or metal phosphate substituting group, described metal phosphate substituting group be-OP (O) is (ONa) 2,-OP (O) (OK) 2,-OP (O) (OLi) 2,-OP (O) O 2Zn or-OP (O) O 2Ca.
To further improvement in the technical proposal: described R 1And R 2In have one at least for the metal phosphate substituting group.
The present invention also provides the pharmaceutical composition that comprises described combretastatin A-4 analogue.
The present invention also provides the described combretastatin A-4 analogue that contains effective dose and the pharmaceutical composition of pharmaceutically acceptable vehicle.
The present invention also provides the preparation method of described combretastatin A-4 analogue, and it may further comprise the steps:
With 4-(3 ', 4 ', 5 '-trimethoxyphenyl)-5-(2 "; 3 "-dihydroxyl-4 " p-methoxy-phenyl)-oxazoles are dissolved in N; in the mixed solvent of dinethylformamide and acetonitrile; in protection of inert gas; under the cold condition; add successively tetracol phenixin; 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 respectively 1:5-15:0.1-0.5:2-8;
Then utilize bromotrimethylsilane to remove benzyl, with one or more react De Dao the phosphoric acid salt crude product of oxazole compounds in sodium methylate, potassium hydroxide, lithium hydroxide, zinc acetate and the calcium hydroxide, the phosphoric acid derivatives of Suo Shu De oxazole compounds and the mol ratio of bromotrimethylsilane are 1:4-8 again; The mol ratio of the phosphoric acid derivatives of Suo Shu De oxazole compounds and sodium methylate, potassium hydroxide, lithium hydroxide is 1:1-5; The mol ratio of the phosphoric acid derivatives of Suo Shu De oxazole compounds and zinc acetate, calcium hydroxide is 1:1-3;
Described phosphoric acid salt crude product is settled out in water/acetone, and crystallization Ji is Deed the phosphoric acid salt of oxazole compounds in water and ethanol again.
To further improvement in the technical proposal: described crude product is soluble in water, add acetone and settle out 3 times, the volume ratio of required acetone and water is 3-5:1, the crystallization in water and ethanol of gained crude product, the volume ratio of water and ethanol is 1:3-6.
The present invention also provides the purposes of described combretastatin A-4 analogue in preparation inhibition tubulin polymerization or antitumor drug.
The present invention also provides the purposes of described pharmaceutical composition in preparation inhibition tubulin polymerization or antitumor drug.
To further improvement in the technical proposal: described tumour is noumenal tumour, and 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 incidence squama cancer, nasopharyngeal carcinoma.
To further improvement in the technical proposal: wherein antineoplastic mechanism is to suppress the endotheliocyte tubulin polymerization, or by destroying the existing blood vessel effect of tumour.
Compared with prior art, advantage of the present invention and positively effect are:
The invention provides the combretastatin A-4 analogue, it by 4-(3 ', 4 ', 5 '-trimethoxyphenyl)-5-(2 ", 3 " dihydroxyl-4 "-p-methoxy-phenyls)-oxazoles react with dibenzyl phosphite and prepare.The good water solubility of this series phosphate derivative, bioavailability is high, can be as the antitumor drug that suppresses tubulin polymerization, target tumor blood vessel.
The present invention links to each other drug molecule and forms phosphate derivative with phosphate group, help drug molecule to intracellular transport, and has before entering drug target good stability and long transformation period; Phosphate prodrug can be hydrolyzed to female medicine by endogenic phosphoesterase in vivo and discharge, and makes hydrolysis have selectivity and cancer cells surface phosphoric acid esterase content is higher.Can improve water-soluble, the selectivity of drug molecule and toxic side effect and the untoward reaction that reduces medicine by the phosphate prodrug administration.
The present invention shows that by experiment the compound of similar combretastatin A4 can for the preparation of suppressing tubulin polymerization or antitumor drug, have a extensive future.
After reading the specific embodiment of the present invention by reference to the accompanying drawings, other characteristics of the present invention and advantage will become clearer.
Description of drawings
Fig. 1 be among the present invention CA-1H to the restraining effect of tubulin polymerization.
Fig. 2 be among the present invention CA-1H on the impact of HUVEC cellular form.
Fig. 3 is that the immunofluorescence detection of drugs is on the figure that affects of HUVEC microtubule among the present invention, 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 the immunofluorescence detection of drugs is on the figure that affects of HUVEC microfilament among the present invention, 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 CA-1H schemes the destruction of the existing tube chamber of HUVEC among the present invention.
Fig. 6 be among 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 Western blotting detects CA-1HP to the figure that affects of tubulin polymerization in the HUVEC among the present invention.
Fig. 8 is that CA-1HP causes the downright bad figure of NCI-H1975 Nude Mice organization internal among the present invention.
Fig. 9 is that CA-1HP causes the downright bad statistical graph of NCI-H1975 Nude Mice organization internal among the present invention.
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 by 4-(3 ', 4 ', 5 '-trimethoxyphenyl)-5-(2 ", 3 " dihydroxyl-4 "-p-methoxy-phenyls)-oxazoles react with dibenzyl phosphite and are prepared, concrete steps are as follows:
Figure BDA00002255032500051
Work as R in the 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)-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 shown in (II):
Figure BDA00002255032500052
Work as R in the formula (I) 1, R 2For-OPO 3Na 2The time, name be called 4-(3 ', 4 ', 5 '-trimethoxyphenyl)-5-(4 " p-methoxy-phenyl)-oxazole-2 ", 3 " referred to as CA-1HP, molecular formula is C for O, O-tetra-na diphosphate salt 19H 17NO 13Na 4P 2, molecular weight is 621.24, is pale solid; Its structural formula is shown in (III):
Figure BDA00002255032500053
Figure BDA00002255032500061
One, the preparation of sodium phosphate derivative of the present invention
With the 4-of 0.7mmol (3 '; 4 '; 5 '-trimethoxyphenyl)-5-(2 "; 3 "-dihydroxyl-4 " p-methoxy-phenyl)-oxazole is dissolved in 6mL N; and in the mixed solvent of dinethylformamide and 6mL acetonitrile; under argon shield, place-10 ℃ low-temperature reactor; drip the tetracol phenixin of 7mmol; stirs after 10 minutes; add the 0.15mmol Dimethylamino pyridine, after stirring 5 minutes, slowly drip the reaction of 4.2mmol dibenzyl phosphite, continue to react 2 hours; and reacted again 2 hours in-5 ℃; add 10mL potassium dihydrogen phosphate (0.5mol/L) termination reaction, and the reaction solution ethyl acetate extraction (3 * 50mL), the extraction liquid anhydrous sodium sulfate drying; concentrating under reduced pressure, silica gel column chromatography (petrol ether/ethyl acetate=2/1) gets white solid bisphosphate four benzyl derivatives of 0.5mmol.Rf=0.2 (petrol ether/ethyl acetate=2/1); 1H NMR (CDCl 3, 600MHz) 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 are dissolved in the 10mL methylene dichloride, drip the bromotrimethylsilane of 3.0mmol under the ice bath, reacted 45 minutes, (3 * 30mL) wash the white solid of underpressure distillation with sherwood oil, white solid is dissolved in the 10mL dehydrated alcohol, the sodium methylate (1mol/L) that adds the fresh preparation of 2mL, concentrating under reduced pressure, the solid of gained is dissolved in 10mL water, add 40mL acetone, separate out solid matter and filter, use again water-ethanol (volume ratio is 1:3-6) crystallization to obtain sodium phosphate derivative of the present invention (CA-1HP) gains. 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 ℃, can aggregate into microtubule in the time of 37 ℃, and its solution raises in time in the absorbancy (OD value) of 340nm, and reaches within a certain period of time plateau value.The medicine of interference microtubule polymerization can affect the variation of microtubule solution O D value.
The tubulin that adopts in the present invention's experiment is extracted from the 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 μ M, the final concentration of compound is 10 μ M, 1 μ M, 0.1 μ M does solvent control and positive control simultaneously.The temperature that microplate reader is set is 37 ℃, and the detection wavelength is 340nm, and the per minute mixing reads once, reads continuously 30min.Experimental result shows that CA-1H has obvious restraining effect to tubulin polymerization as shown in Figure 1.
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 cells, drug level is 1 μ M, establishes normal group, solvent control group (DMSO 0.1%), CA4 positive drug control group; Dosing begins to examine under a microscope cellular form and takes pictures after 0.5 hour, 1 hour, 2 hours.The results are shown in Figure 2.
As can be seen from Figure 2 the normal group cell is the paving stone shape and stretches, administration after 0.5 hour cell begin to shrink and become circle, after 1 hour, cellular contraction is more obvious after 2 hours, shows that described CA-1H can obviously affect the cellular form of HUVEC.
3, the impact of CA-1H Human Umbilical Vein Endothelial Cells skeleton
Spread slide to 24 orifice plates, with serum at 37 ℃ of coated 30min; Digestion HUVEC is with 2 * 10 4/ hole kind is to slide; Add medicine behind the cell attachment, drug level is 1 μ M, establishes blank, solvent control and positive drug CA4 contrast.Behind the drug effect 30min, suck substratum, wash 3 times with PBS; 4% Paraformaldehyde 96 is 30min fixedly, sucks Paraformaldehyde 96, and PBS washes 3 times; The 0.1% Triton-100 10min that punches sucks, and PBS washes 3 times; Add 1%BSA sealing 30min, suck, PBS washes 3 times; Add Tubulin antibody (Sigma company product, 1:500 dilution), 4 ℃ are spent the night; Add the anti-CY3(Sigma of actin antibody (Sigma company product, 1:500 dilution) and Tubulin two company product, the 1:1000 dilution), room temperature placement 30min takes pictures with confocal laser scanning microscope.The results are shown in Figure 3, Fig. 4.
Fig. 3 be medicine on the impact of cell microtubule, Fig. 4 is that medicine is on the impact of Microfilaments In Cells.As can be seen from Figure 3, microtubule becomes filamentary texture in the normal cell, and the microtubule network structure of cell is suffered destruction in various degree behind the drug effect 30min, presents disperse, spot distribution, and fluorescence intensity also weakens.As can be seen from Figure 4, microfilament is evenly distributed in the normal cell, and a small amount of microfilament has gathering across whole cell at the cell periphery.After adding medicine, the distribution of microfilament is significantly different, and a large amount of microfilaments form stress fiber and are gathered in the 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 at Matrigel, in order to simulate the blood vessel of tumor tissues.Endotheliocyte joined contains Matrigel(BD Biosciences company product) 96 orifice bores in, every hole 1.8 * 10 5Individual cell is cultivated for 37 ℃ and was formed complete tube chamber in 12 hours, and after the adding drug level is 1 μ M effect, chooses the unified visual field at each time point and take pictures, statistics tube chamber number, the inhibiting rate that tube chamber forms calculates with following formula:
Inhibiting rate (%)=(tube chamber is counted control wells-tube chamber and counted dosing holes)/tube chamber is counted control wells * 100%, and 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 that HUVEC forms, and acts on 9 hours destructive rates and reaches 83.59%.
5, CA-1HP is on the impact of tubulin polymerization in the HUVEC
The HUVEC that takes the logarithm vegetative period is inoculated in 6 orifice plates, and after cell attachment spent the night, adding respectively concentration was the CA-1HP of 10 μ M, 1 μ M, 0.1 μ M, establishes 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 the centrifuge tube with cell scraper, 37 ℃ 180, the centrifugal 1h of 000g, the tubulin of polymerization is precipitated to get off.Supernatant is transferred in the corresponding centrifuge tube, and every 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 buffer in the precipitation, heat 10min behind the mixing in the boiling water bath.Upper cleer and peaceful precipitation lysate is got respectively equivalent carry out Western blot detection tubulin polymerization situation.The results are shown in Figure the tubulin of the polymerization in 7, the P representative precipitation, S represents the tubulin of the depolymerization in the supernatant liquor.
As shown in Figure 7, compare with the blank group, CA-1HP can make P type microtubule obviously reduce, and S type microtubule increases, and shows that CA-1HP can cause that the tubulin of polymerized form in the cell depolymerizes to the tubulin of free form in dose-dependently ground.
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 gross tumor volume grows to about 100mm 3The time, the random packet administration, and physiological saline blank group, CA4P positive drug group are set, take off neck after the administration after 24 hours and put to death mouse, take out the NCI-H1975 tumor tissue; With tumor tissue with the OCT embedding ,-20 ℃ of frozen sections, HE dye (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).Microscopically is observed and is taken pictures.The results are shown in Figure 8, Fig. 9.
As shown in the figure, along with the increase tumor tissue necrosis area change of CA-1H dosage, when administration concentration is 100mg/kg, tumor group tissue necrosis area accounting is 80.5%, nucleus is cracked, dissolving, compares the border cell that CA-1HP more can the kill tumor tissue with CA4P.N=" necrosis ", V=" survival ".
Formula of the present invention (I) compound can be crystallization or setting thing form.Some crystallized form of formula (I) compound can exist with the polymorphic form form that is included in the scope of the present invention.The invention still further relates to for example pharmaceutical composition of carrier or thinner of the compounds of this invention that contains effective dose and pharmaceutically acceptable vehicle.
The corresponding preparations of the compounds of this invention can be used for treating various diseases and illness, comprises tubulin polymerization and various tumour, is particularly useful for treating various noumenal tumours and suppresses the 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 incidence squama cancer, nasopharyngeal carcinoma, includes but not limited to noumenal tumour.
In a word, the invention provides the compound of similar combretastatin A4, and it is prepared into diphosphate, the good water solubility of this series phosphate derivative, bioavailability is high, can be as the antitumor drug that suppresses tubulin polymerization, target tumor blood vessel.
Above embodiment is only in order to illustrating technical scheme of the present invention, but not limits it; Although with reference to previous embodiment the present invention is had been described in detail, for the person of ordinary skill of the art, still can make amendment to the technical scheme that previous embodiment is put down in writing, perhaps part technical characterictic wherein is equal to replacement; And these modifications or replacement do not make the essence of appropriate technical solution break away from the spirit and scope of the present invention's technical scheme required for protection.

Claims (10)

1. combretastatin A-4 analogue, it is characterized in that: its structure is shown in general formula (I):
(I)
R wherein 1=-H, OH or metal phosphate substituting group, R 2=-OH or metal phosphate substituting group, described metal phosphate substituting group be-OP (O) is (ONa) 2,-OP (O) (OK) 2,-OP (O) (OLi) 2,-OP (O) O 2Zn or-OP (O) O 2Ca.
2. combretastatin A-4 analogue according to claim 1 is characterized in that: described R 1And R 2In have one at least for the metal phosphate substituting group.
3. the pharmaceutical composition that comprises combretastatin A-4 analogue claimed in claim 1.
4. contain the combretastatin A-4 analogue claimed in claim 3 of effective dose and the pharmaceutical composition of pharmaceutically acceptable vehicle.
5. the preparation method of combretastatin A-4 analogue according to claim 1 is characterized in that may further comprise the steps:
With 4-(3 ', 4 ', 5 '-trimethoxyphenyl)-5-(2 "; 3 "-dihydroxyl-4 " p-methoxy-phenyl)-oxazoles are dissolved in N; in the mixed solvent of dinethylformamide and acetonitrile; in protection of inert gas; under the cold condition; add successively tetracol phenixin; 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 respectively 1:5-15:0.1-0.5:2-8;
Then utilize bromotrimethylsilane to remove benzyl, with one or more react De Dao the phosphoric acid salt crude product of oxazole compounds in sodium methylate, potassium hydroxide, lithium hydroxide, zinc acetate and the calcium hydroxide, the phosphoric acid derivatives of Suo Shu De oxazole compounds and the mol ratio of bromotrimethylsilane are 1:4-8 again; The mol ratio of the phosphoric acid derivatives of Suo Shu De oxazole compounds and sodium methylate, potassium hydroxide, lithium hydroxide is 1:1-5; The mol ratio of the phosphoric acid derivatives of Suo Shu De oxazole compounds and zinc acetate, calcium hydroxide is 1:1-3;
Described phosphoric acid salt crude product is settled out in water/acetone, and crystallization Ji is Deed the phosphoric acid salt of oxazole compounds in water and ethanol again.
6. the preparation method of combretastatin A-4 analogue according to claim 5, it is characterized in that: described crude product is soluble in water, add acetone and settle out 3 times, the volume ratio of required acetone and water is 3-5:1, the crystallization in water and ethanol of gained crude product, the volume ratio of water and ethanol are 1:3-6.
7. combretastatin A-4 analogue according to claim 1 is preparing the purposes that suppresses in tubulin polymerization or the antitumor drug.
8. pharmaceutical composition claimed in claim 3 is preparing the purposes that suppresses in tubulin polymerization or the antitumor drug.
According to claim 7 or 8 described preparations suppress purposes in tubulin polymerizations or the antitumor drug, it is characterized in that: described tumour is noumenal tumour, and 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 incidence squama cancer, nasopharyngeal carcinoma.
According to claim 7 or 8 described preparations suppress purposes in tubulin polymerizations or the antitumor drug, it is characterized in that: wherein antineoplastic mechanism is to suppress the endotheliocyte tubulin polymerization, or by destroying the existing blood vessel effect of tumour.
CN201210388825.6A 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 Expired - Fee Related CN102863472B (en)

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 true CN102863472A (en) 2013-01-09
CN102863472B 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)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104817519A (en) * 2015-05-11 2015-08-05 中国药科大学 CA-4 derivatives as well as preparation method and medical application of CA-4 derivatives
CN108088990A (en) * 2017-12-13 2018-05-29 杭州埃锐晶生物医学技术有限公司 For the pleiotropic cellular protein extract and preparation method of arrays of immobilized protein detection

Citations (2)

* Cited by examiner, † Cited by third party
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

Patent Citations (2)

* Cited by examiner, † Cited by third party
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)

* Cited by examiner, † Cited by third party
Title
SUI X. CAI: "Small Molecule Vascular Disrupting Agents: Potential New Drugs for Cancer Treatment", 《RECENT PATENTS ON ANTI-CANCER DRUG DISCOVERY》 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104817519A (en) * 2015-05-11 2015-08-05 中国药科大学 CA-4 derivatives as well as preparation method and medical application of CA-4 derivatives
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
CN108088990A (en) * 2017-12-13 2018-05-29 杭州埃锐晶生物医学技术有限公司 For the pleiotropic cellular protein extract and preparation method of arrays of immobilized protein detection

Also Published As

Publication number Publication date
CN102863472B (en) 2015-05-13

Similar Documents

Publication Publication Date Title
CN108578412A (en) A kind of taxol and diaza * and carbazole compound drug combination compositions
CN105452265B (en) Tamoxifen derivatives for treatment of neoplastic diseases, especially with high HER2 protein level
TWI515184B (en) An improved process for preparation of taxane derivatives
KR20040095342A (en) Angiogenesis inhibitors
CN107929276A (en) A kind of taxol and CDKS kinase inhibitor drug combination compositions
EA023804B1 (en) Oxabicycloheptanes, their preparation and use
CN108125944A (en) A kind of taxol and CDKS kinase inhibitor antineoplastic combination pharmaceutical compositions
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
EP1311514A1 (en) Compositions with vascular damaging activity
CN108727437A (en) One curcuminoids metal aryl complex and its synthetic method and application
CN102198125B (en) Purpose of phenethyl caffeate derivatives in preparation of medicines for inhibiting angiogenesis of tumors
CN101665518B (en) Phosphoryl carboxylic acid salinomycin ester derivative and preparing method thereof
CN101671369B (en) Phosphoryl methyl salinomycin ether derivative and preparation method thereof
CN115364109B (en) Pharmaceutical preparation for treating lung cancer
CN1807405A (en) Charles ketone oxime and its composition , preparation method and uses
KR20060119782A (en) Cancer treatment
Swamy et al. Taxol: occurrence, chemistry, and understanding its molecular mechanisms
CN107383015B (en) The application of amino-pyrazol simultaneously [3,4-d] pyrimidine derivatives and anti-non-small cell lung cancer of alkane sulphur end group widow PEG modification
CN107021942A (en) Bark extract of pinus fenzeliana var dabeshanensis and preparation method thereof and the purposes in pharmacy
CN104529974B (en) Barrenwort glycosides compounds and application thereof
CN103012358A (en) Compound extracted from antrodia camphorate, medical composition containing compound and application of compound
CN106619628A (en) Application of matrine derivatives in preparation of medicines for preventing or treating postmenopausal osteoporosis
CN108586410B (en) Biflavonoid compound and application thereof
CN102070608A (en) 4-substituted phenylamino-7-substituted alkoxy-quinazoline derivant and preparation method and application thereof
CN101781292B (en) E-ring substituted silybin derivative and preparation method and medical application thereof

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

Granted publication date: 20150513

Termination date: 20171015

CF01 Termination of patent right due to non-payment of annual fee