CN113549106B - Combretastatin derivative and preparation method and application thereof - Google Patents
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- 150000004814 combretastatins Chemical class 0.000 title claims abstract description 24
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- 150000001875 compounds Chemical class 0.000 claims abstract description 37
- PTMHPRAIXMAOOB-UHFFFAOYSA-N phosphoramidic acid Chemical class NP(O)(O)=O PTMHPRAIXMAOOB-UHFFFAOYSA-N 0.000 claims description 18
- 238000000034 method Methods 0.000 claims description 11
- 238000006243 chemical reaction Methods 0.000 claims description 10
- KMTRUDSVKNLOMY-UHFFFAOYSA-N Ethylene carbonate Chemical compound O=C1OCCO1 KMTRUDSVKNLOMY-UHFFFAOYSA-N 0.000 claims description 7
- 230000008569 process Effects 0.000 claims description 7
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical group CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 6
- 239000002246 antineoplastic agent Substances 0.000 claims description 6
- 229940041181 antineoplastic drug Drugs 0.000 claims description 6
- 239000003054 catalyst Substances 0.000 claims description 6
- 238000005859 coupling reaction Methods 0.000 claims description 6
- 150000007529 inorganic bases Chemical class 0.000 claims description 6
- 150000007530 organic bases Chemical class 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- 230000009471 action Effects 0.000 claims description 4
- 238000005886 esterification reaction Methods 0.000 claims description 4
- 230000003287 optical effect Effects 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 4
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims description 3
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical group Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 3
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- 238000010992 reflux Methods 0.000 claims description 3
- 238000000746 purification Methods 0.000 claims description 2
- 238000000926 separation method Methods 0.000 claims description 2
- 206010028980 Neoplasm Diseases 0.000 abstract description 15
- 239000003814 drug Substances 0.000 abstract description 8
- 230000000259 anti-tumor effect Effects 0.000 abstract description 7
- 229940079593 drug Drugs 0.000 abstract description 5
- 230000000694 effects Effects 0.000 abstract description 3
- 230000008685 targeting Effects 0.000 abstract description 3
- 210000004881 tumor cell Anatomy 0.000 abstract description 2
- 206010019851 Hepatotoxicity Diseases 0.000 abstract 1
- 230000007686 hepatotoxicity Effects 0.000 abstract 1
- 231100000304 hepatotoxicity Toxicity 0.000 abstract 1
- 238000004896 high resolution mass spectrometry Methods 0.000 description 16
- LGZKGOGODCLQHG-CYBMUJFWSA-N 5-[(2r)-2-hydroxy-2-(3,4,5-trimethoxyphenyl)ethyl]-2-methoxyphenol Chemical compound C1=C(O)C(OC)=CC=C1C[C@@H](O)C1=CC(OC)=C(OC)C(OC)=C1 LGZKGOGODCLQHG-CYBMUJFWSA-N 0.000 description 14
- LGZKGOGODCLQHG-UHFFFAOYSA-N combretastatin Natural products C1=C(O)C(OC)=CC=C1CC(O)C1=CC(OC)=C(OC)C(OC)=C1 LGZKGOGODCLQHG-UHFFFAOYSA-N 0.000 description 14
- 201000011510 cancer Diseases 0.000 description 9
- 210000004027 cell Anatomy 0.000 description 9
- 230000001093 anti-cancer Effects 0.000 description 5
- 231100000419 toxicity Toxicity 0.000 description 5
- 230000001988 toxicity Effects 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- PTMHPRAIXMAOOB-UHFFFAOYSA-L phosphoramidate Chemical compound NP([O-])([O-])=O PTMHPRAIXMAOOB-UHFFFAOYSA-L 0.000 description 4
- 102000004243 Tubulin Human genes 0.000 description 3
- 108090000704 Tubulin Proteins 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 238000000134 MTT assay Methods 0.000 description 2
- 231100000002 MTT assay Toxicity 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 238000002512 chemotherapy Methods 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- 210000003494 hepatocyte Anatomy 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 230000005918 in vitro anti-tumor Effects 0.000 description 2
- 210000005229 liver cell Anatomy 0.000 description 2
- 231100000053 low toxicity Toxicity 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 238000010791 quenching Methods 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 238000002390 rotary evaporation Methods 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 206010059866 Drug resistance Diseases 0.000 description 1
- 230000004668 G2/M phase Effects 0.000 description 1
- 208000005016 Intestinal Neoplasms Diseases 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 102000029749 Microtubule Human genes 0.000 description 1
- 108091022875 Microtubule Proteins 0.000 description 1
- BCXBKOQDEOJNRH-UHFFFAOYSA-N NOP(O)=O Chemical class NOP(O)=O BCXBKOQDEOJNRH-UHFFFAOYSA-N 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- -1 aminophosphonate derivative compounds Chemical class 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 208000036815 beta tubulin Diseases 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000025084 cell cycle arrest Effects 0.000 description 1
- 230000032823 cell division Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 206010017758 gastric cancer Diseases 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 210000005260 human cell Anatomy 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 201000002313 intestinal cancer Diseases 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 230000002147 killing effect Effects 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 210000004688 microtubule Anatomy 0.000 description 1
- 230000000394 mitotic effect Effects 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000041 toxicology testing Toxicity 0.000 description 1
- 239000003744 tubulin modulator Substances 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 Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/40—Esters thereof
- C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
- C07F9/4056—Esters of arylalkanephosphonic acids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/40—Esters thereof
- C07F9/4071—Esters thereof the ester moiety containing a substituent or a structure which is considered as characteristic
- C07F9/4075—Esters with hydroxyalkyl compounds
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- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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Abstract
The invention discloses a combretastatin derivative, a preparation method and application thereof. The combretastatin derivative synthesized by the invention has better anti-tumor activity on various tumor cell lines of human, wherein the tumor activity of the representative compound 3e is better than that of a positive drug CA-4, and the normal hepatotoxicity of the representative compound to human is obviously lower than that of CA-4, thus indicating the application of the compound 3e in the potential targeting treatment of tumor diseases.
Description
Technical Field
The invention belongs to the technical field of medicine synthesis, and relates to a combretastatin derivative, a preparation method and application thereof.
Background
In the modern development of medical technology, many diseases which are difficult to treat in the past have been overcome, however, the incidence rate and the mortality rate of cancers are continuously rising, and the life health of people is seriously threatened. Therefore, how to better treat cancers has become a great problem to be solved in the modern medicine world. The current clinical means for treating cancer mainly comprise chemotherapy, surgical treatment and radiotherapy. Chemotherapy is one of the indispensable options for most cancer patients because of its high efficacy, but it also has certain drawbacks such as lack of selectivity, serious toxic side effects and drug resistance. Therefore, the exploration of anticancer drugs with strong targeting, high curative effect and low toxicity has become a key scientific problem to be solved in the research of new generation anticancer drugs.
Tubulin is a protein polymer formed from heterodimers of alpha-tubulin and beta-tubulin, has a hollow tubular structure, and plays an important role in cell division, intracellular mass transport, signaling, maintenance of cell morphology, and the like. The disruption of microtubules can induce cell cycle arrest in the G2/M phase and form abnormal mitotic spindles, which become one of hot spot targets for development of antitumor drugs. Combretastatin (CA-4) is an anticancer drug which is separated and extracted from natural products and belongs to tubulin inhibitors, and is still in the three-phase clinical research stage at present. Research shows that CA-4 has excellent anticancer activity on various solid tumors of human, but has the defects of high toxicity, poor water solubility and the like, so that the development of novel CA-4 derivatives with high efficiency, targeting and low toxicity has important application value and academic significance.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide a combretastatin derivative, which can enhance the anti-tumor activity by introducing an aminophosphonate derivative with certain anti-tumor activity into the structure of a CA-4 analogue and optimizing the structure. It is another object of the present invention to provide a method for preparing the conjugate.
The invention is realized by the following technical scheme:
a combretastatin derivative has a structural general formula shown in formula I:
wherein R is 1 H, cl or OCH 3 ，R 2 H, F, cl, br, CH of a shape of H, F, cl, br, CH 3 Or OCH (optical wavelength) 3 N=1 or 3.
The invention further improves the scheme as follows:
a process for the preparation of combretastatin derivatives, comprising the steps of:
step one, reacting CA-4 with ethylene carbonate to obtain an intermediate (1);
step two, the intermediate (1) and the aminophosphonate derivative (2) are subjected to coupling reaction to obtain a formula (I);
the reaction equation is shown below:
wherein R is 1 H, cl or OCH 3 ，R 2 H, F, cl, br, CH of a shape of H, F, cl, br, CH 3 Or OCH (optical wavelength) 3 N=1 or 3.
The invention further improves the scheme as follows:
a process for the preparation of combretastatin derivatives, comprising the steps of:
dissolving CA-4 in DMF, and carrying out esterification reaction with ethylene carbonate under the protection of nitrogen under the action of inorganic base to obtain an intermediate (1) compound, wherein the compound consumption is calculated by the mass, and the CA-4: ethylene carbonate: inorganic base=1 (2-4): 2-4;
dissolving the aminophosphonate derivative (2) in DCM, and carrying out coupling reaction with the intermediate (1) under the action of organic base and catalyst to obtain the compound of the formula (I), wherein the compound consumption is calculated by mass, and the intermediate (1): aminophosphonate derivatives (2): organic base: catalyst=1 (1-1.2): 2-2.4): 1.5-1.8.
The invention further improves the scheme as follows:
in the first step, the inorganic base is anhydrous potassium carbonate, the esterification reaction temperature is between 90 and 110 ℃ and the reflux is carried out, and the reaction time is between 10 and 14 hours.
In the second step, the organic base is EDCI, the catalyst is DMAP, and the reaction time is 4-8 h under the ice bath condition that the temperature of the coupling reaction is-5 ℃.
Further, the method comprises the steps of separation and purification.
Furthermore, the combretastatin derivative is applied to preparing antitumor drugs.
The beneficial effects of the invention are as follows:
the invention utilizes the advantage of the anti-tumor activity of the aminophosphonate, and the anti-tumor activity of the aminophosphonate can be enhanced by introducing the aminophosphonate into the structure of the combretastatin analogue.
The combretastatin derivative disclosed by the invention has better anti-tumor activity on various tumor cell lines of human, wherein the anti-tumor activity of a representative compound 3e is better than that of a positive drug CA-4, and the toxicity of the representative compound on normal liver cells of the human is obviously lower than that of the positive drug CA-4, so that the compound 3e has the potential targeted application of treating tumor diseases.
Detailed Description
The structural general formula of the combretastatin derivative provided by the invention is shown in formula I:
the synthetic route is as follows:
wherein R is 1 H, cl or-OCH 3 ，R 2 Is H, F, cl, br, -CH 3 or-OCH 3 N=1 or 3.
Examples 1 to 16
The aminophosphonate derivative compounds 2 used in examples 1 to 16 are shown in Table 1,
TABLE 1 selection of aminophosphonate derivatives 2
| Sequence number | n | R 1 | R 2 |
| Example 1 (3 a) | 1 | H | H |
| Example 2 (3 b) | 1 | H | F |
| Example 3 (3 c) | 1 | H | Cl |
| Example 4 (3 d) | 1 | H | Br |
| Example 5 (3 e) | 1 | H | OCH 3 |
| Example 6 (3 f) | 1 | H | CH 3 |
| Example 7 (3 g) | 1 | OCH 3 | H |
| Example 8 (3 h) | 1 | Cl | H |
| Example 9 (3 i) | 3 | H | H |
| Example 10 (3 j) | 3 | H | F |
| Example 11 (3 k) | 3 | H | Cl |
| Example 12 (3 l) | 3 | H | Br |
| Example 13 (3 m) | 3 | H | OCH 3 |
| Example 14 (3 n) | 3 | H | CH 3 |
| Example 15 (3 o) | 3 | OCH 3 | H |
| Example 16 (3 p) | 3 | Cl | H |
The preparation method comprises the following specific steps:
(1) Preparation of intermediate 1
CA-4 (2.85 g,9.0 mmol) was dissolved in 10mL DMF, ethylene carbonate (2.38 g,27.0 mmol) was added, and finally anhydrous potassium carbonate (3.72 g,27.0 mmol) was added, heated to 100deg.C under nitrogen protection, and reacted under reflux for 12h. After the reaction was completed, ice water was added to the reaction mass to quench the reaction mass, the reaction mass was placed in a 125mL separatory funnel, 50mL of water, 50mL of DCM and a small amount of aqueous NaCl solution were added to extract, the organic layer was collected, repeated 3 times, the organic phase was dried over anhydrous sodium sulfate, DCM was removed by rotary evaporation, and column chromatography was performed to obtain intermediate 1 (1.66 g, 51.2%). 1 H NMR(600MHz,CDCl 3 )δ6.90(dd,J＝8.3,1.9Hz,1H),6.85(d,J＝2.0Hz,1H),6.77(d,J＝8.3Hz,1H),6.50(s,2H),6.48(d,J＝12.1Hz,1H),6.45(d,J＝12.1Hz,1H),3.91(t,J＝4.5Hz,2H),3.84-3.83(m,5H),3.82(s,3H),3.70(s,6H). 13 C NMR(150MHz,CDCl 3 )δ152.99,148.95,147.47,137.09,132.95,130.08,129.48,129.05,123.00,115.20,111.30,105.91,71.10,61.11,60.93,55.98,55.86.
(2) Preparation of midepstein derivatives
Aminophosphonate derivative 2 (150 mg,0.321 mmol) was dissolved in 5mL of CM, EDCI (123 mg, 0.640 mmol) and DMAP (59 mg, 0.480 mmol) were added, and finally intermediate 1 (100 mg,0.289 mmol) was added and reacted for 6h under ice-bath reaction conditions. And judging the end point of the reaction by adopting a TCL thin layer analysis method. After the reaction is finished, adding ice water to the reactant to quench the reaction, placing the reactant into a 125mL separating funnel, adding 50mL of water, 50mL of LDCM and a small amount of NaCl aqueous solution for extraction, collecting an organic layer, repeating for 3 times, drying the organic phase by using anhydrous sodium sulfate, removing DCM by rotary evaporation, and separating by column chromatography to obtain the combretastatin derivative.
CA-4 of the present invention is synthesized according to the report of document [ European Journal of Medicinal Chemistry,2012,56:166-178 ].
The data for the combretastatin derivatives produced in examples 1 to 16 are as follows:
example 1:143mg, yield:68.5%. 1 H NMR(400MHz,CDCl 3 )δ7.45(d,J＝7.4Hz,2H),7.32(t,J＝7.4Hz,2H),7.26-7.23(m,1H),6.99(d,J＝8.3Hz,2H),6.91-6.88(m,1H),6.82(d,J＝1.8Hz,1H),6.76(d,J＝8.3Hz,1H),6.52(d,J＝8.5Hz,2H),6.50(s,2H),6.45(d,J＝2.9Hz,2H),4.72(d,J＝24.3Hz,1H),4.33-4.31(m,2H),4.13-4.07(m,2H),4.02-4.00(m,2H),3.95-3.84(m,2H),3.81(s,3H),3.79(s,3H),3.67(s,7H),3.46(s,2H),1.27(t,J＝7.0Hz,3H),1.10(t,J＝7.0Hz,3H). 13 C NMR(100MHz,CDCl 3 )δ171.97,152.99,149.02,147.45,145.44,145.29,137.17,135.87,132.89,130.06,129.96,129.48,129.02,128.62,127.97,127.94,127.81,127.86,123.49,122.91,114.94,113.92,111.74,105.97,67.07,63.35,63.28,62.91,60.89,56.86,56.00,55.96,55.36,40.08,16.47,16.22.HR-MS(m/z)(ESI):calcd for C 39 H 46 NO 10 P[M+H] + :720.2938；found:720.2946.
Example 2:150mg, yield:70.3%. 1 H NMR(400MHz,CDCl 3 )δ7.42-7.41(m,2H),7.06(d,J＝19.4Hz,1H),7.00(d,J＝8.5Hz,3H),6.89(d,J＝8.3Hz,1H),6.82(s,1H),6.76(d,J＝8.2Hz,1H),6.51-6.49(m,3H),6.45(d,J＝1.8Hz,2H),4.70(d,J＝24.2Hz,1H),4.33–4.31(m,2H),4.13-4.07(m,2H),4.02-3.97(m,2H),3.96-3.86(m,2H),3.81(s,3H),3.80(s,3H),3.67(s,6H),3.46(s,2H),1.27(t,J＝7.0Hz,3H),1.13(t,J＝7.0Hz,3H). 13 C NMR(100MHz,CDCl 3 )δ171.95,152.99,149.01,147.44,145.23,145.08,137.17,132.88,131.62,130.12,129.96,129.47,129.40,129.03,123.72,122.92,115.71,115.50,114.92,113.92,111.73,105.97,67.07,63.41,63.27,62.94,60.88,56.18,56.00,55.95,54.67,40.06,16.46,16.26.HR-MS(m/z)(ESI):calcd for C 39 H 45 FNO 10 P[M+H] + :738.2843；found:738.2872.
Example 3:139mg, yield:63.9%. 1 H NMR(400MHz,CDCl 3 )δ7.39(d,J＝8.4Hz,2H),7.29(d,J＝8.3Hz,2H),7.00(d,J＝8.3Hz,2H),6.91-6.88(m,1H),6.82(d,J＝1.7Hz,1H),6.76(d,J＝8.3Hz,1H),6.50(s,2H),6.48(d,J＝8.5Hz,2H),6.45(d,J＝2.9Hz,2H),4.69(d,J＝24.4Hz,1H),4.33-4.31(m,2H),4.15-4.07(m,2H),4.02-3.99(m,2H),3.97-3.86(m,2H),3.81(s,3H),3.80(s,3H),3.67(s,6H),3.47(s,2H),1.28(t,J＝7.0Hz,3H),1.15(t,J＝7.0Hz,3H). 13 C NMR(100MHz,CDCl 3 )δ171.92,152.99,149.01,147.44,145.15,145.01,137.17,134.58,133.77,132.88,130.13,129.96,129.47,129.17,129.11,129.03,128.83,123.82,122.93,114.93,113.92,111.74,105.97,67.08,63.48,63.39,62.94,60.89,56.34,56.00,55.96,54.85,40.06,16.47,16.28.HR-MS(m/z)(ESI):calcd for C 39 H 45 ClNO 10 P[M+H] + :754.2548；found:754.2587.
Example 4:161mg, yield:69.7%. 1 H NMR(400MHz,CDCl 3 )δ7.44(d,J＝6.8Hz,2H),7.32(d,J＝5.8Hz,2H),6.99(d,J＝7.0Hz,2H),6.89(d,J＝8.0Hz,1H),6.81(d,J＝1.7Hz,1H),6.76(d,J＝8.1Hz,1H),6.49(s,2H),6.45(d,J＝2.5Hz,2H),6.34-6.26(m,2H),4.66(d,J＝24.4Hz,1H),4.31-4.25(m,2H),4.14-4.06(m,2H),4.03-3.96(d,J＝3.4Hz,2H),3.94-3.82(m,2H),3.80(s,3H),3.79(s,3H),3.67(s,6H),3.46(s,2H),1.27(t,J＝7.0Hz,3H),1.12(t,J＝7.0Hz,3H). 13 C NMR(100MHz,CDCl 3 )δ171.92,162.63,152.99,149.05,147.44,145.14,144.09,137.17,135.12,132.89,131.74,130.14,129.97,129.51,129.47,129.03,123.83,122.94,121.91,114.93,113.93,111.75,105.98,67.08,63.51,63.42,62.94,60.89,56.41,56.01,55.97,54.91,40.06,16.47,16.29.HR-MS(m/z)(ESI):calcd for C 39 H 45 BrNO 10 P[M+H] + :798.2043；found:798.2067.
Example 5:156mg, yield:72.1%. 1 H NMR(400MHz,CDCl 3 )δ7.37-7.34(m,2H),6.99(d,J＝8.4Hz,2H),6.90-6.88(m,1H),6.85(d,J＝8.6Hz,2H),6.82(d,J＝1.7Hz,1H),6.76(d,J＝8.3Hz,1H),6.52(d,J＝8.7Hz,2H),6.49(s,2H),6.45(d,J＝3.0Hz,2H),4.66(d,J＝23.8Hz,1H),4.33-4.21(m,2H),4.12-4.06(m,2H),4.02-4.00(m,2H),3.94-3.86(m,2H),3.81(s,3H),3.79(s,3H),3.76(s,3H),3.67(s,6H),3.46(s,2H),1.27(t,J＝7.1Hz,3H),1.12(t,J＝7.1Hz,3H). 13 C NMR(100MHz,CDCl 3 )δ172.03,159.32,152.99,149.01,147.45,145.49,145.34,137.16,132.89,130.04,129.96,129.48,129.02,128.92,127.62,123.43,122.91,114.93,114.,111.74,105.97,67.08,63.30,63.23,62.91,60.89,56.15,56.00,55.95,55.23,54.64,40.09,16.48,16.29.HR-MS(m/z)(ESI):calcd for C 40 H 48 NO 11 P[M+H] + :750.3043；found:750.3030.
Example 6:137mg, yield:64.7%. 1 H NMR(400MHz,CDCl 3 )δ7.27(d,J＝2.2Hz,2H),7.23(d,J＝3.7Hz,1H),7.20(d,J＝7.5Hz,1H),7.07(d,J＝6.7Hz,1H),7.01(d,J＝8.2Hz,2H),6.91(d,J＝8.1Hz,1H),6.84(d,J＝1.2Hz,1H),6.77(d,J＝8.3Hz,1H),6.54(d,J＝8.4Hz,2H),6.51(s,2H),6.47(d,J＝2.9Hz,2H),4.69(d,J＝24.3Hz,1H),4.35-4.33(m,2H),4.14-4.08(m,2H),4.04-4.02(m,2H),3.95-3.88(m,2H),3.83(s,3H),3.81(s,3H),3.69(s,6H),3.48(s,2H),2.34(s,3H),1.29(t,J＝7.0Hz,3H),1.12(t,J＝7.0Hz,3H). 13 C NMR(100MHz,CDCl 3 )δ172.00,152.99,149.01,147.45,145.54,145.40,138.23,137.17,135.75,132.89,130.06,129.96,129.48,129.02,128.81,128.47,128.41,124.98,123.40,122.91,114.94,113.89,111.74,105.97,67.08,63.35,63.26,62.92,60.89,56.82,56.00,55.96,55.33,40.09,21.47,16.46,16.20.HR-MS(m/z)(ESI):calcd for C 40 H 48 NO 10 P[M+H] + :734.3094；found:734.3071.
Example 7:155mg, yield:71.3%. 1 H NMR(400MHz,CDCl 3 )δ7.25-7.21(m,1H),7.03(d,J＝7.6Hz,1H),6.99(d,J＝7.8Hz,2H),6.89(d,J＝8.0Hz,1H),6.81(d,J＝8.9Hz,2H),6.77(d,J＝4.3Hz,1H),6.73(d,J＝13.0Hz,1H),6.53(d,J＝8.2Hz,2H),6.49(s,2H),6.45(d,J＝2.5Hz,2H),4.68(d,J＝24.3Hz,1H),4.33-4.31(m,2H),4.13-4.07(m,2H),4.02-4.00(m,2H),3.95-3.90(m,2H),3.81(s,3H),3.79(s,3H),3.77(s,3H),3.67(s,6H),3.46(s,2H),1.28(t,J＝7.0Hz,3H),1.12(t,J＝7.0Hz,3H). 13 C NMR(100MHz,CDCl 3 )δ171.98,159.82,152.99,149.02,147.45,145.49,145.38,137.55,137.16,132.89,130.06,130.06,129.95,129.59,129.48,129.01,123.51,122.91,120.25,114.94,113.91,113.50,113.42,111.73,105.97,67.08,63.40,63.32,62.92,60.88,56.90,56.00,55.95,55.40,55.22,40.09,16.47,16.25.HR-MS(m/z)(ESI):calcd for C 40 H 48 NO 11 P[M+H] + :750.3043；found:750.3032.
Example 8:136mg, yield:62.3%. 1 H NMR(400MHz,CDCl 3 )δ7.40-7.38(m,2H),7.30(d,J＝8.3Hz,2H),7.00(d,J＝8.5Hz,2H),6.91-6.88(m,1H),6.82(d,J＝1.9Hz,1H),6.76(d,J＝8.3Hz,1H),6.50(s,2H),6.48(s,2H),6.47(d,J＝2.9Hz,2H),6.46(d,J＝2.6Hz,2H),4.69(d,J＝24.5Hz,1H),4.34-4.31(m,2H),4.13-4.07(m,2H),4.03-4.01(m,2H),3.99-3.85(m,2H),3.81(s,3H),3.80(s,3H),3.68(s,6H),3.47(s,2H),1.28(t,J＝7.1Hz,3H),1.15(t,J＝7.1Hz,3H). 13 C NMR(100MHz,CDCl 3 )δ171.92,152.99,149.09,147.63,145.19,145.00,137.17,134.57,133.78,132.88,130.13,129.96,129.46,129.16,129.11,129.03,128.83,123.82,122.92,114.93,113.92,111.73,105.97,67.08,63.48,63.39,62.94,60.89,56.34,56.00,55.96,54.84,40.06,16.46,16.28.HR-MS(m/z)(ESI):calcd for C 39 H 45 ClNO 10 P[M+H] + :754.2548；found:754.2572.
Example 9: 1599 mg, yield:73.5%. 1 H NMR(400MHz,CDCl 3 )δ7.45(d,J＝7.4Hz,2H),7.31(t,J＝7.4Hz,2H),7.26-7.21(m,1H),6.89(s,2H),6.80(d,J＝1.9Hz,1H),6.73(d,J＝8.3Hz,1H),6.51(s,2H),6.48(d,J＝11.6Hz,2H),6.45(d,J＝3.6Hz,2H),4.72(d,J＝24.2Hz,1H),4.32-4.29(m,2H),4.15-4.07(m,2H),4.01-3.98(m,2H),3.95-3.89(m,2H),3.81(s,3H),3.76(s,3H),3.67(s,6H),2.46(t,J＝7.5Hz,2H),2.27(t,J＝7.5Hz,2H),1.86-1.78(m,2H),1.27(t,J＝7.1Hz,3H),1.10(t,J＝7.1Hz,3H). 13 C NMR(100MHz,CDCl 3 )δ173.44,152.98,148.97,147.43,144.55,144.40,137.16,136.03,132.89,131.24,129.90,129.49,129.19,128.99,128.59,127.89,127.83,122.86,114.76,113.95,111.63,105.97,67.07,63.30,63.23,62.49,60.88,57.02,55.96,55.91,55.52,34.14,33.44,26.66,16.46,16.22.HR-MS(m/z)(ESI):calcd for C 41 H 50 NO 10 P[M+H] + :748.3251；found:748.3243.
Example 10:155mg, yield:70.1%. 1 H NMR(400MHz,CDCl 3 )δ7.44-7.41(m,2H),7.01(t,J＝8.5Hz,2H),6.89(d,J＝7.9Hz,3H),6.82(s,1H),6.74(d,J＝8.3Hz,1H),6.50(s,2H),6.48(d,J＝11.6Hz,2H),6.45(d,J＝2.9Hz,2H),4.70(d,J＝24.1Hz,1H),4.32-4.30(m,2H),4.13-4.07(m,2H),4.01-3.99(m,2H),3.97-3.86(m,2H),3.81(s,3H),3.77(s,3H),3.68(s,6H),2.47(t,J＝7.4Hz,2H),2.28(t,J＝7.5Hz,2H),1.86-1.79(m,2H),1.27(t,J＝7.0Hz,3H),1.14(t,J＝7.0Hz,3H). 13 C NMR(100MHz,CDCl 3 )δ173.44,152.99,147.54,144.33,144.18,137.17,132.89,131.79,131.47,129.91,129.50,129.44,129.36,129.24,129.00,122.87,115.68,115.46,114.76,113.95,111.62,105.97,67.08,63.40,63.28,62.50,60.88,56.35,55.96,55.91,54.84,34.13,33.42,26.63,16.46,16.31.HR-MS(m/z)(ESI):calcd for C 41 H 59 FNO 10 P[M+H] + :766.3156；found:766.3166.
Example 11:142mg, yield:62.7%. 1 H NMR(400MHz,CDCl 3 )δ7.40-7.38(m,2H),7.29(d,J＝8.3Hz,2H),6.90-6.87(m,3H),6.82(d,J＝1.8Hz,1H),6.74(d,J＝8.3Hz,1H),6.50(s,2H),6.48(d,J＝2.4Hz,2H),6.45(d,J＝3.5Hz,2H),4.69(d,J＝24.3Hz,1H),4.32-4.30(m,2H),4.14-4.07(m,2H),4.01-3.94(m,2H),4.01-3.99(m,2H),3.81(s,3H),3.77(s,3H),3.68(s,6H),2.47(t,J＝7.5Hz,2H),2.28(t,J＝7.5Hz,2H),1.87-1.79(m,2H),1.27(t,J＝7.1Hz,3H),1.15(t,J＝7.0Hz,3H). 13 C NMR(100MHz,CDCl 3 )δ173.43,152.98,148.96,147.39,144.32,144.09,137.16,134.73,133.70,132.89,131.56,129.90,129.48,129.25,129.19,129.00,128.79,122.87,114.75,113.95,111.62,105.97,67.07,63.49,63.34,62.50,60.88,56.49,55.96,55.91,55.00,34.13,33.42,26.63,16.46,16.27.HR-MS(m/z)(ESI):calcd for C 41 H 59 ClNO 10 P[M+H] + :782.2861；found:782.2865.
Example 12:166mg, yield:69.4%. 1 H NMR(400MHz,CDCl 3 )δ7.45(d,J＝8.3Hz,2H),7.35(d,J＝2.2Hz,1H),7.33(d,J＝2.2Hz,1H),6.91-6.88(m,3H),6.83(d,J＝1.8Hz,1H),6.75(d,J＝8.3Hz,1H),6.50(s,2H),6.48(d,J＝4.4Hz,2H),6.45(d,J＝2.9Hz,2H),4.67(d,J＝24.4Hz,1H),4.33-4.30(m,2H),4.16-4.07(m,2H),4.02-4.00(m,2H),3.97-3.86(m,2H),3.82(s,3H),3.78(s,3H),3.68(s,6H),2.47(t,J＝7.5Hz,2H),2.29(t,J＝7.5Hz,2H),1.87-1.80(m,2H),1.28(t,J＝7.1Hz,3H),1.16(t,J＝7.1Hz,3H). 13 C NMR(100MHz,CDCl 3 )δ173.43,152.99,148.96,147.43,144.23,144.08,137.17,135.27,132.89,131.74,131.58,129.91,129.53,129.48,129.26,129.00,122.88,121.84,114.76,114.00,111.62,105.97,67.08,63.49,63.45,62.51,60.89,56.58,55.97,55.92,55.08,34.13,33.43,26.64,16.47,16.29.HR-MS(m/z)(ESI):calcd for C 41 H 59 BrNO 10 P[M+H] + :826.2356；found:826.2393.
Example 13:165mg, yield 73.3%. 1 H NMR(400MHz,CDCl 3 )δ7.37(d,J＝2.1Hz,1H),7.35(d,J＝2.2Hz,1H),6.88(d,J＝8.4Hz,3H),6.85(d,J＝8.6Hz,2H),6.82(d,J＝1.7Hz,1H),6.74(d,J＝8.3Hz,1H),6.51(d,J＝2.0Hz,1H),6.50(s,2H),6.48(d,J＝8.0Hz,1H),6.45(d,J＝3.6Hz,2H),4.67(d,J＝23.8Hz,1H),4.32-4.30(m,2H),4.12-4.07(m,2H),4.01-3.99(m,2H),3.97-3.86(m,2H),3.81(s,3H),3.76(s,3H),3.76(s,3H),3.68(s,6H),2.46(t,J＝7.5Hz,2H),2.28(t,J＝7.5Hz,2H),1.86-1.79(m,2H),1.27(t,J＝7.1Hz,3H),1.13(t,J＝7.1Hz,3H). 13 C NMR(100MHz,CDCl 3 )δ173.45,159.27,152.98,148.97,147.43,144.59,144.44,137.16,132.89,131.19,129.90,129.48,129.17,128.99,128.93,127.80,122.86,114.78,114.05,113.98,111.62,105.97,67.08,63.24,63.17,62.49,60.88,56.32,55.95,55.91,55.21,54.81,34.15,33.45,26.67,16.48,16.29.HR-MS(m/z)(ESI):calcd for C 42 H 52 NO 11 P[M+H] + :778.3356；found:778.3396.
Example 14:138mg, yield:62.7%. 1 H NMR(400MHz,CDCl 3 )δ7.34(d,J＝1.9Hz,1H),7.32(d,J＝2.0Hz,1H),7.12(d,J＝7.8Hz,2H),6.89-6.84(d,J＝8.2Hz,3H),6.82(d,J＝3.6Hz,1H),6.73(d,J＝8.3Hz,1H),6.51(d,J＝1.4Hz,2H),6.50(s,2H),6.45(d,J＝3.6Hz,2H),4.68(d,J＝24.0Hz,1H),4.32-4.30(m,2H),4.13-4.07(m,2H),4.01-3.99(m,2H),3.96-3.86(m,2H),3.81(s,3H),3.76(s,3H),3.67(s,6H),2.46(t,J＝7.5Hz,2H),2.31(s,3H),2.27(t,J＝7.5Hz,2H),1.86-1.78(m,2H),1.27(t,J＝7.1Hz,3H),1.12(t,J＝7.1Hz,3H). 13 C NMR(100MHz,CDCl 3 )δ173.53,153.13,148.97,147.51,144.62,144.67,137.57,137.16,132.90,131.17,129.90,129.49,129.32,129.17,128.99,127.76,127.64,122.93,114.83,113.96,111.58,105.97,67.08,63.26,63.18,62.49,60.89,56.71,55.96,55.91,55.21,34.15,33.46,26.67,21.14,16.47,16.26.HR-MS(m/z)(ESI):calcd for C 42 H 52 NO 10 P[M+H] + :762.3407；found:762.3437.
Example 15:155mg, yield:68.9%. 1 H NMR(400MHz,CDCl 3 )δ7.22(t,J＝7.9Hz,1H),7.05-7.01(m,2H),6.88(d,J＝8.1Hz,3H),6.82(s,1H),6.78(d,J＝8.3Hz,1H),6.73(d,J＝8.3Hz,1H),6.51(d,J＝8.2Hz,2H),6.49(s,2H),6.45(d,J＝3.7Hz,2H),4.69(d,J＝24.2Hz,1H),4.32-4.31(m,2H),4.13-4.07(m,2H),4.01-3.99(m,2H),3.96-3.85(m,2H),3.81(s,3H),3.76(s,3H),3.73(s,3H),3.67(s,6H),2.46(t,J＝7.4Hz,2H),2.28(t,J＝7.4Hz,2H),1.86-1.79(m,2H),1.27(t,J＝7.0Hz,3H),1.12(t,J＝7.0Hz,3H). 13 C NMR(100MHz,CDCl 3 )δ173.45,159.79,152.98,148.97,147.43,144.60,144.45,137.72,137.16,132.93,131.27,129.89,129.56,129.49,129.19,128.99,122.86,120.29,114.77,113.94,113.46,113.37,111.62,105.97,67.08,63.33,63.26,62.49,60.88,57.07,55.96,55.90,55.58,55.22,34.15,33.46,26.68,16.47,16.25.HR-MS(m/z)(ESI):calcd for C 42 H 52 NO 11 P[M+H] + :778.3356；found:778.3320.
Example 16:167mg, yield:73.7%. 1 H NMR(400MHz,CDCl 3 )δ7.43(d,J＝2.3Hz,1H),7.35(d,J＝6.9Hz,1H),7.28-7.22(m,2H),6.91(d,J＝8.2Hz,2H),6.88(d,J＝1.6Hz,1H),6.83(d,J＝1.5Hz,1H),6.74(d,J＝8.3Hz,1H),6.50(s,2H),6.49(d,J＝8.7Hz,2H),6.45(d,J＝3.6Hz,2H),4.69(d,J＝24.5Hz,1H),4.33-4.21(m,2H),4.14-4.09(m,2H),4.02-3.97(m,2H),3.82(s,3H),3.77(s,3H),3.68(s,6H),2.48(t,J＝7.5Hz,2H),2.29(t,J＝7.4Hz,2H),1.88-1.80(m,2H),1.28(t,J＝7.1Hz,3H),1.15(t,J＝7.1Hz,3H). 13 C NMR(100MHz,CDCl 3 )δ173.43,152.98,148.96,147.37,144.31,144.09,138.50,137.16,134.53,132.89,131.59,129.90,129.85,129.49,129.28,128.99,128.13,127.96,126.01,122.87,114.75,113.90,111.62,105.97,67.07,63.50,63.41,62.50,60.88,56.70,55.96,55.90,55.21,34.13,33.44,26.65,16.45,16.22.HR-MS(m/z)(ESI):calcd for C 41 H 59 ClNO 10 P[M+H] + :782.2861；found:782.2856.
Test example 1
In vitro antitumor Activity study of Compounds 3a-3p prepared in examples 1 to 16.
In order to investigate whether the compounds 3a-3p prepared by the invention have a better killing effect on cancer cells, MTT assay experiments were used for studying, and the results are shown in Table 2. As can be seen from Table 2, the compounds 3a-3p have good toxicity to HepG-2 (liver cancer), HT29 (intestinal cancer), A549 (lung cancer) and MGC-803 (stomach cancer), and some of the compounds such as 3e, 3g and 3l show good anticancer activity, and their IC 50 The values are all smaller than 1 mu M, wherein the anticancer activity of the compound 3e is obviously better than that of other compounds and the positive drug CA-4, and the IC of the compound is applied to the cancer cell HepG-2 50 The value was 0.36. Mu.M; IC for cancer cell HT29 50 The value was 0.31. Mu.M; IC for cancer cell A549 50 The value was 0.19. Mu.M; IC for cancer cell MGC-803 50 The value was 0.42. Mu.M; analysis of the structure of the target compound shows that in the 3i-3p compound, compared with the compound in which the C-4 position of the benzene ring is substituted by halogen, the compound is substituted by-OCH 3 and-CH 3 The substituted compounds 3e and 3f have better in-vitro anti-tumor activity, and in the compound 3i-3p, the phenomenon that the C-4 position of the benzene ring of aminophosphonate is subjected to-OCH also exists 3 and-CH 3 The substituted 3l and 3m are also more active than the halogen substituted 3j, 3h and 3k, indicating the incorporation of-OCH at the para-position of the benzene ring 3 and-CH 3 Is a correct choice. The anticancer activity of the compound 3e is obviously better than that of other compounds compared with the positive control medicine combretastatin.
TABLE 2 IC of Compounds 3a-3p against human cancer cell lines tested 50 Values.
Test example 2
Toxicity study of the Compounds 3a to 3p prepared in examples 1 to 16 on human normal hepatocytes.
In order to investigate the toxicity of the compounds 3a to 3p prepared in the present invention to normal human cells, they were tested by MTT assay, and the results are shown in Table 3. According to Table 3, it was found that the toxicity of the target compounds 3a-3p to human normal hepatocytes was lower than that of the positive drug CA-4 (IC 50 =3.27±0.82 μm) low, IC thereof 50 The values range from 9.33 to 20.14. Mu.M. In addition, compound 3e (IC) 50 The experimental result further shows that the amino phosphonate derivative is introduced into the framework of CA-4, so that the anticancer activity can be improved, and the toxicity of the compound to normal cells can be reduced, thereby indicating that the compound has better selectivity to cancer cells.
TABLE 3 IC of Compounds 3a-3p against human Normal liver cell LO2 50 Values.
Claims (7)
1. The combretastatin derivative is characterized by having a structural general formula shown in a formula (I):
wherein R is 1 H, cl or OCH 3 ，R 2 H, F, cl is a,Br、CH 3 Or OCH (optical wavelength) 3 N=1 or 3.
2. A process for the preparation of combretastatin derivatives as claimed in claim 1, characterized in that it comprises the following steps:
step one, reacting CA-4 with ethylene carbonate to obtain an intermediate (1);
step two, the intermediate (1) and the aminophosphonate derivative (2) are subjected to coupling reaction to obtain a formula (I);
the reaction equation is shown below:
wherein R is 1 H, cl or OCH 3 ，R 2 H, F, cl, br, CH of a shape of H, F, cl, br, CH 3 Or OCH (optical wavelength) 3 N=1 or 3.
3. A process for the preparation of combretastatin derivatives as claimed in claim 2, characterized in that: the method comprises the following steps:
dissolving CA-4 in DMF, and carrying out esterification reaction with ethylene carbonate under the protection of nitrogen under the action of inorganic base to obtain an intermediate (1) compound, wherein the compound consumption is calculated by the mass, and the CA-4: ethylene carbonate: inorganic base=1 (2-4): 2-4;
dissolving the aminophosphonate derivative (2) in DCM, and carrying out coupling reaction with the intermediate (1) under the action of organic base and catalyst to obtain the compound of the formula (I), wherein the compound consumption is calculated by mass, and the intermediate (1): aminophosphonate derivatives (2): organic base: catalyst=1 (1-1.2): 2-2.4): 1.5-1.8.
4. A process for the preparation of combretastatin derivatives as claimed in claim 3, characterized in that: in the first step, the inorganic base is anhydrous potassium carbonate, the esterification reaction temperature is between 90 and 110 ℃ and the reflux is carried out, and the reaction time is between 10 and 14 hours.
5. A process for the preparation of combretastatin derivatives as claimed in claim 3, characterized in that: in the second step, the organic base is EDCI, the catalyst is DMAP, and the reaction time is 4-8 h under the ice bath condition that the temperature of the coupling reaction is-5 ℃.
6. A process for the preparation of combretastatin derivatives as claimed in claim 3, characterized in that: the method also comprises the steps of separation and purification.
7. The use of a combretastatin derivative as claimed in claim 1 for the preparation of antitumor drugs.
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| CN101220054A (en) * | 2008-01-29 | 2008-07-16 | 成都恒基医药科技有限公司 | Method for preparing Combretastatin A-4 phosphoric acid ester disodium salt |
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| CN101220054A (en) * | 2008-01-29 | 2008-07-16 | 成都恒基医药科技有限公司 | Method for preparing Combretastatin A-4 phosphoric acid ester disodium salt |
| CN112209990A (en) * | 2020-11-10 | 2021-01-12 | 上海科技大学 | Combretastatin derivative and antibody drug conjugate thereof |
Non-Patent Citations (2)
| Title |
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| Xiaochao Huang等.Synthesis and biological evaluation of novel millepachine derivative containing aminophosphonate ester species as novel anti-tubulin agents.《Bioorganic Chemistry》.2019,第第94卷卷第103486页. * |
| Xiaochao Huang等.Synthesis, mechanisms of action, and toxicity of novel aminophosphonates derivatives conjugated irinotecan in vitro and in vivo as potent antitumor agents.《European Journal of Medicinal Chemistry》.2020,第第189卷卷第112067页. * |
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