CN113549106A - Combretastatin derivative and preparation method and application thereof - Google Patents
Combretastatin derivative and preparation method and application thereof Download PDFInfo
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- 150000004814 combretastatins Chemical class 0.000 title claims abstract description 25
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- 150000001875 compounds Chemical class 0.000 claims abstract description 33
- PTMHPRAIXMAOOB-UHFFFAOYSA-N phosphoramidic acid Chemical class NP(O)(O)=O PTMHPRAIXMAOOB-UHFFFAOYSA-N 0.000 claims abstract description 16
- 230000000259 anti-tumor effect Effects 0.000 claims abstract description 10
- 239000003814 drug Substances 0.000 claims abstract description 9
- 238000006243 chemical reaction Methods 0.000 claims description 10
- 229910052801 chlorine Inorganic materials 0.000 claims description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 9
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 9
- KMTRUDSVKNLOMY-UHFFFAOYSA-N Ethylene carbonate Chemical compound O=C1OCCO1 KMTRUDSVKNLOMY-UHFFFAOYSA-N 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
- 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
- 229910052794 bromium Inorganic materials 0.000 claims description 5
- 229910052731 fluorine Inorganic materials 0.000 claims description 5
- 230000009471 action Effects 0.000 claims description 4
- 238000005886 esterification reaction Methods 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 4
- 238000000926 separation method Methods 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
- 239000000463 material Substances 0.000 claims description 2
- 238000000746 purification Methods 0.000 claims description 2
- 206010028980 Neoplasm Diseases 0.000 abstract description 15
- 241000282414 Homo sapiens Species 0.000 abstract description 11
- 229940079593 drug Drugs 0.000 abstract description 7
- 231100000419 toxicity Toxicity 0.000 abstract description 7
- 230000001988 toxicity Effects 0.000 abstract description 7
- 230000001093 anti-cancer Effects 0.000 abstract description 6
- 230000000694 effects Effects 0.000 abstract description 4
- 210000005229 liver cell Anatomy 0.000 abstract description 4
- 210000004881 tumor cell Anatomy 0.000 abstract description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 68
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 17
- 238000005160 1H NMR spectroscopy Methods 0.000 description 17
- 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 15
- 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 13
- 201000011510 cancer Diseases 0.000 description 11
- 210000004027 cell Anatomy 0.000 description 9
- 239000002246 antineoplastic agent Substances 0.000 description 6
- 229940041181 antineoplastic drug Drugs 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
- 239000000376 reactant Substances 0.000 description 4
- 102000004243 Tubulin Human genes 0.000 description 3
- 108090000704 Tubulin Proteins 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 239000012044 organic layer Substances 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
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 239000007864 aqueous solution Substances 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
- 210000003494 hepatocyte Anatomy 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 231100000053 low toxicity Toxicity 0.000 description 2
- 238000010791 quenching Methods 0.000 description 2
- 238000002390 rotary evaporation Methods 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 230000008685 targeting Effects 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 230000002588 toxic effect Effects 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
- 238000000134 MTT assay Methods 0.000 description 1
- 231100000002 MTT assay Toxicity 0.000 description 1
- 102000029749 Microtubule Human genes 0.000 description 1
- 108091022875 Microtubule Proteins 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- 229940122429 Tubulin inhibitor Drugs 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- -1 aminophosphonate ester Chemical class 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
- 229940125782 compound 2 Drugs 0.000 description 1
- 230000006378 damage 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
- 229910052736 halogen Inorganic materials 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 210000005260 human cell Anatomy 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000005918 in vitro anti-tumor Effects 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
- 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
- 239000012074 organic phase Substances 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
- 230000003389 potentiating effect Effects 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 230000008054 signal transmission Effects 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000002626 targeted therapy Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
Classifications
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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
-
- 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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- 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
- C07F9/4071—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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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- 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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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
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Abstract
The invention discloses a combretastatin derivative and a preparation method and application thereof, the invention couples an aminophosphonate derivative with a combretastatin analogue, and introduces the aminophosphonate derivative with certain anticancer activity into the structure of a CA-4 analogue to optimize the structure, so as to enhance the antitumor activity of the combretastatin derivative. The combretastatin derivative synthesized by the invention shows good anti-tumor activity on various tumor cell strains of human, wherein the tumor activity of a representative compound 3e is superior to that of a positive drug CA-4, and the toxicity on normal liver cells of the human is obviously lower than that of the CA-4, thus indicating the potential targeted application of the compound 3e in treating tumor diseases.
Description
Technical Field
The invention belongs to the technical field of drug synthesis, and relates to a combretastatin derivative and a preparation method and application thereof.
Background
In the modern period of rapid development of medical technology, people have overcome many diseases which are difficult to treat in the past, however, the incidence rate and the fatality rate of cancer are continuously rising, and the life health of human beings is seriously threatened. Therefore, how to better treat cancer has become a great problem to be solved urgently in modern medicine. 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 due to its high efficacy, but it also has certain drawbacks such as lack of selectivity, severe 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 proteinaceous polymer formed from heterodimers of α -tubulin and β -tubulin, has a hollow tubular structure, and plays an important role in cell division, intracellular material transport, signal transmission, cell morphology maintenance, and the like. The destruction of microtubules can induce cell cycle arrest at the G2/M phase and form abnormal mitotic spindle, which makes it one of the hot targets for the development of anti-tumor drugs. Combretastatin (CA-4) is separated and extracted from natural products, belongs to an anti-cancer drug of a tubulin inhibitor class, and is still in a third-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 a novel CA-4 derivative with high efficiency, targeting property 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. The invention also aims to provide a preparation method of 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 is1Is H,Cl or OCH3，R2Is H, F, Cl, Br, CH3Or OCH3And n is 1 or 3.
The invention further improves the scheme as follows:
a preparation method of combretastatin derivatives comprises the following steps:
step one, reacting CA-4 with ethylene carbonate to obtain an intermediate (1);
step two, carrying out coupling reaction on the intermediate (1) and the aminophosphonate derivative (2) to obtain a formula (I);
the reaction equation is as follows:
wherein R is1Is H, Cl or OCH3，R2Is H, F, Cl, Br, CH3Or OCH3And n is 1 or 3.
The invention further improves the scheme as follows:
a preparation method of combretastatin derivatives 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 dosage of the compound is calculated by the mass amount, and the ratio of CA-4: ethylene carbonate: 1, (2-4) and (2-4) inorganic base;
and step two, dissolving the aminophosphonate derivatives (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 formula (I), wherein the compound is used in an amount of substance, and the intermediate (1): aminophosphonate derivatives (2): organic base: the catalyst is 1 (1-1.2) 2-2.4 (1.5-1.8).
The invention has the further improvement scheme that:
in the first step, the inorganic base is anhydrous potassium carbonate, the temperature of the esterification reaction is 90-110 ℃ and the reflux is carried out, and the reaction time is 10-14 h.
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 coupling reaction temperature is-5 ℃.
Further, each step of the method also comprises a separation and purification step.
Further, the combretastatin derivative is applied to preparation of antitumor drugs.
The invention has the beneficial effects that:
the invention utilizes the advantage that aminophosphonate has anti-tumor activity, and the anti-tumor activity of the aminophosphonate can be enhanced by introducing the aminophosphonate into a combretastatin analogue structure.
The combretastatin derivative shows good anti-tumor activity on various human tumor cell strains, wherein the anti-tumor activity of a representative compound 3e is superior to that of a positive drug CA-4, and the toxicity on normal human liver cells is obviously lower than that of the CA-4, which shows that the compound 3e has the potential application of targeted therapy on tumor diseases.
Detailed Description
The combretastatin derivative provided by the invention has a structural general formula shown in formula I:
the synthetic route is as follows:
wherein R is1Is H, Cl or-OCH3，R2Is H, F, Cl, Br, -CH3or-OCH3And n is 1 or 3.
Examples 1 to 16
The aminophosphonate ester derivatives 2 used in examples 1 to 16 are shown in table 1,
TABLE 1 selection of aminophosphonate derivatives Compound 2
| Serial number | n | R1 | R2 |
| Example 1(3a) | 1 | H | H |
| Example 2(3b) | 1 | H | F |
| Example 3(3c) | 1 | H | Cl |
| Example 4(3d) | 1 | H | Br |
| Example 5(3e) | 1 | H | OCH3 |
| Example 6(3f) | 1 | H | CH3 |
| Example 7(3g) | 1 | OCH3 | H |
| Example 8(3h) | 1 | Cl | H |
| Example 9(3i) | 3 | H | H |
| Example 10(3j) | 3 | H | F |
| Example 11(3k) | 3 | H | Cl |
| Example 12(3l) | 3 | H | Br |
| Example 13(3m) | 3 | H | OCH3 |
| Example 14(3n) | 3 | H | CH3 |
| Example 15(3o) | 3 | OCH3 | H |
| Example 16(3p) | 3 | Cl | H |
The preparation method comprises the following specific steps:
(1) preparation of intermediate 1
Dissolving CA-4(2.85g,9.0mmol) in 10mL DMF, adding ethylene carbonate (2.38g,27.0mmol), finally adding anhydrous potassium carbonate (3.72g,27.0mmol), heating to 100 ℃ under the protection of nitrogen, refluxing for 12h, and judging the end point of the reaction by TCL thin layer analysis. After the reaction is finished, ice water is added into the reactant to quench the reaction, the reactant is placed into a 125mL separating funnel, 50mL of water, 50mL of DCM and a small amount of NaCl aqueous solution are added to extract, an organic layer is collected and repeated for 3 times, the organic phase is dried by anhydrous sodium sulfate, DCM is removed by rotary evaporation, and column chromatography separation is carried out, so that the intermediate 1(1.66g, 51.2%) is finally obtained.1H NMR(600MHz,CDCl3)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＝12.1 Hz,1H),3.91(t,J＝4.5Hz,2H),3.84-3.83(m,5H),3.82(s,3H),3.70(s,6H).13C NMR(150MHz, CDCl3)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 Zhongkang ruitin derivative
Aminophosphonate derivative 2(150mg,0.321mmol) was dissolved in 5mL DCM, EDCI (123 mg,0.642mmol) and DMAP (59mg,0.482mmol) were added, and intermediate 1(100mg,0.289mmol) was added and the reaction was carried out for 6h under ice-bath reaction conditions. The end point of the reaction was judged by TCL thin layer analysis. And after the reaction is finished, adding ice water into the reactant to quench the reaction, putting the reactant into a 125mL separating funnel, adding 50mL of water, 50mL of LPCM and a small amount of NaCl aqueous solution to extract, collecting an organic layer, repeating the extraction for 3 times, drying the organic layer by using anhydrous sodium sulfate, removing DCM by rotary evaporation, and performing column chromatography separation to obtain the combretastatin derivative finally.
In the present invention, CA-4 was synthesized according to the literature [ European Journal of medicinal Chemistry,2012,56: 166-.
Data of combretastatin derivatives prepared in examples 1 to 16 are as follows:
example 1: 143mg, yield 68.5%.1HNMR(400MHz,CDCl3)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＝1.8 Hz,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＝7.0 Hz,3H).13C NMR(100MHz,CDCl3)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 C39H46NO10P[M+H]+:720.2938；found: 720.2946.
Example 2: 150mg, yield 70.3%.1HNMR(400MHz,CDCl3)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).13C NMR(100MHz,CDCl3)δ 171.95,152.99,149.01,147.44,145.23,145.08,137.17,132.88,131.62,130.12,129.96,129.47, 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 C39H45FNO10P[M+H]+:738.2843；found:738.2872.
Example 3: 139mg, yield: 63.9%.1HNMR(400MHz,CDCl3)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).13C NMR(100 MHz,CDCl3)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 C39H45ClNO10P[M+H]+:754.2548；found:754.2587.
Example 4: 161mg, yield: 69.7%.1HNMR(400MHz,CDCl3)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).13C NMR(100MHz,CDCl3)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 C39H45BrNO10P[M+H]+:798.2043；found:798.2067.
Example 5: 156mg, yield: 72.1%.1HNMR(400MHz,CDCl3)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＝8.3 Hz,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).13C NMR(100MHz,CDCl3)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 C40H48NO11P[M+H]+:750.3043；found:750.3030.
Example 6: 137mg, yield: 64.7%.1HNMR(400MHz,CDCl3)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).13C NMR(100MHz,CDCl3)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 C40H48NO10P[M+H]+:734.3094；found:734.3071.
Example 7: 155mg, yield: 71.3%.1HNMR(400MHz,CDCl3)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).13C NMR(100MHz,CDCl3)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 C40H48NO11P [M+H]+:750.3043；found:750.3032.
Example 8: 136mg, yield: 62.3%.1HNMR(400MHz,CDCl3)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＝8.3 Hz,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).13C NMR(100MHz,CDCl3)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 C39H45ClNO10P[M+H]+:754.2548；found:754.2572.
Example 9: 159mg, yield 73.5%.1H NMR(400MHz,CDCl3)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).13C NMR(100MHz,CDCl3)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 C41H50NO10P [M+H]+:748.3251；found:748.3243.
Example 10: 155mg, yield: 70.1%.1H NMR(400MHz,CDCl3)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).13C NMR(100MHz,CDCl3)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 C41H59FNO10P[M+H]+:766.3156；found: 766.3166.
Example 11: 142mg, yield: 62.7%.1H NMR(400MHz,CDCl3)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).13C NMR(100MHz,CDCl3)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 C41H59ClNO10P[M+H]+:782.2861；found: 782.2865.
Example 12: 166mg, yield: 69.4%.1H NMR(400MHz,CDCl3)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).13C NMR(100MHz,CDCl3)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 C41H59BrNO10P[M+H]+:826.2356；found:826.2393.
Example 13: 165mg, yield: 73.3%.1H NMR(400MHz,CDCl3)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＝3.6 Hz,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).13C NMR(100MHz,CDCl3)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 C42H52NO11P[M+H]+:778.3356；found:778.3396.
Example 14: 138mg, yield: 62.7%.1H NMR(400MHz,CDCl3)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).13C NMR(100MHz,CDCl3)δ 173.53,153.13,148.97,147.51,144.62,144.67,137.57,137.16,132.90,131.17,129.90,129.49, 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 C42H52NO10P[M+H]+:762.3407；found:762.3437.
Example 15: 155mg, yield: 68.9%.1H NMR(400MHz,CDCl3)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＝8.3 Hz,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).13C NMR(100MHz,CDCl3)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 C42H52NO11P[M+H]+:778.3356；found:778.3320.
Example 16: 167mg, yield 73.7%.1H NMR(400MHz,CDCl3)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).13C NMR(100MHz,CDCl3)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 C41H59ClNO10P[M+H]+:782.2861；found:782.2856.
Test example 1
Examples 1 to 16 compounds 3a to 3p prepared in example 16 were investigated for their antitumor activity in vitro.
In order to investigate whether the compound 3a-3p prepared by the present invention has a good killing effect on cancer cells, it was investigated by MTT method experiments, and the results are shown in table 2. As can be seen from Table 2, the compounds 3a-3p have better toxic activity to HepG-2 (liver cancer), HT29 (intestinal cancer), A549 (lung cancer) and MGC-803 (stomach cancer), some compounds such as 3e, 3g and 3l have good anticancer activity, and IC thereof50The values are all less than 1 mu M, wherein the anticancer activity of the compound 3e is obviously superior to that of other compounds and positive drugs CA-4, and the IC of the compound on cancer cells HepG-250The value was 0.36. mu.M; IC for cancer cell HT2950The value was 0.31. mu.M; IC for cancer cells A54950The value was 0.19. mu.M; IC against cancer cell MGC-80350The value was 0.42. mu.M; analysis of the structure of the target compound shows that, in the compounds 3i to 3p, the C-4 position of the benzene ring is substituted by-OCH3and-CH3The substituted compounds 3e and 3f haveBetter in vitro antitumor activity, in the compound 3i-3p, the phenomenon that the C-4 position of the benzene ring of the aminophosphonate is OCH3and-CH3Substituted 3l and 3m are also more active than halogen substituted 3j, 3h and 3k, indicating the introduction of-OCH at the para position of the phenyl ring3and-CH3Is a correct choice. Compared with the positive control drug combretastatin, the compound 3e has obviously better anticancer activity than other compounds and better activity.
TABLE 2 IC of Compounds 3a-3p against the human cancer cell lines tested50The value is obtained.
Test example 2
Examples 1 to 16 toxicity of the compounds 3a to 3p prepared in example 1 to human normal hepatocytes.
In order to investigate the toxicity of the compounds 3a-3p prepared according to 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 can be found that the toxicity of the target compounds 3a-3p to human normal liver cells is lower than that of the positive drug CA-4 (IC)503.27 ± 0.82 μ M), IC thereof50The value range is 9.33 to 20.14. mu.M. In addition, compound 3e (IC), which is the most potent anticancer agent5010.45 +/-0.98 mu M) has obviously lower toxicity to normal human liver cells than that of positive drugs, and the experimental result further shows that the aminophosphonate derivatives introduced into the CA-4 skeleton can not only improve the anticancer activity, but also reduce the toxicity of the compound to normal cells, thereby showing that the compound has better selectivity to cancer cells.
TABLE 3 IC of Compounds 3a-3p on human Normal hepatocytes LO250The value is obtained.
Claims (7)
1. A combretastatin derivative is characterized in that the structural general formula is shown as the formula (I):
wherein R is1Is H, Cl or OCH3，R2Is H, F, Cl, Br, CH3Or OCH3And n is 1 or 3.
2. A process for the preparation of a combretastatin derivative as claimed in claim 1, comprising the steps of:
step one, reacting CA-4 with ethylene carbonate to obtain an intermediate (1);
step two, carrying out coupling reaction on the intermediate (1) and the aminophosphonate derivative (2) to obtain a formula (I);
the reaction equation is as follows:
wherein R is1Is H, Cl or OCH3，R2Is H, F, Cl, Br, CH3Or OCH3And n is 1 or 3.
3. The method for preparing a combretastatin derivative according to claim 2, wherein: 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 dosage of the compound is calculated by the mass amount, and the ratio of CA-4: ethylene carbonate: 1, (2-4) and (2-4) inorganic base;
and step two, dissolving the aminophosphonate derivatives (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 formula (I), wherein the compound is used in an amount of material, and the intermediate (1): aminophosphonate derivatives (2): organic base: the catalyst is 1 (1-1.2) 2-2.4 (1.5-1.8).
4. The method for preparing a combretastatin derivative according to claim 3, wherein: in the first step, the inorganic base is anhydrous potassium carbonate, the esterification reaction is performed at the temperature of 90-110 ℃ under reflux, and the reaction time is 10-14 h.
5. The method for preparing a combretastatin derivative according to claim 3, wherein: 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. The method for preparing a combretastatin derivative according to claim 3, wherein: the method also comprises a separation and purification step in each step.
7. The use of a combretastatin derivative according to claim 1 in the preparation of an anti-tumor medicament.
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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 |
| US20160362439A1 (en) * | 2014-02-14 | 2016-12-15 | The Regents Of The University Of California | Cyclic peroxides as prodrugs for selective delivery of agents |
| CN112209990A (en) * | 2020-11-10 | 2021-01-12 | 上海科技大学 | Combretastatin derivative and antibody drug conjugate thereof |
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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 |
| US20160362439A1 (en) * | 2014-02-14 | 2016-12-15 | The Regents Of The University Of California | Cyclic peroxides as prodrugs for selective delivery of agents |
| CN112209990A (en) * | 2020-11-10 | 2021-01-12 | 上海科技大学 | Combretastatin derivative and antibody drug conjugate thereof |
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| XIAOCHAO HUANG等: "Synthesis and biological evaluation of novel millepachine derivative containing aminophosphonate ester species as novel anti-tubulin agents" * |
| XIAOCHAO HUANG等: "Synthesis, mechanisms of action, and toxicity of novel aminophosphonates derivatives conjugated irinotecan in vitro and in vivo as potent antitumor agents" * |
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