CN114989214B - Shikonin phosphoramidate hybrid and synthetic method and application thereof - Google Patents
Shikonin phosphoramidate hybrid and synthetic method and application thereof Download PDFInfo
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- 241001071917 Lithospermum Species 0.000 title claims abstract description 45
- NEZONWMXZKDMKF-JTQLQIEISA-N Alkannin Chemical compound C1=CC(O)=C2C(=O)C([C@@H](O)CC=C(C)C)=CC(=O)C2=C1O NEZONWMXZKDMKF-JTQLQIEISA-N 0.000 title claims abstract description 44
- UNNKKUDWEASWDN-UHFFFAOYSA-N alkannin Natural products CC(=CCC(O)c1cc(O)c2C(=O)C=CC(=O)c2c1O)C UNNKKUDWEASWDN-UHFFFAOYSA-N 0.000 title claims abstract description 44
- PTMHPRAIXMAOOB-UHFFFAOYSA-L phosphoramidate Chemical compound NP([O-])([O-])=O PTMHPRAIXMAOOB-UHFFFAOYSA-L 0.000 title claims abstract description 30
- 238000010189 synthetic method Methods 0.000 title abstract description 3
- 201000007270 liver cancer Diseases 0.000 claims abstract description 17
- 208000014018 liver neoplasm Diseases 0.000 claims abstract description 17
- 239000003560 cancer drug Substances 0.000 claims abstract description 6
- 238000002360 preparation method Methods 0.000 claims abstract description 5
- 238000006243 chemical reaction Methods 0.000 claims description 26
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 18
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 7
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 7
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 6
- 150000001875 compounds Chemical class 0.000 claims description 6
- 238000003756 stirring Methods 0.000 claims description 6
- BXRFQSNOROATLV-UHFFFAOYSA-N 4-nitrobenzaldehyde Chemical compound [O-][N+](=O)C1=CC=C(C=O)C=C1 BXRFQSNOROATLV-UHFFFAOYSA-N 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- CSEWAUGPAQPMDC-UHFFFAOYSA-N 2-(4-aminophenyl)acetic acid Chemical compound NC1=CC=C(CC(O)=O)C=C1 CSEWAUGPAQPMDC-UHFFFAOYSA-N 0.000 claims description 4
- 230000015572 biosynthetic process Effects 0.000 claims description 4
- 238000000034 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 compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 3
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 3
- LXCYSACZTOKNNS-UHFFFAOYSA-N diethoxy(oxo)phosphanium Chemical compound CCO[P+](=O)OCC LXCYSACZTOKNNS-UHFFFAOYSA-N 0.000 claims description 3
- 238000003786 synthesis reaction Methods 0.000 claims description 3
- 238000005406 washing Methods 0.000 claims description 3
- 230000003197 catalytic effect Effects 0.000 claims description 2
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- 206010027476 Metastases Diseases 0.000 abstract description 4
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- 230000002401 inhibitory effect Effects 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract 1
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- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 238000012258 culturing Methods 0.000 description 6
- 206010028980 Neoplasm Diseases 0.000 description 5
- IAKHMKGGTNLKSZ-INIZCTEOSA-N (S)-colchicine Chemical compound C1([C@@H](NC(C)=O)CC2)=CC(=O)C(OC)=CC=C1C1=C2C=C(OC)C(OC)=C1OC IAKHMKGGTNLKSZ-INIZCTEOSA-N 0.000 description 4
- 230000012292 cell migration Effects 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- 230000000259 anti-tumor effect Effects 0.000 description 3
- 239000001963 growth medium Substances 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 108010019160 Pancreatin Proteins 0.000 description 2
- 230000003698 anagen phase Effects 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 239000006285 cell suspension Substances 0.000 description 2
- 229960001338 colchicine Drugs 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000005012 migration Effects 0.000 description 2
- 238000013508 migration Methods 0.000 description 2
- 229940055695 pancreatin Drugs 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- OAVCWZUKQIEFGG-UHFFFAOYSA-O 2-(5-methyl-2H-tetrazol-1-ium-1-yl)-1,3-thiazole Chemical compound CC1=NN=N[NH+]1C1=NC=CS1 OAVCWZUKQIEFGG-UHFFFAOYSA-O 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
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- 230000027311 M phase Effects 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 206010066901 Treatment failure Diseases 0.000 description 1
- 102000004243 Tubulin Human genes 0.000 description 1
- 108090000704 Tubulin Proteins 0.000 description 1
- 229940122429 Tubulin inhibitor Drugs 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000002001 anti-metastasis Effects 0.000 description 1
- 238000011319 anticancer therapy Methods 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
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- 238000003556 assay Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 150000004663 bisphosphonates Chemical group 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
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- 238000004113 cell culture Methods 0.000 description 1
- 229940044683 chemotherapy drug Drugs 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 238000011161 development Methods 0.000 description 1
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- 238000003745 diagnosis Methods 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
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- 208000033065 inborn errors of immunity Diseases 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- PTMHPRAIXMAOOB-UHFFFAOYSA-N phosphoramidic acid Chemical class NP(O)(O)=O PTMHPRAIXMAOOB-UHFFFAOYSA-N 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 208000028529 primary immunodeficiency disease Diseases 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000006748 scratching Methods 0.000 description 1
- 230000002393 scratching effect Effects 0.000 description 1
- 239000004017 serum-free culture medium Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 230000004614 tumor growth Effects 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
- C07F9/4071—Esters thereof the ester moiety containing a substituent or a structure which is considered as characteristic
- C07F9/4075—Esters with hydroxyalkyl compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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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
- C07F9/4003—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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- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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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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Abstract
The invention discloses a shikonin phosphoramidate hybrid and a synthetic method and application thereof, wherein the shikonin phosphoramidate hybrid has the structural formula:the invention also specifically discloses a synthesis method of the shikonin phosphoramidate hybrid and application of the shikonin phosphoramidate hybrid in preparation of anti-liver cancer drugs. The shikonin phosphoramidate hybrid has high liver cancer inhibiting activity and liver cancer metastasis resisting capacity, and provides a new approach for treating liver cancer. The synthesis method of the shikonin-phosphoramidate hybrid provided by the invention is simple, the raw materials are cheap and easy to obtain, and the industrial production and clinical transformation are easy.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry, and in particular relates to a shikonin phosphoramidate hybrid, a synthesis method thereof and application of the shikonin phosphoramidate hybrid in preparation of anti-liver cancer drugs.
Background
Liver cancer is one of the major malignancies leading to death in humans. Despite considerable progress in the diagnosis and treatment of liver cancer, patient five-year survival rates are still less than fifteen percent. The most common causes of death in liver cancer patients are treatment failure and metastasis of cancer cells. Therefore, the development of new drugs for both tumor growth and metastasis is an important and urgent task for next-generation anticancer therapy research.
Shikonin (Shikonin) is an active ingredient of lithospermaceae, plant hard lithospermum. Shikonin has various biological activities of resisting bacteria, inflammation, tumor, hypoimmunity, reducing blood sugar, protecting liver and the like. Shikonin can target the colchicine binding site, inhibit polymerization of tubulin, block formation of M-phase spindle, induce apoptosis of tumor cells, and can be developed as a tubulin inhibitor targeting the colchicine binding site. Recent researches show that the combination of shikonin and its derivatives with chemotherapeutic drugs or radiotherapy means can improve the tumor treatment effect in vivo and in vitro. In addition, some of the interconnected prodrugs containing shikonin also exhibit good synergistic antitumor activity.
In recent years, research shows that a plurality of natural or synthetic aminophosphonate compounds can show moderate cytotoxicity to various human cancer cell lines by inhibiting matrix metalloenzymes, and the antitumor activity and solubility of the medicaments can be effectively improved by introducing phosphate or bisphosphonate parts into the antitumor medicaments.
The shikonin phosphoramidate heterozygote designed and synthesized by the invention has higher liver cancer inhibition activity and liver cancer metastasis resistance, and provides a new approach for treating liver cancer.
Disclosure of Invention
The invention aims to provide a shikonin phosphoramidate hybrid, and another aim of the invention is to provide a synthesis method of the shikonin phosphoramidate hybrid and application of the shikonin phosphoramidate hybrid in preparation of anti-liver cancer drugs.
In order to achieve the above purpose, the invention adopts the following technical scheme that the shikonin phosphoramidate hybrid is characterized in that the structural formula of the shikonin phosphoramidate hybrid is shown as formula I:
the invention also provides a synthesis method of the shikonin phosphoramidate hybrid, which is characterized by comprising the following specific steps:
step S1: dissolving p-nitrobenzaldehyde and p-aminophenylacetic acid in anhydrous methanol, adding anhydrous sodium sulfate into a reaction system, stirring at room temperature for reaction for 10 hours, evaporating the solvent to obtain an intermediate II, adding diethyl phosphite into the intermediate II, stirring at 50 ℃ for reaction for 2 hours, diluting the reaction solution with dichloromethane after the reaction is finished, washing with saturated sodium bicarbonate and saturated sodium chloride in sequence, drying with anhydrous sodium sulfate, filtering, concentrating and purifying to obtain a compound III;
step S2: dissolving the compound III obtained in the step S1 and shikonin in anhydrous dichloromethane, adding EDCI and catalytic amount DMAP into a reaction system, stirring at room temperature for reaction for 12 hours, concentrating and purifying after the reaction is completed to obtain a compound I;
the corresponding reaction equation in the synthesis process is:
further defined, the molar ratio of p-nitrobenzaldehyde, p-aminophenylacetic acid and anhydrous sodium sulfate in step S1 is 6:5:1, and the molar ratio of compound III to shikonin in step S2 is 1:1.
The shikonin phosphoramidate hybrid disclosed by the invention is applied to preparation of anti-liver cancer drugs.
The invention has the following advantages and beneficial effects: the shikonin phosphoramidate hybrid provided by the invention has a strong inhibition effect on a tested liver cancer cell HepG2, and IC thereof 50 6.01. Mu.M. In addition, the compound has weak toxicity (IC) to normal cell LO2 50 =10.04 μΜ), showing high safety. In addition, in the scratch test of the HepG2 cell, the shikonin phosphoramidate hybrid can remarkably inhibit the migration of the HepG2 cell, effectively improve the anti-metastasis capability of shikonin (figure 1), and can be further developed as an anti-liver cancer drug.
Drawings
FIG. 1 shows the effect of the shikonin phosphoramidate hybrids on HepG2 cell migration ability in a HepG2 cell scratch assay.
Detailed Description
The following examples are illustrative of the invention and are not intended to limit the scope of the invention.
Example 1
Synthesis of shikonin phosphoramidate hybrids
P-nitrobenzaldehyde (1.81 g,12 mmol) andp-aminophenylacetic acid (1.51 g,10 mmol) was dissolved in 50mL of anhydrous methanol, anhydrous sodium sulfate (280 mg,2 mmol) was added to the reaction system, the reaction was magnetically stirred at room temperature for 10 hours, then the solvent was evaporated to dryness to give intermediate II, 8mL of diethyl phosphite was added to intermediate II, the reaction was stirred at 50℃for 2 hours, after completion of the reaction, the reaction solution was diluted with methylene chloride (200 mL), washed with saturated sodium bicarbonate and saturated sodium chloride in this order, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and isolated by column chromatography to give 2.53g of pale yellow solid compound III in 60% yield. 1 H NMR(400MHz,DMSO-d 6 )δ:12.13(s,1H),8.21(d,2H,J＝8.8Hz),7.80(dd,2H,J＝2.0,8.8Hz),6.89(d,2H,J＝8.8Hz),6.74(d,2H,J＝8.8Hz),6.52-6.48(m,1H),5.33(dd,1H,J＝10.4,26Hz),4.11-4.05(m,2H),3.99-3.92(m,1H),3.86-3.80(m,1H),3.32(s,2H),1.22-1.19(m,3H),1.11-1.07(m,3H)；HRMS-ESI(m/z):calcd for C 19 H 23 N 2 NaO 7 P[M+Na] + 445.1141,found:445.1138。
The obtained compound III (2.11 g,5 mmol) and shikonin (1.44 g,5 mmol) were dissolved in 200mL of anhydrous dichloromethane, EDCI (1.42 g,7.5 mmol) and DMAP (540 mg,5 mmol) were added to the reaction system, the reaction was stirred at room temperature for 12 hours, after the reaction was completed, the mixture was concentrated, and the obtained reddish-purple solid compound I2.77g was isolated by column chromatography in 80% yield. 1 H NMR(400MHz,DMSO-d 6 )δ:12.32(s,1H),12.20(s,1H),8.19(d,2H,J＝8.8Hz),7.80(dd,2H,J＝6.8,8.4Hz),7.32(s,2H),6.93(d,2H,J＝7.6Hz),6.77(d,2H,J＝7.6Hz),6.55(dd,1H,J＝1.6,7.2Hz),5.80(s,1H),5.38-5.29(m,1H),5.00(t,1H,J＝7.2Hz),4.11-3.82(m,4H),3.57-3.49(m,1H),2.56-2.49(m,1H),2.39-2.32(m,1H),1.99(s,2H),1.55(s,3H),1.45(s,3H),1.22-1.07(m,6H)；HRMS-ESI(m/z):calcd for C 35 H 37 N 2 NaO 11 P[M+Na] + 715.2027,found:715.2025。
Example 2
Test for anti-valueing Activity
Taking HepG2 and LO2 cells in logarithmic growth phase, adding 0.25wt% pancreatin to make into cell suspension with cell concentration of 3×10 4 Per mL, inoculated in 96-well plates with 100. Mu.L per well, blank wells100 mu L of DMEM high-sugar culture medium is placed at 37 ℃ and the volume fraction of CO is 5% 2 Culturing in an incubator for 24 hours, replacing a new culture medium containing samples to be tested with different concentrations by an experimental group, replacing 3 compound wells with each concentration, replacing a culture medium containing an equal volume of solvent by a control group, continuing culturing for 48 hours, adding MTT (methyl thiazolyl tetrazolium), continuing culturing for 4 hours, and detecting the absorbance A value of each well under 570nm wavelength of a full-wavelength multifunctional reader after DMSO is dissolved. The result shows that the shikonin phosphoramidate hybrid has very strong inhibition effect on the tested liver cancer cell HepG2, and the IC thereof 50 6.01. Mu.M. Has weak toxicity to normal cell LO2 (IC) 50 =10.04 μΜ), showing high safety.
Example 3
Cell migration experiments
HepG2 cells in a good growth state and in a logarithmic growth phase were taken and diluted to a cell density of 2.5X10 with MEM complete medium 5 Six-hole plates were connected to each one of the six-hole plates, 2mL of cell suspension per one hole, 37℃and 5% CO by volume 2 Culturing overnight in an incubator. The next day, cytoshikonin (10. Mu.M), compound I (5. Mu.M, 10. Mu.M) and DMSO solvent control groups were treated according to the group, and then placed in 37℃C, volume fraction 5% CO 2 Culturing in a cell culture box for 24 hours. 0.25wt% pancreatin digestion count was about 7.5X10 respectively 5 Individual cells were inoculated into six well plates to ensure confluence the next day at 37℃with a volume fraction of 5% CO 2 The culture was carried out overnight under saturated humidity conditions. Uniformly scratching with sterile gun head, washing cells with PBS for 3 times, removing scratched cells, adding serum-free culture medium, taking 0 hr photograph, placing into 37 deg.C and 5% CO 2 Culturing in an incubator, and photographing for 24 hours. As shown in FIG. 1, the ability of the shikonin phosphoramidate hybrid to resist HepG2 cell migration is characterized by dose dependence. The cell migration inhibition rate of the shikonin phosphoramidate hybrid after treatment at a concentration of 10 mu M is 68%, and the effect is better than that of shikonin (10 mu M). The shikonin phosphoramidate hybrid can remarkably inhibit migration of HepG2 cells and effectively improve transfer resistance of shikonin.
While the basic principles, principal features and advantages of the present invention have been described in the foregoing examples, it will be appreciated by those skilled in the art that the present invention is not limited by the foregoing examples, but is merely illustrative of the principles of the invention, and various changes and modifications can be made without departing from the scope of the invention, which is defined by the appended claims.
Claims (4)
1. The shikonin phosphoramidate hybrid is characterized in that the structural formula of the shikonin phosphoramidate hybrid is shown as formula I:
2. a method for synthesizing a shikonin phosphoramidate hybrid according to claim 1, which is characterized by comprising the following specific steps:
step S1: dissolving p-nitrobenzaldehyde and p-aminophenylacetic acid in anhydrous methanol, adding anhydrous sodium sulfate into a reaction system, stirring at room temperature for reaction for 10 hours, evaporating the solvent to obtain an intermediate II, adding diethyl phosphite into the intermediate II, stirring at 50 ℃ for reaction for 2 hours, diluting the reaction solution with dichloromethane after the reaction is finished, washing with saturated sodium bicarbonate and saturated sodium chloride in sequence, drying with anhydrous sodium sulfate, filtering, concentrating and purifying to obtain a compound III;
step S2: dissolving the compound III obtained in the step S1 and shikonin in anhydrous dichloromethane, adding EDCI and catalytic amount DMAP into a reaction system, stirring at room temperature for reaction for 12 hours, concentrating and purifying after the reaction is completed to obtain a compound I;
the corresponding reaction equation in the synthesis process is:
3. the method for synthesizing shikonin phosphoramidate hybrids of claim 2, wherein: the molar ratio of the p-nitrobenzaldehyde, the p-aminophenylacetic acid and the anhydrous sodium sulfate in the step S1 is 6:5:1, and the molar ratio of the compound III to the shikonin in the step S2 is 1:1.
4. The use of shikonin phosphoramidate hybrids of claim 1 in the preparation of anti-liver cancer drugs.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102424696A (en) * | 2011-09-05 | 2012-04-25 | 江西农业大学 | Shikonin amino deoxy glycosides and application thereof in preparation of antitumor medicines |
| CN103284983A (en) * | 2013-05-10 | 2013-09-11 | 上海市肺科医院 | Application of alkannin and/or derivative thereof in preparing medicine for prohibiting cancer cell metastasis |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102424696A (en) * | 2011-09-05 | 2012-04-25 | 江西农业大学 | Shikonin amino deoxy glycosides and application thereof in preparation of antitumor medicines |
| CN103284983A (en) * | 2013-05-10 | 2013-09-11 | 上海市肺科医院 | Application of alkannin and/or derivative thereof in preparing medicine for prohibiting cancer cell metastasis |
Non-Patent Citations (2)
| Title |
|---|
| Dual-functional antitumor conjugates improving the anti-metastasis effect of combretastatin A4 by targeting tubulin polymerization and matrix metalloproteinases;Limin Yang et al;European Journal of Medicinal Chemistry;第238卷;114439 * |
| Synthesis and biological evaluation of novel millepachine derivative containing aminophosphonate ester species as novel anti-tubulin agents;Xiaochao Huang et al;Bioorganic Chemistry;第94卷;103486 * |
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