CN111944005B - Cholic acid-hexyl-triphenyl phosphonium bromide and preparation method and application thereof - Google Patents
Cholic acid-hexyl-triphenyl phosphonium bromide and preparation method and application thereof Download PDFInfo
- Publication number
- CN111944005B CN111944005B CN201910399159.8A CN201910399159A CN111944005B CN 111944005 B CN111944005 B CN 111944005B CN 201910399159 A CN201910399159 A CN 201910399159A CN 111944005 B CN111944005 B CN 111944005B
- Authority
- CN
- China
- Prior art keywords
- cholic acid
- hexyl
- compound
- bromide
- tumor
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
- C07J9/005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane containing a carboxylic function directly attached or attached by a chain containing only carbon atoms to the cyclopenta[a]hydrophenanthrene skeleton
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Hematology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Diabetes (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Obesity (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Steroid Compounds (AREA)
Abstract
The invention discloses cholic acid-hexyl-triphenyl phosphonium bromide and a preparation method and application thereof. The invention firstly discloses a compound with the chemical name of cholic acid-hexyl-triphenyl phosphonium bromide. The cholic acid-hexyl-triphenyl phosphine bromide is obtained by coupling cholic acid and triphenyl phosphine with amino ends at two ends of 1,6 hexamethylene diamine respectively. Compared with cholic acid, the cholic acid-hexyl-triphenyl phosphonium bromide has mitochondrial targeting property and excellent antitumor activity, and the antitumor activity of the cholic acid-hexyl-triphenyl phosphonium bromide is still better than that of cholic acid under the condition of low dose which is 1200 times lower than that of cholic acid. The cholic acid-hexyl-triphenyl phosphine bromide provides a new way for clinical application of cholic acid derivatives as antitumor preparations.
Description
Technical Field
The invention relates to a compound obtained by modifying cholic acid with triphenylphosphine bromide, and also relates to application of a cholic acid derivative modified with triphenylphosphine bromide in preparation of an anti-tumor lead compound, belonging to the fields of preparation and application of cholic acid derivatives.
Background
The medicine treatment plays an important role in the treatment of tumors, and people focus on natural compounds with anti-tumor activity in recent years to search for high-efficiency and low-toxicity anti-tumor medicines. Bile Acids (BAs) are produced in the liver by enzymatic oxidation of cholesterol, have a stable rigid steroid backbone and alkane branches with terminal carboxyl groups, and are endogenous steroid compounds. Bile acid can promote digestion and absorption of lipid substances by forming mixed micelle with the lipid substances, and regulate cholesterol metabolism. Bile acids are separated from ingested lipid material in the intestine and then returned to the liver where they are reused in the enterohepatic circulation. Bile acid, as an endogenous natural product, is widely used as a drug carrier due to its excellent bioavailability and high organ specificity, thereby achieving liver-targeted drug delivery and improving the bioavailability of the drug. The bile acid and the derivatives thereof have wide biological activities of resisting tumors, bacteria and tuberculosis, and the like, and researches show that the bile acid and the derivatives thereof can inhibit the growth of tumor cells through mechanisms of inducing mitochondrial oxidative stress, inducing apoptosis, cell necrosis and the like. The synthesized bile acid derivatives show an inhibitory effect on tumor cells including glioblastoma multiforme, colon cancer, breast cancer, T-cell leukemia, prostate cancer, cervical cancer, hepatocellular carcinoma, and the like. Ursodeoxycholic acid (UDCA) has been identified as a potent inhibitor of apoptosis. UDCA can prevent recurrence of colorectal adenomas, and is currently in the phase III clinical trial (Im, E.; choi, S. -H.; suh, H.; choi, Y.H.; yoo, Y.H.; kim, N.D. cancer Letters,2005,229,49-57.). Bile acids and derivatives thereof have shown broad application prospects in the study of anticancer agents (Agarwal D.S.; anataraju, H.S.; sriram, D.; yogeeswari, P.; nanjegaowda, S.H.; mallu, P.; sakhuja, R.Steroids,2016,107,87-97.). Unlike other bile acids, cholic Acid (CA) has three hydroxyl groups (C3, C7 and C12) and is an amphiphilic molecule with a hydrophobic convex surface and a hydrophilic concave surface. This structural feature allows bile acids to have higher water solubility and the ability to form micelles than other bile acids. In addition, cholic acid is used as the most abundant bile acid in the four bile acids, has rich source and low price, and has good application prospect.
It is well known that the main problem in cancer therapy is how to target the delivery of antitumor drugs to tumor organs or tissues to improve the therapeutic efficiency while reducing side effects. In tumor targeting ligands, the development of chemotherapeutics with mitochondria as an action target has become a hot spot in tumor treatment in recent years. It is reported in literature that bile acid can induce cell mitochondrial damage to cause tumor cell apoptosis, so that cholic acid derivatives can achieve targeting on mitochondrial damage of tumor cells under the mediation of mitochondrial targeting ligands, thereby causing tumor cell apoptosis. Mitochondria are energy generating plants of eukaryotic cells, and in mitochondria, adenosine Triphosphate (ATP) can be produced through both oxidative phosphorylation and glycolysis to provide energy required for cell growth. Mitochondria are indispensable organelles for maintaining the homeostasis of the cell, and when mitochondria are damaged, the mitochondrial membrane potential is lowered, some membrane proteins such as apoptosis-inducing factor (AIF), cytochrome C, etc. flow from the mitochondria to the cytoplasm to further induce apoptosis of the cell. Triphenylphosphine is commonly used as a mitochondrial targeting ligand due to its positive charge and lipid solubility (Lee, s.y.; cho, h. -j.biomacromolecules,2019,20 (2): 835-845). Three benzene rings in the triphenylphosphine ligand increase the surface area of molecules, so that delocalized positive charges are formed, and the drugs are gathered in a mitochondrial matrix through the driving of mitochondrial membrane potential, so that the mitochondrial targeting effect is achieved.
According to the invention, triphenylphosphine bromide is connected with cholic acid through a flexible chain 1,6-hexamethylenediamine to obtain a novel antitumor lead compound. The cholic acid molecule adopts proper orientation in the process of generating drug effect through a flexible chain under the mediation of triphenylphosphine ligand, so that the cholic acid has mitochondrion targeting property, shows good anti-tumor activity to a lotus S180 sarcoma ICR mouse, and provides a new way for clinical tumor treatment.
Disclosure of Invention
The first technical problem to be solved by the invention is to provide a compound with a chemical name of cholic acid-hexyl-triphenyl phosphonium bromide;
the second technical problem to be solved by the invention is to provide a preparation method of the cholic acid-hexyl-triphenyl phosphonium bromide;
the third technical problem to be solved by the invention is to provide the application of the cholic acid-hexyl-triphenyl phosphonium bromide in preparing the antitumor drugs.
In order to solve the technical problems, the technical scheme adopted by the invention is as follows:
the invention firstly discloses cholic acid-hexyl-triphenyl phosphonium bromide, the structural formula of which is shown as formula I:
the invention further discloses a method for preparing cholic acid-hexyl-triphenyl phosphonium bromide, which is obtained by coupling cholic acid and triphenyl phosphine with amino ends at two ends of 1,6 hexamethylene diamine respectively.
Specifically, the method comprises the following steps:
(1) Reacting cholic acid with N-hydroxy-succinimide (NHS) and Dicyclohexylcarbodiimide (DCC) in Tetrahydrofuran (THF) to generate cholic acid active ester;
(2) In the presence of N, N-Dimethylformamide (DMF), cholic acid active ester reacts with 1,6-hexamethylene diamine to generate a compound 3;
(3) Reacting triphenylphosphine bromide with N-hydroxy-succinimide (NHS) and Dicyclohexylcarbodiimide (DCC) in the presence of N, N-Dimethylformamide (DMF) to generate triphenylphosphine bromide active ester;
(4) Under the existence of N, N-Dimethylformamide (DMF), triphenyl phosphonium bromide active ester reacts with a compound 3 to generate cholic acid-hexyl-triphenyl phosphonium bromide.
The invention further discloses application of the cholic acid-hexyl-triphenyl phosphonium bromide in preparation of antitumor drugs.
In-vivo antitumor activity experiments show that the cholic acid-hexyl-triphenyl phosphonium bromide has excellent antitumor activity. Under the condition of low dose which is 1200 times lower than that of cholic acid, the cholic acid still has certain antitumor activity and is better than that of the cholic acid.
Compared with the prior art, the technical scheme of the invention has the following beneficial effects:
according to the invention, triphenyl phosphine bromide is coupled with cholic acid through 1,6-hexamethylene diamine to form a cholic acid derivative, and the cholic acid derivative can be effectively positioned in tumor cell mitochondria by utilizing the targeting effect of the triphenyl phosphine, so that the cholic acid can cause tumor cell apoptosis by inducing cell mitochondrial damage. The lead compound can more effectively play the role of resisting tumor by obviously reducing the mitochondrial membrane potential, so that the lead compound can play the role of resisting tumor at low dosage, and a new way is provided for clinical tumor treatment.
Drawings
FIG. 1 is a synthetic route of cholic acid-hexyl-triphenylphosphine bromide of the present invention;
FIG. 2 is the structural formula of cholic acid.
Detailed Description
The invention will be further described with reference to specific embodiments, and the advantages and features of the invention will become apparent as the description proceeds. It is to be understood that the described embodiments are exemplary only and are not limiting upon the scope of the invention. It will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention, and that such changes and modifications may be within the scope of the invention.
The synthetic route of the cholic acid-hexyl-triphenyl phosphonium bromide is shown in figure 1. The structural formula of cholic acid is shown in figure 2.
EXAMPLE 1 preparation of cholic acid active ester (2)
Cholic acid (compound 1,1.01g, 2.41mmol) was weighed into a reaction flask, and THF (10 mL) was added to dissolve the cholic acid. After NHS (. 35g, 3.04mmol) was dissolved in ACN (5 mL) with stirring at room temperature, cholic acid solution was slowly added. DCC (0.50g, 2.43mmol) was then dissolved in THF (10 mL) and slowly added to the cholic acid solution to form a clear reaction. After 18h of reaction, the progress of the reaction was monitored by thin layer chromatography, and the cholic acid was found to have substantially disappeared and the reaction was stopped. The reaction solution was filtered under reduced pressure and spin-dried to give a white solid. The white solid was dissolved in EtOAc (60 mL) and then saturated NaHCO 3 The reaction mixture was washed with saturated NaCl in this order for 3 times, and the obtained ethyl acetate solution was dried over anhydrous sodium sulfate for 2 hours, followed by filtration of the sodium sulfate, and the solvent was distilled off from the filtrate under reduced pressure to obtain about 0.82g of cholic acid active ester (Compound 2).
EXAMPLE 2 preparation of Hexamethylene diamine cholate (3)
1,6-hexanediamine (1.20g, 10.30mmol) was weighed out and placed in a reaction flask, DMF (7 mL) was added thereto for dissolution, and Compound 2 (0.80 g) dissolved in DMF (4 mL) was slowly added to the reaction solution at room temperature with stirring. With the addition of compound 2, the reaction solution gradually appeared a large amount of white solid from the clear, and after stirring for about 15min, the reaction progress was monitored by thin layer chromatography, and the reaction was complete. The solvent was removed and column chromatography was performed to give 0.36g (0.73 mmol) of a white solid, i.e., compound 3, in 46.33% yield. Q-TOF (m/z) 508.4201[ 2 ] M + H] + ； 1 H-NMR(300MHz,DMSO-d 6 ):δ/ppm＝7.74(s,1H),4.05(m,2H),3.78(s,1H),3.61(s,1H),3.18(m,5H),2.98-3.00(m,3H),1.96-2.28(m,5H),1.76(m,3H),1.62-1.66(m,3H),1.34-1.39(m,9H),1.24(m,10H),0.91-0.93(m,4H),0.81(s,4H),0.58(s,3H).
EXAMPLE 3 preparation of triphenylphosphine bromide active ester (5)
Triphenylphosphine bromide (compound 4,0.45g, 1.04mmol) was placed in a reaction flask, DMF (6 mL) was added thereto to dissolve it to obtain a clear solution, DCC (0.26g, 1.25mmol) and NHS (0.14g, 1.25mmol) were sequentially added to the solution, and the mixture was stirred at room temperature with exclusion of light. After stirring for half an hour, a large amount of white solid is separated out from the reaction solution, after reacting for 12 hours, monitoring the reaction process by thin layer chromatography, and finding that the triphenylphosphine bromide is basically reacted. The reaction was terminated. The reaction solution was filtered under reduced pressure to remove a white solid in the reaction solution, thereby obtaining a filtrate containing triphenylphosphine bromide active ester (compound 5).
EXAMPLE 4 preparation of cholic acid-hexyl-triphenylphosphine bromide (6)
Compound 3 (0.51g, 1.04mmol) was added to the filtrate containing compound 5 with stirring, and the reaction was left to stir at room temperature. After 15min of reaction, the progress of the reaction was monitored by thin layer chromatography, and it was found that compound 5 had reacted, the reaction was stopped, the solvent was removed, and column chromatography was performed to obtain 0.19g (0.13 mmol) of a white solid, i.e., cholic acid-hexyl-triphenylphosphine bromide (compound 6), in 19.92% yield.
Q-TOF(m/z):838.1507[M+H﹣Br] + ； 1 HNMR(300Hz,DMSO-d 6 ):δ/ppm＝7.74-7.92(m,17H),4.33(s,1H)，4.06(d,J＝24.6Hz,2H),3.77(s,1H)，3.58(m,3H),3.17(s,1H),2.99-3.02(m,4H),2.29-2.34(m,2H),1.96-2.23(m,5H),1.61-1.80(m,8H),1.34-1.38(m,10H),1.21(m,7H),1.11-1.14(m,2H),0.91-0.92(m,4H)，0.80(s,4H),0.57(s,3H)； 13 CNMR(75MHz,DMSO-d6)：δ/ppm＝172.87,170.84,135.37,134.11,130.80,119.48,118.34,71.48,70.89,66.70,46.62,46.19,41.99,41.84,38.93,38.71,35.78,35.61,35.44,35.36,35.21,34.85,33.05,32.28,30.87,29.59,29.48,29.03,27.76,26.69,26.58,26.53,23.27,23.09,20.90,20.23,18.77,17.58,12.80。
Experimental example 1 evaluation of in vivo antitumor Activity of the Compound of the present invention
The method comprises the following steps:
in vivo anti-tumor experiment, the mouse with lotus S180 sarcoma ICR (3-5 weeks old, 23 + -2 g body weight) was subculturedInoculating tumor source mice 7 days later, extracting tumor fluid S180 tumor cell fluid from abdominal cavity under aseptic condition, preparing with sterilized normal saline solution to concentration of 2 × 10 7 one/mL of S180 cell tumor fluid. After one day of rest of healthy ICR male mice, S180 cell tumor solution was inoculated in the right axilla of each mouse at a dose of 0.2 ml/mouse the following day. The mice were then randomly divided into 7 groups of 10 mice each. The administration groups were a blank control group (saline group NS), a positive control group doxorubicin (DOX, 2. Mu. Mol/kg), a negative control group (CA, 6. Mu. Mol/kg), and a compound of the present invention 6 group (0.5. Mu. Mol/kg, 0.05. Mu. Mol/kg, and 0.005. Mu. Mol/kg, respectively). And the administration is performed by intragastric administration at the same time from the third day, once a day for 10 days continuously. And the body weight of each mouse was recorded daily and the survival status was observed. After recording the body weight of each mouse on the thirteenth day, the mouse was sacrificed by removing the neck, and the body weight was weighed, and the subcutaneous tumor body was dissected and detached, and the tumor weight was weighed. Tumors were dissected from each mouse at the same time according to tumor inhibition and survival. And finally, counting the tumor inhibition rate of each group of animals. The efficacy of solid tumors is expressed as percent tumor weight inhibition and is calculated as follows:
percent tumor inhibition = (= average tumor weight in blank group-average tumor weight in experimental group)/average tumor weight in blank group x 100%;
the statistical method comprises the following steps: independent sample T-test and analysis of variance. Results are listed in table 1.
The experimental results are as follows:
the effect of compound 6 of the invention on ICR male mouse tumors is shown in table 1 below:
TABLE 1 Effect of Compound 6 of the present invention on ICR Male mouse tumors (n = 10)
Note: tumor reuse
Denotes, n =10; normal saline is denoted NS, doxorubicin is denoted DOX, cholic acid is denoted CA, cholic acid-hexyl-triphenylphosphonium bromide is denoted compound 6;
a) P <0.01 compared to NS group; b) P >0.05 compared to the NS group; c) P <0.01 compared to CA group; d) P <0.05 compared to compound 6 (0.5 μ M/kg); e) P <0.05 compared to CA group; f) P <0.01 compared to compound 6 (0.05 μ M/kg).
The statistical method comprises the following steps: independent sample T-test and analysis of variance.
And (4) analyzing results:
in an in vivo mouse transplanted tumor model, doxorubicin (DOX), cholic Acid (CA), and compound 6 of the present invention were each evaluated for anti-tumor activity, and the following results were obtained:
(1) The tumor weight of the mice taking the normal saline is 1.87 +/-0.44 g, the tumor weight of the mice taking the adriamycin (DOX) is 0.55 +/-0.10 g, compared with the normal saline, the tumor inhibition rate of the adriamycin (DOX) is 70.54 percent, and compared with the normal saline, p is less than 0.01, and the statistical difference is significant, which indicates that the establishment of the mouse transplantation tumor model is successful.
(2) The tumor weight of mice taking cholic acid (CA at a dose of 6 mu mol/kg) is 1.60 +/-0.38 g, the tumor inhibition rate is 14.79%, and p is greater than 0.05 compared with normal saline, so that the tumor inhibition rate is not statistically different, which indicates that the Cholic Acid (CA) does not show the anti-tumor activity at the dose of 6 mu mol/kg.
(3) The tumor weight of a mouse taking the compound 6 (0.5 mu mol/kg) is 0.87 +/-0.12 g, the tumor inhibition rate is 53.29 percent, p is less than 0.01 compared with normal saline, and the two groups of differences have obvious statistical difference, which indicates that the compound 6 has excellent anti-tumor activity at the dose. The dose of the compound 6 is reduced to 0.05 mu mol/kg), the tumor weight of the mouse is 1.03 +/-0.17 g, the tumor inhibition rate is 45.22%, and compared with physiological saline, p is less than 0.01, and the difference between the two is very significant, which indicates that the compound 6 has better anti-tumor activity under the dose. The dosage of the compound 6 is continuously reduced to 0.005 mu mol/kg, the tumor weight of a mouse is 1.31 +/-0.19 g, the tumor inhibition rate is 30.22%, p is less than 0.01 compared with normal saline, and two groups of differences have very significant significance, so that the compound 6 shows certain antitumor activity under the dosage; compared with cholic acid (6 mu mol/kg), p is less than 0.05, and two groups of differences have significant significance, which indicates that the compound 6 still has better anti-tumor activity than the cholic acid under the condition of low dose which is 1200 times lower than the dose of the cholic acid.
In summary, the following steps: the novel antitumor compound 6 adopts proper orientation in the process of generating drug effect through the flexible chain 1,6-hexanediamine under the mediation of triphenylphosphine, and targets and carries cholic acid to mitochondria of tumor cells, so that the mitochondria of the cholic acid are targeted. The implementation of the invention can achieve the purposes of small dosage of the lead compound and high curative effect. The compound 6 of the present invention has excellent antitumor activity at a dose of 0.5. Mu. Mol/kg, and still has a certain antitumor activity even at a low dose of 0.005. Mu. Mol/kg which is 1200 times lower than that of cholic acid. The anti-tumor lead compound provided by the invention provides a new path for clinical application of cholic acid derivatives, and shows a potential application prospect in the field of tumor treatment.
Claims (4)
1. A compound cholic acid-hexyl-triphenyl phosphonium bromide has a structural formula shown as a formula I:
2. a method for preparing the compound of claim 1, which is obtained by coupling cholic acid and triphenylphosphine with amino terminals at two ends of 1,6 hexamethylenediamine respectively.
3. The method of claim 2, comprising the steps of:
1) Reacting cholic acid with N-hydroxy-succinimide (NHS) and dicyclohexylcarbodiimide in tetrahydrofuran to produce cholic acid active ester of the formula,
2) In the presence of N, N-dimethylformamide, cholic acid active ester reacts with 1,6-hexamethylenediamine to generate monosubstituted hexamethylenediamine derivative of cholic acid with the following formula,
3) Reacting triphenylphosphine bromide with N-hydroxy-succinimide (NHS) and dicyclohexylcarbodiimide in the presence of N, N-dimethylformamide to produce triphenylphosphine bromide active ester of the formula,
4) Reacting an activated ester of triphenylphosphine bromide with a mono-substituted hexamethylenediamine cholic acid derivative in the presence of N, N-dimethylformamide to form the compound cholic acid-hexyl-triphenylphosphine bromide according to claim 1.
4. The use of a compound as claimed in claim 1 in the preparation of an anti-neoplastic medicament.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910399159.8A CN111944005B (en) | 2019-05-14 | 2019-05-14 | Cholic acid-hexyl-triphenyl phosphonium bromide and preparation method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910399159.8A CN111944005B (en) | 2019-05-14 | 2019-05-14 | Cholic acid-hexyl-triphenyl phosphonium bromide and preparation method and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN111944005A CN111944005A (en) | 2020-11-17 |
| CN111944005B true CN111944005B (en) | 2023-04-18 |
Family
ID=73335654
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910399159.8A Active CN111944005B (en) | 2019-05-14 | 2019-05-14 | Cholic acid-hexyl-triphenyl phosphonium bromide and preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN111944005B (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105732758A (en) * | 2016-04-07 | 2016-07-06 | 河南省科学院化学研究所有限公司 | Cholic acid-alpha-amino phosphonate derivative and synthesis method thereof |
| CN108997514A (en) * | 2017-06-06 | 2018-12-14 | 首都医科大学 | The preparation and application of mono- 6- (bendamustine amide groups) -6- deoxidation-beta-cyclodextrin |
| CN109675048A (en) * | 2019-01-07 | 2019-04-26 | 中国科学院化学研究所 | A kind of anticancer prodrug liposome and artemisine liposome Nano medication |
-
2019
- 2019-05-14 CN CN201910399159.8A patent/CN111944005B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105732758A (en) * | 2016-04-07 | 2016-07-06 | 河南省科学院化学研究所有限公司 | Cholic acid-alpha-amino phosphonate derivative and synthesis method thereof |
| CN108997514A (en) * | 2017-06-06 | 2018-12-14 | 首都医科大学 | The preparation and application of mono- 6- (bendamustine amide groups) -6- deoxidation-beta-cyclodextrin |
| CN109675048A (en) * | 2019-01-07 | 2019-04-26 | 中国科学院化学研究所 | A kind of anticancer prodrug liposome and artemisine liposome Nano medication |
Also Published As
| Publication number | Publication date |
|---|---|
| CN111944005A (en) | 2020-11-17 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US9321804B2 (en) | Synthesis and use of anti-tumor drug LQC-Y | |
| JP3697210B2 (en) | Anti-tumor derivative of double dicarboxylic acid diaminoplatin complex, preparation method thereof, pharmaceutical composition containing the same and application method of the derivative | |
| CN104812761B (en) | Double B-carboline alkaloid compounds, its preparation method and its pharmaceutical composition and purposes | |
| CN101181225B (en) | System for transferring nanometer polyalcohol micelle medicament and preparing method as well as application thereof | |
| CN106866572A (en) | Nitric oxide donator type β elemene derivatives and its production and use | |
| CN111944005B (en) | Cholic acid-hexyl-triphenyl phosphonium bromide and preparation method and application thereof | |
| CN100513415C (en) | Bile acid derivative and pharmaceutical use thereof | |
| CN105481946A (en) | Conjugate of 5-aminolevulinic acid and 3-pyridone-4-ketone and preparation method as well as use thereof | |
| CN103570806A (en) | Polypeptide epoxy ketone compound | |
| CN104327156A (en) | Dihydroporphine photosensitizer and sonosensitizer and preparation method and application thereof | |
| NO331833B1 (en) | Bis- (N'N'-bis- (2-haloethyl) amino) phosphoramidate compounds, pharmaceutical composition comprising such compounds, use of the compounds as antitumor agents, and methods for preparing the compounds | |
| JP4598227B2 (en) | Compounds that are sensitizers in radiation and chemotherapy and methods for their production and use | |
| US11267840B1 (en) | Compound or salt thereof | |
| CN105960399B (en) | Enzyme inhibitor epoxy ketone compound | |
| CN102503897B (en) | 5-fluorouracil iodized oil derivative as well as preparation method and application thereof | |
| CN101440113B (en) | Colchicine derivative-bile acid coupling compounds and medical use thereof | |
| CN107200769A (en) | It is a kind of that there is the rotundic acid derivative for preventing and treating metastasis effect | |
| CN102702297B (en) | Preparation method of cholic acid-naphthalimide compound | |
| CN105732758B (en) | Cholic acid α aminophosphonate ester derivatives and its synthetic method | |
| CN111410677A (en) | 2-methoxy estramustine and derivatives, preparation method and application thereof | |
| CN100369914C (en) | 3-ene-8-ethyl-2,7,12,15,18-pentamethyl-13-carboxylic acid-17-propionic acid amino acid amide, its synthetic method and light power therapeutic medicine | |
| CN104974215A (en) | Betulinic acid-amino acid derivative, and preparation method and application thereof | |
| CN102040627A (en) | Phosphorus-containing compound and its medicament application for treatment of bone metabolism abnormity | |
| CN102690313B (en) | Cholic acid-naphthoylimine compounds and application thereof | |
| CN113024450B (en) | Dithio-methyl cobalt (III) complex and preparation method and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |