CN105367575B - A kind of folacin compound, its preparation method and medical usage - Google Patents
A kind of folacin compound, its preparation method and medical usage Download PDFInfo
- Publication number
- CN105367575B CN105367575B CN201510890528.5A CN201510890528A CN105367575B CN 105367575 B CN105367575 B CN 105367575B CN 201510890528 A CN201510890528 A CN 201510890528A CN 105367575 B CN105367575 B CN 105367575B
- Authority
- CN
- China
- Prior art keywords
- folic acid
- acid
- esters
- acyl group
- resina garciniae
- 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
- 0 C*C(c(cc1*)cc(C(c2cccc([*-])c22)=[U])c1C2=C)=[U] Chemical compound C*C(c(cc1*)cc(C(c2cccc([*-])c22)=[U])c1C2=C)=[U] 0.000 description 4
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D475/00—Heterocyclic compounds containing pteridine ring systems
- C07D475/02—Heterocyclic compounds containing pteridine ring systems with an oxygen atom directly attached in position 4
- C07D475/04—Heterocyclic compounds containing pteridine ring systems with an oxygen atom directly attached in position 4 with a nitrogen atom directly attached in position 2
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
Abstract
The present invention relates to pharmaceutical chemistry and pharmacotherapeuticss field, and in particular to folacin compound or its pharmaceutically acceptable salt, the invention further relates to the preparation method of this kind of compound and the drug regimen containing them.Such compound has antitumor action, can be used to prepare antitumor drug.
Description
Technical field
The present invention relates to pharmaceutical chemistry and pharmacotherapeuticss field, and in particular to folacin compound or its can pharmaceutically connect
The salt received, the preparation method containing these compounds and Pharmaceutical composition, their medical usage are particularly preparing anti-swelling
Application in tumor medicine.
Background technology
Malignant tumor is the class disease for seriously threatening human life, what World Health Organization (WHO) issued《Global cancer report
2014》Prediction, global cases of cancer will be presented swift and violent growing trend, and by 14,000,000 people of 2012, cumulative year after year was to 2025
19,000,000 people, be up to 24,000,000 people by 2035.Although clinically there is various antitumor drug available, due to swollen
The factors such as the toxic and side effects of drug resistance and antitumor drug of tumor, still lack the medicine that can effectively cure, and need exploitation badly new
Medicine is meeting tumor patient needs.Target tumor medicine is because of its high specificity, it is possible to reduce the damage of normal tissue, toxicity
(bone marrow depression, alopecia and renal function injury etc.) is significantly reduced, and occupies increasingly consequence in oncotherapy.With tumor
Cell specific molecules target spot is the main trend that the medicament research and development being oriented to has become modern antitumor drug development.
Vitamin is the required material of cell growth, and tumor cell needs to consume substantial amounts of vitamin because of its fast breeding,
In its cell surface often overexpression multivitamin receptor, therefore, some vitamin receptors have becomes knubble biological mark
The important potentiality of will thing.Folic Acid (Folic acid, FA) is water soluble vitamins needed by human, and it is one carbon unit transferring enzyme
The coenzyme of system, participates in one carbon unit metabolism, and the facilitation of key is played in terms of cell growth with division.Research shows, leaf
Acid acceptor (FR) is thin in malignant tumor such as ovarian cancer, renal carcinoma, carcinoma of endometrium, carcinoma of testis, cerebroma, adenocarcinoma of lung, gastric cancer and hepatocarcinoma
Have overexpression in born of the same parents, and in normal cell and tissue low expression, highly combined using Folic Acid and its receptor-specific this
One characteristic and FR are reached in tumor tissues altimeter, FA is coupled with antitumor drug, folate-targeted medicine is prepared, can be passed through tumor
The specificity endocytosiss of cell surface FR mediations are realizing the active targeting conveying function of cancer therapy drug.
Chrysophanic acid (Rhein, 4,5-dihydroxyanthraquinone, RH) be Chinese medicine Radix Et Rhizoma Rhei effective active into
/ mono-, with antiinflammatory, antitumor, anti-Alzheimer disease, antibacterial, antiviral, antioxidation, hypoglycemic fat-regulating, liver protection, anti-fiber
Various pharmacologically actives such as change.Research shows that chrysophanic acid has the antitumor action of wide spectrum, such as to murine melanoma, non-little thin
Born of the same parents' pulmonary carcinoma, colon cancer, hepatocarcinoma, breast carcinoma, P388 leukaemia etc. have certain inhibitory action, and mechanism of action is various,
The propagation of tumor cell, the apoptosis of inducing tumor cell can be suppressed, suppress tumor-blood-vessel growth, containment Nasopharyngeal neoplasms, suppression
Energy metabolism processed and the multidrug resistance of reversing tumor cell.Gamlogic acid (gambogic acid), neogambogic acid
(Gambogenic acid) is the main active of Chinese medicine Resina garciniae.Research shows that gamlogic acid, neogambogic acid are respectively provided with
Strong anti-tumor activity, can pass through inducing cell cycle arrest and apoptosis, suppress telomerase and topoisomerase active, suppression
The different mechanisms such as Antineoplastic angiogenesis processed and neoplasm metastasis, reverse multidrug drug resistance play antitumor action.
Folic Acid and the chrysophanic acid with anti-tumor activity, gamlogic acid and neogambogic acid are coupled by the present invention, design, synthesis
A series of Folic Acid analog derivatives, are specifically bound with folacin receptor using Folic Acid, effectively by chrysophanic acid, gamlogic acid and new Resina garciniae
Acid is transmitted to tumor cell, significantly improves drug target tropism, while improving its therapeutical effect, reduces toxic and side effects；Profit
With the hydrophilic of Folic Acid, increase the water solublity of folate conjugate, improve its bioavailability.
The content of the invention
Present invention firstly discloses a class has folacin compound, its preparation method and its doctor of targeting anti-tumor activity
Medicinal way.It is demonstrated experimentally that such compound water soluble is better than chrysophanic acid, gamlogic acid and neogambogic acid, and it is swollen with good resisting
Tumor activity, therefore, they can be used to treat tumor.
Compound disclosed by the invention is the folacin compound shown in formula I or its pharmaceutically acceptable salt：
Wherein：R represents R1O(CH2)n；
N is 1～6 integer；R1For Radix Et Rhizoma Rhei acyl group (a), Resina garciniae acyl group (b), new Resina garciniae acyl group (c).
Further, compound described in formula I or its pharmaceutically acceptable salt, it is characterised in that：
R represents R1O(CH2)n；N is 2～6；R1For Radix Et Rhizoma Rhei acyl group (a), Resina garciniae acyl group (b), new Resina garciniae acyl group (c).
Specifically, compound described in formula I preferably is selected from following compounds：
Folic Acid -2- Radix Et Rhizoma Rhei methylaminosulfonylethyl esters；
Folic Acid -3- Radix Et Rhizoma Rhei acyl propyl esters；
Folic Acid -4- Radix Et Rhizoma Rhei acyl group butyl esters；
Folic Acid -5- Radix Et Rhizoma Rhei acyl group amyl group esters；
Folic Acid -6- Radix Et Rhizoma Rhei acyl group hexyl esters；
Folic Acid -2- Resina garciniae methylaminosulfonylethyl esters
Folic Acid -3- Resina garciniae acyl propyl esters；
Folic Acid -4- Resina garciniae acyl group butyl esters；
Folic Acid -5- Resina garciniae acyl group amyl group esters；
Folic Acid -6- Resina garciniae acyl group hexyl esters；
The new Resina garciniae methylaminosulfonylethyl esters of Folic Acid -2-；
The new Resina garciniae acyl propyl esters of Folic Acid -3-；
The new Resina garciniae acyl group butyl esters of Folic Acid -4-；
The new Resina garciniae acyl group amyl group esters of Folic Acid -5-；
The new Resina garciniae acyl group hexyl esters of Folic Acid -6-.
The compounds of this invention and its intact part of the present invention is constituted with the salt of pharmaceutically acceptable alkali or acid；In pharmaceutically acceptable alkali
There are basic amino acid, sodium hydroxide, potassium hydroxide, calcium hydroxide etc.；There is hydrochloric acid in pharmaceutically acceptable acid, hydrobromic acid, sulphuric acid, phosphoric acid,
Acetic acid, lactic acid, acetone acid, malonic acid, succinic acid, 1,3-propanedicarboxylic acid, fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid, first
Sulfonic acid, dextrocamphoric acid., oxalic acid etc..
Another object of the present invention is to provide the preparation method of compound described in formula I of the present invention, it is characterised in that bag
Include following steps：
With chrysophanic acid, gamlogic acid or neogambogic acid as raw material, in the basic conditions with two bromoalkane Br- (CH2)n- Br is anti-
Should, corresponding list bromo alcohol ester is obtained, then is reacted with Folic Acid, compound of Formula I is obtained.Synthetic route is as follows：
Wherein：Br-(CH2)nIn-Br and R, n=1-6；
Prepare compound of Formula I to be characterised by, catalyst is KI, and alkali is pyridine (Pyridine), and solvent is DMSO, instead
Temperature is answered for 40～50 DEG C, the response time is 10-12h, and these intermediate or target compound can be according to conventional isolation techniques
Purification in addition, and as needed by its with alkali metal ion, organic base, basic amino acid or pharmaceutically acceptable acid into salt.
It is a further object of the present invention to provide a kind of compound of Formula I of the present invention containing effective dose and can pharmaceutically connect
The carrier received or the pharmaceutical composition of adjuvant.
Another object of the present invention is to provide application of the compound of Formula I in tumor is prepared, and especially controls
Treat the application in hepatocarcinoma, breast carcinoma, gastric cancer, cervical cancer, pulmonary carcinoma, colon cancer and leukemia medicament.
The water solublity and antitumor pharmacological experimental method of the compounds of this invention is as follows with result：
The corresponding structure of the compounds of this invention code name is shown in Table 1.
(1) solubility experiment
Experimental technique：Take in a certain amount of medium of compound of Formula I addition of appropriate excess, 37 DEG C of constant-temperature table 72h, centrifugation
Supernatant is taken, ultraviolet spectrophotometry detects its content, calculates dissolubility.
Test result：Dissolubility of the compounds of this invention in water is listed in table 2, tester is chrysophanic acid, gamlogic acid
And neogambogic acid.
Dissolubility (mg/mL) of the 2 Folic Acid analog derivative of the present invention of table in water
2 experimental data of table shows, chrysophanic acid folate conjugate according to the present invention, gamlogic acid folate conjugate and new Resina garciniae
The water solublity of sour folate conjugate is significantly increased compared with chrysophanic acid, gamlogic acid and neogambogic acid.
(2) anti tumor activity in vitro test
Antiproliferative of the compound of the present invention to 7 kinds of man―machine systems is evaluated using tetramethyl nitrogen azoles indigo plant colorimetry (MTT)
Activity.Mtt assay is widely used in the sensitive measure of large-scale screening anti-tumor medicine, cell toxicity test and tumour radiotherapy
Deng.Positive control drug is chrysophanic acid, gamlogic acid and neogambogic acid.
Cell strain：Hepatocellular carcinoma H22, colon cancer HCT-116, K562 Leukaemia, breast cancer cell MCF-7, palace
Neck cancer cell Hela, stomach cancer cell SGC-7901, pulmonary carcinoma A549.
Experimental technique：Compound DMSO is dissolved, and desired concn is diluted to PBS.Take in exponential phase of growth, growth
One bottle of cell in good condition, adds 0.25% trypsinization, makes attached cell come off, and makes per milliliter containing 2 × 104-4
×104The suspension of individual cell.Obtained cell suspension is inoculated on 96 orifice plates, per 180 μ L of hole, puts constant temperature CO2In incubator, culture 24 is little
When.Liquid is changed, is added by test solution, per 20 μ L of hole, cultivated 48 hours.Add tetramethyl nitrogen azoles blue in 96 orifice plates, per 20 μ L of hole, training
React 4 hours in foster case.Supernatant is sucked, DMSO is added, per 150 μ L of hole, is shaken 5 minutes on plate shaker.Use enzyme linked immunological
Detector is that the trap per hole is determined at 490nm in wavelength, calculates cell inhibitory rate.
Pass through probit using SPSS (Staffstical Package for the Social Science) 17.0
Weighted regression method (Bliss methods) calculates IC50.Experimental result is as shown in table 3.
Inhibitory activity (%) when the compound concentration of 3 present invention of table is 10 μM to tumor cell proliferation
Above pharmacology data shows that chrysophanic acid folate conjugate according to the present invention has stronger suppression tumor cell
The activity of propagation, and apparently higher than positive control drug chrysophanic acid；Gamlogic acid folate conjugate, neogambogic acid folate conjugate suppress
The proliferation activity of tumor cell is suitable or higher with gamlogic acid, neogambogic acid.
Specific embodiment：
Present disclosure is illustrated below by embodiment.In the present invention, example described below is in order to more
The good elaboration present invention, is not for limiting the scope of the present invention.
Embodiment 1
The synthesis of chrysophanic acid -6- bromine hexyl esters
Chrysophanic acid (284mg, 1mmol) is added in 50mL round-bottomed flasks, with THF as solvent, will after being stirred at room temperature 5 minutes
1,6- dibromo-hexane (4mmol), triethylamine (4mmol), tetra-n-butyl ammonium bromide (40.3mg, 0.25mmol) add round-bottomed flask
In, continuing to be stirred at room temperature, TLC detection reaction process is reacted after 18h complete.Concentrating under reduced pressure, silica gel column chromatography are separated.Decompression is dense
Contracting, drying, obtains crocus solid chrysophanic acid -6- bromine hexyl ester 404.1mg, yield 90.6%.m.p.:131.4-132.6℃.
The synthesis of Folic Acid -6- Radix Et Rhizoma Rhei acyl group hexyl esters
Chrysophanic acid -6- bromine hexyl esters (111.5mg, 0.25mmol), Folic Acid (132.3mg, 0.3mmol), pyridine 5 are dripped,
KI (49.8mg, 0.3mmol) is placed in 50mL round-bottomed flasks, plus DMSO 8mL, 45 DEG C of lucifuge reactions, TLC detection reaction process,
React after 12.6h complete.Room temperature is cooled to, add water 50mL, is extracted with ethyl acetate (3 × 20mL), merged organic layer, use saturation
Brine It, concentrating under reduced pressure, silica gel column chromatography are separated.Obtain brown-red powder 129.5mg, yield 64.2%.ESI-MS m/z:
808.6[M+H]+；m.p.:163.6-164.2℃；IR(KBr,cm-1):3402,3039,2927,2854,1731,1629,
1488,1292,1265；1H-NMR(400MHz,DMSO)δ9.18(s,2H),8.65(s,1H),8.21(s,2H),8.05(s,
1H),7.80(m,3H),7.44(s,1H),4.70(t,2H),4.37(t,2H),2.54(m,3H),1.96(m,6H),1.16(m,
6H).Inhibitory activity of the Folic Acid -6- Radix Et Rhizoma Rhei acyl group hexyl esters to hepatocellular carcinoma H22：IC50For 9.4 μM of (chrysophanic acids：IC50>100
μM)。
Embodiment 2
The synthesis of gamlogic acid -2- bromo-ethyl esters
By gamlogic acid (628mg, 1mmol), glycol dibromide (4mmol), potassium carbonate (138mg, 1mmol), DMF15mL
In adding 100mL round-bottomed flasks, it is stirred at room temperature, TLC detection reaction process is reacted after 2h complete.Add water 150mL, ethyl acetate
Extraction (50mL × 3), merges organic layer, uses saturated common salt water washing, anhydrous sodium sulfate drying.Concentrating under reduced pressure, silica gel column chromatography
Separate.Obtain crocus solid gamlogic acid -2- bromo-ethyl ester 589.4mg, yield 80.3%.m.p.:85.6-86.1℃.
The synthesis of Folic Acid -2- Resina garciniae methylaminosulfonylethyl esters
Folic Acid (83.8mg, 0.19mmol) is taken, gamlogic acid -2- bromo-ethyl esters (117.4mg, 0.16mmol), pyridine 4 drip,
DMSO 10mL are placed in 100mL round-bottomed flasks, 45 DEG C of lucifuge reactions, and TLC detection reaction process is reacted after 10.5h complete.It is cold
But to room temperature, add water 20mL, is extracted with ethyl acetate (3 × 20mL), merges organic layer, uses saturated common salt water washing, reduces pressure dense
Contracting, silica gel column chromatography are separated.Obtain 97.6mg yellow waxy things, yield 55.7%.ESI-MS m/z：1096.0[M+H]+；IR
(KBr,cm-1)3417,2965,2929,2853,1735,1701,1630,1588,1457,1370,1325；1H-NMR
(400MHz, DMSO) δ 9.10 (s, 2H), 8.64 (t, J=7.3Hz, 1H), 8.20 (d, J=6.0Hz, 2H), 7.49 (d, J=
7.1Hz,1H),5.88(s,1H),5.11(s,1H),4.68-4.47(m,3H),4.18(s,1H),3.93-3.69(m,2H),
3.44(t,2H),3.34(m,4H),3.12(m,1H),2.80-2.48(m,6H),2.23(m,2H),2.10(m,2H),1.95-
1.44 (m, 21H), 1.32 (m, 6H). Folic Acid -2- Resina garciniae methylaminosulfonylethyl esters are to hepatocellular carcinoma H22 inhibitory activity：IC50For 0.14
μM (gamlogic acid：IC50For 0.59 μM).
Embodiment 3
The synthesis of neogambogic acid -3- bromopropyl esters
In dry 50ml round-bottomed flasks, by neogambogic acid (320mg, 0.5mmol), K2CO3(140mg, 1mmol) and
1,3- dibromopropane (4mmol) is dissolved in 10mL DMF, and 1h is stirred at room temperature.Filter, filtrate adds water 100mL, ethyl acetate (3 ×
30mL) extract, merge organic layer, plus saturated common salt washing, use anhydrous Na2SO4It is dried, filtrate is concentrated after filtration, silicagel column color
Spectrum is separated.Obtain glassy yellow grease neogambogic acid bromo propanol ester 345mg, yield：92%.
The synthesis of the new Resina garciniae acyl propyl esters of Folic Acid -3-
Take Folic Acid (132.3mg, 0.3mmol), neogambogic acid -3- bromopropyl esters (187.5mg, 0.25mmol), pyridine 7
Drop, DMSO 10mL are placed in 100mL round-bottomed flasks, 45 DEG C of lucifuge reactions, and TLC detection reaction process is reacted after 10h complete.It is cold
But to room temperature, add water 20mL, is extracted with ethyl acetate (3*20mL), merges organic layer, uses saturated common salt water washing, reduces pressure dense
Contracting, silica gel column chromatography are separated.Obtain 152.7mg yellow waxy things, yield 55%.ESI-MSm/z：1112.5[M+H]+；IR(KBr,
cm-1)3417,2925,2929,2853,1736,1708,1633,1588,1457,1370,1384,1137；1H-NMR
(500MHz,CDCl3) 12.86 (1H, s, 6-OH), 8.60 (s, 1H), 7.62 (d, 2H), 7.47 (d, 1H, J=6.7Hz), 6.62
(d, 2H), 5.86 (t, 1H, J=6.6Hz), 5.33-5.09 (m, 3H), 4.46 (s, 2H), 4.36 (d, 1H), 4.21-3.36
(m,4H),3.47-3.18(m,5H),3.18-2.88(m,3H),2.00-1.85(m,7H),1.75(s,3H),1.71(s,3H),
1.67 (s, 3H), 1.64 (s, 9H), 1.56 (s, 3H), 1.39 (m, 5H), 1.28 (s, 3H). the new Resina garciniae acyl propyls of Folic Acid -3-
Ester is to hepatocellular carcinoma H22 inhibitory activity：IC50For 0.11 μM of (neogambogic acid：IC50For 3.23 μM).
Claims (7)
1. folacin compound shown in formula I or its pharmaceutically acceptable salt
Wherein：R represents R1O(CH2)n；
N is 1～6 integer；R1For Radix Et Rhizoma Rhei acyl group (a), Resina garciniae acyl group (b), new Resina garciniae acyl group (c).
2. compound of Formula I according to claim 1 or its pharmaceutically acceptable salt, it is characterised in that：
R represents R1O(CH2)n；N is 2～6；R1For Radix Et Rhizoma Rhei acyl group (a), Resina garciniae acyl group (b), new Resina garciniae acyl group (c)
3. folacin compound according to claim 1 or its pharmaceutically acceptable salt, it is characterised in that the chemical combination
Thing is selected from：
Folic Acid -2- Radix Et Rhizoma Rhei methylaminosulfonylethyl esters；
Folic Acid -3- Radix Et Rhizoma Rhei acyl propyl esters；
Folic Acid -4- Radix Et Rhizoma Rhei acyl group butyl esters；
Folic Acid -5- Radix Et Rhizoma Rhei acyl group amyl group esters；
Folic Acid -6- Radix Et Rhizoma Rhei acyl group hexyl esters；
Folic Acid -2- Resina garciniae methylaminosulfonylethyl esters
Folic Acid -3- Resina garciniae acyl propyl esters；
Folic Acid -4- Resina garciniae acyl group butyl esters；
Folic Acid -5- Resina garciniae acyl group amyl group esters；
Folic Acid -6- Resina garciniae acyl group hexyl esters；
The new Resina garciniae methylaminosulfonylethyl esters of Folic Acid -2-；
The new Resina garciniae acyl propyl esters of Folic Acid -3-；
The new Resina garciniae acyl group butyl esters of Folic Acid -4-；
The new Resina garciniae acyl group amyl group esters of Folic Acid -5-；
The new Resina garciniae acyl group hexyl esters of Folic Acid -6-.
4. the preparation method of the folacin compound described in claim 1, it is characterised in that：
With chrysophanic acid, gamlogic acid or neogambogic acid as raw material, in K2CO3Make under conditions of acid binding agent with two bromoalkane Br- (CH2)n-
Br reacts, and obtains corresponding list bromo alcohol ester, then reacts with Folic Acid, and with KI as catalyst, pyridine (Pyridine) is alkali, DMSO
For solvent, reaction temperature is 40～50 DEG C, and the response time is 10-12h, and compound of Formula I is obtained, and synthetic route is as follows：
Wherein：Br-(CH2)nIn-Br and R, n=1-6
5. a kind of pharmaceutical composition, wherein compound of Formula I described in the claim 1 containing therapeutically effective amount or its pharmaceutically
Acceptable salt and carrier.
6. the purposes of the compound of Formula I of claim 1 or its pharmaceutically acceptable salt in the medicine for preparing treatment tumor.
7. the purposes of claim 6, wherein tumor disease is hepatocarcinoma, breast carcinoma, gastric cancer, cervical cancer, leukemia, pulmonary carcinoma, colon
Cancer.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510890528.5A CN105367575B (en) | 2015-12-03 | 2015-12-03 | A kind of folacin compound, its preparation method and medical usage |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510890528.5A CN105367575B (en) | 2015-12-03 | 2015-12-03 | A kind of folacin compound, its preparation method and medical usage |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN105367575A CN105367575A (en) | 2016-03-02 |
| CN105367575B true CN105367575B (en) | 2017-03-29 |
Family
ID=55370260
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510890528.5A Active CN105367575B (en) | 2015-12-03 | 2015-12-03 | A kind of folacin compound, its preparation method and medical usage |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105367575B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106083898B (en) * | 2016-05-31 | 2019-02-12 | 彭咏波 | A kind of tumor-targeting gambogic acid compounds and its preparation method and application |
| CN107098907A (en) * | 2017-06-13 | 2017-08-29 | 佛山科学技术学院 | A kind of bicyclic alcohols folate conjugate and its production and use |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102558193A (en) * | 2012-01-18 | 2012-07-11 | 上海交通大学医学院附属第九人民医院 | Gambogenic acid derivatives, and preparation method and application thereof |
| CN103304575A (en) * | 2012-03-14 | 2013-09-18 | 何黎琴 | Neogambogic acid derivative, preparation method thereof and pharmaceutical application |
| CN102988293B (en) * | 2012-11-23 | 2014-11-05 | 杭州师范大学 | Oxaliplatin folic acid targeted lipidosome and application thereof |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS63227588A (en) * | 1987-03-16 | 1988-09-21 | Meiji Seika Kaisha Ltd | Methotrexate derivative |
| US9415113B2 (en) * | 2009-11-18 | 2016-08-16 | University Of Washington | Targeting monomers and polymers having targeting blocks |
-
2015
- 2015-12-03 CN CN201510890528.5A patent/CN105367575B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102558193A (en) * | 2012-01-18 | 2012-07-11 | 上海交通大学医学院附属第九人民医院 | Gambogenic acid derivatives, and preparation method and application thereof |
| CN103304575A (en) * | 2012-03-14 | 2013-09-18 | 何黎琴 | Neogambogic acid derivative, preparation method thereof and pharmaceutical application |
| CN102988293B (en) * | 2012-11-23 | 2014-11-05 | 杭州师范大学 | Oxaliplatin folic acid targeted lipidosome and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN105367575A (en) | 2016-03-02 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Cao et al. | Synthesis and structure–activity relationships of harmine derivatives as potential antitumor agents | |
| CN104039796B (en) | 1-oxo/acylated Oridonin derivative acylated for-14-, and its preparation method and application | |
| CN105153142B (en) | The Furazan Derivatives and antitumor activity of cumarin parent nucleus | |
| CN102584780B (en) | Glaucocalyxin derivative as well as preparing method and application thereof | |
| CN103965118B (en) | One class pinane base-2-amino-metadiazine compound and synthetic method thereof and application | |
| CN107793424A (en) | Parthenolide derivative, its medical composition and its use | |
| CN105367575B (en) | A kind of folacin compound, its preparation method and medical usage | |
| CN112174940A (en) | 3- (6, 7-bis (2-methoxyethoxy) -quinazoline-4-amido) phenyl-1H-triazole derivative | |
| CN114195814A (en) | Hydroxy naphthalenone-phenylboronic acid compound, preparation method and application | |
| CN104086617A (en) | Cleistanone dimethylamine derivative and preparation method and use thereof | |
| CN102126993A (en) | Resveratrol derivative and application thereof to preparation of antitumor medicaments | |
| CN110002987A (en) | Phenyl acrol cyclohexenone derivates and preparation method and purposes | |
| CN104327156B (en) | Dihydro porphin light, sound sensitiser and preparation method and application | |
| CN106883244B (en) | Scutellarin derivative and its preparation method and application | |
| CN101270102A (en) | Process for synthesizing parthenolide derivative and uses thereof | |
| WO2011131102A1 (en) | Preparation method of lactone and use thereof | |
| CN103864765B (en) | Benzazepine analog derivative containing five-membered ring, Preparation Method And The Use | |
| CN103864810A (en) | Preparation method of novel 10-hydroxycamptothecine 10-position derivatives and application in antitumor drugs | |
| CN102731454A (en) | Dehydrocostunolide derivative, its pharmaceutical composition, preparation method and application thereof | |
| CN102276433B (en) | Longistylin C and derivative thereof and preparing the application in cancer therapy drug | |
| Mustafa et al. | Synthesis, antioxidant and antitumor activities of new coumarins grafted to 5-fluorouracil | |
| CN102516066B (en) | Ostopanic acid analog and Preparation method and use | |
| CN109734715A (en) | A kind of efficient DNA target is to anti-tumor drug and its synthetic method and application | |
| CN106543155B (en) | Chalcone and flavonoid derivative as aurora kinase inhibitor | |
| CN103880793B (en) | Containing furan imine compound and its production and use |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20200727 Address after: 230031 Mei mountain road, 103, Anhui, Hefei Patentee after: ANHUI University OF CHINESE MEDICINE Address before: 230031 Anhui city of Hefei province history River Road No. 8 Patentee before: He Liqin |
|
| TR01 | Transfer of patent right |