CN103772696A - Polyglycerol fatty acid ester derivative of hydroxycamptothecine - Google Patents
Polyglycerol fatty acid ester derivative of hydroxycamptothecine Download PDFInfo
- Publication number
- CN103772696A CN103772696A CN201410003747.2A CN201410003747A CN103772696A CN 103772696 A CN103772696 A CN 103772696A CN 201410003747 A CN201410003747 A CN 201410003747A CN 103772696 A CN103772696 A CN 103772696A
- Authority
- CN
- China
- Prior art keywords
- hydroxycamptothecine
- fatty acid
- acid ester
- polyglycerol fatty
- polyglycerine
- 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.)
- Granted
Links
- 0 CCC=C=CC1=C(CC)C(C)C(CC(*2)C3**4C2=C*=CC4)C3=C1 Chemical compound CCC=C=CC1=C(CC)C(C)C(CC(*2)C3**4C2=C*=CC4)C3=C1 0.000 description 5
- WDKYANXOUCNTSZ-UHFFFAOYSA-N CC(C)(CC(COC1)OC1(C)C=C)OC(C(C)(C)C1C=C1)=O Chemical compound CC(C)(CC(COC1)OC1(C)C=C)OC(C(C)(C)C1C=C1)=O WDKYANXOUCNTSZ-UHFFFAOYSA-N 0.000 description 1
Abstract
The invention relates to a polyglycerol fatty acid ester derivative of hydroxycamptothecine. The polyglycerol fatty acid ester derivative is characterized by being of a structure that polyglyceryl fatty acid and hydroxyl on a 10th position of the hydroxycamptothecine form ester. The invention describes a structure characteristic, a conventional preparation method and an application of the polyglycerol fatty acid ester derivative in the aspect of anti-tumor medicines.
Description
Technical field
Key in herein technical field and describe paragraph.The present invention relates to pharmaceutical field, particularly relate to polyglycerol fatty acid ester derivative of a kind of hydroxycamptothecine and preparation method thereof, with and in the purposes of preparing aspect antitumor drug.
Background technology
Camptothecine (Camptothecin, CPT), its structure, as shown in formula I, is separated and obtains from Chinese endemic plant camplotheca acuminata by American scientist Wall the earliest, is a kind of poisonous alkaloids.Camptothecine has excellent anti-tumor activity, but also has very large toxic side effect.The outstanding representation of camptothecine antitumous effect, causes the interest that people are very large, and analogue naturally occurring to it or synthetic is studied in succession, to find new antitumor drug.At this wherein, hydroxycamptothecine (Hydroxycamptothecin, HCPT) compared with camptothecine, have advantages of that anticancer therapeutic is higher, toxic side effect still less, in the treatment of cancer of the stomach, liver cancer, leukemia, mammary cancer, tumor of head and neck, there is very strong using value, in China is clinical, be widely used; The derivative of hydroxycamptothecine, water-soluble prodrug (the Iriontecan of SN-38 (SN-38), irinotecan), Topotecan (Topotecan, Top is for health) also respectively at 1994 and listing in 1999, for the treatment of colorectal cancer, ovarian cancer and small cell lung cancer.In addition, also have a large amount of camptothecin analogues or derivative still among research and development, as Chinese patent literature I (Granted publication CN100432076/C) has been introduced the camptothecin derivative that contains dihydrofuran ring, Chinese patent literature II (application publication number CN102574866A) has been introduced 14-nitro, 14-amino and 14-substituted-amino camptothecin derivative, and Chinese patent literature III (application publication number CN102731772A) has been introduced the polyethyleneglycol derivative of camptothecine compounds.
The chemical structure of formula (I) camptothecine
Research shows, the anti-tumor activity of camptothecine and analogue thereof is mainly that the activity of the topoisomerase I (Topo I) by inhibition tumor cell plays a role.In the reproduction process of fissional DNA, Topo I and DNA, in conjunction with forming a binary complex, and make DNA in reproduction process, have a temporary transient strand breach, and its semiconservative replication can be carried out smoothly.If give camptothecine or derivatives thereof in this process, it can be at fissional S phase and Topo I-DNA mixture specific binding, form an irreversible Topo I-CPT-DNA ternary complex, make the termination that copies of DNA, thereby produce the lethal effect to cell.
Camptothecine and analogue thereof the unique restraining effect to topoisomerase I, closely related with the lactone structure that its E ring exists.Because there are some researches show, only have camptothecine ability and the Topo I-DNA of lactone form to form stable mixture, this may be important step of its performance antitumous effect.And the camptothecine of lactone form and analogue thereof exist with carboxylic acid form because lactone unstable is easy to reversibility open loop, thereby in human plasma, exist the balance of two kinds of forms.Owing to only having sour environment to be just conducive to the existence of lactone form, and carboxylic acid form and plasma proteins bonding force higher, so camptothecine and analogue thereof enter after blood, the concentration of its lactone form will be well below the concentration of carboxylic acid form.More disadvantageously, the camptothecine of carboxylic acid form and analogue anti-tumor activity thereof strengthen compared with the obvious decline of lactone form and untoward reaction, and the camptothecine of lactone form is water-soluble hardly, and the unfavorable feature such as it is short to have biological half-life, and tissue bond is poor.Therefore, improve the water-soluble of camptothecin analogues, extend the residence time in its body, the stability that increases metabolism becomes the emphasis of this compounds and preparation research thereof.
Camptothecine compounds biological half-life is short, water-fast defect almost, and the formulation of listing does not solve well at present.As " hydroxycamptothecine sodium chloride injection " and " hydroxycamptothecin for injection " in Discussion on Chinese Listed, in order to solve its solubility in water, the reaction of utilization and alkali impels lactonic ring to open formation carboxylate salt.Improve although water-soluble, because the Concentration of Hydroxycamptothecinein of lactone form is too low, still existed anti-tumor activity and obviously reduce, the defect that toxic side effect increases.
For improving clinical efficacy, improve the many unfavorable feature of camptothecin analogues, people's research direction mainly concentrates on two aspects.First, the chemical structure of camptothecine is carried out to various transformations, as increase hydrophilic radical, use prodrug technology etc., there is in this respect a large amount of bibliographical information (Chinese patent literature I ~ III as the aforementioned) both at home and abroad, also obtained certain applicability achievement, if medicine irinotecan and Top are for the listing of health.But these applicability achievements still exist some insoluble problems, as not fully up to expectations distribution and action time in vivo in medicine, use inconvenience etc.In order to solve this class problem, people carry out effort in second aspect in succession, use some novel drug delivery systems (as nanoparticle, liposome, micro emulsion, micella etc.) to reaching desirable effect.These newtype drug delivery systems, change camptothecine and analogue thereof pharmacokinetic parameter and bio distribution characteristic in vivo, having residence time prolongation, useful for drug delivery amount in slowly-releasing, body increases texts, thereby can play raising curative effect, alleviates the object of toxic side effect.
In these newtype drug delivery systems, for strengthening the water-soluble of medicine, the extension body internal recycle time, utilize polyoxyethylene glycol (Polyethylene glycol, PEG) to transmit medicine or drug delivery system itself is modified, be a kind of very common selection.If first liposome medicament Zorubicin of U.S. FDA approval is to adopt polyethyleneglycol modified phosphatide prescription, (the non-patent literature I such as Hong Minghuang, Journal of Controlled Release, 2010, 141:22-29) by Transferrins,iron complexes, polyoxyethylene glycol combines with hydroxycamptothecine, to strengthen its water-soluble and targeting, reach good effect, the people's such as Liu Keliang Chinese patent (Chinese patent literature III) also provides the Preparation method and use of the PEGization derivative of camptothecine compounds, can be with reference to the people's such as Zhang Yue summary (non-patent literature II about utilizing polyoxyethylene glycol to modify more document to medicine, Hebei University of Science and Technology's journal, 2013, 34, 4:355-365).
But, also there is certain problem in medicine and drug delivery system that PEG modifies, after being the most significantly wherein the drug delivery system first administration of Pegylation, the medicine of subsequent dose shortens cycling time in blood, and assemble in a large number in liver and spleen, do not reach effective drug level and action time, this is called as " accelerate blood flow and remove phenomenon (accelerated blood clearance phenomenon, ABC) ".About " ABC phenomenon ", in many medicines or drug delivery system that utilize PEG modification, found by people very early, relevant report is also a lot, cause the IgM of anti-PEG and occur being eliminated fast phenomenon (non-patent literature III with regard to having introduced by polyethyleneglycol modified albumen in 1999 as Cheng TL, Bioconjugate Chemistry, 1999,10:520-528).For " the ABC phenomenon " that caused by PEG, its concrete origin cause of formation does not still have clear and definite conclusion, there is report (non-patent literature IV, Journal of Controlled Release, 2006,115:243-250) think that " ABC phenomenon " is the result of human body innate immune system effect, its mechanism may with PEG in
repeating unit is relevant, and the medicine of modifying as PEG or drug delivery system be while arriving for the first time immune organ spleen,
immunoglobulin (Ig) on the active B cell of chain and splenic marginal zone and combining, B cell is produced to special stimulation, make it secrete the IgM of anti-PEG, thereby cause medicine or its transfer system to be assembled liver and spleen, blood Chinese traditional medicine concentration reduces and goes out " accelerate blood flow and remove phenomenon ", and shortened the action time of medicine.
Polyglycerine (Polyglycerol, PG) is important fine chemical product and synthetic intermediate, is just in the news, but because of product quality problem, is restricted in the application of the aspects such as food, medicine and daily use chemicals as far back as its study on the synthesis of 20 beginnings of the century.In recent years, along with further investigation and the improvement of people to Polyglycerine, its quality improves greatly, at present, more existing major companies (as the Su Wei chemical of Belgian Su Wei group, Japanese Ban Ben pharmaceutical industries Co., Ltd., Italian SPIGA company and the Jinan Dong Run Science and Technology Ltd. etc. that refines) provide commercial high-quality polyglycerol, can directly apply in makeup and pharmaceutical prod.
For fear of or alleviate " the ABC phenomenon " of medicine or drug delivery system, people have carried out many other good tries.Wherein there is document (non-patent literature V, International Journal of Pharmaceutics, 2013, the phosphatidylethanolamine (PG-DSPE) of 456:235-242) Polyglycerine being modified replaces the preparation of polyethyleneglycol modified phosphatidylethanolamine (PEG-DSPE) for Evacet, has effectively avoided " ABC phenomenon ".Its mechanism may be the lipid of modifying with branched polyglycerol,
in repeating unit-CH
2the existence of OH side chain forms sterically hindered, interaction and (or) the effectively combination of B cell immunoglobulin and repeating unit are hindered, make B cell lack effective specific stimulation, cannot secrete or secrete the IgM of few anti-PG, thereby eliminate or minimizing " ABC phenomenon ".But this research is only confined to form the phospholipid material of liposome, can produces which kind of effect to medicine itself with Polyglycerine modification and mention.
Therefore, not good, a kind of non-polyethyleneglycol modified new medicaments derivative of shortcoming exploitation such as action time is short, toxic side effect is strong that distributes in, body low for solubleness in camptothecine compounds water, seems and is more of practical significance.
?
Summary of the invention
The inventor finds by research, camptothecine generates after hydroxycamptothecine 10 hydroxylations, modify through polyglycerol fatty acid ester, its anti-tumor activity is without considerable change, toxic side effect reduces, solubleness in water significantly improves, and extend cycling time in vivo, not obvious " ABC phenomenon ".
The polyglycerol fatty acid ester derivative of the hydroxycamptothecine the present invention relates to, its chemical structure is as shown in formula II.This structure is the straight chain fatty acid of Polyglycerine and the ester structure that 10 hydroxyls of hydroxycamptothecine form.
The polyglycerol fatty acid ester derivatives chemical structure of formula II hydroxycamptothecine
The polyglycerol fatty acid ester derivative of hydroxycamptothecine of the present invention, is characterized in that Polyglycerine part is the Polyglycerine with side chain, and the polymerization degree n of Polyglycerine is 3-50, and preferred value is 10 or 20.
The polyglycerol fatty acid ester derivative of hydroxycamptothecine of the present invention, is characterized in that m is 1-4, and preferred value is 2 or 3.
The polyglycerol fatty acid ester derivative of hydroxycamptothecine of the present invention, its purposes is for the preparation of antitumor drug.
The polyglycerol fatty acid ester derivative of hydroxycamptothecine of the present invention, m value is a definite numerical value, Polyglycerine part can be the well-determined single compound of n value, centered by the n value that also can be to determine, has the macromolecule mixture that the compound of certain molecular weight distribution range forms.The polyglycerol fatty acid ester derivative of hydroxycamptothecine of the present invention, its preferred compound is hydroxycamptothecine Polyglycerine 1500 succinates (code name is PG1500-HCPT).
The polyglycerol fatty acid ester derivative of hydroxycamptothecine of the present invention, can be synthesized into by simple chemical process.Its general synthetic route is as shown in formula III.
The general synthetic route of polyglycerol fatty acid ester derivative of formula III hydroxycamptothecine
The present invention, take ethoxyethyl group glycidyl ether as raw material, has synthesized the polyglycerol fatty acid ester derivative of hydroxycamptothecine.Each compound is analyzed through HPLC and TLC, through mass spectrum and hydrogen spectrum, carbon spectrum nmr analysis, confirms that structure is correct.
According to the present invention, the polyglycerol fatty acid ester derivative of hydroxycamptothecine of the present invention, can be used for preparing the medicine of anticancer usage and these antitumor drugs at various newtype drug delivery systems, include but not limited to the application in the preparations such as nanoparticle, liposome, micro emulsion, micella.
Embodiment
By the form of concrete exemplifying embodiment, foregoing of the present invention is described in further detail below, but scope of the present invention is not limited only to following example.All technology realizing based on foregoing of the present invention are all included within the scope of the present invention.
Embodiment mono-: hydroxycamptothecine Polyglycerine 1500 succinates (PG1500-HCPT) synthetic
1. synthetic (with reference to the non-patent literature IV, Journal of American Chemical Society 2002,124:9698-9699) of Polyglycerine 1500
Potassium tert.-butoxide (0.7g, 6mmol) and ethoxyethyl group glycidyl ether (5.3g, 36mmol) are placed in flask, the pressure reducing and steaming trimethyl carbinol at 120 ℃.Reactant is moved in three-necked bottle, heat to 95 ℃, under continuous stirring and nitrogen gas stream, ethoxyethyl group glycidyl ether (136.8g, 0.96mol) is splashed in above-mentioned reactant with the speed of 4mL/min, be added dropwise to complete rear continuation reaction 6 hours.After reaction finishes, add tetrahydrofuran (THF) and hydrochloric acid in reaction mixture, tetrahydrofuran (THF) is removed in decompression subsequently.Add a small amount of methyl alcohol to make reactants dissolved, then add acetone vibration, leave standstill and discard upper solution, this behaviour repeats twice.Solution removal of solvent under reduced pressure at 80 ℃ of the lower floor that obtains of reaction, obtains molecular-weight average and is 1500 Polyglycerine (48.1g, yield approximately 33%).
2. Polyglycerine 1500 succsinic acids is synthetic
Polyglycerine 1500(3.0g, 2mmol) and Succinic anhydried (0.2g, 2mmol) be dissolved in 100mL dioxane, add a small amount of pyridine to make catalyzer.Above-mentioned vlil 24 hours is above until reaction reaches balance.Reactant is chilled to after room temperature, adds ether to separate out precipitation, and mixture stirs 30 minutes under ice bath, filters to obtain Polyglycerine 1500 succsinic acid crude products.Crude product adds appropriate methylene dichloride to dissolve, then adds ether to separate out precipitation, and mixture stirs 15 minutes under ice bath, and precipitation is leached and is dried, and obtains Polyglycerine 1500 succsinic acids (2.3g, yield 44%).
3. hydroxycamptothecine Polyglycerine 1500 succinates is synthetic
Hydroxycamptothecine (0.29g, 0.8mmol, Polyglycerine 1500 succsinic acids (0.64g, 0.4mmol) are dissolved in the anhydrous DMF of 50mL, add 1-ethyl-3-(3-dimethyl amido propyl group) carbodiimide hydrochloride 280mg and Isosorbide-5-Nitrae-Dimethylamino pyridine 12mg.Mixture stirring reaction 2 hours under ice bath under nitrogen protection, and then room temperature is placed 24 hours.In reaction mixture, add 5% NaHCO
3to remove unnecessary hydroxycamptothecine, dichloromethane extraction for residuum (100mL × 3), and then use respectively 5% NaHCO
3solution, water, hydrochloric acid and the saturated nacl aqueous solution of 0.1mol/L wash, and concentrating under reduced pressure obtains crude product.Crude product is faint yellow solid, then uses ether recrystallization, obtains off-white color hydroxycamptothecine Polyglycerine 1500 succinate solids.
1H?NMR（DMSO）：δ?0.82（t，3H，H–18），?δ?1.91（m，2H，H–19），δ?3.23–4.57（–CH2OH），δ?5.26（s，2H，H–5），?δ?5.46（s，2H，H–17），?δ?7.37?（s，1H，?H–14），?δ?7.60（dd，1H，H–11），δ?7.88（d，1H,?H–9），?δ?8.20?（d，1H，H–12），?δ?8.64?（s，1H，H–7）。
Embodiment bis-: the evaluation of the anti-tumor activity of hydroxycamptothecine Polyglycerine 1500 succinates
Select human liver cancer cell HepG2, two kinds of cell strains of human erythroleukemia K562 cell, inoculating cell, in containing in the DMEM cell culture fluid of 10% foetal calf serum, is placed in 37 ℃ containing 5%CO
2cell culture incubator in, within every 2 days, change liquid once, with 0.25% trysinization cell dispersion, and by Trypan Blue test cell activity, require activity of tumor cells to reach more than 95%.Be inoculated in 96 well culture plates by every hole 10000 cell count, in cell culture incubator, cultivate 4 hours, every hole adds 20 μ L liquids, tested drug level is followed successively by 10.0,5.0,2.5,1.25,0.625,0.3125,0.15625 μ g/mL, every kind of drug level established 5 multiple holes, control group adds DMEM nutrient solution, contains 5%CO at 37 ℃
2cell culture incubator in cultivate 72 hours.Every hole adds the serum-free medium of freshly prepared 0.5 mg/mL tetrazole indigo plant, abandons supernatant in 37 ℃ after cultivating 4 hours again.Every hole adds methyl-sulphoxide 200 μ L, makes abundant dissolving, and setting and detecting wavelength is 570 nm, and reference wavelength is 450 nm, detects absorbancy (OD value) by microplate reader.Press formula (1) and calculate the inhibiting rate to tumour, utilize the mapping of Origin software, obtain half concentration (IC
50), and provide the maximum maximal percentage inhibition (I of actual measurement
max), concrete outcome is in table 1.From data in table, hydroxycamptothecine Polyglycerine 1500 succinates and hydroxycamptothecine are suitable to two kinds of inhibiting tumour cells effects, the two no significant difference.
formula (1)
Table 1 hydroxycamptothecine and the restraining effect of hydroxycamptothecine Polyglycerine 1500 succinates to growth of tumour cell
Claims (5)
1. a polyglycerol fatty acid ester derivative for hydroxycamptothecine, is characterized in that 10 hydroxyls of polyglycerol fatty acid and hydroxycamptothecine form the structure of ester, and its structure is suc as formula shown in I:
Formula I
Wherein, n value is that 3 ~ 50, m value is 1-5.
2. compound claimed in claim 1, is characterized in that Polyglycerine part is the Polyglycerine with side chain.
3. compound claimed in claim 1, is characterized in that the polymerization degree n of Polyglycerine part is preferably 10 or 20.
4. compound claimed in claim 1, is characterized in that the m value of fatty acid part is preferably 2 or 3.
5. compound claimed in claim 1 and composition thereof, its purposes is for the preparation of antitumor drug.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410003747.2A CN103772696B (en) | 2014-01-06 | 2014-01-06 | A kind of polyglycerol fatty acid ester derivative of hydroxycamptothecine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410003747.2A CN103772696B (en) | 2014-01-06 | 2014-01-06 | A kind of polyglycerol fatty acid ester derivative of hydroxycamptothecine |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103772696A true CN103772696A (en) | 2014-05-07 |
| CN103772696B CN103772696B (en) | 2015-12-02 |
Family
ID=50565499
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410003747.2A Active CN103772696B (en) | 2014-01-06 | 2014-01-06 | A kind of polyglycerol fatty acid ester derivative of hydroxycamptothecine |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103772696B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112175103A (en) * | 2020-10-29 | 2021-01-05 | 绍兴文理学院 | Polyglycero fatty acid ester derivative containing polysialic acid group, synthetic method thereof and application thereof in pharmaceutical preparation |
Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1875944A (en) * | 2006-06-29 | 2006-12-13 | 中国科学院上海药物研究所 | A carbowax modified stealthy liposome nanosphere of hydroxycamtothecine and preparation method thereof |
| CN1883455A (en) * | 2006-07-07 | 2006-12-27 | 中国科学院上海药物研究所 | A long-circulating nanoliposome carrier of hydroxycamptothecine and preparation method thereof |
| WO2007075825A2 (en) * | 2005-12-20 | 2007-07-05 | Sonus Pharmaceuticals, Inc. | Lipophilic anticancer drug compounds |
| US20080045559A1 (en) * | 2003-10-29 | 2008-02-21 | Sonus Pharmaceuticals, Inc. | Tocopherol-modified therapeutic drug compounds |
| US20080058364A1 (en) * | 2006-02-09 | 2008-03-06 | Puja Sapra | Treatment of non-hodgkin's lymphomas with multi-arm polymeric conjugates of 7-ethyl-10-hydroxycamtothecin |
| WO2010083154A2 (en) * | 2009-01-13 | 2010-07-22 | The Uab Research Foundation | Heterofunctional segment-poly(ethylene glycol) polymers as delivery vehicles |
| US20110195990A1 (en) * | 2007-02-09 | 2011-08-11 | Enzon Pharmaceuticals, Inc. | Treatment of resistant or refractory cancers with multi-arm polymeric conjugates of 7-ethyl-10-hydroxycamptothecin |
| CN103405480A (en) * | 2013-05-03 | 2013-11-27 | 浙江理工大学 | Conjugate of 10-hydroxycamptothecine-butanedioic acid and adenovirus, as well as production method and use thereof |
-
2014
- 2014-01-06 CN CN201410003747.2A patent/CN103772696B/en active Active
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20080045559A1 (en) * | 2003-10-29 | 2008-02-21 | Sonus Pharmaceuticals, Inc. | Tocopherol-modified therapeutic drug compounds |
| WO2007075825A2 (en) * | 2005-12-20 | 2007-07-05 | Sonus Pharmaceuticals, Inc. | Lipophilic anticancer drug compounds |
| US20080058364A1 (en) * | 2006-02-09 | 2008-03-06 | Puja Sapra | Treatment of non-hodgkin's lymphomas with multi-arm polymeric conjugates of 7-ethyl-10-hydroxycamtothecin |
| CN1875944A (en) * | 2006-06-29 | 2006-12-13 | 中国科学院上海药物研究所 | A carbowax modified stealthy liposome nanosphere of hydroxycamtothecine and preparation method thereof |
| CN1883455A (en) * | 2006-07-07 | 2006-12-27 | 中国科学院上海药物研究所 | A long-circulating nanoliposome carrier of hydroxycamptothecine and preparation method thereof |
| US20110195990A1 (en) * | 2007-02-09 | 2011-08-11 | Enzon Pharmaceuticals, Inc. | Treatment of resistant or refractory cancers with multi-arm polymeric conjugates of 7-ethyl-10-hydroxycamptothecin |
| WO2010083154A2 (en) * | 2009-01-13 | 2010-07-22 | The Uab Research Foundation | Heterofunctional segment-poly(ethylene glycol) polymers as delivery vehicles |
| CN103405480A (en) * | 2013-05-03 | 2013-11-27 | 浙江理工大学 | Conjugate of 10-hydroxycamptothecine-butanedioic acid and adenovirus, as well as production method and use thereof |
Non-Patent Citations (1)
| Title |
|---|
| 皮劲松等: "聚乙二醇-7-乙基-10-羟基喜树碱共聚物的合成及体外表征", 《中国医药工业杂志》, vol. 40, no. 9, 30 September 2009 (2009-09-30) * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112175103A (en) * | 2020-10-29 | 2021-01-05 | 绍兴文理学院 | Polyglycero fatty acid ester derivative containing polysialic acid group, synthetic method thereof and application thereof in pharmaceutical preparation |
| CN112175103B (en) * | 2020-10-29 | 2022-07-15 | 绍兴文理学院 | Polyglycerol fatty acid ester derivative containing polysialic acid group, synthetic method thereof and application thereof in pharmaceutical preparation |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103772696B (en) | 2015-12-02 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN106831805B (en) | A kind of camptothecine-adriamycin prodrug and its preparation method and application | |
| CN105396141B (en) | IRGD- anticancer drug conjugates and its preparation method and application | |
| AU2020442003B2 (en) | A camptothecin drug and its antibody conjugate thereof | |
| CN104163823B (en) | A kind of camptothecine and Artesunate conjugate and preparation method thereof and application | |
| CN102649795B (en) | 10-methoxyl camptothecin derivative, preparation method and application | |
| CN114736214B (en) | Sesquiterpene derivative, pharmaceutical composition thereof, and preparation method and application thereof | |
| WO2007023778A1 (en) | Novel anticancer concomitant drug | |
| CN102746360B (en) | Synthesis and application of four new conjugates of camptothecin-steroid | |
| CN104478890B (en) | A kind of all-trans-retinoic acid-camptothecin cancer therapy drug conjugate and its preparation method and application | |
| CN102336904B (en) | Multivalent polyglycol (PEG) modifier for camptothecin and derivatives thereof and application of multivalent PEG modifier | |
| CN102731442B (en) | Preparation method and application of water-soluble docetaxel compounds | |
| CN103772696B (en) | A kind of polyglycerol fatty acid ester derivative of hydroxycamptothecine | |
| CN114773356B (en) | Sesquiterpene derivative, pharmaceutical composition thereof, and preparation method and application thereof | |
| WO2011047530A1 (en) | Carotenoid derivatives, preparation method and use thereof | |
| CN113024557B (en) | Penamine A alkaloid structure simplified substance and application thereof | |
| CN107513089B (en) | Novel cytidine derivative dimer and application thereof | |
| CN107001617B (en) | PEG derivative | |
| CN100484940C (en) | Water-soluble camptothecine derivative and its preparation process and application thereof | |
| CN102731772A (en) | Camptothecin compound pegylated derivatives | |
| CN109053682B (en) | TDO small molecule inhibitor derivative, anti-tumor conjugate thereof and preparation method | |
| CN106188094B (en) | Isoxazole ring analog derivative and its preparation method and application | |
| CN114644643A (en) | Twin drug and synthesis method and application thereof | |
| CN105801604A (en) | Eriocalyxin B derivatives with tumor targeting as well as preparation method and application | |
| CN104672213A (en) | Amide compound with antitumor activity, and application thereof | |
| CN110746392A (en) | Application of furan compound in preparation of antitumor drugs |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CB03 | Change of inventor or designer information | ||
| CB03 | Change of inventor or designer information |
Inventor after: Li Jian Inventor before: Wang Hailong Inventor before: Liu Shankui Inventor before: Tan Xiaojun |
|
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20170920 Address after: 528300, No. 3, South Road, Xin Kai Industrial Zone, Leliu Town, Shunde District, Guangdong, Foshan, Daliang Patentee after: FOSHAN YINMEI UNITED TECHNOLOGY CO.,LTD. Address before: The central nanxinzhuang Ji'nan Road, No. 336 of 250022 cities in Shandong Province Patentee before: University of Jinan |
|
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20230417 Address after: Unit 2-2, Unit 1, Building 7, No. 8 Jincheng Road, Yubei District, Chongqing, 401120 Patentee after: Li Jian Address before: No. 3, Development South Road, Xinqi Industrial Zone, Daliang Leliu Town, Shunde District, Foshan City, Guangdong Province, 528300 Patentee before: FOSHAN YINMEI UNITED TECHNOLOGY CO.,LTD. |