CN103804472B - A kind of taxone precursor - Google Patents
A kind of taxone precursor Download PDFInfo
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- CN103804472B CN103804472B CN201410031867.3A CN201410031867A CN103804472B CN 103804472 B CN103804472 B CN 103804472B CN 201410031867 A CN201410031867 A CN 201410031867A CN 103804472 B CN103804472 B CN 103804472B
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Abstract
The invention discloses a kind of taxone precursor, described taxone precursor is the C-2 ' position of bearing taxanes or C-7 position hydroxyl is combined, with water solublity targeting peptides, the conjugate formed by cross structure, comprises at least one in ester bond, carbonic acid ester bond, urea key and disulfide bond in described cross structure. Compared with bearing taxanes, this prodrug has fabulous water solublity, and dissolubility reaches 2mg/ml, solves the problem that can only use the dangerous material such as organic solvent and Tween 80 in prior art to dissolve bearing taxanes; The mode of covalent coupling ensure that this taxone precursor has higher stability when preserving in vitro, and can discharge bearing taxanes rapidly after entering cell and play drug effect; Bearing taxanes can be transported to specific tumor cell by targeting peptides, reduces Normocellular lethality, and targeting peptides is aminoacid at intracellular catabolite, therefore has higher biocompatibility.
Description
Technical field
The present invention relates to a kind of taxone precursor, be specifically related to a kind of taxone precursor.
Background technology
Taxone mainly includes paclitaxel and Docetaxel, is current one of maximally effective antitumor drug clinically. Paclitaxel (paclitaxel) is to separate a kind of tetracyclic diterpene compound obtained from the bark of Ramulus et folium taxi cuspidatae of the Pacific Ocean, and molecular formula is C47H51O14N, molecular weight is 853.9, water insoluble. U.S. FDA approval listing in 1992, its mechanism of action is to be combined with cellular tubulin, promotes tubulin polymerization, to resist depolymerization, to block mitosis, thus suppressing tumor growth, inducing apoptosis of tumour cell. Clinical research has been proven that paclitaxel is treating multiple entity tumor, including breast carcinoma, advanced ovarian cancer, pulmonary carcinoma, brain and the aspect such as tumor colli and acute leukemia, has obvious action. Docetaxel (docetaxel) is that the non-cell toxicity precursor compound 10-deacylated tRNA base Tetraol II extracted from Taxus baccata obtains through semi-synthetic, within 1998, obtains U.S. FDA approval listing. The mechanism of action of Docetaxel is similar to paclitaxel, but anti-tumor activity is a lot of times of paclitaxel, and the cancer such as breast carcinoma, nonsmall-cell lung cancer is had obvious therapeutic effect.
Due to the water solublity of taxone relatively low (about 1��10 �� g/mL), the paclitaxel injection therefore used clinically and Docetaxol injection all need the purpose using surfactant polyoxyethylene Oleum Ricini (CremophorEL) and polysorbate 80 (Tween 80) and cosolvent ethanol to reach to dissolve medicine respectively.
The paclitaxel injection (commodity are called " taxol ") of existing listing, with polyoxyethylene castor oil (CremophorEL): ethanol=1: 1 for solvent, concentration is 6mg/mL, during clinical practice, normal saline or dextran dilute 5��20 times, intravenous 3h, dosage is 135mg/m2. Polyoxyethylene castor oil has been demonstrated to cause serious anaphylaxis, neurotoxicity, nephrotoxicity and hypotension etc. Additionally, polyoxyethylene castor oil also can form molecule parcel taxane molecule in blood, affect drug molecule and spread between tissue, reduce antitumous effect.
Similarly, the Docetaxel injection (commodity are called " taxotere ") of listing at present, the double solvent adopting Tween 80 and dehydrated alcohol is prepared from, but the anaphylaxis using easily initiation serious patient of Tween 80, before chemotherapy, patient often needs to take or inject Claritin (corticoid and bisfentidine) in advance, in infusion process, also needing to connect the crystal fine grain entrance patient blood blood circulation that microfilter produces in dilution to prevent medicine, these all bring great risk and inconvenience to clinical practice.
For these reasons, the derivant of a series of taxone or new formulation it are developed in recent years to overcome its water solubility problems. As by chemical coupling method, the hydroxyl in the C-2 ' position of paclitaxel parent nucleus or C-7 position introduces water soluble group and obtains the paclitaxel derivant that water solublity is bigger. Additionally, paclitaxel is imported to liposome, micelle or makes the method for Emulsion and can also reach the effect of solubilising. But these current technology often can only improve the water solublity of taxone, the targeting problem of medicine can not be improved. By coupling, some soluble small molecular polypeptide possessing tumor cell targeting prepare the prodrug of taxone, solubility problem can not only be solved, and medicine targeting ability to tumor cell in vivo can be given, there is very good market prospect and clinical value.
Summary of the invention
The invention provides a kind of taxone precursor, the little molecular targeted peptide of this taxone precursor covalent coupling in bearing taxanes molecule, substantially increase targeting and the water solublity of medicine.
A kind of taxone precursor, described taxone precursor is the C-2 ' position of bearing taxanes or C-7 position hydroxyl is combined, with water solublity targeting peptides, the conjugate formed by cross structure, comprises at least one in ester bond, carbonic acid ester bond, urea key and disulfide bond in described cross structure.
By connecting water solublity targeting peptides on C-2 ' position or C-7 position hydroxyl, the water solublity and the tumor-targeting that make bearing taxanes are greatly improved, only need to water dissolution during use, it is no longer necessary to organic cosolvent, greatly reduce the toxicity produced in drug use process.
As preferably, C-2 ' the position hydroxyl that described taxone precursor is bearing taxanes is combined, with water solublity targeting peptides, the conjugate formed by cross structure. Compared with C-2 ' position, the chemosynthesis difficulty at C-7 position place is bigger.
As preferably, described covalent bond is at least one in ester bond, carbonic acid ester bond, urea key, disulfide bond.
As preferably, described targeting peptides is hepatoma carcinoma cell targeting peptides. As it is preferred that, the aminoacid sequence of described hepatoma carcinoma cell targeting peptides is: SFSIIHTPILPL.Can there is the N end at this aminoacid sequence in coupling, it is possible to occur at C end. As preferably, in one end that coupling occurs, also with connection peptides on described targeting peptides, connection peptides is preferably made up of 2��4 glycine, and connection peptides can avoid bearing taxanes to affect the combination of targeting peptides and tumor cell.
In the present invention, described bearing taxanes is paclitaxel or Docetaxel.
As preferably, shown in the structural formula such as formula I or formula II of described taxone precursor:
Or, as shown in formula III or formula IV:
Wherein, X is water-soluble amino acid, and the number n of water-soluble amino acid is 0��5.
For improving the water solublity of described taxone precursor further, introducing water-soluble amino acid in one end (N end or C end) of targeting peptides Yu bearing taxanes coupling, as preferably, the number n of water-soluble amino acid is 2��5. Described water-soluble amino acid is preferably arginine, lysine, aspartic acid or glutamic acid, more preferably arginine or lysine.
And, the sulfydryl utilizing cysteine carries out coupling with bearing taxanes, sulfydryl is not only easy to reaction, preparation condition is gentle, also being provided that multiple conjugation sites, can there is the sulfydryl at the C end (leucic carboxyl) of targeting peptides, N end (amino of cysteine) or cysteine in coupling, when there is coupling on sulfydryl, stable disulfide bond can also be formed, it is ensured that described taxone front body structure is stable.
Carbonic acid ester bond and disulfide bond is introduced between formula I or formula II hydroxyl and the cysteine sulfydryl of targeting peptides on paclitaxel or Docetaxel C-2 ' position; Formula III or formula IV then introduce ester bond and urea key between hydroxyl and the cysteine sulfydryl of targeting peptides on paclitaxel or Docetaxel C-2 ' position.
As it is preferred that, shown in the structural formula such as formula (V) of described taxone precursor or formula VI:
Or, as shown in formula (VII) or formula (VIII):
In formula (V), (VI), (VII), (VIII), glycine (Gm) as connection peptides, the number m of glycine is preferably 2��4, more preferably 2.
The preparation method of described taxone precursor includes: first introduce corresponding group, the derivant of synthesizing taxone compound in the C-2 ' position of bearing taxanes or C-7 position hydroxyl; Then this derivant is mixed with targeting peptides, be stirred at room temperature down and carry out coupling, it is thus achieved that described taxone precursor.
Present invention also offers the application in preparing medicines resistant to liver cancer of the described taxone precursor. Can be used alone after described taxone precursor is lyophilised, it is also possible to add different excipient post-treatment and become any dosage form, including tablet, pill, capsule, granule, oral liquid and for intravenous aqueous injection or injectable powder.
Compared with prior art, beneficial effects of the present invention is embodied in:
(1) compared with bearing taxanes, the taxone precursor of the present invention has fabulous water solublity, dissolubility, up to 1.8mg/ml, solves the problem that can only use the dangerous material such as organic solvent and Tween 80 in prior art to dissolve bearing taxanes; The taxone precursor obtained, preparation cost is low, and stability is high, and safety is good, meets the requirement of clinical application, meets the requirement of large-scale production, possesses good market prospect;
(2) bearing taxanes can be transported to specific tumor cell by targeting peptides, reduces Normocellular lethality, and targeting peptides is aminoacid at intracellular catabolite, therefore has higher biocompatibility.
Accompanying drawing explanation
Fig. 1 is the synthetic route chart of SP94-paclitaxel in embodiment 1;
Fig. 2 is paclitaxel C '-2 bit derivant in Fig. 11H-NMR nuclear magnetic spectrum;
Fig. 3 is paclitaxel maleimide derivatives in Fig. 11H-NMR nuclear magnetic spectrum;
Fig. 4 is the ESI mass spectrum of SP94-paclitaxel in Fig. 1;
Fig. 5 is the synthetic route chart of SP94-Docetaxel in embodiment 2;
Fig. 6 is Docetaxel derivant in Fig. 51H-NMR nuclear magnetic spectrum;
Fig. 7 is the ESI mass spectrum of SP94-Docetaxel;
Fig. 8 is the anti tumor activity in vitro MTT measurement result figure of SP94-paclitaxel and paclitaxel.
Detailed description of the invention
Embodiment 1 paclitaxel is by the preparation of ester bond with hepatoma-targeting peptide SP94 coupling prodrug
Utilizing paclitaxel and hepatoma-targeting peptide SP94 coupling to prepare taxone precursor, its synthetic route is as it is shown in figure 1, comprise the following steps:
(1) synthesis of paclitaxel C '-2 bit derivant 2
Dry reaction bulb adds paclitaxel 1(300mg, 0.35mmol), dissolve with anhydrous pyridine 2ml; Succinic anhydride (105mg, 1.05mmol) and DMAP DMAP(4.3mg, 0.035mmol is added) in reactant liquor. Being stirred at room temperature 2 hours, TLC shows that reaction terminates reaction after terminating, and vacuum rotary steam removes pyridine; Normal phase silicagel column (dichloromethane: methanol=20:1) separates and obtains white solid, and product yield is 91%. Utilize1H-NMR(Fig. 2) confirm target product 2.
(2) synthesis of paclitaxel maleimide derivatives 3
Take compound 2(100mg, 0.105mmol) it is dissolved in 2ml dry DMF, N-(2-amino-ethyl) maleimide trifluoroacetate (28mg is added in reactant liquor, 0.11mmol), HOBt(15.6mg, 0.115mmol), HBTU(43.7mg, 0.115mmol) and DIPEA(69.3mg, 0.42mmol); Being stirred at room temperature 4 hours, TLC detection display reaction terminates reaction after terminating, and vacuum rotary steam removes DMF; Solid is washed with saturated sodium bicarbonate aqueous solution, 5% citric acid and saturated aqueous common salt after being dissolved in dichloromethane successively, and the dried vacuum rotary steam of anhydrous sodium sulfate removes dichloromethane; Normal phase silicagel column (dichloromethane: methanol=20:1) separates and obtains solid, and product yield is 80%. Utilize1H-NMR(Fig. 3) confirm target product 3.
(4) SP94 polypeptide coupling paclitaxel prodrug synthesis and high-efficient liquid be separated
Take compound 3(10mg, 8.4 ��m of ol) and SP94 polypeptide (13mg, 8.4 ��m of ol) (aminoacid sequence is such as shown in SEQIDNo.1) be dissolved in DMF and Tris buffer (pH8.0), be stirred at room temperature 2 hours, TLC shows that reaction terminates reaction after terminating, and reactant liquor is with efficient liquid phase (CH3CN:H2O=10:90 (0min) �� 90:10 (30min)) separate obtain 18mg white solid. Product yield is 78%, and the ESI mass spectrum of target product 4 is shown in such as Fig. 4. The water solublity of target product 4 is about 2mg/ml.
Embodiment 2 Docetaxel is by the preparation of carbonic acid ester bond and disulfide bond and hepatoma-targeting polypeptide SP94 coupling prodrug
Utilizing Docetaxel and hepatoma-targeting peptide SP94 coupling to prepare taxone precursor, its synthetic route is as it is shown in figure 5, comprise the following steps:
(1) synthesis of compound 9
According to document (E.A.Dubikovskayaetal., Overcomingmultidrugresistanceofsmall-moleculetherapeutic sthroughconjugationwithreleasableoctaargininetransporter s, ProceedingsoftheNationalAcademyofSciences, 2008,105 (34): 12128-12133.), synthesis compound 9.
(2) synthesis of Docetaxel derivant 11
Take Docetaxel 10(40mg, 49.5 ��m of ol) be dissolved in the anhydrous DCM of 2ml, in reactant liquor add compound 9(22mg, 59.4 ��m of ol), DMAP(7.3mg, 59.4 ��m of ol); Being stirred at room temperature 4 hours, TLC shows that reaction terminates reaction after terminating; DCM50ml is added again, then successively with saturated sodium bicarbonate aqueous solution, saturated aqueous common salt washing, the dried vacuum rotary steam removing dichloromethane of anhydrous sodium sulfate in reactant liquor; Normal phase silicagel column (dichloromethane: methanol=20:1) separates and obtains solid 60mg, and product yield is 85%. Utilize1H-NMR(Fig. 6) confirm target product 11.
(3) SP94 polypeptide coupling Docetaxel prodrug synthesis and high-efficient liquid be separated
Take compound 11(10mg, 9.7 ��m of ol) and SP94 polypeptide (15mg, 9.7 ��m of ol) be dissolved in 2mlDMF and Tris buffer (pH8.0), be stirred at room temperature 4 hours, TLC shows that reaction terminates reaction after terminating, and reactant liquor high-efficient liquid is separated and obtains 15mg white solid. Product yield is 60%, and the ESI mass spectrum of target product 12 is shown in Fig. 7. The water solublity of target product 12 is about 1.8mg/ml.
Embodiment 3 antitumor evaluating drug effect
For the target product 4(SP94-PTX that Evaluation operation example 1 obtains) killing ability to tumor cell, for hepatoma cell line 7721, adopt mtt assay to carry out evaluating drug effect, and using paclitaxel as comparison. The cytotoxicity result of hepatocarcinoma 7721 is shown in Fig. 8 by SP94-PTX4. As seen from Figure 8, being dissolved in the SP94-PTX of water with co-culture of cells after 72 hours, its In Vitro Anti liver cancer efficacy shows, SP94-PTX has the cytotoxicity identical with PTX.
Claims (3)
1. a taxone precursor, it is characterised in that shown in the structural formula such as formula I or formula II of described taxone precursor:
Wherein, X is water-soluble amino acid, and the number n of water-soluble amino acid is 2��5;
Or as shown in formula III or formula IV:
Wherein, X is water-soluble amino acid, and the number n of water-soluble amino acid is 2��5.
2. taxone precursor as claimed in claim 1, it is characterised in that described water-soluble amino acid is arginine, lysine, aspartic acid or glutamic acid.
3. taxone precursor as claimed in claim 2, it is characterised in that described water-soluble amino acid is arginine or lysine.
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| CN105198966B (en) * | 2014-06-26 | 2019-06-21 | 中国人民解放军军事医学科学院毒物药物研究所 | GnRH analog-Cytotoxic molecules conjugate, preparation method and the usage |
| CN104667290A (en) * | 2014-10-25 | 2015-06-03 | 中国科学技术大学 | Targeting peptide-modified gold nanoparticle and preparation method thereof as well as application of targeting peptide-modified gold nanoparticle as platinic pro-drug carrier |
| CN104667292B (en) * | 2015-02-02 | 2017-09-05 | 北京大学 | A kind of preparation and its application for reducing response type drug conjugates nanoparticle |
| CN105396141B (en) * | 2015-12-10 | 2018-08-24 | 浙江大学 | IRGD- anticancer drug conjugates and its preparation method and application |
| CN106806905B (en) * | 2017-01-03 | 2020-05-19 | 浙江大学 | Rare earth up-conversion nano-drug carrier integrating fluorescence imaging and drug loading and application thereof |
| CN106806906B (en) * | 2017-01-03 | 2020-05-19 | 浙江大学 | Preparation method of rare earth up-conversion nano-drug carrier integrating fluorescence imaging and drug loading |
| CN109420179B (en) * | 2017-08-22 | 2022-08-26 | 复旦大学 | Docetaxel targeted prodrug and anti-colon cancer medicinal application thereof |
| CN109422799B (en) * | 2017-08-22 | 2022-07-29 | 复旦大学 | Docetaxel liver cancer-resisting targeted prodrug and medicinal application thereof |
| CN110075314B (en) * | 2019-05-20 | 2020-12-29 | 上海交通大学 | Amphiphilic drug conjugate and preparation method of nanoparticle preparation thereof |
| CN115960116A (en) * | 2022-12-19 | 2023-04-14 | 中国药科大学 | Coupled prodrug, nanoparticle, pharmaceutical composition, preparation method and application |
| CN116251195B (en) * | 2022-12-27 | 2023-12-05 | 哈尔滨吉象隆生物技术有限公司 | Paclitaxel targeting peptide conjugate and application thereof |
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| US7550609B2 (en) * | 1999-11-24 | 2009-06-23 | Immunogen Inc. | Cytotoxic agents comprising taxanes and their therapeutic use |
| TW200935055A (en) * | 2007-11-20 | 2009-08-16 | Academia Sinica | Peptides specific for hepatocellular carcinoma cells and applications thereof |
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Patent Citations (3)
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| US7550609B2 (en) * | 1999-11-24 | 2009-06-23 | Immunogen Inc. | Cytotoxic agents comprising taxanes and their therapeutic use |
| CN101791409A (en) * | 2003-04-22 | 2010-08-04 | 研究及应用科学协会股份有限公司 | peptide vectors |
| TW200935055A (en) * | 2007-11-20 | 2009-08-16 | Academia Sinica | Peptides specific for hepatocellular carcinoma cells and applications thereof |
Non-Patent Citations (1)
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