CN109675051A - A kind of natineoplaston-doxorubicin derivative and preparation method thereof and anti-tumor drug - Google Patents
A kind of natineoplaston-doxorubicin derivative and preparation method thereof and anti-tumor drug Download PDFInfo
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Abstract
The present invention relates to biomedicine technical fields, and in particular to a kind of natineoplaston-doxorubicin derivative and preparation method thereof and anti-tumor drug.Adriamycin is with antitumor KLAK peptide by having the hydrazone bond of sour response characteristic to be bonded in natineoplaston-doxorubicin derivative provided by the invention, under faintly acid (pH value is 5.5~6.5) environment in tumour cell, responsiveness discharges two kinds of anticancer drugs (adriamycin and antitumor KLAK peptide), it reduces the toxic side effect of normal tissue and enhances the killing to tumour cell, to play synergistic antitumor effect by respective mechanism of action using two kinds of anticancer drugs of release, it is finally reached ideal therapeutic effect.
Description
Technical field
The present invention relates to biomedicine technical fields, and in particular to a kind of natineoplaston-doxorubicin derivative and its preparation
Method and anti-tumor drug.
Background technique
Cancer, also known as malignant tumour, be by polygenic mutation, it is multifactor cause, the normal frequently-occurring disease of Multi stage development.It is pernicious
The treatment method of tumour mainly has operative treatment, radiotherapy, chemotherapy (anticancer drug therapy) and biological therapy etc., Chemo-Therapy
Treatment is still one of the main means for the treatment of of cancer in quite long period at present and in the future.
Adriamycin (Doxorubicin), also known as Doxorubicin are a kind of anthracycline antibiotic class broad-spectrum anti-cancer drugs, are made
It is, to inhibit the duplication and transcription of DNA, to hinder cancer cell point by forming stable compound in intercalation of DNA base with mechanism
It splits.Clinically for treating acute lymphoblastic leukemia, acute granulocytic leukemia, Huo Qijin and non-Hodgkin's lymph
Tumor, breast cancer, lung cancer, oophoroma, soft tissue sarcoma, osteogenic sarcoma, rhabdomyosarcoma, the nephroblastoma, neuroblastoma,
Bladder tumor, thyroid adenoma, chorioepithelioma, prostate cancer, carcinoma of testis, gastric cancer, liver cancer etc..Currently, adriamycin is most important
Clinical administration is intravenous drip, and be administered after diffuse to each major organs of whole body rapidly, can reach tumor locus Ah
Mycin dose is very limited, has seriously affected the anticancer drug effect of adriamycin and has brought serious cardiac toxic and renal toxicity.Cause
This adriamycin kind anti-cancer drugs of research and development efficiently, less toxic is as extremely urgent.
The Chinese patent of Publication No. CN103638530A discloses a kind of alginic acid-adriamycin bonding medicine, alginic acid
Good biological activity and biocompatibility, alginic acid is connected with adriamycin by oxime key, reach tumor tissues or into the cell
Lower ph under the conditions of can be with the effect of quick release, so as to further prepare with excellent compatibility and medicament slow release
The polymer bond drug of function.The Chinese patent of Publication No. CN103656670A discloses a kind of glucan-adriamycin bonding
The glucan of good biocompatibility is connected to obtain with good biocompatibility and slow release effect by medicine with adriamycin by oxime key
Polymer bond drug.However, the bonding medicine in above-mentioned patent, which plays anticancer therapeutic, leans on adriamycin single medicine, pass through one kind
Approach plays antitumor action.Since the characteristics such as multi-drug resistance of the tumor and easy diffusion transfer cause single therapeutic scheme to be difficult to
Realize effective treatment of tumour.
Summary of the invention
The purpose of the present invention is to provide a kind of natineoplaston-doxorubicin derivative and preparation method thereof and antineoplastics
Object, adriamycin and antitumor KLAK peptide have by chemical bonding in natineoplaston-doxorubicin derivative provided by the invention
Good biocompatibility and synergistic antitumor effect.
In order to achieve the above-mentioned object of the invention, the present invention the following technical schemes are provided:
The present invention provides a kind of natineoplaston-doxorubicin derivative, in the adriamycin by maleimide amino-functionalization
Dimaleoyl imino is prepared with the sulfydryl of cysteine in the KLAK peptide of cysteine through addition reaction with N-terminal；Institute
Stating KLAK peptide of the N-terminal with cysteine has amino acid sequence shown in SEQ ID No.1.
The present invention provides natineoplaston-doxorubicin derivative preparation method described in above-mentioned technical proposal, including it is following
Step:
N-terminal is had into the KLAK peptide of cysteine, the adriamycin of maleimide amino-functionalization, three (2- carbonylethyl) phosphorus
Addition reaction is carried out after hydrochloride and solvent mixing, obtains natineoplaston-doxorubicin derivative.
Preferably, the N-terminal has the adriamycin and three (2- of the KLAK peptide of cysteine, maleimide amino-functionalization
Carbonylethyl) microcosmic salt hydrochlorate molar ratio be 1:(3~10): (10~20).
Preferably, the solvent include phosphate buffer solution, 4- (2- ethoxy) -1- piperazine ethanesulfonic acid buffer solution or
N,N-dimethylformamide.
Preferably, the concentration of the phosphate buffer solution is 18~22mmol/L, and pH value is 6.4~8.2.
Preferably, the concentration of 4- (2- the ethoxy) -1- piperazine ethanesulfonic acid buffer solution is 20~100mmol/L, pH
Value is 6.5~7.5.
Preferably, the temperature of the addition reaction is 22~28 DEG C, and the time is 1.5~2.5h；The addition reaction is being stirred
It is carried out under the conditions of mixing.
Preferably, after the completion of the addition reaction further include:
Ultrafiltration centrifugation is carried out after gained system is stood, and gained concentration material is lyophilized, natineoplaston-Ah mould is obtained
Plain derivative.
The present invention provides a kind of anti-tumor drug, including active constituent and auxiliary material, the active constituent is above-mentioned technology
Natineoplaston-doxorubicin derivative described in scheme.
Preferably, the content of the active constituent is 51.3~78.6wt%.
The present invention provides a kind of natineoplaston-doxorubicin derivative, in the adriamycin by maleimide amino-functionalization
Dimaleoyl imino is prepared with the sulfydryl of cysteine in the KLAK peptide of cysteine through addition reaction with N-terminal；Institute
Stating KLAK peptide of the N-terminal with cysteine has amino acid sequence shown in SEQ ID No.1.It is provided by the invention antitumor
Adriamycin is bonded with antitumor KLAK peptide by the hydrazone bond with sour response characteristic in peptide-doxorubicin derivative, in tumour cell
Under interior faintly acid (pH value is 5.5~6.5) environment, responsiveness discharges two kinds of anticancer drugs (adriamycin and antitumor KLAK
Peptide), it reduces the toxic side effect of normal tissue and enhances the killing to tumour cell, to utilize two kinds of anticarcinogens of release
Object plays synergistic antitumor effect by respective mechanism of action, is finally reached ideal therapeutic effect.
Detailed description of the invention
Fig. 1 is natineoplaston-doxorubicin derivative mass spectral characteristi figure prepared by embodiment 1；
Fig. 2 is natineoplaston-doxorubicin derivative UV absorption figure prepared by embodiment 1；
Fig. 3 is adriamycin and natineoplaston-doxorubicin derivative flow cytometry analysis comparison prepared by embodiment 1
Figure；
Fig. 4 is adriamycin and natineoplaston-doxorubicin derivative laser confocal imaging analysis pair prepared by embodiment 1
Than figure；
Fig. 5 is natineoplaston-Ah mould that Dox and N-terminal are prepared with the KLAK peptide mixer of cysteine with embodiment 1
The cell survival rate comparison diagram of plain derivative.
Specific embodiment
The present invention provides a kind of natineoplaston-doxorubicin derivative, in the adriamycin by maleimide amino-functionalization
Dimaleoyl imino is prepared with the sulfydryl of cysteine in the KLAK peptide of cysteine through addition reaction with N-terminal；Institute
Stating KLAK peptide of the N-terminal with cysteine has amino acid sequence shown in SEQ ID No.1.In the present invention, the end N
The particular sequence of KLAK peptide of the end with cysteine is as follows:
CKLAKLAKKLAKLAK。
In the present invention, the structural formula of the adriamycin (Dox-EMCH) of the maleimide amino-functionalization is as follows:
The present invention provides natineoplaston-doxorubicin derivative preparation method described in above-mentioned technical proposal, including it is following
Step:
N-terminal is had into the KLAK peptide of cysteine, the adriamycin of maleimide amino-functionalization, three (2- carbonylethyl) phosphorus
Addition reaction is carried out after hydrochloride and solvent mixing, obtains natineoplaston-doxorubicin derivative.
The source of KLAK peptide of the present invention for the N-terminal with cysteine does not have special restriction, using ability
Polypeptide solid-state reaction method known to field technique personnel is prepared.
The present invention does not have special restriction for the source of the adriamycin of the maleimide amino-functionalization, using this field
Method known to technical staff is prepared.In the present invention, the preparation of the adriamycin of the maleimide amino-functionalization
Method preferably includes following steps:
Adriamycin (Dox), 6- maleimide hexanoyl hydrazine trifluoroacetate (EMCH) and organic solvent are mixed, in trifluoro
Acetic acid catalysis effect is lower to carry out nucleophilic addition, obtains the adriamycin of maleimide amino-functionalization.
In the present invention, the molar ratio of the adriamycin and 6- maleimide hexanoyl hydrazine trifluoroacetate is preferably 1:(3
~10), more preferably 1:(3~6).In the present invention, the organic solvent preferably includes methanol, ethyl alcohol or N, N- dimethyl methyl
Amide (DMF).The present invention does not have the usage amount of the organic solvent and trifluoroacetic acid special restriction, can guarantee described
Nucleophilic addition is gone on smoothly.
In the present invention, the temperature of the nucleophilic addition is preferably 20~30 DEG C, and more preferably 22~28 DEG C；Time
Preferably 12~120h, more preferably 24~100h, further preferably 24~48h.In the present invention, the nucleophilic addition is anti-
It should preferably be carried out under the conditions of being protected from light.
After completing the nucleophilic addition, present invention preferably employs ether to precipitate gained system, then by institute
It obtains solidliquid mixture and carries out ultrafiltration centrifugation, gained concentration material is lyophilized, the adriamycin of maleimide amino-functionalization is obtained.
In the present invention, the number of the precipitating is preferably 2~3 times；The present invention is centrifuged and is lyophilized specific for the precipitating, ultrafiltration
Operating parameter does not have special restriction, using operating parameter well known to those skilled in the art.
In the present invention, the reaction process for preparing the adriamycin of the maleimide amino-functionalization is as follows:
After obtaining the adriamycin of KLAK peptide and maleimide amino-functionalization of the N-terminal with cysteine, the present invention is by institute
State N-terminal with the KLAK peptide of cysteine, the adriamycin of maleimide amino-functionalization, three (2- carbonylethyl) microcosmic salt hydrochlorates and
Addition reaction is carried out after solvent mixing, obtains natineoplaston-doxorubicin derivative (Dox-KLAK).In the present invention, the end N
End has the adriamycin and three (2- carbonylethyl) microcosmic salt hydrochlorates of the KLAK peptide of cysteine, maleimide amino-functionalization
(TECPHCl) molar ratio is preferably 1:(3~10): (10~20), more preferably 1:(4~6): (12~16).In this hair
In bright, the solvent preferably includes phosphate buffer solution (PBS), 4- (2- ethoxy) -1- piperazine ethanesulfonic acid buffer solution
(HEPES) or N,N-dimethylformamide (DMF).In the present invention, the concentration of the phosphate buffer solution be preferably 18~
22mmol/L, more preferably 18~20mmol/L；PH value is preferably 6.4~8.2, and more preferably 6.4~7.5.In the present invention,
The concentration of 4- (2- the ethoxy) -1- piperazine ethanesulfonic acid buffer solution is preferably 20~100mmol/L, more preferably 50~
100mmol/L；PH value is preferably 6.5~7.5, and more preferably 6.5~7.It is anti-that the present invention carries out the addition in above-mentioned solvent
It answers, can guarantee that the addition reaction is gone on smoothly.
In the present invention, the N-terminal has the KLAK peptide of cysteine, the adriamycin of maleimide amino-functionalization, three
N-terminal is preferably first had KLAK peptide, three (the 2- carbonyl second of cysteine by (2- carbonylethyl) microcosmic salt hydrochlorate and solvent mixing
Base) microcosmic salt hydrochlorate and solvent mixed, then again mixed gained mixed material with the adriamycin of maleimide amino-functionalization.
In the present invention, three reducing agent of (2- carbonylethyl) the microcosmic salt hydrochlorate as disulfide bond, protection N-terminal is with cysteine
The free sulfhydryl group of KLAK peptide is not oxidized, to be conducive to going on smoothly for subsequent addition reaction.The present invention is for each material
Hybrid mode does not have special restriction, material can be made to be sufficiently mixed.
In the present invention, the temperature of the addition reaction is preferably 22~28 DEG C, and the time is preferably 1.5~2.5h.At this
In invention, the addition reaction preferably carries out under agitation；Present invention spy no for the mode and revolving speed of the stirring
Different restriction, using agitating mode well known to those skilled in the art and revolving speed.The present invention carries out institute under the above conditions
Addition reaction is stated, can guarantee that the adriamycin of KLAK peptide and maleimide amino-functionalization of the N-terminal with cysteine is sufficiently anti-
It answers.
In the present invention, after the completion of the addition reaction it is also preferable to include:
Ultrafiltration centrifugation is carried out after gained system is stood, and gained concentration material is lyophilized, natineoplaston-Ah mould is obtained
Plain derivative.
In the present invention, the temperature of the standing is preferably 2~6 DEG C, and more preferably 2~4 DEG C；Time is preferably 20~
25h, more preferably 20~22h.The concrete operations parameter that the present invention is centrifuged the ultrafiltration and is lyophilized does not have special restriction,
Using operating parameter well known to those skilled in the art.
The present invention provides a kind of anti-tumor drug, including active constituent and auxiliary material, the active constituent is above-mentioned technology
Natineoplaston-doxorubicin derivative described in scheme.In the present invention, the content of the active constituent be preferably 51.3~
78.6wt%.The present invention does not have the auxiliary material special restriction, can pharmaceutically be connect using well known to those skilled in the art
The auxiliary material received.
The present invention does not have the preparation method of the anti-tumor drug special restriction, ripe using those skilled in the art
The preparation method known.
Below in conjunction with the embodiment in the present invention, the technical solution in the present invention is clearly and completely described.It is aobvious
So, described embodiments are only a part of the embodiments of the present invention, instead of all the embodiments.Based on the reality in the present invention
Example is applied, every other embodiment obtained by those of ordinary skill in the art without making creative efforts all belongs to
In the scope of protection of the invention.
Embodiment 1
By 1mmol adriamycin, 3mmol 6- maleimide hexanoyl hydrazine trifluoroacetate, 20mL methanol and 0.01mL trifluoro
Acetic acid mixing, be protected from light, 20 DEG C under the conditions of carry out nucleophilic addition for 24 hours；It is successively carried out after gained system is mixed with ethyl alcohol
Precipitating and ultrafiltration centrifugation, gained concentration material is lyophilized, the adriamycin of maleimide amino-functionalization is obtained；
The end 1mmolN is had to KLAK peptide, (2- carbonylethyl) the microcosmic salt hydrochlorate of 15mmol tri- and the 10mL phosphorus of cysteine
Hydrochlorate buffer solution (concentration 20mmol/L, pH value 7.4) mixes, and stirs 1h under the conditions of 25 DEG C；Then the Malaysia 3mmol is added
The adriamycin of acid imide functionalization carries out addition reaction 2h under the conditions of stirring, 25 DEG C；Gained system is quiet under the conditions of 4 DEG C
Ultrafiltration centrifugation is carried out after setting 22h, gained concentration material is lyophilized, natineoplaston-doxorubicin derivative is obtained.
Embodiment 2
By 1mmol adriamycin, 5mmol 6- maleimide hexanoyl hydrazine trifluoroacetate, 20mL methanol and 0.01mL trifluoro
Acetic acid mixing, be protected from light, 20 DEG C under the conditions of carry out nucleophilic addition for 24 hours；It is successively carried out after gained system is mixed with ethyl alcohol
Precipitating and ultrafiltration centrifugation, gained concentration material is lyophilized, the adriamycin of maleimide amino-functionalization is obtained；
The end 1mmolN is had to KLAK peptide, (2- carbonylethyl) the microcosmic salt hydrochlorate of 12mmol tri- and the 10mL4- of cysteine
(2- ethoxy) -1- piperazine ethanesulfonic acid buffer solution (concentration 100mmol/L, pH value 6.5) mixes, and stirs under the conditions of 25 DEG C
1h；Then the adriamycin of 5mmol maleimide amino-functionalization is added, carries out addition reaction 2h under the conditions of stirring, 25 DEG C；By institute
It is proper tie up to 4 DEG C under the conditions of stand 22h after carry out ultrafiltration centrifugation, gained concentration material is lyophilized, natineoplaston-Ah is obtained
Adm derivative.
Embodiment 3
By 1mmol adriamycin, 10mmol 6- maleimide hexanoyl hydrazine trifluoroacetate, 20mL methanol and 0.01mL tri-
Fluoroacetic acid mixing, be protected from light, 20 DEG C under the conditions of carry out nucleophilic addition for 24 hours；After gained system is mixed with ethyl alcohol successively into
Row precipitating and ultrafiltration centrifugation, gained concentration material is lyophilized, the adriamycin of maleimide amino-functionalization is obtained；
The end 1mmolN is had to KLAK peptide, (2- carbonylethyl) the microcosmic salt hydrochlorate of 12mmol tri- and the 10mL of cysteine
N,N-Dimethylformamide mixes, and stirs 1h under the conditions of 25 DEG C, and the adriamycin of 5mmol maleimide amino-functionalization is then added,
Addition reaction 2h is carried out under the conditions of stirring, 25 DEG C；Ultrafiltration centrifugation is carried out after gained system to be stood to 22h under the conditions of 4 DEG C, it will
Gained concentration material is lyophilized, and natineoplaston-doxorubicin derivative is obtained.
Natineoplaston-the doxorubicin derivative prepared to embodiment 1 characterizes, wherein Fig. 1 is prepared by embodiment 1
Natineoplaston-doxorubicin derivative mass spectral characteristi figure is as shown in Figure 1 to occur significantly at 2377.91 in molecular weight
Peak is close with estimation molecular weight 2377.87.Fig. 2 is natineoplaston-doxorubicin derivative UV absorption prepared by embodiment 1
Map, as shown in Figure 2, natineoplaston-doxorubicin derivative have apparent absorption peak at 220nm and 480nm, respectively correspond
The UV absorption of KLAK peptide and adriamycin of the N-terminal with cysteine, natineoplaston-adriamycin prepared by embodiment 2 and 3 spread out
Mass spectral results of biology and Fig. 1 is almost the same, UV absorption and Fig. 2 are almost the same, illustrate that the present invention has successfully been prepared and resist
Tumour peptide-doxorubicin derivative.
Natineoplaston-the doxorubicin derivative prepared to embodiment 1 is tested for the property, specific as follows:
(1) Melanoma B16 cell is inoculated in six orifice plates containing sheet glass, is separately added within second day 10 μm of ol/L
Adriamycin (Dox) and natineoplaston-doxorubicin derivative (Dox-KLAK), after cell incubation 1h, culture solution is discarded, after digestion
Flow cytometry analysis is carried out, as a result as shown in Figure 2.As shown in Figure 2, small molecule adriamycin can rapidly enter into the cell, this
Natineoplaston-doxorubicin derivative that invention provides is slightly slow compared with adriamycin into intracellular speed, but also can be by melanin
Oncocyte endocytosis illustrates that natineoplaston-doxorubicin derivative provided by the invention has preferable cell endocytic efficiency.
(2) Melanoma B16 cell is inoculated in six orifice plates containing sheet glass, is separately added within second day 10 μm of ol/L
Adriamycin (Dox) and natineoplaston-doxorubicin derivative (Dox-KLAK), after cell incubation 1h, discard culture solution, PBS is washed
DAPI dyeing liquor room temperature is added afterwards twice and dyes 15min, PBS is washed carries out laser confocal imaging analysis afterwards twice, as a result such as Fig. 3
It is shown.From the figure 3, it may be seen that adriamycin can rapidly enter in nucleus, natineoplaston-doxorubicin derivative provided by the invention is thin
Speed and the small molecule adriamycin intracellular of gulping down is slower than slightly, is located in nucleus and cytoplasm, illustrates provided by the invention antitumor
Peptide-doxorubicin derivative by melanoma cell endocytic and can be located in nucleus and cytoplasm.
(3) Melanoma B16 cell is inoculated in 96 orifice plates according to the density of every 5000 cells in hole, is added within second day
The Dox and N-terminal of various concentration (respectively 0.1 μm of ol/L, 0.5 μm of ol/L, 1 μm of ol/L, 2 μm of ol/L, 5 μm of ol/L) are with half
Cystine KLAK peptide mixer (be denoted as Dox+KLAK, the molar ratio of the KLAK peptide of Dox and N-terminal with cysteine is 1:
1) it and natineoplaston-doxorubicin derivative (Dox-KLAK), cultivates and MTT reagent is added after 48h detects cell survival rate.As a result
As shown in Figure 3.From the figure 3, it may be seen that the tumor-killing significant effect of natineoplaston-doxorubicin derivative provided by the invention is better than
Dox and N-terminal have the KLAK peptide mixer group of cysteine, show that synergistic antitumor acts on.
Natineoplaston-the doxorubicin derivative prepared according to the method described above to embodiment 2 and embodiment 3 carries out performance survey
Examination, it is as a result consistent with the above-mentioned the performance test results of natineoplaston-doxorubicin derivative prepared by embodiment 1.
The above is only a preferred embodiment of the present invention, it is noted that for the ordinary skill people of the art
For member, various improvements and modifications may be made without departing from the principle of the present invention, these improvements and modifications are also answered
It is considered as protection scope of the present invention.
Sequence table
<110>Beihua University
<120>a kind of natineoplaston-doxorubicin derivative and preparation method thereof and anti-tumor drug
<160> 1
<170> SIPOSequenceListing 1.0
<210> 1
<211> 15
<212> PRT
<213>artificial sequence (Artificial Sequence)
<400> 1
Cys Lys Leu Ala Lys Leu Ala Lys Lys Leu Ala Lys Leu Ala Lys
1 5 10 15
Claims (10)
1. a kind of natineoplaston-doxorubicin derivative, by the dimaleoyl imino and N in the adriamycin of maleimide amino-functionalization
End is prepared with the sulfydryl of cysteine in the KLAK peptide of cysteine through addition reaction；The N-terminal has half Guang
The KLAK peptide of propylhomoserin has amino acid sequence shown in SEQ ID No.1.
2. natineoplaston-doxorubicin derivative preparation method described in claim 1, comprising the following steps:
By N-terminal with the KLAK peptide of cysteine, the adriamycin of maleimide amino-functionalization, three (2- carbonylethyl) microcosmic salts acid
Addition reaction is carried out after salt and solvent mixing, obtains natineoplaston-doxorubicin derivative.
3. preparation method according to claim 2, which is characterized in that the N-terminal has the KLAK peptide of cysteine, horse
The molar ratio of the adriamycin and three (2- carbonylethyl) microcosmic salt hydrochlorates that carry out acid imide functionalization is 1:(3~10): (10~20).
4. preparation method according to claim 2, which is characterized in that the solvent includes phosphate buffer solution, 4- (2-
Ethoxy) -1- piperazine ethanesulfonic acid buffer solution or N,N-dimethylformamide.
5. the preparation method according to claim 4, which is characterized in that the concentration of the phosphate buffer solution be 18~
22mmol/L, pH value are 6.4~8.2.
6. the preparation method according to claim 4, which is characterized in that 4- (2- the ethoxy) -1- piperazine ethanesulfonic acid is slow
The concentration for rushing solution is 20~100mmol/L, and pH value is 6.5~7.5.
7. preparation method according to claim 2, which is characterized in that the temperature of the addition reaction is 22~28 DEG C, when
Between be 1.5~2.5h；The addition reaction carries out under agitation.
8. the preparation method according to claim 2 or 7, which is characterized in that after the completion of the addition reaction further include:
Ultrafiltration centrifugation is carried out after gained system is stood, and gained concentration material is lyophilized, natineoplaston-adriamycin is obtained and spreads out
Biology.
9. a kind of anti-tumor drug, including active constituent and auxiliary material, the active constituent is natineoplaston-described in claim 1
Doxorubicin derivative.
10. anti-tumor drug according to claim 9, which is characterized in that the content of the active constituent be 51.3~
78.6wt%.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910036773.8A CN109675051B (en) | 2019-01-15 | 2019-01-15 | Antitumor peptide-adriamycin derivative, preparation method thereof and antitumor drug |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910036773.8A CN109675051B (en) | 2019-01-15 | 2019-01-15 | Antitumor peptide-adriamycin derivative, preparation method thereof and antitumor drug |
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| Publication Number | Publication Date |
|---|---|
| CN109675051A true CN109675051A (en) | 2019-04-26 |
| CN109675051B CN109675051B (en) | 2021-12-21 |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN110386962A (en) * | 2019-07-04 | 2019-10-29 | 苏州强耀生物科技有限公司 | A kind of synthetic method of adriamycin coupling target polypeptide |
| CN113321692A (en) * | 2020-02-28 | 2021-08-31 | 国家纳米科学中心 | Adriamycin prodrug, preparation method and application thereof |
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| CN107335060A (en) * | 2016-04-28 | 2017-11-10 | 北京大学 | A kind of small molecule conjugate and its nano prodrug system based on rgd peptide-chemotherapeutics |
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| CN107335060A (en) * | 2016-04-28 | 2017-11-10 | 北京大学 | A kind of small molecule conjugate and its nano prodrug system based on rgd peptide-chemotherapeutics |
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| H. MICHAEL ELLERBY,ET AL.: "Anti-cancer activity of targeted pro-apoptotic peptides", 《NATURE MEDICINE》 * |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110386962A (en) * | 2019-07-04 | 2019-10-29 | 苏州强耀生物科技有限公司 | A kind of synthetic method of adriamycin coupling target polypeptide |
| CN113321692A (en) * | 2020-02-28 | 2021-08-31 | 国家纳米科学中心 | Adriamycin prodrug, preparation method and application thereof |
| CN113321692B (en) * | 2020-02-28 | 2022-10-14 | 国家纳米科学中心 | Adriamycin prodrug, preparation method and application thereof |
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