CN109265516A - A kind of hybrid peptide and its preparation method and application - Google Patents
A kind of hybrid peptide and its preparation method and application Download PDFInfo
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- CN109265516A CN109265516A CN201710584934.8A CN201710584934A CN109265516A CN 109265516 A CN109265516 A CN 109265516A CN 201710584934 A CN201710584934 A CN 201710584934A CN 109265516 A CN109265516 A CN 109265516A
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- hybrid peptide
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
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- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
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Abstract
The invention belongs to technical field of medical chemistry, it is related to a kind of hybrid peptide and its preparation method and application.Heterozygosis of the invention has the structure of formula 1, molecular formula C45H71N5O8S；It prepares as follows: first synthesizing cyclization precursors, close big ring to form hybrid peptide FDU1431 of the present invention after removing the end N- and the end C- protecting group.The hybrid peptide further includes prototype compound, the composition containing this compound and its medically acceptable salt.Hybrid peptide of the invention has good inhibiting effect to kinds of tumor cells, there is potential application value in terms of the research and development of field of medicaments especially anti-tumor drug.
Description
Technical field
The invention belongs to technical field of medical chemistry, it is related to a kind of hybrid peptide and its preparation method and application.
Background technique
Prior art discloses Apratoxin be discovered in recent years the strongest marine natural products of anti-tumor activity it
One, to the half-inhibitory concentration of tumour cell nanomole and picomole rank (referring to document: (a) open big etc., organic chemistry,
2014,34,475；(b) Tarsis, E.M.et al.Tetrahedron 2015,71,5029；(c)Doi,
T.Chem.Pharm.Bull.2014,62,735；(d) Luesch, H.et al.J.Am.Chem.Soc.2001,123,5418).
One of member in the family, Apratoxin A have extremely strong anti-tumor activity, but since 35 hydroxyls in molecule hold very much
It easily eliminates, and contains Micheal addition receptor fragments, be allowed to that the defects of window is too narrow is not sufficiently stable and treated there are molecule
(referring to document Chen et al.J.Med.Chem.2014,57,3011)；Another member of the family, apratoxin E
(Matthew, S.et al.J.Nat.Prod.2008,71,1113), without Micheal addition receptor, also without being easy to eliminate
Hydroxyl, but its defect is low very to the lethal effect ratio Apratoxin A of the cancer cells such as colon cancer, cervical carcinoma and osteocarcinoma
It is more.
Status based on the prior art, present inventor is quasi- to provide a kind of new hybrid peptide, and in particular to hybrid peptide
FDU1431 and its preparation method and application.
Summary of the invention
The purpose of the present invention is provide a kind of new hybrid peptide, and in particular to miscellaneous to overcome defect of the existing technology
Close peptide FDU1431 and its preparation method and application.
The present invention is based on the Research foundations of the prior art, by following reaction equations, after apratoxinA and E is carried out heterozygosis,
Double methylations are carried out by its 34- again, and after 30 spatial configurations are changed to R- type by S, resulting molecule is (hereinafter referred to as
For FDU1431) have good anti-tumor activity and overcome natural products stability it is poor, treatment window narrows defect.
Specifically, a kind of hybrid peptide of the invention has the structure (below with number FDU1431 reference) of formula 1, molecule
Formula is C45H71N5O8S；It prepares as follows: first synthesizing cyclization precursors, close big ring after removing the end N- and the end C- protecting group
It closes to form hybrid peptide FDU1431 of the present invention.
The hybrid peptide further includes prototype compound, the composition containing this compound and its medically acceptable salt.
Hybrid peptide of the invention has good inhibiting effect to kinds of tumor cells, especially antitumor in field of medicaments
There is potential application value in terms of the research and development of drug.
More specifically, a kind of hybrid peptide of the invention passes through following methods and prepares comprising step: 1) using such as Formulas I and
The compound of Formula II forms the compound of formula III under condensing agent effect；
Wherein,
R1 is the linear or branched alkyl group of C1~C10, aromatic radical, allyl；R2 be tertbutyloxycarbonyl, 9- fluorenylmethoxycarbonyl,
Benzyloxycarbonyl group, 2,2,2- tri-chloroethoxy base carbonyl；
The condensing agent used is 1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride, 2- (7- azo benzo three
Nitrogen azoles)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester, (3H-1,2,3- triazol [4,5-b] pyridine -3- oxygroup) three -1- pyrroles
Cough up Wan Ji Phosphonium hexafluorophosphate, 3- (diethoxy phosphoryl oxy) -1,2,3- phentriazine -4- ketone or combinations thereof；Solvent for use
For methylene chloride, tetrahydrofuran, N,N-dimethylformamide or combinations thereof；
Reaction temperature is -10~80 degrees Celsius；Reaction time is 0.5~30 hour；
2) by compound III R1 and R2 be converted into hydrogen, then condensing agent effect under form hybrid peptide
FDU1431；
Wherein, according to the difference of R1 and R2, the condition that deprotection base uses can be the molten of the inorganic bases such as sodium hydroxide
Liquid, catalytic hydrogenation, acid cleavage etc.；
The condensing agent used can be 1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride, 2- (7- azobenzene
And triazole)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester, (3H-1,2,3- triazol [4,5-b] pyridine -3- oxygroup) three -
1- Bi coughs up Wan Ji Phosphonium hexafluorophosphate, 3- (diethoxy phosphoryl oxy) -1,2,3- phentriazine -4- ketone or combinations thereof；
Solvent for use is methylene chloride, tetrahydrofuran, N,N-dimethylformamide or combinations thereof；
Reaction temperature is -10~80 degrees Celsius；Reaction time is 0.5~30 hour.
The present invention has carried out tumor cell proliferation inhibition activity test, has carried out active survey using 18 kinds of tumor cell lines
Examination, as a result this shows that hybrid peptide FDU1431 of the invention has the antitumor action of broad spectrum high-effect, to kinds of tumor cells
The half-inhibitory concentration (IC50) of strain is in 30nM or less.
Hybrid peptide of the present invention includes prototype compound, the composition containing this compound and its medically acceptable
Salt can be used for preparing anti-tumor drug.
Detailed description of the invention
Fig. 1, hybrid peptide compound on tumor cell proliferation inhibition activity test of the present invention
It wherein shows, hybrid peptide FDU1431 of the invention has the antitumor action of broad spectrum high-effect, and it is thin to kinds of tumors
The half-inhibitory concentration (IC50) of born of the same parents' strain is in 30nM or less.
Specific embodiment
Embodiment 1 prepares hybrid peptide FDU1431 compound
Hybrid peptide FDU1431 compound is prepared using the commercial reagents progress for being readily synthesized or buying is artificial synthesized,
Specifically includes the following steps:
1) prepare linear peptides III (by taking R1=allyl, R2=9- fluorenylmethoxycarbonyl as an example)
Take compound I (prepare by literature method, referring to Doi, T.et al.Org.Lett.2006,8,531-534.)
4.45g is dissolved in 200mL dry methylene chloride, and compound II is added and (prepares by literature method, referring to Chen et
Al.J.Med.Chem.2014,57,3011) 6.93g and 2- (7- azo benzotriazole)-N, N, N', N'- tetramethylurea hexafluoro
Diisopropyl ethyl amine 3.3mL is added dropwise in phosphate 5.70g, ice bath, and 12h is stirred at room temperature under nitrogen protection, and LC-MS display has been reacted
Entirely, saturated ammonium chloride is quenched, and methylene chloride dilution, the washing of 5% aqueous potassium hydrogen sulfate is closely colourless to water phase for several times, is saturated chlorination
Sodium washing, anhydrous sodium sulfate is dry, is concentrated under reduced pressure, and crude product obtains 7.29g white solid III, yield 65% through silica gel column chromatography.
LC-MS:1144.6[M+Na]+；
2) it removes protecting group, close big ring (by taking R1=allyl, R2=9- fluorenylmethoxycarbonyl as an example)
Compound III (5.61g) is dissolved in 100mL dry tetrahydrofuran, argon gas protection is lower to be added four (triphenylphosphines)
2h is stirred at room temperature in palladium and methylphenylamine, is concentrated under reduced pressure, and concentrate is diluted with ethyl acetate, and 5% aqueous potassium hydrogen sulfate is washed
It washs, saturated sodium-chloride washing, anhydrous sodium sulfate is dry.Crude product obtains white solid through silica gel column chromatography, this solid is dissolved in 50mL
In acetonitrile, diethylamine is added, is stirred at room temperature 1h under argon gas protection, TLC shows fully reacting, be concentrated under reduced pressure, methylene chloride and
Each azeotropic of toluene is primary, this crude product is dissolved in 500mL dry methylene chloride by vacuum after draining 2h, and 2- (7- azobenzene is added
And triazole)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester 3.80g, DIPEA 2.2mL is added dropwise in ice bath, room under nitrogen protection
Temperature stirring 12h, LC-MS show fully reacting, and saturated ammonium chloride is quenched, and the washing of 5% aqueous potassium hydrogen sulfate is close to water phase for several times
Colourless, saturated sodium-chloride washing, anhydrous sodium sulfate is dry, is concentrated under reduced pressure, crude product is through silica gel column chromatography (CHCl3: MeOH=10:
1) 2.1g white solid FDU1431, yield 50% are obtained.LC-MS:864.5[M+Na]+.
2 the compound of the present invention of embodiment tests tumor cell proliferation inhibition activity
Screening technique uses tetrazolium reduction method or Sulforhodamine B protein staining method；
Active testing has been carried out using 18 kinds of tumor cell lines, the results showed that, hybrid peptide FDU1431 of the invention has wide
Potent antitumor action is composed, to the half-inhibitory concentrations (IC50) of various tumor cell strains in 30nM or less；The chemical combination
Object is smaller on the influence of normal cell strain, has preferable selectivity (test cell strain MRC-5, IC50=3600nM).
The compound of the present invention has potential application value in terms of the research and development of field of medicaments especially anti-tumor drug.
Claims (6)
1. a kind of hybrid peptide FDU1431, which is characterized in that its structure with formula 1, molecular formula C45H71N5O8S；
2. the preparation method of hybrid peptide FDU1431 described in claim 1, characterized in that comprising: cyclization precursors are first synthesized,
Big ring is closed behind the removal end N- and the end C- protecting group to form the hybrid peptide FDU1431, comprising steps of
1) using the compound such as Formulas I and Formula II, the compound of formula III is formed under condensing agent effect；
2) by compound III R1 and R2 be converted into hydrogen, then condensing agent effect under formed hybrid peptide FDU1431；
3. method as described in claim 2, which is characterized in that wherein,
R1 is the linear or branched alkyl group of C1~C10, aromatic radical, allyl；
R2 is tertbutyloxycarbonyl, 9- fluorenylmethoxycarbonyl, benzyloxycarbonyl group, 2,2,2- tri-chloroethoxy base carbonyl；
The condensing agent used is 1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride, 2- (three nitrogen of 7- azo benzo
Azoles)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester, (3H-1,2,3- triazol [4,5-b] pyridine -3- oxygroup) three -1- pyrroles
Wan Ji Phosphonium hexafluorophosphate, 3- (diethoxy phosphoryl oxy) -1,2,3- phentriazine -4- ketone or combinations thereof；
Solvent for use is methylene chloride, tetrahydrofuran, N,N-dimethylformamide or combinations thereof；
Reaction temperature is -10~80 degrees Celsius；Reaction time is 0.5~30 hour.
4. method as described in claim 2, which is characterized in that wherein,
According to the difference of R1 and R2, the condition that deprotection base uses is the solution of sodium hydroxide inorganic base, catalytic hydrogenation or acid
Cracking；
The condensing agent used is 1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride, 2- (three nitrogen of 7- azo benzo
Azoles)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester, (3H-1,2,3- triazol [4,5-b] pyridine -3- oxygroup) three -1- pyrroles
Wan Ji Phosphonium hexafluorophosphate, 3- (diethoxy phosphoryl oxy) -1,2,3- phentriazine -4- ketone or combinations thereof；
Solvent for use is methylene chloride, tetrahydrofuran, N,N-dimethylformamide or combinations thereof；
Reaction temperature is -10~80 degrees Celsius；Reaction time is 0.5~30 hour.
5. hybrid peptide FDU1431 described in claim 1, characterized in that the hybrid peptide FDU1431 includes prototype chemical combination
Object, the composition containing this compound and its medically acceptable salt.
6. hybrid peptide FDU1431 and its prototype compound described in claim 5, the composition containing this compound and its medically
Acceptable salt application in preparation of anti-tumor drugs.
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| CN201710584934.8A CN109265516A (en) | 2017-07-18 | 2017-07-18 | A kind of hybrid peptide and its preparation method and application |
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| CN201710584934.8A CN109265516A (en) | 2017-07-18 | 2017-07-18 | A kind of hybrid peptide and its preparation method and application |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR102524528B1 (en) * | 2022-11-24 | 2023-04-21 | 주식회사 리얼이펙트 | Manufacturing method of aluminum palmitoyl dipeptide, an amphiphilic antibacterial peptide |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2015127161A1 (en) * | 2014-02-20 | 2015-08-27 | University Of Florida Research Foundation | Macrocyclic therapeutic agents, methods of manufacture, and methods of treatment |
| CN106674330A (en) * | 2015-11-10 | 2017-05-17 | 复旦大学 | 34-Dimethyl apratoxin A/E preparation method |
-
2017
- 2017-07-18 CN CN201710584934.8A patent/CN109265516A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2015127161A1 (en) * | 2014-02-20 | 2015-08-27 | University Of Florida Research Foundation | Macrocyclic therapeutic agents, methods of manufacture, and methods of treatment |
| CN106674330A (en) * | 2015-11-10 | 2017-05-17 | 复旦大学 | 34-Dimethyl apratoxin A/E preparation method |
Non-Patent Citations (3)
| Title |
|---|
| PING WU ET AL.: ""Synthesis and biological evaluation of oxoapratoxin E and its C30 epimer"", 《TETRAHEDRON LETTERS》 * |
| RUWEN YIN ET AL.: ""Synthesis, conformational analysis and biological evaluation of the lactam analogue of the cyclodepsipeptide apratoxin A"", 《TETRAHEDRON》 * |
| WEIJING CAI ET AL.: ""Apratoxin S10, a Dual Inhibitor of Angiogenesis and Cancer Cell Growth To Treat Highly Vascularized Tumors"", 《ACS MED. CHEM. LETT.》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR102524528B1 (en) * | 2022-11-24 | 2023-04-21 | 주식회사 리얼이펙트 | Manufacturing method of aluminum palmitoyl dipeptide, an amphiphilic antibacterial peptide |
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