CN103159835B - Lys and oligopeptide-modified curcumin derivatives, and synthesis and medical application thereof - Google Patents
Lys and oligopeptide-modified curcumin derivatives, and synthesis and medical application thereof Download PDFInfo
- Publication number
- CN103159835B CN103159835B CN201110415153.9A CN201110415153A CN103159835B CN 103159835 B CN103159835 B CN 103159835B CN 201110415153 A CN201110415153 A CN 201110415153A CN 103159835 B CN103159835 B CN 103159835B
- Authority
- CN
- China
- Prior art keywords
- boc
- lys
- obzl
- ala
- diketone
- 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.)
- Expired - Fee Related
Links
Classifications
-
- 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
Landscapes
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
Abstract
The present invention discloses six pseudo-peptides of the general formula I, wherein R1 is H or CH3, and R2 is Lys or Lys (Pro-Ala-Lys)-Arg-Gly-Asp-Val or Lys (Pro-Ala-Lys)-Ala-Gly-Asp-Val. The present invention further discloses a preparation method and use thereof. The compounds of the present invention have excellent thrombolytic activity, antithrombotic activity, anti-inflammatory activity, and OH radical scavenging activity, and a nanostructure.
Description
Technical field
The present invention relates to 6 kinds of pseudo-peptides of general formula I, R in formula
1for H or CH
3, R
2for Lys or Lys (Pro-Ala-Lys)-Arg-Gly-Asp-Val or Lys (Pro-Ala-Lys)-Ala-Gly-Asp-Val.The invention further relates to their preparation method and purposes.Compound of the present invention is except having outstanding thrombus dissolving activity, antithrombotic acitivity, anti-inflammatory activity, OH free radical scavenging activity and nanostructure.The invention belongs to biomedicine field.
Background technology
Curcumine is one of effective constituent of turmeric, has antithrombotic, anti-inflammatory and Free-radical scavenging activity, is the natural product of safety and low toxicity.Inflammatory reaction promotes release and the platelet activation of thrombin, and lower natural anticoagulant simultaneously and suppress fibrinolytic, thrombosis attends by the process that acute inflammation transforms to unrestrained property inflammation.The inflammation of appropriateness is conducive to suffering the body of various damage to maintain the stable of self environment, is conducive to the recovery that body safeguards the complete of self structure and function.But excessively strong inflammatory reaction may aggravate the damage of body, produce the chain reaction of a sequence, cause vicious cycle.Give and anti-inflammatory drug in thromboembolism treatment, contribute to improving thrombolysis rate, alleviate tissue injury.Ischemical reperfusion injury is the reason causing tissue injury after thrombolysis, and free radical is the important factor causing reperfusion injury.Give and free-radical scavengers in thromboembolism treatment, for ischemical reperfusion injury, there is provide protection.Although curcumine in vitro platelet aggregation-against model, external free radical scavenging model, rat arteriovenous shut intubate antithrombotic model and mice ear anti-inflammation models all shows the activity of expectation; and these activity all have provide protection to cerebral ischemia re-pouring injured, myocardial ischemia-reperfusion injury, lung reperfusion injury; but curcumine does not have thrombus dissolving activity, the prerequisite namely producing ischemia-reperfusion does not exist.Contriver recognizes, only has and introduce the described provide protection that thrombus dissolving oligopeptides could realize it in curcumine.
P6A (Ala-Arg-Pro-Ala-Lys) is one of scleroproein β chain degradation product, has thrombus dissolving activity.Contriver has found meta-bolites PAK in the metabolism research of P6A.On rat arteriovenous shut intubate thrombus dissolving model, P6A is strong for PAK thrombus specific activity parent.According to general understanding, polypeptide all can be degraded rapidly in vivo.Delaying vivo degradation speed by the tie of PAK and improve thrombus dissolving activity, is the important channel of oligopeptides thrombolytic agent research.
According to general understanding, containing the amphipathic molecule of polypeptide, the polypeptide that such as aliphatic alcohol chain is modified, crosses noncovalent intermolecular interactions under suitable condition and can form nanostructure.Polypeptide conveying in vivo can be improved by nanostructure, delay polypeptide degradation rate in vivo and the activity in vivo of raising polypeptide.According to these understanding, inventors herein propose the present invention.
Platelet membrane glycoprotein GPIIb/IIIa receptor activation is the final shared pathway of platelet aggregation, plays an important role in thrombosis.Arg-Gly-Asp (RGD)/Ala-Gly-Asp (AGD) tetrapeptide is the ligands specific of platelet surface GPIIb/IIIa acceptor, not only there is antiplatelet aggregative activity, and optionally combine embodiment antithrombotic targeting to the platelet surface of activation.Utilize the antithrombotic target effect of RGD/AGD tetrapeptide can prepare the targeted drug of the treatment thrombus containing RGD/AGD tetrapeptide.
According to general understanding, containing the amphipathic molecule of polypeptide, can there is self-assembly by noncovalent intermolecular interactions, form nanostructure in the polypeptide that such as aliphatic alcohol chain is modified under suitable condition.Polypeptide conveying in vivo can be improved by nanostructure, delay polypeptide degradation rate in vivo and the activity in vivo of raising polypeptide.According to these understanding and discovery, inventors herein propose the present invention.
Summary of the invention
First content of the present invention is to provide 6 kinds of pseudo-peptides of general formula I.R in formula
1for H or CH
3, R
2for Lys or Lys (Pro-Ala-Lys)-Arg-Gly-Asp-Val or Lys (Pro-Ala-Lys)-Ala-Gly-Asp-Val.
Second content of the present invention is to provide the preparation method of 6 kinds of pseudo-peptides of general formula I, and the method comprises:
(1) under dicyclohexylcarbodiimide (DCC) and N-hydroxy-succinamide (HOSu) exist, Boc-Pro is Boc-Pro-OSu with HOSu condensation in anhydrous THF, at NaHCO
3there is lower Boc-Pro-OSu and L-Ala reaction and generate Boc-Pro-Ala;
(2) under DCC and HOBt exists, Boc-Pro-Ala is Boc-Pro-Ala-Lys (Boc)-OBzl with Lys (Boc)-OBzl condensation in anhydrous THF;
(3) under NaOH exists, in methyl alcohol, Boc-Pro-Ala-Lys (Boc)-OBzl is hydrolyzed to Boc-Pro-Ala-Lys (Boc);
(4) under DCC and HOBt exists, Boc-Asp (OBzl) is Boc-Asp (OBzl)-Val-OBzl with Val-OBzl condensation in anhydrous THF;
(5) in hydrogenchloride-ethyl acetate solution, Boc-Asp (OBzl)-Val-OBzl sloughs Boc and generates Asp (OBzl)-Val-OBzl;
(6) under DCC and HOBt exists, Boc-Ala is Boc-Ala-Gly-OBzl with Gly-OBzl condensation in anhydrous THF;
(7) under NaOH exists, in methyl alcohol, Boc-Ala-Gly-OBzl is hydrolyzed to Boc-Ala-Gly;
(8) under DCC and HOBt exists, Boc-Ala-Gly is Boc-Ala-Gly-Asp (OBzl)-Val-OBzl with Asp (OBzl)-Val-OBzl condensation in anhydrous THF;
(9) in hydrogenchloride-ethyl acetate solution, Boc-Ala-Gly-Asp (OBzl)-Val-OBzl sloughs Boc and generates Ala-Gly-Asp (OBzl)-Val-OBzl;
(10) under DCC and HOBt exists, Boc-Arg is Boc-Arg-Gly-OBzl with Gly-OBzl condensation in anhydrous THF;
(11) under NaOH exists, in methyl alcohol, Boc-Arg-Gly-OBzl is hydrolyzed to Boc-Arg-Gly;
(12) under DCC and HOBt exists, Boc-Arg-Gly is Boc-Arg-Gly-Asp (OBzl)-Val-OBzl with Asp (OBzl)-Val-OBzl condensation in anhydrous THF;
(13) in hydrogenchloride-ethyl acetate solution, Boc-Arg-Gly-Asp (OBzl)-Val-OBzl sloughs Boc and generates Arg-Gly-Asp (OBzl)-Val-OBzl;
(14) in anhydrous K
2cO
3under existence, in anhydrous THF, Vanillin and ethyl bromoacetate are reacted and are generated 3-methoxyl group-4-oxygen acetyl triethyl benzaldehyde;
(15) at B
2o
3, (nBuo)
3it is 6-(3,4-bis--methoxyphenyl)-5,6-hexene-2,4-diketone with methyl ethyl diketone condensation that B and nBu-NH exists lower Veratraldehyde in anhydrous ethyl acetate;
(16) at B
2o
3, (nBuo)
3under B and nBu-NH exists, in anhydrous ethyl acetate, Vanillin and methyl ethyl diketone condensation are 6-(3-methoxyl group-4-hydroxyphenyl)-5,6-hexene-2,4-diketone;
(17) at B
2o
3, (nBuo)
3b and nBu-NH exist under in anhydrous ethyl acetate 6-(3-p-methoxy-phenyl)-5,6-hexene-2,4-diketone and the condensation of 3-methoxyl group-4-oxygen acetyl triethyl benzaldehyde are 1-(3-p-methoxy-phenyl)-7-(4-oxygen acetyl triethyl base-3-p-methoxy-phenyl)-1,6-heptadiene-3,5-diketone, or at B
2o
3, (nBuo)
3under B and nBu-NH exists, 6-(4-methyl-3-p-methoxy-phenyl)-5 in anhydrous ethyl acetate, 6-hexene-2,4-diketone and the condensation of 3-methoxyl group-4-oxygen acetyl triethyl benzaldehyde are 1-(4-methyl-3-p-methoxy-phenyl)-7-(4-oxygen acetyl triethyl base-3-p-methoxy-phenyl)-1,6-heptadiene-3,5-diketone;
(18) NaOH exist under in acetone by 1-(3-p-methoxy-phenyl)-7-(4-oxygen acetyl triethyl base-3-p-methoxy-phenyl)-1, 6-heptadiene-3, 5-diketone is hydrolyzed to 1-(3-p-methoxy-phenyl)-7-(4-fluoroacetic acid base-3-p-methoxy-phenyl)-1, 6-heptadiene-3, 5-diketone, or in acetone by 1-(4-methyl-3-p-methoxy-phenyl)-7-(4-oxygen acetyl triethyl base-3-p-methoxy-phenyl)-1 under NaOH exists, 6-heptadiene-3, 5-diketone is hydrolyzed to 1-(4-methyl-3-p-methoxy-phenyl)-7-(4-fluoroacetic acid base-3-p-methoxy-phenyl)-1, 6-heptadiene-3, 5-diketone,
(19) DCC and HOBt exist under in anhydrous THF 1-(3-p-methoxy-phenyl)-7-(4-fluoroacetic acid base-3-p-methoxy-phenyl)-1, 6-heptadiene-3, 5-diketone and Lys (Boc)-OBzl condensation are 1-(3-p-methoxy-phenyl)-7-(4-oxygen acetyl-Lys (Boc)-OBzl-3-p-methoxy-phenyl)-1, 6-heptadiene-3, 5-diketone, or DCC and HOBt exist under in anhydrous THF 1-(4-methyl-3-p-methoxy-phenyl)-7-(4-fluoroacetic acid base-3-p-methoxy-phenyl)-1, 6-heptadiene-3, 5-diketone and Lys (Boc)-OBzl condensation are 1-(4-methyl-3-p-methoxy-phenyl)-7-(4-oxygen acetyl-Lys (Boc)-OBzl-3-p-methoxy-phenyl)-1, 6-heptadiene-3, 5-diketone,
(20) 1-(3-p-methoxy-phenyl)-7-(4-oxygen acetyl-Lys (Boc)-OBzl-3-p-methoxy-phenyl)-1 in hydrogenchloride-ethyl acetate solution, 6-heptadiene-3, 5-diketone is sloughed Boc and is generated 1-(3-p-methoxy-phenyl)-7-(4-oxygen acetyl-Lys-OBzl-3-p-methoxy-phenyl)-1, 6-heptadiene-3, 5-diketone, or in hydrogenchloride-ethyl acetate solution 1-(4-methyl-3-p-methoxy-phenyl)-7-(4-oxygen acetyl-Lys (Boc)-OBzl-3-p-methoxy-phenyl)-1, 6-heptadiene-3, 5-diketone is sloughed Boc and is generated 1-(4-methyl-3-p-methoxy-phenyl)-7-(4-oxygen acetyl-Lys-OBzl-3-p-methoxy-phenyl)-1, 6-heptadiene-3, 5-diketone,
(21) under NaOH exists, by 1-(3-p-methoxy-phenyl)-7-[4-oxygen acetyl-Lys (Boc)-OBzl-3-p-methoxy-phenyl]-1 in methyl alcohol, 6-heptadiene-3, 5-diketone is hydrolyzed to 1-(3-p-methoxy-phenyl)-7-(4-oxygen acetyl-Lys-3-p-methoxy-phenyl)-1, 6-heptadiene-3, 5-diketone or NaOH exist under, by 1-(4-methyl-3-p-methoxy-phenyl)-7-(4-oxygen acetyl-Lys-OBzl-3-p-methoxy-phenyl)-1 in methyl alcohol, 6-heptadiene-3, 5-diketone is hydrolyzed to 1-(4-methyl-3-p-methoxy-phenyl)-7-(4-oxygen acetyl-Lys-3-p-methoxy-phenyl)-1, 6-heptadiene-3, 5-diketone,
(22) under DCC and HOBt exists in anhydrous THF Boc-Pro-Ala-Lys (Boc) and 1-(3-p-methoxy-phenyl)-7-(4-oxygen acetyl-Lys-OBzl-3-p-methoxy-phenyl)-1, 6-heptadiene-3, the condensation of 5-diketone is 1-(3-p-methoxy-phenyl)-7-{4-oxygen acetyl-Lys [Boc-Pro-Ala-Lys (Boc)-OBzl]-3-p-methoxy-phenyl }-1, 6-heptadiene-3, 5-diketone, or deposit DCC and HOBt exist under in anhydrous THF Boc-Pro-Ala-Lys (Boc) and 1-(4-methyl-3-p-methoxy-phenyl)-7-(4-oxygen acetyl-Lys-OBzl-3-p-methoxy-phenyl)-1, 6-heptadiene-3, the condensation of 5-diketone is 1-(4-methyl-3-p-methoxy-phenyl)-7-{4-oxygen acetyl-Lys [Boc-Pro-Ala-Lys (Boc)-OBzl]-3-p-methoxy-phenyl }-1, 6-heptadiene-3, 5-diketone,
(23) NaOH exist under in methyl alcohol by 1-(3-p-methoxy-phenyl)-7-{4-oxygen acetyl-Lys [Boc-Pro-Ala-Lys (Boc)-OBzl]-3-p-methoxy-phenyl-1, 6-heptadiene-3, 5-diketone is hydrolyzed to 1-(3-p-methoxy-phenyl)-7-{4-oxygen acetyl-Lys [Boc-Pro-Ala-Lys (Boc)]-3-p-methoxy-phenyl }-1, 6-heptadiene-3, 5-diketone, or NaOH exist under in methyl alcohol by 1-(4-methyl-3-p-methoxy-phenyl)-7-{4-oxygen acetyl-Lys-[Boc-Pro-Ala-Lys (Boc)-OBzl]-3-p-methoxy-phenyl-1, 6-heptadiene-3, 5-diketone is hydrolyzed to 1-(4-methyl-3-p-methoxy-phenyl)-7-{4-oxygen acetyl-Lys [Boc-Pro-Ala-Lys (Boc)]-3-p-methoxy-phenyl }-1, 6-heptadiene-3, 5-diketone,
(24) 1-(3-p-methoxy-phenyl)-7-{4-oxygen acetyl-Lys [Boc-Pro-Ala-Lys (Boc)]-3-p-methoxy-phenyl under DCC and HOBt exists }-1,6-heptadiene-3,5-diketone and Arg-Gly-Asp (OBzl)-Val-OBzl condensation are 1-(3-p-methoxy-phenyl)-7-{4-oxygen acetyl-Lys [Boc-Pro-Ala-Lys (Boc)]-Arg-Gly-Asp-(OBzl)-Val-OBzl]-3-p-methoxy-phenyl }-1,6-heptadiene-3,5-diketone;
(25) 1-(3-p-methoxy-phenyl)-7-{4-oxygen acetyl-Lys [Boc-Pro-Ala-Lys (Boc)]-3-p-methoxy-phenyl under DCC and HOBt exists }-1,6-heptadiene-3,5-diketone and Ala-Gly-Asp (OBzl)-Val-OBzl condensation are 1-(3-p-methoxy-phenyl)-7-{4-oxygen acetyl-Lys [Boc-Pro-Ala-Lys (Boc)]-Ala-Gly-Asp-(OBzl)-Val-OBzl]-3-p-methoxy-phenyl }-1,6-heptadiene-3,5-diketone;
(26) 1-(4-methyl-3-p-methoxy-phenyl)-7-{4-oxygen acetyl-Lys [Boc-Pro-Ala-Lys (Boc)]-3-p-methoxy-phenyl under DCC and HOBt exists }-1,6-heptadiene-3,5-diketone and Arg-Gly-Asp (OBzl)-Val-OBzl condensation are 1-(4-methyl-3-p-methoxy-phenyl)-7-{4-oxygen acetyl-Lys [Boc-Pro-Ala-Lys (Boc)]-Arg-Gly-Asp-(OBzl)-Val-OBzl]-3-p-methoxy-phenyl }-1,6-heptadiene-3,5-diketone;
(27) 1-(4-methyl-3-p-methoxy-phenyl)-7-{4-oxygen acetyl-Lys [Boc-Pro-Ala-Lys (Boc)]-3-p-methoxy-phenyl under DCC and HOBt exists }-1,6-heptadiene-3,5-diketone and Arg-Gly-Asp (OBzl)-Val-OBzl condensation are 1-(4-methyl-3-p-methoxy-phenyl)-7-{4-oxygen acetyl-Lys [Boc-Pro-Ala-Lys (Boc)]-Arg-Gly-Asp-(OBzl)-Val-OBzl]-3-p-methoxy-phenyl }-1,6-heptadiene-3,5-diketone;
(28) in the methanol solution of NaOH by 1-(3-p-methoxy-phenyl)-7-{4-oxygen acetyl-Lys [Boc-Pro-Ala-Lys (Boc)]-Arg-Gly-Asp-(OBzl)-Val-OBzl]-3-p-methoxy-phenyl-1,6-heptadiene-3,5-diketone is hydrolyzed to 1-(3-p-methoxy-phenyl)-7-{4-oxygen acetyl-Lys [Boc-Pro-Ala-Lys (Boc)]-Arg-Gly-Asp-Val]-3-p-methoxy-phenyl }-1,6-heptadiene-3,5-diketone;
(29) in the methanol solution of NaOH by 1-(3-p-methoxy-phenyl)-7-{4-oxygen acetyl-Lys [Boc-Pro-Ala-Lys (Boc)]-Ala-Gly-Asp-(OBzl)-Val-OBzl]-3-p-methoxy-phenyl-1,6-heptadiene-3,5-diketone is hydrolyzed to 1-(3-p-methoxy-phenyl)-7-{4-oxygen acetyl-Lys [Boc-Pro-Ala-Lys (Boc)]-Ala-Gly-Asp-Val]-3-p-methoxy-phenyl }-1,6-heptadiene-3,5-diketone;
(30) in the methanol solution of NaOH by 1-(4-methyl-3-p-methoxy-phenyl)-7-{4-oxygen acetyl-Lys [Boc-Pro-Ala-Lys (Boc)]-Arg-Gly-Asp-(OBzl)-Val-OBzl]-3-p-methoxy-phenyl-1,6-heptadiene-3,5-diketone is hydrolyzed to 1-(4-methyl-3-p-methoxy-phenyl)-7-{4-oxygen acetyl-Lys [Boc-Pro-Ala-Lys (Boc)]-Arg-Gly-Asp-Val]-3-p-methoxy-phenyl }-1,6-heptadiene-3,5-diketone;
(31) in the methanol solution of NaOH by 1-(4-methyl-3-p-methoxy-phenyl)-7-{4-oxygen acetyl-Lys [Boc-Pro-Ala-Lys (Boc)]-Ala-Gly-Asp-(OBzl)-Val-OBzl]-3-p-methoxy-phenyl-1,6-heptadiene-3,5-diketone is hydrolyzed to 1-(4-methyl-3-p-methoxy-phenyl)-7-{4-oxygen acetyl-Lys [Boc-Pro-Ala-Lys (Boc)]-Ala-Gly-Asp-Val]-3-p-methoxy-phenyl }-1,6-heptadiene-3,5-diketone;
(32) in the ethyl acetate solution of hydrogenchloride by 1-(3-p-methoxy-phenyl)-7-{4-oxygen acetyl-Lys [Boc-Pro-Ala-Lys (Boc)]-Arg-Gly-Asp-Val]-3-p-methoxy-phenyl-1,6-heptadiene-3,5-diketone is sloughed Boc and is generated 1-(3-p-methoxy-phenyl)-7-{ [4-oxygen acetyl-Lys (Pro-Ala-Lys)-Arg-Gly-Asp-Val]-3-p-methoxy-phenyl }-1,6-heptadiene-3,5-diketone;
(33) in the ethyl acetate solution of hydrogenchloride by 1-(3-p-methoxy-phenyl)-7-{4-oxygen acetyl-Lys [Boc-Pro-Ala-Lys (Boc)]-Ala-Gly-Asp-Val]-3-p-methoxy-phenyl-1,6-heptadiene-3,5-diketone is sloughed Boc and is generated 1-(3-p-methoxy-phenyl)-7-{4-oxygen acetyl-Lys [Pro-Ala-Lys]-Ala-Gly-Asp-Val]-3-p-methoxy-phenyl }-1,6-heptadiene-3,5-diketone;
(34) in the ethyl acetate solution of hydrogenchloride by 1-(4-methyl-3-p-methoxy-phenyl)-7-{4-oxygen acetyl-Lys-[Boc-Pro-Ala-Lys (Boc)]-Arg-Gly-Asp-Val]-3-p-methoxy-phenyl-1,6-heptadiene-3,5-diketone is sloughed Boc and is generated 1-(4-methyl-3-p-methoxy-phenyl)-7-{4-oxygen acetyl-Lys [Pro-Ala-Lys]-Arg-Gly-Asp-Val]-3-p-methoxy-phenyl }-1,6-heptadiene-3,5-diketone;
(35) in the ethyl acetate solution of hydrogenchloride by 1-(4-methyl-3-p-methoxy-phenyl)-7-{4-oxygen acetyl-Lys [Boc-Pro-Ala-Lys (Boc)]-Ala-Gly-Asp-Val]-3-p-methoxy-phenyl-1,6-heptadiene-3,5-diketone is sloughed Boc and is generated 1-(4-methyl-3-p-methoxy-phenyl)-7-{4-oxygen acetyl-Lys [Pro-Ala-Lys]-Ala-Gly-Asp-Val]-3-p-methoxy-phenyl }-1,6-heptadiene-3,5-diketone.
Described step can further describe by the synthetic route of Fig. 1.
3rd content of the present invention is the thrombus dissolving activity of the 6 kinds of pseudo-peptides evaluating general formula I.
4th content of the present invention is the antithrombotic acitivity of the 6 kinds of pseudo-peptides evaluating general formula I.
5th content of the present invention is the anti-inflammatory activity of the 6 kinds of pseudo-peptides evaluating general formula I.
6th content of the present invention is the OH free radical scavenging activity of the 6 kinds of pseudo-peptides evaluating general formula I.
7th content of the present invention is the nanostructure of the 6 kinds of pseudo-peptides characterizing general formula I.
Accompanying drawing explanation
Fig. 1 synthetic route .3a-7a R=H, 3b-7b R=CH
3.
The transmission electron microscope photo of Fig. 2 compound 7a nano-rings.
The transmission electron microscope photo of Fig. 3 compound 7b nanotube.
The transmission electron microscope photo of Fig. 4 compound 7c nanometer ball.
The transmission electron microscope photo of Fig. 5 compound 7d nanometer rod.
Embodiment
In order to set forth the present invention further, provide a series of embodiment below.These embodiments are illustrative completely, and they are only used for being specifically described the present invention, not should be understood to limitation of the present invention.
Embodiment 1 prepares Boc-Pro-Ala-Lys (Boc)
1) preparation of Boc-Pro-Ala
1.075g (5.0mmol) Boc-Pro is dissolved in the anhydrous THF of 20mL, under ice bath, in solution, adds 0.637g (5mmol) N-hydroxy-succinamide (HOSu), and make to dissolve completely.Under ice bath, dicyclohexyl carbonyl diimine (DCC) 1.236g (6.0mmol) being dissolved in a small amount of anhydrous THF is added in reaction solution.Stirring at room temperature 7h, TLC (petrol ether/ethyl acetate, 3: 1) monitor Boc-Pro and disappear.Filtering dicyclohexylurea (DCU) (DCU), filtrate reduced in volume removing THF.Residue with Ethyl acetate dissolves, and solution uses saturated NaHCO successively
3the aqueous solution is washed, the saturated NaCl aqueous solution is washed, and then ethyl acetate layer is evaporated to dry, residue adds 0.489g (5.5mmol) Ala again after adding appropriate THF dissolving the aqueous solution.Mixture NaHCO
3solid adjusts pH 9, room temperature reaction 12h, and reaction mixture concentrating under reduced pressure removing THF, residue adds 5mL water dissolution, the saturated KHSO of the aqueous solution
4the aqueous solution adjusts pH 2, and with 30mL extraction into ethyl acetate 5 times, the ethyl acetate layer of merging is washed till neutrality, anhydrous sodium sulfate drying with the saturated NaCl aqueous solution.Filter, filtrate reduced in volume is to dry, and obtaining 1.35g (94%) title compound, is colorless solid.ESI-MS(m/e)：285[M-H]
-.
2) preparation of Boc-Pro-Ala-Lys (Boc)-OBzl
1.202g (4.2mmol) Boc-Pro-Ala is dissolved in the anhydrous THF of 20mL, in solution, 0.544g (4mmol) HOBt is added under ice bath, add 1.030g (5mmol) DCC after dissolving completely, obtain reaction solution (I), stir 30 minutes.2.168g (4.0mmol) Lys (Boc)-OBzl is suspended in the anhydrous THF of 20mL, then adds 1mLN-methylmorpholine (NMM), adjust pH 9, obtain reaction solution (II).Added by reaction solution (II) in reaction solution (I) after stirring 1h under ice bath, stirring at room temperature 4h, TLC (chloroform/methanol, 15: 1) show Lys (Boc)-OBzl and disappear.Filtering DCU, filtrate reduced in volume removing THF.Residue 50mL acetic acid ethyl dissolution.The solution obtained uses saturated NaHCO successively
3the aqueous solution is washed, the saturated NaCl aqueous solution is washed, 5%KHSO
4the aqueous solution is washed and is washed with the saturated NaCl aqueous solution.Ethyl acetate layer anhydrous Na
2sO
4drying, filters, and filtrate reduced in volume is to dry, and obtaining 1.915g (75%) title compound, is colourless powder.ESI-MS(m/e)：604[M+H]
+。
3) preparation of Boc-Pro-Ala-Lys (Boc)
1.585g (3.0mmol) Boc-Pro-Ala-Lys (Boc)-OBzl is dissolved in 15mL methyl alcohol.Under ice bath, solution NaOH (2N) aqueous solution obtained adjusted pH12 and stir 2h, TLC (dichloro/methyl alcohol, 15: 1) shows Boc-Pro-Ala-Lys (Boc)-OBzl and disappears.Reaction mixture 2N dilute hydrochloric acid adjusts pH 2, and concentrating under reduced pressure is except methyl alcohol.Residue with Ethyl acetate extracts 3 times.The ethyl acetate layer merged is washed till neutrality, anhydrous Na with the saturated NaCl aqueous solution
2sO
4dry.Filter, filtrate reduced in volume is to dry, and obtaining 1.397g (85%) title compound, is colorless solid.ESI-MS(m/e)：514[M-H]
-。
Embodiment 2 prepares Arg-Gly-Asp (OBzl)-Val-OBzl
1) preparation of Boc-Arg-Gly-OBzl
By in embodiment 1 2) preparation method of item reacts by 1.600g (5.0mmol) Boc-Arg and 1.689g (5.0mmol) Gly-OBzl, and obtaining 2.26g (97%) title compound, is faint yellow solid.ESI-MS(m/e)：421.7[M+H]
+。
2) preparation of Boc-Arg-Gly
By in embodiment 1 3) preparation method of item is hydrolyzed to obtain 1.236g (94%) title compound by 1.630g (3.5mmol) Boc-Arg-Gly-Obzl, is colorless solid.ESI-MS(m/e)：331.3[M-H]
-。
3) preparation of Boc-Asp (OBzl)-Val-OBzl
By in embodiment 1 2) preparation method of item obtains 2.871g (97%) title compound by 1.620g (5.0mmol) Boc-D (OBzl) and 1.607g (5.0mmol) Val-OBzl, is colorless oil.ESI-MS(m/e)：512[M+H]
+。
4) preparation of Asp (OBzl)-Val-OBzl
5.12g (10mmol) Boc-Asp (OBzl)-Val-OBzl is dissolved in the hydrogenchloride-ethyl acetate solution of 45mL 4N, ice bath stir 2 hours, TLC (dichloro/methyl alcohol, 15/1) show Boc-Asp (OBzl)-Val-OBzl disappear.Reaction mixture concentrating under reduced pressure removing ethyl acetate, residue repeatedly adds a small amount of ether and carries out concentrating under reduced pressure to remove de-chlorine hydride, and obtaining 4.27g (95%) title compound, is colorless solid.ESI-MS(m/e)：412[M+H]
+。
5) preparation of Boc-Arg-Asp (OBzl)-Val-OBzl
By in embodiment 1 2) preparation method of item reacts by 1.313g (3.5mmol) Boc-Arg-Gly and 1.747g (3.5mmol) Asp (OBzl)-Val-OBzl, obtaining 2.078g (70%) title compound through column chromatography purification, is colorless solid.ESI-MS(m/e)：725[M+H]
+.
6) preparation of Arg-Asp (OBzl)-Val-OBzl
By in embodiment 2 4) preparation method of item obtains 1.56g (95%) title compound by 1.866g (2.2mmo1) Boc-Arg-Asp (OBzl)-Val-OBzl, is faint yellow solid.ESI-MS(m/e)：625[M+H]
+。
Embodiment 3 prepares Ala-Gly-Asp (OBzl)-Val-OBzl
1) preparation of Boc-Ala-Gly-OBzl
By in embodiment 1 2) preparation method of item reacts by 1.600g (5.0mmol) Boc-Ala and 1.689g (5.0mmol) Gly-OBzl, and obtaining 2.26g (97%) title compound, is faint yellow solid.ESI-MS(m/e)：337[M+H]
+。
2) preparation of Boc-Ala-Gly
By in embodiment 1 3) preparation method of item is hydrolyzed to obtain 1.236g (94%) title compound by 1.630g (3.5mmol) Boc-R-G-OBzl, is colorless solid.ESI-MS(m/e)：245[M-H]
-。
3) preparation of Boc-Asp (OBzl)-Val-OBzl
By in embodiment 1 2) preparation method of item obtains 2.871g (97%) title compound by 1.620g (5.0mmol) Boc-Asp (OBzl) and 1.607g (5.0mmol) Val-OBzl, is colorless oil.ESI-MS(m/e)：512[M+H]
+。
4) preparation of Asp (OBzl)-Val-OBzl
By in embodiment 2 4) preparation method of item obtains 4.27g (95%) title compound by 5.12g (10mmol) Boc-Asp (OBzl)-Val-Obzl, is colorless solid.ESI-MS(m/e)：412[M+H]
+。
5) preparation of Boc-Ala-Gly-Asp (OBzl)-Val-OBzl
By in embodiment 1 2) preparation method of item reacts by 1.313g (3.5mmol) Boc-Ala-Gly and 1.747g (3.5mmol) Asp (OBzl)-Val-OBzl, obtaining 2.078g (70%) title compound through column chromatography purification, is colorless solid.ESI-MS(m/e)：641[M+H]
+。
6) preparation of Ala-Gly-Asp (OBzl)-Val-OBzl
By in embodiment 2 4) preparation method of item obtains 1.56g (95%) title compound by 1.866g (2.2mmol) Boc-Ala-Gly-Asp (OBzl)-Val-OBzl, is faint yellow solid.ESI-MS(m/e)：541[M+H]
+。
Embodiment 4 prepares 1-(3-methoxyl group-4-hydroxyphenyl)-7-[(4-fluoroacetic acid base)-3-p-methoxy-phenyl]-1,6-heptadiene-3,5-diketone
1) preparation of 6-(3-methoxyl group-4-hydroxyphenyl)-5,6-hexene-2,4-diketone
31mL (0.3mol) methyl ethyl diketone is placed in 250mL three-necked bottle, add 14.5g (0.21mol) boron trioxide and 70mL ethyl acetate, 70 DEG C of reactions make to become white suspension liquid for one hour, then 29.5mL (0.11mol) tri-n-butyl borate and 15.2g (0.1mol) 3-methoxy-4-hydroxy benzaldehyde is added, 85 DEG C of reactions make solution shoal yellow suspension for 0.5 hour, the ethyl acetate solution of 10.88mL (0.11mol) n-Butyl Amine 99 is dripped by constant pressure funnel, reacting makes solution become redness in 1 hour, be cooled to 50 DEG C, add 200mL 1N hydrochloric acid, react 0.5 hour, stopped reaction.Divide water-yielding stratum, with 40mL extraction into ethyl acetate three times, combined ethyl acetate, with anhydrous sodium sulfate drying, leach sodium sulfate, filtrate decompression except desolventizing, residue purification by silica gel column chromatography, obtaining 8.2g (34.6%) title compound, is faint yellow solid.ESI-MS(m/e)：235[M+H]
+.
2) preparation of 3-methoxyl group-4-oxygen acetyl triethyl benzaldehyde
Be placed in by 7.6g (50mmol) Vanillin in 250mL eggplant bottle and dissolve with anhydrous THF, then add 9.66g (70mmol) Anhydrous potassium carbonate, reaction 30min makes mixture become white opacity liquid.Drip 5.93mL (55mmol) ethyl bromoacetate, reaction 48h, TLC show Vanillin disappearance.Filtering insolubles, removal of solvent under reduced pressure, residue 200mL acetic acid ethyl dissolution, to wash with saturated sodium bicarbonate aqueous solution three times, add anhydrous sodium sulfate drying.Except obtaining 11.316g (95.1%) title compound after desolventizing, it is colorless solid.ESI-MS(m/e)：239[M+H]
-。
3) preparation of 1-(3-methoxyl group-4-hydroxyphenyl)-7-(4-oxygen acetyl triethyl-3-p-methoxy-phenyl)-1,6-heptadiene-3,5-diketone
By in embodiment 2 1) preparation method of item is by 1.097g (4.42mmol) 6-(3-methoxyl group-4-hydroxyphenyl)-5,6-hexene-2,4-diketone and the reaction of 1.088g (4.87mmol) 3-methoxyl group-4-oxygen acetyl triethyl benzaldehyde, after purification by silica gel column chromatography, obtain 0.435g (21.0%) title compound, be faint yellow solid.ESI-MS(m/e)：455[M+H]
+。
4) preparation of 1-(3-methoxyl group-4-hydroxyphenyl)-7-(4-fluoroacetic acid base-3-p-methoxy-phenyl)-1,6-heptadiene-3,5-diketone
By 454mg (1mmol) 1-(3-methoxyl group-4-hydroxyphenyl)-7-(4-oxygen acetyl triethyl base-3-p-methoxy-phenyl)-1,6-heptadiene-3,5-diketone is placed in 100mL eggplant bottle, add acetone makes dissolving, solution yellow transparent.Then dripping the aqueous sodium hydroxide solution of 1mL 4N, solution is reddish black by red stain gradually.After 5min, yellow solid is had to separate out.After 10min, TLC shows 1-(3-methoxyl group-4-hydroxyphenyl)-7-(4-oxygen acetyl triethyl base-3-p-methoxy-phenyl)-1,6-heptadiene-3,5-diketone and disappears.Drip the 2N HCl aqueous solution, adjust ph is to neutral, and decompression removing acetone, residue filters, by tap water precipitation, obtain 424mg (96.4%) title compound, is orange powder.ESI-MS(m/e)：439[M-H]
-。
Embodiment 5 prepares 1-(3-methoxyl group-4-hydroxyphenyl)-7-{ [4-oxygen acetyl-Lys (Pro-Ala-Lys)-Ala-Gly-Asp-Val]-3-p-methoxy-phenyl }-1,6-heptadiene-3,5-diketone (7a)
1) preparation of 6-(3,4-, bis--methoxyphenyl)-5,6-hexene-2,4-diketone
By in embodiment 2 1) preparation method of item is by 16.6g (0.1mol) 3,4-bis--methoxybenzaldehyde and the reaction of 31mL (0.3mol) methyl ethyl diketone, obtaining 8.6g (34.6%) title compound through column chromatography purification, is faint yellow solid.ESI-MS(m/e)：235[M+H]
+。
2) preparation of 1-(3,4-, bis--methoxyphenyl)-7-(4-oxygen acetyl triethyl-3-p-methoxy-phenyl)-1,6-heptadiene-3,5-diketone
By in embodiment 2 1) preparation method of item is by 1.097g (4.42mmol) 6-(3,4-bis--methoxyphenyl)-5,6-hexene-2,4-diketone and the reaction of 1.088g (4.87mmol) 3-methoxyl group-4-oxygen acetyl triethyl benzaldehyde, after purification by silica gel column chromatography, obtain 0.435g (21.0%) title compound, be faint yellow solid.ESI-MS(m/e)：469.6[M+H]
+。
3) preparation of 1-(3,4-, bis--methoxyphenyl)-7-(4-fluoroacetic acid base-3-p-methoxy-phenyl)-1,6-heptadiene-3,5-diketone
By in embodiment 2 4) preparation method of item is by 454mg (1mmol) 1-(3,4-bis--methoxyphenyl)-7-(4-oxygen acetyl triethyl-3-p-methoxy-phenyl)-1,6-heptadiene-3,5-diketone is hydrolyzed to obtain 447mg (98%) title compound, is orange powder.ESI-MS(m/e)：454[M-H]
-。
4) 1-(3-methoxyl group-4-hydroxyphenyl)-7-{ [4-oxygen acetyl-Lys (Boc)-OBzl]-3-p-methoxy-phenyl } preparation of-1,6-heptadiene-3,5-diketone
By in embodiment 1 2) preparation method of item is by 4.4g (10mmol) 1-(3-methoxyl group-4-hydroxyphenyl)-7-(4-fluoroacetic acid base-3-p-methoxy-phenyl)-1,6-heptadiene-3,5-diketone and 5.08g (10mmol) Lys (Boc)-OBzl react, obtaining 7.02g (94%) title compound, is yellow powder.ESI-MS(m/e)：745[M+H]
+.
1H NMR(300MHz，CDCl
3-d1)：δ/ppm＝7.65-7.58(m，2H)，7.45(d，J＝7.2Hz，1H)，7.38-7.33(m，5H)，7.16-7.07(m，4H)，6.97-6.90(m，2H)，6.57-6.48(m，2H)，5.84(s，1H)，5.24-5.15(m，2H)，4.77-4.73(m，1H)，4.71-4.56(m，2H)，4.50(bs，0.91H)，3.97(s，3H)，3.94(s，3H)，3.06-3.04(m，2H)，1.96-1.66(m，2H)，1.45(s，11H)，1.33(m，2H)。
5) preparation of 1-(3-methoxyl group-4-hydroxyphenyl)-7-[(4-oxygen acetyl-Lys-OBzl)-3-p-methoxy-phenyl]-1,6-heptadiene-3,5-diketone
By 3.72g (5mmol) 1-(3-methoxyl group-4-hydroxyphenyl)-7-{ [4-oxygen acetyl-Lys (Boc)-OBzl]-3-p-methoxy-phenyl }-1,6-heptadiene-3,5-diketone is dissolved in the hydrogenchloride-ethyl acetate solution of 40mL4N, ice bath stirs 2 hours, TLC (dichloro/methyl alcohol, 15/1) 1-(3-methoxyl group-4-hydroxyphenyl)-7-(4-oxygen acetyl-Lys (Boc)-OBzl-3-p-methoxy-phenyl)-1 is shown, 6-heptadiene-3,5-diketone disappears.Concentrating under reduced pressure removing ethyl acetate, residue repeatedly add a small amount of ether and carry out concentrating under reduced pressure to remove hydrogen chloride gas, and finally obtaining 3.32g (98%) title compound, is yellow powder.ESI-MS(m/e)：645[M+H]
+。
6) preparation of 1-(3-methoxyl group-4-hydroxyphenyl)-7-[(4-oxygen acetyl-Lys)-3-p-methoxy-phenyl]-1,6-heptadiene-3,5-diketone
By in embodiment 1 3) preparation method of item is by 2.57g (4mmol) 1-(3-methoxyl group-4-hydroxyphenyl)-7-[(4-oxygen acetyl-Lys-OBzl)-3-p-methoxy-phenyl]-1,6-heptadiene-3,5-diketone is hydrolyzed to obtain 2.15g (93%) title compound, is yellow powder.ESI-MS(m/e)：555[M+H]
+.
1H NMR(300MHz，DMSO-d6)：δ/ppm＝8.42-8.40(m，1H)，8.19(bs，0.7H)，7.59(s，1H)，7.54(s，1H)，7.39-7.14(m，4H)，6.97-6.76(m，4H)，6.12(s，1H)，4.64(s，2H)，4.25(m，1H)，3.86(s，3H)，3.83(s，3H)，2.73-2.71(m，2H)，1.74(m，2H)，1.54(m，2H)，1.33(m，2H)。
7) 1-(3-methoxyphenyl)-7-{ [4-oxygen acetyl-Lys (Boc)-OBzl]-3-p-methoxy-phenyl } preparation of-1,6-heptadiene-3,5-diketone
By in embodiment 1 2) preparation method of item is by 4.6g (10mmol) 1-(3-methoxyphenyl)-7-[(4-fluoroacetic acid base)-3-p-methoxy-phenyl]-1,6-heptadiene-3,5-diketone and 5.08g (10mmol) Lys (Boc)-OBzl react, obtaining 7.24g (94%) title compound, is yellow powder.ESI-MS(m/e)：759[M+H]
+.
1H NMR(300MHz，CDCl
3-d1)：δ/ppm＝7.66-7.580(m，2H)，7.45(d，J＝7.2Hz，1H)，7.38-7.33(m，5H)，7.17-7.10(m，4H)，6.92-6.88(m，2H)，6.56-6.50(m，2H)，5.85(s，1H)，5.23-5.14(m，2H)，4.74-4.72(m，1H)，4.66-4.60(m，2H)，4.55(bs，1H)，3.95(s，3H)，3.94(s，3H)，3.93(s，3H)，3.03(m，2H)，1.91-1.73(m，2H)，1.46(s，11H)，1.30(m，2H)。
8) preparation of 1-(3-methoxyphenyl)-7-[(4-oxygen acetyl-Lys-OBzl)-3-p-methoxy-phenyl]-1,6-heptadiene-3,5-diketone
By in embodiment 2 4) preparation method of item by 3.81g (5mmo1) 1-(3-methoxyphenyl)-7-{ [(4-oxygen acetyl-Lys (Boc)-OBzl)-3-p-methoxy-phenyl }-1,6-heptadiene-3,5-diketone removes Boc and obtains 3.45g (98%) title compound, is yellow powder.ESI-MS(m/e)：660[M+H]
+。
9) preparation of 1-(3-methoxyphenyl)-7-[(4-oxygen acetyl-Lys)-3-p-methoxy-phenyl]-1,6-heptadiene-3,5-diketone
By in embodiment 1 3) preparation method of item is by 261mg (0.4mmol) 1-(3-methoxyphenyl)-7-[(4-oxygen acetyl-Lys-OBzl)-3-p-methoxy-phenyl]-1,6-heptadiene-3,5-diketone is hydrolyzed to obtain 223mg (93%) title compound, is yellow powder.ESI-MS(m/e)：569[M+H]
+.
1H NMR(300MHz，DMSO-d6)：δ/ppm＝8.34-8.31(m，0.4H)，7.97(bs，0.7H)，7.61(s，1H)，7.56(s，1H)，7.39-7.28(m，4H)，7.03-6.82(m，4H)，6.13(s，1H)，4.64(s，2H)，4.25(m，1H)，3.87(s，3H)，3.83(s，3H)，3.81(s，3H)，2.76-2.71(m，2H)，1.74(m，2H)，1.54(m，2H)，1.33(m，2H)。
9) 1-(3-methoxyl group-4-hydroxyphenyl)-7-{4-oxygen acetyl-Lys [Boc-Pro-Ala-Lys (Boc)-OBzl]-3-p-methoxy-phenyl } preparation of-1,6-heptadiene-3,5-diketone
By in embodiment 1 2) preparation method of item is by 5.08g (10mmol) Boc-Pro-Ala-Lys (Boc) and 4.4g (10mmol) 1-(3-methoxyl group-4-hydroxyphenyl)-7-[(4-oxygen acetyl-Lys-OBzl)-3-p-methoxy-phenyl]-1,6-heptadiene-3,5-bis-reactive ketone, obtaining 7.02g (94%) title compound, is yellow powder.ESI-MS(m/e)：1141[M +H]
+.
1H NMR(300 MHz，DMSO-d6)：δ/ppm＝7.63-7.53(m，3H)，7.35(s，5H)，7.25(bs，0.5H)，7.14-7.07(m，4H)，6.96-6.90(m，2H)，6.79(m，1H)，6.60-6.48(m，3H)，5.84(s，1H)，5.18(s，2H)，4.68-4.57(m，4H)，4.36-4.18(m，3H)，3.95(s，3H)，3.92(s，3H)，3.50-3.48(m，2H)，3.17(m，2H)，3.08(m，2H)，2.19-1.25(m，42H)。
10) 1-(3-methoxyl group-4-hydroxyphenyl)-7-{ [4-oxygen acetyl-Lys [Boc-Pro-Ala-Lys (Boc)]-3-p-methoxy-phenyl } preparation of-1,6-heptadiene-3,5-diketone
By in embodiment 1 3) preparation method of item is by 456mg (0.4mmol) 1-(3-methoxyl group-4-hydroxyphenyl)-7-{4-oxygen acetyl-Lys [Boc-Pro-Ala-Lys (Boc)-OBzl]-3-p-methoxy-phenyl }-1,6-heptadiene-3,5-diketone is hydrolyzed to obtain 371mg (93%) title compound, is yellow powder.ESI-MS(m/e)：1051[M+H]
+。
11) 1-(3-methoxyl group-4-hydroxyphenyl)-7-{4-oxygen acetyl-Lys [Boc-Pro-Ala-Lys (Boc)]-Ala-Gly-Asp-(OBzl)-Val-OBzl]-3-p-methoxy-phenyl }-1, the preparation of 6-heptadiene-3,5-diketone
By in embodiment 1 2) preparation method of item by 5.08g (5mmol) 1-(3-methoxyl group-4-hydroxyphenyl)-7-{ [4-oxygen acetyl-Lys [Boc-Pro-Ala-Lys (Boc)]-3-p-methoxy-phenyl }-1,6-heptadiene-3,5-diketone and 2.7g (5mmol) Ala-Gly-Asp (OBzl)-Val-OBzl react, obtaining title compound 7.02g (89%), is yellow powder.ESI-MS(m/e)：1573[M+H]
+.
1H NMR(300MHz，DMSO-d6)：δ/ppm＝8.24-8.00(m，6H)，8.00-7.38(m，4H)，7.38-7.35(m，12H)，7.25-7.22(m，2H)，6.98-6.71(m，5H)，6.09(s，0.74H)，5.11-5.06(m，4H)，4.79(m，1H)，4.61(s，2H)，4.32-4.09(m，6H)，3.86(s，3H)，3.84(s，3H)，3.71(m，2H)，3.27(m，2H)，3.08-2.75(m，5H)，2.08-2.06(m，2H)，1.77-1.70(m，6H)，1.38-1.21(m，37H)，0.86-0.83(m，6H)。
12) 1-(3-methoxyl group-4-hydroxyphenyl)-7-{4-oxygen acetyl-Lys [Boc-Pro-Ala-Lys (Boc)]-Ala-Gly-Asp-Val]-3-p-methoxy-phenyl } preparation of-1,6-heptadiene-3,5-diketone
By in embodiment 1 3) preparation method of item is by 629mg (0.4mmol) 1-(3-methoxyl group-4-hydroxyphenyl)-7-{4-oxygen acetyl-Lys [Boc-Pro-Ala-Lys (Boc)]-Ala-Gly-Asp (OBzl)-Val-OBzl]-3-p-methoxy-phenyl }-1,6-heptadiene-3,5-diketone is hydrolyzed to obtain 515.6mg (92.6%) title compound, is yellow powder.ESI-MS(m/e)：1393[M+H]
+。
13) 1-(3-methoxyl group-4-hydroxyphenyl)-7-{ [4-oxygen acetyl-Lys (Pro-Ala-Lys)-Ala-Gly-Asp-Val]-3-p-methoxy-phenyl } preparation of-1,6-heptadiene-3,5-diketone
By in embodiment 2 4) preparation method by 417mg (0.3mmol) 1-(3-methoxyl group-4-hydroxyphenyl)-7-{4-oxygen acetyl-Lys [Boc-Pro-Ala-Lys (Boc)]-Ala-Gly-Asp-Val]-3-p-methoxy-phenyl-1,6-heptadiene-3,5-diketone removes Boc and obtains 348.7mg (98%) title compound, is yellow powder.ESI-MS(m/e)：1193[M+H]
+.
1H NMR(300MHz，DMSO-d6)：δ/ppm＝12.48(bs，1.9H)，10.28(bs，0.49H)，9.85(s，0.59H)，8.91-8.90(d，1H)， 8.44-8.03(m，10H)，7.71-6.85(m，8H)，4.69(s，2H)，4.64(m，1H)，4.36-4.07(m，5H)，3.87(s，3H)，3.84(s，3H)，3.77-3.60(m，2H)，3.22-3.16(m，2H)，3.04-2.89(m，5H)，2.73-2.57(m，4H)，2.23(m，1H)，1.99(m，1H)，1.91(m，3H)，1.76-1.56(m，6H)，1.38-1.22(m，13H)，0.91-0.86(d，6H)。
Embodiment 6 prepares 1-(3,4-, bis--methoxyphenyl)-7-{ [4-oxygen acetyl-Lys (Pro-Ala-Lys)-Ala-Gly-Asp-Val]-3-p-methoxy-phenyl }-1,6-heptadiene-3,5-diketone (7b)
1) 1-(3,4-, bis--methoxyphenyl)-7-{4-oxygen acetyl-Lys [Boc-Pro-Ala-Lys (Boc)-OBzl]-3-p-methoxy-phenyl } preparation of-1,6-heptadiene-3,5-diketone
By in embodiment 1 2) preparation method of item is by 4.6g (10mmol) Boc-Pro-Ala-Lys (Boc) and 5.08g (10mmol) 1-(3,4-bis--methoxyphenyl)-7-[(4-oxygen acetyl-Lys-OBzl)-3-p-methoxy-phenyl]-1,6-heptadiene-3,5-bis-reactive ketone, obtaining 7.24g (94%) title compound, is yellow powder.ESI-MS(m/e)：1155[M+H]
+.
1H NMR(300MHz，CDCl
3-d1)：δ/ppm＝7.66-7.52(m，3H)，7.36(m，5H)，7.17-7.10(m，4H)，6.95-6.89(m，2H)，6.74(m，1H)，6.57-6.51(m，3H)，5.87(s，1H)，5.19(m，2H)，4.68-4.56(m，3H)，4.37-4.16(m，3H)，3.96(s，3H)，3.95(s，3H)，3.93(s，3H)，3.49(m，2H)，3.17-3.07(m，4H)，2.23(m，2H)，2.08(m，2H)，1.92-1.77(m，5H)，1.48-1.35(m，30H)。
2) 1-(3,4-, bis--methoxyphenyl)-7-{4-oxygen acetyl-Lys [Boc-Pro-Ala-Lys (Boc)]-3-p-methoxy-phenyl } preparation of-1,6-heptadiene-3,5-diketone
By in embodiment 1 3) preparation method of item is by 465mg (0.4mmol) 1-(3,4-bis--methoxyphenyl)-7-{4-oxygen acetyl-Lys [Boc-Pro-Ala-Lys (Boc)-OBzl]-3-p-methoxy-phenyl }-1,6-heptadiene-3,5-diketone is hydrolyzed to obtain 401mg (93%) title compound, is yellow powder.ESI-MS(m/e)：1065[M+H]
+。
3) 1-(3,4-bis--methoxyphenyl)-7-{4-oxygen acetyl-Lys [Boc-Pro-Ala-Lys (Boc)]-Ala-Gly-Asp-(OBzl)-Val-OBzl]-3-p-methoxy-phenyl }-1, the preparation of 6-heptadiene-3,5-diketone
By in embodiment 1 2) preparation method of item is by 5.08g (5mmol) 1-(3,4-bis--methoxyphenyl)-7-{4-oxygen acetyl-Lys [Boc-Pro-Ala-Lys (Boc)]-3-p-methoxy-phenyl }-1,6-heptadiene-3,5-diketone and 2.7g (5mmol) Ala-Gly-Asp (OBzl)-Val-OBzl react, obtaining 7.49g (94%) title compound, is yellow powder.ESI-MS(m/e)：1587[M+H]
+.
1H NMR(300MHz，CDCl
3-d6)：δ/ppm＝7.67-7.57(m，4H)，7.43(m，1H)，7.35-7.26(m，10H)，7.10(m，4H)，6.92-6.90(m，4H)，6.56(s，1H)，6.50(s，1H)，5.86(s，1H)，5.19-5.08(m，4H)，4.96-4.94(m，2H)，4.60(s，2H)，4.50(s，2H)，4.24-4.23(m，4H)，3.96(s，3H)，3.95(s，3H)，3.92(s，3H)，3.51-3.49(m，4H)，3.08-2.94(m，5H)，2.27-2.22(m，2H)，2.19(m，2H)，2.06-1.85(m，7H)，1.65-1.59(m，5H)，1.49-1.21(m，37H)，0.93-0.92(m，6H)，0.88-0.86(m，6H)。
4) 1-(3,4-, bis--methoxyphenyl)-7-{4-oxygen acetyl-Lys [Boc-Pro-Ala-Lys (Boc)-Ala-Gly-Asp-Val]-3-p-methoxy-phenyl } preparation of-1,6-heptadiene-3,5-diketone
By in embodiment 1 3) preparation method of item is by 634.8mg (0.4mmol) 1-(3,4-bis--methoxyphenyl)-7-{4-oxygen acetyl-Lys [Boc-Pro-Ala-Lys (Boc)-Ala-Gly-Asp-(OBzl)-Val-OBzl]-3-p-methoxy-phenyl }-1,6-heptadiene-3,5-diketone is hydrolyzed to obtain 513.5mg (91%) title compound, is yellow powder.ESI-MS(m/e)：1407[M+H]
+。
5) 1-(3,4-, bis--methoxyphenyl)-7-{ [4-oxygen acetyl-Lys (Pro-Ala-Lys)-Ala-Gly-Asp-Val]-3-p-methoxy-phenyl } preparation of-1,6-heptadiene-3,5-diketone
By in embodiment 2 4) preparation method of item is by 281.4mg (0.2mmol) 1-(3,4-bis--methoxyphenyl)-7-{4-oxygen acetyl-Lys [Boc-Pro-Ala-Lys (Boc)-Ala-Gly-Asp-Val]-3-p-methoxy-phenyl }-1,6-heptadiene-3,5-diketone removes Boc and obtains 235.4mg (98%) title compound, is yellow powder.ESI-MS(m/e)：1207[M+H]
+.
1H NMR(300MHz，DMSO-d6)：δ/ppm＝12.48(bs，1H)，8.93-8.91(m，1H)，8.30-8.03(m，8H)，7.68-7.57(m，11H)，7.40-7.24(m，3H)，7.04-6.74(m，4H)，6.14(s，0.36H)，4.64(s，2H)，4.56-4.52(m，1H)，4.36-4.12(m，6H)，3.91(s，3H)，3.87(s，3H)，3.83(s，3H)，3.77-3.64(m，1H)，3.27-3.17(m，2H)，3.01-2.95(m，2H)，2.70-2.57(m，4H)，2.32-2.30(m，1H)，2.19(m，2H)，2.07-1.87(m，5H)，1.66-1.55(m，6H)，1.38-1.09(m，12H)，0.88-0.86(m，6H)。
Embodiment 7 prepares 1-(3-methoxyphenyl)-7-{ [4-oxygen acetyl-Lys (Pro-Ala-Lys)-Arg-Gly-Asp-Val]-3-p-methoxy-phenyl }-1,6-heptadiene-3,5-diketone (7c)
1) 1-(3-methoxyphenyl)-7-{4-oxygen acetyl-Lys [Boc-Pro-Ala-Lys (Boc)]-Arg-Gly-Asp (OBzl)-Val-OBzl]-3-p-methoxy-phenyl } preparation of-1,6-heptadiene-3,5-diketone
By in embodiment 1 2) preparation method of item is by 1.06g (1mmol) 1-(3,4-bis--methoxyphenyl)-7-{4-oxygen acetyl-Lys [Boc-Pro-Ala-Lys (Boc)]-3-p-methoxy-phenyl }-1,6-heptadiene-3,5-diketone and 0.74g (1mmol) Arg-Gly-Asp (OBzl)-Val-OBzl react, obtaining 1.45g (87%) title compound, is yellow powder.ESI-MS(m/e)：1658[M+H]
+.
1H NMR(500MHz，DMSO-d6)：δ/ppm＝9.76(s，0.9H)，8.32-8.10(m，4H)，8.07-7.69(m，5H)，7.59(s，1H)，4.61(s，2H)，7.56(s，1H)，7.43-7.31(m，13H)，7.26-7.01(m，3H)，6.98-6.95(m，2H)，6.90-6.74(m，4H)，6.10(s，0.74H)，5.15-5.05(m，4H)，4.79(m，1H)，4.65(m，2H)，4.37-4.11(m，6H)，3.87(s，3H)，3.85(s，3H)，3.82(m，2H)，3.74(m，2H)，3.28(m，3H)，3.09-2.96(m，7H)，2.78(m，2H)，2.64-2.52(m，4H)，2.08(m，2H)，1.80-149(m，11H)，1.39-1.08(m，31H)，0.86-0.84(m，6H)。
2) 1-(3-methoxyphenyl)-7-{4-oxygen acetyl-Lys [Boc-Pro-Ala-Lys (Boc)]-Arg-Gly-Asp-Val]-3-p-methoxy-phenyl } preparation of-1,6-heptadiene-3,5-diketone
By in embodiment 1 3) preparation method of item is by 662.8mg (0.4mmol) 1-(3-methoxyphenyl)-7-{4-oxygen acetyl-Lys [Boc-Pro-Ala-Lys (Boc)]-Arg-Gly-Asp-(OBzl)-Val-OBzl]-3-p-methoxy-phenyl }-1,6-heptadiene-3,5-diketone is hydrolyzed to obtain 541.2mg (92%) title compound, is yellow powder.ESI-MS(m/e)：1478[M+H]
+。
3) 1-(3-methoxyphenyl)-7-{ [4-oxygen acetyl-Lys (Pro-Ala-Lys (Boc)-Arg-Gly-Asp-Val]-3-p-methoxy-phenyl } preparation of-1,6-heptadiene-3,5-diketone
By in embodiment 2 4) preparation method of item is by 443.1mg (0.3mmol) 1-(3-methoxyphenyl)-7-{4-oxygen acetyl-Lys [Boc-Pro-Ala-Lys (Boc)]-Arg-Gly-Asp-Val]-3-p-methoxy-phenyl }-1,6-heptadiene-3,5-diketone removes Boc and obtains 373.5mg (98%) title compound, is yellow powder.ESI-MS(m/e)：1278[M+H]
+.
1H NMR(500MHz，DMSO-d6)：δ/ppm＝9.10-6.77(m，15.87H)，6.1(m，0.28)，4.79(m，1H)，4.65(m，2H)，4.29-3.96(m，6H)，3.87(s，3H)，3.85(s，3H)，3.82-2.74(m，27H)，2.16-1.15(m，23H)，0.81(s，6H)。
Embodiment 8 preparation 1-(3,4-, bis--methoxyphenyl)-7-{ [4-oxygen acetyl-Lys (Pro-Ala-Lys)-Arg-Gly-Asp-Val]-3-p-methoxy-phenyl }-1,6-heptadiene-3,5-diketone (7d)
1) 1-(3,4-bis--methoxyphenyl)-7-{4-oxygen acetyl-Lys [Boc-Pro-Ala-Lys (Boc)]-Arg-Gly-Asp-(OBzl)-Val-OBzl]-3-p-methoxy-phenyl }-1, the preparation of 6-heptadiene-3,5-diketone
By in embodiment 1 2) preparation method of item is by 1.1g (1mmol) 1-(3,4-bis--methoxyphenyl)-7-{4-oxygen acetyl-Lys [Boc-Pro-Ala-Lys (Boc)]-3-p-methoxy-phenyl }-1,6-heptadiene-3,5-diketone and 0.74g (10mmol) Arg-Gly-Asp (OBzl)-Val-OBzl react, obtaining 1.24g (74.4%) title compound, is yellow powder.ESI-MS(m/e)：1672[M+H]
+.
1H NMR(500MHz，DMSO-d6)：δ/ppm＝8.29-6.73(m，41H)，6.12(s，0.12H)，5.11-5.09(m，4H)，4.67-4.63(m，2H)，4.30-4.12(m，6H)，3.86(s，3H)，3.83(s，3H)，3.81(s，3H)，3.73(m，2H)，3.08-2.61(m，8H)，2.06-1.20(m，47H)，0.83(S，9H)。
2) 1-(3,4-, bis--methoxyphenyl)-7-{4-oxygen acetyl-Lys [Boc-Pro-Ala-Lys (Boc)]-Arg-Gly-Asp-Val]-3-p-methoxy-phenyl } preparation of-1,6-heptadiene-3,5-diketone
By in embodiment 1 3) preparation method of item is by 167mg (0.1mmol) 1-(3,4-bis--methoxyphenyl)-7-{4-oxygen acetyl-Lys [Boc-Pro-Ala-Lys (Boc)]-Arg-Gly-Asp-(OBzl)-Val-OBzl]-3-p-methoxy-phenyl }-1,6-heptadiene-3,5-diketone is hydrolyzed to obtain 138mg (93%) title compound, is yellow powder.ESI-MS(m/e)：1492[M+H]
+。
3) 1-(3,4-, bis--methoxyphenyl)-7-{4-oxygen acetyl-Lys [Pro-Ala-Lys]-Arg-Gly-Asp-Val]-3-p-methoxy-phenyl } preparation of-1,6-heptadiene-3,5-diketone
By in embodiment 2 4) preparation method of item is by 149mg (0.1mmol) 1-(3,4-bis--methoxyphenyl)-7-{4-oxygen acetyl-Lys [Boc-Pro-Ala-Lys (Boc)]-Arg-Gly-Asp-Val]-3-p-methoxy-phenyl }-1,6-heptadiene-3,5-diketone removes Boc and obtains 126mg (98%) title compound, is yellow powder.ESI-MS(m/e)：1292[M+H]
+.
1H NMR(500MHz，DMSO-d6)：δ/ppm＝10.28(S，1H)，8.91-6.88(m，25H)，4.67(s，2H)，4.66-4.03(m，8H)，3.88(s，3H)，3.84(s，3H)，3.82(s，3H)，3.72(m，3H)，2.73-1.12(m，31H)，0.87(s，6H)。
The thrombus dissolving activity of the compound intravenous injection of embodiment 9 general formula 1
1) evaluation method
200-220g male SD rat 20% urethane solution (6mL/kg, i.p.) is anaesthetized.Anesthetized rat dorsal position is fixed, and is separated right common carotid artery, in proximal part folder bulldog clamp, proximal part and distal end penetrate surgical thread respectively, the surgical thread of distal end are clamped in fur mosquito forceps, in distal end intubate, unclamp bulldog clamp, release about 1mL arterial blood and be contained in the EP pipe of 1mL.In vertical fixing Glass tubing (long 15mm, internal diameter 2.5mm, external diameter 5.0mm, seal with plug at the bottom of pipe), inject 0.1mL rat artery blood, in pipe, insert rapidly the thrombus standing bolt of a stainless steel material.It is that the Stainless Steel Wire of 0.2mm is coiled into that this thrombus fixes spiral diameter, the long 12mm of spiral part, and containing 15 bung flanges, the diameter of bung flange is 1.0mm, and holder handle is connected with spiral, and long 7.0mm, in question mark type.After blood coagulation 15min, open the plug bottom Glass tubing, fix with tweezers the holder handle that thrombus fixes spiral, the thrombus taken out from Glass tubing by thrombus wraps up fixes spiral, accurately weighs.
Bypass intubate is formed by 3 sections, and stage casing is polyethylene rubber tube, long 60mm, internal diameter 3.5mm, two ends are identical polyethylene tube, long 100mm, internal diameter 1mm, external diameter 2mm, one end of this pipe pulls into point pipe (for inserting rat carotid artery or vein), external diameter 1mm, the outer cover one segment length 7mm of the other end, the polyethylene tube (overstriking, for inserting in the polyethylene rubber tube in stage casing) of external diameter 3.5mm.The equal silanization of inwall of 3 sections of pipes.The thrombus that thrombus wraps up is fixed spiral and puts into stage casing polyethylene rubber tube, the poly butt end that adds is nested with two respectively at the two ends of sebific duct.For subsequent use by filling heparin-saline solution (50IU/kg) in pipe by sharp pipe end with syringe.
Be separated the left external jugular vein of rat, proximal part and distal end penetrate surgical thread respectively, ligation distal end, the left external jugular vein exposed cuts an angle carefully, the sharp pipe of the bypass duct prepared is inserted the proximal part of left external jugular vein opening above by angle, fix the holder handle of spiral simultaneously away from bypass tube stage casing (fixing spiral containing the thrombus of accurately weighing) interior thrombus.Pushed the heparin-saline (50IU/kg) of correct amount by the sharp pipe of the other end with syringe, now syringe does not withdraw polyethylene tube, clamps the flexible pipe between syringe and polyethylene tube with mosquito forceps.Stop blooding at the proximal part bulldog clamp of right common carotid artery, right common carotid artery is being cut an angle carefully nearby from bulldog clamp.Extract syringe from the tip of polyethylene tube, the tip of polyethylene tube is inserted the proximal part of artery angle.The two ends of bypass duct all use No. 4 sutures and arteriovenous to fix.
With scalp acupuncture by physiological saline, the normal saline solution of urokinase or the normal saline solution of different concns compound are by the stage casing (fixing spiral containing the thrombus of accurately weighing) of bypass tube, thrust the nearly vein place fixing spiral away from thrombus, open bulldog clamp, blood flow is made to flow to vein by bypass duct from artery, this i.e. rat arteriovenous shut Thrombolysis Model, slowly the liquid in syringe is injected into (about 6min) in blood, make physiological saline, urokinase or compound of the present invention pass through blood circulation, press the sequential action of vein-heart-artery on thrombus.From inject time timing, after 1h, from bypass duct, removal of thromboses fixes spiral, accurately weighs.What calculate that thrombus in every rat bypass duct fixes before and after spiral administration is of poor quality, statistics thrombolysis activity in the body of assessing compound.Thrombus loss of weight average and standard deviation
represent.
2) dosage
Physiological saline (blank) dosage is 3mL/kg, and urokinase (positive control) dosage is that 20000U/kg is equivalent to 1.68mg/kg, and the dosage of the compound 7a-d of general formula I is 1.0nmol/kg.
3) evaluation result is in table 1.Result shows that the compound 7a-d of general formula I has outstanding thrombus dissolving activity.
Table 1 compound is through the thrombus dissolving activity of intravenous administration
a
A) n=10; B) with physiological saline group than P < 0.01.
The thrombus dissolving activity of compound 7b and 7d of embodiment 10 intravenous injection various dose general formula 1
1) evaluation method is with in experimental example 1 1) item.
2) dosage
Choose the dosage effect dependence that 10nmol/kg, 1nmol/kg, 0.1nmol/kg tri-dosage investigate 7b, d.
3) the results are shown in Table 2 and table 3.Result shows that the thrombus dissolving activity of 7b and 7d and dosage present correlationship.
The dose-effect relationship of table 2 intravenous injection 7b
a
A) n=10; B) with 1nmol/kg group than p < 0.01; C) with 0.1nmol/kg group than p < 0.05; D) with physiological saline group than p < 0.01.
The dose-effect relationship of table 3 intravenous injection 7d
a
A) n=10; B) with 1nmol/kg group than p < 0.05; C) with 0.1nmol/kg group than p < 0.01; D) with physiological saline group than p < 0.01.
The hemolysis in vitro thrombus activity of the compound 7a-d of embodiment 11 general formula 1
1) evaluation method
Male SD rat, 250 ± 10g, weighs, and abdominal injection 20% urethane is anaesthetized, and dorsal position is fixed.Isolate the right common carotid artery of rat, in proximal part folder bulldog clamp, proximal part and distal end penetrate surgical thread respectively, ligation distal end, right common carotid artery is being cut an angle carefully nearby from bulldog clamp, the one end of inserting hexasilane pulls into the polyethylene tube of sharp pipe, unclamps bulldog clamp, each releasing about 5mL arterial blood is also contained in the EP pipe of the hexasilane of 5mL, approximately can put 3 times.With the 5mL syringe of hexasilane toward each vertical fixing Glass tubing (long 18mm, internal diameter 4mm, external diameter 5.5mm, seals with plug at the bottom of pipe) middle injection 0.1mL rat artery blood, the thrombus standing bolt of a rapid insertion stainless steel material in pipe.It is that the Stainless Steel Wire of 0.2mm is coiled into that this thrombus fixes spiral diameter, the long 20mm of spiral part, and the diameter of bung flange is 1.0mm, and holder handle is connected with spiral, and long 7.0mm, in question mark type.After blood coagulation 40min, open the plug bottom Glass tubing, fix with tweezers the holder handle that thrombus fixes spiral, the thrombus taken out from Glass tubing by thrombus wraps up fixes spiral, hanging to immerse fills in the cillin bottle of 8mL high purity water, soaks 1h, the floating blood of removing, taking-up is dipped in dry, accurately weighs, record.Thrombus being fixed coil suspension immersion fills in the cillin bottle of the certain density compound solution of 8mL again, and 37 DEG C of shaking tables hatch 2h, and taking-up is dipped in dry, more accurately weighs, record.To fix before and after spiral of poor quality is thrombus loss of weight for thrombus, statistics thrombolysis activity in the body of assessing compound.Thrombus loss of weight average and standard deviation
represent.
2) medication and concentration
To convert corresponding Plasma Concentration according to thrombus dissolving dosage in body.Blank is physiological saline, and positive control is UK (concentration is 254 μ g/l ml), and the concentration of the compound 7a-d of through type I is 10nM.
3) evaluation result is in table 4.Result shows that the compound of general formula I shows outstanding thrombus dissolving activity in vitro.
The hemolysis in vitro thrombus activity of table 4 compound
a
A) n=6; B) with physiological saline group ratio, P < 0.01.
The antithrombotic acitivity of the compound intravenous injection of experimental example 12 general formula 1
1) evaluation method
Intubate is formed by 3 sections, middle segment length 80mm, internal diameter 3.5mm, and two ends are identical polyethylene tube, long 100mm, internal diameter 1mm, external diameter 2mm, and one end of this pipe pulls into point pipe (for inserting rat carotid artery or vein), the inwall Jun Gui institute of 3 sections of pipes.The silk thread of the long 60mm weighed in advance is put into stage casing polyethylene extra heavy pipe, and the two ends of extra heavy pipe are nested with the non-drawing-down end of two polyethylene tubules respectively (wherein one section silk thread is pushed down 0.5mm fix).For subsequent use by filling heparin-saline solution (50IU/kg) in pipe by sharp pipe end with syringe.
200-220g male SD rat 20% urethane solution (6mL/kg, i.p.) is anaesthetized.Anesthetized rat dorsal position is fixed, isolate the left external jugular vein of rat, proximal part and distal end penetrate surgical thread respectively, ligation distal end, the left external jugular vein exposed cuts an angle carefully, the non-line ball end point pipe of the bypass duct prepared is inserted the proximal part of left external jugular vein opening above by angle, pushed the heparin-saline (50IU/kg) of correct amount by the sharp pipe of the other end with syringe, pull up syringe, again suction there is physiological saline, the syringe of the normal saline solution of urokinase or the normal saline solution of different concns compound inserts the tip of polyethylene tube, liquid is pushed by the tip of polyethylene tube, now syringe does not withdraw polyethylene tube, be separated right common carotid artery, in proximal part folder bulldog clamp, proximal part and distal end penetrate surgical thread respectively, ligation distal end, right common carotid artery is being cut an angle carefully nearby from bulldog clamp.Extract syringe from the tip of polyethylene tube, the tip of polyethylene tube is inserted the proximal part of artery angle.The two ends of bypass duct all use No. 4 sutures and arteriovenous to fix.Open bulldog clamp, make blood flow flow to vein by bypass duct from artery, this i.e. the anti-bolt model of rat arteriovenous shut.From circulation time timing, take out from bypass duct after 15min and hang with the silk thread of thrombus, accurately weigh, of poor quality before and after silk thread is wet weight of thrombus, statistics anti-thrombus activity in the body of assessing compound.Wet weight of thrombus average and standard deviation
represent.
2) dosage
Physiological saline (blank) dosage is 1mL/kg, and acetylsalicylic acid (positive control) dosage is 9mg/kg, and the dosage of the compound 7a-d of general formula I is 1.0nmol/kg.
3) evaluation result is in table 5.Result shows that the compound of general formula I can show outstanding antithrombotic acitivity through intravenous administration.
Table 5 compound is through the antithrombotic acitivity of intravenously administrable
A) n=10; B) with physiological saline group ratio, P < 0.01
The anti-inflammatory activity of the compound oral administration of experimental example 13 general formula 1
1) evaluation method
18-22g ICR male mice is divided into blank group at random, positive medication group and administration group, and tranquillization 1 day before mouse uses, operation room keeps room temp 22 DEG C, often organizes mouse 10.Difference gastric infusion when experiment starts, the left ear gabarit of single administration toward small white mouse after 30 minutes is coated with dimethylbenzene (0.03mL), is put to death by small white mouse cervical dislocation after 2 hours.The left ear of mouse and auris dextra are cut, gets circular auricle with the punch tool of diameter 7mm in the same position of two ears, weigh respectively, obtain the weight difference of two circle auricles as swelling.Swelling=former of left ear weight-auris dextra former weight.
2) dosage
Physiological saline (blank) dosage is 10mL/kg, and acetylsalicylic acid (positive control) dosage is 200mg/kg, and the dosage of the compound 7a-d of general formula I is 1.0nmol/kg.
3) evaluation result is in table 6.Result shows that the compound oral administration administration of general formula I shows outstanding anti-inflammatory activity.
The anti-inflammatory activity of table 6 compound oral administration
a
A) n=10; B) with physiological saline group than P < 0.05; C) with physiological saline group, P < 0.01.
The activity of the compound scavenging hydroxyl of experimental example 14 general formula 1
1) evaluation method
To convert corresponding Plasma Concentration according to thrombus dissolving dosage in body.The compound 7a-d adding distil water of general formula I is made into the solution that concentration is 10nM, and EPR spectrometer measures.
According to standard method by FeSO
47H
2o adding distil water is made into solution A that concentration is 10nM, by 30%H
2o
2it is 1%H that adding distil water is made into concentration
2o
2solution B, DMPO adding distil water is made into the solution C that concentration is 1.1316mg/100mL.
Blank group adds 2.5 μ L solution A, 5 μ L solution C, 5 μ L distilled water and 2.5 μ L solution B successively, sucks quartz capillary, measure hydroxy radical qiao signal and record spectrogram after 1min after violent mixing.
The compound group of general formula 1 adds 2.5 μ L solution A, 5 μ L solution C, the compound of general formula 1 of compound of 5 μ L general formulas 1 and 2.5 μ L solution B successively, sucks quartz capillary, measure hydroxy radical qiao signal and record spectrogram after 1min after violent mixing.
1 sample survey under 1 concentration 5 times, record the spectrogram peak height of each time, calculate Scavenging action to hydroxyl free radical.Calculation formula is: clearance rate=(the compound group peak height of blank group peak height-general formula 1)/blank group peak height.
2) evaluation result is in table 7.Result shows that the compound of general formula I is outstanding hydroxy radical scavenger.
Table 710nM compound is to the clearance rate of hydroxy radical qiao
The nanostructure of the compound of experimental example 15 general formula 1
1) on laser diffraction particle size instrument, observe the particle diameter that the aqueous solution of the compound of general formula I when 25 DEG C and 37 DEG C and pH are the phosphate buffer soln of 7.4.The concentration of compound converts according to thrombus dissolving dosage in body, and the concentration of 7a-d is 10nM., the results are shown in Table 9 and 10.Data show, the compound of general formula I has suitable nanometer ball structure at water and phosphate buffer soln.
The sphere diameter of the nanometer ball that table 8 compound is formed in aqueous
| Compound | Sphere diameter (nm, 25 DEG C) | Sphere diameter (nm, 37 DEG C) |
| 7a | 277.8 | 73.1 |
| 7b | 281.2 | 178.6 |
| 7c | 235.4 | 201.5 |
| 7d | 248.6 | 179.3 |
Table 9 compound is the sphere diameter of the nanometer ball formed in the phosphate buffer soln of 7.4 at pH
| Compound | Sphere diameter (nm, 25 DEG C) | Sphere diameter (nm, 37 DEG C) |
| 7a | 268.9 | 168.1 |
| 7b | 273.3 | 230.5 |
| 7c | 184.1 | 91.0 |
| 7d | 408.6 | 242.0 |
2) be 10 to 6 compound concentrations determining general formula I under transmission electron microscope
-7the transmission electron microscope photo of the aqueous solution of mg/mL.7d representatively, also measured weres 10
-6, 10
-7with 10
-8the transmission electron microscope photo of the aqueous solution of mg/mL tri-concentration.Result shows, 6 compounds of general formula I all can be observed the different nanostructure such as nanometer ball, nanometer rod, nano-rings, nanotube under transmission electron microscope.7d can be observed different nanostructures under different concns and pH condition.The transmission electron microscope photo of 7a, 7b, 7c and 7d is shown in Fig. 2, Fig. 3, Fig. 4 and Fig. 5 respectively.
Claims (5)
1. 4 kinds of pseudo-peptides of general formula I, R in formula
1for H or CH
3, R
2for Lys (Pro-Ala-Lys)-Arg-Gly-Asp-Val or Lys (Pro-Ala-Lys)-Ala-Gly-Asp-Val
2. prepare the method for 4 kinds of pseudo-peptides of general formula I, the method is made up of following steps:
(1) under dicyclohexylcarbodiimide (DCC) and N-hydroxy-succinamide (HOSu) exist, Boc-Pro is Boc-Pro-OSu with HOSu condensation in anhydrous THF, at NaHCO
3there is lower Boc-Pro-OSu and L-Ala reaction and generate Boc-Pro-Ala;
(2) under DCC and HOBt exists, Boc-Pro-Ala is Boc-Pro-Ala-Lys (Boc)-OBzl with Lys (Boc)-OBzl condensation in anhydrous THF;
(3) under NaOH exists, in methyl alcohol, Boc-Pro-Ala-Lys (Boc)-OBzl is hydrolyzed to Boc-Pro-Ala-Lys (Boc);
(4) under DCC and HOBt exists, Boc-Asp (OBzl) is Boc-Asp (OBzl)-Val-OBzl with Val-OBzl condensation in anhydrous THF;
(5) in hydrogenchloride-ethyl acetate solution, Boc-Asp (OBzl)-Val-OBzl sloughs Boc and generates Asp (OBzl)-Val-OBzl;
(6) under DCC and HOBt exists, Boc-Ala is Boc-Ala-Gly-OBzl with Gly-OBzl condensation in anhydrous THF;
(7) under NaOH exists, in methyl alcohol, Boc-Ala-Gly-OBzl is hydrolyzed to Boc-Ala-Gly;
(8) under DCC and HOBt exists, Boc-Ala-Gly is Boc-Ala-Gly-Asp (OBzl)-Val-OBzl with Asp (OBzl)-Val-OBzl condensation in anhydrous THF;
(9) in hydrogenchloride-ethyl acetate solution, Boc-Ala-Gly-Asp (OBzl)-Val-OBzl sloughs Boc and generates Ala-Gly-Asp (OBzl)-Val-OBzl;
(10) under DCC and HOBt exists, Boc-Arg is Boc-Arg-Gly-OBzl with Gly-OBzl condensation in anhydrous THF;
(11) under NaOH exists, in methyl alcohol, Boc-Arg-Gly-OBzl is hydrolyzed to Boc-Arg-Gly;
(12) under DCC and HOBt exists, Boc-Arg-Gly is Boc-Arg-Gly-Asp (OBzl)-Val-OBzl with Asp (OBzl)-Val-OBzl condensation in anhydrous THF;
(13) in hydrogenchloride-ethyl acetate solution, Boc-Arg-Gly-Asp (OBzl)-Val-OBzl sloughs Boc and generates Arg-Gly-Asp (OBzl)-Val-OBzl;
(14) in anhydrous K
2cO
3under existence, in anhydrous THF, Vanillin and ethyl bromoacetate are reacted and are generated 3-methoxyl group-4-oxygen acetyl triethyl benzaldehyde;
(15) at B
2o
3, (nBuo)
3it is 6-(3,4-bis--methoxyphenyl)-5,6-hexene-2,4-diketone with methyl ethyl diketone condensation that B and nBu-NH exists lower Veratraldehyde in anhydrous ethyl acetate;
(16) at B
2o
3, (nBuo)
3under B and nBu-NH exists, in anhydrous ethyl acetate, Vanillin and methyl ethyl diketone condensation are 6-(3-methoxyl group-4-hydroxyphenyl)-5,6-hexene-2,4-diketone;
(17) at B
2o
3, (nBuo)
3under B and nBu-NH exists, 6-(3 in anhydrous ethyl acetate, 4-bis--methoxyphenyl)-5,6-hexene-2,4-diketone and the condensation of 3-methoxyl group-4-oxygen acetyl triethyl benzaldehyde are 1-(3,4-, bis--methoxyphenyl)-7-(4-oxygen acetyl triethyl base-3-p-methoxy-phenyl)-1,6-heptadiene-3,5-diketone, or at B
2o
3, (nBuo)
3under B and nBu-NH exists, 6-(3-methoxyl group-4-hydroxyphenyl)-5 in anhydrous ethyl acetate, 6-hexene-2,4-diketone and the condensation of 3-methoxyl group-4-oxygen acetyl triethyl benzaldehyde are 1-(3-methoxyl group-4-hydroxyphenyl)-7-(4-oxygen acetyl triethyl base-3-p-methoxy-phenyl)-1,6-heptadiene-3,5-diketone;
(18) NaOH exist under in acetone by 1-(3, 4-bis--methoxyphenyl)-7-(4-oxygen acetyl triethyl base-3-p-methoxy-phenyl)-1, 6-heptadiene-3, 5-diketone is hydrolyzed to 1-(3, 4-bis--methoxyphenyl)-7-(4-fluoroacetic acid base-3-p-methoxy-phenyl)-1, 6-heptadiene-3, 5-diketone, or in acetone by 1-(3-methoxyl group-4-hydroxyphenyl)-7-(4-oxygen acetyl triethyl base-3-p-methoxy-phenyl)-1 under NaOH exists, 6-heptadiene-3, 5-diketone is hydrolyzed to 1-(3-methoxyl group-4-hydroxyphenyl)-7-(4-fluoroacetic acid base-3-p-methoxy-phenyl)-1, 6-heptadiene-3, 5-diketone,
(19) DCC and HOBt exist under in anhydrous THF 1-(3, 4-bis--methoxyphenyl)-7-(4-fluoroacetic acid base-3-p-methoxy-phenyl)-1, 6-heptadiene-3, 5-diketone and Lys (Boc)-OBzl condensation are 1-(3, 4-bis--methoxyphenyl)-7-(4-oxygen acetyl-Lys (Boc)-OBzl-3-p-methoxy-phenyl)-1, 6-heptadiene-3, 5-diketone, or DCC and HOBt exist under in anhydrous THF 1-(3-methoxyl group-4-hydroxyphenyl)-7-(4-fluoroacetic acid base-3-p-methoxy-phenyl)-1, 6-heptadiene-3, 5-diketone and Lys (Boc)-OBzl condensation are 1-(3-methoxyl group-4-hydroxyphenyl)-7-(4-oxygen acetyl-Lys (Boc)-OBzl-3-p-methoxy-phenyl)-1, 6-heptadiene-3, 5-diketone,
(20) 1-(3 in hydrogenchloride-ethyl acetate solution, 4-bis--methoxyphenyl)-7-(4-oxygen acetyl-Lys (Boc)-OBzl-3-p-methoxy-phenyl)-1, 6-heptadiene-3, 5-diketone is sloughed Boc and is generated 1-(3, 4-bis--methoxyphenyl)-7-(4-oxygen acetyl-Lys-OBzl-3-p-methoxy-phenyl)-1, 6-heptadiene-3, 5-diketone, or in hydrogenchloride-ethyl acetate solution 1-(3-methoxyl group-4-hydroxyphenyl)-7-(4-oxygen acetyl-Lys (Boc)-OBzl-3-p-methoxy-phenyl)-1, 6-heptadiene-3, 5-diketone is sloughed Boc and is generated 1-(3-methoxyl group-4-hydroxyphenyl)-7-(4-oxygen acetyl-Lys-OBzl-3-p-methoxy-phenyl)-1, 6-heptadiene-3, 5-diketone,
(21) under NaOH exists, by 1-(3 in methyl alcohol, 4-bis--methoxyphenyl)-7-[4-oxygen acetyl-Lys (Boc)-OBzl-3-p-methoxy-phenyl]-1, 6-heptadiene-3, 5-diketone is hydrolyzed to 1-(3, 4-bis--methoxyphenyl)-7-(4-oxygen acetyl-Lys-3-p-methoxy-phenyl)-1, 6-heptadiene-3, 5-diketone or NaOH exist under, by 1-(3-methoxyl group-4-hydroxyphenyl)-7-(4-oxygen acetyl-Lys-OBzl-3-p-methoxy-phenyl)-1 in methyl alcohol, 6-heptadiene-3, 5-diketone is hydrolyzed to 1-(3-methoxyl group-4-hydroxyphenyl)-7-(4-oxygen acetyl-Lys-3-p-methoxy-phenyl)-1, 6-heptadiene-3, 5-diketone,
(22) under DCC and HOBt exists in anhydrous THF Boc-Pro-Ala-Lys (Boc) and 1-(3, 4-bis--methoxyphenyl)-7-(4-oxygen acetyl-Lys-OBzl-3-p-methoxy-phenyl)-1, 6-heptadiene-3, the condensation of 5-diketone is 1-(3, 4-bis--methoxyphenyl)-7-{4-oxygen acetyl-Lys [Boc-Pro-Ala-Lys (Boc)-OBzl]-3-p-methoxy-phenyl }-1, 6-heptadiene-3, 5-diketone, or under DCC and HOBt exists in anhydrous THF Boc-Pro-Ala-Lys (Boc) and 1-(3-methoxyl group-4-hydroxyphenyl)-7-(4-oxygen acetyl-Lys-OBzl-3-p-methoxy-phenyl)-1, 6-heptadiene-3, the condensation of 5-diketone is 1-(3-methoxyl group-4-hydroxyphenyl)-7-{4-oxygen acetyl-Lys [Boc-Pro-Ala-Lys (Boc)-OBzl]-3-p-methoxy-phenyl }-1, 6-heptadiene-3, 5-diketone,
(23) NaOH exist under in methyl alcohol by 1-(3, 4-bis--methoxyphenyl)-7-{4-oxygen acetyl-Lys [Boc-Pro-Ala-Lys (Boc)-OBzl]-3-p-methoxy-phenyl }-1, 6-heptadiene-3, 5-diketone is hydrolyzed to 1-(3, 4-bis--methoxyphenyl)-7-{4-oxygen acetyl-Lys [Boc-Pro-Ala-Lys (Boc)]-3-p-methoxy-phenyl }-1, 6-heptadiene-3, 5-diketone, or NaOH exist under in methyl alcohol by 1-(3-methoxyl group-4-hydroxyphenyl)-7-{4-oxygen acetyl-Lys-[Boc-Pro-Ala-Lys (Boc)-OBzl]-3-p-methoxy-phenyl-1, 6-heptadiene-3, 5-diketone is hydrolyzed to 1-(3-methoxyl group-4-hydroxyphenyl)-7-{4-oxygen acetyl-Lys [Boc-Pro-Ala-Lys (Boc)]-3-p-methoxy-phenyl }-1, 6-heptadiene-3, 5-diketone,
(24) 1-(3 under DCC and HOBt exists, 4-bis--methoxyphenyl)-7-{4-oxygen acetyl-Lys [Boc-Pro-Ala-Lys (Boc)]-3-p-methoxy-phenyl }-1,6-heptadiene-3,5-diketone and Arg-Gly-Asp (OBzl)-Val-OBzl condensation are 1-(3,4-bis--methoxyphenyl)-7-{4-oxygen acetyl-Lys [Boc-Pro-Ala-Lys (Boc)]-Arg-Gly-Asp-(OBzl)-Val-OBzl]-3-p-methoxy-phenyl }-1,6-heptadiene-3,5-diketone;
(25) 1-(3 under DCC and HOBt exists, 4-bis--methoxyphenyl)-7-{4-oxygen acetyl-Lys [Boc-Pro-Ala-Lys (Boc)]-3-p-methoxy-phenyl }-1,6-heptadiene-3,5-diketone and Ala-Gly-Asp (OBzl)-Val-OBzl condensation are 1-(3,4-bis--methoxyphenyl)-7-{4-oxygen acetyl-Lys [Boc-Pro-Ala-Lys (Boc)]-Ala-Gly-Asp-(OBzl)-Val-OBzl]-3-p-methoxy-phenyl }-1,6-heptadiene-3,5-diketone;
(26) 1-(3-methoxyl group-4-hydroxyphenyl)-7-{4-oxygen acetyl-Lys [Boc-Pro-Ala-Lys (Boc)]-3-p-methoxy-phenyl under DCC and HOBt exists }-1,6-heptadiene-3,5-diketone and Arg-Gly-Asp (OBzl)-Val-OBzl condensation are 1-(3-methoxyl group-4-hydroxyphenyl)-7-{4-oxygen acetyl-Lys [Boc-Pro-Ala-Lys (Boc)]-Arg-Gly-Asp-(OBzl)-Val-OBzl]-3-p-methoxy-phenyl }-1,6-heptadiene-3,5-diketone;
(27) 1-(3-methoxyl group-4-hydroxyphenyl)-7-{4-oxygen acetyl-Lys [Boc-Pro-Ala-Lys (Boc)]-3-p-methoxy-phenyl under DCC and HOBt exists }-1,6-heptadiene-3,5-diketone and Arg-Gly-Asp (OBzl)-Val-OBzl condensation are 1-(3-methoxyl group-4-hydroxyphenyl)-7-{4-oxygen acetyl-Lys [Boc-Pro-Ala-Lys (Boc)]-Arg-Gly-Asp-(OBzl)-Val-OBzl]-3-p-methoxy-phenyl }-1,6-heptadiene-3,5-diketone;
(28) in the methanol solution of NaOH by 1-(3,4-bis--methoxyphenyl)-7-{4-oxygen acetyl-Lys [Boc-Pro-Ala-Lys (Boc)]-Arg-Gly-Asp-(OBzl)-Val-OBzl]-3-p-methoxy-phenyl }-1,6-heptadiene-3,5-diketone is hydrolyzed to 1-(3,4-bis--methoxyphenyl)-7-{4-oxygen acetyl-Lys [Boc-Pro-Ala-Lys (Boc)]-Arg-Gly-Asp-Val]-3-p-methoxy-phenyl }-1,6-heptadiene-3,5-diketone;
(29) in the methanol solution of NaOH by 1-(3,4-bis--methoxyphenyl)-7-{4-oxygen acetyl-Lys [Boc-Pro-Ala-Lys (Boc)]-Ala-Gly-Asp-(OBzl)-Val-OBzl]-3-p-methoxy-phenyl }-1,6-heptadiene-3,5-diketone is hydrolyzed to 1-(3,4-bis--methoxyphenyl)-7-{4-oxygen acetyl-Lys [Boc-Pro-Ala-Lys (Boc)]-Ala-Gly-Asp-Val]-3-p-methoxy-phenyl }-1,6-heptadiene-3,5-diketone;
(30) in the methanol solution of NaOH by 1-(3-methoxyl group-4-hydroxyphenyl)-7-{4-oxygen acetyl-Lys [Boc-Pro-Ala-Lys (Boc)]-Arg-Gly-Asp-(OBzl)-Val-OBzl]-3-p-methoxy-phenyl-1,6-heptadiene-3,5-diketone is hydrolyzed to 1-(3-methoxyl group-4-hydroxyphenyl)-7-{4-oxygen acetyl-Lys [Boc-Pro-Ala-Lys (Boc)]-Arg-Gly-Asp-Val]-3-p-methoxy-phenyl }-1,6-heptadiene-3,5-diketone;
(31) in the methanol solution of NaOH by 1-(3-methoxyl group-4-hydroxyphenyl)-7-{4-oxygen acetyl-Lys [Boc-Pro-Ala-Lys (Boc)]-Ala-Gly-Asp-(OBzl)-Val-OBzl]-3-p-methoxy-phenyl-1,6-heptadiene-3,5-diketone is hydrolyzed to 1-(3-methoxyl group-4-hydroxyphenyl)-7-{4-oxygen acetyl-Lys [Boc-Pro-Ala-Lys (Boc)]-Ala-Gly-Asp-Val]-3-p-methoxy-phenyl }-1,6-heptadiene-3,5-diketone;
(32) in the ethyl acetate solution of hydrogenchloride by 1-(3,4-bis--methoxyphenyl)-7-{4-oxygen acetyl-Lys [Boc-Pro-Ala-Lys (Boc)]-Arg-Gly-Asp-Val]-3-p-methoxy-phenyl }-1,6-heptadiene-3,5-diketone is sloughed Boc and is generated 1-(3,4-bis--methoxyphenyl)-7-{ [4-oxygen acetyl-Lys (Pro-Ala-Lys)-Arg-Gly-Asp-Val]-3-p-methoxy-phenyl }-1,6-heptadiene-3,5-diketone;
(33) in the ethyl acetate solution of hydrogenchloride by 1-(3,4-bis--methoxyphenyl)-7-{4-oxygen acetyl-Lys [Boc-Pro-Ala-Lys (Boc)]-Ala-Gly-Asp-Val]-3-p-methoxy-phenyl }-1,6-heptadiene-3,5-diketone is sloughed Boc and is generated 1-(3,4-bis--methoxyphenyl)-7-{4-oxygen acetyl-Lys [Pro-Ala-Lys]-Ala-Gly-Asp-Val]-3-p-methoxy-phenyl }-1,6-heptadiene-3,5-diketone;
(34) in the ethyl acetate solution of hydrogenchloride by 1-(3-methoxyl group-4-hydroxyphenyl)-7-{4-oxygen acetyl-Lys-[Boc-Pro-Ala-Lys (Boc)]-Arg-Gly-Asp-Val]-3-p-methoxy-phenyl-1,6-heptadiene-3,5-diketone is sloughed Boc and is generated 1-(3-methoxyl group-4-hydroxyphenyl)-7-{4-oxygen acetyl-Lys [Pro-Ala-Lys]-Arg-Gly-Asp-Val]-3-p-methoxy-phenyl }-1,6-heptadiene-3,5-diketone;
(35) in the ethyl acetate solution of hydrogenchloride by 1-(3-methoxyl group-4-hydroxyphenyl)-7-{4-oxygen acetyl-Lys [Boc-Pro-Ala-Lys (Boc)]-Ala-Gly-Asp-Val]-3-p-methoxy-phenyl-1,6-heptadiene-3,5-diketone is sloughed Boc and is generated 1-(3-methoxyl group-4-hydroxyphenyl)-7-{4-oxygen acetyl-Lys [Pro-Ala-Lys]-Ala-Gly-Asp-Val]-3-p-methoxy-phenyl }-1,6-heptadiene-3,5-diketone.
3. 4 kinds of pseudo-peptides of claim 1 are preparing the application in thrombus dissolving and antithrombotic reagent.
4. 4 kinds of pseudo-peptides of claim 1 are preparing the application in thrombus dissolving, antithrombotic and anti-inflammatory disease medicament.
5. 4 kinds of pseudo-peptides of claim 1 are preparing the application in thrombus dissolving, antithrombotic, anti-inflammatory and OH free radical scavenging medicine.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110415153.9A CN103159835B (en) | 2011-12-13 | 2011-12-13 | Lys and oligopeptide-modified curcumin derivatives, and synthesis and medical application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110415153.9A CN103159835B (en) | 2011-12-13 | 2011-12-13 | Lys and oligopeptide-modified curcumin derivatives, and synthesis and medical application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103159835A CN103159835A (en) | 2013-06-19 |
| CN103159835B true CN103159835B (en) | 2015-03-25 |
Family
ID=48583399
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201110415153.9A Expired - Fee Related CN103159835B (en) | 2011-12-13 | 2011-12-13 | Lys and oligopeptide-modified curcumin derivatives, and synthesis and medical application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103159835B (en) |
Families Citing this family (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105884905A (en) | 2012-09-05 | 2016-08-24 | 上海晟顺生物科技有限公司 | Novel compound with thrombolytic, free radical scavenging and thrombus targeted functions, and preparation method and purposes thereof |
| CN106317189B (en) * | 2015-06-23 | 2019-07-12 | 首都医科大学 | Five methoxytryptamine base carbonyl propionyl-RPAK peptides, preparation, activity and application |
| CN107698660B (en) * | 2015-06-23 | 2021-06-08 | 首都医科大学 | imidazopyridine-6-formyl-Lys (Lys) -oligopeptides, their synthesis, activity and uses |
| CN106317171B (en) * | 2015-06-23 | 2019-07-26 | 首都医科大学 | Ring histidyl--KK, synthesis, thrombus related activity and application |
| CN106317187B (en) * | 2015-06-23 | 2019-07-12 | 首都医科大学 | Five methoxytryptamine base carbonyl propionyl-PAK peptides, preparation, activity and application |
| CN106279363B (en) * | 2015-06-23 | 2020-01-17 | 首都医科大学 | Pentamyloxycarbonylamino propionyl-GRPAK peptides, their preparation, activity and use |
| CN106317182A (en) * | 2015-06-24 | 2017-01-11 | 首都医科大学 | Leu-Asp-Val modified curcumin, preparation method, biological activity and application thereof |
| CN106317197B (en) * | 2015-06-24 | 2019-07-26 | 首都医科大学 | The curcumin of YIGSR modification, preparation, bioactivity and application |
| CN106279364B (en) * | 2015-06-24 | 2019-10-18 | 首都医科大学 | The curcumin of RGDS modification, preparation, bioactivity and application |
| CN107488213B (en) * | 2016-06-13 | 2021-03-30 | 首都医科大学 | warfarin-4-O-acetyl-YIGSK, its synthesis, pharmacological activity and application |
| CN113754721A (en) * | 2020-06-04 | 2021-12-07 | 首都医科大学 | Synthesis, bioactivity and application of RGDS modified curcumin |
| CN113754723A (en) * | 2020-06-04 | 2021-12-07 | 首都医科大学 | Synthesis, bioactivity and application of RGDF modified curcumin |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101497651A (en) * | 2008-01-30 | 2009-08-05 | 首都医科大学 | Compound with thrombus dissolving activity, as well as preparation and use thereof |
| CN101906139A (en) * | 2009-06-03 | 2010-12-08 | 首都医科大学 | Conjugate of peptide chain, Lys and aliphatic alcohol chain, preparation method and application thereof |
| CN102126938A (en) * | 2010-12-15 | 2011-07-20 | 厦门大学 | Curcumin analog and preparation method and application thereof |
| CN102153623A (en) * | 2006-11-30 | 2011-08-17 | 首都医科大学 | Compound with thrombolytic activity and preparation method and application thereof |
| CN102241740A (en) * | 2008-01-30 | 2011-11-16 | 首都医科大学 | Compounds with thrombolytic activities and preparation methods and applications thereof |
| CN102250204A (en) * | 2010-05-19 | 2011-11-23 | 首都医科大学 | RGD sequence peptidyl methyl curcumin compounds, preparation method thereof, and application thereof |
-
2011
- 2011-12-13 CN CN201110415153.9A patent/CN103159835B/en not_active Expired - Fee Related
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102153623A (en) * | 2006-11-30 | 2011-08-17 | 首都医科大学 | Compound with thrombolytic activity and preparation method and application thereof |
| CN101497651A (en) * | 2008-01-30 | 2009-08-05 | 首都医科大学 | Compound with thrombus dissolving activity, as well as preparation and use thereof |
| CN102241740A (en) * | 2008-01-30 | 2011-11-16 | 首都医科大学 | Compounds with thrombolytic activities and preparation methods and applications thereof |
| CN101906139A (en) * | 2009-06-03 | 2010-12-08 | 首都医科大学 | Conjugate of peptide chain, Lys and aliphatic alcohol chain, preparation method and application thereof |
| CN102250204A (en) * | 2010-05-19 | 2011-11-23 | 首都医科大学 | RGD sequence peptidyl methyl curcumin compounds, preparation method thereof, and application thereof |
| CN102126938A (en) * | 2010-12-15 | 2011-07-20 | 厦门大学 | Curcumin analog and preparation method and application thereof |
Non-Patent Citations (1)
| Title |
|---|
| 靶向寡肽溶栓剂;赵逸松等;《首都医科大学学报》;20080229;第29卷(第1期);摘要，第104页右栏第1段，第105页左栏第1段 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103159835A (en) | 2013-06-19 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103159835B (en) | Lys and oligopeptide-modified curcumin derivatives, and synthesis and medical application thereof | |
| CN104610424A (en) | Lys(Pro-Ala-Lys) curcumin derivatives, synthesis thereof and application thereof in medical science | |
| JP6510500B2 (en) | Novel compounds with three activities of thrombolysis, antithrombosis and free radical scavenging, their synthesis, nanostructures and applications | |
| CN102241675B (en) | (1R,3S)-1-(4-hydroxyl-3-methoxycarboxyl)-1,2,3,4-tetrahydro-beta-carboline-3-formyl amino acid derivatives as well as preparation method and application thereof | |
| CN102807605B (en) | Nalpha-(1,3-dioxo-4,4,5,5-tetramethylimidazoline-2-phenyl-4'-oxyacetyl)-Nomega-fatty acyl-Lys-Arg-Gly-Asp-Phe and preparation method and application thereof | |
| CN103145797B (en) | [(3s)-1,2,3,4-tetrahydroisoquinoline-3-formoxy]-Lys modified RGD tetrapeptide and its synthesis method and use in medical science | |
| CN103159826B (en) | Lys and Lys (Pro-Ala-Lys)-modified curcumin derivatives, and synthesis and medical application thereof | |
| CN104610425A (en) | Lys(Pro-Ala-Lys) curcumin derivatives, and synthesis and application thereof | |
| CN109912693A (en) | Seven ring aldehyde of RGDS modification, synthesis, anti-thrombus activity and application | |
| CN105218629A (en) | Isoquinoline 99.9-3-formyl-RC-OBzl, its preparation, nanostructure, active and application | |
| CN102807604B (en) | N alpha-(1,3-dioxy-4,4,5,5-tetramethyl imidazoline-2-phenyl-4'-oxo acetyl)-N omega-fatty acyl-Lys-Arg-Gly-Asp-Val and preparation method and application thereof | |
| CN102477076B (en) | Oligopeptide compound for thrombolysis, its preparation method and application | |
| CN104610089A (en) | Lys modified curcumin derivatives, synthesis and applications thereof | |
| CN109912694A (en) | Seven ring aldehyde of RGDF modification, preparation, anti-thrombus activity and application | |
| CN109912692A (en) | Seven ring aldehyde of YIGSK modification, preparation, anti-thrombus activity and application | |
| CN102477072B (en) | Thrombolytic oligopeptide compound as well as preparation method and application thereof | |
| CN105585611A (en) | Octapeptide modified dexamethasone, preparation, nano-structure and application thereof | |
| CN102485745B (en) | Thrombolytic oligopeptides, preparation method and application thereof | |
| CN102477075B (en) | Oligopeptide for resisting thrombi and preparation method and application thereof | |
| CN102485744B (en) | Thrombolytic oligopeptide compound, its preparation method and application | |
| CN102485746A (en) | Oligopeptides having target-oriented thrombolytic activity and their preparation method and application | |
| CN102477069B (en) | Pro-Ala-Lys-Asp[OCH2(CH2)nCH3]-OCH2(CH2)nCH3, synthesizing method thereof, and application thereof as thrombolytic agent | |
| CN109912695B (en) | RGDV-modified heptacyclic aldehyde, synthesis, antithrombotic activity and application thereof | |
| CN106317191B (en) | Thr-Val-Gly-Cys-Ser, synthesis, activity and application | |
| CN104211763B (en) | Aspirin Arg Gly Asp Val conjugates, it is synthesized, nanostructured and the application as medicine-carried system |
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 | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20150325 Termination date: 20191213 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |