CN113121647A - Cyclic peptides and methods for their preparation - Google Patents

Cyclic peptides and methods for their preparation Download PDF

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CN113121647A
CN113121647A CN202010050074.1A CN202010050074A CN113121647A CN 113121647 A CN113121647 A CN 113121647A CN 202010050074 A CN202010050074 A CN 202010050074A CN 113121647 A CN113121647 A CN 113121647A
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cyclic peptide
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陈建添
温学贤
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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
    • C07K7/64—Cyclic peptides containing only normal peptide links
    • 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

Abstract

A preparation method of cyclic peptide and the cyclic peptide prepared by the same. Wherein, the method comprises the following steps: (A) provided are compounds represented by the following formulas (I-1) and (I-2):
Figure DDA0002370238860000011
wherein, G, R1、Ra、Rb、Rc、RdAnd ReAs defined in the specification; (B) carrying out a reaction between the compounds of the formulae (I-1) and (I-2) to obtain a compound represented by the following formula (I-3):
Figure DDA0002370238860000012
and (C) subjecting the compound of formula (I-3) to cyclization reaction with the catalyst of formula (II) and deprotection to obtain a compound represented by the following formula (III):
Figure DDA0002370238860000013
M(O)mL1 yL2 z(II) wherein G', Q, M, L1、L2M, y and z are as defined in the specification.

Description

Cyclic peptides and methods for their preparation
Technical Field
The invention relates to a preparation method of cyclic peptide and cyclic peptide prepared by the method, in particular to a preparation method for synthesizing cyclic peptide by a catalyst.
Background
Peptides have been widely used in various fields, such as topical or cosmetic skin care. Among known peptides, a peptide having an arginine (R) -glycine (G) -aspartic acid (D) configuration (R) -glycine (G) -aspartic acid (D) motif) is found as a unit commonly found in cell recognition.
Peptides containing the RGD configuration (motif) are known to bind to the integrin RGD binding site and to enhance cell attachment by coating synthetic scaffolds in tissue engineering to mimic in vivo conditions.
In conventional methods for preparing peptides containing the RGD configuration, a coupling agent is used to catalyze the peptide synthesis, and a large amount of the coupling agent (e.g., 1-5 equivalents) is generally used for the reaction. However, the cost of coupling agents is not low, resulting in high production costs of peptides, and not all of the obtained peptides can be used.
Therefore, there is a need to provide a novel method for preparing cyclic peptides containing RGD configuration, which is suitable for various fields.
Disclosure of Invention
In view of the above, the present invention provides a method for preparing cyclic peptide and cyclic peptide prepared by the method. Wherein, the method uses a catalyst to catalyze the synthesis of cyclic peptide so as to reduce the production cost. In addition, the cyclic peptide thus prepared is advantageous for preservation.
The present invention provides a method for preparing a cyclic peptide, comprising the following steps (a) to (C).
In step (A), prepared from commercial sources or by our method, compounds represented by the following formulas (I-1) and (I-2) are provided:
Figure BDA0002370238840000021
wherein R isa、RbAnd ReEach independently is a protecting group;
Rcand RdEach independently is alkyl, cycloalkyl, aryl or heteroaryl;
g is H or O-t-Bu; and
R1is composed of
Figure BDA0002370238840000022
Wherein R is2And R3Each independently is H or C1-6An alkyl group; x is O, S, CH2Or N-R4Wherein R is4Is H, C1-6Alkyl group, (CH)2CH2O)nH、-C(＝O)-C1-15Alkyl or C (═ O) (C)2H4)2C(＝O)O(C2H4O)nH, wherein n is 1-3.
In step (B), a reaction between the compounds of the formulae (I-1) and (I-2) is carried out to obtain a compound represented by the following formula (I-3):
Figure BDA0002370238840000023
in step (C), the compound of formula (I-3) is subjected to cyclization reaction with the catalyst of formula (II) and deprotection group to obtain a compound represented by the following formula (III):
Figure BDA0002370238840000031
M(O)mL1 yL2 z (II)
wherein G' is H or OH;
q is halogen, OC (O) CF3Or OC (O) CH3；
M is a metal selected from the group consisting of IVB, VB, VIB and actinide;
L1and L2Are each a ligand;
m and y are integers greater than or equal to 1; and
z is an integer greater than or equal to 0.
The present invention also provides another method for preparing a cyclic peptide, comprising the following steps (a) to (d).
In step (a), prepared from commercial sources or by our method, there are provided compounds represented by the following formulas (I-1) and (I-4):
Figure BDA0002370238840000032
wherein R isa、RbAnd ReEach independently is a protecting group;
Rcand RdEach independently is alkyl, cycloalkyl, aryl or heteroaryl;
g is H or O-t-Bu; and
R1is composed of
Figure BDA0002370238840000033
Wherein R is2And R3Each independently is H or C1-6An alkyl group; x is O, S, CH2Or N-R4Wherein R is4Is H, C1-6Alkyl group, (CH)2CH2O)nH、-C(＝O)-C1-15Alkyl or C (═ O) (C)2H4)2C(＝O)O(C2H4O)nH, wherein n is 1-3.
In step (b), the reaction between the compounds of the formulae (I-1) and (I-4) is carried out to obtain a compound represented by the following formula (I-5):
Figure BDA0002370238840000041
in step (c), a reaction between the compound of formula (I-5) and a compound represented by the following formula (I-6) is carried out to obtain a compound represented by the following formula (I-7):
Figure BDA0002370238840000042
wherein R isfIs alkyl, cycloalkyl, aryl or heteroaryl.
In step (d), the compound of formula (I-7) is subjected to cyclization reaction with the catalyst of formula (II) and deprotection group to obtain a compound represented by the following formula (III):
Figure BDA0002370238840000043
M(O)mL1 yL2 z (II)
wherein G' is H or OH;
q is halogen, OC (O) CF3Or OC (O) CH3；
M is a metal selected from the group consisting of IVB, VB, VIB and actinide;
L1and L2Are each a ligand;
m and y are integers greater than or equal to 1; and
z is an integer greater than or equal to 0.
In the present invention, RaAnd ReMay be a Fluorenylmethyloxycarbonyl (Fmoc); and RbMay be MTr (2, 3, 6-trimethyl-4-methoxybenzenesulfonyl), but the present invention is not limited thereto.
In the production process of the present invention, the reaction of the compounds of the formulae (I-1) and (I-2), or the reaction of the compounds of the formulae (I-1) and (I-4), or the reaction of the compounds of the formulae (I-5) and (I-6) may be carried out using a catalyst or a coupling agent of the formula (II).
In a conventional method for preparing a cyclic peptide, 3 to 5 equivalents of a coupling agent such as hydroxybenzotriazole (HOBt), 1-hydroxy-7-azabenzotriazole (1-hydroxy-7-azabenzotriazole, HOAt), 2- (1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium hexafluorophosphate (2- (1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium hexafluorophosphate, HBTU) and benzotriazol-1-yl-oxytriryproliphosphonium hexafluorophosphate (benzotriazole-1-yl-oxytririthiopyrrolidinium hexafluorophosphate, pythophosphate, bop) are used. Since these coupling agents are expensive, the obtained cyclic peptides are not easily commercialized and applied to various fields.
In the process of the present invention for preparing the cyclic peptide, the catalyst of formula (II) is water-soluble and is used to facilitate the reaction. Therefore, the method of the present invention does not require the use of an expensive coupling agent, and therefore, cyclic peptides can be produced in a cheaper manner, and the obtained cyclic peptides can be applied to various fields.
In the preparation process of the present invention, when the reactions of steps (B) to (C) or steps (B) to (d) are carried out with the catalyst of formula (II), the catalysts used in steps (B) to (C) or steps (B) to (d) may be the same or different.
In the catalyst of the formula (II), L1Is a ligand, preferably selected from Cl, OTf, OTs, NTf2Halogen, RC (O) CH2C(O)R、OAc、OC(O)CF3OEt, O-iPr and butyl, wherein R is alkyl (preferably C)1-6An alkyl group; more preferably C1-3Alkyl groups). Furthermore, L2Also a ligand, which is preferably selected from Cl, H2O、CH3OH、EtOH、THF、CH3CN and
Figure BDA0002370238840000061
the group consisting of.
Secondly, in the catalyst of formula (II), M may be a metal, which is preferably selected from the group consisting of IVB, VB, VIB and actinide groups. In one embodiment of the present invention, M is a group IVB transition element, M is 1 and y is 2; wherein M may be Ti, Zr or Hf. In another embodiment of the invention, M is a transition element of group VB, M is 1 and y is 2 or 3; wherein M may be V or Nb. In another embodiment of the invention, M is a transition element of group VIB, M is 1 and y is 4; wherein M may be Mo, W or Cr. In another embodiment of the invention, M is a transition element of group VIB, M is 2 and y is 2; wherein M may be Mo, W or Cr. In another embodiment of the invention, M is selected from the actinide family, M is 2 and y is 2; where M may be U.
In the present invention, a specific example of the catalyst of the formula (II) is MoO2Cl2、V(O)Cl2、V(O)(OAc)2、V(O)(O2CCF3)2、Ti(O)(acac)2、Zr(O)Cl2、Hf(O)Cl2、Nb(O)Cl2、MoO2(acac)2、V(O)(OTs)2、V(O)(NTf2)2Or VO (OTf)2However, the present invention is not limited thereto.
In addition, in the catalyst of formula (II), z may be an integer greater than or equal to 0; and preferably z is 0.
Here, the cyclic peptide synthesized by the production method of the present invention has a structure represented by the following formula (III):
Figure BDA0002370238840000062
wherein G' is H or OH;
R1is composed of
Figure BDA0002370238840000071
Wherein R is2And R3Each independently is H or C1-6An alkyl group; x is O, S, CH2Or N-R4Wherein R is4Is H, C1-6Alkyl group, (CH)2CH2O)nH、-C(＝O)-C1-15Alkyl or C (═ O) (C)2H4)2C(＝O)O(C2H4O)nH, wherein n is 1-3; and
q is halogen, OC (O) CF3Or OC (O) CH3。
In the cyclic peptide represented by the formula (III) of the present invention, X is preferably O, CH2S or N-R4Wherein R is4Is H, C1-6Alkyl, -C (═ O) -C7-15Alkyl group, (CH)2CH2O)nH or C (═ O) (C)2H4)2C(＝O)O(C2H4O)nAnd H, wherein n is 1-3.
In the cyclic peptide represented by the formula (III) of the present invention, R1Preferably, it is
Figure BDA0002370238840000072
Figure BDA0002370238840000073
Wherein R is2Is H or C1-6Alkyl radical, R3Is H or C1-6An alkyl group; and R4Is H, -C (═ O) -C7-15Alkyl or (CH)2CH2O)nH. More preferably, when R1Is composed of
Figure BDA0002370238840000074
When R is2Is H and R3Is H; or when R is1Is composed of
Figure BDA0002370238840000075
When R is2Is isopropyl and R3Is methyl; or when R is1Is composed of
Figure BDA0002370238840000076
When is, or R4Is H or-C (═ O) -heptyl.
In the cyclic peptide represented by the formula (III) of the present invention, G' is preferably H; q is preferably Cl, OC (O) CF3Or OC (O) CH3。
In a preferred embodiment of the present invention, the cyclic peptide of the present invention is represented by any one of the following formulae (III-1) to (III-5):
Figure BDA0002370238840000081
Figure BDA0002370238840000091
wherein R is5Is C1-15An alkyl group; and Q is Cl, OC (O) CF3Or OC (O) CH3。
The cyclic peptide of the present invention comprises amino acids arginine (R) -glycine (G) -aspartic acid (D), which can bind to the RGD binding site of integrin (integrin). When the cyclic peptide of the present invention binds to the integrin RGD-binding site of the skin, the transfer process between the dermal layer and epidermal layer can be restored, and the production of basement membrane (important protein) can be stimulated. Thus, improvements in scarring, wounds, inflammatory processes, aging, and/or wrinkle formation may be achieved. Thus, the cyclic peptides of the present invention may be applied to topical or cosmetic skin care compositions.
In the present invention, unless otherwise specified, alkyl, cycloalkyl, aryl and heteroaryl groups present in a compound all include substituted and unsubstituted groups. Possible substituents on the alkyl, cycloalkyl, aryl and heteroaryl groups include, but are not limited to, alkyl, alkenyl, halogen, alkoxy, ketone, alcohol, thioether, carbamate, amine, heterocyclyl or aryl groups; but the alkyl group cannot be substituted by an alkyl group.
In the present invention, the term "halogen" includes F, Cl, Br and I, and is preferably Cl or Br. The term "alkyl" refers to a straight or branched chain alkyl group; preferably comprising straight and branched chains C1-20An alkyl group; more preferably comprises straight and branched chains C1-12An alkyl group; most preferably comprising straight and branched chains C1-6An alkyl group. Specific examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, neopentyl or hexyl. The term "alkoxy" refers to a group defined herein wherein an alkyl group is coupled to an oxygen atom; preferably comprising straight and branched chains C1-20An alkoxy group; more preferably comprises straight and branched chains C1-12An alkoxy group; most preferably comprising straight and branched chains C1-6An alkoxy group. Specific examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, neopentyloxy, or hexyloxy. The term "alkenyl" refers to a straight or branched hydrocarbon group containing at least one double bond; preferably a hydrocarbon C comprising straight and branched chains containing at least one double bond2-20A group; more preferably a hydrocarbon C comprising straight and branched chains containing at least one double bond2-12A group; most preferably a hydrocarbon C comprising straight and branched chains containing at least one double bond2-6A group. Specific examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, allyl, or 1, 4-butadiene. Operation of the artThe term "aryl" refers to a monovalent 6-carbon monocyclic, 10-carbon bicyclic, or 14-carbon tricyclic aromatic ring system. Specific examples of the aryl group include, but are not limited to, phenyl, naphthyl, pyrenyl (pyrenyl), anthracenyl (anthryl), or phenanthrenyl (phenanthryl); and the aryl group is preferably phenyl. The term "heterocyclyl" refers to a 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic heteroaryl or heterocycloalkyl group having at least one heteroatom selected from the group consisting of O, S and N. Specific examples of heterocyclyl groups include, but are not limited to, pyridyl (pyridil), pyrimidyl (pyridiminyl), furyl (furyl), thiazolyl (thiazolyl), imidazolyl (imidazolyl), or thienyl (thienyl).
Other objects, advantages and novel features of the invention will become apparent from the following detailed description of the invention when considered in conjunction with the drawings.
Drawings
FIG. 1 is a graph showing the inhibition rate of cyclic peptide (III-3) as a function of concentration;
FIG. 2 is a graph showing the inhibition rate of cyclic peptide (III-1) as a function of concentration.
Detailed Description
The present invention has been described in an illustrative manner, and it is to be understood that the terminology which has been used is intended to be in the nature of words of description rather than of limitation. Many modifications and variations of the present invention are possible in light of the above teachings. It is, therefore, to be understood that within the scope of the appended claims, the invention may be practiced otherwise than as specifically described.
The cyclic peptide of a preferred embodiment of the present invention can be prepared by the following method.
[ Process I-1]
Figure BDA0002370238840000101
Fmoc-Gly-OH (5.866g, 20mmol, 1.0 eq.) was dissolved in acetonitrile (200mL) at room temperature under nitrogen, and catalyst ZrOCl was added2(5 mol%), 1-Ethyl- (3-dimethylaminopropyl) carbodiimide (N-ethyl-N' - (3-methylenediaminophenyl) -carbodiimide. HCl) (EDCI. HCl) (4.970g, 26mmol, 1.3 equivalents) and N-hydroxysuccinic acidImide (N-Hydroxysuccinimide (NHS) (2.53g, 22mmol, 1.1 equiv)) the reaction was monitored by TLC analysis. The reaction was stirred at room temperature for 4 hours until the starting Fmoc-Gly-OH was completely consumed and cooled to 0 ℃. H-Asp (O) dissolved in water (100mL) was injected at room temperature by syringe (syring)tBu) -OH (3.98g, 21mmol, 1.05 equiv.) and sodium bicarbonate (1.77g, 21mmol, 1.05 equiv.) were added to the above solution. The reaction mixture was stirred at room temperature for 16 hours. The solvent was evaporated and the remaining residue was acidified to pH 3.2-3.4 with dilute aqueous hydrochloric acid (0.1N) and a white solid precipitated from the aqueous solution. The white solid was filtered and washed with water, and the crude product was taken up in 60% aqueous ethanol to give Fmoc-Gly-Asp (O) as a white solidtBu) -OH (8.521g, 91% yield).1H NMR(500MHz，CDCl3)：δ7.74(d，2H，J＝7.6Hz)，7.56(d，2H，J＝5.0Hz)，7.36(d，3H，J＝7.5Hz)，7.28(d，2H，J＝7.4Hz)，5.83(s，1H)，4.83(q，1H，J＝4.5Hz)，4.34(q，2H，J＝6.5Hz)，4.18(t，2H，J＝6.5Hz)，4.02(d，1H，J＝16Hz)，3.88(d，1H，J＝16.6Hz)，2.94(dd，1H，J＝16.7，3.1Hz)，2.76(dd，1H，J＝16.8，4.2Hz)，1.38(s，9H)；HRMS(ESI)，C25H28N2NaO7([M+Na]Theoretical value of + t: 491.1794, actual value: 491.1797.
[ Process I-2]
Figure BDA0002370238840000111
Fmoc-pip (Boc) -OH (2.33g, 5mmol, 1.0 equiv.), H-Arg (mtr) -OMe (2.2g, 5.5mmol, 1.0 equiv.), catalyst ZrOCl were added to a dry microwave vial (microwave virtual) under argon2(5 mol%) and N, N, N ', N' -tetramethylchloroformamidine hexafluorophosphate (N, N, N ', N' -tetramethylchloroformamidinium hexafluorophosphate) (TCFH) (1.995g, 6mmol, 1.20 equiv.) were dissolved in anhydrous acetonitrile (2 mL/mmol). 1-methylimidazole (NMI) (0.837mL, 10.5mmol, 2.1 equiv.) was then added and the vial was sealed under an oil bath and heated to 70 deg.C for 12 hours (note: heating acetonitrile resulted in reaction)Overpressure). The reaction mixture was cooled to room temperature, diluted with water, saturated aqueous sodium bicarbonate solution, and extracted with ethyl acetate. The collected organic phases were combined and washed with brine, dried over sodium sulfate and concentrated. The crude product was purified by flash column chromatography under the specified conditions to give Fmoc-pip (Boc) -Arg (mtr) -OMe (3.648g, 86% yield) as a pale yellow solid.1H NMR(500MHz，CDCl3)：δ7.73(d，2H，J＝7.5Hz)，7.51(t，2H，J＝3.0Hz)，7.37(t，3H，J＝7.0Hz)，7.26-7.05(m，10H)，7.05(br，1H)，6.52(s，1H)，5.94(br，1H)，4.44-4.39(m，2H)，4.31(q，1H，J＝5.2Hz)，4.13(t，1H，J＝6.5Hz)，3.77(s，3H)，3.82-3.77(m，2H)，3.59(s，3H)，3.59(m，2H)，3.27-3.10(m，3H)，3.08-2.76(m，1H)，2.78-2.61(m，1H)，3.77(s，3h)，2.56(s，3H)，2.00-1.84(m，4H)，1.82(t，1H，J＝6.3Hz)，1.77-1.54(m，2H)，1.40(s，9H)；HRMS(ESI)，C43Hs6N6NaO10S([M+Na]Theoretical value of + t: 871.3676, actual value: 871.3672.
[ Process I-3]
Figure BDA0002370238840000121
Fmoc-pip (Boc) -Arg (mtr) -OMe (2.24g, 2.64mmol, 1.0 eq.) was dissolved in methanol solution (100mL) and stirred. 20 equivalents of piperidine were added and the reaction mixture was stirred until Fmoc-pip (boc) -arg (mtr) -OMe was completely consumed, confirmed by TLC (1h), and then the reaction mixture was evaporated to dryness under reduced pressure at room temperature. The piperidine adduct (piperidine adduct) of dibenzofulvene (dibenzofulvene) was washed with hexane. The resulting H-pip (Boc) -Arg (mtr) -OMe was dried in vacuo and used directly in the next step. Fmoc-D-Phe-OH (1.123g, 2.9mmol, 1.1 equiv.), H-pip (Boc) -Arg (mtr) -OMe (1.0 equiv.), catalyst ZrOCl were added to a dry microwave vial under argon2(5 mol%) and TCFH (1.02g, 3.17mmol, 1.2 equiv.) were dissolved in anhydrous acetonitrile (2 mL/mmol). 1-methylimidazole (NMI) (0.443mL, 5.55mmol, 2.1 equiv.) was then added and the vial was heated to 70 ℃ in a sealed oil bath for 12 hours (note that: heating acetonitrile will cause overpressure in the reactor). The reaction mixture was cooled to room temperature, diluted with water, saturated aqueous sodium bicarbonate solution, and extracted with ethyl acetate. The collected organic phases were combined and washed with brine, dried over sodium sulfate and concentrated. The crude product was purified by flash column chromatography under the specified conditions to give Fmoc-Phe-pip (Boc) -Arg (mtr) -OMe (1.865g, 71% yield (relative to the amount of Fmoc-pip (Boc) -Arg (mtr) -OMe)) as a pale yellow solid.1H NMR(500MHz，CDCl3)：δ7.75(d，2H，J＝7.0Hz)，7.56(t，2H，J＝7.5Hz)，7.39(t，3H，J＝7.4Hz)，7.30-7.17(m，10H)，6.51(s，1H)，6.05(br，1H)，4.46-4.42(m，2H)，4.42-4.23(m，2H)，4.20(t，1H，J＝6.7Hz)，3.88-3.78(m，2H)，3.80(s，3H)，3.66(s，3H)，3.38-3.34(m，1H)，3.19-2.97(m，3H)，32.92-2.76(m，2H)，2.75-2.61(m，2H)，2.67(s，3H)，2.57(s，3H)，2.11(s，3H)，，1.96-1.77(m，4H)，1.76-1.67(m，1H)，1.67-1.54(m，1H)，1.42(t，1H，J＝6.3Hz)，1.37(s，9H)；HRMS(ESI)，C52H65N7NaO11S([M+Na]Theoretical value of + t: 1018.4361, actual value: 1018.4356.
[ Process I-4]
Figure BDA0002370238840000141
Fmoc-D-Phe-pip (Boc) -Arg (mtr) -OMe (996mg, 1.0mmol, 1.0 equiv.) was dissolved in methanol solution (10mL) and stirred. 20 equivalents of piperidine were added and the reaction mixture was stirred to Fmoc-Gly-Asp (O)tBu) -D-Phe-pip (Boc) -Arg (mtr) -OMe was completely consumed, confirmed by TLC (1h), and the reaction mixture was evaporated to dryness at room temperature under reduced pressure. The piperidine adduct (piperidine adduct) of dibenzofulvene (dibenzofulvene) was washed with hexane. The resulting H-D-Phe-pip (Boc) -Arg (mtr) -OMe was dried in vacuo and used directly in the next step. Fmoc-Gly-Asp (O) was added to the dried microwave vialtBu) -OH (535mg, 1.1mmol, 1.1 equiv.), H-D-Phe-pip (Boc) -Arg (mtr) -OMe (1.0 equiv.), catalyst ZrOCl2(5 mol%) and 1-Hydroxy-7-azabenzotriazole (H)OAt) (1.2 eq)) was dissolved in anhydrous acetonitrile (2mL/mmol) and stirred for 10 minutes. 1-Ethyl- (3-dimethylaminopropyl) carbodiimide (EDCI. HCl) (229mg, 1.2mmol, 1.2 equiv.) was then added in four portions followed by N-methylmorpholine (N-methylmorpholine, NMM) (167. mu.L, 2.1mmol, 2.1 equiv.) and the reaction mixture was stirred at room temperature for 12 h. The reaction was diluted with ethyl acetate and washed with dilute sulfuric acid (0.1N), water, saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The collected organic phases were dried over sodium sulfate and concentrated. The crude product was purified by flash column chromatography under the specified conditions to give Fmoc-Gly-Asp (O) as a pale yellow solidtBu) -D-Phe-pip (Boc) -Arg (mtr) -OMe (1.016g, 83% yield (relative to Fmoc-D-Phe-pip (Boc) -Arg (mtr) -OMe)).1H NMR(500MHz，CDCl3)：δ7.74(d，2H，J＝7.0Hz)，7.55(t，2H，J＝7.5Hz)，7.37(t，3H，J＝7.5Hz)，7.30-7.17(m，10H)，6.52(s，1H)，6.05(br，1H)，4.61-4.41(m，2H)，4.41-4.21(m，2H)，4.21(t，1H，J＝6.7Hz)，3.91-3.72(m，2H)，3.82(s，3H)，3.67(s，3H)，3.39-3.32(m，1H)，3.33-3.21(m，2H)，3.18-2.98(m，3H)，2.73-2.86(m，2H)，2.82-2.67(m，2H)，2.66(s，3H)，2.56(s，3H)，2.25-2.03(m，2H)，2.11(s，3H)，1.84-1.82(m，4H)，1.74-1.61(m，3H)，1.42(s，9H)，1.37(s，9H)；HRMS(ESI)，C62H81N9NaO15S([M+Na]Theoretical value of + t: 1246.5471, actual value: 1246.5477.
[ Process I-5]
Figure BDA0002370238840000151
Taking Fmoc-Gly-Asp (O)tBu) -D-Phe-pip (Boc) -Arg (mtr) -OMe (568mg, 0.462mmol, 1.0 equiv) was dissolved in methanol (20 ml). Lithium hydroxide (12mg, 0.485mmol, 1.05 equiv.) was added and the mixture was stirred at 25 ℃ for 2.5 h. After evaporation, the residue was dissolved in water, acidified to pH 3 with dilute hydrochloric acid (0.1N) and extracted with ethyl acetate. The extract was dried over sodium sulfate, evaporated again and the Fmoc-Gly-Asp (O) obtainedtBu)-D-Phe-Pip(Boc)-Arg(Mtr) -OH was stirred with piperidine (15 equiv.) in methanol (10mL) at 25 ℃ for 1 hour. The mixture was evaporated and the piperidine adduct of dibenzofulvene was washed with diethyl ether and the resulting H-Gly-Asp (O)tBu) -D-Phe-pip (Boc) -Arg (mtr) -OH was dissolved in a mixture of dichloromethane (2mL) and acetonitrile (8mL) and cooled to 0 ℃. Adding catalyst ZrOCl into the solution at 0 ℃ in nitrogen atmosphere2(5 mol%), 1-hydroxy-7-azabenzotriazole (HOAt) (1.1 eq.) and 1-ethyl- (3-dimethylaminopropyl) carbodiimide (N-ethyl-N' - (3-dimethylamino propyl) -carbodiimide. HCl) (EDC. HCl) (102mg, 0.531mmol, 1.15 eq.) and stirred for 20 min. N-Methylmorpholine (107 μ L, 0.97mmol, 2.0 equiv.) was added slowly via syringe (syring) at 0 deg.C and the reaction was gradually raised to room temperature and stirred at room temperature for 16 h. The solvent was evaporated, the remaining residue was suspended in ethyl acetate (25mL) and the pH adjusted to 3.5-4.0 with hydrochloric acid (0.1N). The organic layer was separated, washed with water (10mL), saturated aqueous sodium bicarbonate (10mL), brine (10mL), and dried over sodium sulfate. After evaporation of the solvent, the residue remaining was purified by flash column chromatography on silica gel under the conditions specified to afford cyclo-Gly-Asp (O)tBu) -D-Phe-Pip (Boc) -Arg (mtr) (184mg, 41% yield (yield vs Fmoc-Gly-Asp (O)tBu) -D-Phe-pip (Boc) -Arg (mtr) -OMe).1H NMR(500MHz，CDCl3)：δ7.70(br，1H)，7.40-7.38(m，5H)，6.56(s，1H)，6.05(br，1H)，4.46-4.23(m，2H)，3.94-3.77(m，2H)，3.84(s，3H)，3.28-3.21(m，1H)，3.20-3.08(m，3H)，2.92-2.71(m，4H)，2.21-2.08(m，3H)，2.12(s，3H)，1.88-1.83(m，3H)，1.72-1.69(m，2H)，1.62-1.60(m，1H)，1.52-1.47(m，1H)，1.44(s，9H)，1.38(s，9H)，1.29-1.25(m，2H)；HRMS(ESI)，C46H67N9NaO12S([M+Na]Theoretical value of + t: 992.4527, actual value: 992.4521.
[ Process I-6]
Figure BDA0002370238840000161
The protected cyclic peptide cyclo-Gly-Asp (O) was treated with a solution (2mL) of trifluoroacetic acid (TFA) (80%), phenol (5%), water (2.5%), phenylmethyl sulfide (thioanisole) (5%), triisopropylsilane (trisisopropylbenzenesulfonane) (2.5%) and 1, 2-ethanedithiol (5%) at ambient temperaturetBu) -D-Phe-pip (Boc) -Arg (mtr) (120mg, 0.124 mmol). After 9 hours, the solvent was evaporated in vacuo. The residue was dissolved in hydrochloric acid (0.1M) and freeze-dried, and the operation was repeated 6 times. The resulting solid was precipitated with cold ether (5 mL. times.2), centrifuged, and the resulting particles were washed several times with cold ether to provide cyclo-Gly-Asp-D-Phe-Pip-Arg.2HCl (78mg, 94% yield relative to cyclo-Gly-Asp (O) as a pale yellow solidtBu) -D-Phe-pip (Boc) -Arg (mtr)).1H NMR(500MHz，D2O)：δ7.26-7.08(m，5H)，4.51(t，1H，J＝6.7Hz)，4.47-4.23(m，2H)，4.41-4.37(m，1H)，3.84-3.79(m，1H)，3.78-3.76(m，1H)，3.70-3.67(m，1H)，3.54-3.50(m，1H)，3.19-3.17(m，3H)，3.06-3.02(m，4H)，3.02-2.97(m，3H)，2.75-2.72(m，2H)，2.66-2.63(q，2H，J＝7.9Hz)，2.46-2.39(m，4H)，2.14-2.10(m，2H)，2.09-2.01(m，4H)，1.82-1.77(m，2H)，1.68-1.61(m，2H)，1.50-1.46(m，2H)，1.44-1.40(m，2H)，1.29-1.25(m，2H)；HRMS(ESI)，C27H43Cl2N9NaO7([M+Na+2H+]) Theoretical value: 698.25602, actual value: 698.2572.
the cyclic peptide of a preferred embodiment of the present invention can also be prepared by the following method.
[ Process II-1]
Figure BDA0002370238840000171
C5P-1(740mg, 0.76mmol, 1.0 equiv.) was dissolved in dichloromethane or tetrahydrofuran (3.5mL) and stirred, 10-15 equiv piperidine (8.4mmol) was added and the reaction mixture was stirred until C5P-1 was completely consumed and confirmed by TLC (0.5-1 h). The reaction mixture was then evaporated to dryness with toluene at 60 ℃ under reduced pressure. Washing piperidine adduct (piperididi) of dibenzofulvene (dibenzofulvene) with hexanene adduct), and the generated C5P-2 (LC-MS: t is tR5.2 min, 91% purity) was dried under vacuum and used directly in the next step. A dry microwave vial was charged with C5P-2(900mg, 1.2mmol, 1.0 equiv.), Fmoc-Asp (O) under argontBu) -OH (986mg, 2.4mmol, 2.0 equiv.), catalyst ZrOCl2(5 mol%), 1-Ethyl- (3-dimethylaminopropyl) carbodiimide (EDCI) (344mg, 1.8mmol, 1.5 equiv.) and hydroxybenzotriazole (HOBt) (278mg, 1.8mmol, 1.5 equiv.) were dissolved in anhydrous acetonitrile (6 mL). N, N-Diisopropylethylamine (N, N-Diisopropylethylamine) (DIPEA) (232mg, 1.8mmol, 1.5 equiv.) was then added, and the vial was sealed at 20-25 ℃ for reaction for 0.5 hour. The reaction mixture was diluted with water, saturated aqueous sodium bicarbonate solution, and extracted with ethyl acetate. The collected organic phases were combined and washed with brine, dried over sodium sulfate and concentrated. The crude product was purified by flash column chromatography under the specified conditions to give C5P-3 as a pale yellow solid (1.370g, conversion yield 72.2%; LC-MS: tR7.15 minutes).
[ Process II-2]
Figure BDA0002370238840000181
To a solution of ethyl acetate/methanol (25/25mL) were placed C5P-3(685mg, 0.6mmol, 1 equiv.) and Pd/C (10% wt, 70 mg). The hydrogenolysis reaction (hydrogenolysis) was carried out at ambient temperature for 18 hours. The reaction mixture was filtered and concentrated to give crude compound C5P-4(645mg, conversion yield 71.6%; LC-MS: t)R5.50 minutes). Crude acid (cride acid) C5P-4(645mg, 0.61mmol, 1.0 equiv.) obtained after debenzylation was reacted with glycine methyl ester hydrochloride (152mg, 1.22mmol, 2 equiv.) and ZrOCl catalyst in dry acetonitrile (6mL) under argon2(5 mol%), 1-Ethyl- (3-dimethylaminopropyl) carbodiimide (EDCI) (174mg, 0.91mmol, 1.5 equiv.) and hydroxybenzotriazole (HOBt-H)2O) (142mg, 0.91mmol, 1.5 equiv.). N, N-Diisopropylethylamine (DIPEA) (275mg, 2.13mmol, 3.5 equiv.) was then added and the reaction wasStirring for 2.5 hours at 20-25 ℃. The reaction mixture was diluted with water (4mL) and saturated aqueous sodium bicarbonate (4mL) and extracted with ethyl acetate. The collected organic phases were combined, washed with brine, dried over sodium sulfate and concentrated. The crude product was purified by flash column chromatography under the specified conditions to give C5P-5 as a pale yellow oil (417mg, conversion yield 97.53%; LC-MS: t)R6.56 minutes).
[ Process II-3]
Figure BDA0002370238840000191
CP5-5(834mg, 0.76mmol, 1.0 equiv.) was dissolved in dichloromethane or tetrahydrofuran (3.5mL) and stirred, 10-15 equiv of piperidine (8.14mmol) was added. The reaction mixture was stirred until C5P-5 was completely consumed and confirmed by TLC (0.5-1 h). The reaction mixture was then evaporated to dryness at ambient temperature under reduced pressure. The piperidine adduct (piperidine adduct) of dibenzofulvene (dibenzofulvene) was washed with hexane. The resulting C5P-6 (LC-MS: t)R5.06 min, 92.84% purity) was dried under vacuum and used directly in the next step. A dry reaction flask was charged with C5P-6(200mg, 0.22mmol, 1.0 equiv.), catalyst V (O) Cl2、Ti(O)(acac)2Or ZrOCl2(5-10 mol%) in anhydrous acetonitrile, cyclopentyl methyl ether (CPME) or toluene (1.6-2.2 mL). Followed by the addition of 1, 8-diazabicyclo [5.4.0 ]]Undec-7-ene (1, 8-Diazabicyclo (5.4.0) undec-7-ene) (DBU) (10mg, 0.066mmol, 0.3 equiv.) and the vial sealed for reaction at 80-110 deg.C for 7-23.5 hours. The reaction mixture was concentrated and diluted with water, saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The collected organic phases were combined, washed with brine, dried over sodium sulfate and concentrated. The crude product was purified by flash column chromatography under the specified conditions to give C5P-7 as a pale yellow solid (1.370g, conversion yield 7.55%; LC-MS: t)R4.98 minutes).
[ Process II-4]
Figure BDA0002370238840000192
C5P-7(300mg, 0.34mmol, 1 eq.) was dissolved in tetrahydrofuran (15mL) and stirred at ambient temperature for 18-19 h. The reaction mixture was concentrated to give crude compound C5P (. about.200 mg, conversion yield 94.4%; LC-MS: t)R2.03 minutes). Crude compound C5P was washed with isopropanol/isopropyl ether (IPA/IPE) (2/1) to afford pure compound C5P, and 1 equivalent of trifluoroacetic acid was added to preserve as trifluoroacetate.
Evaluation of aging resistance
Type I collagen is the major component of the skin dermis. Both the amount and quality of extracellular collagen are primarily associated with skin aging. Therefore, the present experiment examined the induction of Procollagen secretion and cytotoxicity by Hs68 human fibroblasts (human fibroblastits) using EIA kit for Procollagen Type I C-peptide (Procollagen Type IC-peptide (pip)), and the results are shown in table 1 below.
[ Table 11
Figure BDA0002370238840000201
a: the test was carried out using (III-5) in which Q is Cl
b: cell viability (%) - (sample/control group) x 100%
From the experimental results, it was found that each of the tested concentrations of cyclic peptide promotes the secretion of Procollagen Type I (Procollagen Type I) by cells, and when the concentration of cyclic peptide is 0.0008 μ M, the secretion of Procollagen Type I by cells is about 2.5 times higher, which is presumed to improve the problems associated with skin aging. In addition, the cell survival rate is maintained to be more than 80%, which shows that the cell has no toxicity.
NMP-1 inhibition assay
Matrix Metalloproteinase-1 (NMP-1) is one of the collagenases (collagenases) and is involved in the degradation of the extracellular Matrix (ECM). In more detail, exposure of fibroblasts (fibroplasts) to UV radiation results in overexpression of MMP-1, and thus the ECM is subsequently degraded by MMP-1.
To examine the effect of the cyclic peptides of the present invention, MMP-1 inhibition assays were therefore performed.
Matrix Metalloproteinases (MMPs) are involved in skin physiological functions such as wound healing, aging (aging) and inflammatory responses. MMPs play an important role in maintaining normal physiological functions or pathological phenomena of the skin. In addition, skin aging causes various effects on the skin, including wrinkles, dryness, skin laxity (anetoderma), inhibition of collagen production, and promotion of MMPs, thereby accelerating degradation of extracellular matrix (ECM). As a result of which the elasticity of the skin and the water-holding capacity of the skin are lost.
In this assay, a test compound is co-cultured with human fibroblasts (human fibroblasts), and then cytokine (cytokine) TNF-alpha (Tumor Necrosis Factor, Tumor Necrosis Factor-alpha) is added as an inducer to induce the cells to express MMP-1 in a large amount.
Materials and methods
Test compounds: the cyclic peptide (III-3) of the present invention, wherein Q is Cl
Cell lines: skin fibroblast (Skin fibroblast) Hs68
First, skin fibroblast Hs68 was seeded overnight in a petri dish and various concentrations (0.05. mu.M, 0.25. mu.M, 1.25. mu.M, 2.5. mu.M and 5. mu.M) of cyclic peptide (III-3) were added to the skin fibroblasts for 6 hours followed by incubation with TNF-. alpha. (20ng/mL) for 42 hours. Thereafter, the concentration of MMP-1 was measured for each group by ELISA, and the results are shown in Table 2.
[ Table 2]
Figure BDA0002370238840000211
c: group without TNF-alpha, cyclic peptide and Retinoic Acid (RA) as control group
d: RA is known MMP-1 inhibitor, and the group with RA added is used as positive control group
From the above results, it was found that 0.05. mu.M of the cyclic peptide (III-3) inhibited MMP-1 by about 60% and 0.25. mu.M of the cyclic peptide (III-3) inhibited MMP-1 by about 80% relative to 3.3mM of RA (taken as 100%); 1.25 μ M of cyclic peptide (III-3) inhibits almost 87% of MMP-1; 2.5 μ M of the cyclic peptide (III-3) inhibited almost 91% of MMP-1.
Furthermore, by detecting the inhibitory concentration of the cyclic peptide (III-3), the results shown in FIG. 1 were obtained, and the IC of the cyclic peptide (III-3) was calculated50It was 0.02. mu.M.
Similarly, the above MMP-1 inhibition experiments were conducted with different concentrations (0.05. mu.M, 0.25. mu.M, 1.25. mu.M, 2.5. mu.M and 5. mu.M) of cyclic peptide (III-1) (Q is Cl), and the results are shown in Table 3 below. As can be seen from Table 3, 0.05. mu.M of cyclic peptide (III-1) inhibited about 12% of MMP-1, and 0.25. mu.M of cyclic peptide (III-1) inhibited about 38% of MMP-1; whereas 1.25. mu.M of cyclic peptide (III-1) inhibited about 90% of MMP-1.
[ Table 3]
Figure BDA0002370238840000221
c: group without TNF-alpha, cyclic peptide and Retinoic Acid (RA) as control group
d: RA is known MMP-1 inhibitor, and the group with RA added is used as positive control group
Furthermore, by detecting the inhibitory concentration of the cyclic peptide (III-1), the results shown in FIG. 2 were obtained, and the IC of the cyclic peptide (III-1) was calculated50It was 0.7. mu.M.
Although the present invention has been described in terms of preferred embodiments, it is to be understood that other possible modifications or variations may be made without departing from the spirit and scope of the invention as hereinafter claimed.

Claims (30)

1. A method for preparing a cyclic peptide, comprising the steps of:
provided are compounds represented by the following formulas (I-1) and (I-2):
Figure FDA0002370238830000011
wherein R isa、RbAnd ReEach independently is a protecting group;
Rcand RdEach independently is alkyl, cycloalkyl, aryl or heteroaryl;
g is H or O-t-Bu; and
R1is composed of
Figure FDA0002370238830000012
Wherein R is2And R3Each independently is H or C1-6An alkyl group; x is O, S, CH2Or N-R4Wherein R is4Is H, C1-6Alkyl group, (CH)2CH2O)nH、-C(＝O)-C1-15Alkyl or C (═ O) (C)2H4)2C(＝O)O(C2H4O)nH, wherein n is 1-3;
carrying out a reaction between the compounds of the formulae (I-1) and (I-2) to obtain a compound represented by the following formula (I-3):
Figure FDA0002370238830000013
and
subjecting a compound of formula (I-3) to cyclization reaction with a catalyst of formula (II) and deprotection to obtain a compound represented by the following formula (III):
Figure FDA0002370238830000021
M(O)mL1 yL2 z (II)；
wherein G' is H or OH;
q is halogen, OC (O) CF3Or OC (O) CH3；
M is a metal selected from the group consisting of IVB, VB, VIB and actinide;
L1and L2Are each a ligand;
m and y are integers greater than or equal to 1; and
z is an integer greater than or equal to 0.
2. The method of claim 1, wherein L1Is selected from Cl, OTf, OTs, NTf2Halogen, RC (O) CH2C(O)R、OAc、OC(O)CF3OEt, O-iPr and butyl, wherein R is alkyl.
3. The method of claim 1, wherein L2Is selected from Cl, H2O、CH3OH、EtOH、THF、CH3CN and
Figure FDA0002370238830000022
the group consisting of.
4. The method of claim 1, wherein RaAnd ReIs fluorenyl methoxy carbonyl, and RbIs 2, 3, 6, -trimethyl-4-methoxy benzenesulfonyl.
5. The method of claim 1, wherein M is a group IVB transition element, M is 1 and y is 2.
6. The method of claim 1, wherein M is a group VB transition element, M is 1 and y is 2 or 3.
7. The process of claim 1, wherein M is a group VIB transition element, M is 1 and y is 4.
8. The process of claim 1, wherein M is a group VIB transition element, M is 2 and y is 2.
9. The method of claim 1, wherein M is selected from the actinide family, M is 2 and y is 2.
10. The process of claim 1, wherein the catalyst of formula (II) is MoO2Cl2、V(O)Cl2、V(O)(OAc)2、V(O)(O2CCF3)2、Ti(O)(acac)2、Zr(O)Cl2、Hf(O)Cl2、Nb(O)Cl2、MoO2(acac)2、V(O)(OTs)2、VO(OTf)2Or V (O) (NTf)2)2。
11. The method of claim 1, wherein z is 0.
12. The method of claim 1, wherein the compound of formula (III) is any one of the following formulae (III-1) to (III-5):
Figure FDA0002370238830000031
Figure FDA0002370238830000041
wherein R is5Is C1-15An alkyl group.
13. A method for preparing a cyclic peptide, comprising the steps of:
provided are compounds represented by the following formulas (I-1) and (I-4):
Figure FDA0002370238830000042
wherein R isa、RbAnd ReEach independently is a protecting group;
Rcand RdEach independently is alkyl, cycloalkyl, aryl or heteroaryl;
g is H or O-t-Bu; and
R1is composed of
Figure FDA0002370238830000051
Wherein R is2And R3Each independently is H or C1-6An alkyl group; x is O, S, CH2Or N-R4Wherein R is4Is H, C1-6Alkyl group, (CH)2CH2O)nH、-C(＝O)-C1-15Alkyl or C (═ O) (C)2H4)2C(＝O)O(C2H4O)nH, wherein n is 1-3;
carrying out a reaction between the compounds of the formulae (I-1) and (I-4) to obtain a compound represented by the following formula (I-5):
Figure FDA0002370238830000052
carrying out a reaction between the compound of the formula (I-5) and a compound represented by the following formula (I-6) to obtain a compound represented by the following formula (I-7):
Figure FDA0002370238830000053
wherein R isfIs alkyl, cycloalkyl, aryl or heteroaryl; and
subjecting a compound of formula (I-7) to cyclization reaction with a catalyst of formula (II) and deprotection to obtain a compound represented by the following formula (III):
Figure FDA0002370238830000061
M(O)mLl yL2 z (II)；
wherein G' is H or OH;
q is halogen, OC (O) CF3Or OC (O) CH3；
M is a metal selected from the group consisting of IVB, VB, VIB and actinide;
L1and L2Are each a ligand;
m and y are integers greater than or equal to 1; and
z is an integer greater than or equal to 0.
14. The method of claim 13, wherein L1Is selected from Cl, OTf, OTs, NTf2Halogen, RC (O) CH2C(O)R、OAc、OC(O)CF3OEt, O-iPr and butyl, wherein R is alkyl.
15. The method of claim 13, wherein L2Is selected from Cl, H2O、CH3OH、EtOH、THF、CH3CN and
Figure FDA0002370238830000062
the group consisting of.
16. The method of claim 13, wherein RaAnd ReIs fluorenyl methoxy carbonyl, and RbIs 2, 3, 6, -trimethyl-4-methoxy benzenesulfonyl.
17. The method of claim 13, wherein M is a group IVB transition element, M is 1 and y is 2.
18. The method of claim 13, wherein M is a group VB transition element, M is 1 and y is 2 or 3.
19. The method of claim 13, wherein M is a group VIB transition element, M is 1 and y is 4.
20. The method of claim 13, wherein M is a group VIB transition element, M is 2 and y is 2.
21. The method of claim 13, wherein M is selected from the actinide family, M is 2 and y is 2.
22. The process of claim 13, wherein the catalyst of formula (II) is MoO2Cl2、V(O)Cl2、V(O)(OAc)2、V(O)(O2CCF3)2、Ti(O)(acac)2、Zr(O)Cl2、Hf(O)Cl2、Nb(O)Cl2、MoO2(acac)2、V(O)(OTs)2、VO(OTf)2Or V (O) (NTf2)2。
23. The method of claim 13, wherein z is 0.
24. The method of claim 13, wherein the compound of formula (III) is any one of the following formulae (III-1) to (III-5):
Figure FDA0002370238830000071
Figure FDA0002370238830000081
wherein R is5Is C1-15An alkyl group.
25. A cyclic peptide represented by the following formula (III):
Figure FDA0002370238830000082
wherein G' is H or OH;
q is halogen, OC (O) CF3Or OC (O) CH3(ii) a And
R1is composed of
Figure FDA0002370238830000083
Wherein R is2And R3Each independently is H or C1-6An alkyl group; x is O, S, CH2Or N-R4Wherein R is4Is H, C1-6Alkyl group, (CH)2CH2O)nH、-C(＝O)-C1-15Alkyl or C (═ O) (C)2H4)2C(＝O)O(C2H4O)nH, wherein n is 1-3.
26. The cyclic peptide of claim 25, wherein X is O, CH2S or N-R4Wherein R is4Is H, C1-6Alkyl, -C (═ O) -C7-15Alkyl group, (CH)2CH2O)nH or C (═ O) (C)2H4)2C(＝O)O(C2H4O)nAnd H, wherein n is 1-3.
27. The cyclic peptide of claim 25, wherein R1Is composed of
Figure FDA0002370238830000091
Wherein R is2Is H or C1-6Alkyl radical, R3Is H or C1-6An alkyl group; and R4Is H, -C (═ O) -C7-15Alkyl or (CH)2CH2O)nH。
28. The cyclic peptide of claim 27, wherein R2Is H, and R3Is H.
29. The cyclic peptide of claim 27, wherein R4Is H or-C (═ O) -heptyl.
30. The cyclic peptide of claim 25, wherein the cyclic peptide is represented by any one of the following formulae (III-1) to (III-5):
Figure FDA0002370238830000092
Figure FDA0002370238830000101
wherein R is5Is C1-15An alkyl group.
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009124754A1 (en) * 2008-04-08 2009-10-15 Merck Patent Gmbh Compositions containing cyclic peptides and methods of use
CN108727468A (en) * 2017-04-17 2018-11-02 陈建添 Cyclic peptide, the medicine comprising it or cosmetic composition and preparation method thereof

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009124754A1 (en) * 2008-04-08 2009-10-15 Merck Patent Gmbh Compositions containing cyclic peptides and methods of use
CN108727468A (en) * 2017-04-17 2018-11-02 陈建添 Cyclic peptide, the medicine comprising it or cosmetic composition and preparation method thereof

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