Cyclic peptides, method for preparing and use as angiogenesis inhibitors or activators

Abstract

The invention relates to cyclopeptides, the method of their preparation and their utilization as inhibitors or activators of angiogenesis.

These cyclopeptides comprise contain the following peptide sequence:
-Arg-Ile-Lys-Pro-His-Gln-Gly-   (SEQ ID NO: 1).
They can be used in systems for inhibition of angiogenesis that comprises include a support (1), to which the cyclopeptide is affixed by means of coupled via an organic spacer arm (3) that may be provided with a moiety (4) capable of being spliced cleaved by an enzyme system.

Description

TECHNICAL FIELD

The object of the present invention is novel cyclopeptides and systems comprising them that enable control of angiogenesis.

Angiogenesis is a mechanism of neovascularization originating from a pre-existing capillary network. It is particularly important and indispensable in the course of many physiological processes such as embryonic development, implantation of the placenta, but also in different pathologies, in particular in tumor growth, development of metastases, ischemia, vascular diseases of the eye and chronic inflammatory diseases (see Ferrara et al, Nature Medicine, Vol. 5, N^o 12, December 1999, pp. 1361-1364 [1] and Hagedorn and Bikfalvi [2]). Angiogenesis is also essential in tissue regeneration and permanent colonization of the biomaterial implants such as bone replacements.

Angiogenesis is a multistage process that initially invokes migration, the attachment and adhesion of the endothelial cells and then their proliferation and organization into tubes, in order to form the vascular network necessary to the development of the tissues.

Among the factors regulating angiogenesis, vascular endothelial growth factor (VEGF) appears to be the most important ones.

VEGF exists in four isoforms: A, B, C and D and of these, isoform A, which comprises 165 amino acids, is a powerful regulator of tumor angiogenesis and appears to be involved in other pathologies such as diabetic retinopathy or chronic inflammatory diseases.

VEGF-A is produced by normal or transformed cells. Its expression can be induced by hypoxia, oncogene activation or activation by growth factors such as fibroblast growth factor PGF-2.

VEGF-A binds to different receptors, especially the kinase domain receptor KDR (VEGFR-2), which appears to be a very important effector in pathological angiogenesis. Also, inhibition of angiogenesis through the KDR receptor could constitute an interesting therapeutic approach.

The structure of VEGF-A which comprises 165 amino acids, was described at the end of 1997 and was accessible at the end of June 1998, as disclosed in the document (see Muller Y. A. in Structure, 1997, 5, pp. 1325-1338 [3]).

BACKGROUND ART

A certain number of strategies have been developed for the purpose of interfering with the function of the KDR receptor of VEGF. They include inhibition of VEGF

• • by humanized antibodies such as is described by Presta et al in Cancer Research, 57 1997, pp. 4593-4599 [4];
  • by anti-idiotype antibodies as is described by Ortéga et al in Am. J. Pathol., November 1997, 151(5), pp. 1215-1224 [5];
  • by inhibitors of the tyrosine kinase domain of the KDR receptor as is described by Piossek et al in The Journal of Biological Chemistry, Vol. 274,
    • • for the KDR receptor of VEGF.

    However, it does not provide any results on the possible inhibition of the KDR receptor by this

    In this peptide sequence, the presence of three amino acids Arg, Lys and His is essential for obtaining a desired interaction with the KDR receptor of the VEGF.

    In the invention, the Arg and Gly residues of the cyclopeptide are connected by a chain that can comprise one or a plurality of organic molecules chosen from the group comprising the natural and synthetic amino acids, or compounds comprising a COOH group and an NH₂ group possibly substituted. The amino acids can be in the L form or in the D form.

    The synthetic amino acids can be, for example, aromatic and/or heterocyclic compounds comprising a COOH group and an NH₂ group on a structure allowing a spatial conformation close to that of VEGF at the peptide sequence of interest

    which comprises two carboxylic functions capable of reacting with the hydroxy or amino functions of the side changes of the amino acids of the cyclopeptide.

    The organic compounds that can be used can also comprise aromatic parts and/or heteroatoms so as to maintain, on the one hand, the two cyclopeptides in an efficacious configuration and to allow, on the other hand, fixation of the two cyclopeptides in this configuration on different supports.

    The aromatic parts can be derivates of benzene, naphthalene, dibenzofurane.

    The heteroatoms can be oxygen. nitrogen, silicon, germanium, tin or phosphorous atoms.

    According to an advantageous disposition of the invention, the spacer arm can comprise in addition bioactive compounds that will also be released to the desired location at the time of cutting the spacer arm.

    Said bioactive compounds can be cytotoxic agents, anticancer agents or any other active principle, for example, that one would want to use at the level of the KDR receptors.

    According to the invention, the support on which the cyclopeptide(s) can be affixed can be an organic or inorganic solid. In particular, an organic polymer in solid form or in gel form could be used as the support.

    The polymer utilized is advantageously a biocompatible polymer, biodegradable or nonbiodegradable.

    By way of example of polymers that can be used, one can cite ethylene polyterephthalate, the copolymers of vinylidene fluoride and hexafluoropropylene, the polyvinyl alcohols, polyhydroxy ethyl methacrylate, polysaccharides and the copolymers obtained from monomers entering into the constitution of the aforesaid polymers.

    The cyclopeptides of the invention can be prepared by methods implementing an automatic synthesis step of a linear peptide on a solid phase by a conventional process, followed by coupling of the ends of the linear peptide either after having released the peptide from the solid phase or by then releasing it from the solid phase.

    Thus, according to a first embodiment, the process comprises:

    a) preparing a linear peptide by chemical synthesis on a solid phase;

    b) releasing the linear peptide from the solid phase, and

    c) coupling the ends of the linear peptide to form the cyclopeptide.

    According to a second embodiment, the process comprises:

    a) preparing a linear peptide by chemical synthesis on a solid phase;

    b) coupling the free end of the linear peptide with a terminal function of an amino acid residue of the linear peptide, and

    c) releasing the cyclopeptide from the solid phase.

    Further still, an object of the invention is a method for preparing a system comprising a support on which the cyclopeptide(s) is (are) affixed, which comprises subjecting an organic polymer support to irradiation by ionizing, plasma or photon beams on defined zones of the support and to then grafting onto said zones of the support an organic spacer arm on which the cyclopeptide will be attached.

    Generally, the radiation is done using a mask in order to define the zones to be modified on the support. The ionizing radiation used can be electron beams or accelerated heavy ion beams.

    In this process, the cyclopeptides can be affixed on the organic spacer arms prior to grafting. Their fixation can also be realized after grafting and in this instance, the process further includes a step for fixation of the cyclopeptides on the organic spacer arm after grafting of same.

    Other features and advantages of the invention will become more apparent when reading the following description exemplary embodiments given are understood to be illustrative and non-limiting—with reference to the attached figures.

    BRIEF DESCRIPTION OF THE DRAWINGS

    FIG. 1 represents the first embodiment of synthesis of a cyclopeptide according to the invention (schematic representation using the (Pmoc)

    The spacer arm is attached to the NH group of this compound, and it corresponds to the formula:
    CH₂═CH—CO—NH—(CH₂)₅—CO—P—CO  (Compound 2)

    wherein P represents the peptide that is a substrate of the metalloprotease of the extra-cellular matrix.

    The organic compound 1 is prepared in the following steps:

    Step N^o 1

    Condensation of Hexaethylene Glycol on Tertiobutyl Acrylate.

    For this step, the operational procedure described by O. Seitz, H. Kunz, J. Org. Chem., 62, 813 (1997) [12] is followed:

    ##STR00002##

    In a three-necked flask, the anhydrous THF is mixed with the hexaethylene glycol under nitrogen and while stirring. Then Na is added and allowed to dissolve. The tertiobutyl acrylate is then added. This is turned for 20 hours at room temperature. HCl is added in order to neutralize the solution. The THF is evaporated under reduced pressure, then the solution is flooded with saturated saline solution. The solution is then extracted three times using ethyl acetate. The entire organic phase is again flooded in saturated saline solution. The organic phase is collected and the ethyl acetate evaporated. The pure product (Compound 3) is recovered with a yield of 96%.

    Step N^o 2

    Functionalizing of the Other End of Compound 3 by Azidation.

    • • a) tosylation according to the operational procedure described by D. S. Wilbur et al., Bioconjugate Chem., 9, 813 (1998) [13]:

    ##STR00003##

    The pyridine and the starting Compound 3 are placed in a two-necked flask. The entirety is placed at 0° C. under N₂. Then the TsCl is added. After 15 hours of reaction, the solution is flooded in ice and extracted 3 times using CH₂Cl₂. The organic phase is washed with a solution of 2% acetic acid, then with water. The organic phase is then collected, dried over MgSO₄ and evaporated under reduced pressure. The product is purified by passage over a silica column (70/230) with 100% ethyl acetate used as the eluant. The product (Compound 4) is collected with a yield of 65%.

    • • b) Azidation according to the operational procedure described by K. D. Reynolds, Bioconjugate Chem., 10, 1021-31 (1999) [14]:

    ##STR00004##

    The Compound 4 with some DMF is placed in a two-necked flask under N₂, then NaN₃ is added. It is turned for 20 hours; the solution becomes opaque. The solution is passed over a frit, then the DMF is coevaporated with toluene. A white precipitate is obtained that is diluted with ether. The solution is again passed over the frit and the ether is evaporated.

    Thus Compound 5 is obtained with a yield of 95%.

    Step N^o 3

    Functionalizing of the Other End of Compound 3 by Allylation.

    ##STR00005##

    Allylaton is performed by nucleophilic substitution of commercial allyl bromide by the sodium salt of hexaethylene glycol. The derivative obtained is

    ##STR00006##

    then isolated by chromatography over a silica column with a yield of 50%.

    Synthesis is done in THF.

    Step N^o 4

    Hydroboration.

    This is done according to the method described by Carboni et al, J. Org. Chem., 1993, 58, 3736-3741 [15] by reacting Compound 5 with Compound 6 to which dichloroborane has been added. Compound 7 is obtained.
    tBuOOCCH₂CH₂O(CH₂CH₂)₅CH₂ CH₂CH₂HN(CH₂CH₂O)₅CH₂CH₂—COOtBu  (compound 7)
    Step N^o 5
    Protection of the Nitrogen.

    Compound 7 is treated with FmocOSu according to the method used by Chetyrkina et al., Tetrahedron Letters 2000, 41, 1923-1926 [16], for example.

    Compound 8 is obtained.

    ##STR00007##
    Step N^o 6
    Deprotection of the Tertiobutyloxy Carbonyle Groups.

    Compound 8, to which the anisol has been added, is placed in a two-necked flask and then the TFA. The reaction is allowed to turn for 1 h 30 minutes at 25° C., then the TFA is evaporated under reduced pressure. The crude is then passed over a silica column (70/230) using 95/5 CH₂Cl₂/MeOH, then 90/10 CH₂Cl₂/MeOH as the eluent. Pure compound 9 is then collected with a yield of 65%.

    ##STR00008##

    The P23 cyclopeptides are attached to the two functional groups (COOH) of Compound 9 by proceeding in the following manner.

    The Compound 9 is placed in solution in some THF and then activated by means of N,N-dimethylpropyl, ethyl carbodiimide.

    Then a quantity corresponding to the molar equivalent of each cyclopeptide is added and the mixture is left for a period of 12 hours at room temperature, then lyophilized. The lyophilysate is collected using chloroform, the urea is eliminated that is formed by filtration and the filtrate is evaporated under reduced pressure.

    The product obtained is identified by infrared spectrometry using Fourier transformation, RMN of the proton and mass spectrometry. It corresponds to the desired product.

    In order to assure fixation of this product on a support, at the very beginning a spacer arm is attached to the NH group, said spacer aim comprising a polymerizable function. One then proceeds as follows

    Deprotection of the NH Group.

    Firstly deprotection of the NH group of compound 9 is carried out by treatment with piperidine.

    Besides, the spacer arm is being prepared by carrying out the following reaction:

    ##STR00009##

    The salt and the water are placed in a three-necked flask, then the H₂N (CH₂)₅—COOH amino acid; the entire mixture is cooled to 0° C. While agitating briskly, the acrylic acid chloride is added at a rate of around 3 mL per minute.

    It is allowed to turn for 10 minutes at room temperature, then the solution is passed over a frit. The flask is brought again to 0° C. under brisk agitation. Then the concentrated HCl is added to obtain a pH=2. This provokes precipitation of the product. The mixture is then filtered and the dried product (Compound 10) is pure.

    The yield is 75%.

    Condensation of Compound 10

    Compound 10 is condensed over the peptide P which is the substrate of the metalloproteases of the extra-cellular matrix at the time of the last step of its synthesis on solid phase, then the entirety is freed from the resin without deprotection of the side chains.

    The molecule obtained is then condensed using dicyclohexyl carbodiimide over the deprotected Compound 9. Then the side chains of the peptide of the spacer arm are deprotected, then the arm is attached onto the polymer support with the aid of the acrylic functions of the arm.

    An industrial film made of ethylene polyterephthalate with a 25 μm thickness is used as the support and it is previously extracted using the Soxhlet using reflux toluene at a temperature of 110° C. over a period of 12 hours, in order to eliminate any trace of organic monomer.

    A nickel or copper metallic grid having a thickness of approximately 50 μm is then placed on the polymer film, said grid is pierced with circular holes having a diameter of from 5 to 10 μm regularly distributed over its entire surface with an interval of approximately 100 μm. The grid has been manufactured by electroforming in order to have perfect reproducibility and a very high precision of the order of a micrometer.

    Then the polymer film is then subjected to irradiation by means of electron beam for irradiation only the zones corresponding to the holes of the grid. The electron beam has the following characteristics:

    energy Ep=2.5 MeV

    maximal intensity Imax=1 μA

    maximal dose=500 kGy.

    Irradiation is done in an oxygen-containing atmosphere.

    After irradiation, the grid is removed from the polymer film and the irradiated polymer film is placed in contact with the organic compound, on which the two cyclopeptides are attached for grafting this compound with the aid of the spacer arm onto the polymer film. This fixation is done by placing the film in contact with a 10⁻² M solution of the organic compound previously obtained by working at 40° C.

    Thus, the organic compound is grafted by the acrylic functions of the spacer arm onto the irradiated zones of the polymer film.

    The final product is characterized by FT-IR and spectrometry and XPS.

    EXAMPLE 2

    Production of a System Comprising Two Cyclopeptides.

    In this example, the same operational procedure is followed as previously used in the above example for coupling the two P23 cyclopeptides on two functions of the organic compound described.

    In order to perform this coupling, the organic compound is put into solution in some chloroform and activated using dicyclohexyl carbodiimide DCCl DCCI, then a quantity is added corresponding to 1 molar equivalent of each cyclopeptide and the reaction environment is maintained at 4° C. over a period of 12 hours. The precipitate of dicyclohexylurea is removed by filtration, then the filtrate is evaporated under reduced pressure.

    The product obtained is characterized by infrared spectrometry using Fourier transformation, proton RMN and mass spectrometry, as previously done.

    The a spacer arm is attached to the NH group of the organic compound as in Example 1.

    The assembly is then attached to a support comprised of an 25 μm thick industrial film made of poly (vinylidene fluoride/hexafluoropropylene) PVDF/HFP. The film is previously subjected to extraction on the Soxhlet in some reflux dichloromethane at a temperature of 40° C. for 12 hours in order to eliminate any trace of organic monomer.

    The film is then subjected to irradiation under air by accelerated heavy ions. The ions used are oxygen ions haven a primary energy Ep of around 10 MeV/uma at fluences of between 10⁷ and 10⁹ ions/cm² and at intensities of the order of 10² to 5×10² nA. Operation at low fluence was chosen in such a way that there was no recovery of latent traces.

    This operation is determined directly by the irradiation parameters (atomic number of the ion, primary energy, fluence). In this case, the random distribution of the active centers in the disturbed zone created at the time of irradiation (emergence of latent traces) allows radiografting by means of two organic spacer arms each carrying a cyclopeptide by blocking the distance between the anchoring points in such a way that the distance d between two cyclopeptides favors dimerization of the VEGF receptors.

    The irradiated zones are used for grafting organic spacer arms carrying the cyclopeptides obtained as described above, by reaction of their acrylic type function with the irradiated support, by virtue of free radicals created along the latent trace of the ion and the emergence of same at the surface of the polymer film.

    This coupling is done by heating the irradiated film, placed in the presence of a 10⁻³ M solution of the organic arms carrying the cyclopeptides, to 40° C. in tetrahydrofurane.

    The final compound is characterized using FT-IR spectrometry and XPS.

    CITED DOCUMENTS

    • [1]: Ferrara el al, Nature Medicine, vol. 5, n^o12, Décembre 1999, pages. 1361-1364.
    • [2]: Hagedorn et Bikfalvi, Critical Reviews in Oncology/Hematology, 34, 2000, pages 89-110.
    • [3]: Muller Y. A., Structure, 1997, 5, n^o10, pages 1325-1338.
    • [4]: Presla et al, Cancer Research, 57 1997, pages 4593-4599.
    • [5]: Ortega et al, Am. J. Pathol. November 1997, 11 (5), pages 1215-1224.
    • [6]: Piossck et al, The Journal of Biological Chemistry, vol. 274, n^o, 1999, pages 5612-5619.
    • [7]: Fairbrother et al, Biochemisty 37, 1998, pages 17754-17764.
    • [8]: U.S. Pat. No. 5,939,383
    • [9]: Bekele et al, J. Org. Chem. 62, 1997, pages 2259-2262.
    • [10]: Binétruy-Tournaire et al, EMBO Journal, 19, (7), 2000, pages 1525-1533.
    • [11]: Jonca et al, J. Biol. Chem., 1997, 272, pages 24203.
    • [12]: O. Seitz, H. Kunz, J. Org. Chem., 62, 813 (1997).
    • [13]: Wilbur et al, Bioconjugate Chem., 9, 813 (1998).
    • [14]: J. K. D. Reynolds, Bioconjugate Chem., 10, 1021-31 (1999).
    • [15]: Carboni et al, J. Org. Chem., 1993, 58, pages 3736-3741.
    • [16]: Chetyrkina et al, Tetrahedron Letters, 2000, 41, pages 1 923-1 926.
    • [17]: Sato et Rifkin (J. Cell Biol., September, 1988, (107 (3): 1199-205).

    TABLE 1
    SEQ ID	P1	H-Arg-Ile-Lys-Pro-His-OH
    NO: 14
    SEQ ID	P2	H-Gln-Ile-Met-Arg-Ile-Lys-Pro-His-OH
    NO: 15
    SEQ ID	P3	H-Arg-Ile-Lys-Pro-His-Gln-Gly-OH
    NO: 16
    SEQ ID	P4	H-Gln-Ile-Met-Arg-Ile-Lys-Pro-His-
    NO: 17		Gln-Gly-Gln-His-Ile-Gly-Glu-OH
    SEQ ID	P5	H-Gln-Ile-Met-Arg-Ile-Lys-Pro-His-
    NO: 18		Gln-Gly-Gln-His-Ile-Gly-OH
    SEQ ID	P6	H-Gly-Arg-Ile-Lys-DPro-His-Gln-Gly-
    NO: 19		Gln-His-OH
    SEQ ID	P7	cyclo(Gly-Arg-Ile-Lys-DPro-His-Gln-
    NO: 2		Gly-Gln-His)
    SEQ ID	P8	cyclo(Gly-Arg-Ile-Lys-Pro-His-Gln-Gly-
    NO: 3		His)
    SEQ ID	P9	cyclo(Pro-Arg-Ile-Lys-Pro-His-Gln-Gly-
    NO: 4		Gln-His)
    SEQ ID	P10	H-Gln-Ile-Met-Arg-Ile-Lys-Pro-His-Gln-
    NO: 20		Gly-Gln-His-Ile-Gly-Glu-Oallyle
    SEQ ID	P11	cyclo(DPhe-Pro-Gln-Ile-Met-Arg-Ile-
    NO: 5		Lys-Pro-His-Gln-Gly-Gln-His-Ile-Gly-
    		Glu)
    SEQ ID	P12	cyclo(Gly-Gln-Ile-Met-Arg-Ile-Lys-Pro-
    NO: 6		His-Gln-Gly-Gln-His-Ile-Gly-Glu)
    SEQ ID	P13	cyclo(Pro-Gln-Ile-Met-Arg-Ile-Lys-Pro-
    NO: 7		His-Gln-Gly-Gln-His-Ile-Gly-Glu)
    SEQ ID	P14	H-Pro-Gln-Ile-Met-Arg-Ile-Lys-Pro-His-
    NO: 21		Gln-Gly-Gln-His-Ile-Gly-Glu-OH
    SEQ ID	P15	H-Gly-Gln-Ile-Met-Arg-Ile-Lys-Pro-His-
    NO: 22		Gln-Gly-Gln-His-Ile-Gly-Glu-OH
    SEQ ID	P16	cyclo(Arg-Ile-Lys-Pro-His-Gln-Gly)
    NO: 8
    SEQ ID	P17	cyclo(Pro-Arg-Ile-Lys-Pro-His-Gln-Gly)
    NO: 9
    SEQ ID	P18	cyclo(DPhe-Arg-Ile-Lys-Pro-His-Gln)
    NO: 23
    SEQ ID	P19	cyclo(Gln-Ile-Met-Arg-Ile-Lys-Pro-His-
    NO: 10		Gln-Gly-Gln-His-Ile-Gly-Glu)
    SEQ ID	P20	cyclo(DPhe-Pro-Gln-Ile-Met-Arg-Ile-
    NO: 11		Lys-Pro-His-Gln-Gly-Gln-His-Ile-Gly)
    SEQ ID	P21	cyclo(DPhe-Pro-Ile-Met-Arg-Ile-Lys-
    NO: 12		Pro-His-Gln-Gly-Gln-His-Ile)
    SEQ ID	P22	cyclo(Glu-Gln-Ile-Met-Arg-Ile-Lys-Pro-
    NO: 24		His-Gln)
    SEQ ID	P23	cyclo(DTyr-Pro-Arg-Ile-Lys-Pro-His-
    NO: 13		Gln)
    SEQ ID	P24	cyclo(Gly-Arg-Ile-Lys-Pro-His)
    NO: 25

    TABLE 2
    				Molecular
    				weight
    		Number		calculée
    	VEGF165	of amino	Synthesis	calcu-	trouvée	IC50
    Peptide	amino acid sequence	acids	Method	lated	found	(μM)
    P1	82-86	5		649.8	650.3	>300.0
    P2	79-86	8		1022.3	1022.1	>300.0
    P3	82-88	7		835.0	836.6	>300.0
    P4	79-93	15		1772.1	1773.3	>300.0
    P5	79-92	14		1642.9	1644.1	>300.0
    P6	Gly81-82-90-DPro85	10		1157.3	1158.4	>300.0
    P7	(Gly81-82-90)DPro85	10	A	1139.3	1139.9	>300.0
    P8	(Gly81-82-88-His89)	9	A	1011.2	1012.0	200.0
    P9	(Pro81-82-90)	10	A	1179.6	1180.6	300.0
    P10	79-93-Oallyle	15		1821.1	1813.1	>300.0
    P11	(DPhe77-Pro78-79-93)	17	A	1998.3	1998.7	2.0
    P12	(Gly78-79-93)	16	A, B	1811.1	1813.1	300.0
    P13	(Pro78-79-93)	16	A, B	1851.2	1851.4	>300.0
    P14	Pro78-79-93	16		1869.2	1869.0	>300.0
    P15	Gly78-79-93	16		1829.1	1828.5	>300.0
    P16	(82-88)	7	A	817.0	817.9	32.0
    P17	(Pro81-82-88)	8	A	914.1	915.6	10.0
    P18	(DPhe81-82-87)	7	A	1004.2	1004.7	>300.0
    P19	(79-93)	15	B	1754.0	1755.0	5.0
    P20	(DPhe77-Pro78-79-92)	16	B	1869.2	1869.7	10.0
    P21	(DPhe78-Pro79-80-91)	14	B	1684.0	1685.4	200.0
    P22	(Glu78-79-87)	10	B	1261.5	1262.7	>300.0
    P23	(DTyr80-Pro81-82-87)	8	A	1020.2	1021.7	8.0
    P24	(Gly81-82-86)	6	A	688.8	689.9	8.0

Claims

1. A cyclopeptide chosen from among the following compounds:

2. A pharmaceutical composition for inhibiting angiogenesis comprising a cyclopeptide chosen among the following cyclopeptides:

3. A pharmaceutical composition for activating angiogenesis comprising two identical or different cyclopeptides, coupled with to a pharmaceutically acceptable organic compound, the cyclopeptides being chosen from among the following cyclopeptides:

4. The A system comprising a cyclopeptide according to claim 1, covalently bound to an organic spacer arm.

5. The system according to claim 4, wherein the organic spacer arm is covalently bound to a support.

6. A system comprising two cyclopeptides according to 1 covalently bound to an organic compound.

7. The system according to claim 6, wherein the distance between the two cyclopeptides is such that, when the system is brought into contact with cells expressing vascular endothelium growth factor (VEGF) receptors, it allows dimerization of said receptors.

8. The system according to claim 6, wherein the organic compound is covalently bound to a support with the aid of via an organic spacer arm.

9. The system according to claim 7, wherein the organic compound is covalently bound to a support with the aid of via an organic spacer arm.

10. A system comprising a solid support upon where upon and one or more cyclopeptides according to claim 1, wherein each of the one or more cyclopeptides are attached by covalent bonding, each of said cyclopeptides being bound to the support by via an organic spacer arm, and wherein the support is in solid form or gel form.

11. The system according to claim 4, wherein the organic spacer arm comprises a hydrocarbon, a fluorocarbon, a polyether, a polyethylene glycol, a polyamine, a polyamide, a polyester, a polysiloxane chain or a combination of these that thereof, and wherein the organic spacer arm is functionalized at each end on one end for forming a covalent bond on the one hand with the cyclopeptide and on the other hand is functionalized on another end for forming a covalent bond with the support.

12. The system according to claim 5, wherein the organic spacer arm comprises a hydrocarbon, a fluorocarbon, a polyether, a polyethylene glycol, a polyamine, a polyamide, a polyester, a polysiloxane chain or a combination of these that thereof, and wherein the organic spacer arm is functionalized at each on one end for forming a covalent bond on the one hand with the cyclopeptide and on the other hand is functionalized on another end for forming a covalent bond with the support.

13. The system according to claim 6, wherein the organic spacer arm comprises a hydrocarbon, a fluorocarbon, a polyether, a polyethylene glycol, a polyamine, a polyamide, a polyester, a polysiloxane chain or a combination of these that thereof, and wherein the organic spacer arm is functionalized at each on one end for forming a covalent bond on the one hand with the cyclopeptide and on the other hand is functionalized on another end for forming a covalent bond with the support.

14. The system according to claim 7, wherein the organic spacer arm comprises a hydrocarbon, a fluorocarbon, a polyether, a polyethylene glycol, a polyamine, a polyamide, a polyester, a polysiloxane chain or a combination of these that thereof, and wherein the organic spacer arm is functionalized at each on one end for forming a covalent bond on the one hand with the cyclopeptide and on the other hand is functionalized on another end for forming a covalent bond with the support.

15. The system according to claim 8, wherein the organic spacer arm comprises a hydrocarbon, a fluorocarbon, a polyether, a polyethylene glycol, a polyamine, a polyamide, a polyester, a polysiloxane chain or a combination of these that thereof, and wherein the organic spacer arm is functionalized at each on one end for forming a covalent bond on the one hand with the cyclopeptide and on the other hand is functionalized on another end for forming a covalent bond with the support.

16. The system according to claim 9, wherein the organic spacer arm comprises a hydrocarbon, a fluorocarbon, a polyether, a polyethylene glycol, a polyamine, a polyamide, a polyester, a polysiloxane chain or a combination of these that thereof, and wherein the organic spacer arm is functionalized at each on one end for forming a covalent bond on the one hand with the cyclopeptide and on the other hand is functionalized on another end for forming a covalent bond with the support.

17. The system according to claim 10, wherein the organic spacer arm comprises a hydrocarbon, a fluorocarbon, a polyether, a polyethylene glycol, a polyamine, a polyamide, a polyester, a polysiloxane chain or a combination of these that thereof, and wherein the organic spacer arm is functionalized at each on one end for forming a covalent bond on the one hand with the cyclopeptide and on the other hand is functionalized on another end for forming a covalent bond with the support.

18. The system according to claim 4, wherein the organic spacer arm further comprises a moiety capable of being cut cleaved by an enzymatic system.

19. The system according to claim 5, wherein the organic spacer arm further comprises a moiety capable of being cut cleaved by an enzymatic system.

20. The system according to claim 6, wherein the organic spacer arm further comprises a moiety capable of being cut cleaved by an enzymatic system.

21. The system according to claim 7, wherein the organic spacer arm further comprises a moiety capable of being cut cleaved by an enzymatic system.

22. The system according to claim 8, wherein the organic spacer arm further comprises a moiety capable of being cut cleaved by an enzymatic system.

23. The system according to claim 9, wherein the organic spacer arm further comprises a moiety capable of being cut cleaved by an enzymatic system.

24. The system according to claim 10, wherein the organic spacer arm further comprises a moiety capable of being cut cleaved by an enzymatic system.

25. The system according to claim 11, wherein the organic spacer arm further comprises a moiety capable of being cut cleaved by an enzymatic system.

26. The system according to claim 12, wherein the organic spacer arm further comprises a moiety capable of being cut cleaved by an enzymatic system.

27. The system according to claim 13, wherein the organic spacer arm further comprises a moiety capable of being cut cleaved by an enzymatic system.

28. The system according to claim 14, wherein the organic spacer arm further comprises a moiety capable of being cut cleaved by an enzymatic system.

29. The system according to claim 15, wherein the organic spacer arm further comprises a moiety capable of being cut cleaved by an enzymatic system.

30. The system according to claim 16, wherein the organic spacer arm further comprises a moiety capable of being cut cleaved by an enzymatic system.

31. The system according to claim 17, wherein the organic spacer arm further comprises a moiety capable of being cut cleaved by an enzymatic system.

32. The system according to claim 11, wherein the organic spacer arm further comprises a bioactive compound.

33. The system according to claim 12, wherein the organic spacer arm further comprises a bioactive compound.

34. The system according to claim 13, wherein the organic spacer arm further comprises a bioactive compound.

35. The system according to claim 14, wherein the organic spacer arm further comprises a bioactive compound.

36. The system according to claim 15, wherein the organic spacer arm further comprises a bioactive compound.

37. The system according to claim 16, wherein the organic spacer arm further comprises a bioactive compound.

38. The system according to claim 17, wherein the organic spacer arm further comprises a bioactive compound.

39. The system according to claim 18, wherein the organic spacer arm further comprises a bioactive compound.

40. The system according to claim 19, wherein the organic spacer arm further comprises a bioactive compound.

41. The system according to claim 20, wherein the organic spacer arm further comprises a bioactive compound.

42. The system according to claim 21, wherein the organic spacer arm further comprises a bioactive compound.

43. The system according to claim 22, wherein the organic spacer arm further comprises a bioactive compound.

44. The system according to claim 23, wherein the organic spacer arm further comprises a bioactive compound.

45. The system according to claim 24, wherein the organic spacer arm further comprises a bioactive compound.

46. The system according to claim 25, wherein the organic spacer arm further comprises a bioactive compound.

47. The system according to claim 26, wherein the organic spacer arm further comprises a bioactive compound.

48. The system according to claim 27, wherein the organic spacer arm further comprises a bioactive compound.

49. The system according to claim 28, wherein the organic spacer arm further comprises a bioactive compound.

50. The system according to claim 29, wherein the organic spacer arm further comprises a bioactive compound.

51. The system according to claim 30, wherein the organic spacer arm further comprises a bioactive compound.

52. The system according to claim 31, wherein the organic spacer arm further comprises a bioactive compound.

53. The system according to claim 5, wherein the support is an organic or an inorganic solid.

54. The system according to claim 8, wherein the support is an organic or an inorganic solid.

55. The system according to claim 9, wherein the support is an organic or an inorganic solid.

56. The system according to claim 10, wherein the support is an organic or an inorganic solid.

57. The system according to claim 5, wherein the support is an organic polymer in solid form or gel form.

58. The system according to claim 8, wherein the support is an organic polymer in solid form or gel form.

59. The system according to claim 9, wherein the support is an organic polymer in solid form or gel form.

60. The system according to claim 10, wherein the support is an organic polymer in solid form or gel form.

61. The system according to claim 57, wherein the organic polymer is a biocompatible, biodegradable polymer or a non biocompatible, non biodegradable non-biodegradable polymer.

62. The system according to claim 58, wherein the organic polymer is a biocompatible, biodegradable polymer or a non biocompatible, non biodegradable non-biodegradable polymer.

63. The system according to claim 59, wherein the organic polymer is a biocompatible, biodegradable polymer or a non biocompatible, non biodegradable non-biodegradable polymer.

64. The system according to claim 60, wherein the organic polymer is a biocompatible, biodegradable polymer or a non biocompatible, non biodegradable non-biodegradable polymer.

65. The system according to claim 61, wherein the organic polymer is chosen from among ethylene polyterephthalate, the copolymers of vinylidene fluoride, and hexafluoro propylene, the polyvinyl alcohols, the polyhydroxyethyl methacrylates, the polysaccharides and their copolymers.

66. The system according to claim 62, wherein the organic polymer is chosen from among ethylene polyterephthalate, the copolymers of vinylidene fluoride, and hexafluoro propylene, the polyvinyl alcohols, the polyhydroxyethyl methacrylates, the polysaccharides and their copolymers.

67. The system according to claim 63, wherein the organic polymer is chosen from among ethylene polyterephthalate, the copolymers of vinylidene fluoride, and hexafluoro propylene, the polyvinyl alcohols, the polyhydroxyethyl methacrylates, the polysaccharides and their copolymers.

68. The system according to claim 64, wherein the organic polymer is chosen from among ethylene polyterephthalate, the copolymers of vinylidene fluoride, and hexafluoro propylene, the polyvinyl alcohols, the polyhydroxyethyl methacrylates, the polysaccharides and their copolymers.

69. The system for activating angiogenesis according to claim 6, wherein the cyclopeptide is chosen from among the following cyclopeptides:

70. The system for activating angiogenesis according to claim 7, wherein the cyclopeptide is chosen from among the following cyclopeptides:

71. The system for activating angiogenesis according to claim 8, wherein the cyclopeptide is chosen from among the following cyclopeptides:

72. The system for activating angiogenesis according to claim 9, wherein the cyclopeptide is chosen from among the following cyclopeptides:

73. The method of preparing a system according to claim 57, which consists in subjecting a support made of organic polymer to irradiation by means of ionizing radiations, plasma, or photons onto defined zones of the support and then grafting the organic spacer arms onto said zones of the support.

74. The method of preparing a system according to claim 58, which consists in subjecting a support made of organic polymer to irradiation by means of ionizing radiations, plasma, or photons onto defined zones of the support and then grafting the organic spacer arms onto said zones of the support.

75. The method of preparing a system according to claim 59, which consists in subjecting a support made of organic polymer to irradiation by means of ionizing radiations, plasma, or photons onto defined zones of the support and then grafting the organic spacer arms onto said zones of the support.

76. The method of preparing a system according to claim 60, which consists in subjecting a support made of organic polymer to irradiation by means of ionizing radiations, plasma, or photons onto defined zones of the support and then grafting the organic spacer arms onto said zones of the support.

77. The method of preparing a system according to claim 61, which consists in subjecting a support made of organic polymer to irradiation by means of ionizing radiations, plasma, or photons onto defined zones of the support and then grafting the organic spacer arms onto said zones of the support.

78. The method of preparing a system according to claim 62, which consists in subjecting a support made of organic polymer to irradiation by means of ionizing radiations, plasma, or photons onto defined zones of the support and then grafting the organic spacer arms onto said zones of the support.

79. The method of preparing a system according to claim 63, which consists in subjecting a support made of organic polymer to irradiation by means of ionizing radiations, plasma, or photons onto defined zones of the support and then grafting the organic spacer arms onto said zones of the support.

80. The method of preparing a system according to claim 64, which consists in subjecting a support made of organic polymer to irradiation by means of ionizing radiations, plasma, or photons onto defined zones of the support and then grafting the organic spacer arms onto said zones of the support.

81. The method of preparing a system according to claim 65, which consists in subjecting a support made of organic polymer to irradiation by means of ionizing radiations, plasma, or photons onto defined zones of the support and then grafting the organic spacer arms onto said zones of the support.

82. The method of preparing a system according to claim 66, which consists in subjecting a support made of organic polymer to irradiation by means of ionizing radiations, plasma, or photons onto defined zones of the support and then grafting the organic spacer arms onto said zones of the support.

83. The method of preparing a system according to claim 67, which consists in subjecting a support made of organic polymer to irradiation by means of ionizing radiations, plasma, or photons onto defined zones of the support and then grafting the organic spacer arms onto said zones of the support.

84. The method of preparing a system according to claim 68, which consists in subjecting a support made of organic polymer to irradiation by means of ionizing radiations, plasma, or photons onto defined zones of the support and then grafting the organic spacer arms onto said zones of the support.

85. The method according to claim 73, wherein the irradiation is carried out through a mask.

86. The method according to claim 74, wherein the irradiation is carried out through a mask.

87. The method according to claim 75, wherein the irradiation is carried out through a mask.

88. The method according to claim 76, wherein the irradiation is carried out through a mask.

89. The method according to claim 77, wherein the irradiation is carried out through a mask.

90. The method according to claim 78, wherein the irradiation is carried out through a mask.

91. The method according to claim 79, wherein the irradiation is carried out through a mask.

92. The method according to claim 80, wherein the irradiation is carried out through a mask.

93. The method according to claim 81, wherein the irradiation is carried out through a mask.

94. The method according to claim 82, wherein the irradiation is carried out through a mask.

95. The method according to claim 83, wherein the irradiation is carried out through a mask.

96. The method according to claim 84, wherein the irradiation is carried out through a mask.

97. The method according to claim 73, wherein the ionizing radiations are a beam of electrons or fast heavy ions.

98. The method according to claim 74, wherein the ionizing radiations are a beam of electrons or fast heavy ions.

99. The method according to claim 75, wherein the ionizing radiations are a beam of electrons or fast heavy ions.

100. The method according to claim 76, wherein the ionizing radiations are a beam of electrons or fast heavy ions.

101. The method according to claim 77, wherein the ionizing radiations are a beam of electrons or fast heavy ions.

102. The method according to claim 78, wherein the ionizing radiations are a beam of electrons or fast heavy ions.

103. The method according to claim 79, wherein the ionizing radiations are a beam of electrons or fast heavy ions.

104. The method according to claim 80, wherein the ionizing radiations are a beam of electrons or fast heavy ions.

105. The method according to claim 81, wherein the ionizing radiations are a beam of electrons or fast heavy ions.

106. The method according to claim 82, wherein the ionizing radiations are a beam of electrons or fast heavy ions.

107. The method according to claim 83, wherein the ionizing radiations are a beam of electrons or fast heavy ions.

108. The method according to claim 84, wherein the ionizing radiations are a beam of electrons or fast heavy ions.

109. The method according to claim 73, wherein the cyclopeptides are attached on the organic spacer arms prior to grafting.

110. The method according to claim 74, wherein the cyclopeptides are attached on the organic spacer arms prior to grafting.

111. The method according to claim 75, wherein the cyclopeptides are attached on the organic spacer arms prior to grafting.

112. The method according to claim 76, wherein the cyclopeptides are attached on the organic spacer arms prior to grafting.

113. The method according to claim 77, wherein the cyclopeptides are attached on the organic spacer arms prior to grafting.

114. The method according to claim 78, wherein the cyclopeptides are attached on the organic spacer arms prior to grafting.

115. The method according to claim 79, wherein the cyclopeptides are attached on the organic spacer arms prior to grafting.

116. The method according to claim 80, wherein the cyclopeptides are attached on the organic spacer arms prior to grafting.

117. The method according to claim 81, wherein the cyclopeptides are attached on the organic spacer arms prior to grafting.

118. The method according to claim 82, wherein the cyclopeptides are attached on the organic spacer arms prior to grafting.

119. The method according to claim 83, wherein the cyclopeptides are attached on the organic spacer arms prior to grafting.

120. The method according to claim 84, wherein the cyclopeptides are attached an the organic spacer arms prior to grafting.

121. The method according to claim 73, which further comprises a step of fixation of the cyclopeptides on the organic spacer arms after grafting of same.

122. The method according to claim 74, which further comprises a step of fixation of the cyclopeptides on the organic spacer arms after grafting of same.

123. The method according to claim 75, which further comprises a step of fixation of the cyclopeptides on the organic spacer arms after grafting of same.

124. The method according to claim 76, which further comprises a step of fixation of the cyclopeptides on the organic spacer arms after grafting of same.

125. The method according to claim 77, which further comprises a step of fixation of the cyclopeptides on the organic spacer arms after grafting of same.

126. The method according to claim 78, which further comprises a step of fixation of the cyclopeptides on the organic spacer arms after grafting of same.

127. The method according to claim 79, which further comprises a step of fixation of the cyclopeptides on the organic spacer arms after grafting of same.

128. The method according to claim 80, which further comprises a step of fixation of the cyclopeptides on the organic spacer arms after grafting of same.

129. The method according to claim 81, which further comprises a step of fixation of the cyclopeptides on the organic spacer arms after grafting of same.

130. The method according to claim 82, which further comprises a step of fixation of the cyclopeptides on the organic spacer arms after grafting of same.