1. A method for coating at least one surface of a substrate comprising a sulphur polymer, comprising, prior to depositing the coating onto the surface of the substrate, a treating step of said surface using a treating composition comprising at least one reducing agent which is able to reduce C\u2014S, S\u2014S, CON bonds and salts in the sulphur polymer forming the substrate, causing the sulphur polymer to functionalize through the creation of SH bonds near the surface by contact with the reducing agent,
wherein the treating step comprises at least the steps of:
dipping the substrate into at least a bath comprising the treating composition, and
rinsing off the substrate by dipping it into a deionized water bath.
2. The method of claim 1, wherein the at least one reducing agent is a thioacid or salt thereof.
3. The method of claim 1, wherein the at least one reducing agent is thioglycolic acid, potassium thioglycolate, sodium thioglycolate, calcium thioglycolate, magnesium thioglycolate, glycerol monothioglycolate, ammonium thioglycolate, an amine thioglycolate, diammonium dithioglycolate, thiolactic acid, ammonium thiolactate, guanidine thioglycolate, thiomalic acid, 2-mercaptoproprionic acid, 3-mercaptoproprionic acid, lipoic acid, dihydrolipoic acid, thiosalicylic acid, dithioerythritol, thioglycerol, thioglycol, dithioerythritol, dithiothreitol, 1,3-dithiopropanol, thioxanthine, cysteine, homocysteine, N-acetyl-L-cysteine, cysteamine, N-acetyl-cysteamine, N-propionyl-cysteamine, pantheteine, NaHSO3, LiS, Na2S, K2S, MgS, CaS, SrS, BaS, (NH4)2S, sodium dihydrolipoate 6,8-dithiooctanoate, sodium 6,8-dithiooctanoate, a hydrogen sulfide salt, thioglycolamide, glutathione, thioglycol hydrazide, keratinase, hydrazine sulfate, hydrazine disulfate, triisocyanate, 2,3-dimercaptosuccinic acid, N-(mercaptoalkyl)-\u03c9-hydroxyalkyl amide, N-mono or N,N-dialkylmercapto-4-butyramide, aminomercapto-alkyl amide, N-(mercaptoalkyl)succinamic acid derivative and N-(mercaptoalkyl)succinimide derivative, alkylamino mercaptoalkyl amide, azeotropic mixture of 2-hydroxypropyl thioglycolate and (2-hydroxy-1-methyl)ethyl thioglycolate, mercaptoalkyl aminoamide, N-mercapto-alkylalkane diamide and formamidine sulfinic acid derivative, sulfite, or bisulfite, or salts thereof.
4. The method of claim 3, wherein the at least one reducing agent is sodium thioglycolate, potassium thioglycolate, ammonium thioglycolate or amine thioglycolate.
5. The method of claim 3, wherein the amine thioglycolate is monoethanol amine thioglycolate.
6. The method of claim 3, wherein the hydrogen sulfide salt is NaSH or KSH.
7. The method of claim 1, wherein the pH value of the treating composition is higher than 10.
8. The method of claim 7, wherein the pH value of the treating composition is higher than 12.
9. The method of claim 1, wherein the treating composition comprises from 2 to 30% by weight, based on the total weight of the composition, of the at least one reducing agent.
10. The method of claim 9, wherein the treating composition comprises from 2 to 15% by weight, based on the total weight of the composition, of the at least one reducing agent.
11. The method of claim 10, wherein the treating composition comprises from 5 to 10% by weight, based on the total weight of the composition, of the at least one reducing agent.
12. The method of claim 1, wherein the treating composition comprises at least one metal sulphur.
13. The method of claim 1, wherein the method does not comprise a subsequent step of applying a soda solution onto the substrate.
14. The method of claim 1, further comprising an additional treating step with an oxidizing composition comprising at least one oxidizing agent.
15. The method of claim 14, wherein the at least one oxidizing agent is hydrogen peroxide, alkali bromate, polythionate andor a persalt.
16. The method of claim 15, wherein the persalt is further defined as a perborate, percarbonate, persulfate andor permanganate.
17. The method of claim 14, wherein the at least one oxidizing agent is H2O2 or KMnO4.
18. The method of claim 14, wherein the oxidizing composition comprises from 2 to 15% by weight, based on the total weight of the composition, of the at least one oxidizing agent.
19. The method of claim 18, wherein the oxidizing composition comprises from 5 to 10% by weight, based on the total weight of the composition, of the at least one oxidizing agent.
20. The method of claim 1, further comprising an additional treating step with a phosphorylation composition comprising at least one phosphorylating agent.
21. The method of claim 20, wherein the at least one phosphorylating agent is a trialkylphosphite, phosphonic acid andor phosphinic acid.
22. The method of claim 20, wherein the phosphorylation composition comprises from 2 to 15% by weight, based on the total weight of the composition, of the at least one phosphorylating agent.
23. The method of claim 22, wherein the phosphorylation composition comprises from 5 to 10% by weight, based on the total weight of the composition, of the at least one phosphorylating agent.
24. The method of claim 1, wherein the sulphur polymer in the substrate is a polythio(meth)acrylate, polythiourethane, polythiourethane-urea andor polyepisulfide.
25. The method of claim 24, wherein the sulphur polymer is a polythiourethane resulting from the polymerization of at least one polyisocyanate monomer and at least one polythiol monomer.
26. The method of claim 25, wherein the polyisocyanate monomer is the compound of formula C6H4(CH2NCO)2 and the polythiol monomer is the compound of formula C(CH2OC(O)CH2CH2SH)4.
27. The method of claim 25, wherein the polyisocyanate monomer is the compound of formula C6H4(CH2NCO)2 or the bis(isocyanomethyl) norbornane, and the polythiol monomer is the compound of formula:
28. The method of claim 1, wherein the substrate has a roughness Ra lower than 4 nm.
29. The method of claim 1, wherein the substrate has a roughness Ra ranging from 1 to 4 nm.
30. The method of claim 1, wherein the substrate has a roughness Ra ranging from 5 to 30 to nm.
31. The method of claim 1, wherein the substrate is further defined as an ophthalmic lens.
32. The method of claim 31, wherein the ophthalmic lens is a glass for eyeglasses.
33. The method of claim 1, wherein the coating is an abrasion-resistant polymer coating.
34. The method of claim 33, wherein the polymer coating is a coating based on an epoxyalkoxysilane hydrolyzate.
35. The method of claim 34, wherein the polymer coating is an epoxydialkoxysilane or an epoxytrialkoxysilane hydrolyzate.
36. The method of claim 33, wherein the thickness of the coating is 1 to 10 \u03bcm.
37. The method of claim 36, wherein the thickness of the coating is 2 to 6 \u03bcm.
38. The method of claim 37, wherein the thickness of the coating is 3 to 5 \u03bcm.
The claims below are in addition to those above.
All refrences to claim(s) which appear below refer to the numbering after this setence.
1. A compound or a derivative thereof, capable of binding to MDM2, particularly human DM2, and specifically inhibiting or blocking the binding of MDM2 to the p53 protein, particularly human p53, in vitro or in vivo.
2. A compound according to claim 1, wherein the compound is a peptide or derivative thereof.
3. A peptide according to claim 2 which comprises an amino acid motif of the formula
R1XFXR2R3WXXR4 (I)
wherein
R1 and is a proline (P), leucine (L), glutamic acid (E), cysteine (C) or glutamine (Q),
X stands for one (any) natural amino acid,
R2 is arginine (R), histidine (H), glutamic acid, cysteine, serine, or preferably aspartic acid (D),
R3 is histidine (H), phenylalanine (F) or tyrosine (Y),
R4 is phenylalanine (F), glutamine (Q) or leucine (L); and
F is phenylalanine and w is tryptophan;
or a derivative of said peptide.
4. A peptide according to claim 3 comprising the amino acid motif of formula (I) consisting of no more than fifteen amino acids (15mers), or a derivative thereof.
5. A peptide according to claim 3 selected from the group consisting of the peptides with the sequences M-P-R-F-M-D-Y-W-E-G-L-N, Q-P-T-F-S-D-Y-W-K-L-L-P, and P-X-F-X-D-Y-W-X-X-L, or a derivative thereof.
6. A derivative of a peptide according to claim 3 which is a fragment comprising at least eight consecutive amino acids of the sequence of formula (I), or a derivative thereof.
7. A fragment according to claim 6, which is an 8mer peptide of formula
FX2R2R3WX3X4R4 (Ib),
wherein
R2, R3 and R4, independently from one another, each have the meanings and preferences given for formula (I),
X2 is methionine, isoleucine, threonine, arginine, alanine or serine, preferably methionine;
X3 is glutamic acid, threonine, alanine, phenylalanine or serine, preferably glutamic acid;
X4 is glycine, glutamine, threonine, alanine or aspartic acid, preferably glycine,
or a derivative of such fragment.
8. A fragment according to claim 6 having the formula
X1FX2R2R3WX3X4R4 (Ic),
wherein
R1, R2, R3 and R4, independently from one another, each have the meanings and preferences given for formula (I),
X1 is arginine, asparagine, alanine, threonine or valine; particularly arginine
X2 is methionine, isoleucine, threonine, arginine, alanine or serine; preferably methionine;
X3 is glutamic acid, threonine, alanine, phenylalanine or serine; preferably glutamic acid;
X4 is glycine, glutamine, threonine, alanine or aspartic acid, preferably glycine,
or a derivative of such fragment.
9. A fragment according to claim 6 selected from the group of fragments consisting of: P-A-F-T-H-Y-W-P, P-T-F-S-D-Y-W-P and P-R-F-M-D-Y-W-P, or a derivative thereof.
10. Use of a compound according to any of claims 1 to 9 for the identification of a molecule binding to MDM2.
11. Use of a compound according to any of claims 1 to 9 for the purification of a binding partner, particularly MDM2.
12. Use of a compound according to any of claims 1 to 9 in a method aiming at identifying or designing compounds which interfere with the binding of MDM2 to p53.
13. Use of a compound according to any of claims 1 to 9 for diagnosis of a disease.
14. A pharmaceutical composition that is suitable for administration to a warm-blooded animal, including humans, or to cells or cell lines derivable from a warm-blooded animal, including a human, for the treatment or prevention of a disease that responds to inhibition of the interaction of p53 with MDM2, said composition comprising an amount of a compound according to any of claims 1 to 9, which is effective for said inhibition, together with at least one pharmaceutically acceptable carrier.
15. The use of a compound according to any of claims 1 to 9 for the preparation of a pharmaceutical composition for the treatment or prevention of a disease that responds to inhibition of the interaction of p53 with MDM2.
16. A process for the preparation of a peptide or a derivative thereof according to any of claims 2 to 9 comprising reacting a fragment of such peptide, which has a free carboxy group, or a reactive derivative thereof, with a complementary fragment that has an amino group with at least one free hydrogen atom, or with a reactive derivative thereof, resulting in the formation of a peptide bond, and, if desired, removing a present protecting group, or derivatising said peptide or derivative.
17. A method of treating or preventing a disease comprising administering a therapeutically useful amount of a compound according to any of claims 1 to 9.
18. A method for inducing growth arrest or apoptosis in tumor cells which contain wild type p53 and non-elevated MDM2 levels comprising inhibiting the interaction between MDM2 and p53 in vivos or in vitro.
19. The method of claim 18 wherein the inhibiting step further comprises interfering with expression of MDM2 by administering antisense oligonucleotides to a cell.
20. The method of claim 19 wherein the inhibiting step further comprises interfering with expression of MDM2 by administering triple strand forming oligonucleotides.
21. The method of claim 19 wherein the inhibiting step further comprises administering to a cell a DNA molecule which expresses a peptide capable of binding to MDM2.
22. The method of claim 21 wherein the DNA molecule expresses a peptide or a derivative thereof according to any of claims 2 to 9.
23. A method of treating or preventing a hyperproliferative disease comprising tumor cells having wild type p53 and a non-elevated MDM2 level, the method comprising interfering with the interaction of human p53 and human MDM2.