Peptide having activity for inhibiting adhesion of marine fouling

Abstract

Provided is a compound which is synthesized using an amino acid that can be easily procured in the marketplace and used industrially, has activity for inhibiting adhesion of fouling present in sea water, and has low toxicity. The present invention relates to: a dipeptide containing a proline residue which is represented by formula (1), or a tripeptide containing a proline residue and a phenylalanine residue [in the formula, R1 denotes a substituted or unsubstituted C3-10 hydrocarbon group, R2 and R3 each denote a hydrogen atom or a substituted or unsubstituted C1-8 hydrocarbon group or the like, and R4 denotes a hydrogen atom or a substituted or unsubstituted C1-6 hydrocarbon group or the like]; and a composition for inhibiting adhesion of marine fouling, which contains this compound.

Description

Peptides with anti-adhesion activity against marine sessile organisms

[0001] This patent application claims priority under the Paris Convention and the benefit of Japanese Patent Application No. 2023-174771 (filed October 6, 2023), as well as priority under Article 41 of the Japanese Patent Act, the entire contents of which are incorporated herein by reference.

[0002] The present invention relates to a compound for inhibiting adhesion of marine sessile organisms and a composition containing the same. More specifically, the present invention relates to a specific dipeptide having a proline skeleton or a specific tripeptide having a dipeptide consisting of proline and phenylalanine as a skeleton, and a composition for inhibiting adhesion of marine sessile organisms containing the peptide of the present invention.

[0003] Marine sessile organisms exist in the ocean, attaching to marine structures and ship bottoms. These organisms adversely affect human activities by reducing ship fuel efficiency and clogging cooling pipes in power plants. For this reason, various anti-fouling substances have been developed. Harmful substances such as organolead compounds have been used as anti-fouling substances in the past, and organotin compounds have been used since the 1960s, resulting in a high environmental impact. In recent years, both industry and academia have been developing environmentally friendly compositions for inhibiting the adhesion of marine sessile organisms. For example, Patent Documents 1 and 2 and Non-Patent Documents 1 and 2 propose isocyanate or isothiocyanate compounds as adhesion inhibitors. However, while these isocyanates and isothiocyanates exhibit excellent adhesion inhibitory properties, they suffer from the problem of being easily hydrolyzed and converted to formamide, which is known to be toxic. The present inventors also began developing an environmentally friendly adhesion inhibitor and confirmed that glucosamine derivatives exhibited strong adhesion inhibitory effects on the cypris larvae of the barnacle, but did not exhibit adhesion inhibitory effects on Mytilus edulis, raising doubts about their applicability to a wide range of sessile organisms [Non-Patent Document 3].

[0004] Formula (a): Dolastatin 16, represented by the formula (I), is a natural organic compound isolated from the sea hare Dorabella auricularia. It is a cyclic depsipeptide containing two unusual amino acids (dolafenvaline and doramethylleucine). The isolated dolastatin 16 was confirmed to have antiproliferative effects on NCI-H460 (a human lung cancer cell line), KM20L2 (a human colon cancer cell line), and SF-295 (a human glioblastoma cell line) [Non-Patent Document 4]. Furthermore, dolastatin 16 has been shown to inhibit the adhesion of barnacle larvae [Non-Patent Document 5].

[0005] The present inventors focused on the adhesion inhibitory effect of dolastatin 16 and attempted to synthesize it in total, successfully synthesizing two unusual amino acids contained in dolastatin 16: dolafenvaline and dolamethylleucine [Non-Patent Document 6]. Furthermore, the present inventors also succeeded in the total synthesis of dolastatin 16 and confirmed that synthetic dolastatin 16 has an adhesion inhibitory effect equivalent to that of natural dolastatin 16 [Non-Patent Document 7]. In addition, two peptides represented by formulas (b) and (c), respectively, which serve as precursors for the total synthesis of dolastatin 16, were also found to have promising adhesion inhibitory effects.

[0006] Synthetic dolastatin 16 is a promising adhesion inhibitor, but requires a complex synthesis route. Therefore, the present inventors focused on the potential of the above two peptides as adhesion inhibitors, synthesized tripeptides containing dolafenvaline and dolamethylleucine, two unusual amino acids contained in dolastatin 16, and investigated their adhesion inhibitory effects [Non-Patent Document 8]. The adhesion inhibitory effect (EC ５０ = 1.17 μg / mL) was converted to tripeptide Boc-3, in which the amino group was modified with a tert-butoxycarbonyl group (Boc group), and EC ５０ = 0.79 μg / mL.

[0007] JP 2015-042622 A JP 2019-167335 A

[0008] Fukuda, T. et al., Chem. Biodivers., 2016, 13, 1502Tanikawa, A. et al., Chem. Biodivers., 2023, 20, e202200953Umezawa, T. et al., Mar. Drugs, 2017, 15, 203; doi:10.3390 / md15070203Pettit, GR et al., J. Nat. Prod. 1997, 60, 752Tan, LK et al., Biofouling 2010, 26, 685Umezawa, T. et al., Tetrahedron Letters, 2015, 56, 168Casalme, LO et al., Org. Biomol. Chem., 2017, 15, 1140Casalme, LO et al., Mar. Drugs 2022, 20, 124

[0009] The present inventors have discovered that tripeptides containing dolafenvaline and dolamethylleucine, two unusual amino acids contained in dolastatin 16, have an anti-fouling effect against marine sessile organisms. However, because the synthesis of such tripeptides requires unusual amino acids that are not commercially available, the synthesis is extremely expensive and there are problems with mass production. Therefore, an objective of the present invention is to synthesize tripeptides that have anti-fouling effects and low toxicity using inexpensive amino acids that are readily available on the market and easy to use industrially.

[0010] Through extensive research, the present inventors have found that tripeptides composed solely of α-amino acids do not exhibit adhesion inhibitory effects, while dipeptides and tripeptides containing β-amino acids exhibit adhesion inhibitory effects on cypris larvae of the barnacle Balanus nigricans. Furthermore, some tripeptides have also been shown to be effective against blue mussels. Furthermore, while the peptides of the present invention are stable to hydrolysis in seawater, they are biomolecules and therefore are expected to exhibit moderate biodegradability by enzymes and other agents. In other words, even if the compounds exhibit adhesion inhibitory effects for an appropriate period of time and then undergo biodegradation and are released into the ocean, their adverse effects on the ecosystem are expected to be minimal.

[0011] That is, the present invention includes the following aspects: <Dipeptides and tripeptides> [1] Formula (1): [In the formula, R １ is a substituted or unsubstituted C ３～１０ is a hydrocarbon group, R ２ and R ３ represents a hydrogen atom or a substituted or unsubstituted C １～８ a hydrocarbon group or R ２ and R ３ together with the adjacent carbon atoms to form a substituted or unsubstituted cyclic C １～１０ Forming a hydrocarbon group, R ４ represents a hydrogen atom, a substituted or unsubstituted C １～６ Hydrocarbon group, formula (2): (In the formula, R ５ is a hydrogen atom or C １～６ a hydrocarbon group, and the symbol * indicates the bonding site with the pyrrolidine group.), or a carboxyl group or an alkoxyacyl group represented by formula (3) or formula (3'): (In the formula, R ６ is a hydrogen atom, C １～６ is a hydrocarbon group, or a carboxyl group or alkoxyacyl group represented by formula (2), Ph is a phenyl group, and the symbol * indicates the bonding site with the pyrrolidine group. １ is a benzyl group, R ２ and R ３ are both phenyl groups, and R４ [2] A dipeptide containing a proline residue, or a tripeptide containing a proline residue and a phenylalanine residue, represented by the formula: [3] wherein R is a t-butoxycarbonyl group. １ , R ２ and R ３ [3] The dipeptide containing a proline residue or the tripeptide containing a proline residue and a phenylalanine residue according to [1], wherein the cumulative carbon number in R is 7 or more, preferably 9 or more, and more preferably 11 or more. １ Substituted or unsubstituted C in ３～１０ The hydrocarbon group may be a substituted or unsubstituted linear or branched C ３～１０ Alkyl group; substituted or unsubstituted straight or branched C ３～１０ Alkenyl group; substituted or unsubstituted cyclic C ３～１０ alkyl group; substituted or unsubstituted cyclic C ３～１０ alkenyl groups; and substituted or unsubstituted C ３～１０ alkyl-substituted aryl groups; R ２ and R ３ Substituted or unsubstituted C in １～８ The hydrocarbon groups are each independently substituted or unsubstituted, linear or branched C １～８ Alkyl group; substituted or unsubstituted straight or branched C １～８ Alkenyl group; substituted or unsubstituted cyclic C １～８ alkyl group; substituted or unsubstituted cyclic C １～８ alkenyl groups; and substituted or unsubstituted C １～８ alkyl-substituted aryl groups, and R ２ and R ３ together with the adjacent carbon atoms to form a substituted or unsubstituted cyclic C １～１０ When the cyclic C is a hydrocarbon group １～１０ The hydrocarbon groups are each independently a substituted or unsubstituted cyclic C １～１０ alkyl group; substituted or unsubstituted cyclic C １～１０ alkenyl groups; and substituted or unsubstituted C １～１０ alkyl-substituted aryl groups; R ４Substituted or unsubstituted C in １～６ The hydrocarbon group may be a substituted or unsubstituted linear or branched C １～６ Alkyl group; substituted or unsubstituted straight or branched C １～６ Alkenyl group; substituted or unsubstituted cyclic C １～６ alkyl group; substituted or unsubstituted cyclic C １～６ alkenyl groups; and substituted or unsubstituted C １～６ alkyl-substituted aryl groups, and R ５ and R ６ Substituted or unsubstituted C in １～６ The hydrocarbon groups are each independently substituted or unsubstituted, linear or branched C １～６ Alkyl group; substituted or unsubstituted straight or branched C １～６ Alkenyl group; substituted or unsubstituted cyclic C １～６ alkyl group; substituted or unsubstituted cyclic C １～６ [4] The dipeptide containing a proline residue or the tripeptide containing a proline residue and a phenylalanine residue according to [1] or [2], wherein R is selected from an alkenyl group; and a substituted or unsubstituted phenyl group. １ Substituted or unsubstituted C in ３～１０ C of hydrocarbon group ３～１０The hydrocarbon group is a linear or branched alkyl group selected from the group consisting of a propyl group, a butyl group, a pentyl group, a hexyl group, a heptyl group, an octyl group, a nonyl group, and a decyl group; a linear or branched alkenyl group selected from the group consisting of a propenyl group, a butenyl group, a pentenyl group, a hexenyl group, a heptenyl group, an octenyl group, a nonenyl group, and a decenyl group; a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooct ... R is selected from the group consisting of a cyclic alkyl group selected from the group consisting of a cycloalkyl group, a cyclononyl group, and a cyclodecyl group; a cyclic alkenyl group selected from the group consisting of a cyclopropenyl group, a cyclobutenyl group, a cyclopentenyl group, a cyclohexenyl group, a cycloheptenyl group, a cyclooctenyl group, a cyclononenyl group, and a cyclodecenyl group; an aryl group selected from the group consisting of a phenyl group, an alkyl-substituted phenyl group such as a naphthyl group, a tolyl group, an ethylphenyl group, a xylyl group, and a benzyl group; ２ and R ３ Substituted or unsubstituted C in １～８ C of hydrocarbon group １～８ The hydrocarbon groups are each independently selected from the group consisting of a linear or branched alkyl group selected from the group consisting of a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group, a heptyl group, and an octyl group; a linear or branched alkenyl group selected from the group consisting of an ethenyl group, a propenyl group, a butenyl group, a pentenyl group, a hexenyl group, a heptenyl group, and an octenyl group; a cyclic alkyl group selected from the group consisting of a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and a cyclooctyl group; a cyclic alkenyl group selected from the group consisting of a cyclopropenyl group, a cyclobutenyl group, a cyclopentenyl group, a cyclohexenyl group, a cycloheptenyl group, and a cyclooctenyl group; an aryl group selected from a phenyl group, an alkyl-substituted phenyl group such as a tolyl group, an ethylphenyl group, or a xylyl group, and a benzyl group; and R ５ and R ６ Substituted or unsubstituted C in １～６ C of hydrocarbon group １～６The hydrocarbon groups are each independently selected from the group consisting of a linear or branched alkyl group selected from the group consisting of a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, and a hexyl group; a linear or branched alkenyl group selected from the group consisting of an ethenyl group, a propenyl group, a butenyl group, a pentenyl group, and a hexenyl group; a cyclic alkyl group selected from the group consisting of a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group; a cyclic alkenyl group selected from the group consisting of a cyclopropenyl group, a cyclobutenyl group, a cyclopentenyl group, and a cyclohexenyl group; and a phenyl group.

[0012] <Composition for inhibiting adhesion of marine sessile organisms> [5] A compound represented by the formula (1): [In the formula, R １ is a substituted or unsubstituted C ３～１０ is a hydrocarbon group, R ２ and R ３ represents a hydrogen atom or a substituted or unsubstituted C １～８ a hydrocarbon group or R ２ and R ３ together with the adjacent carbon atoms to form a substituted or unsubstituted cyclic C １～１０ Forming a hydrocarbon group, R ４ is a hydrogen atom, C １～６ Hydrocarbon group, formula (2): (In the formula, R ５ is a hydrogen atom or C １～６ a hydrocarbon group, and the symbol * indicates the bonding site with the pyrrolidine group.), or a carboxyl group or an alkoxyacyl group represented by formula (3) or formula (3'): (In the formula, R ６ is a hydrogen atom, C １～６ a hydrocarbon group, or a carboxyl group or alkoxyacyl group represented by formula (2), where Ph is a phenyl group, and the symbol * indicates the bond to the pyrrolidine group. １ , R ２ and R３ The cumulative number of carbon atoms in the formula (I) is 7 or more, preferably 9 or more, and more preferably 11 or more.

[0013] [6] A composition for inhibiting adhesion of marine sessile organisms, comprising a dipeptide containing a proline residue or a tripeptide containing a proline residue and a phenylalanine residue according to any one of [1] to [4].

[0014] According to the present invention, an adhesion inhibitor that inhibits adhesion of marine sessile organisms and has extremely little adverse effect on the ecosystem has been easily synthesized from inexpensive amino acids that are readily available on the market and can be used industrially.

[0015] The upper diagram of Figure 1 shows the structure of compound 14. 1 H NMR (500 MHz, CDCl3) 13The C NMR (126 MHz, CDCl3) spectra are shown. Figure 2 shows data and a graph indicating the results of evaluation of the adhesion inhibitory activity and toxicity against Balanus nautilus cypris larvae (results for tripeptides 2 and 3). Figure 3 shows data and a graph indicating the results of evaluation of the adhesion inhibitory activity and toxicity against Balanus nautilus cypris larvae (results for tripeptides 4 and 5 and copper sulfate). Figure 4 shows data and a graph indicating the results of evaluation of the adhesion inhibitory activity and toxicity against Balanus nautilus cypris larvae (results for tripeptides 6 to 8). Figure 5 shows data and a graph indicating the results of evaluation of the adhesion inhibitory activity and toxicity against Balanus nautilus cypris larvae (results for tripeptides 9 and 10 and dipeptide 11). Figure 6 shows data and a graph indicating the results of evaluation of the adhesion inhibitory activity and toxicity against Balanus nautilus cypris larvae (results for tripeptides 12). Figure 7 shows data and a graph showing the results of evaluation of adhesion inhibitory activity and toxicity against cypris larvae of the harp striped barnacle (results for dipeptide 13). Figure 8 shows data and a graph showing the results of evaluation of adhesion inhibitory activity and toxicity against cypris larvae of the harp striped barnacle (results for dipeptide 14). Figure 9 shows data and a graph showing the results of evaluation of adhesion inhibitory activity and toxicity against cypris larvae of the harp striped barnacle (results for copper sulfate).

[0016] <Dipeptides and Tripeptides> In one aspect, the present invention provides a dipeptide or tripeptide of formula (1): [In the formula, R １ is a substituted or unsubstituted C ３～１０ is a hydrocarbon group, R ２ and R ３ represents a hydrogen atom or a substituted or unsubstituted C １～８ a hydrocarbon group or R ２ and R ３ together with the adjacent carbon atoms to form a substituted or unsubstituted cyclic C １～１０ Forming a hydrocarbon group, R ４ represents a hydrogen atom, a substituted or unsubstituted C １～６ Hydrocarbon group, formula (2): (In the formula, R ５ is a hydrogen atom or C １～６a hydrocarbon group, and the symbol * indicates the bonding site with the pyrrolidine group.), or a carboxyl group or an alkoxyacyl group represented by formula (3) or formula (3'): (In the formula, R ６ is a hydrogen atom, C １～６ is a hydrocarbon group, or a carboxyl group or alkoxyacyl group represented by formula (2), Ph is a phenyl group, and the symbol * indicates the bonding site with the pyrrolidine group. １ is a benzyl group, R ２ and R ３ are both phenyl groups, and R ４ The present invention provides a dipeptide containing a proline residue or a tripeptide containing a proline residue and a phenylalanine residue, which is represented by the formula:

[0017] Here, the excluded compound [R １ is a benzyl group, R ２ and R ３ are both phenyl groups, and R ４ is a t-butoxycarbonyl group] is a compound of the formula: The dipeptide 13 compound is shown in Reference Example 1. Dipeptide 13 is described in Tetrahedron, 2011, 67, 3969, but is only described there as a model substance for asymmetric reactions, and is not described as an anti-adhesion substance.

[0018] In one embodiment, the present invention provides a dipeptide containing a proline residue, or a tripeptide containing a proline residue and a phenylalanine residue, represented by formula (1) (wherein the definitions of each substituent are as defined above), wherein the substituents R １ , R ２ and R ３ The total number of carbon atoms in the formula (I) is 7 or more, preferably 9 or more, and more preferably 11 or more.

[0019] In this embodiment, the present invention provides, as one embodiment, a dipeptide containing a proline residue or a tripeptide containing a proline residue and a phenylalanine residue represented by formula (1), wherein R １ Substituted or unsubstituted C in ３～１０ The hydrocarbon group may be a substituted or unsubstituted linear or branched C ３～１０ Alkyl group; substituted or unsubstituted straight or branched C ３～１０ Alkenyl group; substituted or unsubstituted cyclic C ３～１０ Alkyl group; cyclic C ３～１０ alkenyl groups; and substituted or unsubstituted C ３～１０ alkyl-substituted aryl groups; R ２ and R ３ Substituted or unsubstituted C in １～８ The hydrocarbon groups are each independently substituted or unsubstituted, linear or branched C １～８ Alkyl group; substituted or unsubstituted straight or branched C １～８ Alkenyl group; substituted or unsubstituted cyclic C １～８ alkyl group; substituted or unsubstituted cyclic C １～８ alkenyl groups; and substituted or unsubstituted C １～８ alkyl-substituted aryl groups, and R ２ and R ３ together with the adjacent carbon atoms to form a substituted or unsubstituted cyclic C １～１０ When the cyclic C is a hydrocarbon group １～１０ The hydrocarbon groups are each independently a substituted or unsubstituted cyclic C １～１０ alkyl group; substituted or unsubstituted cyclic C １～１０ alkenyl groups; and substituted or unsubstituted C １～１０ alkyl-substituted aryl groups; R ４ Substituted or unsubstituted C in １～６ The hydrocarbon group may be a substituted or unsubstituted linear or branched C １～６ Alkyl group; substituted or unsubstituted straight or branched C １～６ Alkenyl group; substituted or unsubstituted cyclic C １～６ alkyl group; substituted or unsubstituted cyclic C １～６alkenyl groups; and substituted or unsubstituted C １～６ alkyl-substituted aryl groups, and R ５ and R ６ Substituted or unsubstituted C in １～６ The hydrocarbon groups are each independently substituted or unsubstituted, linear or branched C １～６ Alkyl group; substituted or unsubstituted straight or branched C １～６ Alkenyl group; substituted or unsubstituted cyclic C １～６ alkyl group; substituted or unsubstituted cyclic C １～６ and a substituted or unsubstituted phenyl group.

[0020] In the present invention, the term "alkyl" refers to a group consisting of carbon and hydrogen atoms, containing no unsaturation, such as "C １～６ " or "C ３～１０ " means a straight or branched hydrocarbon chain radical containing a carbon atom designated "R" and connected to the remainder of the molecule by a single bond. Specifically, the radical is selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, and decyl.

[0021] In the present invention, the term "alkenyl" has the same definition as the term "alkyl", except that it contains at least one double bond, and is specifically selected from the group consisting of ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, and decenyl groups.

[0022] In the present invention, the term "cyclic alkyl group" has the same definition as the term "alkyl", except that it is cyclic, and is specifically selected from the group consisting of a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, a cyclononyl group, and a cyclodecyl group.

[0023] In the present invention, the term "cyclic alkenyl group" has the same definition as the term "alkenyl", except that it is cyclic, and is specifically selected from the group consisting of a cyclopropenyl group, a cyclobutenyl group, a cyclopentenyl group, a cyclohexenyl group, a cycloheptenyl group, a cyclooctenyl group, a cyclononenyl group, and a cyclodecenyl group.

[0024] In the present invention, the term "aryl group" means "C １～６ " or "C ３～１０ " means a cyclic ring containing at least one aromatic ring containing a carbon atom designated as "aromatic ring," and specifically, is selected from the group consisting of a phenyl group, a naphthyl group, an alkyl-substituted phenyl group such as a tolyl group, an ethylphenyl group, or a xylyl group, and a benzyl group.

[0025] In the present invention, the substituent in the "substituted" part of "substituted or unsubstituted" includes hydroxy, halogen (e.g., fluoro, chloro, bromo), C １～４ Alkyl (e.g., methyl, ethyl), C １～４ fluoroalkyl (e.g., trifluoromethyl), C １～４ It is selected from the group consisting of alkoxy (e.g., methoxy, ethoxy, n-propoxy), nitro group, amino group, N-alkylamino group, N,N-dialkylamino group, carboxyl group, aldehyde group, acetal group, alkyl ester group, alkyl ketone group, phenyl, and benzyl.

[0026] In one embodiment, the present invention provides a dipeptide containing a proline residue or a tripeptide containing a proline residue and a phenylalanine residue, represented by formula (1), wherein R １ Substituted or unsubstituted C in ３～１０ C of hydrocarbon group ３～１０The hydrocarbon group is a linear or branched alkyl group selected from the group consisting of a propyl group, a butyl group, a pentyl group, a hexyl group, a heptyl group, an octyl group, a nonyl group, and a decyl group; a linear or branched alkenyl group selected from the group consisting of a propenyl group, a butenyl group, a pentenyl group, a hexenyl group, a heptenyl group, an octenyl group, a nonenyl group, and a decenyl group; a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooct ... R is selected from the group consisting of a cyclic alkyl group selected from the group consisting of a cycloalkyl group, a cyclononyl group, and a cyclodecyl group; a cyclic alkenyl group selected from the group consisting of a cyclopropenyl group, a cyclobutenyl group, a cyclopentenyl group, a cyclohexenyl group, a cycloheptenyl group, a cyclooctenyl group, a cyclononenyl group, and a cyclodecenyl group; an aryl group selected from the group consisting of a phenyl group, an alkyl-substituted phenyl group such as a naphthyl group, a tolyl group, an ethylphenyl group, a xylyl group, and a benzyl group; ２ and R ３ Substituted or unsubstituted C in １～８ C of hydrocarbon group １～８ The hydrocarbon groups are each independently selected from the group consisting of a linear or branched alkyl group selected from the group consisting of a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group, a heptyl group, and an octyl group; a linear or branched alkenyl group selected from the group consisting of an ethenyl group, a propenyl group, a butenyl group, a pentenyl group, a hexenyl group, a heptenyl group, and an octenyl group; a cyclic alkyl group selected from the group consisting of a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and a cyclooctyl group; a cyclic alkenyl group selected from the group consisting of a cyclopropenyl group, a cyclobutenyl group, a cyclopentenyl group, a cyclohexenyl group, a cycloheptenyl group, and a cyclooctenyl group; an aryl group selected from a phenyl group, an alkyl-substituted phenyl group such as a tolyl group, an ethylphenyl group, or a xylyl group, and a benzyl group; and R ５ and R ６ Substituted or unsubstituted C in １～６ C of hydrocarbon group １～６The hydrocarbon groups are each independently selected from the group consisting of a linear or branched alkyl group selected from the group consisting of a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, and a hexyl group; a linear or branched alkenyl group selected from the group consisting of an ethenyl group, a propenyl group, a butenyl group, a pentenyl group, and a hexenyl group; a cyclic alkyl group selected from the group consisting of a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group; a cyclic alkenyl group selected from the group consisting of a cyclopropenyl group, a cyclobutenyl group, a cyclopentenyl group, and a cyclohexenyl group; and a phenyl group.

[0027] A method for synthesizing the compound of the present invention will be generally described below. The dipeptide or tripeptide represented by formula (1) according to the present invention can be synthesized, for example, by the following steps.

[0028] Formula (4): (In the formula, R １ is a substituted or unsubstituted C ３～１０ is a hydrocarbon group, R ２ and R ３ is a hydrogen atom or C １～８ a hydrocarbon group or R ２ and R ３ together with the adjacent carbon atoms to form a substituted or unsubstituted cyclic C １～１０ A β-amino acid ester represented by formula (5): [In the formula, R ４ is a hydrogen atom, C １～６ Hydrocarbon group, formula (2): (In the formula, R ５ is a hydrogen atom or C １～６ a hydrocarbon group, and the symbol * indicates the bonding site with the pyrrolidine group.), or a carboxyl group or an alkoxyacyl group represented by formula (3) or formula (3'): (In the formula, R ６ is a hydrogen atom, C １～６The compound can be synthesized by reacting a monopeptide containing a proline residue, or a dipeptide containing a proline residue and a phenylalanine residue, represented by the formula (2), in which Ph is a phenyl group and the symbol * indicates the bond to the pyrrolidine group. The compound can be synthesized by reacting a monopeptide containing a proline residue, or a dipeptide containing a proline residue and a phenylalanine residue, represented by the formula (2), in an organic solvent.

[0029] Organic solvents that can be used in the synthesis of the oligopeptide of the present invention are preferably those in which the starting materials and the amino acids or peptides that will be produced can be dissolved or dispersed. Suitable solvents or dispersion media are not particularly limited, as long as they are substantially inert to these reactions and exhibit liquid or fluid properties at the reaction temperature. Among these, those in which the starting materials and the amino acids or peptides that will be produced can be dissolved are particularly preferred.

[0030] Specific examples of organic solvents that can be used in the synthesis include aliphatic hydrocarbons such as hexane, heptane, octane, cyclohexane, and cyclohexene; aromatic hydrocarbons such as toluene, xylene, ethylbenzene, and naphthalene; linear ethers such as diethyl ether, methyl butyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, propylene glycol dimethyl ether, and diethylene glycol dimethyl ether; cyclic ethers such as dioxane, tetrahydrofuran, methyltetrahydrofuran, and dimethylfuran; linear ethers such as acetone, methyl ethyl ketone, and methyl butyl ketone. nitriles such as acetonitrile, propionitrile, and benzonitrile; esters such as ethyl acetate, butyl acetate, propylene glycol monomethyl ether acetate, and diethylene glycol monomethyl ether acetate; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, trichloroethylene, dichloropropane, bromoform, chlorobenzene, and dichlorobenzene; alkyl sulfoxides such as dimethyl sulfoxide; alkyl amides such as dimethylacetamide; and supercritical gases such as supercritical carbon dioxide.

[0031] <Composition for inhibiting adhesion of marine sessile organisms> In another aspect, the present invention provides a composition comprising a compound of formula (1): [In the formula, R １ is a substituted or unsubstituted C ３～１０ is a hydrocarbon group, R ２ and R ３ represents a hydrogen atom or a substituted or unsubstituted C １～８ a hydrocarbon group or R ２ and R ３ together with the adjacent carbon atoms to form a substituted or unsubstituted cyclic C １～１０ Forming a hydrocarbon group, R ４ is a hydrogen atom, C １～６ Hydrocarbon group, formula (2): (In the formula, R ５ is a hydrogen atom or C １～６ a hydrocarbon group, and the symbol * indicates the bonding site with the pyrrolidine group.), or a carboxyl group or an alkoxyacyl group represented by formula (3) or formula (3'): (In the formula, R ６ is a hydrogen atom, C １～６ a hydrocarbon group, or a carboxyl group or alkoxyacyl group represented by formula (2), where Ph is a phenyl group, and the symbol * indicates the bond to the pyrrolidine group. １ , R ２ and R ３ The total number of carbon atoms in the formula (I) is 7 or more, preferably 9 or more, and more preferably 11 or more.] The present invention relates to a composition for inhibiting adhesion of marine sessile organisms, which contains a dipeptide containing a proline residue or a tripeptide containing a proline residue and a phenylalanine residue,

[0032] In this embodiment, from the viewpoint of the activity of inhibiting adhesion of marine sessile organisms, the substituent R １ , R ２ and R ３ There may be a preferred number for the total number of carbon atoms in each of the groups, i.e., the "cumulative number of carbon atoms." １ , R ２and R ３ The cumulative carbon number of the alkyl group may be 7 or more and 26 or less, 10 or more and 20 or less, or 11 or more and 16 or less.

[0033] In this aspect, one embodiment of the present invention relates to a composition for inhibiting adhesion of marine sessile organisms, which contains a compound according to any of the embodiments of the compound of the present invention.

[0034] In the present invention, marine sessile organisms present in the sea include barnacles, mussels, hydrozoans, bryozoans, etc. When the nauplius larvae hatch from eggs and grow into cypris larvae, barnacles cease their planktonic life and secrete cement (larval cement) from the tip of the attachment disk at the tip of the first antenna to become juveniles, leading to a sessile life. Even as they grow from juveniles to adults, they secrete cement material (adult cement) from their bottom plates to maintain their attachment. On the other hand, mussels attach to underwater rocks and ship bottoms using multiple adhesive protein threads (byssus threads). A composition for inhibiting the attachment of marine sessile organisms, containing the dipeptide or tripeptide of the present invention, can inhibit the attachment of these marine sessile organisms to ship bottoms.

[0035] The composition for inhibiting the adhesion of marine sessile organisms of the present invention can contain, in addition to the dipeptide or tripeptide of the present invention, binders and resins for the purpose of imparting shaping properties, i.e., moldability and film-forming properties, fillers, crosslinking agents, and curing agents for the purpose of improving the mechanical properties of molded products, dispersants for imparting dispersibility, pigments and dyes for coloring, heat stabilizers and light stabilizers for imparting durability, plasticizers for improving flexibility, (reactive) solvents for improving fluidity before shaping, etc. The composition of the present invention can also additionally contain other marine organism adhesion-inhibiting substances.

[0036] The composition can be suitably used for applications such as paints and materials for ships, paints and materials for marine-related facilities such as power generation and transmission facilities, port facilities, navigation aids, observation facilities, and aquariums, and fishing gear including aquaculture.

[0037] In another aspect, the present invention relates to a method for inhibiting the adhesion of marine sessile organisms, the method comprising applying the dipeptide or tripeptide of the present invention. Furthermore, in another aspect, the present invention relates to a dipeptide or tripeptide of the present invention for inhibiting the adhesion of marine sessile organisms.

[0038] The present invention will be described in detail below with reference to examples, but it should be noted that these examples are merely illustrative and do not limit the scope of the present invention. Overview of Dipeptide or Tripeptide Synthesis Novel tripeptides 2 to 10 were synthesized by condensing various esters of α-, β-, or γ-amino acids with commercially available dipeptide 1, which is composed of proline and phenylalanine, as the parent skeleton. In dipeptide 1, the amino group of phenylalanine is protected with a tert-butoxycarbonyl group (Boc group).

[0039] Tripeptide ethyl esters 2-5 were synthesized using inexpensive amino acid ethyl ester hydrochlorides.

[0040] To investigate the effect of the β-amino acid at this introduction site, tripeptide benzyl ester 6 and tripeptide 7 were synthesized using the β-amino acid benzyl ester synthesized by the present inventors [first step in the synthesis scheme for dipeptide 11]. wherein Bn is a benzyl group.

[0041] Furthermore, benzyl esters and ethyl esters 8 to 10 were synthesized using commercially available β-amino acids, and dipeptide 11, consisting of a β-amino acid ester and proline, was also synthesized.

[0042] Synthesis examples of tripeptides 2 to 11 are described in detail below. [Synthesis of tripeptide 8]

[0043] After dissolving 16 mg of the above β-amino acid benzyl ester in 0.3 mL of acetonitrile, 0.4 mL of an acetonitrile solution of 36 mg of dipeptide 1, 0.035 mL of diisopropylethylamine, 0.017 mL of a 4 M dioxane solution of hydrochloric acid, and 55 mg of bromotripyrrolidinophosphonium hexafluorophosphate (PyBroP) were added and stirred for 6 hours. A diluted aqueous solution of sodium hydroxide was added to the reaction mixture, which was extracted with ethyl acetate and purified by silica gel chromatography (hexane:ethyl acetate = 90:10 to 70:30) to obtain 37 mg of the desired tripeptide compound 8. The NMR and mass spectrometry data for compound 8 are shown below. 1 H NMR (400 MHz, CDCL3, as a 1:1 mixture of rotamers) δ 0.82-0.91 (m, 6H), 1.16-1.61 (m, 13H), 1.83-2.26 (m, 4H), 2.45-2.62 (m, 2H), 2.83-2.93 (m, 1H), 3.02 (dd, J = 13.9, 6.1 Hz, 0.5H), 3.14-3.20 (m, 0.5H), 3.39-3.60 (m, 2H), 4.27-4.34 (m, 1.5H), 4.44-4.46 (m, 0.5H), 4.64 (q, J = 7.8 Hz, 0.5H). 5.02-5.17 (m, 2H), 5.28 (d, J = 8.3 Hz, 0.5H), 6.93 (d, J = 8.8 Hz, 0.5H), 7.17-7.38 (m, 10H), 7.49 (d, J = 9.3 Hz, 0.5H) 13C NMR (101 MHz, CDCl3) δ 21.6, 21.8, 22.1, 22.8, 23.1, 24.9, 25.0, 27.4, 28.2, 28.3, 30.5, 38.8, 39.0, 39.2, 39.4, 42.7, 43.1, 44.5, 45.1, 46.4, 47.3, 53.2, 54.1, 60.2, 60.9, 66.2, 66.3, 79.7, 80.2, 126.8, 127.4, 128.1, 128.2, 128.2, 128.3, 128.4, 128.5, 128.8, 129.3, 129.3, 135.7, 135.9, 136.3, 155.1, 155.6, 169.8, 170.0, 171.2, 171.3, 171.4, 171.9; + C 33 H 45 Calculated for N3O6Na: 602.3201; Found: 602.3228.

[0044] [Synthesis of Tripeptides 2 to 5] Tripeptides 2 to 5 were synthesized in the same manner as tripeptide 8, except that the β-amino acid benzyl ester was changed.

[0045] [Synthesis of Tripeptides 6, 9, and 10] Tripeptides 6, 9, and 10 were synthesized in the same manner as tripeptide 8, except that the β-amino acid benzyl ester was changed.

[0046] [Synthesis of Tripeptide 7] Tripeptide 7 was synthesized in the same manner as tripeptide 8, except that the β-amino acid benzyl ester was changed to a β-amino acid.

[0047] [Synthesis of dipeptide 11]

[0048] 36 mg of a known Boc-β-amino acid benzyl ester was dissolved in 0.6 mL of dichloromethane, and then 0.2 mL of trifluoroacetic acid was added and stirred for 40 minutes. A diluted aqueous solution of sodium hydroxide was added to the reaction solution, and the mixture was extracted with dichloromethane to obtain the β-amino acid benzyl ester.

[0049] The above β-amino acid benzyl ester was dissolved in 0.6 mL of acetonitrile, followed by the addition of 25 mg of Boc-proline, 0.055 mL of diisopropylethylamine, 0.026 mL of a 4 M dioxane solution of hydrochloric acid, and 25 mg of bromotripyrrolidinophosphonium hexafluorophosphate (PyBroP), and the mixture was stirred for 6 hours. A diluted aqueous solution of sodium hydroxide was added to the reaction mixture, followed by extraction with ethyl acetate and purification by silica gel chromatography (hexane:ethyl acetate = 90:10 to 70:30) to obtain 32 mg of the desired dipeptide 11. The NMR and mass spectrometry data for compound 11 are shown below. 1 H NMR (400 MHz, CDCl3) δ 0.89 (3H, d, J = 6.6 Hz), 0.92 (3H, d, J = 6.5 Hz), 1.16 (3H, d, J = 7.1 Hz), 1.46 (9H, s), 1.62-1.86 (3H, m), 1.90-2.20 (2H, m), 2.85 (1H, brs), 3.46 (2H, br), 3.77 (1H, brs), 4.31 (1H, brs), 5.07 (1H, d, J = 12.3 Hz), 5.13 (1H, d, J = 12.3 Hz), 6.83-7.05 (1H, m), 7.26-7.36 (5H, m); 13 C NMR (101 MHz, CDCl3) δ 15.8, 15.9, 19.5, 19.8, 28.3, 31.2, 31.7, 39.9, 40.4, 46.9, 56.7, 61.6, 66.3, 128.2, 128.3, 128.6, 135.6, 154.9, 175.3. HRMS (ESI) m / z: [M + Na] + C 24 H 36 Calculated for N2O5Na: 455.2516; Found: 455.2512.

[0050] [Synthesis of tripeptide 12] Tripeptide 12 was synthesized in the same manner as tripeptide 8, except that the β-amino acid benzyl ester was changed to a β-amino acid. The NMR and mass spectrometry data for compound 12 are shown below. 1H NMR (500 MHz, CDCl3) δ 0.86 (6H, d, J = 6.6 Hz), 1.21-1.27 (1H, m), 1.40-1.47 (1H, m), 1.45 (9H, s), 1.55-1.59 (1H, m), 1.84-2.04 (5H, m), 2.25 (1H, t, J = 8.5 Hz), 2.44-2.53 (2H, m), 2.66-2.76 (2H, m), 3.27-3.31 (1H, m), 3.46-3.49 (1H, m), 4.25-4.30 (1H, m), 4.42-4.52 (2H, m), 4.98 (1H, d, J = 13C NMR (126 MHz, CDCl3) δ 21.9, 22.9, 24.9, 27.5, 28.3, 31.5, 34.7, 39.1, 43.1, 44.2, 46.9, 51.2, 60.0, 66.2, 79.6, 126.0, 128.2, 128.39, 128.46, 128.47, 128.60, 135.6, 140.9, 155.5, 170.2, 171.3, 172.4; HRMS (ESI) m / z: [M + Na]+ C 34 H 47 Calculated for N3O6Na: 616.3357; Found: 616.3342.

[0051] [Synthesis of dipeptide 14] Dipeptide 14 was synthesized in the same manner as dipeptide 11, except that the Boc-β amino acid benzyl ester was changed. 1 H NMR (500 MHz, CDCl3) and 13 The C NMR (126 MHz, CDCl) spectra are shown in Figure 1. 1 H NMR (top) and 13Both C NMR (bottom) and C NMR (top) show that compound 14 is a mixture of unresolvable rotamers. Mass spectrometry data for compound 14 is as follows: HRMS (ESI) m / z: [M + Na] + C 26 H 32 Calculated for N2O5Na: 475.2203; Found: 475.2205.

[0052] Reference Example 1 Synthesis of dipeptide 13 Dipeptide 13 was synthesized in the same manner as dipeptide 11, except that the Boc-β-amino acid benzyl ester was changed. Note that dipeptide 13 is a compound described in Tetrahedron, 2011, 67, 3969, but is described here only as a model substance for asymmetric reactions. 1 H NMR (500 MHz, CDCl3, as a 1.5:1 mixture of rotamers) δ 1.38 (9H x 1.5 / 2.5, s), 1.50 (9H x 1 / 2.5, s), 1.92-2.35 (4H, m), 3.45-3.80 (2H, m), 4.28-4.30 (1H x 1.5 / 2.5, m), 4.58-4.66 (1H x 1 / 2.5, m), 5.33 (2H, s), 7.02-7.11 (1H, m), 7.32-7.44 (5H, m), 7.49-7.61 (1H, m), 8.05-8.12 (1H, m), 8.72-8.80 (1H, m), 11.54 (1H×1.5 / 2.5, s), 11.60 (1H×1 / 2.5, s); 13C NMR (126 MHz, CDCl3) δ 23.8, 24.3, 28.0, 28.2, 28.4, 30.5, 31.5, 46.8, 47.1, 62.1, 62.7, 66.7, 67.0, 80.1, 80.3, 115.2, 120.0, 120.3, 122.5, 122.6, 128.1, 128.3, 128.4, 128.6, 130.7, 130.9, 134.6, 134.7, 135.4, 141.1, 154.2, 167.6, 172.4; HRMS (ESI) m / z: [M + Na]+: Calculated for C24H28N2O5Na: 447.1890; Found: 447.1901.

[0053] Test Example 1: Evaluation of adhesion inhibitory activity and toxicity against Balanus fasciatus (1) Evaluation of adhesion inhibitory activity and toxicity against Balanus fasciatus cypris larvae The adhesion inhibitory activity of the synthesized tripeptides against Balanus fasciatus cypris larvae was evaluated. Approximately 2 mL of an ethanol solution of the test compound (tripeptides 2 to 10 and dipeptide 11) was dispensed into each well of a 24-well polystyrene multiwell plate (3.2 mL / well, well diameter 15.5 mm, well height 17.6 mm, Corning Incorporated), and the multiwell plate was then air-dried to evaporate the ethanol. The test compounds were dispensed to final concentrations of 0.03, 0.1, 0.3, 1, 3, and 10 μg / mL. Six cypris larvae of Balanus arvensis (hereinafter simply referred to as "barnacle larvae") were then transplanted into each well along with 2 mL of pre-filtered natural seawater. The multiwell plate was placed in an incubator at 25°C, and the barnacle larvae were allowed to grow at 25°C for two days. Following the same procedure, a control test was conducted by dispensing an ethanol solution containing no test compound. The natural seawater used in the test was natural seawater (salt concentration: 36 g / kg) collected from the coastal area near Onjuku, Chiba Prefecture, diluted with distilled water to a salt concentration of 32 g / kg. Following the same procedure, a comparison test was conducted by dispensing a copper sulfate solution for comparison. Four replicates (four wells) were tested for each concentration of each test compound in each of the test, control, and comparison groups.

[0054] Forty-eight hours after the start of the test, the number of attached and dead barnacle larvae in each well was counted under a stereomicroscope. The attachment rate (%) and mortality rate (%) of barnacle larvae in each well were calculated. A dose-attachment response curve was prepared for each test compound, and the median effective concentration (48hEC) required to inhibit 50% of barnacle larval attachment was calculated. ５０ Similarly, a dose-mortality response curve was prepared for each test compound, and the median lethal concentration (48hLC) at which 50% of the barnacle larvae died was determined. ５０The results are shown in Table 1 and Figures 1 to 5. For reference, the value for Boc-3 obtained in Non-Patent Document 8 is also shown.

[0055] 1 to 5, "mortality rate" refers to the ratio of the number of dead individuals to the total number of individuals, and "metamorphosis rate" refers to the ratio of the number of individuals that metamorphosed from larvae to attached adults to the total number of individuals. In particular, a lower metamorphosis rate indicates a stronger attachment inhibitory effect.

[0056]

[0057] Tripeptides 2–5, synthesized from inexpensive amino acids such as alanine, leucine, β-alanine, and GABA, did not exhibit adhesion inhibitory activity within the range of concentrations tested. Tripeptide 6, which incorporated a synthetic β-amino acid ester contained in the reference tripeptide, exhibited moderate adhesion inhibitory activity, while tripeptide 7, whose C-terminus is a carboxylic acid rather than an ester, did not. Based on this observation, we speculated that the presence of a β-amino acid ester at this position is important for adhesion inhibition. Based on this speculation, we introduced benzyl esters (Bn) or ethyl esters (Et) derived from commercially available β-amino acids into the tripeptides. As a result, benzyl esters exhibited adhesion inhibitory activity, but ethyl esters did not. We believe that the difference between the esters is due to the hydrophobicity of the substituents. Very few individuals died in these tests.

[0058] Test Example 2: Evaluation of Anti-Adhesion Activity and Toxicity Against Mussel Sprouts Tripeptides 8-10 were evaluated for their anti-adhesion activity against mussel juveniles. Samples were dissolved in ethanol to a concentration of 1 mg / mL. 30 and 100 μL of sample solution (30 and 100 μg) were mixed with solvent to make a 500 μL solution. This was spread on the bottom of a glass beaker used as a test vessel and shaken overnight to evaporate the solvent. This allowed the sample to adhere only to the bottom of the glass beaker. 10 mL of test seawater was added to the glass beaker used as a test vessel. Twelve test organisms were placed in each beaker of test seawater and the test was initiated. The test was completed after three days, and observations were made. At the end of the test at two concentrations, 3.0 μg / mL and 10 μg / mL, the condition of the mussel juveniles and the number of attached disks were examined. The results are shown in Table 2. Table 2 shows the proportion of non-adherent individuals (individuals that fell over or had their shells closed) at 3.0 μg / mL.

[0059] In Table 2, "bottom-attaching individuals" and "wall-attaching individuals" refer to individuals attached to the bottom and wall of the beaker, respectively; "bottom-crawling individuals" refer to individuals moving along the bottom without attaching; "overturned individuals / closed-shell individuals (unattached)" refer to individuals that have overturned or closed their shells without attaching to the bottom; and "number of byssus threads attached to the bottom" refers to the number of byssus threads attached to the bottom. In particular, the greater the decrease in the number of attached discs, the stronger the adhesion-inhibiting effect. No individuals died in these tests.

[0060]

[0061] [Control area] There were many adhered disks, and all of the individuals were attached to the bottom or walls. Therefore, it was an effective control area, and the test was successful. [Tripeptide 8] Adhesion to the bottom was observed, but the number of individuals was small. There were many overturned individuals and individuals with closed shells, and this increased with increasing concentration. The number of adhered disks decreased with increasing concentration. Therefore, it is determined that tripeptide 8 has an anti-adhesion effect.

[0062] [Tripeptide 9] Adhesion to the bottom surface was observed. With an increase in concentration, the number of bottom-adhering individuals decreased, the number of tipping individuals increased, and the number of adherent disks decreased. Therefore, compound 9 is concentration-dependent and is considered to be effective. [Tripeptide 10] Adhesion to the bottom surface was observed. With an increase in concentration, the number of bottom-adhering individuals and the number of tipping individuals did not change, but the number of adherent disks increased. Therefore, compound 10 is not concentration-dependent and is considered to be ineffective.

[0063] [Dolastatin 16] Adhesion to the bottom surface was observed, and the number of individuals was large. With an increase in concentration, there was no decrease in the number of bottom-adhering individuals, no increase in the number of overturned individuals, and the number of sessile disks decreased. Therefore, it is determined that Dolastatin 16 has no effect on preventing adhesion. [Boc-3] Adhesion to the bottom surface was observed, but the number of individuals was small. With an increase in concentration, the number of bottom-adhering individuals decreased, the number of overturned individuals increased, and the number of sessile disks decreased. Therefore, it is determined that Boc-3 is concentration-dependent and likely to be effective. [Copper sulfate] No adherent individuals were observed on either the bottom surface or the walls, and all were overturned individuals or individuals with closed shells. Only a small number of sessile disks were observed. The adhesion inhibitory effect was high.

[0064] [General] Interestingly, the results obtained were consistent with the above evaluation of the cyprid larvae of the barnacle, Mytilus edulis. That is, Compound 8 was effective against both barnacles and mussels.

[0065] Test Example 3 Evaluation of adhesion inhibitory activity and toxicity against Balanus nigricans (2) Tripeptide 12, dipeptide 13, and dipeptide 14 were tested in the same manner as in Test Example 1, and their adhesion inhibitory activity and toxicity were evaluated. The results obtained are shown in Table 3 and Figures 6 to 9, along with those of copper sulfate, which has been shown to have adhesion inhibitory activity.

[0066]

[0067] In one aspect, the present invention provides a compound represented by formula (1): [In the formula, R １ , R ２ , R ３ and R ４The present invention relates to a composition for inhibiting adhesion of marine sessile organisms, which comprises a dipeptide containing a proline residue or a tripeptide containing a proline residue and a phenylalanine residue, and the dipeptide is represented by the formula: １ , R ２ and R ３ The relationship between the cumulative carbon number and the effect of inhibiting adhesion of marine sessile organisms is summarized in Table 4 based on the results of Test Examples 1 to 3.

[0068] From Table 4, R １ , R ２ and R ３ From the viewpoint of the cumulative carbon number, it can be seen that the effect is weak up to 6, activity becomes clear from around 8, and activity is strengthened when it exceeds 10.

[0069] The compound was non-toxic and effective in inhibiting adhesion of barnacle larvae and mussels, which attach in different ways to marine structures and ship bottoms. Thus, a promising candidate for an effective inhibitor of adhesion against various sessile organisms present in the ocean was obtained.

[0070] According to the present invention, compositions for inhibiting the adhesion of marine sessile organisms (dipeptides consisting of a β-amino acid ester and a proline derivative, and tripeptides consisting of a β-amino acid ester, a proline derivative, and a phenylalanine derivative) have been synthesized inexpensively, simply, and with low environmental impact.

Claims

1. Formula (1): [In the formula, R １ is a substituted or unsubstituted C ３～１０ is a hydrocarbon group, R ２ and R ３ is a hydrogen atom or a substituted or unsubstituted C １～８ is a hydrocarbon group or R ２ and R ３ together with the adjacent carbon atoms to form a substituted or unsubstituted cyclic C １～１０ Form a hydrocarbon group, R ４ is a hydrogen atom, a substituted or unsubstituted C １～６ Hydrocarbon group, formula (2): (In the formula, R ５ is a hydrogen atom or C １～６ A carboxyl group or an alkoxyacyl group represented by the formula (3) or the formula (3'): (In the formula, R ６ is a hydrogen atom, C １～６ is a hydrocarbon group, or a carboxyl group or an alkoxyacyl group represented by the formula (2), Ph is a phenyl group, and the symbol * indicates the bond to the pyrrolidine group. １ is a benzyl group, R ２ and R ３ are both phenyl groups, and R ４ is a t-butoxycarbonyl group.] A dipeptide containing a proline residue, or a tripeptide containing a proline residue and a phenylalanine residue, represented by the following formula:

2. Substituent: R １ , R ２ and R ３ 2. The dipeptide containing a proline residue or the tripeptide containing a proline residue and a phenylalanine residue according to claim 1, wherein the cumulative carbon number in the dipeptide is 7 or more, preferably 9 or more, and more preferably 11 or more.

3. R １ Substituted or unsubstituted C in ３～１０ The hydrocarbon group is a substituted or unsubstituted linear or branched C ３～１０ Alkyl group; substituted or unsubstituted linear or branched C ３～１０ Alkenyl group; substituted or unsubstituted cyclic C ３～１０ Alkyl group; substituted or unsubstituted cyclic C ３～１０ alkenyl groups; and substituted or unsubstituted C ３～１０ alkyl-substituted aryl groups; R ２ and R ３ Substituted or unsubstituted C in １～８ The hydrocarbon groups are each independently substituted or unsubstituted linear or branched C １～８ Alkyl group; substituted or unsubstituted linear or branched C １～８ Alkenyl group; substituted or unsubstituted cyclic C １～８ Alkyl group; substituted or unsubstituted cyclic C １～８ alkenyl groups; and substituted or unsubstituted C １～８ alkyl-substituted aryl groups, and R ２ and R ３ together with the adjacent carbon atoms to form a substituted or unsubstituted cyclic C １～１０ Cyclic C when it is a hydrocarbon group １～１０ The hydrocarbon groups are each independently a substituted or unsubstituted cyclic C １～１０ Alkyl group; substituted or unsubstituted cyclic C １～１０ alkenyl groups; and substituted or unsubstituted C １～１０ alkyl-substituted aryl groups; R ４ Substituted or unsubstituted C in １～６ The hydrocarbon group is a substituted or unsubstituted linear or branched C １～６ Alkyl group; substituted or unsubstituted linear or branched C １～６ Alkenyl group; substituted or unsubstituted cyclic C １～６ Alkyl group; substituted or unsubstituted cyclic C １～６ alkenyl groups; and substituted or unsubstituted C １～６ alkyl-substituted aryl groups; and R ５ and R ６ Substituted or unsubstituted C in １～６ The hydrocarbon groups are each independently substituted or unsubstituted linear or branched C １～６ Alkyl group; substituted or unsubstituted linear or branched C １～６ Alkenyl group; substituted or unsubstituted cyclic C １～６ Alkyl group; substituted or unsubstituted cyclic C １～６ 2. A dipeptide containing a proline residue or a tripeptide containing a proline residue and a phenylalanine residue according to claim 1, wherein the dipeptide is selected from an alkenyl group; and a substituted or unsubstituted phenyl group.

4. R １ Substituted or unsubstituted C in ３～１０ Hydrocarbon group C ３～１０ The hydrocarbon group is a linear or branched alkyl group selected from the group consisting of a propyl group, a butyl group, a pentyl group, a hexyl group, a heptyl group, an octyl group, a nonyl group, and a decyl group; a linear or branched alkenyl group selected from the group consisting of a propenyl group, a butenyl group, a pentenyl group, a hexenyl group, a heptenyl group, an octenyl group, a nonenyl group, and a decenyl group; a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, a cyclohex ... R is selected from the group consisting of a cyclic alkyl group selected from the group consisting of a cycloalkyl group, a cyclononyl group, and a cyclodecyl group; a cyclic alkenyl group selected from the group consisting of a cyclopropenyl group, a cyclobutenyl group, a cyclopentenyl group, a cyclohexenyl group, a cycloheptenyl group, a cyclooctenyl group, a cyclononenyl group, and a cyclodecenyl group; an aryl group selected from the group consisting of a phenyl group, an alkyl-substituted phenyl group such as a naphthyl group, a tolyl group, an ethylphenyl group, a xylyl group, and the like, and a benzyl group; ２ and R ３ Substituted or unsubstituted C in １～８ Hydrocarbon group C １～８ each of the hydrocarbon groups is independently selected from the group consisting of a linear or branched alkyl group selected from the group consisting of a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group, a heptyl group, and an octyl group; a linear or branched alkenyl group selected from the group consisting of an ethenyl group, a propenyl group, a butenyl group, a pentenyl group, a hexenyl group, a heptenyl group, and an octenyl group; a cyclic alkyl group selected from the group consisting of a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and a cyclooctyl group; a cyclic alkenyl group selected from the group consisting of a cyclopropenyl group, a cyclobutenyl group, a cyclopentenyl group, a cyclohexenyl group, a cycloheptenyl group, and a cyclooctenyl group; an aryl group selected from a phenyl group, an alkyl-substituted phenyl group such as a tolyl group, an ethylphenyl group, and a xylyl group, and a benzyl group; ５ and R ６ Substituted or unsubstituted C in １～６ Hydrocarbon group C １～６ 2. The dipeptide containing a proline residue or the tripeptide containing a proline residue and a phenylalanine residue according to claim 1, wherein the hydrocarbon groups are each independently selected from the group consisting of a linear or branched alkyl group selected from the group consisting of a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, and a hexyl group; a linear or branched alkenyl group selected from the group consisting of an ethenyl group, a propenyl group, a butenyl group, a pentenyl group, and a hexenyl group; a cyclic alkyl group selected from the group consisting of a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group; a cyclic alkenyl group selected from the group consisting of a cyclopropenyl group, a cyclobutenyl group, a cyclopentenyl group, and a cyclohexenyl group; and a phenyl group.

5. Formula (1): [In the formula, R １ is a substituted or unsubstituted C ３～１０ is a hydrocarbon group, R ２ and R ３ is a hydrogen atom or a substituted or unsubstituted C １～８ is a hydrocarbon group or R ２ and R ３ together with the adjacent carbon atoms to form a substituted or unsubstituted cyclic C １～１０ Form a hydrocarbon group, R ４ is a hydrogen atom, C １～６ Hydrocarbon group, formula (2): (In the formula, R ５ is a hydrogen atom or C １～６ A carboxyl group or an alkoxyacyl group represented by the formula (3) or the formula (3'): (In the formula, R ６ is a hydrogen atom, C １～６ A hydrocarbon group, or a carboxyl group or an alkoxyacyl group represented by the formula (2), where Ph is a phenyl group, and the symbol * indicates the bond to the pyrrolidine group. １ , R ２ and R ３ The cumulative carbon number in the formula (I) is 7 or more, preferably 9 or more, and more preferably 11 or more.