Macrocyclic compound including peptide structure and method for producing same

Abstract

[Problem] To provide: a macrocyclic compound which includes an oligoamino acid or an oligo-peptide, and which has been conventionally difficult to synthesize; and a method for producing the same. [Solution] The present inventors have newly discovered that, by reacting a dicarboxylic acid compound (diester compound) having amino acid residues at both ends of a spacer with a diamine acid compound having amino acid residues at both ends of a spacer, it is possible to synthesize a macrocyclic compound which includes an oligoamino acid or an oligopeptide in a molecule and in which the type and / or the composition ratio of amino acids can be changed.

Description

Macrocyclic compounds containing peptide structures and methods for producing the same

[0001] The present invention relates to a macrocyclic compound containing an oligoamino acid or oligopeptide in its structure, and a method for producing the same.

[0002] Compared to small molecule drugs, peptides have the advantage of being able to recognize target molecules three-dimensionally, resulting in greater effectiveness. In particular, by forming them into cyclic peptides, the conformation of the main chain can be fixed, greatly improving specificity. Cyclic peptides are useful as target-specific pharmaceutical materials, and various synthetic methods have been developed to synthesize cyclic peptide compounds with novel structures (Patent Documents 1 to 5).

[0003] In general, it is difficult to synthesize macrocyclic compounds in high yields by chemical synthesis. When synthesizing by ring-closure reaction, the reaction is carried out in a dilute solution to suppress the formation of high-molecular-weight linear compounds, and specific synthesis conditions are required to obtain the target compound in high yield. For example, the synthesis of crown ethers, which are cyclic compounds, is carried out in the presence of metal ions (Non-Patent Document 1).

[0004] Meanwhile, the production of polyamino acids, oligopeptides, and polypeptides by enzymatic synthesis using enzymes such as papain and proteinase K has been reported (Non-Patent Documents 2 to 8). Compared with chemical synthesis methods such as Fmoc (Fluorenyl-Methoxy-Carbonyl) solid-phase synthesis, a conventional method for producing peptides, enzymatic synthesis has excellent stereoisomeric selectivity, high yield, low cost, and atom economy, and is expected to be applied as a green chemical synthesis method. However, the synthesis of cyclic peptides and cyclic compounds containing peptides using enzymatic synthesis methods has not been successful.

[0005] International Publication WO2008 / 117833 International Publication WO2012 / 005313 International Publication WO2012 / 157674 International Publication WO2021 / 132661 International Publication WO2023 / 068215

[0006] Reed M. I. Baker J. et al., Chemical Reviews 1991; 91: 1721-2085. P. et al., Biomacromolecules 2012; 13: 947-951 Fagerland J. et al. Biomacromolecules 2014; 15: 735-743 Ageitos M. et al. J. et al., Macromol. Biosci. 2015; 15: 990-1003 Tsuchiya K. et al., Macromol. Biosci. 2016; 16: 1001-1008 Tsuchiya K. et al., ACS Macro Lett. 2017; 6: 103-106; Tsuchiya K. et al., Polym. Chem. 2020; 11: 560-567; Terada K. et al., Macromolecules 2022; 55: 6992-7002

[0007] Therefore, an object of the present invention is to provide a macrocyclic compound containing an oligoamino acid or oligopeptide, which has been difficult to synthesize in the past, and a method for producing the same.

[0008] In response to this problem, the present inventors have newly discovered that a macrocyclic compound containing an oligoamino acid or oligopeptide in the molecule and capable of varying the type and / or composition ratio of amino acids can be synthesized by reacting a dicarboxylic acid compound (a diester compound having a protecting group) having amino acid residues at both ends of a spacer with a diamine acid compound having amino acid residues at both ends of a spacer, and have thus completed the present invention.

[0009] That is, the present invention relates to a macrocyclic compound containing an oligoamino acid or an oligopeptide in the molecule, and more specifically, to <1> a cyclic compound containing an oligopeptide moiety represented by the following formula (1): (wherein each X is independently a residue of a natural or unnatural amino acid, which may be the same or different; n is a natural number from 2 to 10; and spacer L １ and L ２are each independently a divalent linking group selected from the group consisting of alkylene, alkenylene, alkynylene, which may have any substituent, and a group in which one or more carbon atoms constituting the alkylene, alkenylene, or alkynylene are substituted with -O-, -S-, -NH-, -, or -C(=O)-; <2> X is a residue of an amino acid selected from the group consisting of glycine, alanine, valine, leucine, isoleucine, phenylalanine, tryptophan, methionine, cysteine, proline, serine, threonine, tyrosine, asparagine, glutamine, aspartic acid, glutamic acid, lysine, arginine, histidine, and an amino acid represented by formula (2), In formula (2), R １ represents a hydrogen atom or an alkyl group having 1 to 20 carbon atoms which may have an optional substituent; Y represents a divalent group represented by the following formula (3) or (4) or a combination thereof: In formulas (3) and (4), each R ２ are each independently selected from the group consisting of a hydrogen atom, an alkyl group having 1 to 20 carbon atoms which may have an optional substituent, and an aryl group having 6 to 20 carbon atoms which may have an optional substituent; and m is a natural number of 1 to 10; <3> The cyclic compound according to the above <2>, wherein the amino acid represented by formula (2) is a compound represented by the following formula (2-1), (2-2), or (2-3): (In these formulas, R ２ and m are defined as in claim 2; and m' in formula (2-2) is a natural number from 2 to 20.); <4> The cyclic compound according to the above <1>, having a ring structure of 50 or more members; <5> The cyclic compound according to the above <1>, in which [X]n is a combination of two or more types of amino acid residues; <6> The cyclic compound according to the above <1>, in which [X]n is composed of residues of the same amino acid; <7> L １ or L ２ The cyclic compound according to the above <1>, wherein L contains an ether chain; and <8> L １ and L ２The cyclic compound according to the above item <1>, wherein the compound (I) contains an oligoethylene glycol chain having 2 to 16 carbon atoms.

[0010] In another aspect, the present invention relates to a method for producing the cyclic compound, more specifically, <9> a method for producing the cyclic compound according to any one of <1> to <8> above, comprising: L １ a dicarboxylic acid compound having one or more amino acid residues linked to both ends of the compound and further having carboxyl groups at both ends, or a diester compound in which the carboxyl groups are protected with any protecting group; and L ２ <10> the production method according to the above item <9>, in which the reaction is carried out in the presence of an enzyme; and <11> the production method according to the above item <10>, in which the enzyme is an endopeptidase.

[0011] According to the present invention, it is possible to provide macrocyclic compounds having 50 or more members containing oligoamino acids or oligopeptides, which have been difficult to synthesize in the past. Furthermore, according to the production method of the present invention, it is possible to efficiently synthesize such macrocyclic compounds while freely changing the types and / or composition ratios of the amino acids that constitute the macrocyclic compounds.

[0012] The following describes embodiments of the present invention. The scope of the present invention is not limited to these descriptions, and other than the following examples, the present invention can be implemented with appropriate modifications within the scope that does not depart from the spirit of the present invention.

[0013] (1) Definitions In this specification, the term "amino acid residue" refers to a structure corresponding to the partial structure (acyl group) remaining after removing the hydroxyl group from the carboxyl group of an amino acid. Furthermore, the term "amino acid" refers to any compound having both an amino group and a carboxyl group, including natural and unnatural amino acids. Neutral, basic, or acidic amino acids may be used. In addition to amino acids that function as neurotransmitters and other transmitters, amino acids that are components of polypeptide compounds such as physiologically active peptides (including dipeptides, tripeptides, tetrapeptides, and oligopeptides) and proteins may also be used. For example, α-amino acids, β-amino acids, γ-amino acids, etc. may be used. Optically active amino acids are preferably used as amino acids. For example, while either D- or L-amino acids may be used for α-amino acids, it may be preferable to select optically active amino acids that function in living organisms.

[0014] In this specification, "alkyl (or alkyl group)" may be any of a linear, branched, or cyclic aliphatic hydrocarbon groups, or a combination thereof. The number of carbon atoms in the alkyl group is not particularly limited, but for example, alkyl groups having 1 to 20 carbon atoms (C １～２０ ), carbon number 1 to 15 (C １～１５ ), carbon number 1 to 10 (C １～１０ In the present specification, the alkyl group may have one or more optional substituents. For example, C １～８Alkyl includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neo-pentyl, n-hexyl, isohexyl, n-heptyl, n-octyl, and the like. Examples of the substituent include, but are not limited to, an alkoxy group, a halogen atom (which may be a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom), an amino group, a mono- or di-substituted amino group, a substituted silyl group, or an acyl. When an alkyl group has two or more substituents, these may be the same or different. The same applies to the alkyl moiety of other substituents containing an alkyl moiety (e.g., an alkoxy group, an arylalkyl group, and the like).

[0015] In the present specification, "alkylene" refers to a divalent group consisting of a linear or branched saturated hydrocarbon, and examples thereof include methylene, 1-methylmethylene, 1,1-dimethylmethylene, ethylene, 1-methylethylene, 1-ethylethylene, 1,1-dimethylethylene, 1,2-dimethylethylene, 1,1-diethylethylene, 1,2-diethylethylene, 1-ethyl-2-methylethylene, trimethylene, 1-methyltrimethylene, 2-methyltrimethylene, 1,1-dimethyltrimethylene, 1,2 2-dimethyltrimethylene, 2,2-dimethyltrimethylene, 1-ethyltrimethylene, 2-ethyltrimethylene, 1,1-diethyltrimethylene, 1,2-diethyltrimethylene, 2,2-diethyltrimethylene, 2-ethyl-2-methyltrimethylene, tetramethylene, 1-methyltetramethylene, 2-methyltetramethylene, 1,1-dimethyltetramethylene, 1,2-dimethyltetramethylene, 2,2-dimethyltetramethylene, 2,2-di-n-propyltrimethylene, and the like.

[0016] In the present specification, the term "alkenylene" refers to a divalent group consisting of a straight-chain or branched unsaturated hydrocarbon having at least one carbon-carbon double bond, and examples thereof include ethenylene, 1-methylethenylene, 1-ethylethenylene, 1,2-dimethylethenylene, 1,2-diethylethenylene, 1-ethyl-2-methylethenylene, propenylene, 1-methyl-2-propenylene, 2-methyl-2-propenylene, Examples include 1,1-dimethyl-2-propenylene, 1,2-dimethyl-2-propenylene, 1-ethyl-2-propenylene, 2-ethyl-2-propenylene, 1,1-diethyl-2-propenylene, 1,2-diethyl-2-propenylene, 1-butenylene, 2-butenylene, 1-methyl-2-butenylene, 2-methyl-2-butenylene, 1,1-dimethyl-2-butenylene, and 1,2-dimethyl-2-butenylene.

[0017] In the present specification, the term "alkynylene" refers to a divalent group consisting of a straight-chain or branched unsaturated hydrocarbon having at least one carbon-carbon triple bond, and examples thereof include ethynylene, 1-propynylene, 2-propynylene, 1-butynylene, 1-pentynylene, 2-pentynyl, 1-hexynylene, 2-hexynylene, 1-heptynylene, 1-octynylene, and the like.

[0018] In this specification, the term "aryl (or aryl group)" may be either a monocyclic or fused polycyclic aromatic hydrocarbon group, or may be an aromatic heterocycle containing one or more heteroatoms (e.g., oxygen, nitrogen, or sulfur atoms) as ring-constituting atoms. In this case, it is referred to as a "heteroaryl group" or a "heteroaromatic group." Whether the aryl is a monocyclic or fused ring, it may be bonded at any available position. Non-limiting examples of monocyclic aryls include a phenyl group (Phe), a thienyl group (2- or 3-thienyl group), a pyridyl group, a furyl group, a thiazolyl group, an oxazolyl group, a pyrazolyl group, a 2-pyrazinyl group, a pyrimidinyl group, a pyrrolyl group, an imidazolyl group, a pyridazinyl group, a 3-isothiazolyl group, a 3-isoxazolyl group, a 1,2,4-oxadiazol-5-yl group, or a 1,2,4-oxadiazol-3-yl group. Non-limiting examples of fused polycyclic aryls include 1-naphthyl, 2-naphthyl, 1-indenyl, 2-indenyl, 2,3-dihydroinden-1-yl, 2,3-dihydroinden-2-yl, 2-anthryl, indazolyl, quinolyl, isoquinolyl, 1,2-dihydroisoquinolyl, 1,2,3,4-tetrahydroisoquinolyl, indolyl, isoindolyl, phthalazinyl, quinoxalinyl, benzofuranyl, 2,3-dihydrobenzofuran- Examples of the aryl group include a 1-yl group, a 2,3-dihydrobenzofuran-2-yl group, a naphthyridinyl group, a dihydronaphthyridinyl group, a tetrahydronaphthyridinyl group, an imidazopyridinyl group, a pteridinyl group, a purinyl group, a quinolidinyl group, an indolizinyl group, a tetrahydroquinolidinyl group, and a tetrahydroindolizinyl group, a 2,3-dihydrobenzothiophen-1-yl group, a 2,3-dihydrobenzothiophen-2-yl group, a benzothiazolyl group, a benzimidazolyl group, a fluorenyl group, and a thioxanthenyl group. In the present specification, the aryl group may have one or more optional substituents on the ring. Examples of the substituent include, but are not limited to, an alkoxy group, a halogen atom, an amino group, a mono- or di-substituted amino group, a substituted silyl group, and an acyl group. When the aryl group has two or more substituents, the substituents may be the same or different.The same applies to the aryl moiety of other substituents containing an aryl moiety (for example, an aryloxy group or an arylalkyl group).

[0019] As used herein, an "ether group" refers to a functional group having at least one ether bond (-O-) in the alkyl chain. Similarly, a "thioether group" refers to a functional group having at least one thioether bond (-S-) in the alkyl chain.

[0020] As used herein, "amide" includes both RNR'CO-- (when R=alkyl, alkylaminocarbonyl-) and RCONR'-- (when R=alkyl, alkylcarbonylamino-).

[0021] As used herein, "ester" includes both ROCO--(when R=alkyl, alkoxycarbonyl-) and RCOO--(when R=alkyl, alkylcarbonyloxy-).

[0022] In this specification, when a functional group is defined as "optionally having a substituent," the type, substitution position, and number of the substituent are not particularly limited, and when two or more substituents are present, they may be the same or different. Examples of the substituent include, but are not limited to, alkyl groups, alkoxy groups, hydroxyl groups, carboxyl groups, halogen atoms, sulfo groups, amino groups, alkoxycarbonyl groups, and oxo groups. These substituents may further have a substituent. Examples of such substituents include, but are not limited to, halogenated alkyl groups.

[0023] As used herein, the term "ring structure" means a heterocyclic or carbocyclic ring when formed by the combination of two substituents, and such rings can be saturated, unsaturated, or aromatic, and thus includes cycloalkyl, cycloalkenyl, aryl, and heteroaryl, as defined above.

[0024] As used herein, certain substituents can form ring structures with other substituents, and when such substituents are bonded together, those skilled in the art will understand that certain substitutions, such as bonds to hydrogen, are formed. Thus, when certain substituents are described as forming a ring structure, those skilled in the art will understand that such ring structures can be formed and are readily produced by conventional chemical reactions. Both such ring structures and the processes for their formation are within the knowledge of those skilled in the art. Furthermore, such ring structures may have optional substituents on the ring.

[0025] (2) Cyclic Compound of the Present Invention The cyclic compound containing an oligopeptide moiety of the present invention is characterized by having a structure represented by the following formula (1):

[0026] In formula (1), each X is independently a residue of a natural or unnatural amino acid, which may be the same or different. As described above, "amino acid residue" refers to a structure corresponding to the partial structure remaining after removing the hydroxyl group from the carboxyl group of an amino acid. Adjacent Xs are linked to each other by forming an amide bond, as in a normal peptide chain.

[0027] The amino acid for X includes not only the 20 types of α-amino acids (glycine, alanine, valine, leucine, isoleucine, phenylalanine, tryptophan, methionine, cysteine, proline, serine, threonine, tyrosine, asparagine, glutamine, aspartic acid, glutamic acid, lysine, arginine, and histidine) that constitute natural proteins, but also other amino acids. In this specification, the 20 types of α-amino acids are referred to as "natural amino acids," and amino acids other than the natural amino acids are referred to as "unnatural amino acids." The amino acids may be naturally occurring, or may be artificially synthesized or modified amino acids or amino acid derivatives.

[0028] A preferred example of the unnatural amino acid is an amino acid represented by the following formula (2):

[0029] In formula (2), R １is a hydrogen atom or an alkyl group having 1 to 20 carbon atoms which may have any substituent. The alkyl group may be linear, branched, or cyclic, and specific examples thereof include a methyl group, an ethyl group, a propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group, a hexyl group, a cyclohexyl group, a heptyl group, an octyl group, a nonyl group, a decyl group, and a dodecyl group. Preferably, R １ is an alkyl group having 1 to 10 carbon atoms. Particularly preferably, R １ is a methyl group.

[0030] R １ Examples of the optional substituent that R may have include, but are not limited to, a halogen atom (which may be any of a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom); a hydroxy group; an amino group; a mono- or di-substituted amino group; a substituted silyl group; a carboxyl group; and an aryl group. Alternatively, R may be a protecting group such as a tert-butoxycarbonyl (Boc) group, a 9-fluorenylmethyloxycarbonyl (Fmoc) group, a benzyloxycarbonyl (Cbz) group, a trityl group, or a benzyl group. １ When has two or more substituents, they may be the same or different.

[0031] In formula (2), Y is a divalent group represented by the following formula (3) or (4), or a combination thereof.

[0032] In both formulas (3) and (4), each R ２ are each independently selected from the group consisting of a hydrogen atom, an alkyl group having 1 to 20 carbon atoms which may have an optional substituent, and an aryl group having 6 to 20 carbon atoms which may have an optional substituent. The alkyl group may be linear, branched, or cyclic, and specific examples thereof include a methyl group, an ethyl group, a propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group, a hexyl group, a cyclohexyl group, a heptyl group, an octyl group, a nonyl group, a decyl group, and a dodecyl group. Preferably, R １is an alkyl group having 1 to 10 carbon atoms. Particularly preferably, R １ is a methyl group.

[0033] Also, R ２ The aryl group having 6 to 20 carbon atoms, which may have any substituent, in the formula (I) may be monocyclic or polycyclic, and specific examples thereof include a phenyl group, a benzyl group, a tolyl group, a xylyl group, and a naphthyl group.

[0034] R ２ Examples of the optional substituent that R may have include, but are not limited to, a halogen atom (which may be any of a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom); a hydroxy group; an amino group; a mono- or di-substituted amino group; a substituted silyl group; a carboxyl group; and an aryl group. Alternatively, R may be a protecting group such as a tert-butoxycarbonyl (Boc) group, a 9-fluorenylmethyloxycarbonyl (Fmoc) group, a benzyloxycarbonyl (Cbz) group, a trityl group, or a benzyl group. ２ When has two or more substituents, they may be the same or different.

[0035] In both formulas (3) and (4), m is a natural number of 1 to 10, preferably 2 to 5.

[0036] In a preferred embodiment, the unnatural amino acid represented by formula (2) can be a compound represented by the following formula (2-1), (2-2), or (2-3).

[0037] In formulas (2-1) to (2-3), R ２ and m are as defined above. In formula (2-2), m' is a natural number of 2 to 20, preferably 2 to 5.

[0038] As described above, each X in formula (1) may be independently the same or different, but in a preferred embodiment, each X may represent two or more different types of amino acids. In this case, [X]n is an oligopeptide consisting of a combination of two or more types of amino acid residues.

[0039] In another preferred embodiment, each X can be the same single amino acid, in which case [X]n becomes an oligopeptide (oligoamino acid) consisting of residues of the same amino acid.

[0040] In formula (1), n ​​is a natural number of 2 to 10, preferably 2 to 5.

[0041] L in formula (1) １ and L ２ are spacers, and each independently may be an alkylene, alkenylene, alkynylene, or a combination thereof, which may have any substituent. Alternatively, they may be a divalent linking group selected from the group consisting of groups in which one or more carbon atoms constituting these alkylenes, alkenylenes, and alkynylenes are substituted with -O-, -S-, -NH-, -, or -C(=O)-. For example, such divalent linking groups in which one or more carbon atoms are substituted include ether chains containing one or more oxygen atoms (-O-), alkylene-C(=O)-alkylene, and alkylene-N(H)-C(=O)-alkylene. Furthermore, the branched structure may have a branched structure having a substituent on the side chain.

[0042] L １ and L ２ The number of carbon atoms in the group is not particularly limited, but may be, for example, 1 to 30, and preferably 3 to 20.

[0043] In a preferred embodiment, L １ and / or L ２ can contain a structure in which some of the carbon atoms in the alkylene are replaced with oxygen atoms (—O—), i.e., an ether chain. More preferably, L １ and / or L ２ may contain an oligoethylene glycol chain having 2 to 16 carbon atoms. １ and L ２ However, both of them contain an oligoethylene glycol chain. １ and / or L ２ may further have a carbonyl group or an amide group in the chain.

[0044] The cyclic compound of the present invention represented by formula (1) preferably has a ring structure of 50 or more members. Such macrocyclic compounds containing an oligopeptide moiety are novel compounds that could not be obtained by conventional synthetic methods. Preferably, the cyclic compound of the present invention has a ring structure of 50 to 80 members, more preferably 50 to 80 members.

[0045] (2) Cyclic Compound of the Present Invention In another aspect, the present invention also relates to a method for producing the cyclic compound. As described above, the inventors have newly discovered that a macrocyclic compound containing an oligoamino acid or oligopeptide in the molecule and capable of varying the type and / or composition ratio of amino acids can be synthesized by reacting a dicarboxylic acid compound or a diester compound having amino acid residues at both ends of a spacer with a diamine acid compound having amino acid residues at both ends of a spacer.

[0046] More specifically, the manufacturing method of the present invention is １ and a dicarboxylic acid compound having carboxyl groups at both ends thereof or a diester compound in which the carboxyl groups are protected with any protecting group; and ２ The method is characterized by comprising a step of linking one or more amino acid residues to both ends of the diester compound and further reacting the resulting compound with a diamine compound having amino groups at both ends. As the protecting group in the diester compound, any group generally known in the art as a protecting group for a carboxyl group can be used, and examples thereof include a methyl group, an ethyl group, and a phenyl group.

[0047] Here, L １ and L ２ represents the spacer L in formula (1). １ and L ２ The "amino acid residue" in the dicarboxylic acid compound (diester compound) and the diamine compound corresponds to X in formula (1), and the details thereof are as described above.

[0048] The production method of the present invention is a method for producing a cyclic compound by chemical synthesis, particularly by chemical enzymatic polymerization, using the above-mentioned dicarboxylic acid compound (diester compound) and diamine compound as raw materials. Therefore, in a preferred embodiment, the production method of the present invention can be carried out in the presence of an enzyme.

[0049] As used herein, "chemical synthesis" refers to the production of a target compound using a chemical reaction, and does not include reactions carried out using living organisms such as microorganisms, for example, methods of producing polypeptides or proteins using microorganisms by introducing recombinant genes. Furthermore, the term "chemical synthesis" as used herein includes the production of a desired compound using an enzyme isolated or separated from an organism, or an enzyme contained in a composition derived from an organism. As used herein, the term "chemical synthesis method" refers to a method for carrying out the aforementioned "chemical synthesis."

[0050] As used herein, "enzymatic synthesis" refers to a reaction catalyzed by an enzyme without using a living organism such as a microorganism, and the substrates, products, and / or reaction conditions in the reaction do not necessarily correspond to those of an enzymatic reaction carried out in a living organism. Furthermore, as used herein, "enzymatic synthesis method" refers to a method for carrying out "enzymatic synthesis." Therefore, in a preferred embodiment, the production method of the present invention can be carried out in the presence of an enzyme. Such an enzyme is preferably an endopeptidase.

[0051] For example, papain, an endopeptidase and a type of cysteine ​​protease, catalyzes the reaction of cleaving peptide bonds in proteins (aminolysis), i.e., the reaction of hydrolyzing peptide bonds, hence the name. In this hydrolysis reaction, a peptide coordinates with the catalytic site of papain, forming an acyl-enzyme intermediate, where the H ２ O undergoes a nucleophilic reaction, cleaving the peptide bond and generating an amine and a carboxylic acid. However, papain reacts with the acyl-enzyme intermediate in the presence of an amino acid ester derivative. ２The amino group of the amino acid ester derivative, instead of O, undergoes a nucleophilic reaction, bonding the amino group and acyl group of a different molecule of the amino acid derivative substrate to form a peptide bond. By this mechanism, a cyclic compound containing an oligopeptide moiety can be synthesized from the dicarboxylic acid compound and diamine compound.

[0052] In addition, the production method of the present invention can also be carried out using enzymes known in the technical field other than papain, which is used in the examples described below. Examples of such other enzymes include those described in Non-Patent Documents 4 to 15.

[0053] The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these examples.

[0054] 1. Experimental Materials and Methods (1) Reagents Papain (EC number 3.4.22.2) was purchased from Wako Pure Chemical Industries, Ltd. (Osaka) and used as is. The enzyme activity of papain was approximately 0.5 Ug －１ (One unit is defined as the amount of enzyme that decomposes 1 μmol of N-benzoyl-DL-arginine p-nitroanilide in 1 minute at pH 7.5 and 25°C.) N-methyl-2-pyrrolidone (NMP), N,N-dimethylacetamide (DMAc), diethyl ether, and triethylamine were used after drying with 4 Å molecular sieves. Other reagents were purchased from Tokyo Chemical Industry Co., Ltd. (Tokyo) and, unless otherwise noted, were used as is without purification.

[0055] (2) １ H-NMR measurement １ H-nuclear magnetic resonance (NMR) spectra were measured at 25°C using a JNM-EX400 (400 MHz, JEOL Ltd., Tokyo) at a frequency of 400 MHz. Sample solutions of the synthesized compounds were prepared using chloroform-d (CDCl) containing tetramethylsilane as an internal standard. ３ ), dimethyl sulfoxide-d ６ (DMSO-d ６ ), or trifluoroacetic acid-d (TFA-d) was used as the solvent.

[0056] (3) MALDI-TOF MS Measurements Matrix-assisted laser desorption / ionization time-of-flight (MALDI-TOF) mass spectrometry was performed using an Autoflex Speed ​​MALDI-TOF-MS system spectrophotometer (Bruker, Germany) in linear positive ion mode. The sample was prepared in a water / acetonitrile (0.8 mg mL) solution containing 0.1% TFA. －１ ) and a water / acetonitrile solution of α-cyano-4-hydroxycinnamic acid (CHCA) (10 mg mL －１ ) and dropped onto a MTP 384 ground steel BC target plate.

[0057] (4) WAXD Measurement Synchrotron wide-angle X-ray diffraction (WAXD) measurements were performed on the polypeptide powder sample using the BL05XU beamline of SPring-8 with an X-ray energy of 12.4 keV (wavelength: 0.1 nm).

[0058] 2. Synthesis of Cyclic Compounds of the Present Invention 2-1 Synthesis of Diester Compounds and Diamine Compounds (1) Synthesis of OEt-G-OEG First, dicarboxylic acid compound 1 was synthesized by the following method.

[0059] To a flask equipped with a dropping funnel and a stirrer, 20 mL of ethyl acetate, Diethylene Glycol Bis(3-aminopropyl) Ether (6.54 mL, 30 mmol), and triethylamine (8.31 mL, 60 mmol) were added under a simple argon atmosphere using a rubber balloon. A solution of succinic anhydride (6.00 g, 60 mmol) in ethyl acetate (150 mL) was added dropwise to the flask. Stirring was continued after the dropwise addition, and the mixture was allowed to react for 16 hours, yielding a dark brown, viscous precipitate. The resulting precipitate was decanted and washed twice with ethyl acetate, and then dried under vacuum. The synthesized 4,20-dioxo-9,12,15-trioxa-5,19-diazatricosanedioic acid was designated as dicarboxylic acid compound 1. The sticky precipitate obtained after drying was a mixture of three compounds: dicarboxylic acid compound 1, ethyl acetate, and triethylamine. １The respective quantitative ratios were determined from the integrated values ​​of H-NMR. １ The molar ratio of dicarboxylic acid compound 1 to ethyl acetate and triethylamine determined by H-NMR was 100:21:78, and therefore the weight ratio of dicarboxylic acid compound 1 was calculated to be 81%. The weight of the obtained raw product was 14.4 g, and the yield of dicarboxylic acid compound 1 was 11.6 g (93%).

[0060] Subsequently, OEt-G-OEG having a glycine residue was synthesized from dicarboxylic acid compound 1.

[0061] Glycine ethyl ester hydrochloride (7.15 g, 51 mmol), HOBt (anhydrous) (6.92 g, 51 mmol), and triethylamine (14.20 mL, 102 mmol) were added to a chloroform (50 mL) solution of 13.3 g of the resulting raw product of dicarboxylic acid compound 1 (dicarboxylic acid compound 1: 10.8 g, 26 mmol) under ice-cooling, and the atmosphere was simply purged with argon using a rubber balloon. A chloroform (150 mL) solution of WSCI.HCl (9.82 g, 51 mmol) was added dropwise to the flask.

[0062] After the dropwise addition, the ice cooling was removed and the mixture was stirred at room temperature for 24 hours. The resulting mixture was washed successively with pure water and 3% aqueous sodium bicarbonate solution. The washed organic layer was dried over magnesium sulfate and concentrated using a rotary evaporator. The resulting product was dried under vacuum to give an ochre sandy solid, OEt-G-OEG, in a yield of 1.68 g (12%).

[0063] (3) NH ２ Synthesis of Boc-G-OEG First, Boc-G-OEG was synthesized by the following procedure.

[0064] Diethylene Glycol Bis(3-aminopropyl) Ether (1.56 mL, 7.2 mmol), HOBt (anhydrous) (1.94 g, 14 mmol), and triethylamine (1.99 mL, 14 mmol) were added to a flask equipped with a dropping funnel and a stirrer bar. While stirring under ice cooling, a solution of WSCI·HCl (2.75 g, 14 mmol) in chloroform (70 mL) was added dropwise. After the dropwise addition, the ice cooling was removed and the mixture was stirred for 24 hours. The resulting mixture was washed with purified water, 1 M hydrochloric acid, and 3% aqueous sodium bicarbonate. Magnesium sulfate was then added, the mixture was dried, and the mixture was concentrated on a rotary evaporator. Further drying under vacuum yielded a colorless, transparent, viscous crude product (3.85 g).

[0065] １ When the crude product was confirmed by H-NMR, it was found that chloroform remained after removal. １ The ratio of the amount of the target product to chloroform was determined from H-NMR, and the net yield and net yield were calculated. In this system, the molar ratio of the target product to chloroform was 10:7, which indicated a purity of 86%. From this, the net yield was calculated to be 3.33 g (87%).

[0066] Subsequently, the obtained Boc-G-OEG was subjected to deprotection of the Boc group to give an NH having a glycine residue. ２ -G-OEG was synthesized.

[0067] ​The resulting Boc-G-OEG (3.33 g, 6.2 mmol), chloroform (3.74 mL, 47 mmol), and trifluoroacetic acid (TFA) (4.77 mL, 62 mmol) were added to a flask equipped with a stir bar and stirred at room temperature for 3 hours. After completion of the reaction, the mixture was vacuum dried for 2.5 hours using a vacuum pump. After drying, the mixture was decanted with diethyl ether, and then washed with diethyl ether (20 mL) by adding and stirring for 20 hours. After washing, the mixture was vacuum dried, yielding a dark yellow, highly viscous liquid. The yield was 4.27 g, and since it was thought that the product had been converted to a trifluoroacetate salt, 1,4-dioxane HCl (4 mol / L) (3.10 mL, 12.4 mmol) was added and stirred overnight. After the reaction, the solution was decanted with diethyl ether, and then washed again with diethyl ether (20 mL) by stirring for 4 hours. After washing, the solid was dried in vacuo to give a white solid in a yield of 2.54 g (100%).

[0068] (4) NH ２ Synthesis of Boc-GG-OEG First, Boc-GG-OEG was synthesized in the same manner as Boc-G-OEG.

[0069] Boc-GG-OEG was synthesized in the same manner as for Boc-G-OEG using Boc-glycylglycine (6.00 g), Diethylene Glycol Bis(3-aminopropyl) Ether (2.82 mL), triethylamine (3.58 mL), WSCI·HCl (4.95 g), and HOBt (anhydrous) (3.49 g) in chloroform (50 mL). The yield was 4.16 g (50%).

[0070] Subsequently, the obtained Boc-GG-OEG (1.41 g) was used to prepare NH ２ -G-OEG was synthesized using the same method as ２ -GG-OEG was synthesized in a yield of 1.53 g (100%).

[0071] (5) Synthesis of OMe-K(Z)-OEG OMe-K(Z)-OEG having a lysine residue with the side chain protected by a Z group was synthesized from dicarboxylic acid compound 1.

[0072] OMe-K(Z)-OEG was synthesized in the same manner as OEt-G-OEG using dicarboxylic acid compound 1 (0.64 g), lysine(Z) methyl ester hydrochloride (1.0 g), triethylamine (0.84 ml), WSCI·HCl (0.58 g), and HOBt (anhydrous) (0.41 g) in chloroform (30 mL). The yield was 0.99 g (68%).

[0073] (6) NH ２ Synthesis of -K(Z)-OEG First, Boc-K(Z)-OEG was synthesized by the same method as Boc-G-OEG.

[0074] Boc-K(Z)-OEG was synthesized in the same manner as for Boc-G-OEG using Nα-Boc-Nε-Z-lysine (2.5 g), Diethylene Glycol Bis(3-aminopropyl) Ether (0.72 mL), triethylamine (0.91 mL), WSCI·HCl (1.26 g), and HOBt (anhydrous) (0.89 g) in chloroform (40 mL). The yield was 2.79 g (90%).

[0075] Subsequently, the obtained Boc-K(Z)-OEG (1.4 g) was used, and chloroform (2.0 mL) and trifluoroacetic acid (TFA) (2.5 mL) were added to prepare NH ２ -G-OEG was synthesized using the same method as ２ -K(Z)-OEG was synthesized in a yield of 1.3 g (100%).

[0076] (7) Synthesis of OEt-GA-Boc

[0077] OEt-GA-Boc was synthesized in the same manner as for Boc-G-OEG using Boc-alanine (2.71 g), glycine ethyl ester hydrochloride (2.00 g), triethylamine (3.97 mL), WSCI·HCl (2.75 g), and HOBt (anhydrous) (1.94 g) in chloroform (90 mL). The yield was 3.70 g (94%).

[0078] (8) OEt-GA-NH ２ Synthesis of

[0079] Subsequently, the obtained OEt-GA-Boc (3.70 g) was used, and trifluoroacetic acid (TFA) (7.65 mL) was added to form NH ２ -G-OEG was synthesized in the same manner as OEt-GA-NH ２ The crude product obtained contained 1,4-dioxane and diethyl ether in addition to the target compound. １ The purity was determined by H-NMR. The crude yield was 3.05 g, and the purity was determined to be 84%, with a yield of 2.57 g (109%).

[0080] (9) Synthesis of OEt-GA-OEG

[0081] OEt-GA-OEG was synthesized in the same manner as OEt-G-OEG using dicarboxylic acid compound 1 (2.56 g), OEt-GA-OEG (2.57 g), triethylamine (3.38 ml), WSCI·HCl (2.34 g), and HOBt (anhydrous) (1.65 g) in chloroform (120 mL) in the yield of 1.508 g (34%).

[0082] (10) Synthesis of OEt-G-6EG First, dicarboxylic acid compound 2 was synthesized by the following method.

[0083] To a flask equipped with a dropping funnel and a stirrer, 20 mL of ethyl acetate, 3,6,9,12,15,18-hexaoxaicosane-1,20-diamine (1.02 g, 3.14 mmol), and triethylamine (0.87 mL, 6.29 mmol) were added under a simple argon atmosphere using a rubber balloon. To the flask, a solution of succinic anhydride (0.63 g, 6.29 mmol) in ethyl acetate (20 mL) was added dropwise. After the dropwise addition, stirring was continued and the mixture was allowed to react for 16 hours, resulting in the production of a white, viscous precipitate. The resulting precipitate was decanted and washed twice with ethyl acetate, and then dried under vacuum. The synthesized product was designated dicarboxylic acid compound 2. Since the viscous precipitate obtained after drying was a mixture of dicarboxylic acid compound 2, ethyl acetate, and triethylamine, １ The respective quantitative ratios were determined from the integrated values ​​of H-NMR. １ The molar ratio of dicarboxylic acid compound 2 to ethyl acetate and triethylamine determined by H-NMR was 100:69:35, and therefore the weight ratio of dicarboxylic acid compound 2 was calculated to be 83.5%. Since the weight of the obtained raw product was 1.98 g, the yield of dicarboxylic acid compound 2 was 1.65 g (100%).

[0084] Subsequently, OEt-G-6EG having a glycine residue was synthesized from dicarboxylic acid compound 2.

[0085] To a chloroform (20 mL) solution of 1.86 g of the resulting raw product of dicarboxylic acid compound 2 (dicarboxylic acid compound 2: 1.55 g, 2.96 mmol), glycine ethyl ester hydrochloride (0.88 g, 6.22 mmol), HOBt (anhydrous) (0.81 g, 5.92 mmol), and triethylamine (1.67 mL, 11.85 mmol) were added under ice cooling, and the atmosphere was briefly purged with argon using a rubber balloon. A chloroform (20 mL) solution of WSCI·HCl (1.16 g, 5.92 mmol) was added dropwise to the flask. After the addition, the ice cooling was removed, and the mixture was stirred at room temperature for 24 hours. The resulting mixture was washed successively with pure water and 3% aqueous sodium bicarbonate. The washed organic layer was dried over magnesium sulfate and concentrated using a rotary evaporator. The resulting product was dried under vacuum to give an ochre sandy solid, OEt-G-6EG, in a yield of 0.92 g (44.96%).

[0086] (11) Synthesis of Boc-D(Bzl)-OEG

[0087] Diethylene Glycol Bis(3-aminopropyl)Ether (1.01 mL, 4.64 mmol), HOBt (anhydrous) (1.25 g, 9.28 mmol), and triethylamine (1.29 mL, 9.28 mmol) were added to a chloroform (40 mL) solution of N-Boc-aspartic acid (3.00 g, 9.23 mmol) whose side chain was protected with a benzyl ester in a flask equipped with a dropping funnel and a stirrer. While stirring under ice cooling, a chloroform (20 mL) solution of WSCI·HCl (1.78 g, 9.28 mmol) was added dropwise. After the dropwise addition, the ice cooling was removed and the mixture was stirred for 24 hours. The resulting mixture was washed with purified water, 1 M hydrochloric acid, and 3% aqueous sodium bicarbonate. Magnesium sulfate was then added, the mixture was dried, and the mixture was concentrated using a rotary evaporator. Further drying under vacuum gave 3.85 g (99.87%) of a yellowish, clear, viscous crude product.

[0088] (12) NH ２ Synthesis of -D(Bzl)-OEG

[0089] The obtained Boc-D(Bzl)-OEG (3.83 g, 4.60 mmol), chloroform (5.57 mL, 34.53 mmol), and trifluoroacetic acid (TFA) (7.05 mL, 92.09 mmol) were added to a flask equipped with a stirrer, and the mixture was stirred at room temperature for 3 hours. After the reaction was completed, the mixture was dried under vacuum using a vacuum pump for 2 hours, and 1,4-dioxane HCl (4 mol / L) (2.30 mL, 9.21 mmol) was added and stirred overnight. After the reaction, the solution was decanted with diethyl ether, and then washed again by adding diethyl ether and stirring for 12 hours. After washing, the mixture was dried under vacuum, and a white solid was obtained in a yield of 3.35 g. The product was NH ２ Since it was a mixture of -D(Bzl)-OEG, diethyl ether, and dioxane, the ratio of each component was determined from the integrated value of 1H-NMR. ２ The molar ratio of -D(Bzl)-OEG, diethyl ether, and dioxane was 100:11:14, so NH ２ The weight ratio of -D(Bzl)-OEG was calculated to be 96.8%. ２ The yield of -D(Bzl)-OEG was 3.24 g (100%).

[0090] (13) Synthesis of Boc-GD(Bzl)-OEG

[0091] Boc-glycine (0.64 g, 1.74 mmol), NH ２ Boc-GD(Bzl)-OEG was synthesized in chloroform (20 mL) using -D(Bzl)-OEG (1.22 g, 3.65 mmol), triethylamine (0.96 mL, 6.95 mmol), WSCI·HCl (0.67 g, 3.47 mmol), and HOBt (anhydrous) (0.47 g, 3.47 mmol) in the same manner as for Boc-D(Bzl)-OEG to give Boc-GD(Bzl)-OEG in a yield of 1.33 g (81.29%).

[0092] (14) NH ２ Synthesis of -GD(Bzl)-OEG

[0093] The obtained Boc-GD(Bzl)-OEG (1.28 g, 1.35 mmol) was mixed with trifluoroacetic acid (TFA) (2.07 mL, 27.02 mmol) to prepare NH ２ -D(Bzl)-OEG was synthesized in the same manner as ２ -GD(Bzl)-OEG was synthesized in a yield of 1.09 g (98.19%).

[0094] 2-2 Synthesis of cyclic compounds by enzymatic synthesis (15) Synthesis of cyclic-GG by enzymatic synthesis Next, OEt-G-OEG (a dicarboxylic acid compound modified with a protecting group) synthesized above was reacted with NH ２ A cyclic compound containing linked glycine residues (cyclic-GG) was enzymatically synthesized from -G-OEG (a diamine compound).

[0095] OEt-G-OEG (0.35 g) and papain (0.30 g) were placed in a test tube equipped with a stirrer. ２ A solution of OEt-GG-OEG (0.201 g) in sodium phosphate buffer (6.00 mL) was added. ２ -GG-OEG) and papain at final concentrations of 0.1 M and 50 mg mL －１ The mixture was stirred at 700 rpm and 40°C for 2.5 hours using an EYELA ChemStation PPS-5511 (Tokyo Rikakikai Co., Ltd., Tokyo). After cooling to room temperature, the precipitate was collected by centrifugation at 9000 rpm for 15 minutes at room temperature. The crude product was washed twice with pure water, centrifuged, and lyophilized to obtain cyclic-GG as a slightly yellowish granular solid. The yield was 0.059 g (21%).

[0096] The obtained product is a cyclic compound having the above cyclic-GG structure, １ The crystal structure was confirmed by H-NMR and MALDI-TOF MS. The crystal structure was also confirmed by WAXD measurement of the product.

[0097] (16) Synthesis of cyclic-GGG by enzymatic synthesis Similarly, the following cyclic compound (cyclic-GGG) with an additional glycine residue was synthesized by the following procedure.

[0098] OEt-G-OEG (0.10 g) and papain (0.085 g) were placed in a test tube equipped with a stirrer. A solution of NH2-GG-OEG (0.076 g) in sodium phosphate buffer (1.70 mL) was then added. ２ -GG-OEG) and papain at final concentrations of 0.1 M and 50 mg mL －１ The mixture was stirred at 700 rpm and 40°C for 2.5 hours using an EYELA ChemStation PPS-5511 (Tokyo Rikakikai Co., Ltd., Tokyo). After cooling to room temperature, the precipitate was collected by centrifugation at 9000 rpm for 15 minutes at room temperature. The crude product was washed twice with pure water, centrifuged, and lyophilized to obtain cyclic-GGG as a solid. The yield was 0.056 g (35%).

[0099] The obtained product is a cyclic compound having the cyclic-GGG structure. １ The results were confirmed by H-NMR and MALDI-TOF MS.

[0100] (17) Synthesis of cyclic-K(Z)K(Z) by enzymatic synthesis Similarly, the following cyclic compound (cyclic-K(Z)K(Z)) in which the glycine residue was replaced with a lysine residue having a Z protecting group in the side chain was synthesized by the following procedure.

[0101] OEt-K(Z)-OEG (0.050 g, 0.051 mmol) and papain (0.026 g) were placed in a test tube equipped with a stirrer. A solution of NH2-K(Z)-OEG (0.042 g, 0.051 mmol) in potassium phosphate buffer (0.514 mL) was then added. The final concentrations of the monomer and papain were 0.1 M and 50 mg mL, respectively. －１The mixture was stirred at 700 rpm and 40°C for 2.5 hours using an EYELA ChemStation PPS-5511 (Tokyo Rikakikai Co., Ltd., Tokyo). After cooling to room temperature, the precipitate was collected by centrifugation at 9000 rpm for 15 minutes at room temperature. The crude product was washed twice with pure water, centrifuged, and lyophilized to obtain cyclic-K(Z)K(Z) as a solid. The yield was 0.021 g (25%).

[0102] The obtained product is a cyclic compound having the above cyclic-K(Z)K(Z) structure, １ The results were confirmed by H-NMR and MALDI-TOF MS.

[0103] (18) Synthesis of cyclic-AGG by enzymatic synthesis Next, the OEt-GA-OEG (a dicarboxylic acid compound modified with a protecting group) synthesized above was reacted with NH ２ A cyclic compound (cyclic-AGG) containing linked glycine residues was enzymatically synthesized from -G-OEG (a diamine compound).

[0104] OEt-GA-OEG (0.10 g) and papain (0.068 g) were placed in a test tube equipped with a stirrer. ２ A solution of OEt-GA-OEG (0.056 g) in sodium phosphate buffer (1.36 mL) was added. ２ -G-OEG) and papain at final concentrations of 0.1 M and 50 mg mL －１ The mixture was stirred at 700 rpm and 40°C for 2.5 hours using an EYELA Chemstation PPS-5511 (Tokyo Rikakikai Co., Ltd., Tokyo). The reaction solution was frozen at -30°C and then freeze-dried. When water was added to the obtained crude product, some residue remained, which was collected using a tabletop centrifuge to obtain cyclic-AGG. The yield was 0.009 g (6.8%).

[0105] The obtained product is a cyclic compound having a cyclic-AGG structure. １ The results were confirmed by H-NMR and MALDI-TOF MS.

[0106] (19) Synthesis of cyclic-GGD(Bzl) by enzymatic synthesis ２ A cyclic compound containing linked glycine residues (cyclic-GGD(Bzl)) was enzymatically synthesized from -GD(Bzl)-OEG (a diamine compound) and OEt-G-OEG (a dicarboxylic acid compound modified with a protecting group) under the same conditions as for cyclic-GG.

[0107] OEt-G-OEG (0.032g), NH ２ -GD(Bzl)-OEG (0.055 g) was placed in a microtube. Then, sodium phosphate buffer (0.51 mL) was added. Papain (0.025 g) was then added. ２ The final concentrations of α-GD(Bzl)-OEG) and papain were 0.1 M and 50 mg mL , respectively. －１ The mixture was stirred at 2000 rpm and 40°C for 2.5 hours using an Eppendorf Thermomixer C (Eppendorf Co., Ltd.). After cooling to room temperature, the precipitate was collected by centrifugation at room temperature. The crude product was washed twice with pure water, centrifuged, and lyophilized to obtain cyclic-GGD(Bzl) as a slightly yellowish granular solid. The yield was 0.041 g (65.0%).

[0108] The obtained product is a cyclic compound having the structure cyclic-GGD(Bzl). １ The results were confirmed by H-NMR and MALDI-TOF MS.

[0109] (20) Synthesis of cyclic-GGD(Bzl) (6) by enzymatic synthesis Similarly, NH ２ A cyclic compound containing linked glycine residues (cyclic-GGD(Bzl)(6)) was enzymatically synthesized from -GD(Bzl)-OEG (a diamine compound) and OEt-G-6EG (a dicarboxylic acid compound modified with a protecting group) under the same conditions as for cyclic-GG.

[0110] OEt-G-6EG (0.033g), NH ２0.052 g of OEt-GD(Bzl)-OEG was placed in a microtube. Then, 0.48 mL of sodium phosphate buffer solution was added. 0.024 g of papain was then added. ２ The final concentrations of α-GD(Bzl)-OEG) and papain were 0.1 M and 50 mg mL , respectively. －１ The mixture was stirred at 2000 rpm and 40°C for 2.5 hours using an Eppendorf Thermomixer C (Eppendorf Co., Ltd.). After cooling to room temperature, the precipitate was collected by centrifugation at room temperature. The crude product was washed twice with pure water, centrifuged, and lyophilized to obtain cyclic-GGD(Bzl) (6) as a white granular solid. The yield was 0.033 g (50.8%).

[0111] The obtained product was confirmed to be a cyclic compound having the structure cyclic-GGD(Bzl)(6). １ The results were confirmed by H-NMR and MALDI-TOF MS.

Claims

1. A cyclic compound containing an oligopeptide moiety represented by the following formula (1): (wherein each X is independently a residue of a natural or unnatural amino acid, which may be the same or different; n is a natural number from 2 to 10; spacer L １ and L ２ are each independently a divalent linking group selected from the group consisting of alkylene, alkenylene, alkynylene, which may have any substituent, and groups in which one or more carbon atoms constituting such alkylene, alkenylene, or alkynylene are substituted with —O—, —S—, —NH—, —, or —C(═O)—.

2. X is a residue of an amino acid selected from the group consisting of glycine, alanine, valine, leucine, isoleucine, phenylalanine, tryptophan, methionine, cysteine, proline, serine, threonine, tyrosine, asparagine, glutamine, aspartic acid, glutamic acid, lysine, arginine, histidine, and an amino acid represented by formula (2), In formula (2), R １ represents a hydrogen atom or an alkyl group having 1 to 20 carbon atoms which may have an optional substituent; Y represents a divalent group represented by the following formula (3) or (4) or a combination thereof: In formulas (3) and (4), each R ２ are each independently selected from the group consisting of a hydrogen atom, an alkyl group having 1 to 20 carbon atoms which may have an optional substituent, and an aryl group having 6 to 20 carbon atoms which may have an optional substituent; and m is a natural number from 1 to 10.

3. The cyclic compound according to claim 2, wherein the amino acid represented by formula (2) is a compound represented by the following formula (2-1), (2-2), or (2-3): (In these formulas, R ２ and m are defined as in claim 2; and m' in formula (2-2) is a natural number from 2 to 20.

4. The cyclic compound according to claim 1, having a ring structure of 50 or more members.

5. The cyclic compound according to claim 1, wherein [X]n is a combination of two or more types of amino acid residues.

6. The cyclic compound of claim 1, wherein [X]n consists of residues of the same amino acid.

7. L １ or L ２ The cyclic compound according to claim 1 , wherein the cyclic compound contains an ether chain.

8. L １ and L ２ The cyclic compound according to claim 1, wherein the cyclic compound contains an oligoethylene glycol chain having 2 to 16 carbon atoms.

9. A method for producing the cyclic compound according to any one of claims 1 to 8, comprising: L １ a dicarboxylic acid compound having one or more amino acid residues linked to both ends of the compound and further having carboxyl groups at both ends, or a diester compound in which the carboxyl groups are protected with any protecting group; and L ２ and reacting the resulting polymer with a diamine compound having amino groups at both ends.

10. The method of claim 9, wherein the reaction is carried out in the presence of an enzyme.

11. The method of claim 10, wherein the enzyme is an endopeptidase.

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