Metal-organic framework for inhibiting m2 macrophage activity, and pharmaceutical composition comprising same

Abstract

The present invention relates to a metal-organic framework for inhibiting the activity of M2 macrophages, and a pharmaceutical composition comprising same, wherein the metal-organic framework of the present invention is non-toxic to cells and can exhibit an effect of inhibiting the activity of M2 macrophages. More specifically, the metal-organic framework of the present invention can be provided as an anticancer composition for tumor-related macrophage-mediated diseases, particularly solid cancer, through the inhibition of M2 macrophages capable of increasing the expression of genes associated with parasite invasion, tissue remodeling, and tumor proliferation (immunomodulatory function), and can also be provided as a pharmaceutical composition for treating chronic infectious diseases, liver cirrhosis, obesity-related metabolic diseases, scar formation and idiopathic lung diseases.

Description

Metal-organic framework for inhibiting the activity of M2 macrophages and pharmaceutical composition containing the same

[0001] The present invention relates to a metal-organic framework for inhibiting the activity of M2 macrophages and a pharmaceutical composition containing the same.

[0002] Conventional anticancer treatments have focused on directly attacking cancer cells or enhancing the activity of the body's immune cells that attack them. However, these anticancer drugs also attack normal cells, leading to numerous side effects such as hair loss, nausea, and vomiting, as well as causing adverse reactions due to the excessive proliferation of immune cells. Consequently, efforts are being accelerated to develop treatments that possess anticancer effects by regulating only the tumor microenvironment without directly affecting tumor cells or immune cells, thereby blocking the supply of nutrients to tumor cells and the formation of new angiogenesis around them.

[0003] The tumor microenvironment is considered a major therapeutic target as it contributes to the proliferation and survival of malignant cells, angiogenesis, metastasis, abnormal adaptive immunity, and reduced response to hormones and chemotherapy agents. Numerous studies have demonstrated that tumor-associated macrophages (TAMs) are key factors in the tumor microenvironment and act as important regulators of angiogenesis, which is essential for tumor progression, by supplying oxygen and nutrients to hypoxic tumor regions. Consequently, it has been reported that the presence of a large number of tumor-associated macrophages surrounding the tumor in cancer patients is associated with poor prognosis and survival rates.

[0004] The role of tumor-associated macrophages in the tumor microenvironment remains highly debated. Tumor-associated macrophages are classified into two phenotypes: tumor suppressor M1 or tumor supportive M2 macrophages. M1-type tumor-associated macrophages possess a strong ability to present antigens and typically present CD86 and TNF-α. In contrast, M2-type tumor-associated macrophages have low antigen-presenting ability and high phagocytic capacity.

[0005] M2 macrophages are known to promote immunosuppression, tumorigenesis, and angiogenesis by releasing various extracellular matrix components, angiogenic factors, and chemotactic factors. M2 tumor-associated macrophages are distinguished from M1 tumor-associated macrophages by expressing certain markers such as CD163, CD204, CD206, and IL-10. In most tumors, such as breast, ovarian, prostate, lung cancer, and cutaneous melanoma, the tumor microenvironment contains CSF-1, VEGF, CCL2, IL-4, IL-13, TGF-β, and IL-10, which can induce the influx of mononuclear cells and induce differentiation into an M2-like phenotype. Previous studies have shown that depletion of macrophages by encapsulated chlorideronate can reduce angiogenesis in tumor tissues. Furthermore, blocking macrophage infiltration via CSF-1R and CCR2 antibodies can reduce tumor-initiating characteristics and increase the activity of cytotoxic T lymphocytes. Therefore, since the presence of large amounts of M2 tumor-associated macrophages in the tumor microenvironment actively induces tumor growth, differentiation, and metastasis, targeting M2 tumor-associated macrophages can lead to potential treatments that inhibit tumor growth and metastasis.

[0006] There is a need to develop a composition that can not only enhance anticancer effects by inhibiting the activity of these M2 macrophages, but also increase the therapeutic effects of specific diseases resulting from the inhibition of M2 macrophage activity.

[0007] [Prior Art Literature]

[0008] [Patent Literature]

[0009] KR 10-2019-0036551 A1

[0010] The object of the present invention is to provide a metal-organic framework for inhibiting the activity of M2 macrophages and a pharmaceutical composition containing the same.

[0011] Another objective of the present invention is to provide a metal-organic framework that is non-cytotoxic and capable of exhibiting an inhibitory effect on the activity of M2 macrophages.

[0012] Another objective of the present invention is to provide a pharmaceutical composition for the treatment of tumor-associated macrophage-mediated diseases, chronic infectious diseases, liver cirrhosis, obesity-associated metabolic diseases, scar formation, and idiopathic lung diseases.

[0013] To achieve the above-mentioned objective, the present invention relates to a metal-organic framework that inhibits the activity of M2 macrophages.

[0014] In addition, the metal-organic framework is a metal selected from the group consisting of Li, Na, Mg, Ca, Sr, Ba, Sc, Y, Ti, Zr, Hf, V, Nb, Ta, Cr, Mo, W, Mn, Re, Fe, Ru, Os, Co, Rh, Ir, Ni, Pd, Pt, Cu, Ag, Au, Zn, Cd, Hg, Al, Ga, In, Tl, Si, Ge, Sn, Pb, As, Sb, and Bi, or Li + , Na + , Mg 2+ , Ca 2+ , Sr 2+ , Ba 2+ , Sc 3+ , Y 3+ , Ti 4+ , Zr 4+ , Hf 4+ , V 4+ , V 3+ , V 2+ , Nb 3+ , Ta 3+ , Cr 3+ , Mo 3+ , W 3+ , Mn 3+ , Mn 2+ , Re 3+ , Re 2+ , Fe 3+ , Fe 2+ , Ru 3+ , Ru 2+ , Os 3+ , Os2+ , Co 3+ , Co 2+ , Rh 2+ , Rh + , Ir 3+ , Ir 2+ , Ir + , Ni 2+ , Ni + , Pd 2+ , Pd + , Pt 2+ , Pt + , Cu 2+ , Cu + , Ag + , Au + , Zn 2+ , Cd 2+ , Hg 2+ , Al 3+ , Ga 3+ , In 3+ , Tl 3+ , Si 4+ , Si 2+ , Ge 4+ , Ge 2+ , Sn 4+ , Sn 2+ , Pb 4+ , Pb 2+ , As 5+ , As 3+ , As + , Sb 5+ , Sb 3+ , Sb + , Bi 5+ , Bi 3+ and Bi + It may include metal ions selected from the group consisting of

[0015] In addition, the metal-organic framework may be selected from the group consisting of aluminum-based metal-organic frameworks, iron-based metal-organic frameworks, zirconium-based metal-organic frameworks, and mixtures thereof.

[0016] In addition, the metal-organic framework may comprise a metal cluster and a ligand compound represented by the following chemical formula 1 that coordinates to the metal cluster:

[0017] [Chemical Formula 1]

[0018]

[0019] Here,

[0020] n is an integer of 1 or 2, and

[0021] EDP ​​refers to a group containing an electron pair donor atom, and

[0022] L is selected from the group consisting of a substituted or unsubstituted alkyl group having 1 to 30 carbon atoms, a substituted or unsubstituted cycloalkyl group having 3 to 20 carbon atoms, a substituted or unsubstituted aralkyl group having 7 to 30 carbon atoms, a substituted or unsubstituted aryl group having 6 to 30 carbon atoms, a substituted or unsubstituted heteroaryl group having 1 to 60 carbon atoms, and a substituted or unsubstituted heteroarylalkyl group having 2 to 30 carbon atoms.

[0023] In addition, the ligand compound represented by Chemical Formula 1 above may be a ligand compound represented by Chemical Formula 2 or Chemical Formula 3 below:

[0024] [Chemical Formula 2]

[0025]

[0026] [Chemical Formula 3]

[0027]

[0028] Here,

[0029] m is an integer of 1 or 2, and

[0030] p is an integer of 0 or 1, and

[0031] EDP ​​refers to a group containing an electron pair donor atom, and

[0032] R1 and R2 are identical or different from each other and each independently hydrogen, deuterium, cyano group, nitro group, halogen group, hydroxyl group, substituted or unsubstituted C1 to C4 alkyl thio group, substituted or unsubstituted C1 to C30 alkyl group, substituted or unsubstituted C3 to C20 cycloalkyl group, substituted or unsubstituted C2 to C30 alkenyl group, substituted or unsubstituted C2 to C24 alkynyl group, substituted or unsubstituted C7 to C30 aralkyl group, substituted or unsubstituted C6 to C30 aryl group, substituted or unsubstituted C1 to C60 heteroaryl group, substituted or unsubstituted C2 to C30 heteroarylalkyl group, substituted or unsubstituted C1 to C30 alkoxy group, substituted or unsubstituted C1 to C30 of It is selected from the group consisting of an alkylamino group, a substituted or unsubstituted arylamino group having 6 to 30 carbon atoms, a substituted or unsubstituted aralkylamino group having 7 to 30 carbon atoms, a substituted or unsubstituted heteroarylamino group having 1 to 24 carbon atoms, a substituted or unsubstituted alkylsilyl group having 1 to 30 carbon atoms, a substituted or unsubstituted arylsilyl group having 6 to 30 carbon atoms, and a substituted or unsubstituted aryloxy group having 6 to 30 carbon atoms.

[0033] To achieve the above-mentioned purpose, the present invention is an anticancer composition comprising the metal-organic framework.

[0034] In addition, the above cancer may be colorectal cancer, liver cancer, lung cancer, breast cancer, melanoma, stomach cancer, colon cancer, skin cancer, ovarian cancer, cervical cancer, thyroid cancer, kidney cancer, prostate cancer, bladder cancer, pancreatic cancer, esophageal cancer, or fibrosarcoma.

[0035] To achieve the above-mentioned purpose, the present invention is a pharmaceutical composition for the prevention or treatment of liver cirrhosis comprising the metal-organic framework described above.

[0036] To achieve the above-mentioned purpose, the present invention is a pharmaceutical composition for the prevention or treatment of obesity-related metabolic diseases comprising the metal-organic framework.

[0037] To achieve the above-mentioned purpose, the present invention is a pharmaceutical composition for the prevention or treatment of scar formation comprising the metal-organic framework.

[0038] To achieve the above-mentioned purpose, the present invention is a pharmaceutical composition for the prevention or treatment of idiopathic lung disease comprising the metal-organic framework described above.

[0039] To achieve the above-mentioned purpose, the present invention is a pharmaceutical composition for the prevention or treatment of chronic infectious diseases comprising the metal-organic framework.

[0040] In the present invention, “hydrogen” is hydrogen, light hydrogen, deuterium, or tritium unless specifically limited otherwise.

[0041] In the present invention, the “halogen group” is fluorine, chlorine, bromine, or iodine.

[0042] In the present invention, “alkyl” means a monovalent substituent derived from a straight-chain or side-chain saturated hydrocarbon having 1 to 40 carbon atoms. Examples thereof include, but are not limited to, methyl, ethyl, propyl, isobutyl, sec-butyl, pentyl, iso-amyl, hexyl, etc.

[0043] In the present invention, “alkenyl” refers to a monovalent substituent derived from a straight-chain or side-chain unsaturated hydrocarbon having 2 to 40 carbon atoms and one or more carbon-carbon double bonds. Examples thereof include, but are not limited to, vinyl, allyl, isopropenyl, and 2-butenyl.

[0044] In the present invention, “alkynyl” refers to a monovalent substituent derived from a straight-chain or side-chain unsaturated hydrocarbon having 2 to 40 carbon atoms and one or more carbon-carbon triple bonds. Examples thereof include, but are not limited to, ethynyl and 2-propynyl.

[0045] In the present invention, "alkylthio" refers to the alkyl group described above bonded through a sulfur linkage (-S-).

[0046] In the present invention, “aryl” refers to a monovalent substituent derived from an aromatic hydrocarbon having 6 to 60 carbon atoms, consisting of a single ring or a combination of two or more rings. Additionally, forms in which two or more rings are simply pendent or condensed may be included. Specifically, they may be naphthyl groups, anthracenyl groups, phenanthryl groups, triphenyl groups, pyrenyl groups, phenalenyl groups, perylenyl groups, chrysenyl groups, fluorenyl groups, etc., but are not limited thereto. The fluorenyl groups may be substituted, and adjacent groups may combine to form a ring.

[0047] In the present invention, “heteroaryl” refers to a monovalent substituent derived from a monoheterocyclic or polyheterocyclic aromatic hydrocarbon having 6 to 30 carbon atoms. In this case, one or more carbons in the ring, preferably 1 to 3 carbons, are substituted with heteroatoms such as N, O, S, or Se. Additionally, forms in which two or more rings are simply pendent or condensed with each other may be included, and furthermore, forms condensed with an aryl group may also be included. Examples of such heteroaryls include, but are not limited to, 6-membered monocyclic rings such as pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, and triazinyl; polycyclic rings such as phenoxathienyl, indolizinyl, indolyl, purinyl, quinolyl, benzothiazole, and carbazolyl; and 2-furanyl, N-imidazolyl, 2-isoxazolyl, 2-pyridinyl, and 2-pyrimidinyl.

[0048] In the present invention, “aryloxy” refers to a monovalent substituent represented by RO-, where R means an aryl having 6 to 60 carbon atoms. Examples of such aryloxy include, but are not limited to, phenyloxy, naphthyloxy, and diphenyloxy.

[0049] In the present invention, “alkyloxy” refers to a monovalent substituent represented by R’O-, where R’ means an alkyl group having 1 to 40 carbon atoms, and may include a linear, branched, or cyclic structure. Examples of alkyloxy include, but are not limited to, methoxy, ethoxy, n-propoxy, 1-propoxy, t-butoxy, n-butoxy, pentoxy, etc.

[0050] In the present invention, the “alkoxy” may be a straight chain, a branched chain, or a cyclic chain. The number of carbon atoms in the alkoxy is not particularly limited, but it is preferred to have 1 to 20 carbon atoms. Specifically, it may be methoxy, ethoxy, n-propoxy, isopropoxy, i-propyloxy, n-butoxy, isobutoxy, tert-butoxy, sec-butoxy, n-pentyloxy, neopentyloxy, isopentyloxy, n-hexyloxy, 3,3-dimethylbutyloxy, 2-ethylbutyloxy, n-octyloxy, n-nonyloxy, n-decyloxy, benzyloxy, p-methylbenzyloxy, etc., but is not limited thereto.

[0051] In the present invention, "aralkyl" refers to an aryl-alkyl group such as aryl and alkyl as described above. Preferred aralkyls include lower alkyl groups. Non-limiting examples of suitable aralkyl groups include benzyl, 2-phenethyl, and naphthalenylmethyl. Bonding to the parent residue is made through alkyl groups.

[0052] In the present invention, “arylamino group” means an amine substituted with an aryl group having 6 to 30 carbon atoms.

[0053] In the present invention, “alkylamino group” means an amine substituted with an alkyl group having 1 to 30 carbon atoms.

[0054] In the present invention, “aralkylamino group” means an amine substituted with an aryl-alkyl group having 6 to 30 carbon atoms.

[0055] In the present invention, “heteroarylamino group” means an amine group substituted with an aryl group having 6 to 30 carbon atoms and a heterocyclic group.

[0056] In the present invention, “heteroaralkyl group” refers to an aryl-alkyl group substituted with a heterocyclic group.

[0057] In the present invention, “cycloalkyl” refers to a monovalent substituent derived from a monocyclic or polycyclic non-aromatic hydrocarbon having 3 to 40 carbon atoms. Examples of such cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, and adamantine.

[0058] In the present invention, “heterocycloalkyl” refers to a monovalent substituent derived from a non-aromatic hydrocarbon having 3 to 40 carbon atoms, wherein one or more carbons in the ring, preferably 1 to 3 carbons, are substituted with heteroatoms such as N, O, S, or Se. Examples of such heterocycloalkyls include, but are not limited to, morpholine and piperazine.

[0059] In the present invention, “alkylsilyl” means a silyl substituted with an alkyl group having 1 to 40 carbon atoms, and “arylsilyl” means a silyl substituted with an aryl group having 6 to 60 carbon atoms.

[0060] In the present invention, “condensed ring” means a condensed aliphatic ring, a condensed aromatic ring, a condensed heteroaliphatic ring, a condensed heteroaromatic ring, or a combination thereof.

[0061] In the present invention, "forming a ring by combining with adjacent groups" means combining with adjacent groups to form a substituted or unsubstituted aliphatic hydrocarbon ring; a substituted or unsubstituted aromatic hydrocarbon ring; a substituted or unsubstituted aliphatic heteroring; a substituted or unsubstituted aromatic heteroring; or a condensed ring thereof.

[0062] Examples of “aromatic hydrocarbon rings” in the present invention include phenyl groups, naphthyl groups, anthracenyl groups, etc., but are not limited to these.

[0063] In the present invention, “aliphatic heterocycle” means an aliphatic ring containing one or more heteroatoms.

[0064] In the present invention, "aromatic heterocycle" means an aromatic ring containing one or more heteroatoms.

[0065] In the present invention, "substitution" means that a hydrogen atom bonded to a carbon atom of a compound is replaced with another substituent, and the substitution location is not limited to the location where the hydrogen atom is substituted, that is, any location where a substituent can be substituted, and in the case of two or more substitutions, the two or more substituents may be the same or different from each other. The above substituents are hydrogen, a cyano group, a nitro group, a halogen group, a hydroxyl group, an alkyl group having 1 to 30 carbon atoms, an alkenyl group having 2 to 30 carbon atoms, an alkynyl group having 2 to 24 carbon atoms, a heteroalkyl group having 2 to 30 carbon atoms, an aralkyl group having 6 to 30 carbon atoms, an aryl group having 5 to 30 carbon atoms, a heteroaryl group having 2 to 30 carbon atoms, a heteroarylalkyl group having 3 to 30 carbon atoms, an alkoxy group having 1 to 30 carbon atoms, an alkylamino group having 1 to 30 carbon atoms, an arylamino group having 6 to 30 carbon atoms, an aralkylamino group having 6 to 30 carbon atoms, a heteroarylamino group having 2 to 24 carbon atoms, a substituted or unsubstituted alkylsilyl group having 1 to 30 carbon atoms, a substituted or unsubstituted substituent having 6 to 30 carbon atoms It may be substituted with one or more substituents selected from the group consisting of an arylsilyl group and a substituted or unsubstituted aryloxy group having 6 to 30 carbon atoms, but is not limited to the above examples.

[0066] The present invention relates to a metal-organic framework that is non-cytotoxic and capable of inhibiting the activity of M2 macrophages.

[0067] In addition, it can be provided as an anticancer composition for tumor-associated macrophage-mediated diseases, particularly solid tumors, and can also be provided as a pharmaceutical composition for the treatment of chronic infectious diseases, liver cirrhosis, obesity-related metabolic diseases, scar formation, and idiopathic lung diseases.

[0068] Figure 1 is a scanning electron microscope observation result of another MOF in one embodiment of the present invention.

[0069] Figure 2 is the result of X-ray diffraction analysis of a MOF according to one embodiment of the present invention.

[0070] Figure 3 is a scanning electron microscope observation result of another MOF in one embodiment of the present invention.

[0071] Figure 4 is the result of X-ray diffraction analysis of a MOF according to one embodiment of the present invention.

[0072] Figure 5 is a scanning electron microscope observation result of another MOF in one embodiment of the present invention.

[0073] Figure 6 is the result of X-ray diffraction analysis of a MOF according to one embodiment of the present invention.

[0074] Figure 7 is a scanning electron microscope observation result of another MOF in one embodiment of the present invention.

[0075] Figure 8 is the result of X-ray diffraction analysis of a MOF according to one embodiment of the present invention.

[0076] Figure 9 is a scanning electron microscope observation result of another MOF in one embodiment of the present invention.

[0077] Figure 10 is the result of X-ray diffraction analysis of a MOF according to one embodiment of the present invention.

[0078] Figure 11 is a scanning electron microscope observation result of another MOF in one embodiment of the present invention.

[0079] Figure 12 is the result of X-ray diffraction analysis of a MOF according to one embodiment of the present invention.

[0080] Figure 13 is a scanning electron microscope observation result of another MOF in one embodiment of the present invention.

[0081] Figure 14 is the result of X-ray diffraction analysis of a MOF according to one embodiment of the present invention.

[0082] Figure 15 is a scanning electron microscope observation result of another MOF in one embodiment of the present invention.

[0083] Figure 16 is the result of X-ray diffraction analysis of a MOF according to one embodiment of the present invention.

[0084] Figure 17 is the result of a cytotoxicity test of MOF according to one embodiment of the present invention.

[0085] Figure 18 is the result of a cytotoxicity test of MOF according to one embodiment of the present invention.

[0086] Figure 19 is the result of a cytotoxicity test of MOF according to one embodiment of the present invention.

[0087] Figure 20 is the result of a cytotoxicity test of an MOF according to one embodiment of the present invention.

[0088] Figure 21 is the result of a cytotoxicity test of an MOF according to one embodiment of the present invention.

[0089] Figure 22 is the result of a cytotoxicity test of MOF according to one embodiment of the present invention.

[0090] Figure 23 is the result of a cytotoxicity test of MOF according to one embodiment of the present invention.

[0091] Figure 24 is the result of a cytotoxicity test of MOF according to one embodiment of the present invention.

[0092] The present invention relates to a metal-organic framework that inhibits the activity of M2 macrophages.

[0093] Hereinafter, embodiments of the present invention are described in detail so that those skilled in the art can easily implement the invention. However, the present invention may be embodied in various different forms and is not limited to the embodiments described herein.

[0094] After the discovery in 1989 that helper T cells differentiate between Th1 and Th2, Abramson discovered that IL-4 produced in Th2 cells activates macrophages into another form. Unlike interferon gamma, IL-4 inhibited the production of reactive oxygen species and IL-1β and increased the expression of Major Histocompatibility Complex class II antigens (MHC-II).

[0095] In addition, in 1992, it was discovered that the expression of MR-1 (mannose receptor 1) is increased by IL-4 / IL13, and macrophages with such increased expression of MHC-II and MR-1 began to be called alternatively activated macrophages (AAM) or M2 macrophages.

[0096] Subsequently, through various studies, alternative macrophage activation was observed to occur in response to stimulation by immune complexes (IC), IL-1, TGF-β, IL-10, and glucocorticoids. Since these macrophages exhibited properties similar to activation by IL-4 / IL-13, they are sometimes classified as having an M2-like phenotype.

[0097] The aforementioned M2 macrophages increase the expression of genes such as Fizz1 (resistin-like-α), Arg1 (Arginase 1), Ym1 (chitinase 3-like 3), IL-10, and Mrc1 (CD206), which are associated with parasitic invasion, tissue remodeling, and tumor proliferation (immune regulatory function). M2 macrophages are known to aid in cancer progression because they play a role in suppressing activated immune responses. In particular, tumor-associated macrophages are a typical example of M2 cells, serving as a key component in forming and maintaining the tumor microenvironment.

[0098] Accordingly, the present invention aims to provide a metal-organic framework capable of inhibiting the activity of such M2 macrophages.

[0099] The above metal-organic framework is formed by coordination bonding between a metal or metal cluster and an organic material or linker. Specifically, a "metal-organic framework (MOF)" refers to a porous material in which metal clusters and organic linkers (or organic bridging ligands) are connected by coordination bonds to form a three-dimensional structure, and various MOFs can be created depending on the selection of metal ions and organic ligands. The MOF is characterized by its porosity, which contains empty spaces within its structure, and the pore size, porosity, three-dimensional structure, and surface area can be designed in various ways depending on the types and bonding methods of the metal ions and organic ligands constituting the MOF. Due to this porosity, MOFs not only have a very large surface area but also possess an open pore structure, allowing for the movement of large amounts of molecules or solvents compared to other known porous materials. Furthermore, when used as catalysts or gas storage materials, they have the advantage of maximizing efficiency due to the abundance of active sites. Additionally, the MOF does not easily deform at high temperatures and possesses a rigid framework, resulting in excellent chemical and thermal stability.

[0100] The above metal cluster is specifically a metal selected from the group consisting of Li, Na, Mg, Ca, Sr, Ba, Sc, Y, Ti, Zr, Hf, V, Nb, Ta, Cr, Mo, W, Mn, Re, Fe, Ru, Os, Co, Rh, Ir, Ni, Pd, Pt, Cu, Ag, Au, Zn, Cd, Hg, Al, Ga, In, Tl, Si, Ge, Sn, Pb, As, Sb, and Bi, or Li + , Na + , Mg 2+ , Ca 2+ , Sr 2+ , Ba 2+ , Sc3+ , Y 3+ , You 4+ , Zr 4+ , Hf 4+ , V 4+ , V 3+ , V 2+ , Nb 3+ , Yes 3+ , Cr 3+ , My 3+ , W 3+ , Mr. 3+ , Mr. 2+ , Re 3+ , Re 2+ , Fe 3+ , Fe 2+ , Ru 3+ , Ru 2+ , If 3+ , If 2+ , Co 3+ , Co 2+ , Rh 2+ , Rh + , Ireland 3+ , Ireland 2+ , Ireland + , We 2+ , We + , Pd 2+ , Pd + , Pt 2+ , Pt + , Dog 2+ , Dog + , At + , Oh + , Zn 2+ , CD 2+ , Hg 2+ , Al 3+ , Ga 3+ , In 3+ , Tl 3+ , Yes 4+ , Yes 2+ , Ge 4+ , Ge 2+ , Sn 4+ , Sn 2+ , Pb 4+ , Pb 2+ , As 5+ , As 3+ , As + , Sb 5+ , Sb3+ , Sb + , Bi 5+ , Bi 3+ and Bi + It may include metal ions selected from the group consisting of

[0101] More specifically, the metal-organic framework may be selected from the group consisting of aluminum-based metal-organic frameworks, iron-based metal-organic frameworks, zirconium-based metal-organic frameworks, and mixtures thereof, and preferably may be a zirconium-based metal-organic framework.

[0102] In addition, the organic linker is 1,3,5-benzenetricarboxylic acid, 4,4'-biphenyldicarboxilic acid, benzene-1,4-dicarboxylic acid, 9,10-anthracenedicarboxylic acid, biphenyl-3,3,5,5'-tetracarboxylic acid, biphenyl-3,4',5-tricarboxylic acid, 5-bromoisophthalic acid, 5-cyano-1,3-benzenedicarboxylic acid, 2,2-diamino4,4'-stilbenedicarboxylic acid, 2,5-diaminoterephthalic acid, 1,1,2,2-tetra(4-carboxylphenyl)ethylene, 2,5-dihydroxyterephthalic acid, 2,2-dinitro-4,4-stilbenedicarboxylic acid, 5-ethynyl-1,3-benzenedicarboxylic acid, 2-hydroxyterephthalic acid, 2,6-naphthalenedicarboxylic acid, 1,2,4,5-tetrakis(4-carboxyphenyl)benzene, 4,4,4''-s-triazine-2,4,6-triyl-tribenzoic acidIt may be one or more selected from the group consisting of 4,6-triyltribenzoic acid), 1,4,7,10-tetraazacyclododecane-N,N',N'',N''-tetraacetic acid, 1,3,5-tris(4-carboxy[1,1'-biphenyl]-4-yl)benzene, 1,3,5-tris(4-carboxyphenyl)benzene, and 1,3,5-triscarboxyphenylethynylbenzene, but is not limited thereto.

[0103] The above metal-organic framework is UIO66, UIO66-NH2, UIO67, UIO67-NH2, PCN128, PCN222, PCN223, PCN224, MOF525, MOF545, MOF801, MOF808, MOF867, Al-MIL53, Al-MIL53-NH2, Al-MIL88, Al-MIL88-NH2, Al-MIL100, Al-MIL100-NH2, Al-MIL101, Al-MIL101-NH2, Al-MIL125, Al-MIL125-NH2, Fe-MIL53, Fe-MIL53-NH2, Fe-MIL88, Fe-MIL88-NH2, Fe-MIL100, Fe-MIL100-NH2, Metal-organic frameworks capable of inhibiting the activity of M2 macrophages may be selected from the group consisting of Fe-MIL101, Fe-MIL101-NH2, Fe-MIL125, and Fe-MIL125-NH2, but are not limited to the above examples, and any metal-organic framework capable of inhibiting the activity of M2 macrophages may be used without limitation.

[0104] The metal-organic framework may comprise a metal cluster and a ligand compound represented by the following chemical formula 1 that coordinates to the metal cluster:

[0105] [Chemical Formula 1]

[0106]

[0107] Here,

[0108] n is an integer of 1 or 2, and

[0109] EDP ​​refers to a group containing an electron pair donor atom, and

[0110] L is selected from the group consisting of a substituted or unsubstituted alkyl group having 1 to 30 carbon atoms, a substituted or unsubstituted cycloalkyl group having 3 to 20 carbon atoms, a substituted or unsubstituted aralkyl group having 7 to 30 carbon atoms, a substituted or unsubstituted aryl group having 6 to 30 carbon atoms, a substituted or unsubstituted heteroaryl group having 1 to 60 carbon atoms, and a substituted or unsubstituted heteroarylalkyl group having 2 to 30 carbon atoms.

[0111] As described above, the metal-organic framework of the present invention is a metal cluster and an organic linker coordinately bonded, and a ligand compound represented by the chemical formula 1 described above may be additionally coordinately bonded.

[0112] The ligand compound represented by the above chemical formula 1 may be a ligand compound represented by the following chemical formula 2 or chemical formula 3:

[0113] [Chemical Formula 2]

[0114]

[0115] [Chemical Formula 3]

[0116]

[0117] Here,

[0118] m is an integer of 1 or 2, and

[0119] p is an integer of 0 or 1, and

[0120] EDP ​​refers to a group containing an electron pair donor atom, and

[0121] R1 and R2 are identical or different from each other and each independently hydrogen, deuterium, cyano group, nitro group, halogen group, hydroxyl group, substituted or unsubstituted C1 to C4 alkyl thio group, substituted or unsubstituted C1 to C30 alkyl group, substituted or unsubstituted C3 to C20 cycloalkyl group, substituted or unsubstituted C2 to C30 alkenyl group, substituted or unsubstituted C2 to C24 alkynyl group, substituted or unsubstituted C7 to C30 aralkyl group, substituted or unsubstituted C6 to C30 aryl group, substituted or unsubstituted C1 to C60 heteroaryl group, substituted or unsubstituted C2 to C30 heteroarylalkyl group, substituted or unsubstituted C1 to C30 alkoxy group, substituted or unsubstituted C1 to C30 of It is selected from the group consisting of an alkylamino group, a substituted or unsubstituted arylamino group having 6 to 30 carbon atoms, a substituted or unsubstituted aralkylamino group having 7 to 30 carbon atoms, a substituted or unsubstituted heteroarylamino group having 1 to 24 carbon atoms, a substituted or unsubstituted alkylsilyl group having 1 to 30 carbon atoms, a substituted or unsubstituted arylsilyl group having 6 to 30 carbon atoms, and a substituted or unsubstituted aryloxy group having 6 to 30 carbon atoms.

[0122] The compound represented by the above chemical formula 2 may be a compound represented by the following chemical formula 4 or chemical formula 5:

[0123] [Chemical Formula 4]

[0124]

[0125] [Chemical Formula 5]

[0126]

[0127] Here,

[0128] R3 and R4 are identical or different from each other and each independently hydrogen, deuterium, cyano group, nitro group, halogen group, hydroxyl group, substituted or unsubstituted C1 to C4 alkylthio group, substituted or unsubstituted C1 to C30 alkyl group, substituted or unsubstituted C3 to C20 cycloalkyl group, substituted or unsubstituted C2 to C30 alkenyl group, substituted or unsubstituted C2 to C24 alkynyl group, substituted or unsubstituted C7 to C30 aralkyl group, substituted or unsubstituted C6 to C30 aryl group, substituted or unsubstituted C1 to C60 heteroaryl group, substituted or unsubstituted C2 to C30 heteroarylalkyl group, substituted or unsubstituted C1 to C30 alkoxy group, substituted or unsubstituted C1 to C30 of It is selected from the group consisting of an alkylamino group, a substituted or unsubstituted arylamino group having 6 to 30 carbon atoms, a substituted or unsubstituted aralkylamino group having 7 to 30 carbon atoms, a substituted or unsubstituted heteroarylamino group having 1 to 24 carbon atoms, a substituted or unsubstituted alkylsilyl group having 1 to 30 carbon atoms, a substituted or unsubstituted arylsilyl group having 6 to 30 carbon atoms, and a substituted or unsubstituted aryloxy group having 6 to 30 carbon atoms.

[0129] The above R3 and R4 may be substituted or unsubstituted alkyl groups having 1 to 30 carbon atoms, more preferably methyl groups, but are not limited to the above examples.

[0130] The compound represented by the above chemical formula 3 may be selected from the group consisting of the following compounds:

[0131]

[0132] An anticancer composition according to another embodiment of the present invention may include a metal-organic framework for inhibiting the activity of the M2 macrophage.

[0133] The above cancer may be colorectal cancer, liver cancer, lung cancer, breast cancer, melanoma, stomach cancer, colon cancer, skin cancer, ovarian cancer, cervical cancer, thyroid cancer, kidney cancer, prostate cancer, bladder cancer, pancreatic cancer, esophageal cancer, or fibrosarcoma, but is not limited to the above examples and may be used as an anticancer composition for solid tumors.

[0134] More specifically, M2 macrophages can play a role in promoting tumor growth and metastasis in the tumor microenvironment. These M2 macrophages aid in the survival of tumor cells, induce immunosuppression, and promote tumor angiogenesis, thereby creating an environment in which cancer cells can grow. Accordingly, the metal-organic framework of the present invention can enhance the anticancer effect for the treatment of the aforementioned solid tumor by inhibiting M2 macrophages, thereby suppressing tumor growth and metastasis.

[0135] A composition for the prevention or treatment of chronic infectious diseases according to another embodiment of the present invention may include a composition for inhibiting the activity of M2 macrophages.

[0136] More specifically, pathogens can utilize M2 macrophages to evade host immune responses and survive. In cases of tuberculosis or chronic viral infections, the inhibition of M2 macrophages can facilitate the elimination of pathogens. In the case of asthma, M2 macrophages are known to play a crucial role in the development of the condition. M2 macrophages have beneficial effects on tissue regeneration and the restoration of homeostasis within the lung microenvironment. However, excessive M2 macrophages can lead to hypersensitivity of the lung airways by increasing cell replenishment and mucus secretion. Accordingly, by regulating the balance of M2 macrophage polarization using the metal-organic framework of the present invention, a novel solution for the clinical treatment of asthma can be provided.

[0137] In addition, in the case of parasitic infection, it is observed that macrophages rapidly transform into the M2 phenotype upon infection. In such cases, a therapeutic effect can be achieved by inhibiting the activity of M2 macrophages using the metal-organic framework of the present invention.

[0138] A composition for the prevention or treatment of liver cirrhosis according to another embodiment of the present invention may include a metal-organic framework for inhibiting the activity of the M2 macrophages.

[0139] More specifically, M2 macrophages play a role in promoting fibrosis during the process of liver cirrhosis. This leads to the progression of liver fibrosis and can worsen liver function. Accordingly, the metal-organic framework of the present invention inhibits M2 macrophages, thereby slowing down the process of liver fibrosis and protecting liver function.

[0140] A composition for the prevention or treatment of obesity-related metabolic diseases according to another embodiment of the present invention may include a metal-organic framework for inhibiting the activity of M2 macrophages.

[0141] More specifically, in obese conditions, M2 macrophages regulate inflammatory responses in adipose tissue, and excessive activation of M2 macrophages can exacerbate metabolic problems such as insulin resistance. Accordingly, the metal-organic framework of the present invention can help improve metabolism by inhibiting M2 macrophages. The obesity-related metabolic diseases mentioned above may include type 2 diabetes, dyslipidemia, hypertension, fatty liver, gallbladder disease, coronary artery disease (angina pectoris, myocardial infarction), stroke, sleep apnea, gout, osteoarthritis, etc., and any metabolic disease caused or exacerbated by the activation of M2 macrophages may be subject to this invention without limitation.

[0142] A pharmaceutical composition for preventing scar formation according to another embodiment of the present invention may include a metal-organic framework for inhibiting the activity of the M2 macrophage.

[0143] More specifically, excessive activity of M2 macrophages can induce abnormal scar formation, namely keloid or hypertrophic scar formation. Accordingly, the metal-organic framework of the present invention can prevent excessive scar formation by inhibiting M2 macrophages.

[0144] A pharmaceutical composition for the prevention or treatment of idiopathic lung disease according to another embodiment of the present invention may include a metal-organic framework for inhibiting the activity of M2 macrophages.

[0145] More specifically, in the case of idiopathic lung disease, it can be confirmed that macrophages and monocytes, particularly classical monocytes, significantly increase in lung tissue, and in particular, significant activation of M2 macrophages (type 2 macrophage, M2) is observed. By inhibiting the activation of these M2 macrophages, a preventive or therapeutic effect for idiopathic lung disease can be achieved.

[0146] The pharmaceutical composition of the present invention may additionally contain a pharmaceutically acceptable carrier.

[0147] The above pharmaceutically acceptable carriers are those commonly used in formulations and include, but are not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methylcellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil.

[0148] The composition of the present invention may additionally include, in addition to the above components, lubricants, wetting agents, sweeteners, flavoring agents, emulsifiers, suspending agents, preservatives, etc. Suitable pharmaceutically acceptable carriers and formulations are described in detail in Remington's Pharmaceutical Sciences (19th ed., 1995).

[0149] The composition of the present invention may be prepared in a unit volume form or contained in a multi-volume container by formulation using a pharmaceutically acceptable carrier and / or excipient, according to a method that can be easily carried out by a person skilled in the art to which the invention belongs. In this case, the formulation may be in the form of a solution, suspension, or emulsion in an oil or aqueous medium, or in the form of an extract, powder, granule, tablet, or capsule, and may additionally include a dispersant or a stabilizer.

[0150] In the present invention, "administration" means providing a specific composition of the present invention to an individual by any appropriate method.

[0151] The composition of the present invention may be administered parenterally, and subcutaneous injection or local administration through the skin (transdermal administration) is preferred but not limited thereto.

[0152] Suitable dosages of the pharmaceutical composition of the present invention may vary depending on factors such as the formulation method, mode of administration, age, body weight, sex, pathological condition of the patient, food, time of administration, route of administration, excretion rate, and response responsiveness. When the composition of the present invention inhibits the activity of M2 macrophages in vitro, 20 μg / ml to 50 μg / m² is preferred but not limited thereto.

[0153] Preparation Example

[0154] UIO66 Synthetic

[0155] 136 mg of benzoic acid, 112 mg of BDC (benzene-1,4-dicarboxylic acid), and 212 mg of ZrCl4 (zirconia(IV) chloride) were added to 250 ml of DMF and dissolved. Subsequently, the mixture was reacted at 110°C for 24 hours. The synthesized particles were washed three times each with DMF and ethanol, and dried at 80°C to obtain a powder.

[0156] UIO67 synthesis

[0157] 1.24 g of BPDC (4,4'-Biphenyldicarboxylic acid) and 1.23 g of ZrCl4 (Zirconium(IV) chloride) were added to 80 ml of DMF and dissolved. Subsequently, the mixture was reacted at 95°C for 17 hours. The synthesized particles were washed three times each with DMF and ethanol, and dried at 80°C to obtain a powder.

[0158] MOF808 synthesis

[0159] 1.59 g of 1,3,5-BTC (1,3,5-Benzenetricarboxylic acid), 264 mg of ZrOCl2 (Zirconium(IV) oxide chloride), and 5.32 ml of Formic acid were added to 51.2 ml of DMF and dissolved. Subsequently, the mixture was reacted at 100°C for 36 hours. The synthesized particles were washed three times each with DMF and ethanol, respectively, and dried at 80°C to obtain a powder.

[0160] UIO66-DAT synthesis

[0161] 136 mg of benzoic acid, 112 mg of BDC (benzene-1,4-dicarboxylic acid), and 212 mg of ZrCl4 (zirconia(IV) chloride) were added to 250 ml of DMF and dissolved. Subsequently, the mixture was reacted at 110°C for 24 hours. The synthesized particles were washed three times each with DMF and ethanol, and dried at 80°C to obtain a powder.

[0162] The obtained powder was subjected to removing residual solution from within the pores for 8 hours in a vacuum environment at 150°C. A suspension was prepared by suspending 200 mg of the powder from which the residual solution had been removed and 133 mg of DAT (3,4-Diaminotoluene) in 50 ml of toluene. The suspension was placed in a round flask, the flask was connected to a reflux condenser, and stirred at 110°C for 6 hours. Subsequently, the synthesized particles were washed three times each with toluene and ethanol, respectively, and dried at 80°C to obtain the powder.

[0163] UIO66-MNA synthesis

[0164] 136 mg of benzoic acid, 112 mg of BDC (benzene-1,4-dicarboxylic acid), and 212 mg of ZrCl4 (zirconia(IV) chloride) were added to 250 ml of DMF and dissolved. Subsequently, the mixture was reacted at 110°C for 24 hours. The synthesized particles were washed three times each with DMF and ethanol, and dried at 80°C to obtain a powder.

[0165] The obtained powder was subjected to removing residual solution from within the pores for 8 hours in a vacuum environment at 150°C. A suspension was prepared by suspending 200 mg of the powder from which the residual solution had been removed and 176 mg of MNA (4-methyl-3-nitroaniline) in 50 ml of toluene. The suspension was placed in a round flask, the flask was connected to a reflux condenser, and stirred at 110°C for 6 hours. Subsequently, the synthesized particles were washed three times each with toluene and ethanol, respectively, and dried at 80°C to obtain the powder.

[0166] UIO67-DAT synthesis

[0167] 1.24 g of BPDC (4,4'-Biphenyldicarboxylic acid) and 1.23 g of ZrCl4 (Zirconium(IV) chloride) were added to 80 ml of DMF and dissolved. Subsequently, the mixture was reacted at 95°C for 17 hours.

[0168] The synthesized particles were washed three times each with DMF and ethanol, and dried at 80°C to obtain a powder. The residual solution within the pores of the obtained powder was removed for 8 hours in a vacuum environment at 150°C. A suspension was prepared by suspending 200 mg of the powder from which the residual solution had been removed and 115 mg of DAT (3,4-Diaminotoluene) in 50 ml of toluene. The suspension was placed in a round flask, the flask was connected to a reflux condenser, and stirred at 110°C for 6 hours. The synthesized particles were washed three times each with toluene and ethanol, and dried at 80°C to obtain a powder.

[0169] MOF808-ED synthesis

[0170] 1.59 g of 1,3,5-BTC (1,3,5-Benzenetricarboxylic acid), 264 mg of ZrOCl2 (Zirconium(IV) oxide chloride), and 5.32 ml of Formic acid were added to 51.2 ml of DMF and dissolved. Subsequently, the mixture was reacted at 100°C for 36 hours.

[0171] The synthesized particles were washed three times each with DMF and ethanol, and dried at 80°C to obtain a powder. The residual solution within the pores of the obtained powder was removed for 8 hours in a vacuum environment at 150°C. 200 mg of the powder from which the residual solution had been removed was added to 50 ml of toluene to prepare a suspension. 250 µl of ED (Ethylenediamine) was added to the suspension, the mixed suspension was placed in a round flask, the flask was connected to a reflux condenser, and the mixture was stirred at 110°C for 6 hours. The synthesized particles were washed three times each with toluene and ethanol, and dried at 80°C to obtain a powder.

[0172] MOF808-MB synthesis

[0173] 1.59 g of 1,3,5-BTC (1,3,5-Benzenetricarboxylic acid), 264 mg of ZrOCl2 (Zirconium(IV) oxide chloride), and 5.32 ml of Formic acid were added to 51.2 ml of DMF and dissolved. The mixture was reacted at 100°C for 36 hours.

[0174] The synthesized particles were washed three times each with DMF and ethanol, and dried at 80°C to obtain a powder.

[0175] The obtained powder was subjected to removing residual solution from within the pores for 8 hours in a vacuum environment at 150°C. 200 mg of the powder from which the residual solution had been removed was placed in 50 ml of toluene to prepare a suspension. 114 mg of MB (2-Methylbutylamine) was added to the suspension, the mixed suspension was placed in a round flask, the flask was connected to a reflux condenser, and the mixture was stirred at 110°C for 6 hours. The synthesized particles were washed three times each with toluene and ethanol, respectively, and dried at 80°C to obtain the powder.

[0176]

[0177] Scanning electron microscope observation results and X-ray diffraction analysis results of the MOF synthesized by the above-described manufacturing example are as shown in FIGS. 1 to 16.

[0178] Specifically, Figure 1 shows the scanning electron microscope observation results of UIO66, and Figure 2 shows the X-ray diffraction analysis results. This confirmed that the manufactured particles were synthesized with the crystal structure of UIO66.

[0179] Figure 3 shows the scanning electron microscope observation results of UIO67, and the X-ray diffraction analysis results are as shown in Figure 4. This confirmed that the manufactured particles were synthesized with the crystal structure of UIO67.

[0180] Figure 5 shows the scanning electron microscope observation results of MOF808, and the X-ray diffraction analysis results are as shown in Figure 6. This confirmed that the manufactured particles were synthesized with the crystal structure of MOF808.

[0181] Figure 7 shows the scanning electron microscope observation results of UIO66-DAT, and the X-ray diffraction analysis results are as shown in Figure 8. This confirmed that the manufactured particles were synthesized with the crystal structure of UIO66-DAT.

[0182] Figure 9 shows the scanning electron microscope observation results of UIO67-DAT, and the X-ray diffraction analysis results are as shown in Figure 10. This confirmed that the manufactured particles were synthesized with the crystal structure of UIO67-DAT.

[0183] Figure 11 shows the scanning electron microscope observation results of UIO66-MNA, and the X-ray diffraction analysis results are as shown in Figure 12. This confirmed that the prepared particles were synthesized with the crystal structure of UIO66-MNA.

[0184] Figure 13 shows the scanning electron microscope observation results of MOF808-ED, and the X-ray diffraction analysis results are as shown in Figure 14. This confirmed that the prepared particles were synthesized with the crystal structure of MOF808-ED.

[0185] Figure 15 shows the scanning electron microscope observation results of MOF808-MB, and the X-ray diffraction analysis results are as shown in Figure 16. This confirmed that the prepared particles were synthesized with the crystal structure of MOF808-MB.

[0186]

[0187] Experimental Example 1

[0188] Cytotoxicity evaluation of MOFs

[0189] L929 (mouse fibroblasts) were seeded into a 96-well plate at a density of 10,000 cells / well and cultured for 24 hours in a 37°C, 5% CO2 incubator. After 24 hours, the existing medium was removed from each well, and test solutions were prepared by suspending the particles to be tested in the medium at concentrations of 100, 50, 25, 10, 5, and 1 µg / ml. 100 µl of these solutions were then added to each well. After incubating for 24 hours in a 37°C, 5% CO2 incubator, the medium was removed and the cells were washed three times with PBS. 10% EZ-cytox medium was added to each well and incubated for 1 hour. Absorbance at 450 nm and 600 nm was measured using a microplate reader to compare cell viability with that of the control group.

[0190] The test results are as shown in FIGS. 17 to 24. According to FIGS. 17 to 24, it was confirmed that all MOFs synthesized by the manufacturing examples of the present invention were non-cytotoxic.

[0191] Experimental Example 2

[0192] Immunocyte differentiation experiment method

[0193] Bone marrow stem cells were isolated from the femur of BALB / c mice. Cells were collected from the bone marrow stem cell slurry using a 70 µm cell strainer filter, and red blood cells were removed using lysis buffer. After separating the cells by centrifugation at 500xg for 5 minutes, they were cultured in macrophage differentiation media for 3 days. Additional media was added on the 3rd day.

[0194] After incubation, 1 x 10⁶ in a 96-well plate 5 After seeding cells at a cells / well concentration, the reagents and experimental groups were treated.

[0195] For the MOF experimental group, DMEM medium was prepared at concentrations of 25 µg / ml and 50 µg / ml, and the cells were treated and cultured for 24 hours. The control group was cultured in DMEM medium, while the M2 polarization group was cultured in DMEM and 20 ng / ml IL-4 for 24 hours. Arginase-1, CD11b, F4 / 80, and BV510 live cell reagents were diluted to a 1:100 concentration, and cells in each well were stained and cultured at 4°C for 30 minutes. Flow cytometry was performed.

[0196] The test results are as shown in Table 1 below:

[0197] Difference from experimental group average control M2 suppression (%)Argnase 1+ gap (%)UIO66-DAT 25 ug / ml29.36-1.460UIO66-DAT 50 ug / ml12.53-18.290UIO67-DAT 25 ug / ml2.50-40.507UIO67-DAT 50 ug / ml2.26-40.753UIO66-MNA 25 ug / ml7.05-2.017MOF808-ED 25 ug / ml10.98-3.793MOF808-MB 25 ug / ml5.83-8.943MOF808-MB 50 ug / ml9.17-5.607MOF808 25 ug / ml51.220.000MOF808 50 ug / ml57.130.000UIO66 25 ug / ml55.670.000UIO66 50 ug / ml62.950.000UIO67 25 ug / ml47.760.000UIO67 50 ug / ml60.440.000

[0198] According to the above test results, it was confirmed that the conventionally known MOFs UIO66, UIO67, and MOF808 did not have an inhibitory effect on M2 macrophage activity compared to the control group. On the other hand, UIO66-DAT, UIO67-DAT, UIO66-MNA, MOF808-ED, and MOF808-MB, to which the ligand compound of the present invention is coordinately bound, were found to exhibit an inhibitory effect on M2 macrophage activity ranging from a minimum of -1.460% to a maximum of -40.753% compared to the control group, thereby confirming that they demonstrate an excellent inhibitory effect on M2 macrophage activity. As described above, this inhibitory effect on M2 macrophage activity may manifest as an excellent anticancer effect against solid tumors, a preventive or therapeutic effect against liver cirrhosis, a preventive or therapeutic effect against obesity-related metabolic diseases, an effect against scar formation, a preventive or therapeutic effect against idiopathic lung disease, and a preventive or therapeutic effect against chronic infectious diseases.

[0199] Although preferred embodiments of the present invention have been described in detail above, the scope of the present invention is not limited thereto, and various modifications and improvements by those skilled in the art using the basic concept of the present invention as defined in the following claims also fall within the scope of the present invention.

[0200] The present invention relates to a metal-organic framework for inhibiting the activity of M2 macrophages and a pharmaceutical composition containing the same.

Claims

1. Inhibiting the activity of M2 macrophages Metal-organic framework.

2. In Paragraph 1, The above metal-organic framework is a metal selected from the group consisting of Li, Na, Mg, Ca, Sr, Ba, Sc, Y, Ti, Zr, Hf, V, Nb, Ta, Cr, Mo, W, Mn, Re, Fe, Ru, Os, Co, Rh, Ir, Ni, Pd, Pt, Cu, Ag, Au, Zn, Cd, Hg, Al, Ga, In, Tl, Si, Ge, Sn, Pb, As, Sb, and Bi, or Li + , Na + , Mg 2+ , Ca 2+ , Sr 2+ , Ba 2+ , Sc 3+ , Y 3+ , Ti 4+ , Zr 4+ , Hf 4+ , V 4+ , V 3+ , V 2+ , Nb 3+ , Ta 3+ , Cr 3+ , Mo 3+ , W 3+ , Mn 3+ , Mn 2+ , Re 3+ , Re 2+ , Fe 3+ , Fe 2+ , Ru 3+ , Ru 2+ , Os 3+ , Os 2+ , Co 3+ , Co 2+ , Rh 2+ , Rh + , Ir 3+ , Ir 2+ , Ir + , Ni 2+ , Ni + , Pd 2+ , Pd + , Pt 2+ , Pt + , Cu 2+ , Cu + , Ag + , Au + , Zn 2+ , Cd 2+ , Hg 2+ , Al 3+ , Ga 3+ , In 3+ , Tl 3+ , Si 4+ , Si 2+ , Ge 4+ , Ge 2+ , Sn 4+ , Sn 2+ , Pb 4+ , Pb 2+ , As 5+ , As 3+ , As + , Sb 5+ , Sb 3+ , Sb + , Bi 5+ , Bi 3+ and Bi + A metal ion selected from the group consisting of Metal-organic framework.

3. In Paragraph 2, The above metal-organic framework is selected from the group consisting of aluminum-based metal-organic frameworks, iron-based metal-organic frameworks, zirconium-based metal-organic frameworks, and mixtures thereof. Metal-organic framework.

4. In Paragraph 1, The above metal-organic framework is, Metal clusters and A ligand compound represented by the following chemical formula 1 that coordinates to the metal cluster above Metal-organic framework: [Chemical Formula 1] Here, n is an integer of 1 or 2, and EDP ​​refers to a group containing an electron pair donor atom, and L is selected from the group consisting of a substituted or unsubstituted alkyl group having 1 to 30 carbon atoms, a substituted or unsubstituted cycloalkyl group having 3 to 20 carbon atoms, a substituted or unsubstituted aralkyl group having 7 to 30 carbon atoms, a substituted or unsubstituted aryl group having 6 to 30 carbon atoms, a substituted or unsubstituted heteroaryl group having 1 to 60 carbon atoms, and a substituted or unsubstituted heteroarylalkyl group having 2 to 30 carbon atoms.

5. In Paragraph 4, The ligand compound represented by the above chemical formula 1 is a ligand compound represented by the following chemical formula 2 or chemical formula 3. Metal-organic framework: [Chemical Formula 2] [Chemical Formula 3] Here, m is an integer of 1 or 2, and p is an integer of 0 or 1, and EDP ​​refers to a group containing an electron pair donor atom, and R1 and R2 are identical or different from each other and each independently hydrogen, deuterium, cyano group, nitro group, halogen group, hydroxyl group, substituted or unsubstituted C1 to C4 alkyl thio group, substituted or unsubstituted C1 to C30 alkyl group, substituted or unsubstituted C3 to C20 cycloalkyl group, substituted or unsubstituted C2 to C30 alkenyl group, substituted or unsubstituted C2 to C24 alkynyl group, substituted or unsubstituted C7 to C30 aralkyl group, substituted or unsubstituted C6 to C30 aryl group, substituted or unsubstituted C1 to C60 heteroaryl group, substituted or unsubstituted C2 to C30 heteroarylalkyl group, substituted or unsubstituted C1 to C30 alkoxy group, substituted or unsubstituted C1 to C30 of It is selected from the group consisting of an alkylamino group, a substituted or unsubstituted arylamino group having 6 to 30 carbon atoms, a substituted or unsubstituted aralkylamino group having 7 to 30 carbon atoms, a substituted or unsubstituted heteroarylamino group having 1 to 24 carbon atoms, a substituted or unsubstituted alkylsilyl group having 1 to 30 carbon atoms, a substituted or unsubstituted arylsilyl group having 6 to 30 carbon atoms, and a substituted or unsubstituted aryloxy group having 6 to 30 carbon atoms.

6. A metal-organic framework according to any one of paragraphs 1 to 5 Anticancer composition.

7. In Paragraph 6, The above cancer is colorectal cancer, liver cancer, lung cancer, breast cancer, melanoma, stomach cancer, colon cancer, skin cancer, ovarian cancer, cervical cancer, thyroid cancer, kidney cancer, prostate cancer, bladder cancer, pancreatic cancer, esophageal cancer, or fibrosarcoma Anticancer composition.

8. A metal-organic framework according to any one of paragraphs 1 to 5 Pharmaceutical composition for the prevention or treatment of liver cirrhosis.

9. A metal-organic framework according to any one of paragraphs 1 to 5 Pharmaceutical composition for the prevention or treatment of obesity-related metabolic diseases.

10. A metal-organic framework according to any one of claims 1 to 5 Pharmaceutical composition for preventing scar formation.

11. A metal-organic framework according to any one of paragraphs 1 to 5 Pharmaceutical composition for the prevention or treatment of idiopathic lung disease.

12. A metal-organic framework according to any one of paragraphs 1 to 5 Pharmaceutical composition for the prevention or treatment of chronic infectious diseases.

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