CN105566293A - Macrophage migration inhibition factor tetracyclic small-molecule inhibitor and application thereof - Google Patents

Macrophage migration inhibition factor tetracyclic small-molecule inhibitor and application thereof Download PDF

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Publication number
CN105566293A
CN105566293A CN201610018572.1A CN201610018572A CN105566293A CN 105566293 A CN105566293 A CN 105566293A CN 201610018572 A CN201610018572 A CN 201610018572A CN 105566293 A CN105566293 A CN 105566293A
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mif
fgh
macrophage migration
ring
inhibition factor
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范国煌
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Abstract

The invention discloses a macrophage migration inhibition factor (MIF) tetracyclic small-molecule inhibitor. The molecular structural formula of the MIF tetracyclic small-molecule inhibitor is shown in the specification, wherein R1 can indicate benzene rings or dioxane or diethylene oximide or diazine; R2, R3 and R4 are independently selected from combinations containing hydrogen, halogen, C1-C3 alkyl groups, hetero alkyl groups, aryl groups, hetero aryl groups, naphthenic bases, heterocycles and halogenated alkyl groups; R5 indicates halogen or -(CH2)n-, and n can be 0 or 1; R6 can indicate hydroxyl groups or halogen or hetero alkyl groups or aryl groups or aryloxy groups or hetero aralkyl groups or naphthenic bases or heterocycles or halogenated alkyl groups or the like. The MIF tetracyclic small-molecule inhibitor can be used for treating various diseases caused by MIF expression or activity increasing.

Description

A kind of macrophage migration inhibition factor Fourth Ring micromolecular inhibitor and application thereof
Technical field
The invention belongs to biomedicine field, relate to a kind of macrophage migration inhibition factor (MIF) Fourth Ring micromolecular inhibitor, particularly relate to inflammation that a kind of tautomerase activity to MIF and MIF receive, micromolecular compound that cell proliferation has strongly inhibited effect.
Background technology
Macrophage migration inhibition factor (MIF) is a kind of protein containing 115 amino-acid residues, and molecular weight is 12.5kDa, the three-dimensional structure be made up of α chain and β chain.The albumin crystal structure of MIF is a homotrimer, and each monomer is made up of two parallel α spirals and 6 β chains.
One of important sources of MIF is pituitary gland, accounts for 0.05% of hypophysis Tot Prot.Monocyte/macrophage is also one of important sources of MIF.In addition, lymphocyte also expresses MIF.MIF can be combined with the extracellular group of surface of cell membrane PROTEIN C D74 and play a role.The extracellular group of MIF and CD74, i.e. the high affine combination of the amino-acid residue of 73-232 position, activates ERK1/2 and AKT protein kinase, thus causes the propagation of various cell and the release of inflammatory factor, produce various physiology and pathologic reaction.MIF is a kind of protein of uniqueness, and it participates in inflammatory reaction, immune response, cell proliferation, vasculogenesis etc.MIF is relevant to various diseases, includes but not limited to atherosclerosis, glomerulonephritis, Crohn disease, rheumatoid arthritis, systemic lupus erythematous, tumour, delayed hypersensitivity, graft-rejection, nerve degenerative diseases, diabetes, apoplexy, Spinal injury.
MIF has tautomerase activity, can catalysis D-dopachrome, phenyl-pyruvic acid tautomerization.MIF can also the redox reaction of catalyze thiol albumen.Owing to relating to inflammation, immunity, tumour, the generation of nerve degenerative diseases, development, MIF has become the important target spot of above-mentioned disease.
At present for therapeutic strategy mainly its tautomerase activity center of target development micromolecular inhibitor of MIF.But the general activity of MIF micromolecular inhibitor found at present is lower, also successfully do not go on the market for the micromolecular inhibitor of MIF so far.Therefore, develop highly active MIF micromolecular inhibitor for treatment comprise atherosclerosis, glomerulonephritis, Crohn disease, rheumatoid arthritis, systemic lupus erythematous, tumour, delayed hypersensitivity, graft-rejection, nerve degenerative diseases, diabetes, apoplexy, Spinal injury various diseases significant.
Summary of the invention
For overcoming shortcoming of the prior art, purport of the present invention provides a kind of macrophage migration inhibition factor (MIF) Fourth Ring micromolecular inhibitor, to suppressing inflammation, immunity and the cell proliferation function of MIF mediation.
For realizing above-mentioned technical purpose, the molecular structural formula of macrophage migration inhibition factor of the present invention (MIF) Fourth Ring micromolecular inhibitor is as follows:
Wherein, R 1can be phenyl ring, dioxane, hexacyclic ring of nitrogen oxygen, Anteper; R 2, R 3and R 4independently be selected from the combination comprising following group: hydrogen, halogen, C1-C3 alkyl, assorted alkyl, aromatic base, heteroaralkyl, cycloalkyl, heterocycle and haloalkyl; R 5be Lu Su Huo – (CH2) n –, n can be 0 or 1 here; R 6can be hydroxyl, halogen, assorted alkyl, aromatic base, aryloxy, heteroaralkyl, cycloalkyl, heterocycle and haloalkyl etc.
Further, one of derivative of described MIF Fourth Ring micromolecular inhibitor is FGH-001, and its molecular structural formula is as follows:
The crystalline structure that the present invention is based on MIF carries out virtual screening to comprising to surpass to Chembridge and Specs two compound databases of 1,000,000 compounds, obtain the micromolecular compound tautomerase activity of MIF to high strength selective inhibitory, comprise its pharmacy acceptable salt and precursor medicine, the activation of the ERK1/2 that MIF can be suppressed to mediate in test in vitro, suppress mononuclear cell proliferation, inhibition tumor cell is bred, and inflammation-inhibiting reacts.
Compared with prior art, the present invention has following beneficial effect:
MIF Fourth Ring of the present invention micromolecular inhibitor suppresses to be used for the treatment of the various diseases comprising atherosclerosis, glomerulonephritis, Crohn disease, rheumatoid arthritis, systemic lupus erythematous, tumour, delayed hypersensitivity, graft-rejection, nerve degenerative diseases, diabetes, apoplexy, Spinal injury.
Accompanying drawing explanation
Accompanying drawing described herein is used to provide a further understanding of the present invention, and form a application's part, schematic description and description of the present invention, for explaining the present invention, does not form inappropriate limitation of the present invention.In the accompanying drawings:
Fig. 1 is the restraining effect schematic diagram of FGH-001 of the present invention to the tautomerase activity of MIF.
Fig. 2 is FGH-001 of the present invention to the restraining effect schematic diagram of BV2 cell ERK1/2 and AKT phosphorylation.
Fig. 3 is the restraining effect schematic diagram of FGH-001 of the present invention to BV2 cell proliferation.
Fig. 4 is the restraining effect schematic diagram of FGH-001 of the present invention to U251 cell proliferation.
Fig. 5 is that FGH-001 of the present invention is to Cell Proliferation of Pancreatic Cancer Cell and swollen neoplastic restraining effect schematic diagram
Fig. 6 is the promoter action schematic diagram of FGH-001 of the present invention to apoptosis of pancreatic cancer cell.
Fig. 7 is the restraining effect schematic diagram of FGH-001 of the present invention to the inflammation of inducing LPS.
Fig. 8 is that FGH-001 of the present invention affects schematic diagram to type-II diabetes (db/db) mouse blood sugar.
Embodiment
The present embodiment, based on the crystalline structure of MIF, carries out virtual screening to comprising to surpass to Chembridge and Specs two compound databases of 1,000,000 compounds.Through REOS rule-based filtering and based on the cluster analysis of molecular fingerprint after, carry out the activity test of D-dopachrome tautomerase to 170 compounds, obtain a series of MIF tautomerism enzyme inhibitors with micromole's level activity, its molecular structural formula is as follows:
Wherein, R 1can be phenyl ring, dioxane, hexacyclic ring of nitrogen oxygen, Anteper; R 2, R 3and R 4independently be selected from the combination comprising following group: hydrogen, halogen, C1-C3 alkyl, assorted alkyl, aromatic base, heteroaralkyl, cycloalkyl, heterocycle and haloalkyl; R 5be Lu Su Huo – (CH2) n –, n can be 0 or 1 here; R 6can be hydroxyl, halogen, assorted alkyl, aromatic base, aryloxy, heteroaralkyl, cycloalkyl, heterocycle and haloalkyl etc.
Preferably, one of derivative of described MIF Fourth Ring micromolecular inhibitor is FGH-001, and its molecular formula is as follows:
As shown in Figure 1, described MIF Fourth Ring micromolecular inhibitor FGH-001 suppresses the tautomerase activity of MIF.As shown in the figure, FGH-001 and the 10nMMIF of different concns and 1 μM of D dopachrome is reacted, measure the relative reactivity of MIF by dopachrome isomerase ELISA detection kit, obtain product pIC50 value.Result is the mean number ± standard deviation of three experiment gained.Result: FGH-001 concentration dependent ground suppresses the tautomerase activity of MIF.PIC50 is 6.4 ± 0.3.
As shown in Figure 2, described MIF Fourth Ring micromolecular inhibitor FGH-001 to the restraining effect of BV2 cell ERK1/2 and AKT phosphorylation, as shown in the figure, by FGH-001 and the BV2 of different concns cell (5x10 6) hatch lysing cell after 12 hours, detect the phosphorylation level of ERK1/2 and AKT and the protein expression level of total ERK2 and AKT by SDS-PAGE and Westernblot detection method.Result: FGH-001 concentration dependent ground suppresses the phosphorylation of BV2 cell ERK1/2 and AKT.
As shown in Figure 3, described MIF Fourth Ring micromolecular inhibitor FGH-001 to the restraining effect of BV2 cell proliferation, as shown in the figure, by FGH-001 and the BV2 of different concns cell (5x10 6) hatch the propagation degree measuring cell after 24 hours by MTT detection method.Result: FGH-001 concentration dependent ground suppresses BV2 cell proliferation.
As shown in Figure 4, described MIF Fourth Ring micromolecular inhibitor FGH-001 is to the restraining effect to U251 cell proliferation.By FGH-001 and the U251 of different concns cell (5x10 6) hatch the propagation degree measuring cell after 24 hours by MTT detection method.The propagation of result: FGH-001 to U251 cell does not make significant difference.
Embodiment 1:
The FGH-001 of the present embodiment is to Cell Proliferation of Pancreatic Cancer Cell and swollen neoplastic restraining effect.
MIF expresses rising in the multiple noumenal tumours such as carcinoma of the pancreas, mammary cancer, nonsmall-cell lung cancer, colorectal carcinoma.Large quantifier elimination shows that the expression level of MIF and the generation development of above-mentioned tumour have substantial connection.
First we observe the impact of FGH-001 on the propagation of pancreatic cancer cell PANC-1.By 1 μM of FGH-001 and pancreatic carcinoma PANC-1 cell (1x10 4) hatch the propagation degree measuring cell after different time by MTT detection method.Result display FGH-001 significantly suppresses the propagation of PANC-1 cell.
We observe the impact of FGH-001 on soft agar clonogenic assay further.By 1 μM of FGH-001 and pancreatic carcinoma PANC-1 cell (1x10 4) hatch 24 hours after observe Colony forming.Result display FGH-001 significantly suppresses the formation number of PANC-1 cell colony.
We observe the impact that PANC-1 cell becomes knurl in nude mouse.By PANC-1 cell (5x10 6) plant in BALB/C nude mice by subcutaneous, then give FGH-001 (50mg/kg, b.i.d) to mouse stomach, and measure tumor size in the different time with vernier callipers.Result display FGH-001 significantly suppresses PANC-1 tumour to form (as shown in Figure 5).
Embodiment 2:
The FGH-001 of the present embodiment is to the promoter action of FGH-001 to apoptosis of pancreatic cancer cell.
As shown in Figure 6, by 1 μM of FGH-001 and pancreatic carcinoma PANC-1 cell (5x10 6) hatch 24 hours after use Flow cytometry AnnexinV, to determine the apoptosis of tumour cell.Result display FGH-001 significantly promotes the apoptosis of PANC-1 cell.
Embodiment 3:
The FGH-001 of the present embodiment is to the restraining effect of the inflammation that LPS induces.
Shown in Figure 7, MIF causes scavenger cell to M1 (struvite) direction polarization by suppressing the approach such as glucocorticosteroid, thus participates in inflammatory process.This experimental observation impact of FGH-001 on the inflammatory reaction that LPS induces.The male C57 mouse in six week age is divided into two groups at random, often organize 10, gavage gives solvent (control group) or FGH-001 (30mg/kg respectively, b.i.d.) within three days, animal abdominal injection 100 μ lLPS (10ng/ml) is given afterwards, then collect peritoneal macrophage when phenylethyl barbituric acid deep anaesthesia, detect the level of cytokine with Suspension array technique (Luminex).Result shows, and FGH-001 significantly suppresses the generation of inflammatory cytokine.
Embodiment 4:
The restraining effect that the FGH-001FGH-001 of the present embodiment raises type-II diabetes mouse blood sugar.
Large quantifier elimination shows, MIF is up-regulated in type-II diabetes patient monocyte, causes Monocytes/Macrophages to produce a large amount of inflammatory cytokines, insulin receptor is desensitized, thus produces insulin resistant, causes blood sugar increasing.This experimental observation impact of FGH-001 on type-II diabetes (db/db) mouse blood sugar.Two groups are divided into by purchased from after the db/db (type-II diabetes) of U.S. JacksonLab and db/m (normal control) mouse support 8 week age, one group gives solvent (control group), another group gives FGH-001 (30mg/kg, b.i.d.), take a blood sample with different time points, measure blood sugar concentration.Result shows, and FHG-001 significantly suppresses blood glucose in diabetic mice to raise, shown in Figure 8.
Embodiment 5:
In view of FGH-001 is to the significance restraining effect of the tautomerase activity of MIF and to the activity of ERK1/2 and AKT and the restraining effect of on cell proliferation in the cell of MIF mediation, we carry out structure of modification to this compound, to obtaining a series of effect compound similar or more excellent with Pharmacokinetics Parameter.By structure of modification, we have found the selective depressant of a series of MIF.
Preferably, FGH-002 is the derivative of FGH-001, and its molecular structure is as follows:
Preferably, FGH-003 is the derivative of FGH-001, and its molecular structure is as follows:
Preferably, FGH-004 is the derivative of FGH-001, and its molecular structure is as follows:
Preferably, described FGH-005 is the derivative of FGH-001, and its molecular structure is as follows:
Preferably, FGH-006 is the derivative of FGH-001, and its molecular structure is as follows:
Preferably, FGH-007 is the derivative of FGH-001, and its molecular structure is as follows:
Preferably, described FGH-008 is the derivative of FGH-001, and its molecular structure is as follows:
Preferably, FGH-009 is the derivative of FGH-001, and its molecular structure is as follows:
Preferably, FGH-0010 is the derivative of FGH-001, and its molecular structure is as follows:
Preferably, FGH-0011 is the derivative of FGH-001, and its molecular structure is as follows:
Preferably, FGH-0012 is the derivative of FGH-001, and its molecular structure is as follows:
The foregoing is only the preferred embodiments of the present invention, be not limited to the present invention, for a person skilled in the art, the present invention can have various modifications and variations.Within the spirit and principles in the present invention all, any amendment done, equivalent replacement, improvement etc., all should be included within protection scope of the present invention.

Claims (4)

1. a macrophage migration inhibition factor Fourth Ring micromolecular inhibitor, is characterized in that, described macrophage migration inhibition factor Fourth Ring micromolecular inhibitor molecular structural formula is as follows:
，
Wherein, R 1can be phenyl ring, dioxane, hexacyclic ring of nitrogen oxygen, Anteper; R 2, R 3and R 4independently be selected from the combination comprising following group: hydrogen, halogen, C1-C3 alkyl, assorted alkyl, aromatic base, heteroaralkyl, cycloalkyl, heterocycle and haloalkyl; R 5be Lu Su Huo – (CH2) n –, n can be 0 or 1 here; R 6can be hydroxyl, halogen, assorted alkyl, aromatic base, aryloxy, heteroaralkyl, cycloalkyl, heterocycle and haloalkyl.
2. macrophage migration inhibition factor Fourth Ring according to claim 2 micromolecular inhibitor, is characterized in that: described macrophage migration inhibition factor Fourth Ring micromolecular inhibitor is FGH-001, and its molecular formula is as follows:
3. macrophage migration inhibition factor Fourth Ring according to claim 1 and 2 micromolecular inhibitor, for the preparation of the application of the disease medicament suppressing MIF to mediate.
4. macrophage migration inhibition factor Fourth Ring according to claim 3 micromolecular inhibitor, for the preparation of atherosclerosis, glomerulonephritis, Crohn disease, rheumatoid arthritis, systemic lupus erythematous, tumour, delayed hypersensitivity, graft-rejection, nerve degenerative diseases, diabetes, apoplexy, Spinal injury in the application of interior medicine.
CN201610018572.1A 2016-01-12 2016-01-12 Macrophage migration inhibition factor tetracyclic small-molecule inhibitor and application thereof Pending CN105566293A (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023020534A1 (en) * 2021-08-18 2023-02-23 Nanjing Immunophage Biotech Co., Ltd Compounds and their uses as mif inhibitors

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* Cited by examiner, † Cited by third party
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STN: "CAS号315698-40-9", 《STN数据库》 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023020534A1 (en) * 2021-08-18 2023-02-23 Nanjing Immunophage Biotech Co., Ltd Compounds and their uses as mif inhibitors

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Application publication date: 20160511