CN105541803A - Macrophage migration inhibitory factor bicyclic small-molecule inhibitor and application thereof - Google Patents
Macrophage migration inhibitory factor bicyclic small-molecule inhibitor and application thereof Download PDFInfo
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- CN105541803A CN105541803A CN201610018606.7A CN201610018606A CN105541803A CN 105541803 A CN105541803 A CN 105541803A CN 201610018606 A CN201610018606 A CN 201610018606A CN 105541803 A CN105541803 A CN 105541803A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D241/18—Oxygen or sulfur atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D333/30—Hetero atoms other than halogen
- C07D333/32—Oxygen atoms
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
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Abstract
The invention discloses a macrophage migration inhibitory factor (MIF) bicyclic small-molecule inhibitor. The molecular structural formula of the MIF bicyclic small-molecule inhibitor is shown in the specification, wherein R1-R6 are independently selected from a combination including sulfhydryl groups, oxygroups, nitrogenous groups, hetero-alkyl groups, aromatic groups, hetero-aralkyl groups, halogen, C1-C3 alkyl groups, hetero-alkyl groups, aromatic groups, hetero-aralkyl groups, naphthenic groups, heterocycles and halogenated alkyl groups. The MIF bicyclic small-molecule inhibitor can be used for treating various diseases caused by MIF expression or activity increasing, wherein the diseases include but not limited to atherosclerosis, glomerulonephritis, Crohn diseases, rheumatoid arthritis, systemic lupus erythematosus, tumors, delayed hypersensitivity, transplantation rejection, neurodegenerative diseases, diabetes mellitus, apoplexia and spinal cord injury.
Description
Technical field
The invention belongs to biomedicine field, relate to a kind of macrophage migration inhibition factor (MIF) two 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) two 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) two ring micromolecular inhibitor is as follows:
Wherein, R
1-R
6independently be selected from the combination comprising following group: sulfenyl, oxygen base, nitrogen base, assorted alkyl, aromatic base, heteroaralkyl, halogen, C1-C3 alkyl, assorted alkyl, aromatic base, heteroaralkyl, cycloalkyl, heterocycle and haloalkyl.
Further, one of derivative of described MIF bis-ring micromolecular inhibitor is FGH-2001, 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 bis-ring micromolecular inhibitor of the present invention 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-2001 of the present invention to the tautomerase activity of MIF.
Fig. 2 is FGH-2001 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-2001 of the present invention to BV2 cell proliferation.
Fig. 4 is the restraining effect schematic diagram of FGH-2001 of the present invention to U251 cell proliferation.
Fig. 5 is the promoter action schematic diagram of FGH-2001 of the present invention to apoptosis of pancreatic cancer cell.
Fig. 6 is the restraining effect schematic diagram that FGH-2001 of the present invention attacks pancreatic cancer cell.
Fig. 7 is that FGH-2001 of the present invention is to Cell Proliferation of Pancreatic Cancer Cell and swollen neoplastic restraining effect schematic diagram.
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
1-R
6independently be selected from the combination comprising following group: sulfenyl, oxygen base, nitrogen base, assorted alkyl, aromatic base, heteroaralkyl, halogen, C1-C3 alkyl, assorted alkyl, aromatic base, heteroaralkyl, cycloalkyl, heterocycle and haloalkyl.
Embodiment 1:
Preferably, one of derivative of described MIF bis-ring micromolecular inhibitor is FGH-2001, and its molecular formula is as follows:
As shown in Figure 1, described MIF bis-ring micromolecular inhibitor FGH-2001 suppresses the tautomerase activity of MIF.As shown in the figure, FGH-2001 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-2001 concentration dependent ground suppresses the tautomerase activity of MIF.PIC50 is 5.9 ± 0.26.
As shown in Figure 2, described MIF bis-ring micromolecular inhibitor FGH-2001 suppresses the activity of ERK1/2 and AKT of MIF mediation.As shown in the figure, by FGH-2001 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-2001 concentration dependent ground suppresses the phosphorylation of BV2 cell ERK1/2 and AKT.
As shown in Figure 3,4, described MIF bis-ring micromolecular inhibitor FGH-2001 suppresses MIF mediates cell proliferation.Known in Fig. 3, by FGH-2001 and the BV2 of different concns cell (5x10
6) hatch the propagation degree measuring cell after 24 hours by MTT detection method.Result: FGH-2001 concentration dependent ground suppresses BV2 cell proliferation, three interpretations, pIC50=6.4 ± 0.56.Known in Fig. 4, by FGH-2001 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-2001 to U251 cell does not make significant difference.
The FGH-2001 of the present embodiment is to Cell Proliferation of Pancreatic Cancer Cell and to be swollenly neoplasticly inhibitingly analyzed as follows:
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-2001 on pancreatic cancer cell PANC-1 apoptosis.Shown in Figure 5, by the FGH-2001 of different concns and pancreatic carcinoma PANC-1 cell (5x10
6) hatch the apoptosis with Flow cytometry tumour cell after 24 hours.Result display FGH-2001 significantly promotes the apoptosis of PANC-1 cell.
Observe the impact of FGH-2001 on tumor cell invasion further.Shown in Figure 6, by pancreatic carcinoma PANC-1 cell (5x10
6) be incubated at the upper part of BoydenChamber, the FGH-2001 of different concns is dissolved in nutrient solution the lower part being placed in BoydenChamber.Hatch dyeing in 24 hours, calculate the cell count through film.Result display FGH-2001 significantly suppresses the invasion and attack of PANC-1 cell.
Also further study FGH-2001 to Cell Proliferation of Pancreatic Cancer Cell and swollen neoplastic restraining effect.Shown in Figure 7, by PANC-1 cell (5x10
6) plant in BALB/C nude mice by subcutaneous, then give the FGH-2001 (b.i.d) of various dose to mouse stomach, and measure tumor size in the different time with vernier callipers.Result: FGH-2001 significantly suppresses PANC-1 tumour to be formed, * P<0.05; * P<0.01.
Embodiment 2:
In view of FGH-2001 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-2002 is the derivative of FGH-2001, and its molecular structure is as follows:
Preferably, FGH-2003 is the derivative of FGH-2001, and its molecular structure is as follows:
Preferably, FGH-2004 is the derivative of FGH-2001, and its molecular structure is as follows:
Preferably, FGH-2005 is the derivative of FGH-2001, and its molecular structure is as follows:
Preferably, FGH-2006 is the derivative of FGH-2001, and its molecular structure is as follows:
Preferably, FGH-2007 is the derivative of FGH-2001, and its molecular structure is as follows:
Preferably, FGH-2008 is the derivative of FGH-2001, and its molecular structure is as follows:
Preferably, FGH-2009 is the derivative of FGH-2001, and its molecular structure is as follows:
Preferably, FGH-20010 is the derivative of FGH-2001, and its molecular structure is as follows:
Preferably, FGH-20011 is the derivative of FGH-2001, 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 two ring micromolecular inhibitor, is characterized in that, described macrophage migration inhibition factor two ring micromolecular inhibitor molecular structural formula is as follows:
，
Wherein, R
1-R
6independently be selected from the combination comprising following group: sulfenyl, oxygen base, nitrogen base, assorted alkyl, aromatic base, heteroaralkyl, halogen, C1-C3 alkyl, assorted alkyl, aromatic base, heteroaralkyl, cycloalkyl, heterocycle and haloalkyl.
2. macrophage migration inhibition factor two ring micromolecular inhibitor according to claim 2, is characterized in that: described macrophage migration inhibition factor two ring micromolecular inhibitor is FGH-2001, and its molecular formula is as follows:
3. macrophage migration inhibition factor two ring micromolecular inhibitor according to claim 1 and 2, for the preparation of the application of the disease medicament suppressing MIF to mediate.
4. macrophage migration inhibition factor two ring micromolecular inhibitor according to claim 3, 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.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107158022A (en) * | 2017-06-08 | 2017-09-15 | 南京大学 | One species specificity suppresses MIF shRNA medicines and its application |
| CN111481668A (en) * | 2020-04-14 | 2020-08-04 | 上海交通大学医学院附属仁济医院 | Application of macrophage migration inhibitory factor as drug target in treating perioperative stroke |
| US11230547B2 (en) | 2017-12-18 | 2022-01-25 | Merck Sharp & Dohme Corp. | Purine inhibitors of human phosphatidylinositol 3-kinase delta |
-
2016
- 2016-01-12 CN CN201610018606.7A patent/CN105541803A/en active Pending
Non-Patent Citations (1)
| Title |
|---|
| STN: "CAS号1001502-59-5", 《STN数据库》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107158022A (en) * | 2017-06-08 | 2017-09-15 | 南京大学 | One species specificity suppresses MIF shRNA medicines and its application |
| US11230547B2 (en) | 2017-12-18 | 2022-01-25 | Merck Sharp & Dohme Corp. | Purine inhibitors of human phosphatidylinositol 3-kinase delta |
| EP3727380A4 (en) * | 2017-12-18 | 2022-02-23 | Merck Sharp & Dohme Corp. | Purine inhibitors of human phosphatidylinositol 3-kinase delta |
| CN111481668A (en) * | 2020-04-14 | 2020-08-04 | 上海交通大学医学院附属仁济医院 | Application of macrophage migration inhibitory factor as drug target in treating perioperative stroke |
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Application publication date: 20160504 |