CN109293663A - KDM5B inhibitor and preparation method thereof - Google Patents
KDM5B inhibitor and preparation method thereof Download PDFInfo
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- CN109293663A CN109293663A CN201811291147.5A CN201811291147A CN109293663A CN 109293663 A CN109293663 A CN 109293663A CN 201811291147 A CN201811291147 A CN 201811291147A CN 109293663 A CN109293663 A CN 109293663A
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Abstract
The present invention provides a kind of KDM5B inhibitor, chemical name 4,5,6,7- tetrahydro -8H- cyclopenta [d] [1,2,4] triazol [1,5-a] pyrimidin-8-ones, structural formula is
Description
Technical field
The invention belongs to field of medicinal chemistry, and in particular to a kind of KDM5B inhibitor and preparation method thereof.
Background technique
Cancer is a kind of disease for seriously threatening human health and life, the global cancer announced according to the World Health Organization
Statistical data shows, newly-increased about 14,100,000 cases of cancer in the whole world in 2012 and 8,200,000 deaths, wherein lung cancer be the whole world the most
The highest cancer of the common and death rate.Lung cancer seriously threatens human health, since aging of population, smoking and environmental pollution etc. are outer
The influence of boundary's factor, the incidence and the death rate of lung cancer are much higher than other cancers.KDM5B goes first as a kind of important histone
Base enzyme, the high expression in lung cancer patient tissue, proliferation, invasion and transfer, poor prognosis and multidrug resistant with lung cancer etc. are close
Cut phase is closed.Though existing KDM5B inhibitor report, does not enter clinical development.Therefore, novel lung cancer targeting is developed
KDM5B small molecule compound has great novelty and scientific meaning.
Istone lysine specificity demethylase can be divided into the monoamine oxidase LSD1 of FAD dependence and tie comprising JmjC
The JMJD protein family in structure domain.LSD1 specificity removes the mono- double methylations of H3K4, H3K9, and then activates or inhibits gene expression,
And JMJD family protein relies on Fe2+It is modified with a-ketoglutaric acid (2-OG) catalysis demethylation, including KDM2A/B, KDM3A/B,
KDM4A-E, KDM5A-D (or JARID1A-D), KDM6A-B, JHDM1D, multiple subfamilies such as KDM8, selective catalysis difference bottom
Object.JMJD family protein JmjC structural domain is highly conserved, has 2 histidines (His) and 1 glutamic acid (Glu), in 2-OG and O2
Participation under, histone methyl lysine can be catalyzed without hydrogen donor and generate unstable hydroxylated intermediate, while generating 1
Molecule CO2And succinate, intermediate, which further decomposes, generates demethylation lysine and formaldehyde.In JMJD family, KDM5
Be divided into tetra- hypotypes of KAM5A-D, be the subfamily of most study, specificity removal H3K4 methylation modification, wherein KDM5C/D with
The associated research report of tumour is less.Demethylase KDM5 high expression in patient's cancerous lung tissue, and it is much higher than cancer beside organism
And normal tissue, the invasion and transfer with lung cancer are closely related, and it is thin that the KDM5B expression quantity reduction of siRNA induction can inhibit tumour
Intracellular growth, invasion and transfer.KDM5 is overexpressed in the kinds of tumors tissue such as breast cancer, prostate cancer, melanoma, gastric cancer,
Key effect, and the deterioration journey of its expression and tumour are played to the processes such as proliferation, cycle regulating, transfer and invasion, differentiation
Degree is related, and KDM5 expression reduces or knock out the transfer that can obviously inhibit tumour and invasion etc..Based on the important tumour of KDM5B
Biological function and its potentiality in terms of overcoming tumor drug resistance have become important epigenetic regulation target spot, design target
An important directions of tumor-targeting drug development field are had become to the small molecule compound of KDM5B.
KDM5 is as a kind of important commitment demethylase, the high expression in lung cancer patient tissue, with lung cancer
Proliferation, invasion and transfer and poor prognosis, multidrug resistant etc. are closely related, and KDM5 is knocked out or micromolecular inhibitor can be removed effectively
Drug resistance of lung cancer cell, the processes such as Inhibit proliferaton, transfer and invasion, apoptosis, differentiation.Though existing different structure framework types
KDM5A/B inhibitor report, but because poor selectivity, mechanism of action is indefinite, undershooting-effect is obvious, shortage intracellular reactive or compared with
The PD/PK attribute etc. of difference, there is no micromolecular inhibitor to enter clinical development.Therefore, high-activity high-selectivity class medicine is developed
The good KDM5B small molecule compound of attribute is the important directions of tumor-targeting drug research field.
Summary of the invention
In view of this, the present invention is it is necessory to provide a kind of novel KDM5B inhibitor and preparation method thereof.
The present invention provides a kind of KDM5B inhibitor, 4,5,6,7- tetrahydro -8H- cyclopenta [d] of chemical name [1,
2,4] triazol [1,5-a] pyrimidin-8-ones, structural formula are
The present invention also provides a kind of preparation methods of KDM5B inhibitor, and the method comprising the steps of: by compound M (3- ammonia
Base -4- hydrogen -1,2,4- triazole) and 2- oxocyclopentanecarboxylic acid methyl esters C4H7(CO)2OCH3Under the action of acid flux material, in
It is reacted at a temperature of 115 DEG C -125 DEG C, synthesizes the KDM5B inhibitor, wherein the acid flux material is glacial acetic acid, salt
The organic acids such as acid, sulfuric acid, trifluoroacetic acid or trifluoromethanesulfonic acid.Wherein, the preparation route of the KDM5B inhibitor is as follows:
Based on above-mentioned, the preparation method of the KDM5B inhibitor further comprises the steps of: 3- amino -4- hydrogen -1,2,4- triazole
KDM5B inhibitor mixed liquid is obtained with after 2- oxocyclopentanecarboxylic acid's methyl esters fully reacting；Then the acid flux material is removed, is obtained
To KDM5B inhibitor semi-finished product；By the KDM5B inhibitor semi-finished product in 55 DEG C of -65 DEG C of dryings, KDM5B inhibitor sterling is obtained.
Therefore, the chemical name of KDM5B inhibitor provided by the invention is 4,5,6,7- tetrahydro -8H- cyclopentas [d]
[1,2,4] triazol [1,5-a] pyrimidin-8-ones, with the unit structure unit of 1,2,4-triazole of pyrimido in structural formula,
The compound with anti-tumor activity of KDM5B can be targeted based on 1,2,4-triazole basic framework of pyrimido preparation series,
It is simultaneously to find the new type antineoplastic medicine that targeting KDM5B is target spot to open up new way.In addition, KDM5B suppression provided by the invention
The synthetic method of preparation is feasible, high income, and yield is up to 82% or more.
Detailed description of the invention
Fig. 1 is suppression curve figure of the inhibitor provided by the invention to KDM5B enzymatic activity.
Fig. 2 is suppression curve figure of the inhibitor provided by the invention to KDM5B enzymatic activity.
Specific embodiment
Below by specific embodiment, technical scheme of the present invention will be described in further detail.
The embodiment of the present invention provides a kind of KDM5B inhibitor, 4,5,6,7- tetrahydro -8H- cyclopenta of chemical name
[d] [1,2,4] triazol [1,5-a] pyrimidin-8-ones, structural formula areThe preparation route of the compound is as follows:
By 1g (about 11.89mmoL) 3- amino -4- hydrogen -1,2,4- triazole is added to reaction flask, adds 20mL ice vinegar
Then acid is slowly added dropwise 2.22mL (about 17.84mmoL) 2- oxocyclopentanecarboxylic acid methyl esters and is heated to reflux at 120 DEG C, use
TLC monitoring reaction.After reaction, reaction system is put into ice water, there are a large amount of white solids to be precipitated, directly filters white
Solid.After acetone cleans white solid, it is placed in 60 DEG C of baking ovens dry 6h and obtains above-mentioned KDM5B inhibitor sterling.Through weightometer
Calculation can obtain, yield 82.70%, white solid, and 211.2-216.6 DEG C of fusing point；1H NMR(400MHz,DMSO-d6)δ13.39(s,
1H), 8.16 (s, 1H), 2.91 (t, J=7.7Hz, 2H), 2.68 (t, J=7.3Hz, 2H), 2.17-1.99 (m, 2H)；13C NMR
(100MHz,DMSO-d6)δ155.83,154.93,152.11,151.43,110.37,31.78,27.21,22.20；HRMS
(ESI):m/z calcd for C8H9N4O(M+H)+,177.07764；Found, 177.07671, thus it is confirmed that of the invention
The structure for the KDM5B inhibitor that embodiment provides is as shown above.
Inhibitory activity measurement
Inhibitory activity experimental method reaction system is 10 μ L, including detection buffer, histone H 3 peptide substrate, demethyl
Change enzyme KDM5B and untested compound KDM5B inhibitor, reaction carries out in 384 orifice plates, reacts at room temperature 60min.First by 3 μ L
KDM5B inhibitor and 4 μ L demethylase KDM5B room temperature preincubate 30min, then add 3 μ L histone H 3 peptide substrates,
5 μ L are coated with the Acceptor beads and 5 μ L histone lysine methylation primary antibodies of rabbit-anti；DMSO content is 1% in reaction system；Room
Warm slowly shaking is incubated for 30min.Be eventually adding 10 μ L couple Streptavidin donor microballon (Perkin, with 1:1 dilution 1:
125 detection buffers).In 30min, sample measures numerical value (EnSpire Alpha in AlphaScreen
2390Multilabel Reader, PerkinElmer).
The verifying of 1.1 experimental method feasibilities
It selects KDM5B inhibitor KDOAM-25 reported in the literature for control, is being the concentration of 100ng and H3 polypeptide with enzyme amount
Under conditions of 10 μM, the activity using above-mentioned inhibitory activity determination of experimental method inhibitor KDOAM-25 is 36nM, and before
Activity data reported in the literature is consistent, demonstrates the feasibility of this method.Wherein, the text of KDM5B inhibitor KDOAM-25 is reported
Offer entitled " Potent and Selective KDM5Inhibitor Stops Cellular Demethylation of
H3K4me3at Transcription Start Sites and Proliferation of MM1S Myeloma Cells ",
Author is A.Tumber et al., is reported in " Cell Chem Biol ", 2017,24 (3): 371-380.
The activity experiment of 1.2 KDM5B inhibitor provided in an embodiment of the present invention
KDM5B inhibitors 4 provided in an embodiment of the present invention, 5,6,7- tetrahydro -8H- cyclopenta [d] [1,2,4] triazole
And [1,5-a] pyrimidin-8-ones, hereinafter referred to as compound I.
Sample is synthesized KDM5B inhibitor compound I sterling, stock sample solution: weighs 1-2mg sample in 1.5mL
EP pipe in, be configured to the solution that concentration is 10mM with DMSO, 4 DEG C of preservations, in experimentation, then needed for being diluted to DMSO it is dense
Degree.Using above-mentioned inhibitory activity determination of experimental method compound I to the inhibitory activity of KDM5B, detection data is as shown in table 1.
Inhibitory activity result table of the 1 compound I of table to KDM5B enzymatic activity
Data according to table 1 draw compound I to the suppression curve of KDM5B enzymatic activity, as depicted in figs. 1 and 2.From Fig. 1
In it can be seen that compound I repeat experiment 1 in 503nhibiting concentration IC50For 369.7nM, compound I is in repeating experiment 2
503nhibiting concentration IC50For 236.3nM, the average IC of the two50For 303.0nM, inequality 66.7；And compound I is being repeated
Suppression curve figure when experiment 1 and 2 is consistent, so as to prove compound I provided in an embodiment of the present invention to KDM5B
Enzyme has inhibiting effect, may be used as KDM5B inhibitor.
Finally it should be noted that: the above embodiments are merely illustrative of the technical scheme of the present invention and are not intended to be limiting thereof；To the greatest extent
The present invention is described in detail with reference to preferred embodiments for pipe, it should be understood by those ordinary skilled in the art that: still
It can modify to a specific embodiment of the invention or some technical features can be equivalently replaced；Without departing from this hair
The spirit of bright technical solution should all cover within the scope of the technical scheme claimed by the invention.
Claims (3)
1. a kind of KDM5B inhibitor, which is characterized in that 4,5,6,7- tetrahydro -8H- cyclopenta [d] of chemical name [1,2,
4] triazol [1,5-a] pyrimidin-8-ones, structural formula are
2. a kind of preparation method of KDM5B inhibitor described in claim 1, comprising steps of by compound 3- amino -4- hydrogen -
1,2,4- triazole and 2- oxocyclopentanecarboxylic acid methyl esters C4H7(CO)2OCH3Under the action of acid flux material, in 115 DEG C -125
It is reacted at a temperature of DEG C, synthesizes the KDM5B inhibitor, wherein the acid flux material is glacial acetic acid, hydrochloric acid, sulfuric acid, three
Fluoroacetic acid or trifluoromethanesulfonic acid.
3. the preparation method of KDM5B inhibitor according to claim 2, which is characterized in that further comprise the steps of: 3- amino-
KDM5B inhibitor mixed liquid is obtained after 4- hydrogen -1,2,4- triazole and 2- oxocyclopentanecarboxylic acid methyl esters fully reacting；Then it removes
The acid flux material in the mixed liquor is removed, KDM5B inhibitor crude product is obtained；The KDM5B inhibitor semi-finished product acetone is clear
In 55 DEG C of -65 DEG C of dryings after washing, KDM5B inhibitor sterling is obtained.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN108484612A (en) * | 2018-05-08 | 2018-09-04 | 郑州大学 | 1,2,4-triazole compound of pyrimido and its preparation method and application |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN108484612A (en) * | 2018-05-08 | 2018-09-04 | 郑州大学 | 1,2,4-triazole compound of pyrimido and its preparation method and application |
Non-Patent Citations (1)
| Title |
|---|
| 栗娜等，: "1,2,3-三氮唑[4,5-d]嘧啶衍生物的合成及抗肿瘤活性评价", 《有机化学》 * |
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