CN106905347B - BRD4 inhibitor and its application in tumor therapeutic agent - Google Patents
BRD4 inhibitor and its application in tumor therapeutic agent Download PDFInfo
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- CN106905347B CN106905347B CN201710253407.9A CN201710253407A CN106905347B CN 106905347 B CN106905347 B CN 106905347B CN 201710253407 A CN201710253407 A CN 201710253407A CN 106905347 B CN106905347 B CN 106905347B
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D495/14—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to the inhibitor of targeting BRD4 and its applications in tumor therapeutic agent, belong to antitumor pharmaceutical technology.The technical problem to be solved by the present invention is to provide a kind of compounds as BRD4 inhibitor.The compound includes compound or its pharmaceutically acceptable salt as follows.The compound of the present invention or its pharmaceutically acceptable salt, can be used as BRD4 inhibitor, have obvious anti-breast cancer therapeutic effect.
Description
Technical field
Application the present invention relates to BRD4 inhibitor and its in tumor therapeutic agent belongs to tumor therapeutic agent discovery skill
Art field.
Background technique
Bromine (BRD4) containing protein 4 is the member of bromine and additional terminal (BET) protein family, in cell division and transcription
Regulation transmits epigenetic memory as a central location.In addition to BRD4, there are also other three members, such as BRD2, BRD3 and
BRDT, they may regulate and control many cell processes and pass through the interaction between bromine structural domain.BRD4 is a kind of core of wide expression
Albumen, molecular weight 200kDa are conservative in structure but have not containing there are two concatenated bromine structural domain (BD1 and BD2)
Identical function and an ET structural domain.Recently, BRD4, which is reported, participates in oncogene rearrangement, leads to height oncogenic fusion egg
It is white, to be played a key role in the development of the cancer of many types, such as breast cancer.BRD4 adjusts breast cancer cell transfer
It is the rna plymerase ii and group for passing through influence breast cancer by adjusting active and adjusting ER α induction the gene expression of Sipa1 enzyme
The mono- ubiquitination of albumen H2B extends relevant phosphorylation.In addition, BRD4 adjusts the expression of extracellular matrix, in branch prediction
Often occur in gene signal；And the progress and/or existence of breast cancer can be predicted by its activation signal.
Autophagy be guarded in a kind of evolution, the lysosomal degradation process of multi-step, for removing impaired or extra egg
White matter and organelle.Autophagy machine includes more than 36 autophagy related genes (ATGs) and UNC-51- sample kinases 1 (ULK1), it is
The direct homologous gene of saccharomycete Atg1 is unique serine threonine kinases, is the starting in these autophagy related genes
Enzyme.The complexity of ULK is mutually fit, including ULK1, mAtg13, FIP200 and Atg101, these are necessary to starting autophagy process
[17].In autophagy, mTORC1 and AMPK can carry out negative regulation to ULK1 activity by Direct Phosphorylation.AMPK-mTORC1-
ULK1 axis may play key effect in the formation of autophagosome and the regulation of autophagy.The function and its ginseng of AMPK mTORC1, ULK1
With many pathophysiological processes such as breast cancer be set forth.Autophagy is a kind of physiological mechanism, can be used as temporary existence
Means, thus referred to as protectiveness cell autophagy.On the contrary, if cellular stress leads to autophagy that is continuous or excessively inducing, cell
The dead or relevant cell death of cell autophagy (ACD) will come one after another.The autophagy for targeting small-molecule drug induction is relevant thin
Born of the same parents are dead to be used as a promising strategy now.Therefore, the relevant cell of targeting AMPK-mTORC1-ULK1 modulation autophagy is dead
Die be breast cancer treatment new way.
Recently, (+) JQ1 is verified in terms of protectiveness cell autophagy as first BRD4 inhibitor.Example
Such as, in acute myeloid leukemia (AML), the protection autophagy that AMPK-ULK1 is adjusted produces BRD4 inhibitor (+) JQ1 resistance to
Pharmacological property.(+) JQ1 has been reported inhibition protection cell autophagy also to increase NPM1 and HEXIM1 expression in AML cell.It can
See, long-term administration can lead oncogenic recurrence and transfer with the drug resistance of tumour cell.Although (+) JQ1 has good work
Property, but its lack specificity, be a kind of inhibitor of general BET family, can not specificity inhibition BRD4.In addition, (+)
The internal pharmacodynamic property of JQ1 is very poor, and druggability is very low, hinders it into clinical test.Therefore, it is necessary to develop one kind
Novel BRD4 inhibitor.
Summary of the invention
The technical problem to be solved by the present invention is to provide a kind of noval chemical compounds as BRD4 inhibitor.
The present invention provides structural formula such as I compound represented of formula or its pharmaceutically acceptable salt:
Wherein, R1And R2It independently is hydrogen or C1-C4 alkyl, and R1And R2It is not simultaneously hydrogen；Or R1And R2Connection is formed
Cyclic structure, the cyclic structure are
R3For phenyl ring or substituted phenyl ring；
N is 0 or 1.
The present invention also provides the use of above compound or its pharmaceutically acceptable salt in preparation treatment breast cancer medicines
On the way.
Further, the treatment breast cancer medicines are preferably BRD4 inhibitor class drug.
The present invention also provides a kind of pharmaceutical composition for treating breast cancer, it include effective dose above compound or its
Pharmaceutically acceptable salt.
The compound of the present invention or its pharmaceutically acceptable salt, can be used as BRD4 inhibitor, have significantly anti-
Breast cancer treatment effect.Especially compound 36 is capable of in conjunction with the BD1 structural domain with BRD4 of specificity, in breast cancer it
The autophagy cell death that BRD4-AMPK can be induced to adjust in vivo and in vitro, this is first and targets BRD4 while be reported
With the micromolecular inhibitor of BRD4-AMPK interaction, will in treatment breast cancer treatment, develop have new structure and
The BRD4 inhibitor of PPIs effect provides an effective example.
Detailed description of the invention
Fig. 1 be respectively with processing MCF-7 and the MDA-MB-231 cell of 1.5 or 3 μM of FL-411 after a certain period of time, then
Cell detects MDC fluorescent staining picture with fluorescence microscope.
Fig. 2 be respectively with processing MCF-7 and the MDA-MB-231 cell of 1.5 or 3 μM of FL-411 after a certain period of time, then
With the picture of Electron microscopy.
Fig. 3 is with GFP-LC3 plasmid transfection MCF-7 and MDA-MB-231 cell, then with 1.5 or 3 μM of FL-411's
Processing, the picture detected under fluorescence microscope.
Fig. 4 is respectively with processing MCF-7 and MDA-MB-231 cell 24 hours of 1.5 or 3 μM of FL-411, by being immunized
The expression of groupization detection LC3B.
Processing MCF-7 and MDA-MB-231 cell of the Fig. 5 to use FL-411 respectively after a certain period of time, is examined with Western blot
Survey the expression of Beclin-1, p62 and LC3.
Fig. 6 be in the presence of BafA1, with using processing MCF-7 and MDA-MB-231 cell 24 hours of FL-411 respectively,
With the expression of Western blot detection p62 and LC3.
Fig. 7 be respectively with processing MCF-7 and the MDA-MB-231 cell of 1.5 or 3 μM of FL-411 after a certain period of time, then use
3-MA is added before FL-411 processing, then detects cell survival rate with MTT.
Fig. 8 be respectively with processing MCF-7 and the MDA-MB-231 cell of 1.5 or 3 μM of FL-411 after a certain period of time, with exempting from
The expression quantity of the detection of epidemic disease blotting AKT, p-AKT, mTOR, p-mTOR, p70S6K and p-p70S6K.
Fig. 9 be respectively with processing MCF-7 and the MDA-MB-231 cell of 1.5 or 3 μM of FL-411 after a certain period of time, with exempting from
The expression quantity of the detection of epidemic disease blotting ULK1, p-ULK1, ATG13, p-ATG13, FIP200 and ATG101.
Figure 10 is thin with siRNA and negative control siRNA the transfection MCF-7 and MDA-MB-231 of two species specificity BRD4
Born of the same parents detect BRD4, c-Myc, the expression of AMPK α, p-AMPK α, ULK1, p-ULK1, p62 and LC3 with Western blot.
Figure 11 is that the mouse of inoculation MCF-7 or MDA-MB-231 uses the FL-411 of blank control or various concentration to handle daily
Once.Gross tumor volume is indicated with standard error (mean ± SEM).
Figure 12 is the tumor volume change for analyzing last day.* p < 0.001 p < 0.05, * * *, makes comparisons with control group.
Figure 13 is the tumor weight of each group mouse.* p < 0.001 p < 0.05, * * *, makes comparisons with control group.
The changes of weight of mouse during Figure 14 is FL-411 processing.
Figure 15 is the proliferation marker KI67 and autophagy marker LC3II in immunohistochemical analysis mouse tumor.Quantitative point
Analyse the percentage of each group picture positive staining.Tumour is derived from control and FL-411 (100mg/kg) processing group mouse.***p<
0.001, it makes comparisons with control group.Scale is 200 μm.
Figure 16 is the tumor tissues for taking MCF-7 and MDA-MB-231 xenograft mouse, cracking.Western blot analysis
The expression of BRD4, c-Myc, LC3, and caspase3.
Figure 17 is antitumor vigor of the FL-411 in zebra fish model.CM-DIL label MCF7 cell be added blank or
12.5,25,50 μM of FL-411 processing, captures bright field and fluorescence picture with fluorescence microscope.
Figure 18 is that the tumour fluorescence intensive analysis (mean ± SEM) and each concentration FL-411 in zebra fish model handle 48h
The inhibiting rate (p < 0.001 * * p < 0.01, * * *, make comparisons with control group) of each group gross tumor volume afterwards.
Specific embodiment
The present invention is provided such as I compound represented of formula:
Wherein, R1And R2It independently is hydrogen or C1-C4 alkyl, and R1And R2It is not simultaneously hydrogen；Or R1And R2Connection is formed
Cyclic structure, the cyclic structure areR3For phenyl ring or substituted
Phenyl ring；N is 0 or 1.
As one of embodiment, n 0；R1And R2It independently is hydrogen or C1-C4 alkyl, and R1And R2It is not simultaneously
Hydrogen；Or R1And R2Connection forms cyclic structure, and the cyclic structure is R3For phenyl ring or substituted phenyl ring.
The following are several preferred embodiments that n is 0.
One is R1And R2Connection is formedR3For phenyl ring or substituted phenyl ring.
It is preferred that R1And R2Connection is formed
More preferable R1And R2Connection is formedR3For
Second is R1And R2It is preferably independently hydrogen or C1-C4 alkyl, and R1And R2It is not simultaneously hydrogen；R3For phenyl ring or by
Substituted phenyl ring.
It is preferred that R1For hydrogen；R2For C1-C4 alkyl；R3For
More preferable R1For hydrogen；R2ForR3For
Further preferred R1For hydrogen；R2ForR3For
The third is R1And R2Connection is formedR3For phenyl ring or substituted phenyl ring.
More preferable R1And R2Connection is formedR3For
4th kind is R1And R2Connection is formedR3For phenyl ring or substituted phenyl ring.
It is preferred that R1And R2Connection is formedR3For
More preferable R1And R2Connection is formedR3For
It is R there are also one kind1And R2Connection is formedR3For phenyl ring or substituted phenyl ring.
It is preferred that R1And R2Connection is formedR3For
As another embodiment, 1 n；R1And R2It independently is hydrogen or C1-C4 alkyl, and R1And R2It is not simultaneously
Hydrogen；Or R1And R2Connection forms cyclic structure, and the cyclic structure is
R3For phenyl ring or substituted phenyl ring.
Preferably, 1, R n1And R2Connection is formedR3For
More preferable n is 1, R1And R2Connection is formedR3For
Here is some preferred structures of the compound of the present invention.
The present invention also provides the pharmaceutically acceptable salts of compound of the present invention.The salt can for nitrate,
Hydrochloride, sulfate or phosphate etc..
The present invention also provides the use of above compound or its pharmaceutically acceptable salt in preparation treatment breast cancer medicines
On the way.Further, the treatment breast cancer medicines are preferably BRD4 inhibitor class drug, the associated treatment for breast cancer.
The present invention also provides a kind of pharmaceutical composition for treating breast cancer, it be the above compound comprising effective dose or
The preparation of its pharmaceutically acceptable salt.The compounds of this invention can be made to following shape by methods known in the art
Formula: tablet, capsule, aqueous or oily solutions, suspension, emulsion, cream, ointment, gelling agent, nasal spray, suppository,
The pulvis or aerosol or spray of tiny dispersion for sucking are used for parenteral (including intravenous, intramuscular or infusion)
Sterile aqueous or oily solution or suspension or without bacterial emulsion.Sterile water or water-propylene glycol solution can be used as solvent
Liquid preparation is prepared, it can also be by active ingredients in polyethylene glycol solution.It can lead to for the oral aqueous solution given
It crosses and active component is dissolved in water to and is added as needed suitable colorant, corrigent, stabilizer and thickener to prepare.Mouthful
Taking the aqueous suspension used can be by the way that the active component of tiny dispersion to be dispersed in water together with stickum, the viscosity
Suspending agent known to substance for example natural synthetic gums, resin, methylcellulose, carboxymethyl cellulose and other pharmaceutical arts.
Pharmaceutical composition can be unit dosage form.In these forms, the composition is divided into containing appropriate active group
The unit dose divided.The unit dosage form can be packaged preparation, include the preparation of separation amount in packaging, such as box-packed tablet,
Capsule and the pulvis in phial or ampoule.Unit dosage form can also be capsule, cachet or tablet or its can be
An appropriate number of any of these packaged forms.
Pharmaceutical composition of the invention, active constituent can be only the compound of the present invention, can also be with other anti-breast cancers
Compound combination is as active constituent.
During treating breast cancer, pharmaceutical composition of the invention can be used and combined with other anti-breast cancer medicines
Treatment.
When treating breast cancer, can by simultaneously, it is sequential or individually give various therapeutic components can realize it is this combine control
It treats.Other pharmaceutical actives in the compounds of this invention and allowance dosage range in such combination product application effective dosage ranges
Agent.
A specific embodiment of the invention is further described below with reference to embodiment, is not therefore limited the present invention
System is among the embodiment described range.
The synthesis of 1 compound 1~42 of embodiment
Method is led in the synthesis of intermediate 2a-e:
Take ketone or aldehyde (30.0mmol), cyan-acetic ester (30.0mmol), elemental sulfur (30.0mmol) be dissolved in 200ml without
In water-ethanol, triethylamine (35.0mmol) .The resulting was allowed to refluxed for is added
12h. reaction mixture is warming up to reflux, and insulation reaction 12 hours or so.After completion of the reaction, it is cooled to room temperature filtering, use is anhydrous
Solvent is removed under reduced pressure in ethanol washing (30ml x 3), merging filtrate, and crude product purifies to obtain intermediate by silica gel column chromatography, pale yellow
Color solid.
Intermediate 2a1H-NMR(400MHz,CDCl3-d6), δ (ppm): 5.73 (1H, s), 4.18 (2H, q, J=
7.1Hz), 2.47 (2H, m), 1.53 (2H, m), 1.25 (3H, t, J=7.0Hz), 0.87 (3H, t, J=7.2Hz) .HRMS
(ESI)+calculated forC10H15NO2S,[M+H]+:m/z 214.0902,found 214.0910.
Intermediate 2b1H-NMR(400MHz,CDCl3),δ(ppm):5.85(2H,s),4.24(2H,m),2.84(2H,m),
2.72 (2H, m), 2,30 (2H, m), 1.32 (3H, t, J=7.1Hz)；HRMS(ESI)+calculated for C10H14NO2S,
[M+H]+:m/z 212.0745,found 212.0752.
Intermediate 2c1H-NMR(400MHz,CDCl3), δ (ppm): 5.73 (2H, s), 4.26 (2H, q, J=6.9Hz),
2.94 (2H, t, J=5.3Hz), 2.55 (2H, t, J=5.3Hz), 1.79 (2H, m), 1.60 (4H, m), 1.32 (3H, t, J=
7.2Hz).
Intermediate 2d1H-NMR(400MHz,DMSO-d6), δ (ppm): 5.92 (2H, s), 4.26 (2H, q, J=14.2,
7.13Hz), 2.87 (1H, m), 2.56 (2H, m), 2.12 (1H, m), 1.81 (2H, m), 1.33 (4H, t, J=7.1Hz), 1.04
(3H, d, J=6.5Hz)；HRMS(ESI)+calculated for C12H18NO2S,[M+H]+:m/z 240.1058,found
240.1067.
Intermediate 2e1H-NMR(400MHz,CDCl3),δ(ppm):5.98(2H,s),4.26(2H,m),3.37(2H,t,J
=2.0Hz), 2.84 (2H, m), 2.66 (2H, t, J=5.9Hz), 2,44 (3H, s), 1.33 (3H, t, J=7.1Hz)
Method is led in the synthesis of compound 1~42:
Intermediate made from step (2.0mmol) is taken to be dissolved in the anhydrous dioxane of 3ml hydrogen chloride gas saturation respectively, then plus
Enter carbonitrile derivatives (2.2mmol).Mixture is heated to 100 DEG C of insulation reactions 6-12 hours.It is cooled to room temperature, uses after completion of the reaction
The sodium bicarbonate aqueous solution of 20ml saturation quenches reaction.The solid of precipitation is collected by filtration and is produced with the off-white powder that methanol washs
Object.
Reaction reagent and reaction condition: (a) NCCH2CO2Et,S8,EtOH,Et3N, reflux, 12h；(b) nitrile, dioxane/
HCl,100℃,12h。
It is nuclear-magnetism result below:
Compound 1
1H-NMR(400MHz,DMSO-d6), δ (ppm): 7.85 (2H, m), 7.25 (1H, t, J=7.9Hz), 6.88 (1H,
Ddd, J=8.4,2.7,1.0Hz), 6.78 (1H, br s), 3.80 (3H, s), 2.71 (2H, t, J=7.3Hz), 1.65 (2H,
M), 0.94 (3H, t, J=7.3Hz)；13C-NMR(100MHz,CF3COOD),δ(ppm):160.6,155.2,150.5,149.1,
131.7,124.3,123.9,123.0,120.4,118.4,118.0,112.4,55.1,31.6,23.6,11.4；HRMS(ESI)+
calculated for C16H17N2O2S,[M+H]+:m/z 301.1011,found 301.1020.
Compound 2
1H-NMR(400MHz,DMSO-d6), δ (ppm): 8.42 (1H, t, J=1.6Hz), 8.26 (1H, dt, J=7.8,
1.3Hz), 7.49 (1H, dq, J=7.8,1.0Hz), 7.32 (1H, t, J=7.8Hz), 6.79 (1H, br s), 2.71 (2H, t, J
=7.0Hz), 1.65 (2H, m), 0.94 (3H, t, J=7.3Hz)；13C-NMR(100MHz,CF3COOD),δ(ppm):159.5,
156.6,153.2,151.8,141.5,133.8,133.0,128.5,127.6,126.8,126.5,120.4,34.0,26.0,
13.8；HRMS(ESI)+calculated for C15H14BrN2OS,[M+H]+:m/z 349.0010,found 349.0017.
Compound 3
1H-NMR(400MHz,DMSO-d6), δ (ppm): 8.09 (2H, d, J=8.3Hz), 6.72 (2H, t, J=8.2Hz),
2.69 (2H, t, J=7.4Hz), 1.63 (2H, q, J=14.4,7.1Hz), 0.93 (3H, t, J=7.5Hz)；13C-NMR
(100MHz,CF3COOD),δ(ppm):159.5,156.6,153.2,151.8,141.5,133.8,133.0,128.5,
127.6,124.8,113.8,111.6,34.0,26.0,13.8；HRMS(ESI)+calculated for C15H15N2O2S,[M+
H]+:m/z 287.0854,found 287.0863.
Compound 4
1H-NMR(400MHz,DMSO-d6), δ (ppm): 7.62 (2H, dd, J=8.4,1.3Hz), 7.55 (2H, d, J=
8.4Hz), 7.41 (4H, m), 7.32 (1H, m), 6.81 (1H, s), 3.80 (2H, s), 2.70 (2H, t, J=7.0Hz), 1.61
(1H, m), 0.91 (3H, t, J=7.5Hz)；13C-NMR(100MHz,CF3COOD),δ(ppm):162.1,152.6,152.6,
150.7,145.6,141.5,132.3,132.3,130.8,130.8,130.6,130.6,130.0,128.8,128.8,
126.5,120.3,120.3,39.8,33.9,26.1,13.9；HRMS(ESI)+calculated for C22H21N2OS,[M+H]+:
m/z 361.1375,found 361.1381.
Reaction reagent and reaction condition: (a) NCCH2CO2Et,S8,EtOH,Et3N, reflux, 12h；(b) nitrile, dioxane/
HCl,100℃,12h。
Compound 5
1H-NMR (400MHz, DMSO-d6), δ (ppm): 12.60 (1H, s), 7.71 (2H, m), 7.45 (1H, dd, J=
), 8.8,6.1Hz 7.13 (1H, d, J=6.1Hz), 3.86 (3H, s), 2.41 (4H, m), 2.95 (2H, m)；13C-NMR
(100MHz,CF3COOD),δ(ppm):161.6,155.5,151.2,150.7,146.4,142.7,132.7,125.5,
124.0,121.4,113.2,112.6,56.1,29.4,28.6,28.4；HRMS(ESI)+calculated for
C16H15N2O2S,[M+H]+:m/z 299.0854,found 299.0860.
Compound 6
1H-NMR (400MHz, DMSO-d6), δ (ppm): 12.83 (1H, s), 8.33 (2H, d, J=8.1Hz), 7.90
(2H, d, J=8.1Hz), 2.96 (4H, m), 2.95 (2H, m)；13C-NMR(100MHz,CF3COOD),δ(ppm):159.7,
157.3,153.1,151.8,136.4,136.4,135.2,135.2,131.3,131.3,126.4,124.5,120.6,34.2,
26.2,14.0；HRMS(ESI)+calculated for C16H12F3N2OS,[M+H]+:m/z 337.0622,found
337.0630.
Compound 71H-NMR (400MHz, DMSO-d6), δ (ppm): 12.69 (1H, s), 8.34 (1H, dd, J=1.8,
1.7Hz), 8.12 (1H, d, J=8.0Hz), 7.73 (1H, d, J=7.8Hz), 7.47 (1H, dd, J=8.0,7.8Hz), 2.93
(4H,m),2.40(2H,m)；13C-NMR(100MHz,CF3COOD),δ(ppm):161.3,159.2,155.5,152.1,
151.6,130.3,130.3,129.1,129.1,128.8,125.8,116.4,30.4,29.5,29.3；HRMS(ESI)+
calculated for C15H12BrN2OS,[M+H]+:m/z 346.9854,found 346.9863.
Compound 81H-NMR(400MHz,DMSO-d6),δ(ppm):12.54(1H,s),7.32(4H,m),7.25(1H,
m),3.93(2H,s),2.88(4H,m),2.36(2H,m)；13C-NMR(100MHz,CF3COOD),δ(ppm):168.8,
158.7,156.2,139.8,137.2,137.0,129.3,129.3,129.0,129.0,127.3,118.6,29.4,29.1,
27.9；HRMS(ESI)+calculated for C16H15N2OS,[M+H]+:m/z 283.0905,found 283.0914.
Compound 91H-NMR (400MHz, DMSO-d6), δ (ppm): 12.70 (1H, s), 8.07 (2H, d J=
8.6Hz), 7.73 (2H, d J=8.6Hz), 2.95 (4H, m), 2.41 (2H, m)；13C-NMR(100MHz,CF3COOD),δ
(ppm):161.3,159.2,155.5,152.1,151.6,130.3,130.3,129.1,129.1,128.8,125.8,
116.4,30.4,29.5,29.3；HRMS(ESI)+calculated for C15H12BrN2OS,[M+H]+:m/z 346.9854,
found 346.9864.
Compound 101H-NMR(400MHz,DMSO-d6),δ(ppm):12.22(1H,s),8.99(1H,s),7.81
(2H,s),2.92(4H,m),2.39(2H,m),2.23(6H,s)；13C-NMR(100MHz,CF3COOD),δ(ppm):162.8,
156.7,155.6,146.4,144.0,136.5,131.1,130.9,130.9,129.6,125.0,116.5,30.8,30.1,
29.9,16.5,16.5；HRMS(ESI)+calculated for C17H17N2O2S,[M+H]+:m/z 313.1011,found
313.1020.
Compound 111H-NMR(400MHz,DMSO-d6),δ(ppm):12.61(1H,s),8.13(2H,m),7.55
(3H,m),2.96(4H,m),2.41(2H,m)；13C-NMR(100MHz,CF3COOD),δ(ppm):162.9,157.3,151.8,
133.6,133.6,129.3,129.3,128.1,128.1,126.9,121.6,117.0,29.8,29.0,28.8；HRMS
(ESI)+calculated for C15H13N2OS,[M+H]+:m/z 269.0749,found 269.0753.
Compound 121H-NMR(400MHz,DMSO-d6), δ (ppm): 12.73 (1H, s), 8.32 (2H, d, J=
8.0Hz), 7.90 (2H, d, J=8.0Hz), 3.28 (2H, m), 2.87 (2H, m), 1.87 (2H, m), 1.60 (4H, m)；13C-NMR
(100MHz,CF3COOD),δ(ppm):160.9,157.8,153.3,146.7,144.7,138.9,138.0,,128.3,
127.1,126.5,123.8,122.8,121.1,31.3,29.2,26.8,26.8,25.8；HRMS(ESI)+calculated
for C18H16F3N2OS,[M+H]+: m/z 365.0935, found 365.0942. compound 131H-NMR(400MHz,DMSO-
d6), δ (ppm): 8.33 (1H, m), 8.15 (1H, d, J=7.8Hz), 7.70 (1H, d, J=7.8Hz), 7.44 (1H, t, J=
7.8Hz),3.29(2H,m),2.83(2H,m),1.85(2H,m),1.61(4H,m)；13C-NMR(100MHz,CF3COOD),δ
(ppm):160.1,155.6,149.0,146.7,141.4,141.2,133.8,132.8,128.4,127.3,126.8,
125.0,33.7,31.6,29.2,28.8,28.1；HRMS(ESI)+calculated for C17H16BrN2OS,[M+H]+:m/
z375.0167,found 375.0174.
Compound 141H-NMR(400MHz,DMSO-d6),δ(ppm):12.39(1H,s),9.71(1H,s),7.52(2H,
M), 7.30 (1H, t, J=7.5Hz), 6.95 (1H, d, J=6.7Hz), 3.29 (2H, br s), 2.84 (2H, br s), 1.85
(2H,br s),1.64(4H,m)；13C-NMR(100MHz,CF3COOD),δ(ppm):160.6,158.3,158.3,156.4,
149.0,146.3,141.0,134.2,126.8,125.8,123.0,116.5,33.6,31.4,29.1,28.7,28.1；HRMS
(ESI)+calculated for C17H17N2O2S,[M+H]+:m/z313.1011,found 313.1020.
Compound 151H-NMR(400MHz,DMSO-d6),δ(ppm):12.20(1H,s),10.04(1H,s),8.00
(2H, d, J=8.8Hz), 6.86 (2H, d, J=8.8Hz), 3.27 (2H, m), 2.82 (2H, m), 1.85 (2H, br s), 1.62
(4H,m)；13C-NMR(100MHz,CF3COOD),δ(ppm):160.4,157.6,155.8,149.3,147.0,141.4,
132.5,132.5,125.3,125.3,125.1,124.9,34.0,31.8,29.4,29.0,28.4；HRMS(ESI)+
calculated for C17H17N2O2S,[M+H]+:m/z 313.1011,found 313.1019.
Compound 161H-NMR (400MHz, DMSO-d6), δ (ppm): 12.61 (1H, s), 8.07 (2H, d, J=
8.1Hz), 7,75 (2H, d, J=8.1Hz), 3.32 (2H, m), 2.88 (2H, m), 1.89 (2H, br s), 1.65 (4H, m)；13C-
NMR(100MHz,CF3COOD),δ(ppm):160.5,156.3,152.7,146.6,141.3,136.3,136.3,135.0,
131.2,131.2,124.9,116.9,33.9,31.7,29.3,29.0,28.3；HRMS(ESI)+calculated for
C17H16BrN2OS,[M+H]+:m/z 375.0167,found 375.0174.
Compound 171H-NMR(400MHz,DMSO-d6),δ(ppm):12.11(1H,s),8.97(1H,s),7.80
(2H,s),3.28(2H,m),2.83(2H,m),2.23(6H,s),1.86(2H,br s),1.63(4H,m)；13C-NMR
(100MHz,CF3COOD),δ(ppm):162.6,156.2,152.6,149.6,145.0,140.9,136.3,130.9,
130.8,130.8,129.5,129.5,33.9,31.5,29.3,28.9,28.3,16.4,16.4；HRMS(ESI)+
calculated for C19H21N2O2S,[M+H]+:m/z 341.1324,found 341.1331.
Compound 181H-NMR(400MHz,DMSO-d6),δ(ppm):12.52(1H,s),7.41-7.29(4H,m),
7.25(1H,br s)3.91(2H,s),3.23(2H,br s),2.80(2H,br s),1.84(2H,s),1.59(4H,m)；13C-
NMR(100MHz,CF3COOD),δ(ppm):160.8,152.4,151.9,131.9,131.9,131.8,131.8,131.6,
131.6,129.8,129.8,116.6,39.7,33.6,31.1,29.0,28.7,28.0；HRMS(ESI)+calculated
for C18H19N2OS,[M+H]+:m/z 311.1218,found 311.1223.
Compound 191H-NMR(400MHz,DMSO-d6),δ(ppm):7.63(4H,m),7.44(4H,m),7.34(1H,
m),3.92(2H,s),3.23(2H,m),2.77(2H,m),1.82(2H,m),1.56(4H,m)；13C-NMR(100MHz,
CF3COOD),δ(ppm):160.2,158.6,157.4,145.9,143.6,143.1,139.2,138.5,129.8,129.8,
128.4,128.4,128.2,128.2,127.6,126.4,126.4,122.5,37.2,31.4,29.0,26.8,26.5,
25.8；HRMS(ESI)+calculated for C24H23N2OS,[M+H]+:m/z 387.1531,found 387.1540.
Reaction reagent and condition: (a) NCCH2CO2Et,S8,EtOH,Et3N, reflux, 12h；(b) nitrile, dioxane/HCl,
100℃,12h。
Compound 201H-NMR(400MHz,DMSO-d6), δ (ppm): 12.51 (1H, s), 7.73 (1H, d, J=
7.9Hz), 7.68 (1H, t, J=1.9Hz), 7.42 (1H, t, J=8.2Hz), 7.13 (1H, dq, J=8.2,0.7Hz), 3.85
(3H, s), 3.13 (1H, m), 2.87 (1H, dd, J=16.5,4.9Hz), 2.76 (1H, m), 2.36 (1H, m), 1.89 (2H, m),
1.41 (1H, m), 1.07 (3H, d, J=6.6Hz)；13C-NMR(100MHz,CF3COOD),δ(ppm):13C-NMR(100MHz,
CF3COOD),δ(ppm):163.0,160.0,157.0,151.2,142.0,135.1,134.1,126.7,125.4,124.5,
122.8,114.6,57.5,34.5,31.3,31.1,26.5,21.6；HRMS(ESI)+calculated for C18H19N2O2S,
[M+H]+:m/z 327.1167,found 327.1170.
Compound 211H-NMR(400MHz,DMSO-d6), δ (ppm): 12.74 (1H, s), 8.33 (2H, d, J=8.4Hz),
7.90 (2H, d, J=8.4Hz), 3.13 (1H, m), 2.90 (1H, dd, J=17.8,5.5Hz), 2.83 (1H, m), 2.40 (1H,
M), 1.90 (2H, m), 1.40 (1H, m), 1.07 (3H, d, J=6.5Hz)；13C-NMR(100MHz,CF3COOD),δ(ppm):
159.9,156.3,151.4,142.8,135.3,130.9,130.9,129.7,129.6,129.2,126.3,125.0,
123.6,34.7,31.4,31.1,26.5,21.7；HRMS(ESI)+calculated for C18H16F3N2OS,[M+H]+:m/z
365.0935,found 365.0941.
Compound 221H-NMR(400MHz,DMSO-d6),δ(ppm):12.60(1H,s),8.31(1H,s),8.13(1H,
D, J=8.0Hz), 7.77 (1H, d, J=7.9Hz), 7.48 (1H, t, J=8.0Hz), 3.13 (1H, m), 2.88 (1H, dd, J=
), 17.2,4.7Hz 2.80 (1H, m), 2.38 1H, m), 1.90 (2H, m), 1.38 (1H, m), 1.07 (3H, d, J=6.4Hz)；13C-NMR(100MHz,CF3COOD),δ(ppm):161.0,156.0,151.2,142.4,141.5,141.5,135.1,
133.9,133.9,133.0,128.5,127.4,126.8,34.5,31.3,31.0,26.5,21.6；HRMS(ESI)+
calculated for C17H16BrN2OS,[M+H]+:m/z 375.0167,found 375.0178.
Compound 231H-NMR(400MHz,DMSO-d6),δ(ppm):12.65(1H,m),8.10(2H,m),3.13(1H,
M), 2.89 (1H, m), 2.78 (1H, m), 2.39 (1H, m), 1.89 (2H, m), 1.38 (1H, m), 1.07 (3H, d, J=
6.7Hz)；13C-NMR(100MHz,CF3COOD),δ(ppm):159.9,156.2,154.5,153.7,151.8,148.8,
146.1,142.9,135.2,124.9,122.1,115.8,34.7,31.4,31.1,26.6,21.7；HRMS(ESI)+
calculated for C17H14F3N2OS,[M+H]+:m/z 351.0779,found 351.0087.
Compound 241H-NMR(400MHz,DMSO-d6),δ(ppm):12.4(1H,s),9.73(1H,s),7.55(2H,
M), 7.30 (1H, t, J=7.7Hz), 6.95 (1H, ddd, J=8.1,2.4,0.8Hz), 3.12 (1H, m), 2.83 (1H, dd, J
=16.6,4.7Hz), 2.75 (1H, m), 2.36 (1H, m), 1.87 (2H, m), 1.38 (1H, m), 1.06 (3H, d, J=
6.6Hz)；13C-NMR(100MHz,CF3COOD),δ(ppm):159.9,158.6,157.2,151.2,142.2,135.2,
134.5,127.1,126.1,124.7,123.3,116.7,34.7,31.4,31.2,26.6,21.7；HRMS(ESI)+
calculated for C17H17N2O2S,[M+H]+:m/z 313.1011,found 313.1020.
Compound 251H-NMR(400MHz,DMSO-d6),δ(ppm):12.25(1H,s),10.15(1H,s),8.01
(2H, d, J=8.7Hz), 6.87 (2H, d, J=8.7Hz), 6.87 (2H, d, J=8.7Hz), 3.11 (1H, m), 2.84 (1H,
M), 2.75 (1H, m), 2.35 (1H, m), 1.88 (2H, m), 1.40 (1H, m), 1.06 (3H, d, J=6.5Hz)；13C-NMR
(100MHz,CF3COOD),δ(ppm):165.2,160.0,156.5,151.3,141.1,134.9,132.6,132.6,
123.7,119.9,119.9,117.4,34.4,31.3,31.1,26.4,21.6；HRMS(ESI)+calculated for
C17H17N2O2S,[M+H]+:m/z 313.1011,found 313.1022.
Compound 261H-NMR(400MHz,DMSO-d6), δ (ppm): 12.59 (1H, s), 8.07 (2H, d, J=
8.5Hz), 7.73 (2H, dt, J=8.7,1.9Hz), 3.13 (1H, m), 2.88 (1H, dd, J=16.6,4.8Hz), 2.78 (1H,
M), 2.33 (1H, m), 1.88 (2H, m), 1.39 (1H, m), 1.07 (3H, d, J=6.6Hz)；13C-NMR(100MHz,
CF3COOD),δ(ppm):160.3,156.7,151.5,142.2,136.4,136.4,135.2,135.1,131.2,131.2,
124.6,124.3,34.6,31.4,31.1,26.5,21.7；HRMS(ESI)+calculated for C17H16BrN2OS,[M+
H]+:m/z 375.0088,found 375.0093.
Compound 271H-NMR(400MHz,DMSO-d6),δ(ppm):12.12(1H,s),8.97(1H,s),7.79(2H,
S), 3.10 (1H, m), 2.83 (1H, dd, J=16.6,4.6Hz), 2.73 (1H, m), 2.34 (1H, m), 2.22 (6H, s), 1.87
(2H, m), 1.37 (1H, m), 1.06 (3H, d, J=6.5Hz)；13C-NMR(100MHz,CF3COOD),δ(ppm):162.7,
160.2,156.6,151.5,140.7,134.9,130.9,130.9,129.6,129.6,123.5,116.4,34.5,31.4,
31.1,26.5,21.6,16.4,16.4；HRMS(ESI)+calculated for C19H21N2O2S,[M+H]+:m/z
341.1324,found 341.1330.
Compound 281H-NMR(400MHz,DMSO-d6),δ(ppm):12.57(1H,s),9.78(1H,s),7.52(2H,
M), 7.32 (1H, t, J=7.9Hz), 6.98 (1H, ddd, J=8.1,2.4,0.6Hz), 4.03 (2H, s), 3.11 (4H, s),
2.66(3H,s)；13C-NMR(100MHz,CF3COOD),δ(ppm):159.6,158.8,154.4,134.6,134.6,131.5,
129.6,127.1,126.7,123.7,123.4,117.1,54.4,54.1,45.3,45.3,24.6；HRMS(ESI)+
calculated for C17H17N2OS,[M+H]+:m/z 297.1062,found 297.1071.
Compound 291H-NMR(400MHz,DMSO-d6),δ(ppm):12.45(1H,s),7.31(4H,m),7.24(1H,
M), 3.90 (2H, s), 3.01 (1H, m), 2.77 (1H, dd, J=16.8,4.8Hz), 2.69 (1H, m), 2.31 (1H, m), 1.84
(2H, m), 1.34 (1H, m), 1.03 (3H, d, J=6.6Hz)；13C-NMR(100MHz,CF3COOD),δ(ppm):161.8,
159.4,150.5,141.7,134.9,132.3,132.3,132.1,131.9,131.9,130.1,124.7,40.1,34.5,
31.4,31.1,26.5,21.6；HRMS(ESI)+calculated for C18H19N2OS,[M+H]+:m/z 311.1218,
found 311.1222.
Compound 301H-NMR(400MHz,DMSO-d6),δ(ppm):12.50(1H,s),7.64(4H,m),7.45(4H,
M), 7.34 (1H, m), 3.96 (2H, s), 3.06 (1H, m), 2.81 (1H, dd, J=16.6,4.7Hz), 2.71 (1H, m), 2.32
(1H, m), 1.85 (2H, m), 1.35 (1H, m), 1.03 (3H, d, J=6.5Hz)；13C-NMR(100MHz,CF3COOD),δ
(ppm):161.4,159.4,150.5,145.4,141.7,141.6,134.8,132.4,132.4,130.9,130.9,
130.6,130.6,130.1,129.4,128.8,128.8,124.7,39.7,34.5,31.4,31.1,26.5,21.7；HRMS
(ESI)+calculated for C24H23N2OS,[M+H]+:m/z 387.1531,found 387.1540.
Compound 311H-NMR (400MHz, DMSO-d6), δ (ppm): 12.57 (1H, s), 7.73 (1H, d, J=
7.8Hz), 7.69 (1H, m), 7.44 (1H, dd, J=8.5,7.8Hz), 7.13 (1H, dd, J=8.5,2.5Hz), 3.85 (3H,
s),3.60(2H,s),2.99(2H,m),2.70(2H,m),2.39(3H,s)；13C-NMR(100MHz,CF3COOD),δ(ppm):
160.1,158.6,156.3,141.8,134.0,133.4,131.4,129.4,128.9,128.4,127.0,123.4,54.5,
54.3,45.4,45.4,24.7；HRMS(ESI)+calculated for C17H18N3O2S,[M+H]+:m/z 328.1120,
found 328.1131.
Compound 321H-NMR (400MHz, DMSO-d6), δ (ppm): 12.83 (1H, s), 8.34 (2H, d, J=
8.2Hz), 7.96 (2H, d, J=8.2Hz), 3.61 (2H, s), 2.99 (2H, m), 2.69 (2H, m), 2.39 (3H, s)；13C-NMR
(100MHz,CF3COOD),δ(ppm):160.0,159.8,154.7,134.4,134.4,131.6,129.4,127.0,
126.3,123.3,123.3,115.0,115.0,57.7,54.4,45.4,24.6；HRMS(ESI)+calculated for
C17H15F3N3OS,[M+H]+:m/z 366.0888,found 366.0897.
Compound 331H-NMR (400MHz, DMSO-d6), δ (ppm): 12.83 (1H, s), 8.40 (1H, t, J=1.8,
1.7Hz), 8.23 (1H, ddd, J=8.0,1.4,1.1Hz), 7.58 (1H, m), 7.37 (1H, dd, J=8.0,7.8Hz), 3.50
(2H,s),2.96(2H,m),2.63(2H,m),2.37(3H,s)；13C-NMR(100MHz,CF3COOD),δ(ppm):160.7,
158.4,158.4,140.3,140.0,131.1,129.5,129.5,129.3,126.5,123.8,123.3,54.6,54.4,
45.4,24.7；HRMS(ESI)+calculated for C16H15BrN3OS,[M+H]+:m/z 376.0119,found
376.0126.
Compound 341H-NMR (400MHz, DMSO-d6), δ (ppm): 12.55 (1H, s), 8.12 (2H, d, J=
8.0Hz), 7.54 (2H, d, J=8.0Hz), 3.12 (2H, s), 2.82 (2H, m), 2.38 (2H, m), 1.90 (3H, s)；13C-NMR
(100MHz,CF3COOD),δ(ppm):160.2,157.5,157.5,151.2,141.9,138.8,135.1,132.7,
132.7,130.0,125.5,124.7,34.5,31.3,26.5,21.6；HRMS(ESI)+calculated for
C16H16N3O2S,[M+H]+:m/z 314.0963,found 314.0973.
Compound 351H-NMR (400MHz, DMSO-d6), δ (ppm): 8.05 (2H, d, J=8.7Hz), 6.78 (2H, d,
), J=8.7Hz 3.49 (2H, s), 2.95 (2H, m), 2.63 (2H, m), 2.36 (3H, s)；13C-NMR(100MHz,CF3COOD),
δ(ppm):165.2,160.0,156.5,151.3,141.1,134.9,132.6,132.6,123.7,119.9,119.9,
117.4,34.4,31.3,31.1,26.4；HRMS(ESI)+calculated for C17H18N3O2,[M+H]+:m/z
296.1399,found 296.1402.
Compound 361H-NMR(400MHz,DMSO-d6),δ(ppm):12.18(1H,s),8.99(1H,s),7.83
(2H,s),3.56(2H,s),2.96(2H,m),2.67(2H,m),2.38(3H,s),2.23(6H,s)；13C-NMR(100MHz,
CF3COOD),δ(ppm):160.3,159.9,158.9,154.0,131.5,131.5,131.5,129.9,129.9,128.2,
122.1,115.8,54.4,54.2,45.4,24.5,16.5,16.5；HRMS(ESI)+calculated for C18H20N3O2S,
[M+H]+:m/z 342.1276,found 342.1280.
Compound 371H-NMR(400MHz,DMSO-d6),δ(ppm):12.58(1H,s),7.63(4H,m),7.44
(4H,m),7.35(1H,m),3.97(2H,s),3.52(2H,m),2.91(2H,m),2.67(2H,m)2.35(3H,s)；13C-
NMR(100MHz,CF3COOD),δ(ppm):164.7,159.0,153.5,145.9,141.7,132.6,132.6,131.4,
131.0,131.0,130.8,130.8,130.2,130.2,129.4,129.0,129.0,128.5,54.3,54.1,45.4,
40.3,24.5；HRMS(ESI)+calculated for C23H22N3OS,[M+H]+:m/z 388.1484,found
388.1494.
Compound 381H-NMR(400MHz,DMSO-d6),δ(ppm):12.58(1H,br s),7.74-7.69(2H,
M), 7.45-7.28 (6H, m), 7.13 (1H, d, J=7.0Hz), 3.85 (3H, s), 3.72 (2H, s), 3.64 (2H, s), 2.98
(2H,br s),2.79(2H,br s)；13C-NMR(100MHz,CF3COOD),δ(ppm):162.8,159.1,154.1,
152.1,133.8,133.3,132.3,132.3,131.7,131.7,130.0,128.2,126.5,125.8,122.8,
119.4,116.5,114.3,63.6,57.2,51.7,51.3,24.2；HRMS(ESI)+calculated for
C23H22N3O2S,[M+H]+:m/z 404.1433,found 404.1434.
Compound 391H-NMR(400MHz,DMSO-d6),δ(ppm):12.19(1H,s),8.99(1H,s),7.81
(2H,s),7.39-7.27(5H,m),3.72(2H,s),3.62(2H,s),2.96(2H,br s),2.79(2H,br s),2.22
(6H,s)；13C-NMR(100MHz,CF3COOD),δ(ppm):164.0,157.7,156.6,151.7,131.6,130.6,
130.6,130.0,130.0,129.6,129.3,129.3,127.7,127.7,126.5,126.4,119.9,113.6,61.9,
50.0,49.6,22.4,14.3,14.3；
HRMS(ESI)+calculated for C24H24N3O2S,[M+H]+:m/z 418.1589,found 418.1597.
Compound 401H-NMR (400MHz, DMSO-d6), δ (ppm): 12.57 (1H, s), 8.13 (2H, d, J=
7.0Hz),7.59-7.50(3H,m),7.39-7.26(5H,m),3.72(2H,s),3.64(2H,s),2.98(2H,br s),
2.79(2H,br s)；13C-NMR(100MHz,CF3COOD),δ(ppm):162.2,159.2,159.2,153.7,152.1,
139.1,133.3,132.5,132.5,132.3,132.3,131.7,131.7,130.0,130.0,129.3,125.0,
122.7,63.7,51.7,51.4,24.2；HRMS(ESI)+calculated for C22H20N3OS,[M+H]+:m/z
374.1327,found 374.1330.
Compound 411H-NMR (400MHz, DMSO-d6), δ (ppm): 12.80 (1H, s), 8.33 (2H, d, J=
8.2Hz), 7.89 (2H, d, J=8.2Hz), 7.39-7.26 (5H, m), 3.72 (2H, s), 3.65 (2H, s), 2.89 (2H, t, J
=5.8Hz), 2.72 (2H, t, J=5.8Hz)；13C-NMR(100MHz,CF3COOD),δ(ppm):164.0,157.9,155.7,
155.4,137.5,131.1,130.1,130.1,129.5,129.5,128.8,128.4,128.4,128.2,126.8,
126.0,123.9,121.2,120.6,61.3,49.6,49.3,22.0；HRMS(ESI)+calculated for
C23H19F3N3OS,[M+H]+:m/z 442.1201,found 442.1210.
Compound 421H-NMR (400MHz, DMSO-d6), δ (ppm): 8.08 (2H, d, J=8.7Hz), 7.39-7.26
(5H, m), 6.76 (2H, d, J=8.7Hz), 3.68 (2H, s), 3.54 (2H, s), 2.89 (2H, t, J=5.8Hz), 2.72 (2H,
T, J=5.8Hz)；13C-NMR(100MHz,CF3COOD),δ(ppm):164.2,157.4,156.6,151.6,131.5,
131.0,131.0,130.4,130.4,129.8,129.8,129.5,126.5,126.3,120.0,118.7,118.7,
118.0,61.8,49.9,49.8,22.3；HRMS(ESI)+calculated for C22H20N3O2S,[M+H]+:m/z
390.1276,found 390.1280.
The BRD4 inhibitory activity and autophagy rate activity of 1 compound 1~42 of test example
It is living to external BRD4 inhibitory activity, and to the autophagy rate of cell that the purpose of this experiment is detection the compound of the present invention
Property, the result is shown in tables 1.
1, AlphaScreen is detected
All reagent dilutions add in 50 millimeters of hepes, 100mM NaCl, 0.1% bovine serum albumin(BSA), pH value 7.4
0.05%CHAPS is added to allow to balance to room temperature.Ligand concentration range is formulated as 0~100 μM, and 4 μ L is taken to be added in 384 plates, then
4 μ LBRD4 (1) enzymes (250nM) are added, Room-temperature seal is incubated for 30 minutes, and equimolar biotin peptide H-SGRGK is added later
(Ac)GGK(Ac)GLGK-(Ac)GGAK(Ac)RHRK(Biotin)-OH.Under low light condition, sealing is further incubated for 30 minutes
After 4 μ L Streptavidins (25 μ grams per milliliter) and 4 μ l nickel chelate acceptor beads (25 μ grams per milliliter) are added.The sealing of plate foil, is protected from light,
It is incubated at room temperature 60min, upper plate reader is read (PHERAstar FS BMG LABTECH) and encouraged using AlphaScreen 680
Magnetic/570 emission filter groups.IC50It calculates and uses Prism 6.0.
2, cytoactive detection
MCF-7 and MDA-MB-231 cell is 5 × 104 cells/mls in the density of 96 hole flat-bottom microtiter plates.It is incubated for
After 24 hours, the compound of cell various concentration is handled.Cell survival experiment is measured using mtt assay.5mg/mL MTT addition
Into each hole.After being incubated for 4 hours, solvent is removed, 150 microlitres of soluble crystal of DMSO are being added.Absorbance is measured in 570nm
Value.
3, autophagy screening active ingredients
MCF-7 cell is handled with 5 μM of compound, is incubated for 6 hours.Then it is incubated in 37 DEG C of addition 0.05mM MDC
30min.Utilize Flow Cytometry Assay cell fluorescence intensity.
1 compound of table, 1~42 BRD4 inhibitory activity and autophagy rate activity
The experimental results showed that the compound of the present invention has different degrees of inhibitory activity and autophagy activity to BRD4,
In, compound 5, compound 15, compound 17, compound 18, compound 35, the effect of compound 36 are preferable, optimal, chemical combination
Object 36 (being denoted as FL-411) has stronger inhibitory activity and autophagy activity to BRD4.
The relevant cell death of autophagy occurs for 2 FL-411 inducing mammary cancer cell of test example
It is observed that FL-411 can induce a large amount of cytoplasmic vacuoles in processing MCF-7 and MDA-MB-231 cell
When, this is closely related with autophagy.Therefore, we, which examine whether FL-411, can induce breast cancer cell generation autophagy.MDC is a kind of
The detection probe of autophagic vacuole is applied to FL-411 and handles cell, fluorescence microscopy under the microscope and discovery of taking pictures generate it is a large amount of green
Color phosphor dot (Fig. 1).Then, we produce extensive vacuole (figure in cytoplasm in the morphological landmarks of electric microscopic observation autophagy
2).Cell autophagy confirms (Fig. 3, Fig. 4) by the transfection of GFP-LC3 and LC3 immunofluorescence.In order to further confirm FL-411 energy
Enough induce autophagy, it has been found that the processed cell Beclin-1 expression of FL-411 increases, and autophagy substrate p62/SQSTM1 occurs
It lowers；The aggregation (Fig. 5) of time dependence is presented in autophagy marker LC3 II simultaneously.Next, we used lysosome inhibition
Agent, BafA1, to verify the generation of autophagy stream.We have found that LC3-II and p62/SQSTM1 has occurred obviously in the presence of BafA1
Aggregation, show that autophagy stream strengthens (Fig. 6) by FL-411.Autophagy in order to further determine FL-411 induction is cytotoxicity
And cytoprotection, we apply autophagy inhibitor 3-MA, it can inhibit the formation of cell autophagy body to pass through suppression
Type III phosphatidylinositol 3-kinase processed.Cell viability is had evaluated using mtt assay.We have found that cell survival rate is significantly increased to
After being handled with 3-MA (Fig. 7).The above result shows that FL-411 has arrived the relevant cell death of autophagy in MCF-7 and MDA-MB- again
In 231 cells.
The autophagy of 3 FL-411 of test example induction is by BRD4-AMPK-mTOR-ULK signal path
Because BRD4 is the feedback of many tyrosine kinase activations, including PI3K/AKT.Therefore, we have studied autophagy letters
Number upstream mechanism come illustrate FL-411 induction autophagy.Firstly, we have detected AKT, p-AKT (Ser473), p-Akt
(Thr308), the expression of mTOR and p-mTOR (ser2448) are after FL-411 processing.As expected, FL-411 can be bright
The aobvious expression for reducing p-Akt (Ser473), p-Akt (Thr308) and p-mTOR (ser2448), while the expression of Akt and mTOR
Constant (Fig. 8).Because the formation of ULK1 complex and autophagosome is closely related.We have been then checked for ULK1, p-ulk1
(ser317), the expression of Atg13, p-atg13 (ser318) and FIP200.The result shows that FL-411 processing after, ULK1 and
Atg13 phosphorylation dramatically increases；And ULK1, Atg13 and FIP200 are slightly lowered；Show that FL-411 can be by ULK1 complex
It adjusts autophagy (Fig. 9).It is special we used two kinds in order to which whether the autophagy for exploring FL-411 induction is only related to BRD4 inhibition
Property siRNA inhibit BRD4 expression.What is interesting is, it has been found that silencing BRD4 can reduce the expression of c-myc proto-oncogene, this
It is consistent with FL-411 treatment effect.But different from the processing of FL-411, the expression of AMPK α and ULK1 and phosphorylation and LC3-
II aggregation and p62 degradation can be changed after BRD4 strikes drop.This shows that the silencing of BRD4 can not induce autophagy (Figure 10).It is comprehensive
On, the autophagy of FL-411 induction is by BRD4-AMPK-mTOR-ULK signal path.
The autophagy that there is 4 FL-411 of test example potential treatment to act through targeting BRD4 regulation in vivo
In order to evaluate anti-tumor activity in FL-411 body, two tumor of breast heteroplastic transplantation model, that is, MCF-7 and MDA-MB-
231 cell models are used respectively.We used the FL-411 In vivo studies of three kinds of various doses: 25 mg/kgs, 50 millis
G kg and 100 mgs/kg.In all models, FL-411 shows the inhibiting effect of apparent tumour growth and is in
Dose dependent is respectively 80% and 76% (Figure 11, figure in the inhibition rate of tumor growth of MCF-7 and MDA-MB-231 cell model
12).It is observed that in all significant reduction (Figure 13) of tumor weight of all dosage groups.Also, FL-411 is shown in all control
(Figure 14) is all had no significant effect to weight in treatment group.In order to which the internal inhibition tumour growth for checking whether that FL-411 is adjusted is and subtracts
Few cell Proliferation is related to autophagy cell death is increased.We have carried out the immunohistochemistry point of Ki-67 and LC3 to tumor tissues
Analysis.We have found that FL-411 can substantially reduce Ki-67 positive cell quantity and increase autophagy level (Figure 15).Next,
We conducted immunoblotting assays, further clarify mechanism in FL-411 body.We have found that FL-411 is capable of significant LC3's II
Accumulation and caspase3 activation and the expression for inhibiting BRD4 and c-Myc.This is obtained with immunohistochemical analysis result and in vitro substantially
Result it is consistent (Figure 16).In addition, we utilize zebra fish heteroplastic transplantation model, further confirm the antitumor work of FL-411
With.Compared with the control group, it has been found that the FL-411 of all three dosage obviously inhibits the growth (Figure 17, Figure 18) of tumour.It is comprehensive
On, these are the result shows that FL-411 has good anti-tumor activity in mouse xenografts and zebra fish model.
Claims (7)
1. structural formula such as I compound represented of formula or its pharmaceutically acceptable salt:
N is 0；
R1For hydrogen；R2For C1-C4 alkyl；R3For
2. compound according to claim 1 or its pharmaceutically acceptable salt, it is characterised in that: R1For hydrogen；R2ForR3For
3. compound according to claim 2 or its pharmaceutically acceptable salt, it is characterised in that: R1For hydrogen；R2ForR3For
4. compound or its pharmaceutically acceptable salt, it is characterised in that: the compound is such as flowering structure:
5. the described in any item compounds of Claims 1 to 4 or its pharmaceutically acceptable salt treat breast cancer medicines in preparation
In purposes.
6. the use of compound according to claim 5 or its pharmaceutically acceptable salt in preparation treatment breast cancer medicines
On the way, it is characterised in that: the breast cancer treatment drug is BRD4 inhibitor class drug.
7. a kind of pharmaceutical composition for treating breast cancer, it is characterised in that: its active constituent includes the claim 1 of effective dose
~4 described in any item compounds or its pharmaceutically acceptable salt.
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| Synthetic strategy for increasing solubility of potential FLT3 inhibitor thieno[2,3-d]pyrimidine derivatives through structural modifications at the C2 and C6 positions;Changmok Oh，等;《Bioorganic & Medicinal Chemistry Letters》;20161223;第27卷;第498页式11结构,第499页table1产物13h、13i |
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