CN106565551A - Novel bipropoxyphenyl-methylsulfonylamide compound for adjusting activity of estrogen-related receptor and medical purpose thereof - Google Patents
Novel bipropoxyphenyl-methylsulfonylamide compound for adjusting activity of estrogen-related receptor and medical purpose thereof Download PDFInfo
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- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
- C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
- C07C311/08—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
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Abstract
The invention discloses a novel bipropoxyphenyl-methylsulfonylamide compound (as shown in the formula I) for adjusting activity of an estrogen-related receptor and pharmaceutically acceptable salt and application thereof. The compound and the pharmaceutically acceptable salt can be used in preparation of medicines for adjusting activity of the estrogen-related receptor ERR-alpha (Estrogen-related receptor alpha, ERR-alpha or ERRalpha) and preventing and treating malignant tumors such as breast cancer, prostate cancer, stomach cancer, colorectal carcinoma, ovarian cancer, cervical carcinoma, etc.
Description
Technical field
The present invention relates to a kind of new dipropyl oxygen phenyl-methane-sulfonamide class compound and its pharmaceutically acceptable salt conduct
Adjust estrogen-related receptor ERR-alpha（Estrogen-related receptor alpha, ERR-alpha or ERR α）
Regulator and its drug regimen and its prepare prevention and/or treat breast carcinoma, carcinoma of prostate, gastric cancer, colon cancer, ovarian cancer,
Purposes in the medicine of the tumor such as cervical cancer or carcinoma of endometrium.
Background technology
ERR α are in 1988 by clone identifications such as Giguere.As orphan nuclear receptor（Orphan nuclear
receptor）, ERR α endogenic ligands are undiscovered always.ERR α wide expressions in vivo, from cardiac muscle, digestive tract, brain, bone
Malignant tumor such as bone flesh, brown fat and breast carcinoma, ovarian cancer etc. can be detected.ERR α and estrogen receptor alpha（ERα）Have
Higher homology：DNA binding domain（DNA binding domain, DBD）Amino acid similarity 68%, ligand binding domain
（Ligand binding domain, LBD）Similarity 33%.Different from estrogen receptor ER α, ERR α can not be tied with estrogen
Close, but can be with ER α competition binding estrogen response elements（Estrogen response elemnt, ERE）, recognition sequence is
AGGTCAnnn TGACCT；And ERR α also can be reacted with monomer or dimeric form with reference to a class I type Steroidgenesis factor
Element TnAAGGTCA, also referred to as estrogen-related receptor response element（ERR response element, ERRE）, show
ERR α and ER α have juxtaposition when DNA is recognized.
Nearest research prompting, except participating in ER signal paths, ERR α are in cellular energy metabolism, mitochondrial oxidation and biology
Synthesis etc. has an important physiological action, the development of the histoorgan that wields influence of its function, the aging of cell, the generation of tumor and
Development etc..
Oncobiology basic research shows, orphan nuclear receptor-estrogen-related receptor α（ERRα）Can promote hormone according to
The growth of the breast carcinoma of bad/non-dependent, invasion and attack, promote vascular smooth muscle cell proliferation, the formation of endothelium micro-pipe and tumor vessel new
It is raw, it is meant that the medicine of targeting ERR α has the effect of anti-breast cancer concurrently, and for Molecular Targeted Therapy for Breast Cancer New Policy is provided.
In recent years, research disclose the estrogen such as the ERR α breast carcinoma related to estrogen, carcinoma of endometrium and cervical cancer according to
Bad property tumor is closely related, more there are some researches show numerous non-estrogen-dependent tumors such as carcinoma of prostate, adenocarcinoma of stomach and Colon and rectum
The generation development of cancer etc. and clinical prognosis are also related to the expression of ERR α.Clinical research confirmation, ERR α breast carcinoma, colon cancer,
Express in the tumor such as ovarian cancer and carcinoma of prostate and significantly raise, be the independent risk factor of a prognosis malas.By raise/under
Adjust ERR alpha expressions or using ERR alpha inhibitors, can effectively suppress the transcriptional activity of hypoxia genes, so as to reduce internal solid tumor
Angiogenesis with increase.These researchs show that ERR α are probably the potential therapy target of kinds of tumors.ERR α inverse agonists
XCT790 inhibits the propagation and angiogenesiss of kinds of tumor cells.ERR α inverse agonists SR16388 effectively inhibit nude mice
The growth of carcinoma of prostate in lotus knurl model.These researchs show that the regulator of targeting ERR α is possible as clinically effective
Antitumor drug.
In sum, estrogen-related receptor ERR α can be as the novel therapeutic target spot of kinds of tumors, based on estrogen phase
Close the small-molecule modulators that receptor ERR α are developed, it is most likely that become the novel drugs molecule of therapy-related Diseases Tumor.
The content of the invention
1st, it is an object of the invention to provide there is a class estrogen-related receptor ERR-alpha such as following formula I structure to adjust
Section agent or its pharmaceutically acceptable salt.
2nd, a further object of the present invention is the compound or its pharmaceutically acceptable salt for providing Formulas I structure.
3rd, it is still another object of the present invention to provide compound shown in Formulas I or its pharmaceutically acceptable salt are preparing prevention
And/or the application in the medicine for the treatment of tumor disease.Preferably, the tumor disease is breast carcinoma, carcinoma of prostate, gastric cancer, knot
The tumors such as intestinal cancer, ovarian cancer, cervical cancer or carcinoma of endometrium.
4th, a kind of pharmaceutical composition, including the compound of formula I described in the claim 1 of therapeutically effective amount or its pharmaceutically may be used
The salt of acceptance.
5th, it is according to claim 4 to require compositionss, it is characterized in that, the pharmaceutical composition further containing a kind of or
Various pharmaceutically acceptable carriers or excipient.
6th, pharmaceutical composition according to claim 4, is characterized in that, described compound of formula I or its pharmaceutically may be used
The salt of acceptance accounts for gross weight than 50% ~ 99.5% as active component.
Description of the drawings
Fig. 1：Formula I on molecular level（Compound）Competition binding activity figure to ERR α.
Fig. 2：Formula I suppresses MDA-MB-231 cell migration at 5,10,20 μM.
Specific embodiment
The present invention is described in more detail below by specific embodiment, to be better understood from the present invention, but
Following embodiments are not intended to limit the scope of the invention, will be detailed below biological activity and the pharmacology of formula I
Evaluate.
Implement row 1 and test transcripting regulating activity of the compound of formula I to ERR-alpha using reporter gene
This example illustrates compound of formula I according to the present invention can effectively suppress ERR- in HEKC HEK-293
The expression of the reporter gene that alpha is regulated and controled, illustrates that compound of formula I involved in the present invention has effectively regulated and controled ERR-alpha
Function.Reporter gene measuring technology is technology familiar to the staff of this area.
We test compound of formula I to ERRs transcriptional regulatory activities using GAL4 fusion receptors activation method.GAL4 fusions are received
Body activation method is based on mammalian cell single crosses principle, i.e., receptor LBD and yeast transcription factor DBD to be built into fusion egg
White expression plasmid, the LBD for making receptor serves as activation domain (Activation domain, AD).When GAL4 fusion receptors matter
During the common transfectional cell of reporter plasmid of grain and GAL4DNA response elements (UAS) driving, in the effect of receptor stimulating agent
Under, GAL4 fusion receptors are incorporated on 5 × UAS, drive the expression of reporter gene.And in receptor inverse agonists or antagonist
In the presence of, the combination of GAL4 fusion receptors and 5 × UAS is reduced, and will suppress the expression of reporter gene.
In the experiment of the present invention, we by Gal4-ERR-alpha plasmids with express 5 × UAS and to be coupled Lampyridea glimmering
It is thin that plasmid (using β-gal expression plasmids as the internal reference) transient cotransfection of light element enzyme reporter gene enters mammal HEK-293
In born of the same parents, the compound of formula I effect 24h of variable concentrations is added, detect the activity change of luciferase and β-gal.
1st, transfect：Inoculation HEK-293 cells in 6cm culture dishs, 6 .0 × 104/ wares, culture fluid is 10%FBS
DMEM so as to which growth conditions are good.37 DEG C of 5%CO2Culture will be inoculated in 96 holes in 24 hours per the cell in hole 6 × 103 afterwards
Costar Tissue Culture Plates, overnight incubation.When cell density reaches 70%, take the serum-free medium (DMEM) of 50mL in
In the centrifuge tube of 1.5mL, then add the transfection reagent 3000Transfection Reagent of 2mL, flicked several times with handss, mixing
Afterwards room temperature places 5min.By recombiant plasmid and 3000Transfection Reagent with 1:5 ratio is mixed, and takes 20pmol
During recombiant plasmid (pGal4-ERRs LBD, p5 × UAS-Luc and p β-gal) is added to DMEM, soft mixing.By serum-free
The recombiant plasmid that DMEM has diluted flicks mixing, room with the mixture of the 3000Transfection Reagent of DMEM dilutions again
Temperature places 20min to form the complex of DNA/lipofectamine.By answering for the DNA/lipofectamine being incubated
Compound is added dropwise in the culture dish containing cell and culture fluid, and Tissue Culture Dish is gently rocked back and forth makes cell transfecting
Efficiency is improved, and culture dish is put into into 37 DEG C, 5%CO2Cultivate 6 hours in incubator, change fresh medium and (reduce liposome
Cytotoxicity).Cell is re-digested, is inoculated in 96 hole Costar Tissue Culture Plates with the cell in 1 × 104/ hole.
2nd, compound of formula I and positive drug XCT790 are added：After transfection 8h, addition compound of formula I is in 96 orifice plates.By the positive
Control XCT790 and compound of formula I are diluted to 10 × aimed concn and add 96 hole Costar Tissue Culture Plates, and volume is 10 μ l, after
24 hours each multiple holes of concentration 3 of continuous culture, after cultivating 24 hours, discard culture fluid in culture plate, add the μ of cell pyrolysis liquid 100
L, respectively take 50 μ l carries out the determination of activity of LUC Photinus pyralis LUC Photinus pyralis FL and beta galactosidase with MD multi-function microplate readers respectively, with phase
Compound of formula I is calculated uciferase activity (ratio of LUC Photinus pyralis LUC Photinus pyralis FL activity/betagalactosidase activity) to ERR-
The transcripting regulating activity of alpha.
Test result indicate that, compound of formula I according to the present invention can dose-dependently suppress the transcriptional activation of ERR α,
(IC50=0.63 ± 0.24 μM), (IC consistent with positive control XCT790 trend50=0.32 ± 0.02 μM).
Detection technique (the Time-Resolved of the use time resolved fluorescent resonance energy transfer of embodiment 2
Fluoresen-ce Resonance Energy Transfer assay, TR-FRET assay) test on a molecular scale
Competition binding activity of the formula I to ERR α
This example illustrates compound according to the present invention can effectively suppress the combination of ERR α and PGC1 α, this is illustrated
Bright involved compound competitive binding ERR α (molecular level).TR-FRET is technology familiar to the staff of this area.
FRET (Fluorescence Resonance Energy Transfer) is FRET (fluorescence resonance energy transfer), is glimmering based on two
The energy transfer of light group (donor and receptor), in two fluorophors in the case of.Biomacromolecule interphase interaction
Can be determined with energy transfer with fluorescence labels and between the two.When two group close enoughs, excitaton source is (such as
Flash lamp or laser) fluorogenic donor is excited, energy transfer can be caused to receptor, so as to receptor sends specific wavelength
Fluorescence.TR-FR ET are usually used in the screening of medicine compared with FRET, and we use La ntha ScreenT M Es trog
EnRelated Receptor alpha TR-FRET Coactivator Assay are used for analyzing the LBD and coactivity factor 1 of ERR α
The interaction of sub- PGC-1 α, after the LBD of ERR α is combined with its inverse agonist, conformation changes, with auxiliary activation
Factor PGC-1 α adhesions weaken, and in the signal weakening of 520nm, therefore can be used to screen the chemical combination with ERR α competition bindings
Thing.
Experiment concrete operations are as follows：Plus 30 μ l the .97ml of 1M DTT to 5 TR-FRET auxiliary adjustment factor buffer G
In；Plus in DMSO to TR-FRET auxiliary adjustment factor buffer G as to (final concentration of 2%) of DMSO, and 384 holes experiment
The above-mentioned solution of 10 μ l is added in plate；With DMSO stepwise dilution compound or XCT790 by a certain percentage, 12 concentration are diluted to
Gradient；Above-claimed cpd or XCT790 are diluted with TR-FRET auxiliary adjustment factor buffer G；Divide after mixing, by previous step
Compound be transferred in 384 hole brassboards.
4 × ERR α-LBD buffer is prepared with the TR-FRET auxiliary adjustment factor buffer G of pre-cooling；By the 4 of above-mentioned preparation
× ERR α-LBD buffer is added in 384 hole brassboards under room temperature and prepares 2 μM with TR-FRET auxiliary adjustment factor buffer G
Fluorescein-labeled PGC1 α (4X) and the anti-GST antibody (4X) of 20nMTb；The above-mentioned antibody-solutions for preparing are added to
In 384 hole brassboards；After jiggling mixing, by 384 hole brassboard lucifuge incubation at room temperature 8h；At 520nm and 495nm wavelength
Detection, with emissive porwer ratio (520/495) competition binding activity of the compound to ERR α is calculated.
Test result indicate that, compound according to the present invention can dose-dependently antagonism ERR α and PGC1 α combination,
Show that compound can competitively combine ERR α (IC50=0 .64 μM), (IC consistent with positive control XCT790 trend50
=0 .22 μM), as a result see Fig. 1.
Embodiment 3 determines inhibitory effects on proliferation of the compound to various tumor cell strains using CCK-8 cell proliferation experiment
This example illustrates compound according to the present invention can effectively suppress the propagation of various tumor cell strains, this is illustrated
The involved compound of invention shows effective anti tumor activity in vitro.CCK-8 cell proliferation experiment is this area work people
Technology familiar to member.
（1）Tumor cell culture and the porocyte culture plates of cover plant 96：The tumor for taking out exponential phase in good condition is thin
Born of the same parents, after observation of cell form, such as after cell 80% fusion, start to pass on.The old culture fluid abandoned in culture dish is washed, is used
Aseptic 1mL PBS wash 3-5 after, the pancreatin 1mL for adding temperature to bathe, and level rocks culture dish makes pancreatin be evenly distributed, digestion
Fully.Cell is put into into incubator 1-2min, cell is taken out, observation of cell digestion situation, works as iuntercellular under inverted microscope
Gap becomes greatly and cell withdraws projection and is rounded, and the termination digestion of 10%FBS culture fluid is added immediately, is gently blown with liquid-transfering gun
Cell is beaten, the cell for having digested softly is blown and beaten repeatedly to be made its de- wall and disperse, form uniform cell suspension, adjustment cell is close
Degree.With 5 × 103/hole of cell number by cell suspension inoculation to 96 orifice plates, per the μ L of hole 200,37 DEG C of 5%CO2 cultures are put into
Cultivate in case.After cell attachment, former 10%FBS culture fluid is abandoned in suction, and washes 3-5 after with aseptic PBS, is changed to 0 .1%
FBS culture fluid, then hungry culture 24h, make cell be in homogenization state in the G0/G1 phases.
（2）Compound intervenes tumor cell：96 orifice plate outermost Mondays circle is easy to evaporation, therefore only cell is inoculated in into 96 holes
The zone line of plate, adds 100 μ L sterilizing distilled waters in every hole that makes a circle in its week, prevents volatilization.During intervention, former 0 is discarded
.1%FBS culture fluid, is changed to the DMEM culture fluid of fresh 10%FBS, and adds the compound of variable concentrations (with DMSO as molten
Agent), DMSO final concentration of 0.5%, effect of the detection compound to tumor cell proliferation is detected after culture 48h.
（2）Detection：Reach and specify after intervention time, inhale the old culture fluid abandoned in 96 orifice plates, add new culture fluid, and every
Hole adds 10 μ L CCK-8 reagents, is placed in 37 DEG C of 5%CO22h is incubated in incubator.Using 9602 enzyme micro-plate readers, in Single wavelength
Absorbance (A450) is detected at 450nm.Each concentration sets 6 multiple holes, averages, and experiment is repeated 3 times.Suppression ratio is calculated
Formula：Suppression ratio (%)=(OD compound-ODbasic)/(ODcontrol-OD basic) × 100.Test result indicate that,
Compound according to the present invention can dose-dependently suppress kinds of tumor cells, and (breast carcinoma, carcinoma of prostate and pulmonary carcinoma etc. are thin
Born of the same parents' strain) propagation, particularly to the especially pronounced (IC of inhibitory effects on proliferation of ER (-) breast cancer cell MDA-MB-23150=
1.58 ± 0.12 μM), the results are shown in Table 1.
Table 1：Formula I suppresses kinds of tumor cells proliferation experiment data.
Embodiment 4 is using Transwell tumor cell migration measuring compounds to breast cancer cell MDA-MB-
The impact of 231 shift functions
This example illustrates compound according to the present invention can effectively suppress the migration of breast cancer cell MDA-MB-231,
Illustrate that compound involved in the present invention shows effectively external anti-breast cancer cell migration activity.Transwell tumors are thin
Born of the same parents' migration experiment is technology familiar to the staff of this area.
（1）Prepare Transwell cells：With Matrigel 1:8 (50mg/L) diluents are coated with Transwell cells
The upper room face of bottom film is used for being coated with basement membrane, and air-dries in 4 DEG C.After waiting to air-dry, aquation basement membrane is suctioned out residual in culture plate
Extraction raffinate body, BSA serum-free DMEM culture fluid of the 50uL containing 10g/L is added per hole, and in 37 DEG C of incubators, is incubated 30min.
（2）Prepare cell suspension：The good cell of growth conditions is taken, after passage is adherent, changes 1%FBS's into
The hungry culture 12-24h of DMEM cell culture fluids, removes the impact of serum cell migration；Peptic cell, terminates being centrifuged after digestion
Culture fluid is discarded, is washed 1-2 time with PBS, the DMEM cell culture fluids with 1%FBS are resuspended.Cell density is adjusted to 1-10 × 105,
And ensure that matched group is consistent with treatment group cell density as far as possible.
（3）Inoculating cell：The μ L of obtained cell suspension 200 add Transwell cells, and the indoor addition on Transwell
1st, 5,10,20 μM of XCT790；Room adds culture medium of the 500 μ L containing 10ng/ml VEGF (will when kind of plate under 24 orifice plates
Pay most careful attention to, once there is bubble, cell is lifted, and removes bubble removing, then puts cell into culture plate)；By 37 DEG C of 24 orifice plate,
5%CO26,12,24h are cultivated in incubator.
（4）Dyeing：Kong Zhongpei liquid is discarded, with 90% ethanol room temperature 30min is fixed；Prepare with 0 .1% crystal violets, then
10min is dyeed with 0 .1% crystal violets room temperature, clear water is rinsed, and with cotton swab the non-migrating cell in upper strata is dabbed off.
（5）Cell counting：Microscope is just being put using Leica DC 300F observed and taken pictures (100 ×),
In turn bottom is then clearly visible upward the cell that the upper and lower room side of cell counterdie is adhered to Transwell cells.Randomly select 5 to regard
Open country counts number of cells.Suppression ratio computing formula is：Suppression ratio (%)=(cellular control unit counting-experimental group cell counting)/
Cellular control unit counts × 100%.
Test result indicate that, the compound according to the present invention of MDA-MB-231 breast cancer cell Jing variable concentrations (0,
1st, 5,10 μM) process 24h after, positive controls are the migration that 10%FBS intervention groups remarkably promote MDA-MB -231.Migration is real
Test result to show, the suppression MDA-MB-231 cell migration of formula I dose dependent, and compound concentration is got over
Greatly, it is more obvious to MDA-MB -231 cellular migration inhibitions, as a result see Fig. 2.
Embodiment described above, only expresses the several embodiments of the present invention, and its description is more concrete and detailed, but and
Therefore the restriction to the scope of the claims of the present invention can not be interpreted as.It should be pointed out that for one of ordinary skill in the art
For, without departing from the inventive concept of the premise, some deformations and improvement can also be made, these belong to the guarantor of the present invention
Shield scope.Therefore, the protection domain of patent of the present invention should be defined by appended right.
Claims (6)
1. a kind of compound and its pharmaceutically acceptable salt are preparing regulation estrogen-related receptor ERR-alpha
（Estrogen-related receptor alpha, ERR-alpha or ERR α）Purposes in the medicine of regulator, its feature
Be, the compound be N- { 4- [3- (3- the bromophenyls)-urea methyl] propoxy phenyls of -2,5- bis- }-Methanesulfomide, structural formula such as formula
Shown in I.
2. the purposes according to claim 1, is characterized in that, the pharmaceutically acceptable salt be the compound of formula I with
Salt produced by various mineral acids, inorganic base, organic acid, organic alkali reaction.
3. the purposes according to claim 1, is characterized in that, the compound of formula I and its pharmaceutically acceptable salt are in system
In the medicine of standby prevention and/or treatment breast carcinoma, carcinoma of prostate, gastric cancer, colon cancer, ovarian cancer, cervical cancer or carcinoma of endometrium
Purposes.
4. a kind of pharmaceutical composition, including the compound of formula I described in the claim 1 of therapeutically effective amount or its is pharmaceutically acceptable
Salt.
5. it is according to claim 4 to require compositionss, it is characterized in that, the pharmaceutical composition further contains one or more
Pharmaceutically acceptable carrier or excipient.
6. pharmaceutical composition according to claim 4, is characterized in that, described compound of formula I or its is pharmaceutically acceptable
Salt account for gross weight than 50% ~ 99.5% as active component.
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| CN201610858252.7A CN106565551B (en) | 2016-09-28 | 2016-09-28 | A kind of new dipropyl oxygen phenyl-methane-sulfonamide class adjusts the compound and its medical usage of estrogen-related receptor activity |
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| WO2010146236A1 (en) * | 2009-06-16 | 2010-12-23 | Biotie Therapies Corp. | Urea substituted sulphonamide derivatives |
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