CN103880707B - STAT3 micromolecular inhibitor and application thereof - Google Patents
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Abstract
The invention discloses a kind of STAT3 micromolecular inhibitor and application thereof, there is provided a kind of with the N ˊ shown in formula (1) or formula (1a)-(1-(2,4 dihydroxy phenyls) ethylidene) benzoyl hydrazine derivative or its pharmacologically acceptable salt be the STAT3 inhibitor of effective constituent.In formula, R on A ring
1and R
2can be hydroxyl, methoxyl group, carboxyl and fat base, B can be ring-type or chain.STAT3 micromolecular inhibitor provided by the invention has selectivity and high reactivity, tertiary structure according to STAT3 designs, biosynthesizing transformation and optimization, then study such inhibitor grow at inhibition tumor cell by the method such as fluorescence polarization and CCK-8 detection of active, promote the mechanism of differentiation apoptosis aspect, thus illustrate the effect of STAT3 micromolecular inhibitor in prophylaxis of tumours generation and treatment tumour.
Description
Technical field
The present invention relates to tumour medicine field, particularly relate to the active small molecular inhibitor that the transduction of a kind of basis signal designs with the tertiary structure of transcription factor 3 (STAT3).
Background technology
Signal transduction and transcription factor 3(STAT3) belong to STATs family, this family has seven member STAT1-STAT7 respectively by different genes encodings, wherein STAT1, STAT3, STAT5 very high homology.STATs family is stimulated as EGFR, IL-6, PDGF etc. by cell growth factor and tyrosine phosphorylation occurs thus mediate cell growth, differentiation, migration, the physiological functions such as apoptosis.Research shows, in prostate cancer, mammary cancer, head and neck cancer, ovarian cancer, melanoma, the STAT3 of excess phosphoric acid all can be detected, and normal epithelium cell pSTAT3 level is obviously low in myelomatosis.
STAT3 is made up of four structural domains: auxiliary DNA binding domain, DNA specific recognition territory, forms dimerisation domain (SH2), transcription activation domain, wherein in formation dimerization domain, have a Tyr phosphorylation site, this site plays keying action in STAT3 dimerisation process.As extracellular somatomedin or cytokine (EGF, IL-6, TNF) corresponding acceptor on film is stimulated to make it dimerization, activate JAK, and recruit STAT3 monomer and make it tyrosine 705 phosphorylations occur, pSTAT3 monomer enters nucleus and starts original paper with corresponding DNA by mutually identifying the SH2domain of the other side and form dimer and striding across nuclear membrane and be combined, then key protein (the Bcl)-Xl of the adjustment signal conduction in downstream is started, (Mcl-1), the transcriptional expression of cyclinD1/D2andc-Myc etc., thus regulating cell growth, propagation, differentiation, apoptosis.But STAT3 dimerization plays node effect in JAK/STAT3 signal path, and STAT3 in 1997 by as antitumor drug target spot, therefore suppression STAT3 forms dimer can contain the STAT3 apoptosis of tumor cells of excess activation potential method as promotion, thus contains the one strategy of the tumour of the STAT3 of excess activation as treatment.
At present, can be divided into following several with the inhibitor for STAT3 of report: phosphated peptide section, phosphated peptide section analogue (pTyr-Xxx-Xxx-Gln), non-phosphorylating small molecules (Stattic, STA-21, S31-201, BP-1-102), oligonucleotide (5 '-CATTTCCCGTAAATC-3 ' and3 '-GTAAAGGGCATTTAC-3 '), kinase inhibitor.But, peptide inhibitor cell permeability is poor, easy metabolism, biological utilisation rate variance, kinase inhibitor can not suppress downstream STAT3 pathway activity completely, and the micromolecular inhibitor inhibit activities of non-peptide section is limited and go up clinical medicine at present also not for STAT3, therefore, develop new optionally and there is highly active STAT3 inhibitor to have huge challenge another aspect on the one hand be also a major opportunity of capturing tumour.
Summary of the invention
First technical problem to be solved by this invention is, provides a kind of having optionally newly, highly active STAT3 micromolecular inhibitor.
Second technical problem to be solved by this invention is, provides STAT3 micromolecular inhibitor preparing the application in tumour medicine.
In order to solve above-mentioned first technical problem, the invention provides a kind of STAT3 micromolecular inhibitor, described inhibitor contains the N'-(1-(2 shown in formula (1), 4 dihydroxy phenyls) ethylidene) benzoyl hydrazine derivative or its pharmacologically acceptable salt;
In formula (1), R on A ring
1and R
2identical or different, represent hydrogen atom, replacement or non-substituted hydroxyl, replacement or non-substituted methoxyl group, replacement or non-substituted carboxyl, replacement or non-substituted methoxycarbonyl, replacement or non-substituted ethoxycarbonyl;
In formula (1), R on B ring
3, R
4, R
5, R
6and R
7identical or different, represent hydrogen atom, halogen, described halogen refers to fluorine, chlorine, bromine and iodine, substituted or non-substituted alkyl, substituted or non-substituted cycloalkyl, substituted or non-substituted thiazolinyl, substituted or non-substituted alkynyl, substituted or non-substituted ester ring type heterocyclic radical, substituted or non-substituted aralkyl, substituted or non-substituted aromatic heterocycle, replacement or unsubstituted aromatic Heterocyclylalkyl, or hydroxyl, nitro, amino, sulphonamide, sulfydryl, methoxyl group, oxyethyl group, benzyloxy, methyl, cyano group; In B ring, V, W, X, Y, Z are monosubstituted or polysubstituted carbon atom or nitrogen-atoms; B ring is originally as phenyl ring, pyridine ring, furan nucleus, thiphene ring, pyrrole ring, pyrazole ring, imidazoles, oxazole, isoxazole, indoles, triazole, tetrazole, piperidine ring, naphthalene nucleus or anthracene nucleus;
Substituted or non-substituted derivative is formed with hydrazides in the middle of A ring and B ring.
As a preferred version, in formula (1), B ring portion is divided into furan nucleus, and substituted or non-substituted nitro, replacement or non-substituted amino, replacement or non-substituted hydroxyl, replacement or non-substituted cyano group, replacement or non-substituted methoxyl group, replacement or non-substituted benzyloxy, replacement or non-substituted methyl, replacement or non-substituted halogen, described halogen refers to fluorine, chlorine, bromine, iodine.
As a preferred version, in formula (1), B ring portion is divided into thiphene ring, and substituted or non-substituted nitro, replacement or non-substituted amino, replacement or non-substituted hydroxyl, replacement or non-substituted cyano group, replacement or non-substituted methoxyl group, replacement or non-substituted benzyloxy, replacement or non-substituted methyl, replacement or non-substituted halogen, described halogen refers to fluorine, chlorine, bromine, iodine.
As a preferred version, in formula (1), B ring portion is divided into phenyl ring, and substituted or non-substituted nitro, replacement or non-substituted amino, replacement or non-substituted hydroxyl, replacement or non-substituted cyano group, replacement or non-substituted methoxyl group, replacement or non-substituted benzyloxy, replacement or non-substituted methyl, replacement or non-substituted halogen, described halogen refers to fluorine, chlorine, bromine, iodine.
As a preferred version, in formula (1), B ring portion is divided into pyridine ring, and substituted or non-substituted nitro, replacement or non-substituted amino, replacement or non-substituted hydroxyl, replacement or non-substituted cyano group, replacement or non-substituted methoxyl group, replacement or non-substituted benzyloxy, replacement or non-substituted methyl, replacement or non-substituted halogen, described halogen refers to fluorine, chlorine, bromine, iodine.
As a preferred version, in formula (1), B ring portion is divided into heterocycle, described heterocyclic radical is pyrryl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, triazol radical, tetrazole base, piperidyl, pyranyl, pyrazinyl, pyrimidyl, isothiazolyl, triazinyl, and substituted or non-substituted nitro, replace or non-substituted amino, replace or non-substituted hydroxyl, replace or non-substituted cyano group, replace or non-substituted methoxyl group, replace or non-substituted benzyloxy, replace or non-substituted methyl, replace or non-substituted halogen, described halogen refers to fluorine, chlorine, bromine, iodine.
As a preferred version, in formula (1), B ring portion is divided into ring and ring, described ring cyclic group comprises naphthyl, quinolyl, isoquinolyl, indyl, purine radicals, pteridine radicals, quinazolyl, benzothienyl, benzofuryl, benzoxazolyl, benzopyrazines base, benzo pyrimidyl, Pyridopyrimidine base, pyrimido-pyrimidine base, thianthrenyl, benzo indazolyl, benzotriazole base, , and substituted or non-substituted nitro, replace or non-substituted amino, replace or non-substituted hydroxyl, replace or non-substituted cyano group, replace or non-substituted methoxyl group, replace or non-substituted benzyloxy, replace or non-substituted methyl, replace or non-substituted halogen, described halogen refers to fluorine, chlorine, bromine, iodine.
Invention also provides a kind of STAT3 micromolecular inhibitor, described inhibitor contains the N'-(1-(2 shown in formula (1a), 4 dihydroxy phenyls) ethylidene) benzoyl hydrazine derivative or its pharmacologically acceptable salt;
In formula (1a), R on A ring
1and R
2identical or different, represent hydrogen atom, replacement or non-substituted hydroxyl, replacement or non-substituted methoxyl group, replacement or non-substituted carboxyl, replacement or non-substituted methoxycarbonyl, replacement or non-substituted ethoxycarbonyl;
In formula (1a), part B R
8be expressed as aliphatics chain-like structure, described aliphatics chain-like structure refers to ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, cyclopropyl, cyclobutyl, n-pentyl, isopentyl, cyclopentyl, n-hexyl, cyclohexyl, n-heptyl, suberyl, allyl group and derivative thereof, or substituted or non-substituted styracin, comprise substituted or non-substituted nitro, replace or non-substituted amino, replace or non-substituted hydroxyl, replace or non-substituted cyano group, replace or non-substituted methoxyl group, replace or non-substituted benzyloxy, replace or non-substituted methyl, replace or non-substituted halogen, described halogen refers to fluorine, chlorine, bromine, iodine,
Substituted or non-substituted derivative is formed with hydrazides in the middle of A ring and part B.
As a preferred version, with R on A ring in formula (1a) in formula (1)
1and R
2identical or different, represent hydroxyl or carboxyl.
In order to solve above-mentioned second technical problem, the invention provides STAT3 micromolecular inhibitor and preparing the application in Therapeutic cancer medicine.
The invention has the advantages that, the invention provides a kind of having optionally newly, highly active STAT3 micromolecular inhibitor, tertiary structure according to STAT3 designs its active small molecular inhibitor, biosynthesizing transformation and optimization, then study such inhibitor grow at inhibition tumor cell by the method such as fluorescence polarization and CCK-8 detection of active, promote the mechanism of differentiation apoptosis aspect, thus the micromolecular inhibitor of illustrating STAT3 occurs in prophylaxis of tumours and treats the effect in tumour.
Accompanying drawing explanation
Fig. 1 is the fluorescence polarization value of micromolecular compound, is analyzed the IC obtaining each micromolecular compound by robustfit
50value, the IC of 1-177
50for the IC of 8.972uM, 1-078
50for 16.05uM.
Fig. 2 is the growth-inhibiting of micromolecular compound to cancer cell DU145, and 1-078 is IC in competitive assay in vitro
50for 16.05uM, but it is water-soluble and permeable membrane is slightly weak relative to 1-177, the IC of 1-177 and 1-078
5025.42uM, 222.5uM respectively.
Fig. 3 is that WesternBlot detects 1-177 to the retarding effect of pSTAT3 in MDA-MB-468 cell.
Embodiment
Below in conjunction with specific embodiment, set forth the present invention further.The experimental technique used in following embodiment if no special instructions, is ordinary method.Material used in following embodiment, reagent etc., if no special instructions, all can obtain from commercial channels.Should be understood that these embodiments are only not used in for illustration of the present invention to limit the scope of the invention.The experimental technique of unreceipted actual conditions in the following example, usual conveniently condition, the people such as such as Sambrook, molecular cloning: laboratory manual (NewYork:ColdSpringHarborLaboratoryPress, 1989) condition described in, or according to the condition that manufacturer advises.
The preparation of embodiment 1. compound formula (2a)
The particular compound kind that general formula (2a) is general formula (1) and general formula (1a), because part B can be ring-type or chain-like structure, represents with R in general formula (2a).
To replace or non-phenyl ring, heterocycle, styracin or the aliphatic acid got refluxes 9h in dehydrated alcohol-vitriol oil (20:1) solution, be spin-dried for the solvent of 2/3, in debris getting, add appropriate trash ice, then use NaHCO
3solution regulates PH to neutral, is extracted with ethyl acetate product, then washs with saturated nacl aqueous solution, anhydrous sodium sulfate drying, filters, is spin-dried for solvent and obtains colourless liquid, be product 3.Above-mentioned gained ester is dissolved in dehydrated alcohol, adds the hydrazine hydrate of equivalent, backflow 24h.Spin off partial solvent, then add appropriate trash ice, namely have solid to separate out, filter, washing, dry, then use the ethyl alcohol recrystallization of 90%, obtain product 4.Produce 2 methods, enumerate and with methyl alcohol or ethanol, or can use reaction of sodium azide, or with methyl iodide and alkali reaction, such as, can enumerate sodium hydroxide, salt of wormwood, the mineral alkalis such as potassium tert.-butoxide.
Product 3 and 2,4 dihydroxyl-methyl phenyl ketone is dissolved in dehydrated alcohol with the ratio of 1:1, then adds monovalent acetic acid, refluxes 4 hours, and reaction liquid cooling causes room temperature, filters, and filter cake washing with alcohol is also dry, and gained solid is product 5.React acid used and can be enumerated as acetic acid or hydrochloric acid etc.
In above manufacture method; when the group of definition changes or is not suitable for implementation method under the condition of implementation method, object compound can be obtained by using the importing of protecting group conventional in organic chemistry and disengaging method (" protecting group in organic synthesis " press of East China University of Science) etc.In addition, the conversion of the functional group contained in each replacement can be carried out according to the known method outside above-mentioned manufacture method, in compound formula (2a), synthetic intermediate sometimes can be it can be used as to pour other derivatives into.
The intermediate of above-mentioned manufacture method and object compound such as can neutralize, filter, extract, clean with method of purification conventional in Synthetic Organic Chemistry, dry, concentrate, recrystallization, various chromatograms etc. carry out separation and purification.In addition, in intermediate, the reaction that can not be supplied to below by special purifying.
When wishing to get the salt of compound formula (2a), when compound (2a) obtains in a salt form, can directly refine, or, when obtaining in a free form, as long as with dissolving in suitable organic solvent or being suspended, add acid and form salt by usual method later.
The form of compound formula (2a) and the pharmacologically affixture of acceptable salt or various solution thereof exists in addition, and these affixtures also can use as STAT3 inhibitor of the present invention.
Preparation scheme one:
Preparation scheme two:
Preparation scheme three:
Preparation scheme four:
The object lesson of the compound formula (2a) that the above-mentioned manufacturing process of table 1. obtains
The preparation of embodiment 2. compound formula (3a)
Equally, the particular compound kind that general formula (3a) is general formula (1) and general formula (1a), because part B can be ring-type or chain-like structure, represents with R in general formula (3a).
To replace or non-phenyl ring, heterocycle, styracin or the aliphatic acid got refluxes 9h in dehydrated alcohol-vitriol oil (20:1) solution, be spin-dried for the solvent of 2/3, in debris getting, add appropriate trash ice, then use NaHCO
3solution regulates PH to neutral, is extracted with ethyl acetate product, then washs with saturated nacl aqueous solution, anhydrous sodium sulfate drying, filters, is spin-dried for solvent and obtains colourless liquid, be product 3.Above-mentioned gained ester is dissolved in dehydrated alcohol, adds the hydrazine hydrate of equivalent, backflow 24h.Spin off partial solvent, then add appropriate trash ice, namely have solid to separate out, filter, washing, dry, then use the ethyl alcohol recrystallization of 90%, obtain product 4.Produce 2 methods, enumerate and with methyl alcohol or ethanol, or can use reaction of sodium azide, or with methyl iodide and alkali reaction, such as, can enumerate sodium hydroxide, salt of wormwood, the mineral alkalis such as potassium tert.-butoxide.
M-Salicylic acid and acetic anhydride (1:1.1), the vitriol oil (1 ~ 2), reflux 3h in solvent toluene.Reaction liquid cooling causes room temperature, has solid to separate out, reaction solution is dissolved in ethyl acetate, washing, anhydrous Na SO
4drying, is concentrated into dry.Re-crystallizing in ethyl acetate is utilized to obtain white crystal.By the anhydrous AlCl of above-mentioned gained white solid and 4 times amount
3mixing, is warming up to 160 DEG C, reaction 3h.Reaction solution is poured in frozen water, add a certain amount of chlorohydric acid pickling, be extracted with ethyl acetate, then be washed to neutrality, anhydrous Na SO
4drying, is concentrated into dry, obtains garnet syrupy shape solid, then this solids crude is crossed post obtains dark yellow solid, then with dehydrated alcohol or ethyl acetate repeatedly recrystallization purifying product obtain compound 8.
Compound 4 and 3-hydroxyl-4-ethanoyl-phenylformic acid are dissolved in dehydrated alcohol with the ratio of 1:1, then add monovalent acetic acid, backflow 4h, and reaction liquid cooling causes room temperature, filters, filter cake washing with alcohol, and dry, gained solid is product 9.React acid used and can enumerate acetic acid or hydrochloric acid etc.
In above manufacture method; when the group of definition changes or is not suitable for implementation method under the condition of implementation method, object compound can be obtained by using the importing of protecting group conventional in organic chemistry and disengaging method (" protecting group in organic synthesis " press of East China University of Science) etc.In addition, the conversion of the functional group contained in each replacement can be carried out according to the known method outside above-mentioned manufacture method, in compound formula (3a), synthetic intermediate sometimes can be it can be used as to pour other derivatives into.
The intermediate of above-mentioned manufacture method and object compound such as can neutralize, filter, extract, clean with method of purification conventional in Synthetic Organic Chemistry, dry, concentrate, recrystallization, various chromatograms etc. carry out separation and purification.In addition, in intermediate, the reaction that can not be supplied to below by special purifying.
When wishing to get the salt of compound formula (3a), when compound (3a) obtains in a salt form, can directly refine, or, when obtaining in a free form, as long as with dissolving in suitable organic solvent or being suspended, add acid and form salt by usual method later.
The form of compound formula (3a) and the pharmacologically affixture of acceptable salt or various solution thereof exists in addition, and these affixtures also can use as STAT3 inhibitor of the present invention.
Preparation scheme five:
Preparation scheme six:
Preparation scheme seven:
Preparation scheme eight:
Preparation scheme nine:
The object lesson of the compound formula (3a) that the above-mentioned manufacturing process of table 2 obtains
It is active that the experiment of embodiment 3. competitiveness detects STAT3 micromolecular inhibitor
This experiment detects micromolecular compound to the avidity of STAT3 by fluorescence polarization (FP) method, by micromolecular compound competition fluorescence peptide section FITC-pYLPQTV-NH2 and STAT3 protein binding, Ac-pYLPQTV-NH2 is as robust positive control, the weak positive control of Ac-YLPQTV-NH2, Ac-pYLKTKF negative control.When STAT3 albumen and the fluorescence peptide section polarized light that fluorophor can be made to produce that be combined with each other increases, and add these peptide sections in contrast and can compete fluorescence peptide section and STAT3 protein binding, polarization value is reduced.To test STAT3 concentration used be 5uM, FITC-pYLPQTV-NH2 concentration is 1nM.Experiment grouping: negative control is STAT3 albumen and FITC-pYLPQTV-NH2; Positive control is STAT3 albumen, FITC-pYLPQTV-NH2, and the peptide section of each different activities grade; Sample sets is STAT3 albumen, FITC-pYLPQTV-NH2, and micromolecular compound.Micromolecular compound or positive peptide section are carried out gradient dilution in 96 orifice plates of corningnbs3995#, then the mixture of STAT3 albumen and FITC-pYLPQTV-NH2 is added in each hole, lucifuge, shaker mixes 3 hours until reaction reaches balance, Biotekreader is used to measure, excitation wavelength is 485nm, and wavelength of transmitted light is 525nm, reads fluorescence polarization value.
Use Graphpadprimz5 software processes fluorescence polarization value, analyzed the IC obtaining each micromolecular compound by robustfit
50value, the IC of 1-177
50for the IC of 8.972uM, 1-078
50for 16.05uM, as shown in Figure 1.
This series compound of embodiment 4. is to the growth Survival Effects of cancer cell
Tested by FP, this series compound in vitro molecular level has higher affinity to STAT3, and next whether this series compound of checking has growth inhibitory effect to the breast cancer cell of overexpression STAT3.Cellcountingkit-8 (CCK-8) is used to detect the growth effect of K series compound to DU145, cell is planted in 96 orifice plates, 10000Cells/well, add K series compound by presetting concentration after 24h, then 24h adds 10uLcck-8/well, 37 DEG C, 4h, use BioTekreader to measure the light absorption value at 450nm place, K series compound to the growth-inhibiting of DU145 as Fig. 2, although 1-078 IC in competitive assay in vitro
50for 16.05uM but its water-soluble and permeable membrane is slightly weak relative to 1-177, the IC of 1-177 and 1-078
5025.42uM, 222.5uM respectively.Therefore function below and Mechanism Study are mainly for 1-177.
Embodiment 5.WesternBlot detects 1-177 to the retarding effect of pSTAT3 in MDA-MB-468 cell
MDA-MB-468 cell after 2 hours in the process of 1-177 different concns, stimulates with IL-6 (10ng/ul), receives cell after 24 hours, then the method for westernblot and the p-STAT3 of CST company is used, STAT3, p-AKT, AKT, P-Src, Src antibody detects.As shown in Figure 3, use DMSO and 0uM respectively, the 1-177 process cell of 10uM, 30uM, after 10uM process, p-STAT3 and p-AKT obviously reduces, and after 30uM process, p-STAT3 and p-AKT band is very weak, is 0 substantially.Therefore illustrate that K116 has obvious inhibition to STAT3 phosphorylation, does not affect the kinases P-Src of STAT3 upstream simultaneously.
The above is only the preferred embodiment of the present invention; it should be pointed out that for those skilled in the art, under the premise without departing from the principles of the invention; can also make some improvements and modifications, these improvements and modifications also should be considered as protection scope of the present invention.
Claims (1)
1. the application of compound 1-078 in preparation STAT3 micromolecular inhibitor, the structural formula of described 1-078 is as follows:
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| CN111072610B (en) * | 2019-12-16 | 2022-08-30 | 杭州师范大学 | Preparation and application of substituted benzofuran 2-formyl hydrazone LSD1 inhibitor |
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