CN103880707A - STAT3 small-molecule inhibitor and its application - Google Patents

STAT3 small-molecule inhibitor and its application Download PDF

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CN103880707A
CN103880707A CN201210557307.2A CN201210557307A CN103880707A CN 103880707 A CN103880707 A CN 103880707A CN 201210557307 A CN201210557307 A CN 201210557307A CN 103880707 A CN103880707 A CN 103880707A
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stat3
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张健
陈颖毅
黄敏
黄志敏
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Shanghai Yu Dao Biotechnology Co., Ltd.
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Shanghai Jiaotong University School of Medicine
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Abstract

The invention discloses a STAT3 small-molecule inhibitor and its application, and the STAT3 inhibitor takes an N'-(1-(2,4 dihydroxy phenyl)ethylidene) benzoyl hydrazine derivative or its pharmacologically acceptable salt shown in a formula (1) or a formula (1a) as an effective component. In the formula, R1 and R2 on A ring can be hydroxyl, methoxy carboxyl and ester, and B can be an annular or a chain state. The STAT3 small-molecule inhibitor has selectivity and high activity, According to a three-grade structural design, biosynthesis and reconstructing optimization of STAT3, then a fluorescence polarization method and a CCK-8 method are employed for detecting activity and researching the mechanism on inhibition of tumor cells growth and promotion of differentiation apoptosis, so that effect of the STAT3 small-molecule inhibitor on prevention and control of tumor formation and tumor treatment can be described.

Description

STAT3 micromolecular inhibitor and application thereof
Technical field
The present invention relates to tumour medicine field, relate in particular to the active small molecular inhibitor of the tertiary structure design of a kind of basis signal transduction and 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 height homology.STATs family by cell growth factor as EGFR, IL-6, thus PDGF etc. stimulate and the growth of tyrosine phosphorylation mediated cell, differentiation, migration, the physiological functions such as apoptosis occur.Research shows, in prostate cancer, and 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 is in conjunction with territory, DNA specific recognition territory, forms dimerization territory (SH2), transcriptional activity territory, wherein in formation dimerization structural domain, have a Tyr phosphorylation site, keying action is brought into play in this site in STAT3 dimerization process.As extracellular somatomedin or cytokine (EGF, IL-6, TNF) stimulate corresponding acceptor on film to make it dimerization, activate JAK, and recruit STAT3 monomer and make it to occur 705 phosphorylations of tyrosine, pSTAT3 monomer forms dimer by mutual identification the other side's SH2domain and strides across nuclear membrane and enters nucleus and be combined with corresponding DNA startup original paper, then start key protein (the Bcl)-Xl of the adjustment signal conduction in downstream, (Mcl-1), the transcriptional expression of cyclinD1/D2and c-Myc etc., thereby regulating cell growth, propagation, differentiation, apoptosis.But STAT3 dimerization is brought into play node effect in JAK/STAT3 signal path, and STAT3 has been used as antitumor drug target spot in 1997, therefore suppress STAT3 formation dimer and can be used as the potential method that promotes the STAT3 apoptosis of tumor cells that contains excess activation, thus the one strategy of the tumour of the STAT3 that contains excess activation as treatment.
At present, the inhibitor for STAT3 with report can be divided into following several: 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, easily metabolism, biological utilisation rate variance, kinase inhibitor can not suppress downstream STAT3 pathway activity completely, but not the micromolecular inhibitor of peptide section suppresses active limited and at present also not for the clinical medicine of go up of STAT3, therefore, develop new optionally and there is highly active STAT3 inhibitor one side to have huge challenge be also a major opportunity of capturing tumour on the other hand.
Summary of the invention
First technical problem to be solved by this invention is, provides a kind of and new has optionally, highly active STAT3 micromolecular inhibitor.
Second technical problem to be solved by this invention is to provide STAT3 micromolecular inhibitor in the application of preparing 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) acceptable salt on benzoyl hydrazine derivative or its pharmacology;
Figure BDA00002616478200021
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 non-substituted heteroaromatic alkyl, 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;
In the middle of A ring and B ring, form substituted or non-substituted derivative with hydrazides.
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 be encircled and encircles, described ring cyclic group comprise naphthyl, quinolyl, isoquinolyl, indyl, purine radicals, pteridine radicals, quinazolyl, benzothienyl, benzofuryl, benzoxazolyl, benzopyrazines base, benzo pyrimidyl, Pyridopyrimidine base, Kui Linpyrimido quinoline pyrimidyl, 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.
The present invention also provides a kind of STAT3 micromolecular inhibitor, and described inhibitor contains the N'-(1-(2 shown in formula (1a), 4 dihydroxy phenyls) ethylidene) acceptable salt on benzoyl hydrazine derivative or its pharmacology;
Figure BDA00002616478200041
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), B part R 8be expressed as aliphatics chain structure, described aliphatics chain 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,
In the middle of A ring and B part, form substituted or non-substituted derivative with hydrazides.
As a preferred version, R on A ring in formula (1) and in formula (1a) 1and R 2identical or different, represent hydroxyl or carboxyl.
In order to solve above-mentioned second technical problem, the invention provides the application of STAT3 micromolecular inhibitor in preparation treatment cancer drug.
The invention has the advantages that, the invention provides a kind ofly new have optionally, highly active STAT3 micromolecular inhibitor, design its active small molecular inhibitor according to the tertiary structure of STAT3, biosynthesizing transformation and optimization, then by the method such as fluorescence polarization and CCK-8 detection of active and study such inhibitor and grow at inhibition tumor cell, promote the mechanism of differentiation apoptosis aspect, thus the micromolecular inhibitor of illustrating STAT3 prophylaxis of tumours occur and treatment tumour aspect effect.
Brief description of the drawings
Fig. 1 is the fluorescence polarization value of micromolecular compound, analyzes the IC that obtains each micromolecular compound by robust fit 50value, the IC of 1-177 50for 8.972uM, the IC of 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 its water-soluble and permeable membrane with respect to 1-177 slightly a little less than, the IC of 1-177 and 1-078 50respectively 25.42uM, 222.5uM.
Fig. 3 is that Western Blot detects the retarding effect of 1-177 to pSTAT3 in MDA-MB-468 cell.
Embodiment
Below in conjunction with specific embodiment, further set forth the present invention.The experimental technique using in following embodiment if no special instructions, is ordinary method.Material, reagent etc. used in following embodiment, if no special instructions, all can obtain from commercial channels.Should be understood that these embodiment are only not used in and limit the scope of the invention for the present invention is described.The experimental technique of unreceipted actual conditions in the following example, conventionally according to normal condition, the people such as such as Sambrook, molecular cloning: laboratory manual (New York:Cold Spring Harbor Laboratory Press, 1989) condition described in, or the condition of advising according to manufacturer.
The preparation of embodiment 1. compound general formulas (2a)
General formula (2a) is the particular compound kind of general formula (1) and general formula (1a), because B part can be ring-type or chain-like structure, in general formula (2a), represents with R.
Figure BDA00002616478200061
Replace or the non-phenyl ring of getting, heterocycle, styracin or the aliphatic acid 9h that refluxes in dehydrated alcohol-vitriol oil (20:1) solution, be spin-dried for 2/3 solvent, in residual thing, add appropriate trash ice, then use NaHCO 3solution regulates PH to neutral, is extracted with ethyl acetate product, then with saturated nacl aqueous solution washing, anhydrous sodium sulfate drying, filters, and is spin-dried for solvent and obtains colourless liquid, is product 3.Above-mentioned gained ester is dissolved in to dehydrated alcohol, adds the hydrazine hydrate of equivalent, backflow 24h.Spin off partial solvent, then add appropriate trash ice, have solid to separate out, filter, washing, dry, then use 90% ethyl alcohol recrystallization, obtain product 4.Produce 2 methods, enumerating can be with methyl alcohol or ethanol, or can use reaction of sodium azide, or with methyl iodide and alkali reaction, for example, can enumerate the mineral alkalis such as sodium hydroxide, salt of wormwood, potassium tert.-butoxide.
Figure BDA00002616478200062
Product 3 and 2,4 dihydroxyl-methyl phenyl ketone are dissolved in dehydrated alcohol with the ratio of 1:1, then add monovalent acetic acid, reflux 4 hours, and reaction liquid cooling causes room temperature, filter, and washing with alcohol dry for filter cake, 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, can obtain object compound by the importing and the disengaging method (" protecting group in organic synthesis " press of East China University of Science) etc. that use protecting group conventional in organic chemistry.In addition, the conversion of the functional group of containing in each replacement can be carried out according to the known method outside above-mentioned manufacture method, in compound general formula (2a), sometimes can set it as synthetic intermediate and pour other derivatives into.
The intermediate of above-mentioned manufacture method and object compound can be with method of purification conventional in Synthetic Organic Chemistry, for example, neutralize, filter, extract, clean, be dried, concentrate, recrystallization, various chromatograms etc. carry out separation and purification.In addition, in intermediate, can not offer reaction below by special purifying.
In the time wishing to get the salt of compound general formula (2a), in the time that compound (2a) obtains with the form of salt, can directly refine, or, while obtaining with the form of dissociating later, as long as with dissolving in suitable organic solvent or being suspended, add sour and form salt by usual method.
On compound general formula (2a) and pharmacology thereof, the form of the affixture of acceptable salt or various solution exists in addition, and these affixtures also can be served as STAT3 inhibitor of the present invention and be used.
Preparation scheme one:
Figure BDA00002616478200071
Preparation scheme two:
Figure BDA00002616478200072
Preparation scheme three:
Figure BDA00002616478200081
Preparation scheme four:
The object lesson of the compound general formula (2a) that the above-mentioned manufacturing process of table 1. obtains
Figure BDA00002616478200091
Figure BDA00002616478200101
Figure BDA00002616478200121
Figure BDA00002616478200131
Figure BDA00002616478200141
Figure BDA00002616478200151
Figure BDA00002616478200161
Figure BDA00002616478200171
Figure BDA00002616478200191
Figure BDA00002616478200201
Figure BDA00002616478200211
Figure BDA00002616478200221
Figure BDA00002616478200241
Figure BDA00002616478200251
The preparation of embodiment 2. compound general formulas (3a)
Figure BDA00002616478200252
Equally, general formula (3a) is the particular compound kind of general formula (1) and general formula (1a), because B part can be ring-type or chain-like structure, in general formula (3a), represents with R.
Figure BDA00002616478200261
Replace or the non-phenyl ring of getting, heterocycle, styracin or the aliphatic acid 9h that refluxes in dehydrated alcohol-vitriol oil (20:1) solution, be spin-dried for 2/3 solvent, in residual thing, add appropriate trash ice, then use NaHCO 3solution regulates PH to neutral, is extracted with ethyl acetate product, then with saturated nacl aqueous solution washing, anhydrous sodium sulfate drying, filters, and is spin-dried for solvent and obtains colourless liquid, is product 3.Above-mentioned gained ester is dissolved in to dehydrated alcohol, adds the hydrazine hydrate of equivalent, backflow 24h.Spin off partial solvent, then add appropriate trash ice, have solid to separate out, filter, washing, dry, then use 90% ethyl alcohol recrystallization, obtain product 4.Produce 2 methods, enumerating can be with methyl alcohol or ethanol, or can use reaction of sodium azide, or with methyl iodide and alkali reaction, for example, can enumerate the mineral alkalis such as sodium hydroxide, salt of wormwood, potassium tert.-butoxide.
Figure BDA00002616478200262
M-Salicylic acid and acetic anhydride (1:1.1), the vitriol oil (1～2), 3h refluxes in solvent toluene.Reaction liquid cooling causes room temperature, has solid to separate out, and reaction solution is dissolved in to ethyl acetate, washing, anhydrous Na SO 4dry, be concentrated into dry.Utilize re-crystallizing in ethyl acetate to obtain white crystal.By the anhydrous AlCl of above-mentioned gained white solid and 4 times of amounts 3mix, be warming up to 160 DEG C, reaction 3h.Reaction solution is poured in frozen water, added a certain amount of chlorohydric acid pickling, be extracted with ethyl acetate, then be washed to neutrality, anhydrous Na SO 4dry, be concentrated into dryly, obtain garnet syrupy shape solid, then this solids crude is crossed to post obtain deep yellow solid, then with dehydrated alcohol or ethyl acetate repeatedly recrystallization purifying product obtain compound 8.
Compound 4 is dissolved in dehydrated alcohol with the ratio of 1:1 with 3-hydroxyl-4-ethanoyl-phenylformic acid, then adds monovalent acetic acid, backflow 4h, and reaction liquid cooling causes room temperature, filters, filter cake washing with alcohol, 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, can obtain object compound by the importing and the disengaging method (" protecting group in organic synthesis " press of East China University of Science) etc. that use protecting group conventional in organic chemistry.In addition, the conversion of the functional group of containing in each replacement can be carried out according to the known method outside above-mentioned manufacture method, in compound general formula (3a), sometimes can set it as synthetic intermediate and pour other derivatives into.
The intermediate of above-mentioned manufacture method and object compound can be with method of purification conventional in Synthetic Organic Chemistry, for example, neutralize, filter, extract, clean, be dried, concentrate, recrystallization, various chromatograms etc. carry out separation and purification.In addition, in intermediate, can not offer reaction below by special purifying.
In the time wishing to get the salt of compound general formula (3a), in the time that compound (3a) obtains with the form of salt, can directly refine, or, while obtaining with the form of dissociating later, as long as with dissolving in suitable organic solvent or being suspended, add sour and form salt by usual method.
On compound general formula (3a) and pharmacology thereof, the form of the affixture of acceptable salt or various solution exists in addition, and these affixtures also can be served as STAT3 inhibitor of the present invention and be used.
Preparation scheme five:
Figure BDA00002616478200281
Preparation scheme six:
Figure BDA00002616478200282
Preparation scheme seven:
Figure BDA00002616478200283
Preparation scheme eight:
Figure BDA00002616478200284
Preparation scheme nine:
Figure BDA00002616478200291
The object lesson of the compound general formula (3a) that the above-mentioned manufacturing process of table 2 obtains
Figure BDA00002616478200301
Figure BDA00002616478200321
Figure BDA00002616478200331
Figure BDA00002616478200341
Figure BDA00002616478200371
Figure BDA00002616478200381
Figure BDA00002616478200391
Figure BDA00002616478200401
Figure BDA00002616478200411
Figure BDA00002616478200421
Figure BDA00002616478200431
Figure BDA00002616478200441
Figure BDA00002616478200451
The competitive experiment of embodiment 3. detects STAT3 micromolecular inhibitor activity
This experiment detects the avidity of micromolecular compound to STAT3 by fluorescence polarization (FP) method, by micromolecular compound competition fluorescence peptide section FITC-pYLPQTV-NH2 and STAT3 protein binding, Ac-pYLPQTV-NH2 contrasts as strong positive, the weak positive control of Ac-YLPQTV-NH2, Ac-pYLKTKF negative control.Can make the polarized light that fluorophor produces increase when STAT3 albumen and fluorescence peptide section mutually combine, and add these peptide sections in contrast can compete fluorescence peptide section and STAT3 protein binding, make polarization value reduction.Testing STAT3 concentration used is 5uM, and 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 to gradient dilution in 96 orifice plates of corning nbs3995#, then the mixture of STAT3 albumen and FITC-pYLPQTV-NH2 is added in each hole, lucifuge, on shaker, mix 3 hours until reaction reaches balance, use Biotek reader to measure, excitation wavelength is 485nm, and wavelength of transmitted light is 525nm, reads fluorescence polarization value.
Use Graph pad primz5 software processes fluorescence polarization value, analyze the IC that obtains each micromolecular compound by robust fit 50value, the IC of 1-177 50for 8.972uM, the IC of 1-078 50for 16.05uM, as shown in Figure 1.
The growth Survival Effects of embodiment 4. these series compounds to cancer cell
Test by FP, this series compound in vitro molecular level has higher affinity to STAT3, next verifies whether this series compound has growth inhibitory effect to the breast cancer cell of overexpression STAT3.Use Cell counting kit-8 (CCK-8) to detect the growth effect of K series compound to DU145, in 96 orifice plates, plant cell, 10000Cells/well, after 24h, add K series compound by presetting concentration, then 24h adds 10uL cck-8/well, 37 DEG C, 4h, use BioTek reader 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 with respect to 1-177 slightly a little less than, the IC of 1-177 and 1-078 50respectively 25.42uM, 222.5uM.Therefore function below and Mechanism Study are mainly for 1-177.
Embodiment 5.Western Blot detects the retarding effect of 1-177 to pSTAT3 in MDA-MB-468 cell
MDA-MB-468 cell is processed after 2 hours at 1-177 different concns, with IL-6 (10ng/ul) stimulation, after 24 hours, receives cell, then use the method for western blot and the p-STAT3 of CST company, STAT3, p-AKT, AKT, P-Src, Src antibody detects.As shown in Figure 3, use respectively DMSO and 0uM, 10uM, the 1-177 of 30uM processes cell, and after 10uM processes, p-STAT3 and p-AKT obviously reduce, and after 30uM processes, p-STAT3 and p-AKT band are very weak, are 0 substantially.Therefore illustrate that K116 has obvious inhibition to STAT3 phosphorylation, the kinases P-Src of STAT3 upstream is not affected 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 (10)

1. a STAT3 micromolecular inhibitor, is characterized in that, described inhibitor contains the N'-(1-(2 shown in formula (1), 4 dihydroxy phenyls) ethylidene) acceptable salt on benzoyl hydrazine derivative or its pharmacology;
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 non-substituted heteroaromatic alkyl, 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;
In the middle of A ring and B ring, form substituted or non-substituted derivative with hydrazides.
2. a kind of STAT3 micromolecular inhibitor according to claim 1, it is characterized in that, 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.
3. a kind of STAT3 micromolecular inhibitor according to claim 1, it is characterized in that, 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.
4. a kind of STAT3 micromolecular inhibitor according to claim 1, it is characterized in that, 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.
5. a kind of STAT3 micromolecular inhibitor according to claim 1, it is characterized in that, 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.
6. a kind of STAT3 micromolecular inhibitor according to claim 1, it is characterized in that, 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.
7. a kind of STAT3 micromolecular inhibitor according to claim 1, it is characterized in that, in formula (1), B ring portion is divided into be encircled and encircles, described ring cyclic group comprise naphthyl, quinolyl, isoquinolyl, indyl, purine radicals, pteridine radicals, quinazolyl, benzothienyl, benzofuryl, benzoxazolyl, benzopyrazines base, benzo pyrimidyl, Pyridopyrimidine base, Kui Linpyrimido quinoline pyrimidyl, 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.
8. a STAT3 micromolecular inhibitor, is characterized in that, described inhibitor contains the N'-(1-(2 shown in formula (1a), 4 dihydroxy phenyls) ethylidene) acceptable salt on benzoyl hydrazine derivative or its pharmacology;
Figure FDA00002616478100031
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), B part R 8be expressed as aliphatics chain structure, described aliphatics chain 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,
In the middle of A ring and B part, form substituted or non-substituted derivative with hydrazides.
9. according to a kind of STAT3 micromolecular inhibitor described in claim 1 or 8, it is characterized in that R on described A ring 1and R 2identical or different, represent hydroxyl or carboxyl.
10. the application of the arbitrary described STAT3 micromolecular inhibitor of claim 1-8 in preparation treatment cancer drug.
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Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105523961A (en) * 2016-03-04 2016-04-27 南京大学 Design, synthesis and biological activity evaluation of multi-methoxy anti-tumor compound with cinnamon acylhydrazone skeletons
CN106749135A (en) * 2016-12-14 2017-05-31 浙江大学 Substituted benzofuran formyl hydrazone analog derivative and preparation method thereof
CN106957242A (en) * 2017-04-24 2017-07-18 四川省人民医院 A kind of schiff base compounds and preparation method thereof and pharmaceutical applications
CN107118166A (en) * 2017-04-21 2017-09-01 潍坊医学院 A kind of ligustrazine acylhydrazone, preparation method and applications
CN110128343A (en) * 2019-06-18 2019-08-16 四川省人民医院 A kind of hydrazide kind compound
CN110218198A (en) * 2019-05-22 2019-09-10 广州中医药大学(广州中医药研究院) A kind of naphthoquinones and triazole core skeleton derivative compound and its preparation method and application
EP3487490A4 (en) * 2016-07-19 2020-01-15 The General Hospital Corporation Compounds for targeting cancer stem cells
CN111072610A (en) * 2019-12-16 2020-04-28 杭州师范大学 Preparation and application of substituted benzofuran 2-formyl hydrazone LSD1 inhibitor
CN113845476A (en) * 2021-11-08 2021-12-28 中国药科大学 Quinolone derivative and preparation method and application thereof
WO2022134043A1 (en) * 2020-12-25 2022-06-30 高雄医学大学 Glycine n-methyltransferase enhancer, preparation method therefor and use thereof
WO2023010191A1 (en) * 2021-08-02 2023-02-09 Eurofarma Laboratórios S.A. N-acylhydrazone compounds capable of inhibiting nav1.7 and/or nav1.8, processes for the preparation thereof, compositions, uses, methods for treatment using same, and kits
US11820747B2 (en) 2021-11-02 2023-11-21 Flare Therapeutics Inc. PPARG inverse agonists and uses thereof
WO2023249288A1 (en) * 2022-06-22 2023-12-28 한국생명공학연구원 Novel cinnamamide derivative and use thereof

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1863764A (en) * 2003-10-09 2006-11-15 默克专利股份公司 Acylhydrazone derivatives and their use in the inhibition, regulation and/or modulation of the signal transduction of kinases
WO2006136008A1 (en) * 2005-05-24 2006-12-28 University Health Network Salicylic acid hydrazones as inhibitors of the erk mapkinase pathway and for the treatment of cancer
CN101522657A (en) * 2006-10-02 2009-09-02 大塚制药株式会社 STAT3/5 activation inhibitor
US20100099683A1 (en) * 2007-04-10 2010-04-22 Tomkinson Alan E Compounds that inhibit human dna ligases and methods of treating cancer
WO2011020883A1 (en) * 2009-08-20 2011-02-24 Max-Delbrück-Centrum für Molekulare Medizin Enhancers of protein degradation
US20110189306A1 (en) * 2010-01-13 2011-08-04 Norbert Kartner COMPOUNDS, COMPOSITIONS AND TREATMENTS FOR V-ATPase RELATED DISEASES
CN102219755A (en) * 2011-05-05 2011-10-19 南京大学 Micromolecule selective depressant for STAT3 (Signal transducer and activator of transcription 3), as well as preparation method and applications thereof

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1863764A (en) * 2003-10-09 2006-11-15 默克专利股份公司 Acylhydrazone derivatives and their use in the inhibition, regulation and/or modulation of the signal transduction of kinases
WO2006136008A1 (en) * 2005-05-24 2006-12-28 University Health Network Salicylic acid hydrazones as inhibitors of the erk mapkinase pathway and for the treatment of cancer
CN101522657A (en) * 2006-10-02 2009-09-02 大塚制药株式会社 STAT3/5 activation inhibitor
US20100099683A1 (en) * 2007-04-10 2010-04-22 Tomkinson Alan E Compounds that inhibit human dna ligases and methods of treating cancer
WO2011020883A1 (en) * 2009-08-20 2011-02-24 Max-Delbrück-Centrum für Molekulare Medizin Enhancers of protein degradation
US20110189306A1 (en) * 2010-01-13 2011-08-04 Norbert Kartner COMPOUNDS, COMPOSITIONS AND TREATMENTS FOR V-ATPase RELATED DISEASES
CN102219755A (en) * 2011-05-05 2011-10-19 南京大学 Micromolecule selective depressant for STAT3 (Signal transducer and activator of transcription 3), as well as preparation method and applications thereof

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACT SERVICE: "RN：683800-66-0等", 《CA网络版STN REGISTRY数据库》, 23 February 2009 (2009-02-23) *
KHALID MOHAMMED KHAN等: "Acylhydrazide Schiff Bases: DPPH Radical and Superoxide Anion Scavengers", 《MEDICINAL CHEMISTRY》, vol. 8, no. 4, 31 July 2012 (2012-07-31), pages 705 - 710 *
PETER AXERIO-CILIES等: "Cheminformatics-Driven Discovery of Selective, Nanomolar Inhibitors for Staphylococcal Pyruvate Kinase", 《ACS CHEM. BIOL.》, vol. 7, no. 2, 8 November 2011 (2011-11-08), pages 350 - 359 *
梁芳珍等: "含有氮杂环的酰腙配合物Cu(C15H11BrN2O4)(C5H5N)的合成和晶体结构", 《无机化学学报》, vol. 24, no. 7, 31 July 2008 (2008-07-31), pages 1155 - 1158 *

Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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