CN103724251B - STAT3 (Signal Transducer and Activator of Transcription 3)-targeting small molecular compound as well as preparation method and application thereof - Google Patents

STAT3 (Signal Transducer and Activator of Transcription 3)-targeting small molecular compound as well as preparation method and application thereof Download PDF

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CN103724251B
CN103724251B CN201410021907.6A CN201410021907A CN103724251B CN 103724251 B CN103724251 B CN 103724251B CN 201410021907 A CN201410021907 A CN 201410021907A CN 103724251 B CN103724251 B CN 103724251B
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stat3
compound
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cancer
hydrogen
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CN103724251A (en
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陈海军
周小斌
王爱兰
俞雪梅
胡子旋
郑小梅
欧敏锐
高瑜
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Fuzhou University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

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Abstract

The invention discloses an STAT3 (Signal Transducer and Activator of Transcription 3)-targeting small molecular compound as well as a preparation method and application thereof. The STAT3 inhibitor is a compound shown as a general formula I in the specification, wherein R<1> is 5-chloro-2-hydroxyphenyl, (E)-3-(6-bromo-2-pyridine)-2-cyan or 4-(2-phenylquinoline); R<2> is hydrogen or C1-C6 linear alkyl or branched alkyl. The compound has the advantages that the proliferation and the survival of various tumor cells of breast cancer, lung cancer, liver cancer, cervical cancer, prostate cancer and the like can be remarkably inhibited; the STAT3 signal channel of the tumor cells is inhibited; therefore, the tumor cell apoptosis is induced and the effect of treating the tumor diseases is achieved.

Description

Micromolecular compound of a kind of target STAT3 and its preparation method and application
Technical field
The invention belongs to medicinal chemistry art, relate to STAT3 inhibitor, be specifically related to micromolecular compound of a kind of target STAT3 and its preparation method and application.
Background technology
Signal transduction and activating transcription factor (Signal Transducers and Activators of Transcription, STATs) plasmosin of family to be molecule amount be 79-113kDa, wide expression is in the biological cells and tissues that body is dissimilar, participate in the regulation and control of the different physiological roles such as Growth of Cells, differentiation, apoptosis, and close with inflammation, tumour and immune response pathologic, physiologic functional relationship.This kind of STATs family protein had not only had an intracellular signaling function but also have transcription activating function as difunctional plasmosin, can combine from different cytokine receptors, extracellular signal is passed in nucleus, and is combined with specific DNA promoter sequence in core thus causes transcribing of corresponding target genes.Up to the present, the STATs member found has STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B and STAT6.
As one of STATs family important member, STAT3 plays an important role in promotion tumor cell proliferation, inhibition tumor cell apoptosis, promotion Invasion and Metastasis and immunologic escape, thus enjoys researchist to pay close attention to.Increasing result of study display, the activation of STAT3 albumen is strictly controlled under normal physiological conditions, but all can find this albumen excessive activation and high level expression in the cell of nearly all solid tumor and blood bome tumor (as mammary cancer, ovarian cancer, prostate cancer, malignant melanoma, multiple myeloma, lymphoma, squamous cell carcinoma of the head and neck, brain tumor, nonsmall-cell lung cancer and various leukemia etc.).Therefore, STAT3 signalling channel becomes as one of developing anti-tumor medicaments new action target spot the focus studied in recent years.
STAT3 is found by now from 1994, existing in a large number about the inhibitor of STAT3 and the research report of anti-tumor activity, comprising polypeptide or class peptide compounds and small molecules non-peptide compound, only have at present only a few small molecules non-peptide compound enter I phase/II clinical trial phase, also do not ratify so far go on the market medicine.Wherein hindering effective STAT3 micromolecular inhibitor to enter a clinical principal element is that druggability is poor, and physicochemical property difference (as poorly water-soluble), the biochemical property (such as anti-tumor activity is not high) of such as polypeptide or class peptide compounds are undesirable; Bad, the easy generation untoward reaction of the pharmacokinetic property of small molecules non-peptide compound or toxic side effect large; Enter I phase/the cLogP value as higher in OPB-31121 has of a few micromolecular non-peptide compounds of II clinical trial phase and molecular weight, affect its further clinical development.Therefore, actively find there is high anti-cancer activity, low toxicity and the good New type of S TAT3 inhibitor of druggability has very important meaning for cancer therapy.The outstanding advantages that the present invention has comprises: STAT3 inhibitor of the present invention is small molecule selective depressant, by measuring its result to its activity of evaluation of effect of cancer cells, can show that small molecules STAT3 selective depressant of the present invention can be used for the exploitation of the cancer treatment drugs of being correlated with, there is very wide purposes.Small molecules STAT3 selective depressant of the present invention, preparation method is simple, and kind is many, and product purity is high, and yield is high, practical.
Summary of the invention
The object of the present invention is to provide micromolecular compound of a kind of target STAT3 and its preparation method and application, this compound significantly can suppress propagation and the survival of the kinds of tumor cells such as mammary cancer, lung cancer, liver cancer, cervical cancer and prostate cancer, inhibition tumor cell STAT3 signal path, thus inducing apoptosis of tumour cell, reach the effect for the treatment of tumor disease.
For achieving the above object, the present invention adopts following technical scheme:
A kind of STAT3 inhibitor is the compound had shown in general formula I , wherein R 1for 5-chlorine-2-hydroxyl phenyl, (E)-3-(6-bromo-2-pyridyl)-2-cyano group or 4-(2-phenylquinoline); R 2for the straight or branched alkyl of hydrogen, C1-C6.
A kind of method preparing STAT3 inhibitor as above comprises the following steps:
(1) 6-nitroindoline and iodo-alkyl are obtained by reacting , R 1for the straight or branched alkyl of hydrogen, C1-C6, then obtain through reduction reaction , R 1for the straight or branched alkyl of hydrogen, C1-C6;
(2) will , R 1for the straight or branched alkyl of hydrogen, C1-C6, and acid-respons obtains , or , R 1for the straight or branched alkyl of hydrogen, C1-C6;
(3) will , R 1for the straight or branched alkyl of hydrogen, C1-C6, obtain under the catalysis of ammonium acetate with 6-bromopyridine 2-formaldehyde , R 1for the straight or branched alkyl of hydrogen, C1-C6.
Described STAT3 inhibitor is for the preparation of the medicine for the treatment of mammary cancer, lung cancer, liver cancer, cervical cancer and prostate cancer.
Remarkable advantage of the present invention is: the micromolecular compound of target STAT3 of the present invention significantly can suppress propagation and the survival of the kinds of tumor cells such as mammary cancer, lung cancer, liver cancer, cervical cancer and prostate cancer, inhibition tumor cell STAT3 signal path, thus inducing apoptosis of tumour cell, reach the effect for the treatment of tumor disease.
Embodiment
Compound shown in formula I is as STAT3 inhibitor, and its structural formula is as follows:
Wherein R 1for 5-chlorine-2-hydroxyl phenyl, (E)-3-(6-bromo-2-pyridyl)-2-cyano group, 4-(2-phenylquinoline); R 2for the straight or branched alkyl of hydrogen, C1-C6.
Concrete compound structure is as follows:
Wherein R 2for the straight or branched alkyl of hydrogen, C1-C6.
The concrete reaction formula of preparation method is as follows:
Wherein: NaH is sodium hydride, DMF is dimethyl formamide, NH 4cl is ammonium chloride, and MeOH is methyl alcohol, and 5-chlorosalicylic acid is 5-chloro-salicylic acid, and HBTU is benzotriazole-N, N, N', N'-tetramethyl-urea phosphofluoric acid ester; NH 4oAc is ammonium acetate, and EtOH is ethanol.
6-nitroindoline and different iodo-alkyls are obtained by reacting intermediate 2, and intermediate 2 obtains 6-amino intermediate 3 by reduction.Intermediate 3 and different acid-responss obtain formula II, intermediate 4 and IV.The compound of formula III can be obtained under the effect of ammonium acetate by intermediate 4 and 6-bromopyridine 2-formaldehyde.
The structure of compound shown in formula I, II, III and IV and the research of compound on tumor cell inhibitory activity.Further investigation through applicant finds, compound shown in formula I, II, III and IV is mainly through suppressing STAT3 signal path, and then the growth of inhibition tumor cell.In addition, total protein of cell is extracted through sds gel electrophoresis analysis after the MDA-MB-231 of compound treatment breast carcinoma cell strain shown in formula I, II, III and IV, after primary antibodie two process resistant, result shows it can suppress STAT3 tyrosine 705 phosphorylation, suppress the expression of downstream albumen Bcl-xl and c-Myc, and activate Caspase-3, thus suppress STAT3 signal path.
The inhibitor be made up of compound shown in the formula I of significant quantity, II, III and IV and pharmaceutically acceptable auxiliary material.Describedly accept the auxiliary material that auxiliary material can adopt this area routine, conveniently prepared by preparation method, of the present inventionly accepts auxiliary material preferably from sorbyl alcohol, N.F,USP MANNITOL, Xylitol, cyclodextrin, sucrose.Wherein, described STAT3 inhibitor is preferably oral preparations, and described oral preparations is preferably tablet.
Compound shown in formula I, II, III and IV significantly can suppress propagation and the survival of the kinds of tumor cells such as mammary cancer, lung cancer, prostate cancer and cervical cancer, inhibition tumor cell STAT3 signal path, thus inducing apoptosis of tumour cell, reach the effect for the treatment of tumor disease.
Described STAT3 inhibitor can be applicable to treat tumor disease, and described tumor disease is preferably mammary cancer, lung cancer, liver cancer, cervical cancer and prostate cancer.
Below in conjunction with following examples, the present invention is further elaborated, but these embodiments do not limit the scope of the invention.
Preparation embodiment:
Embodiment 1:5-chlorine-2-hydroxyl- n-(1-methyl-6-indoles) benzamide (preparation of Compound II per a)
Step 1:1-methyl-6-nitroindoline (intermediate 2): the 60%NaH adding 800mg in the DMF solution of 20mL, adds the 6-nitroindoline of 4g in batches at 0 DEG C.Mixed solution stirs after 10 minutes and is added dropwise to 1.86mL methyl iodide at 0 DEG C.After mixed solution at room temperature stirs 24 hours, slowly join in 100mL frozen water and then add 100mL ethyl acetate.After extracting the organic phase saturated sodium-chloride washing obtained, after being spin-dried for after organic phase anhydrous sodium sulfate drying, obtain 4.50g intermediate 2. 1H NMR (400 MHz, CDCl 3) δ8.27 (d, 1H), 7.97 (d, 1H), 7.61 (d, 1H), 7.33 (d, 1H), 6.56 (d, 1H), 3.87 (s, 3H)。
Step 2: be dissolved in 20mL methyl alcohol by 1g intermediate 2, adds 100mg zinc powder.20mL saturated aqueous ammonium chloride is added, stirred overnight at room temperature at 0 DEG C.Vacuum rotating removing methanol solution, the sodium hydrogen carbonate solution adjust pH of aqueous phase 20mL10% is to neutral, then use 50mL extraction into ethyl acetate, after extracting the organic phase saturated sodium-chloride washing obtained, after being spin-dried for after organic phase anhydrous sodium sulfate drying, obtain 950mg intermediate 3.Purifying is not needed to be directly used in next step reaction.
Step 3:146mg intermediate 3 is dissolved in the DMF of 10mL, add the 5-chloro-salicylic acid of 200mg, add the HBTU(benzotriazole-N of 500mg, N, N', N'-tetramethyl-urea phosphofluoric acid ester) and the DIPEA(diisopropylethylamine of 0.5mL), stirring at room temperature is after 24 hours, add 10mL water and 30mL ethyl acetate, extract the organic phase obtained to extract with 10mL water again, after extracting the organic phase saturated sodium-chloride washing obtained, after being spin-dried for after organic phase anhydrous sodium sulfate drying, crude product is crossed silicagel column and is obtained 100mg final product IIa. 1H NMR (400 MHz, DMSO- d 6) δ12.01 (s, 1H), 10.28 (s, 1H), 7.89 (s, 1H), 7.81 (d, 1H), 7.78 (d, 1H), 7.48-7.59 (m, 4H), 6.58 (d, 1H), 3.82 (s, 3H)。
Embodiment 2:(E)-3-(6-bromopyridine-2)-2-cyano group- n-(1-methyl-6-indoles) acrylamide (preparation of compound III a)
Step 1 is identical with synthetic compound IIa with step 2, and 5 chloro-salicylic acids of step 3 change 2-cyanoacetic acid into.Being specially 146mg intermediate 3 is dissolved in 10mLDMF, add 100mg2-cyanoacetic acid, add 500mgHBTU and 0.5mLDIPEA, stirring at room temperature is after 24 hours, add 10mL water and 30mL ethyl acetate, extract the organic phase obtained and extract with 10mL water again, after extracting the organic phase saturated sodium-chloride washing obtained, after being spin-dried for after organic phase anhydrous sodium sulfate drying, crude product is crossed silicagel column and is obtained 120mg intermediate 4. 1H NMR (400 MHz, DMSO- d 6) δ10.83 (s, 1H), 8.26 (d, 1H), 7.95 (d, 1H), 7.60 (d, 1H), 7.32 (d, 1H), 6.55(d,1H), 3.97 (s, 2H), 3.82 (s, 3H)。
Step 4: be dissolved in 5mL ethanolic soln by 213mg intermediate 4, adds 39mg ammonium acetate, and add 6-bromopyridine 2-formaldehyde, room temperature reaction spends the night, and obtains solid.Solid filtering removing ethanol, with water and washing with alcohol solid, drying obtains 350mg final product IIIa. 1H NMR (400 MHz, DMSO- d 6) δ 10.97 (s, 1H), 8.29 (s, 1H), 8.15 (s, 1H), 7.96 (d, 1H), 7.91-7.93 (m, 2H), 7.85 (d, 1H), 7.34 (d, 1H), 6.55(d, 1H), 3.89 (s, 3H)。
Embodiment 3: n-(1-methyl-6-indoles)-2-phenylquinoline-4-methane amide (preparation of compound IV a)
Step 1 is identical with synthetic compound IIa with step 2, and in the preparation of Compound II per a, 5 chloro-salicylic acids of step 3 change 2-phenylquinoline-4-acetic acid into.Being specially 146mg intermediate 3 is dissolved in 10mLDMF, add 300mg2-phenylquinoline-4-acetic acid, add 500mgHBTU and 0.5mLDIPEA, stirring at room temperature is after 24 hours, add 210mL water and 50mL ethyl acetate, extract the organic phase obtained and extract with 20mL water again, after extracting the organic phase saturated sodium-chloride washing obtained, after being spin-dried for after organic phase anhydrous sodium sulfate drying, crude product is crossed silicagel column and is obtained 220mg final product IVa. 1H NMR (400 MHz, DMSO- d 6) δ11.31 (s, 1H), 8.45 (s, 1H), 8.39 (d, 2H), 8.35 (s, 1H), 8.21 (d, 2H), 7.92 (d, 1H), 7.89 (t, 1H), 7.55-7.75 (m, 6H), 6.54 (d, 1H), 3.89 (s, 3H)。
Embodiment 4:5-chlorine-2-hydroxyl- n-(1-sec.-propyl-6-indoles) benzamide (preparation of Compound II per b)
The preparation of Compound II per b and the preparation of Compound II per a similar, 2-iodopropane is replaced methyl iodide. 1H NMR (400 MHz, DMSO- d 6) δ12.00 (s, 1H), 10.27 (s, 1H), 7.88 (s, 1H), 7.85 (d, 1H), 7.75 (d, 1H), 7.46-7.55 (m, 4H), 6.59 (d, 1H), 4.05-4.09 (m, 3H), 1.60 (d, 6H)。
Embodiment 5:(E)-3-(6-bromopyridine-2)-2-cyano group- nthe preparation of-(1-sec.-propyl-6-indoles) acrylamide (preparation of compound III b) compound III b and the preparation of compound III b similar, 2-iodopropane is replaced methyl iodide. 1H NMR (400 MHz, DMSO- d 6) δ10.91 (s, 1H), 8.49 (s, 1H), 8.25 (s, 1H), 7.90 (d, 1H), 7.90-7.93 (m, 2H), 7.86 (d, 1H), 7.39 (d, 1H), 6.54 (d,1H), 4.04-4.09 (m, 3H), 1.61 (d, 6H)。
Embodiment 6: nthe preparation of-(1-sec.-propyl-6-indoles)-2-phenylquinoline-4-methane amide (preparation of compound IV b) compound IV b and the preparation of compound IV a similar, 2-iodopropane is replaced methyl iodide. 1H NMR (400 MHz, DMSO- d 6) δ11.38 (s, 1H), 8.46 (s, 1H), 8.39 (d, 2H), 8.35 (s, 1H), 8.21 (d, 2H), 7.91 (d, 1H), 7.88 (t, 1H), 7.56-7.78 (m, 6H), 6.55 (d, 1H), 4.08-4.09 (m, 3H), 1.65 (d, 6H)。
Application Example:
Embodiment 1: the restraining effect of compound on tumor cell proliferation and survival
Material: breast cancer cell MDA-MB-231, lung cancer cell line Α 549, hepatoma H22 cells, cervical cancer cell lines HeLa and prostate cancer PC3 cell strain.
Test medicine: 0, the compound of 7 concentration of 0.1 μ Μ, 0.5 μ Μ, 1.0 μ Μ, 5 μ Μ, 10 μ Μ, 50 μ Μ.
The restraining effect that Compound II per a breeds breast cancer cell MDA-MB-231 and survives: after MDA-MB-231 cell cultures, add compound incubation 72h respectively, then the decline of microscopic examination and MTS method analytical results display MDA-MB-231 cell proliferation capacity, cell density significance reduces, and cell presents apoptosis performance.Find in MTS analytical results that the viability of Compound II per a to MDA-MB-231 cell is consistent with microscopy results, the survival rate of cell is on a declining curve along with IIa concentration increase (0,0.1 μ Μ, 0.5 μ Μ, 1.0 μ Μ, 5 μ Μ, 10 μ Μ, 50 μ Μ), is down to nearly 70% at 1.0 μMs.
Embodiment 2: the impact of compound on signal path
Material: breast cancer cell MDA-MB-231;
Test medicine: 0, the compound of 7 concentration of 0.1 μ Μ, 0.5 μ Μ, 1.0 μ Μ, 5 μ Μ, 10 μ Μ, 50 μ Μ.
Impact on STAT3 signal path: IIa processes MDA-MB-231 cell after 48 hours respectively, extract total protein of cell, be separated through sds gel electrophoresis, the total STAT3 of Western blot, the STAT3 (p-STAT3) of phosphorylation and the expression level of downstream albumen Bcl-xl and c-Myc, result display can find IIa dose-dependent inhibition STAT3 tyrosine 705 phosphorylation, suppress the expression of downstream albumen Bcl-xl and c-Myc, and activate Caspase-3, thus suppress STAT3 signal path.
Embodiment 3: the preparation of lyophilized injectable powder
Get IIa(100 mg) be dissolved in ethanol (1 mL), add beta-cyclodextrin (1g is dissolved in 10 mL water), stir after 1 hour, after vacuum rotating removing ethanol, freeze-drying obtains powder injection.
Embodiment 4: the preparation of tablet
Get IIa, sucrose and the cyclodextrin ratio by weight 1:2:2, make tablet according to a conventional method.
The foregoing is only preferred embodiment of the present invention, all equalizations done according to the present patent application the scope of the claims change and modify, and all should belong to covering scope of the present invention.

Claims (1)

1. a preparation method for STAT3 inhibitor, is characterized in that: comprise the following steps:
(1) 6-nitroindoline and iodo-alkyl are obtained by reacting , R 1for the straight or branched alkyl of hydrogen, C1-C6, then obtain through reduction reaction , R 1for the straight or branched alkyl of hydrogen, C1-C6;
(2) will , R 1for the straight or branched alkyl of hydrogen, C1-C6, and acid-respons obtains , or , R 1for the straight or branched alkyl of hydrogen, C1-C6;
(3) will , R 1for the straight or branched alkyl of hydrogen, C1-C6, obtain under the catalysis of ammonium acetate with 6-bromopyridine 2-formaldehyde , R 1for the straight or branched alkyl of hydrogen, C1-C6.
CN201410021907.6A 2014-01-18 2014-01-18 STAT3 (Signal Transducer and Activator of Transcription 3)-targeting small molecular compound as well as preparation method and application thereof Expired - Fee Related CN103724251B (en)

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