CN104974222A - Coupled peptide compound as protein tyrosine kinase inhibitor - Google Patents
Coupled peptide compound as protein tyrosine kinase inhibitor Download PDFInfo
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- CN104974222A CN104974222A CN201510322699.8A CN201510322699A CN104974222A CN 104974222 A CN104974222 A CN 104974222A CN 201510322699 A CN201510322699 A CN 201510322699A CN 104974222 A CN104974222 A CN 104974222A
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Abstract
The invention relates to a coupled peptide compound as a protein tyrosine kinase inhibitor. The coupled peptide compound is shown in the formula (I). The coupled peptide compound can be used for treating one or more protein tyrosine kinase-mediated diseases.
Description
Technical field
The invention belongs to chemical field, specifically, the present invention relates to anticancer compound.
Background technology
Protein kinase (PKs) is the enzyme of specific Serine, Threonine or tyrosine residues phosphorylation in activated cell protein.The posttranslational modification of these substrate protein white matters is as the molecular switch of regulating cell propagation, activation and/or differentiation.Comprise in optimum and malignant proliferative disorders in numerous disease state and observed abnormal or excessive PK activity.Under many circumstances, utilize PK inhibitor external treatment disease such as proliferative disease to be feasible, and under many circumstances, utilize PK inhibitor interior therapeutic disease such as proliferative disease to be feasible.Described kinases is mainly divided into two groups: the kinases of pecific phosphorylation Serine and Threonine and the kinases of pecific phosphorylation tyrosine.In addition, some be called " dual specific " kinase whose kinases can phosphorylated tyrosine and serine/threonine residue.
WO2006/000420 (particularly 1-8 page) discloses the details of the relation about PKs, their binding mode and they and the illness that will treat or sufferer.The document also discloses that the Heteroarylaryl ureas being used for the treatment of protein kinase dependent diseases.In addition, W003/023004 and W002/102972 discloses the illness produced by FGFR3 sudden change.In addition, W005/118580 is from the quinoline disclosed generically as hiv inhibitor.In the reference drawn in these documents relating to protein kinase and literary composition, reasonably can expect that the adjustment (suppression of especially described kinase activity) of abnormal activity is useful for the disease mentioned in document.
Although think that above with reference to molecule disclosed in document be activated, they still have some shortcomings.Therefore, it is active and solve the clinical manifestation relevant to said mutation thus and for (the such as highly affine and/or optionally) molecule regulating the improvement of various biological function, still there is the demand be not satisfied for the active particularly FGFR of abnormal composition receptor protein tyrosine kinase can be blocked.Consider a large amount of kinases inhibitors and numerous proliferative disease disease relevant with other PK, the demand providing as PK inhibitor and be used for the treatment of the novel cpd of described protein tyrosine kinase (PTK) relative disease is thus provided always.
Summary of the invention
The object of the invention is to for the deficiencies in the prior art, the compound that the peptide chain that a kind of toxicity is little, anticancer effect is good replaces is provided.
The present invention is according to some and the interactional micromolecular compound of protein tyrosine kinase, and it introduces peptide (amino acid) chain on precursor skeleton, obtains the interactional peptidyl substitution compound with protein tyrosine kinase.
Above-mentioned technical purpose of the present invention is achieved through the following technical solutions above-mentioned purpose:
(formula I)
Peptidyl replace a compound, structural formula such as formula shown in I,
Described R1 is tripeptides, tetrapeptide.
The aminoacid sequence of described R1 is GTH, GAK, GKR, GKD, GRQ, GAS, GLA, GEKL, GMAW, GSEH, GRKG.Wherein each capitalization represents amino acid well known in the art.
The preparation method of above-mentioned peptidyl substitution compound is further provided, comprises the following steps:
(1) by [5-[[(2,4,6-trimethylphenyl) amino] carbonyl]-4-methyl-2-thiazolyl] carboxylamine, 1, trifluoroacetic acid (100mL) solution of 1-dimethyl ethyl ester (10g, 26.63mmol) at room temperature stirs 3 hours.Concentrated by this solution decompression, residue with ethyl acetate (700 mL) dilutes, and uses 5% KHCO
3the aqueous solution (400mL, 2x), water and salt are washed; Dry (MgSO
4), filter and concentrate.Residue with diethyl ether (200mL) and acetonitrile (100mL) are washed, and obtain compound S 1, are white solid;
（S1）
(2) S1 and Mono Chloro Acetic Acid are carried out hydrocarbyl reaction in alkaline environment, then carry out chlorination with sulfur oxychloride again, obtain compound S 2 or adopt other the mode commonly used of this area to realize the replacement of Cl;
（S2）
(3) S2 and glycine are carried out substitution reaction, obtain compound S 3;
（S3）；
(4) compound of S3 is connected to respectively Rink Amide AM resin from the different amino acid by Fmoc radical protection and then the compound (shown in I) that condensation reaction obtains object occurs.Described condensation reaction, after carrying out condensation reaction by polypeptide solid-state reaction method, sloughs resin with trifluoroacetic acid, the peptidyl substitution compound described in final acquisition.
Above-mentioned peptidyl substitution compound is further provided to prepare the application in cancer therapy drug.
The formulation of described cancer therapy drug is tablet, pill, capsule, injection, suspension agent or emulsion.
Compared with prior art, the present invention has following beneficial effect:
1. novel peptidyl substitution compound protein tyrosine kinase of the present invention suppresses, and shows the good inhibit activities to cancer cells, thus has significant restraining effect to multiple JEG-3;
2. novel peptidyl substitution compound of the present invention is little to normal cytotoxicity, and in the application preparing cancer therapy drug, security is high;
3. novel peptidyl substitution compound of the present invention can be made into the cancer therapy drug of various formulation, has very high medical value and wide market outlook.
Embodiment
The preparation of embodiment 1 peptidyl substitution compound
(1) by [5-[[(2,4,6-trimethylphenyl) amino] carbonyl]-4-methyl-2-thiazolyl] carboxylamine, 1, trifluoroacetic acid (100mL) solution of 1-dimethyl ethyl ester (10g, 26.63mmol) at room temperature stirs 3 hours.Concentrated by this solution decompression, residue with ethyl acetate (700 mL) dilutes, and uses 5% KHCO
3the aqueous solution (400mL, 2x), water and salt are washed; Dry (MgSO
4), filter and concentrate.Residue with diethyl ether (200mL) and acetonitrile (100mL) are washed, and obtain compound S 1, are white solid;
(2) S1 and Mono Chloro Acetic Acid are carried out hydrocarbyl reaction in alkaline environment, then carry out chlorination with sulfur oxychloride again, obtain compound S 2 or adopt other the mode commonly used of this area to realize the replacement of Cl;
(3) S2 and glycine are carried out substitution reaction, obtain compound S 3;
(4) compound of S3 is connected to Rink Amide AM resin from the different amino acid (GTH, GAK, GKR, GKD, GRQ, GAS, GLA, GEKL, GMAW, GSEH, GRKG) by Fmoc radical protection and then the compound that condensation reaction obtains object occurs respectively.Described condensation reaction, after carrying out condensation reaction by polypeptide solid-state reaction method, sloughs resin with trifluoroacetic acid, the peptidyl substitution compound described in final acquisition.By the qualification of series connection liquid matter, compound structure is correct.
The functional verification of embodiment 2 peptidyl substitution compound
Human A459 lung cancer cell line, cultivates with RPMI1640 nutrient solution (containing 10% deactivation calf serum, 100 U/mL penicillin and 100 U/mL Streptomycin sulphates), is grown on 37 DEG C, in 5%CO2 incubator.
Cell suspension 1 × 105/mL is prepared in digestion, and in 96 orifice plates, every hole adds 100 μ L cell suspensions, cultivates 24 h adherent.Change liquid, add the nutrient solution containing different concns medicine, every hole 100 μ L, each concentration establishes 4 parallel holes, and final compound concentration is 2.0 mg/L.Continue cultivation 72 h.Every hole adds 20 μ L MTT(5 mg/mL), put back to incubator, continue to hatch 4 h.Abandon supernatant, every hole adds 150 μ L DMSO, and slight oscillatory 15 min, makes crystallization fully dissolve, and blank control wells returns to zero, and in 20 min, selects 490 nm wavelength, automatic fluorescence microplate reader measures the absorbance (A) in each hole.Experiment repetition 3 times, averages.Calculate cell proliferation inhibition rate: inhibiting rate %=(1-experimental group A value/control group A value) × 100%.Suppress result as follows:
| Classes of compounds | Human A459 lung cancer cell line inhibiting rate % | Normal human epidermal inhibiting rate % |
| Compound S 1 | 30% | 20.8% |
| Formula I-GTH replaces | 90.2% | 1.2% |
| Formula I-GAK replaces | 91.3% | 2.1% |
| Formula I-GKR replaces | 92.5% | 1.7% |
| Formula I-GKD replaces | 89.7% | 1.5% |
| Formula I-GRQ replaces | 89.1% | 1.1% |
| Formula I-GAS replaces | 90.2% | 1.8% |
| Formula I-GLA replaces | 91.5% | 2.0% |
| Formula I-GEKL replaces | 88.3% | 2.3% |
| Formula I-GMAW replaces | 92.4% | 1.4% |
| Formula I-GSEH replaces | 93.5% | 1.8% |
| Formula I-GRKG replaces | 90.1% | 1.7% |
Compound described in this patent, when concentration is 2mg/L, has obvious restraining effect to cancer cells.Can be good at action character and structure activity relationship that this compounds is described.Therefore peptidyl substitution compound of the present invention can be used for the cancer therapy drug that preparation take kinases as target spot.
Adopt MCF-7 cell to test simultaneously, obtain basically identical experimental result.Illustrate that compound has the anticancer effect of wide spectrum.
Claims (5)
1. a compound, is characterized in that, structural formula such as formula shown in I,
formula I,
Described R1 is any applicable group.
2. compound as claimed in claim 1, it is coupling peptide compounds, and described R1 is GTH, GAK, GKR, GKD, GRQ, GAS, GLA, GEKL, GMAW, GSEH or GRKG.
3. the compound according to any one of claim 1-2 is preparing the application in cancer therapy drug.
4. the compound according to any one of claim 1-2, preparing the application in cancer therapy drug, is characterized in that, the formulation of described cancer therapy drug is tablet, pill, capsule, injection, suspension agent or emulsion.
5. the compound according to any one of claim 1-2, preparing the application in cancer therapy drug, is characterized in that, described cancer therapy drug is anti-lung cancer or breast cancer medicines.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1348370A (en) * | 1999-04-15 | 2002-05-08 | 布里斯托尔-迈尔斯斯奎布公司 | Cyclic protein tyrosine kinase inhibitors |
| CN1764454A (en) * | 2003-03-24 | 2006-04-26 | 布里斯托尔-迈尔斯斯奎布公司 | Cyclic protein tyrosine kinase inhibitors |
| CN101291675A (en) * | 2005-08-22 | 2008-10-22 | 中外制药株式会社 | Novel anticancer concomitant drug |
-
2015
- 2015-06-14 CN CN201510322699.8A patent/CN104974222B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1348370A (en) * | 1999-04-15 | 2002-05-08 | 布里斯托尔-迈尔斯斯奎布公司 | Cyclic protein tyrosine kinase inhibitors |
| CN101481359A (en) * | 1999-04-15 | 2009-07-15 | 布里斯托尔-迈尔斯斯奎布公司 | Cyclic protein tyrosine kinase inhibitors |
| CN1764454A (en) * | 2003-03-24 | 2006-04-26 | 布里斯托尔-迈尔斯斯奎布公司 | Cyclic protein tyrosine kinase inhibitors |
| CN101291675A (en) * | 2005-08-22 | 2008-10-22 | 中外制药株式会社 | Novel anticancer concomitant drug |
Non-Patent Citations (2)
| Title |
|---|
| JAGABANDHU DAS ET AL.,: "Molecular Design, Synthesis, and Structure–Activity Relationships Leading to the Potent and Selective P56lck Inhibitor BMS-243117", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 * |
| JIAZHONG LI ET AL.,: "Validated quantitative structure–activity relationship analysis of a series of 2-aminothiazole based p56Lck inhibitors", 《ANALYTICA CHIMICA ACTA》 * |
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Inventor after: Yang Yang Inventor after: Fang Qiaohui Inventor after: Gao Hua Inventor after: Zhang Wenle Inventor before: Yang Yang |
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Effective date of registration: 20200508 Address after: Room 2 407, Shenzhen biological incubation base, No. 10, Gaoxin Middle Road, Yuehai street, Nanshan District, Shenzhen City, Guangdong Province Applicant after: SHENZHEN CURE & SURE BIOTECH Ltd. Address before: 100711, No. 46 West Fourth Street, Beijing, Dongcheng District Applicant before: Yang Yang |
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