CN105434432A - Application of N-hydroxyphthalimide compounds in preparation of anti-tumor medicine - Google Patents
Application of N-hydroxyphthalimide compounds in preparation of anti-tumor medicine Download PDFInfo
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Abstract
The invention provides application of N-hydroxyphthalimide compounds or pharmaceutically-acceptable salt of N-hydroxyphthalimide compounds in preparation of mTOR signal path inhibitor, and application in preparation of anti-tumor medicine. It is proved that compounds N-hydroxyphthalimide (NHPI) can restrain mTOR signal paths, tumor cell proliferation can be restrained, tumor cell apoptosis can be induced, growth of breast cancer tumor transplanted subcutaneously in nude mice can be restrained, and the good in-vivo and in-vitro anti-tumor effect is displayed. The compounds are used for preparing anti-tumor medicine, a good choice is provided for the field of tumor treatment, and quite high application value is achieved.
Description
Technical field
The invention belongs to field of medicaments, be specifically related to the application of HP compounds as mTOR signal pathway inhibitor, and it is preparing the application in antitumor drug.
Background technology
Tumor is the major disease threatening human health, and the clinical treatment medicine used at present mostly is cell toxicity medicament, and targeting is poor, and toxic and side effects is large, and therapeutic effect is unsatisfactory.Molecular targeted agents, for the specific gene of tumor cell and normal cell differential expression or gene expression product, forms targeting specific to tumor and kills and wounds, significantly improve the clinical therapeutic efficacy of tumor.
Mammal rapamycin target protein (mammaliantargetofrapamycin, mTOR) be the protein of a high conservative, belong to serine/threonine protein kitase PIKK family, it can integrate the signal that somatomedin, aminoacid, energy etc. excite, there is closely-related multiple pathophysiological process as growth and proliferation of cell, migration, cell cycle regulating etc. so as to regulation and control and tumor, in the developing of tumor, play the part of important role.MTOR exists with the form of mTOR complex 1 (mTORC1) and mTORC2 two kinds of complex at organism.S6K1 and 4E-BPl is two substrates studying mTORC1 the most widely, and they are the key regulator in protein translation process.Research shows, mTORC2 complex can produce phosphorylation to Akt thus the structure of participation cytoskeletal protein as the upstream signaling molecule of Akt in Ser473 site, many cellular activities such as the synthesis of Function protein matter, cell survival, propagation and metabolism.Not normal and a lot of cancer of the adjustment of mTOR, comprising breast carcinoma, renal carcinoma, pulmonary carcinoma are closely related with the generation of hepatocarcinoma etc., is clinical by the active drug target spot of confirming.
Rapamycin is the mTORC1 specific inhibitor be found the earliest, its multiple derivant is used for clinical cancer therapy by U.S. FDA approval, the Temsirolimus (CCI-779) of such as Hui Shi pharmaceutical manufacturing is for the treatment of advanced renal cell carcinoma, and the Everolimus (RAD001) that Novartis produces is except being used for the treatment of renal carcinoma, also for malignant pancreatic cancer and HR
+/ HER2
-breast cancer treatment.But the up to the present the most promising treatment of rapamycin derivative is only limitted to the tumor of above type, in other principal entities tumor, use its objective effective reaction rate of rapamycin derivative all very low, this makes the application of rapamycin derivative in chemotherapy of tumors single drug have significant limitation.In recent years, PI3K/mTOR double inhibitor or mTORC1/2 selective depressant are proved and kinds of tumors can be suppressed to grow, and multiple PI3K/mTOR double inhibitor and mTORC1/2 selective depressant enter clinical research.But it is large that some compounds still exist toxic and side effects, the shortcoming of pharmacokinetics difference, therefore, new mTOR inhibitors is found thus to research and develop the antitumor drug made new advances very necessary.
Up to now, the HP compounds of novel structure is used as mTOR signal pathway inhibitor, and there is not been reported to possess anti-tumor activity.
Summary of the invention
The object of the invention is to provide a kind of HP compounds and is used as mTOR inhibitors, and preparing the application in antitumor drug, be the pharmaceutical composition of active component containing this compounds and preparing the novelty teabag in antitumor drug.
In order to realize above-mentioned purpose of the present invention, the invention provides following technical scheme:
HP compounds shown in structural formula I or the application of its pharmaceutically acceptable salt in preparation mTOR signal pathway inhibitor,
Wherein, described compound is HP (NHPI), or have on phenyl ring substituent group or and the HP analog derivative of ring structure; Described pharmaceutically acceptable salt formed by HP compounds and acid salt or acid proton the sodium salt, potassium salt, magnesium salt, the calcium salt that replace by metal ion; Described is hydrochlorate, hydrobromate, mesylate, sulfate, phosphate, acetate, trifluoroacetate, fluoroform sulphonate, tosilate, tartrate, maleate, fumarate, succinate or malate with salt formed by acid.
HP compounds shown in structural formula I or its pharmaceutically acceptable salt are preparing the application in antitumor drug,
Wherein, described compound is HP (NHPI), or have on phenyl ring substituent group or and the HP analog derivative of ring structure; Described pharmaceutically acceptable salt formed by HP compounds and acid salt or acid proton the sodium salt, potassium salt, magnesium salt, the calcium salt that replace by metal ion; Described is hydrochlorate, hydrobromate, mesylate, sulfate, phosphate, acetate, trifluoroacetate, fluoroform sulphonate, tosilate, tartrate, maleate, fumarate, succinate or malate with salt formed by acid.
As described in HP compounds preparing the application in antitumor drug, wherein said compound N HPI antitumor action can significantly suppress mTOR signal path based on it, the phosphorylation level of the remarkable classical Protein S 6K and 4E-BP1 in suppression mTORC1 downstream, and the phosphorylation of mTORC2 downstream albumen Akt in S473 position, and then the propagation of inhibition tumor cell, induce its apoptosis.
As described in HP compounds preparing the application in antitumor drug, wherein said compound N HPI antitumor action is the propagation by suppressing BT-20 cell, Lovo cell and HT-29 cell, and retardance human colon cancer cell week is aspire to G
2/ M the phase, the apoptosis of induction human breast cancer cell BT-20, suppresses the growth of tumor-bearing mice tumor, and tool dose dependent.
As described in HP compounds preparing the application in antitumor drug, wherein said tumor is tumor of head and neck, respiratory system tumor, digestive system tumor, urologic neoplasms, skeletal system tumor, gynecological tumor, hematological system tumor, other types tumor.
As described in HP compounds preparing the application in antitumor drug, wherein said tumor of head and neck is thyroid carcinoma, nasopharyngeal carcinoma, meninges cancer, acoustic neuroma, pituitary tumor, oral cancer, craniopharyngioma, thalamus and brain stem tumor, angiogenic tumor or intracranial metastatic tumor.
As described in HP compounds preparing the application in antitumor drug, wherein said respiratory system tumor is pulmonary carcinoma; Described digestive system tumor is hepatocarcinoma, gastric cancer, the esophageal carcinoma, colorectal cancer, rectal cancer, colon cancer or cancer of pancreas; Described urologic neoplasms is renal carcinoma, bladder cancer, carcinoma of prostate or carcinoma of testis; Described skeletal system tumor is osteocarcinoma; Described gynecological tumor is breast carcinoma, cervical cancer or ovarian cancer; Described hematological system tumor is leukemia, malignant lymphoma or multiple myeloma.
As described in HP compounds preparing the application in antitumor drug, wherein said other types tumor is malignant melanoma, glioma or skin carcinoma.
Pharmaceutical composition, comprises the HP compounds or pharmaceutically acceptable salt and pharmaceutically acceptable carrier or excipient for the treatment of anti-tumor effective amount.
As described in pharmaceutical composition, wherein said pharmaceutical composition is tablet, capsule, aqueous suspension, Oil suspensions, dispersible powder, granule, lozenge, Emulsion, syrup, ointment, ointment, suppository or injection.
As described in pharmaceutical composition, wherein said pharmaceutically acceptable salt formed by HP compounds and acid salt or acid proton the sodium salt, potassium salt, magnesium salt, the calcium salt that replace by metal ion; Described is hydrochlorate, hydrobromate, mesylate, sulfate, phosphate, acetate, trifluoroacetate, fluoroform sulphonate, tosilate, tartrate, maleate, fumarate, succinate or malate with salt formed by acid.
HP compounds shown in structural formula I or its pharmaceutically acceptable salt are used as mTOR signal pathway inhibitor or antitumor inhibitor,
Compound N HPI disclosed by the invention can significantly suppress mTOR signal path, and main manifestations is the phosphorylation level significantly suppressing the classical Protein S 6K and 4E-BP1 in mTORC1 downstream, and the phosphorylation of mTORC2 downstream albumen Akt in S473 position; And then the propagation of inhibition tumor cell effectively, induce its apoptosis, there is significant anti-tumor activity.
Pharmaceutical composition of the present invention can make tablet, capsule, aqueous suspension, Oil suspensions, dispersible powder, granule, lozenge, Emulsion, syrup, ointment, ointment, suppository or injection.The various dosage forms of pharmaceutical composition of the present invention can be prepared according to the method known in pharmaceutical field.Can containing such as 0.05% ~ 90% wt. Active ingredient with carrier combinations in these pharmaceutical formulations, more common active component about between 15% ~ 60%.The compounds of this invention dosage can be 0.005 ~ 5000mg/kg/ days, also can exceed this dosage range according to the different using dosages of disease severity or dosage form.
Compared with prior art, the excellent beneficial effect that possesses of the present invention is as follows:
The mTOR inhibitors HP compounds of novel structure of the present invention can be used for preparing mTOR signal pathway inhibitor and the antitumor drug of the novelty being different from existing clinical research compound.The present invention proves that NHPI significantly can suppress phosphorylation level and the phosphorylation level of mTORC2 downstream Akt albumen in S473 position of the classical Protein S 6K and 4E-BP1 in mTORC1 downstream first; Significantly can suppress the propagation of BT-20 cell, Lovo cell and HT-29 cell, and present dose dependent; Significantly can block human colon cancer cell week aspire to G
2/ M the phase, and present dose dependent; Significantly can induce the apoptosis of human breast cancer cell BT-20, and present dose dependent; Significantly can suppress the growth of tumor-bearing mice tumor, while performance antitumor action, the body weight of tumor-bearing mice significantly not affected.NHPI is that tumor patient provides new medicine, has dosage moderate, moderate cost, and medication is convenient, evident in efficacy, the advantages such as toxic and side effects is little.
Accompanying drawing illustrates:
Fig. 1 schemes the WesternBlot of mTOR signal path impact after the different tumor cell of NHPI process in embodiment 1;
Fig. 2 be in embodiment 2 NHPI on the impact of different tumor cell proliferation;
Fig. 3 be in embodiment 3 NHPI on the impact of human colon carcinoma Lovo cell cycle regulating;
Fig. 4 be in embodiment 4 NHPI on the apoptotic impact of human breast carcinoma BT-20;
Fig. 5 is the graph of a relation of nude mice body weight and administration natural law in embodiment 5;
Fig. 6 is the graph of a relation of nude mouse tumor volume and administration natural law in embodiment 5.
Detailed description of the invention:
Below in conjunction with accompanying drawing, further illustrate essentiality content of the present invention with embodiments of the invention, but do not limit the present invention with this.
Embodiment 1:
NHPI significantly suppresses different tumor cell mTORC1 and mTORC2 signal path.
1. cell strain: human breast carcinoma BT-20 cell, human colon carcinoma Lovo cell are all purchased from Chinese Academy of Sciences's Shanghai cell bank.Cell is placed in 37 DEG C, 5%CO
2incubator in cellar culture, culture fluid be containing 10% calf serum, pH value 7.4 MEM and F12-K.
2. experimental technique: take the logarithm trophophase BT-20 and Lovo cell, makes 3 × 10 with culture fluid
5/ ml cell suspension inoculation is in 6 orifice plates.Cultivate 24h, after cell attachment, absorb original fluid, the every hole of experimental group adds the NHPI (purchased from Shanghai Shao Yuan Science and Technology Ltd.) of variable concentrations respectively, and matched group adds the culture fluid not containing NHPI of equivalent.After 24h, collecting cell, extracts total protein of cell, through SDS-PAGE gel electrophoresis, uses detection of specific antibody p-S6K, p-4E-BP1, p-AKT (S473) and β-actin etc. respectively, and Fig. 1 is the WesternBlot figure after NHPI process cell.
3. experimental result: NHPI significantly suppresses phosphorylation level and the phosphorylation level (Fig. 1) of mTORC2 downstream Akt albumen in S473 position of the classical Protein S 6K and 4E-BP1 in mTORC1 downstream.
Embodiment 2:
NHPI significantly suppresses the propagation of different tumor cell.
1. cell strain: human breast carcinoma BT-20 cell, human colon carcinoma Lovo and HT-29 cell are all purchased from Chinese Academy of Sciences's Shanghai cell bank.
2. experimental technique: take the logarithm trophophase BT-20 cell, Lovo cell and HT-29 cell, makes 1 × 10 with culture fluid
4/ ml cell suspension inoculation is in 96 orifice plates.Cultivate 24h, after cell attachment, absorb original fluid, the every hole of experimental group adds the NHPI (purchased from Shanghai Shao Yuan Science and Technology Ltd.) of variable concentrations respectively, and matched group adds the culture fluid not containing NHPI of equivalent, and often group establishes 3 multiple holes.After often organizing cell culture 48h, every hole adds 20 μ lMTS (Promega, Madison, USA), then after cultivating 1-2h, microplate reader detects 490nm absorbance.
3. experimental result: NHPI significantly can suppress the propagation of BT-20 cell, Lovo cell and HT-29 cell, and presents dose dependent (Fig. 2).
Embodiment 3:
NHPI blocks Lovo cell cycle in G
2/ M the phase.
1. experimental technique: trophophase Lovo cell of taking the logarithm, makes 1 × 10 with culture fluid
5/ ml cell suspension inoculation is in 6 orifice plates.Cultivate 24h, after cell attachment, absorb original fluid, the every hole of experimental group adds the NHPI (purchased from Shanghai Shao Yuan Science and Technology Ltd.) of variable concentrations respectively, and matched group adds the culture fluid not containing NHPI of equivalent.At the end of process, trypsinization centrifugal collecting cell, the PBS washing of pre-cooling once, adds 75% ethanol (-20 DEG C of pre-coolings) fixed cell and spends the night.Centrifugal collecting cell also adds RNA enzyme and hatches 30 minutes in 37 DEG C, then adds propidium iodide (PropidiumIodide, PI, Sigma company) dyeing, and room temperature lucifuge places 30 minutes, uses flow cytomery cell cycle.
2. experimental result: NHPI significantly can block human colon cancer cell week aspire to G
2/ M the phase, and present dose dependent (Fig. 3).
Embodiment 4:
NHPI significantly induces BT-20 apoptosis.
1. experimental technique: trophophase BT-20 cell of taking the logarithm, makes 1 × 10 with culture fluid
5/ ml cell suspension inoculation is in 6 orifice plates.Cultivate 24h, after cell attachment, absorb original fluid, the every hole of experimental group adds the NHPI (purchased from Shanghai Shao Yuan Science and Technology Ltd.) of variable concentrations respectively, and matched group adds the culture fluid not containing NHPI of equivalent.After 48 hours, trypsinization centrifugal collecting cell, the PBS washing of pre-cooling is once, cell is resuspended in bindingbuffer, add Annexin-V-FITC and PI (BDBiosciences) to mix gently, lucifuge places 20 minutes, with flow cytomery analysis of cells apoptosis rate.
2. experimental result: NHPI significantly can induce the apoptosis of human breast cancer cell BT-20, and presents dose dependent (Fig. 4).
Embodiment 5:
NHPI suppresses the growth of human breast carcinoma BT-20 cell transplanted tumor in nude mice.
1. experimental technique: 4 week age female BAl BIc/c nude mouse (Beijing Vital River Experimental Animals Technology Co., Ltd.), experimental day, with Matrigel glue (BDBiosciences) and human breast carcinoma BT-20 cell (6 × 10
6) by 1:1 mixing subcutaneous injection, treat that tumor grows to 200mm
3time, lumbar injection 40mg/kg/dNHPI (purchased from Shanghai Shao Yuan Science and Technology Ltd.), matched group injection equivalent solvent (normal saline is containing 10% ethanol and 30%PEG400), continuous 43 days, within 44 days, rise and increase dosage to 80mg/kg/d, successive administration 12 days.Within every 2 days, measure the change of gross tumor volume, monitor the body weight change of mice, accompanying drawing 5 and 6 is respectively the graph of a relation of Mouse Weight and gross tumor volume and administration natural law simultaneously.
2. experimental result: compared with matched group, NHPI administration group Mouse Weight does not have significant change; NHPI significantly suppress the growth of tumor-bearing mice tumor, and administration 22 days, NHPI administration group mouse tumor volume had significant difference (* p ﹤ 0.05) compared with matched group.Illustrate that mTOR inhibitors NHPI disclosed by the invention significantly can suppress the growth of tumor-bearing mice tumor; While performance antitumor action, the body weight of tumor-bearing mice is not significantly affected.
Embodiment 6:
NHPI, adds the ethanol solution of sulfuric acid of 4%, PH=4, filters, dry, makes sulphate cpd.
Embodiment 7:
NHPI, adds the hydrochloric acid solution of 4%, PH=4, filters, dry, makes hydrochloride compound.
Embodiment 8:
NHPI, adds the tartaric acid solution of 4%, PH=4, filters, dry, makes tartrate compound.
Embodiment 9:
NHPI, adds the citric acid solution of 4%, PH=4, filters, dry, makes citrate compound.
Embodiment 10:
Tablet: the salt 10mg obtained by NHPI or embodiment 6-9, adds lactose 180mg, the adjuvant mix homogeneously such as starch 55mg, and granule will be made after its moistening and drying with water, then add the rear tabletting of magnesium stearate 5mg mixing, every sheet nearly weighs 250mg.
Embodiment 11:
Ampulla: the salt 2mg obtained by NHPI or embodiment 6-9, sodium chloride 10mg, is dissolved in appropriate water for injection, filters gained solution, aseptically loads in ampoule bottle.
Embodiment 12:
Injection lyophilized preparation: the salt 10mg obtained by NHPI or embodiment 6-9, sodium bicarbonate 2mg, mannitol 252mg.
Preparation method: by sodium bicarbonate, mannitol, be dissolved in water for injection, adds activated carbon adsorption 30min depyrogenation, cross and filter active carbon, in filtrate, add compound or its salt, supersound process makes dissolving, PH is regulated to be 5.0-7.0 with 1N hydrochloric acid, microporous filter membrane filters, and injects with water, subpackage, lyophilization, top plug, rolls lid, to obtain final product.
Embodiment 13:
Capsule: the salt 10mg obtained by NHPI or embodiment 6-9, lactose 187mg, magnesium stearate 3mg; Preparation method: compound or its salt and cosolvent are mixed, sieve, Homogeneous phase mixing, loads hard gelatin capsule the mixture obtained, and the heavy 200mg of each capsule, active component content is 10mg.
Claims (10)
1. the HP compounds shown in structural formula I or the application of its pharmaceutically acceptable salt in preparation mTOR signal pathway inhibitor,
Wherein, described compound is HP NHPI, or have on phenyl ring substituent group or and the HP analog derivative of ring structure; Described pharmaceutically acceptable salt formed by HP compounds and acid salt or acid proton the sodium salt, potassium salt, magnesium salt, the calcium salt that replace by metal ion; Described is hydrochlorate, hydrobromate, mesylate, sulfate, phosphate, acetate, trifluoroacetate, fluoroform sulphonate, tosilate, tartrate, maleate, fumarate, succinate or malate with salt formed by acid.
2. the HP compounds shown in structural formula I or its pharmaceutically acceptable salt are preparing the application in antitumor drug,
Wherein, described compound is HP NHPI, or have on phenyl ring substituent group or and the HP analog derivative of ring structure; Described pharmaceutically acceptable salt formed by HP compounds and acid salt or acid proton the sodium salt, potassium salt, magnesium salt, the calcium salt that replace by metal ion; Described is hydrochlorate, hydrobromate, mesylate, sulfate, phosphate, acetate, trifluoroacetate, fluoroform sulphonate, tosilate, tartrate, maleate, fumarate, succinate or malate with salt formed by acid.
3. HP compounds as claimed in claim 2 is preparing the application in antitumor drug, it is characterized in that described compound N HPI antitumor action is by suppressing mTOR signal path, suppress the phosphorylation level of the classical Protein S 6K and 4E-BP1 in mTORC1 downstream, and the phosphorylation of mTORC2 downstream albumen Akt in S473 position, and then the propagation of inhibition tumor cell, induce its apoptosis.
4. HP compounds as claimed in claim 2 is preparing the application in antitumor drug, it is characterized in that described compound N HPI antitumor action is the propagation by suppressing BT-20 cell, Lovo cell and HT-29 cell, retardance human colon cancer cell week is aspire to G
2/ M the phase, the apoptosis of induction human breast cancer cell BT-20, suppresses the growth of tumor-bearing mice tumor, and tool dose dependent.
5. HP compounds as claimed in claim 2 is preparing the application in antitumor drug, it is characterized in that described tumor is tumor of head and neck, respiratory system tumor, digestive system tumor, urologic neoplasms, skeletal system tumor, gynecological tumor, hematological system tumor, other types tumor.
6. HP compounds as claimed in claim 5 is preparing the application in antitumor drug, it is characterized in that wherein said tumor of head and neck is thyroid carcinoma, nasopharyngeal carcinoma, meninges cancer, acoustic neuroma, pituitary tumor, oral cancer, craniopharyngioma, thalamus and brain stem tumor, angiogenic tumor or intracranial metastatic tumor; Described respiratory system tumor is pulmonary carcinoma; Described digestive system tumor is hepatocarcinoma, gastric cancer, the esophageal carcinoma, colorectal cancer, rectal cancer, colon cancer or cancer of pancreas; Described urologic neoplasms is renal carcinoma, bladder cancer, carcinoma of prostate or carcinoma of testis; Described skeletal system tumor is osteocarcinoma; Described gynecological tumor is breast carcinoma, cervical cancer or ovarian cancer; Described hematological system tumor is leukemia, malignant lymphoma or multiple myeloma.
7. HP compounds as claimed in claim 5 is preparing the application in antitumor drug, it is characterized in that wherein said other types tumor is malignant melanoma, glioma or skin carcinoma.
8. pharmaceutical composition, comprise the treatment HP compounds according to claim 1 of anti-tumor effective amount or pharmaceutically acceptable salt and pharmaceutically acceptable carrier or excipient, wherein said pharmaceutically acceptable salt formed by HP compounds and acid salt or acid proton the sodium salt, potassium salt, magnesium salt, the calcium salt that replace by metal ion; Described is hydrochlorate, hydrobromate, mesylate, sulfate, phosphate, acetate, trifluoroacetate, fluoroform sulphonate, tosilate, tartrate, maleate, fumarate, succinate or malate with salt formed by acid.
9. pharmaceutical composition as claimed in claim 7, is characterized in that wherein said pharmaceutical composition is tablet, capsule, aqueous suspension, Oil suspensions, dispersible powder, granule, lozenge, Emulsion, syrup, ointment, ointment, suppository or injection.
10. the HP compounds shown in structural formula I or its pharmaceutically acceptable salt are used as mTOR signal pathway inhibitor or antitumor inhibitor,
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN108676882A (en) * | 2018-05-30 | 2018-10-19 | 中山大学肿瘤防治中心（中山大学附属肿瘤医院、中山大学肿瘤研究所） | The application of NOP14 genes and its albumen as tumour to the marker of mTOR inhibitors sensibility |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108676882A (en) * | 2018-05-30 | 2018-10-19 | 中山大学肿瘤防治中心（中山大学附属肿瘤医院、中山大学肿瘤研究所） | The application of NOP14 genes and its albumen as tumour to the marker of mTOR inhibitors sensibility |
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| Publication number | Publication date |
|---|---|
| CN105434432B (en) | 2018-11-13 |
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