CN104784179A - Application of tipranavir to breast cancer-resistant drug and breast cancer-resistant drug - Google Patents
Application of tipranavir to breast cancer-resistant drug and breast cancer-resistant drug Download PDFInfo
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- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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Abstract
The invention discloses application of tipranavir to a breast cancer-resistant drug and the breast cancer-resistant drug. The tipranavir is used for preparing the breast cancer-resistant drug. The invention provides the breast cancer-resistant drug comprising the tipranavir. The tipranavir serves as a main active component for resisting the breast cancer. By using a computer virtual screening method, a molecule namely the tipranavir is selected, and the matching degree between the tipranavir and an SIRT1 active pocket is highest; the proliferation inhibition rate of breast cancer cells further reaches 82.10 percent after the cancer is treated by the tipranavir for 72 hours through the verification of a cell experiment; a flow cell experiment result shows that the tipranavir has an apoptosis-inducing effect on the breast cancer cells; an experiment result shows that the tipranavir can remarkably inhibit the activity of breast cancer tumor cells and has a broad application prospect.
Description
Technical field
The invention belongs to medical art, relate to the application of tipranavir (Tipranavir), be specifically related to the application of tipranavir in anti-breast cancer medicines and anti-breast cancer medicines.
Background technology
Cancer, i.e. malignant tumor are the major diseases of serious harm human life.The treatment of cancer is subject to the extensive concern of society.The same with other most countries, breast carcinoma is the modal cancer of Chinese women.Annual Chinese Breast Cancer newly sends out quantity and dead quantity accounts for global 12.2% and 9.6% respectively.Since the nineties, Chinese breast cancer incidence growth rate is that the twice in the whole world is many, and urban area is particularly remarkable.At present, breast carcinoma is the cancer that Chinese women sickness rate is the highest.Chemotherapy is one of three large basic means of mammary gland therapeutic, although the chemotherapy of breast carcinoma has obtained many progress at present, but these cancer therapy drug toxic and side effects are large at present, and poor selectivity and drug resistance, make breast cancer treatment not reach expected effect.Thus seek new toxic and side effects little, the medicine that therapeutic dose is low is significant.
Acetylation and deacetylation are approaches and methods important in Adjust System multiple pathophysiological process; histon deacetylase (HDAC) (HDAC), by catalysis DNA methylase inhibitor, regulates and controls a series of biological effects such as chromatin remodeling, transcription activating and suppression, cell cycle, cell differentiation and apoptosis.Cell is under the state transformed, and the activity of histon deacetylase (HDAC) significantly strengthens, and causes the developed by molecule of cell proliferation and cell cycle regulation unbalance, thus causes malignant change of cell.Antibiotic FR 901228 (HDACI) is the molecular targeted agents of a class new antitumoral of development in recent years.Research confirms, HDACI has antitumor action and good market prospect widely, as ratified the Vorinostat (Zolinza) for cutaneous T cell lymphoma treatment, the romidepsin (Istodax) of listing by FDA and all belonging to this type of medicine for lymphoma peripheral T cell treatment Baily department he (Beleodaq).Therapeutic dose needed for these medicines is low, tolerates, and untoward reaction is few, thus receives much concern.
SIRT1 (Silentinformation regulator1 silent message regulatory factor 1) is a deacetylase relying on NAD+, is normal fetal development, differentiation and the requisite enzyme of maintenance Equilibrium.Most of functions of SIRT1 by the Function protein played a crucial role in gene expression process targetedly deacetylation realize.The action target spot of SIRT1 comprises the cofactors in transcription factor and Metabolism regulation.Find under study for action; SIRT1 is as class I histone deacetylase; it not only makes DNA methylase inhibitor and modifies histone; and interact with multiple nonhistone protein; participate in the multiple physiology of cell, pathological process, as gene silencing, cell ageing, anti-oxidation stress, energy metabolism regulation, DNA damage reparation, tumor generation etc.Taking SIRT1 as target, being suppressed causing the expression of the albumen relevant with cell differentiation, cell cycle arrest, tumour immunity, damaged cell apoptosis etc.In recent years, increasing research proves that SIRT1 take part in generation and the development of breast carcinoma.In breast carcinoma, the c-Myc of overexpression enhances the function of SIRT1 in several ways.First, c-Myc activates Nampt enzyme (it is the rate-limiting enzyme of NAD+ synthesis), promotes the synthesis of NAD+, then activates SIRT1; Secondly c-Myc has blocked the function of the inhibitive factor DBC1 of SIRT1; Conversely, SIRT1 regulates it to express after c-Myc transcribes; Last SIRT1 reduces c-Myc degradation speed by strengthening inherent effects, and final result is that c-Myc and SIRT1 constantly gathers in breast cancer cell, forms a positive feedback loop, promotes the generation of breast carcinoma, development.SIRT1 and c-Myc presents high expressed in breast carcinoma, the two may interact jointly facilitate breast carcinoma generation, development and transfer, SIRT1 also can be used as the individual index of patient with breast cancer's prognosis, and this has great importance to the treatment of patient with breast cancer and Index for diagnosis.
Hiv protease inhibitor belongs to very effective medicine in anti-AIDS drug, can life-span of significant prolongation patient.Evidence suggests, along with the use of highly active antiretroviral therapy (HAART, HAART therapy), the sickness rate of the cancer relevant to acquired immune deficiency syndrome (AIDS) significantly reduces.Thus excite people to the research of hiv protease inhibitor to anti-tumor activity, research shows the growth as the equal energy such as hiv protease inhibitor ritonavir, Saquinavir, NELFINAVIR Tumor suppression.But, tipranavir is only used as the medicine for the treatment of acquired immune deficiency syndrome (AIDS) throughout the year, it has Anticancer activity not have correlational study to prove, particularly not having correlational study to prove, tipranavir has with SIRT1 is anti-breast cancer effect of target, and making not occur at present take SIRT1 as the cancer therapy drug of target.Thus, for this target, carry out drug screening significant.
Summary of the invention
For prior art above shortcomings, the object of this invention is to provide the novelty teabag of tipranavir Tipranavir, namely to growth inhibited and the apoptosis-induced effect of breast cancer cell, provide tipranavir preparing the application in anti-breast cancer medicines further.
Another object of the present invention is to provide a kind of anti-breast cancer medicines.
Realize above-mentioned purpose, the present invention adopts following technical scheme: specifically, the present invention relates to tipranavir Tipranavir, chemical name: N-[3-[(1R)-1-[(6R)-2-hydroxyl-4-oxo-6-phenethyl-6-propyl group-5H-pyrans-3-base] propyl group] phenyl]-5-(trifluoromethyl) pyridine-2-sulfuryl amine; Chinese name: tipranavir, CAS:174484-41-4; C
31h
33f
3n
2o
5s; Structural formula:
The application of above-mentioned tipranavir in breast cancer medicines.
Above-mentioned tipranavir is preparing the application in anti-breast cancer medicines.
A medicine for anti-breast cancer, comprises above-mentioned tipranavir, and wherein tipranavir is as the main active of anti-breast cancer.
The dosage form of described medicine is tablet, comprises the raw material of following parts by weight: tipranavir 23 ~ 37 parts, ipsapirone 8 ~ 15 parts, pre-gelatinized starch 13 ~ 27 parts, hydroxypropyl cellulose 12 ~ 18 parts, crospolyvinylpyrrolidone 6 ~ 14 parts, sodium lauryl sulphate 2 ~ 5 parts and magnesium stearate 1 ~ 3 part.
Compared to existing technology, the present invention has following beneficial effect:
1, the present invention is found by research, and tipranavir can suppress the virus-specific process of viral Gag and Gag-Pok polyprotein in HIV cell, thus can stop the formation of mature virion; Also find the non-peptide class formation of tipranavir with the hiv protease variant of drug resistance in conjunction with time have more motility, and be conducive to delaying the speed that HIV drug resistance produces; Further, the method that the present invention uses computer virtual to screen, utilize molecular docking software SYBYL2.0, to the compound molecule in micromolecular compound storehouse, carry out molecular docking marking, select wherein the highest with SIRT1 active pocket matching degree molecule tipranavir Tipranavir, find that tipranavir has very strong affinity to SIRT1 target.
2, the present invention passes through cell experiment, demonstrate Tipranavir of the present invention and have remarkable inhibitory action to breast cancer cell, experimental result shows, after tipranavir process in 72 hours, 82.10% is reached to the proliferation inhibition rate of breast cancer cell, demonstrates beyond thought proliferation inhibiting effect.
3, the present invention passes through Flow cytometry experiments, according to the apoptosis that the two dye of AnnexinV/PI detects, find MB-MDA231 breast cancer cell after EX527 and the Tipranavir tipranavir process 48h of variable concentrations, apoptosis rate all with drug level correlation; And the apoptosis rate after the process of Tipranavir tipranavir is all higher than the apoptosis rate after the EX527 process of same concentration, demonstrates tipranavir and there is apoptosis-induced effect to breast cancer cell.
4, the present invention's method of using computer virtual to screen, filters out and has very strong affinity micromolecular compound tipranavir to SIRT1 target; And by cell experiment and Flow cytometry experiments, demonstrate the inhibitor that Tipranavir tipranavir can be used as SIRT1, there is the growth inhibited to breast cancer cell and apoptosis-induced effect, can be used for the treatment of breast carcinoma, proposing first with SIRT1 is the cancer therapy drug of target, is significant.
Accompanying drawing explanation
Fig. 1 is the tipranavir amino acid residue be combined with avtive spot one alive;
Fig. 2 is the amino acid residue that tipranavir is combined with active site two;
Fig. 3 is endogenous inhibitor binding activities site one;
Fig. 4 is exogenous inhibitor binding activities site two;
Fig. 5 is tipranavir avtive spot one and two;
Fig. 6 is the apoptosis of MB-MDA231 cell after EX527 process fluidic cell figure-blank group process 48h;
Fig. 7 is the apoptosis processing MB-MDA231 cell after 48h through EX527 process fluidic cell figure-0.1umol/L;
Fig. 8 is the apoptosis processing MB-MDA231 cell after 48h through EX527 process fluidic cell figure-1umol/L;
Fig. 9 is the apoptosis processing MB-MDA231 cell after 48h through EX527 process fluidic cell figure-10umol/L;
Figure 10 is the apoptosis processing MB-MDA231 cell after 48h through EX527 process fluidic cell figure-25umol/L;
Figure 11 is the apoptosis processing MB-MDA231 cell after 48h through EX527 process fluidic cell figure-50umol/L;
Figure 12 is the apoptosis of MB-MDA231 cell after Tipranavir process fluidic cell figure-blank group process 48h;
Figure 13 is the apoptosis processing MB-MDA231 cell after 48h through Tipranavir process fluidic cell figure-0.1umol/L;
Figure 14 is the apoptosis processing MB-MDA231 cell after 48h through Tipranavir process fluidic cell figure-1umol/L;
Figure 15 is the apoptosis processing MB-MDA231 cell after 48h through Tipranavir process fluidic cell figure-10umol/L;
Figure 16 is the apoptosis processing MB-MDA231 cell after 48h through Tipranavir process fluidic cell figure-25umol/L;
Figure 17 is the apoptosis processing MB-MDA231 cell after 48h through Tipranavir process fluidic cell figure-50umol/L.
Detailed description of the invention
Below in conjunction with the drawings and specific embodiments, the present invention is described in further detail, if no special instructions raw materials used in embodiment, be common commercially available.
One, virtual screening
Utilize the suflex-docking module analysis Tipranavir avtive spot one (A1 in SYBYL2.0, the binding site of endogenous inhibitor niacin amide) combination of (Fig. 1 and Fig. 3) and avtive spot two (A2, the binding site of exogenous inhibitor EX527) (Fig. 2 and Fig. 4) and amino acid residue.
After virtual screening is carried out to avtive spot one and two (Fig. 5), draw front 100 molecules (leaving out the different conformation of 24 same moleculars) that docking marking is the highest, result is as shown in table 1, and 932 are filtered out SIRT1 inhibitor Tipranavir tipranavir.
Table 1 virtual screening result
Two, pharmacological evaluation
1.CCK8 surveys Proliferation Ability
Experimental technique is CCK8 Proliferation Ability.Breast cancer lines and MB-MDA-2312 cell derived are in immunology teaching and research room of Third Military Medical University; The cell in good condition that is in exponential phase is got for experiment during experiment.Tipranavir buys in the triumphant chemical Science and Technology Ltd. of Shanghai one hundred generation.CCK8 test kit is bought in Japanese colleague.EX527, Sirtnol are purchased from Shanghai Selleck company.DMEM culture medium is purchased from Hyclone company.
(1) MB-MDA-231 cell (Breast cancer lines) process: with not being in exponential phase containing the trypsinization of EDTA and the good MB-MDA-231 cell of growth conditions, remove pancreatin, the DMEM culture medium adding 1 milliliter is made single cell suspension and is carried out cell counting, and cell density is adjusted to 5 × 10
4individual/milliliter, mixing.
(2) bed board: the cell of trophophase of taking the logarithm is inoculated in 96 orifice plates by cell concentration 6000/hole, above-mentioned cell suspension 90uL/ hole, 96 orifice plates after bed board are placed in the adherent 10h of carbon dioxide constant incubator (37 DEG C, saturated humidity, 5%CO
2).The test of experimental group, positive controls and blank group is carried out respectively after 10 hours; Experiment component is 8 concentration batch, add in the experimental port of 96 orifice plates successively 10 μ L2000 of the variable concentrations with the configuration of DMEM culture medium, 1000,500,250,100,10,1, the Tipranavir tipranavir of 0.5umol/L concentration; Positive controls investigates three kinds of positive controls, EX527, Nicotinamide (niacin amide) and Sirtinol (specificity sirt1 and sirt2 inhibitor), often kind of tester is divided into 8 concentration batch, add in experimental port successively 10 μ L2000,1000,500,250,100,10,1, the positive control of 0.5umol/L concentration; Make in the experimental port of experimental group and positive controls, the final concentration of tipranavir, EX527, Nicotinamide (niacin amide) and Sirtinol is 200,100,50,25,10,1,0.1,0.05umol/L, (DMSO final concentration is less than 4 ‰); Blank group is plasma-free DMEM medium (Control group---blank group); Often group arranges 5 parallel laboratory test groups.After having added, 96 porocyte culture plates are placed in carbon dioxide constant incubator continue to hatch 24 hours, 48 hours, 72 hours respectively after observation of cell state taking pictures.
(3) CCK8 surveys Proliferation Ability
Under lucifuge condition, CCK8 and culture medium join Homogeneous phase mixing in the ratio of 1:10 (v/v); Sucking-off has cultivated 24 hours respectively, the culture medium in 96 plates of 48 hours and 72 hours, and lucifuge adds the mixture of 110ul/ hole CCK8 and culture medium in 96 orifice plates, the postscript record time to be added.Then put into carbon dioxide constant incubator to continue to hatch 2-3h, under wavelength 450nm, the light absorption value A in each hole is measured by the long microplate reader of all-wave, and press formula suppression ratio=(A matched group-A experimental group)/A matched group × 100%, calculate the growth inhibition ratio of each group.
Table 2 drug treating is suppression ratio after 24 hours
Table 3 drug treating is suppression ratio after 48 hours
Table 4 drug treating is suppression ratio after 72 hours
As can be seen from above-mentioned table 2,3 and 4, compared with other three kinds of positive control medicines, after the administration process of different time sections, tipranavir is best to the proliferation inhibiting effect of breast carcinoma, and concentration is higher, and inhibition is more remarkable; Drug exposure times is more of a specified duration, and the proliferation inhibition rate of tipranavir to breast carcinoma significantly improves, and after process in 72 hours, the proliferation inhibition rate of tipranavir to breast cancer cell reaches 82.10%, achieves beyond thought high suppression ratio.
2, the proliferation inhibition test of Jurkat cell:
Adopt test method same in " 1, CCK8 survey proliferation inhibition test method ", carry out the proliferation inhibition test of Jurkat cell, experimental result is as shown in table 5 below:
The compound of table 5 variable concentrations is to the 48h suppression ratio (IR%) of Jurkat cell
Table 5 shows, the positive control medicine of variable concentrations and tipranavir do not have obvious proliferation inhibiting effect to Jurkat cell after the drug treating of 48 hours, with the increase of concentration, its inhibition does not present certain dependency with the increase of concentration yet.
3, the two dye of fluidic cell: AV-PI detects apoptosis
(1) with deionized water, 10 × Binding Buffer is diluted to 1 × Binding Buffer;
(2) cell harvesting: with containing after the collected by trypsinisation breast cancer cell of EDTA, in room temperature 2000rpm centrifugal 5 ~ 10 minutes, collecting cell;
(3) cell washing: use pre-cooling 1 × PBS (4 DEG C) re-suspended cell once, centrifugal 5 ~ 10 minutes of 2000rpm, washed cell;
(4) 1 × Binding Buffer suspension cell that 300 μ L prepare is added;
(5) Annexin V-FITC labelling: after adding the Annexin V-FITC mixing of 5 μ L, lucifuge, incubated at room 15 minutes;
(6) PI labelling: upper machine adds the PI dyeing of 5 μ L for first 5 minutes again;
(7), before upper machine, 1 × Binding Buffer of 200 μ L is added.
(8) flow cytometer showed: with standardization program flow cytomery, general counting 2-3 ten thousand cells, result cell cycle fits software ModFit and analyzes.
Adopt positive control substance EX527 and experiment tipranavir of the present invention to carry out Flow cytometry experiments respectively, experimental result is as shown in Fig. 6 ~ 17; According to the apoptosis that the two dye of AnnexinV/PI detects, find the MB-MDA231 breast cancer cell after EX527 and the Tipranavir tipranavir process 48h of variable concentrations, apoptosis rate all with drug level correlation; And the apoptosis rate after the process of Tipranavir tipranavir is all higher than the apoptosis rate after the EX527 process of same concentration, further demonstrates tipranavir and there is apoptosis-induced effect to breast cancer cell.
Three, a medicine for anti-breast cancer, comprises tipranavir, and wherein tipranavir is as the main active of anti-breast cancer; The dosage form of this medicine can injection, injectable powder, oral administration solution, oral administration mixed suspension, injectable emulsion, Orally taken emulsion, slow releasing tablet or controlled release tablet.
Particularly, the medicine of above-mentioned anti-breast cancer, dosage form is tablet, and the diameter of tablet is 7 ~ 9mm, comprises the raw material of following weight, and wherein said ipsapirone chemical formula is C
27h
42n
2o
5s:
Table 6 material composition table
Through checking, the tablet that embodiment 1-3 formula is made, after patient with breast cancer in various degree takes 5-8 week, checks that breast cancer cell all has obvious apoptosis, proves that it has obvious curative effect to breast carcinoma.
What finally illustrate is, above embodiment is only in order to illustrate technical scheme of the present invention and unrestricted, although with reference to preferred embodiment to invention has been detailed description, those of ordinary skill in the art is to be understood that, can modify to the technical scheme of invention or equivalent replacement, and not departing from aim and the scope of technical solution of the present invention, it all should be encompassed in the middle of right of the present invention.
Claims (7)
1. the application of tipranavir, is characterized in that, the application of tipranavir in breast cancer medicines;
The Chinese name of described tipranavir: tipranavir, CAS:174484-41-4; Chemical name: N-[3-[(1R)-1-[(6R)-2-hydroxyl-4-oxo-6-phenethyl-6-propyl group-5H-pyrans-3-base] propyl group] phenyl]-5-(trifluoromethyl) pyridine-2-sulfuryl amine; C
31h
33f
3n
2o
5s; Structural formula:
。
2. tipranavir described in claim 1 is preparing the application in anti-breast cancer medicines.
3. a medicine for anti-breast cancer, is characterized in that, comprises tipranavir, and wherein tipranavir is as the main active of anti-breast cancer.
4. the medicine of anti-breast cancer according to claim 3, it is characterized in that, the dosage form of described medicine comprises tablet, capsule, granule, injection, injectable powder, oral administration solution, oral administration mixed suspension, injectable emulsion, Orally taken emulsion, slow releasing tablet or controlled release tablet.
5. the medicine of anti-breast cancer according to claim 4, it is characterized in that, the dosage form of described medicine is tablet, comprises the raw material of following parts by weight: tipranavir 23 ~ 37 parts, ipsapirone 8 ~ 15 parts, pre-gelatinized starch 13 ~ 27 parts, hydroxypropyl cellulose 12 ~ 18 parts, crospolyvinylpyrrolidone 6 ~ 14 parts, sodium lauryl sulphate 2 ~ 5 parts and magnesium stearate 1 ~ 3 part.
6. the medicine of anti-breast cancer according to claim 5, it is characterized in that, the parts by weight of described raw material are preferred: tipranavir 29 parts, ipsapirone 11 parts, pre-gelatinized starch 23 parts, hydroxypropyl cellulose 15 parts, crospolyvinylpyrrolidone 13 parts, sodium lauryl sulphate 4 parts and magnesium stearate 2 parts.
7. the medicine of arbitrary anti-breast cancer according to claim 5 or 6, it is characterized in that, the diameter of described tablet is 7 ~ 9 mm.
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| CN201510151531.5A CN104784179A (en) | 2015-04-01 | 2015-04-01 | Application of tipranavir to breast cancer-resistant drug and breast cancer-resistant drug |
| CN201610144660.6A CN105769863B (en) | 2015-04-01 | 2016-03-14 | Application and anticancer medicine of the tipranavir in anticancer medicine |
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| CN201610144660.6A Active CN105769863B (en) | 2015-04-01 | 2016-03-14 | Application and anticancer medicine of the tipranavir in anticancer medicine |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105769863A (en) * | 2015-04-01 | 2016-07-20 | 重庆理工大学 | Application of Tipranavir in anti-cancer drug and anti-cancer drug |
| CN112263578A (en) * | 2020-11-27 | 2021-01-26 | 深圳大学 | Application of Tipranavir in preparation of cancer treatment medicine for killing tumor stem cells and tumor cells |
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| EP1880715A1 (en) * | 2006-07-19 | 2008-01-23 | Abbott GmbH & Co. KG | Pharmaceutically acceptable solubilizing composition and pharmaceutical dosage form containing same |
| AU2013295549B2 (en) * | 2012-07-27 | 2018-04-19 | Izumi Technology, Llc | Efflux inhibitor compositions and methods of treatment using the same |
| WO2014080251A1 (en) * | 2012-11-24 | 2014-05-30 | Hangzhou Dac Biotech Co., Ltd. | Hydrophilic linkers and their uses for conjugation of drugs to cell binding molecules |
| PL3524618T3 (en) * | 2013-03-15 | 2023-07-10 | GLAdiator Biosciences, Inc. | Gla domains as targeting agents |
| CN104784179A (en) * | 2015-04-01 | 2015-07-22 | 重庆理工大学 | Application of tipranavir to breast cancer-resistant drug and breast cancer-resistant drug |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105769863A (en) * | 2015-04-01 | 2016-07-20 | 重庆理工大学 | Application of Tipranavir in anti-cancer drug and anti-cancer drug |
| CN105769863B (en) * | 2015-04-01 | 2018-11-27 | 重庆理工大学 | Application and anticancer medicine of the tipranavir in anticancer medicine |
| CN112263578A (en) * | 2020-11-27 | 2021-01-26 | 深圳大学 | Application of Tipranavir in preparation of cancer treatment medicine for killing tumor stem cells and tumor cells |
| CN112263578B (en) * | 2020-11-27 | 2022-02-11 | 深圳大学 | Application of Tipranavir in preparation of cancer treatment medicine for killing tumor stem cells and tumor cells |
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| CN105769863B (en) | 2018-11-27 |
| CN105769863A (en) | 2016-07-20 |
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