CN103202835B - Application of artemisinin derivative and medicinal salt thereof in preparing medicine for treating acute leukemia - Google Patents
Application of artemisinin derivative and medicinal salt thereof in preparing medicine for treating acute leukemia Download PDFInfo
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- 239000003814 drug Substances 0.000 title claims abstract description 17
- 150000003839 salts Chemical class 0.000 title claims abstract description 9
- 206010000830 Acute leukaemia Diseases 0.000 title abstract description 7
- 208000031261 Acute myeloid leukaemia Diseases 0.000 claims abstract description 25
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- SXYIRMFQILZOAM-HVNFFKDJSA-N dihydroartemisinin methyl ether Chemical compound C1C[C@H]2[C@H](C)CC[C@H]3[C@@H](C)[C@@H](OC)O[C@H]4[C@]32OO[C@@]1(C)O4 SXYIRMFQILZOAM-HVNFFKDJSA-N 0.000 description 2
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicines Containing Plant Substances (AREA)
Abstract
The invention discloses application of arteether dimer amine and medicinal salts thereof. The artemisinin derivative-arteether dimer amine and the medicinal salt thereof can inhibit the proliferation of leukemia cells and induce the apoptosis of tumor cells. The artemisinin derivative arteether dimer amine and the medicinal salt thereof can be used for preparing medicaments for treating leukemia, particularly acute leukemia, more particularly acute myelocytic leukemia, and especially M5 subtype acute myelocytic leukemia.
Description
Technical field
The invention belongs to medical domain, specifically, relate to the application of a kind of artemisinin derivative and pharmaceutical salts thereof.
Background technology
Leukemia is the malignant tumor of blood system, is the malignant clone disease of a class hematopoietic stem cell, serious harm human health.Wherein, acute leukemia is the booming disease of a class, and it causes immature hemocyte in bone marrow and blood to accumulate in a large number, comprises acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL).Wherein, acute myeloid leukemia is also called acute nonlymphocytic leukemia (ANLL), can be divided into M0, M1, M2, M3, M4, M5, M6 and M7 eight kinds of hypotypes, and acute lymphoblastic leukemia can be divided into L1, L2 and L3 tri-kinds of hypotypes.
Acute myeloid leukemia (acute myelocytic leukemia, AML) or acute nonlymphocytic leukemia (ANLL) comprise the acute leukemia in all non-lymphocytes source.It is that the precursor caryogram of pluripotent stem cell or slightly differentiation is undergone mutation formed a class disease, is the Clonal malignant disease of hemopoietic system.The diagnostic criteria of acute myeloid leukemia eight kinds of hypotypes is as follows: (1) M0 (the small differentiated of acute myelocytic leukemia): germinal cell is similar L2 type cell under light microscopic, kernel is obvious, endochylema is transparent, basophilia, without azurophilic granule and Auer body.Myeloperoxidase (MPO) (MPO) and the positive < 3% of Sudan black B.Under Electronic Speculum, MPO is (+), and the medullary system marks such as CD33 or CD13 can be (+).Usual lymphatic system antigen is (-), but CD7+, TdT+ sometimes; (2) M1 (acute myeloblastic leukemia undifferentiated type): not breaking up more than 90%, at least 3% cell that myeloblast (I type+II type) accounts for the non-erythroid cells of bone marrow is peroxidase stain (+); (3) M2 (acute myeloblastic leukemia partial differentiation type): myeloblast (I type+II type) accounts for 30% ~ 89% of the non-erythroid cells of bone marrow, mononuclear cell < 20%, other granulocytes > 10%; (4) M3 (acute promyelocytic leukemia): based on granose promyelocyte in bone marrow, this type of cell in non-erythroid cells >=30%.Chromosome t (15 can be detected; 17) transposition and PML/RAR alpha fusion gene; (5) M4 (acute myelo monocytic leukemia): in bone marrow, germinal cell accounts for more than 30% of non-erythroid cells, each stage granulocyte accounts for 30% ~ < 80%, each stage mononuclear cell > 20%, CD14 is positive; (6) M5 (acute monocytic leukemia): bone marrow non-erythroid cells Central Plains monokaryon, young monokaryon >=30%, CD14 are positive; (7) M6 (Di Guglielmo syndrome): bone marrow polychromatophilic erythroblast >=50%, germinal cell (I type+II type) >=30% in non-erythroid cells; (8) M7 (acute megakaryocytic leukemia): Megakaryoblast >=30% in bone marrow, CD41, CD61 and CD42 are positive.
The standard method of current treatment leukemia comprises conventional chemotherapy, bone marrow transplantation and radiotherapy.But the prognosis of most patient is still very poor.Serious side reaction (as infected, hemorrhage, the rejection etc. after transplanting) after treatment or disease palindromia seriously have impact on the survival rate of patient.Therefore find novel efficient antitumor drug to improve complete remission rate and the life cycle of patient, seem particularly important.Further, because leukemia hypotype is different, diagnostic criteria also has difference, and therapeutic scheme and prognosis are also not quite similar.Therefore classification diagnosis and hypotype diagnosis should be made further according to the morphology of leukaemia, immunology and cytogenetics feature.
Summary of the invention
The object of the present invention is to provide the application of a kind of artemisinin derivative two arteether base amine and pharmaceutical salts thereof, for leukaemic provides a kind of novel medicine.
Artemisinin derivative of the present invention is two arteether base amine, has following structure:
Through the research that inventor is extensive and deep, find that water miscible artemisinin derivative two arteether base amine maleate (being labeled as SM1044) can suppress Leukemia Cell Proliferation, cell death inducing.Show that artemisinin derivative two arteether base amine of the present invention can for the preparation of the leukemic medicine for the treatment of, especially for the medicine of preparation treatment acute leukemia, more especially for the preparation of the medicine for the treatment of acute myeloid leukemia, especially especially for the medicine of preparation treatment acute myeloid leukemia M5 hypotype.
Accompanying drawing explanation
Fig. 1 is the growth inhibited curve chart of acute myeloid leukemia M5 cell strain U937 cell after SM1044 process.
Fig. 2 is flow cytomery U937 cell apoptosis rate curve chart after SM1044 process.
Fig. 3 is flow cytomery U937 cell mitochondrial transmembrane potentials result figure after SM1044 process.
Fig. 4 is that western blot detects U937 cell apoptosis-related protein result figure after SM1044 process.
Fig. 5 is the U937 cell transplantation tumor growth curve chart that SM1044 suppresses mice.
Detailed description of the invention
Below in conjunction with specific embodiment, the present invention will be further described.Should be understood that following examples only for illustration of the present invention but not for limiting the scope of the invention.
The U937 cell used in following examples is acute myeloid leukemia M5 cell strain, derives from Shanghai Blood Research Institute.
The preparation of embodiment 1 artemisinin derivative two arteether base amine maleate
The present embodiment is from known compound hydroxyl arteether (list of references: Li Ying etc., Acta Pharmaceutica Sinica, 1981,16:429-439) set out, first make its p-toluenesulfonic esters, then react with ammonia in solvent dimethylformamide and namely obtain two arteether base amine, reaction scheme is:
Subsequently two obtained arteether base amine are made maleate again.
Concrete operations are as follows:
The p-toluenesulfonic esters (1.54g) of hydroxyl arteether is dissolved in dimethyl formamide (10mL), then adds ammonia (0.5mL) and be heated with stirring to 40-50 DEG C, reaction about 20h.After TLC detection raw material point disappears substantially, pour reactant liquor into frozen water, repeatedly extract by ethyl acetate, merge organic facies, then wash with saturated brine, anhydrous sodium sulfate drying.Pressure reducing and steaming solvent, residue is by column chromatography (silica gel, eluant is the mixed solvent of ethyl acetate/petroleum ether/triethylamine, and the concentration of gradient elution is 1/19/1 → 1/10/1, v/v/v).Obtain pale yellowish oil product 0.4g, yield 40%.Oil product, with after a little acetic acid ethyl dissolution, slowly instills maleic acid/ethyl acetate solution to faintly acid, namely has solid to separate out, is filtered by this maleate, and ethanol/petroleum ether recrystallization, obtains white crystal.Fusing point: 140 ~ 142 DEG C.
1hNMR (free alkali, 300MHz, CDCl
3) δ: 5.40 (s, 2H), 4.82 (d, J=3.3Hz, 2H), 3.97 (m, 2H), 3.56 (m, 2H), 2.84 (m, 4H), 1.43 (s, 6H), 0.95 (d, J=6.0Hz, 6H), 0.90 (d, J=7.2Hz, 6H).Mass spectral analysis (free alkali C
34h
55nO
10): m/z 638 (M+1)
+.Elementary analysis (maleate, C
38h
59nO
14): value of calculation is C60.53, H 7.89, N 1.86; Measured value is C60.72, H 8.00, N 1.73.
The structure that above analytical data confirms two arteether base amine maleates (SM 1044) is as follows:
Embodiment 2 SM1044 is to the inhibition test of leukaemia
First be dissolved in tri-distilled water by SM1044, concentration is 1mg/ml, then chooses typical acute myeloid leukemia M5 cell strain U937 cell and tests.We are by 5 × 10
4individual cell is suspended from 200 μ l culture medium, is inoculated in 96 orifice plates.Arrange respectively blank group, the matched group of not dosing, variable concentrations (0.005 μM, 0.01 μM, 0.02 μM, 0.04 μM, 0.4 μM, 0.8 μM, 1.6 μMs SM1044) dosing group, often kind of concentration arranges 3 parallel holes.Add MTT (5mg/ml) after cultivating 24h, 48h and 72h respectively to continue to cultivate 4h.Centrifugal, sop up 180 μ l supernatants, every hole adds 180 μ l DMSO, is placed in shaking table vibration 15min.Microplate reader detects 570nm light absorption value (A), calculation of half inhibitory concentration IC
50.As shown in Figure 1, U937 cell is responsive to SM1044, IC during 48h for result
50be 0.02 μM, show that SM1044 can suppress the propagation of leukemia cell line U937.
Embodiment 3 SM1044 induces U937 Apoptosis assay
By 5 × 10
5individual U937 cell is suspended from 1ml culture medium, is inoculated in 24 orifice plates.Matched group (0 μM) is set respectively, variable concentrations (0.5 μM, 1 μM, 5 μMs of SM1044) dosing group, cultivate 24h and 48h respectively, collect cell to be detected, the phosphate buffer (PBS) of pre-cooling is resuspended with 200 μ l binding buffer liquid (binding buffer) after washing twice, add 5 μ l Annexin V-FITC and 5 μ l propidium iodides (PI), mix gently, 15min is hatched in room temperature lucifuge, 1h in-flow cell instrument detects, result as shown in Figure 2, SM1044 concentration is between 0.1 μM ~ 1 μM, act on U937 cell 24 ~ 48 hours energy cell death inducings.Show that SM1044 can induce U937 apoptosis, apoptotic cell ratio increases with the increase of drug level and the prolongation in processing time.
Embodiment 4 SM1044 induces U937 cell mitochondrial transmembrane potential to lose test
By 1 × 10
6individual U937 cell is suspended from 2ml culture medium, is inoculated in 6 orifice plates.Matched group (0 μM), variable concentrations (0.5 μM, 1 μM, 5 μMs of SM1044) dosing group are set respectively, after cultivating 24h and 48h respectively, add 20nM DiOC
6(3) hatch 15min in 37 DEG C of lucifuges, PBS washes cell 2 times, then uses 100 μ lPBS re-suspended cells, flow cytomery.DiOC
6(3) negative cell is the cell that mitochondrial transmembrane potentials is lost.Fig. 3 shows SM1044 and induces the mitochondrial transmembrane potentials of U937 cell to lose, and current potential loses dependency that is free and drug level simultaneously.Apoptosis comprise inherent by way of with external approach, wherein the loss of mitochondrial transmembrane potentials be apoptosis inherent by way of important behaviour, result shows that SM1044 is by the apoptosis of inherence by way of induction U937 cell.
Embodiment 5 SM1044 induces U937 cell death related protein detection experiment
By U937 cell with 5 × 10
5individual/ml concentration is inoculated in Tissue Culture Dish.Matched group (0 μM), variable concentrations (0.5 μM are set respectively, 1 μM, 5 μMs of SM1044) dosing group, total protein of cell is extracted after cultivating 24h, by the method for western blot, with the change of anti-apoptotic associated protein (caspase-3, caspase-9) antibody test apoptosis-related protein amount.Caspase family plays very important effect in the process of mediating apoptosis.And apoptotic approach mainly contains two: one is by the apoptosis enzyme caspase-8 etc. in extracellular signal active cell; Another is by mitochondrion release apoptosis enzyme activition factor activator caspase-9 etc.The caspase of these activation and then activation apoptosis perform albumen caspase-3 and cause apoptosis.As shown in Figure 4, after SM1044 process, the caspase-9 amount of apoptosis-related protein activation increases, and shows that SM1044 is by inherent approach induction U937 apoptosis.
Embodiment 6 SM1044 suppresses the U937 cell transplantation tumor growth test of mice
Set up acute myeloid leukemia M5 cell strain U937 cell mouse Transplanted tumor model, subcutaneous injection 1 × 10
7individual U937 cell, mice lump grows to diameter about 0.5cm, mice is divided into five groups, is respectively the dosing group of matched group (Con), 0.5mg/kg, 1mg/kg, 5mg/kg and 10mg/kg SM1044.Give lumbar injection SM1044 every day, per injection amount is 0.1ml, and matched group injection normal saline, the course for the treatment of is 35 days, Timing measurement mice Tumor size.As shown in Figure 5, in mice-transplanted tumor model, the SM1044 of 1mg/kg, 5mg/kg, 10mg/kg all can the growth of Tumor suppression, illustrates that SM1044 can affect the growth of tumor cell in Mice Body.
Arteannuin (artemisinin) is the sesquiterpene lactones with peroxy-radical extracted from plant Artemisia annua, and artesunate (artesunate), Artemether (artemether) and dihydroartemisinine (dihydroartemisinin) etc. are the derivant of arteannuin.Current above-mentioned artemisinin-based drug has become the First Line medicine of worldwide treating malaria.Although over nearly 20 years, Chinese scholars has carried out the research of the antitumor action of artemisine compounds, proved that the external antitumor spectra of artemisine compounds is wide, concrete implement in vivo in often unsatisfactory curative effect, and finally could not to further investigate further.We attempt on original basis, study a kind of novel artemisinin derivative, to improving the effect of antitumor action.This experiment adopts novel water-soluble arteannuin derivant two arteether base amine maleate, the tests such as suppression Leukemia Cell Proliferation are investigated, show that SM1044 can suppress Leukemia Cell Proliferation, cell death inducing, and there is the dependency of time and dosage, results of animal shows, SM1044 can Tumor suppression growth.SM1044 can be used in the leukemic medicine of preparation treatment, especially for the medicine for the treatment of acute leukemia, more especially for the preparation of the medicine for the treatment of acute myeloid leukemia, especially especially for the medicine of preparation treatment acute myeloid leukemia M5 hypotype.
Be to be understood that; above embodiment is only in order to illustrate technical scheme of the present invention; but not limiting the scope of the invention; although done to explain to the present invention with reference to preferred embodiment; those of ordinary skill in the art is to be understood that; can modifying to technical scheme of the present invention or equivalent replacement, as adopted other water soluble salt of two arteether base amine, also can reach technique effect of the present invention.Artemisinin derivative two arteether base amine of the present invention is comparatively strong to leukemic apoptosis-induced ability, can the short time, low dose of in inhibition tumor cell, and toxic and side effects is less, significant to leukemic clinical treatment.
Claims (1)
1. an application for artemisinin derivative and pharmaceutical salts thereof, is characterized in that, for the preparation of the medicine for the treatment of AML type acute myeloid leukemia M5 hypotype, wherein, described artemisinin derivative is two arteether base amine, and structure is:
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| CN102038678A (en) * | 2010-11-26 | 2011-05-04 | 浙江大学 | Application of dihydroartemisinin to preparation of tumor cell autophagy induction medicament |
| CN102614168A (en) * | 2011-01-31 | 2012-08-01 | 上海交通大学医学院附属瑞金医院 | Application of artemisinin derivative and medicinal salt thereof |
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| CN102038678A (en) * | 2010-11-26 | 2011-05-04 | 浙江大学 | Application of dihydroartemisinin to preparation of tumor cell autophagy induction medicament |
| CN102614168A (en) * | 2011-01-31 | 2012-08-01 | 上海交通大学医学院附属瑞金医院 | Application of artemisinin derivative and medicinal salt thereof |
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| Title |
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| 新型青蒿素衍生物SM1044诱导Kasumi-1细胞凋亡及机制的研究;刘静静等;《中国实验血液学杂志》;20111231;第19卷(第3期);607-611 * |
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Inventor after: Mi Jianqing Inventor after: Li Ying Inventor after: Nie Ruimin Inventor after: Cui Wen Inventor after: Zhang Yu Inventor after: Wang Jin Inventor after: Cai Xun Inventor after: Wang Zhenyi Inventor before: Mi Jianqing Inventor before: Li Ying Inventor before: Nie Ruimin Inventor before: Zhang Yu Inventor before: Wang Jin Inventor before: Cai Xun Inventor before: Wang Zhenyi |
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Free format text: CORRECT: INVENTOR; FROM: MI JIANQING LI YING NIE RUIMIN ZHANG YU WANG JIN CAI XUN WANG ZHENYI TO: MI JIANQING LI YING NIE RUIMIN CUI WEN ZHANG YU WANG JIN CAI XUN WANG ZHENYI |