CN115350180B - Application of marine-source tetrabromospirohexadienyl isoxazole compound in preparation of blood tumor treatment drugs - Google Patents
Application of marine-source tetrabromospirohexadienyl isoxazole compound in preparation of blood tumor treatment drugs Download PDFInfo
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Abstract
The invention discloses an application of a marine-source tetrabromospirohexdienyl isoxazole compound in preparing a medicine for treating blood tumors, wherein the structure of the tetrabromospirohexdienyl isoxazole compound is shown as follows:or alternatively, the first and second heat exchangers may be,the preparation method of the compound is simple, and the antitumor activity is obvious. The invention provides a new lead compound for researching and developing blood tumor, especially anti-leukemia and lymphoma drugs, and provides scientific basis for reasonably developing and utilizing ocean medicinal resources in China.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a tetrabromospirohexadienyl isoxazole compound obtained by extraction, separation and purification from a cisapra sponge Aplysinopsis sp.
Background
Aplysinopsis sp. sponge belongs to the class Demospongiae, the family of the armature spongidae (Thectidae) of the order Pegyoceratida, mainly distributed in Australia and China sea areas. Aplysinopsis sp. The chemical composition of sponges was reported since the early 70 th 20 th century (Aplysinopsin, a new tryptophan derivative from asponge [ J ] Tetrahedron Lett.1977, 18:61-64.), but there are few studies on sponges of this genus, mainly Aplysinopsis digitata (Aplysinopides A-C, cytotoxic Sesterterpenes from the Marine Sponge Aplysinopsis digitata [ J ] J.Nat. Prod.2008,71 (6): 1089-1091) and Aplysinopsis elegans (Using spectroscopic and database strategies to unravel structures of polycyclic bioactive marine sponge sesterterpenes [ J ] Tetrahedron,1991,47 (22): 3585-3600.), and up to date, the subjects at home and abroad separated and identified compounds from sponges of this genus were mainly alkaloids and terpenoids. These metabolites exhibit a broad range of biological activities, such as cytotoxicity (Aplysinopalides A-C, cytotoxic Sesterterpenes from the Marine Sponge Aplysinopsis digitata [ J ]. J.Nat.Prod.2008,71 (6): 1089-1091.), antidepressant (New antiinfective and human 5-HT2receptor binding natural and semisynthetic compounds from the Jamaican sponge Smenospongia aurea [ J ]. J.Nat.Prod.2002, 65:476-480.), antimalarial parasite (Indole and aminoimidazole moieties appear as key structural units in antiplasmodial molecules [ J ]. Phytomedicine.2011, 18:1118-1125.), antileishmania (Discovery of novelantileishmanial agents in an attempt to synthesize pentamidine-aplysinopsin hybrid molecule [ J ]. J Med Chem 2009,52:5793-5802 ]), antitumor (Microwave assisted synthesis and in vitro cytotoxicities of substituted (Z) -2-amino-5- (1-benzoyl-1H-indol-3-yl) methyl-1-methyl-1H-idazol-4 (5H) -ones against human tumor cell lines [ J ]. Bioorg Med Chem Lett, 20:591-593 ]), modulating the binding of glycine to the receptor (Irvine) and the like, and physiological receptor (Irvine) of the receptor (J.10:29121-35).
In addition, bromine-containing compounds derived from nature also have excellent application in the treatment of human diseases, and many have been developed as commercially available drugs with clinical value. Such as bromocoler (C) 29 H 48 Br 2 O 2 ) Plays an important role in sedative hypnotic; azachlor (Cl) 3 H 33 Br 2 N 3 ) Belongs to a biquaternary ammonium salt, and is clinically used as an antihypertensive drug; bismuth bromophenol (C) as common disinfecting preservative for ophthalmology 6 HBiBr 4 O 3 ) Also inThe structure contains 4 Br atoms.
The tetrabromospirohexdienylisoxazoles aerothin and homoaerothin extracted from sponge aplysiopsis sp. Each containing 4 Br atoms, which were isolated from sponge verogicid suberaea collected from the red sea, were confirmed to exhibit cytotoxic activity against cervical cancer (HeLa) (Bioactive Secondary Metabolites from the Red Sea Marine Verongid Sponge Suberea Speces. Marine Drugs 2015, 13:1621-1631) and breast cancer (MCF-7) cells (New antiplasmodial bromotyrosine derivatives from Suberea ianthelliformis lendenfeld,1888.chem. Biodivers.2012, 9:1436-1451.) and inactivate clinical isolates of multidrug resistant mycobacterium tuberculosis (aerothin, abromotyrosine derivative with antimycobacterial activity from the marine sponge aplysina gerardogreeni (demosporia) pharm. Biol.2003,41:384-387. In addition, aerothionin also has shown the potential to inhibit the adenosine A1 receptor (Iantasine e, a new bromotyrosine-derived metabolite from the great barrier reef sponge pseudoceratina sp.Nat.Prod.Res.2008, 22:1257-1263.). At the same time, both compounds also showed good activity against chloroquine-resistant strains of malaria carriers plasmodium falciparum (Ianthesine, a new bromotyrosine-derived metabolite from the great barrier reef sponge pseudoceratina sp.chem. Biodivers.2012, 9:1436-1451.).
However, up to now, no report has been made on the effect of these two compounds in hematological tumors.
Disclosure of Invention
The invention aims to provide an application of a tetrabromospirocyclic hexadienyl isoxazole compound of marine origin in preparing a medicine for treating blood tumor.
In order to achieve the above purpose, the technical scheme adopted by the invention is as follows:
the invention provides application of a marine tetrabromospirohexdienyl isoxazole compound in preparing a medicine for treating blood tumor.
The structure of the marine tetrabromospirohexadienyl isoxazole compound is shown as follows:
(I)Aerothionin
or alternatively, the first and second heat exchangers may be,
the hematological neoplasm is selected from leukemia or lymphoma.
The leukemia cells are selected from human acute promyelocytic leukemia (NB 4 cell line, HL-60 cell line), human monocytic leukemia (THP-1 cell line), human chronic myelogenous leukemia (K-652 cell line), human acute myelogenous leukemia cell (KG-1 cell line) and the like.
The lymphoma cells are selected from human Burkitt's lymphoma (Raji cell line, daudi cell line, ramos cell line), human diffuse tissue lymphoma (SU-DHL-4 cell line), human T cell lymphoma (SNK 6 cell line), etc.
The marine tetrabromospirohexadienyl isoxazole compound is obtained by extracting and separating from a Xisha sponge Aplysinopsis sp.
The method for extracting the marine tetrabromospirohexadienyl isoxazole compound comprises the following steps of:
first, preparing a coarse extract of a dichloromethane layer
Cutting refrigerated Xisha sponge Aplysinopsis sp, percolating with methanol/dichloromethane (v: v 1/1) at room temperature, mixing the extractive solutions, and concentrating under reduced pressure (45deg.C) to obtain total extract;
dispersing the total extract suspension in water, extracting with ethyl acetate, concentrating the extract to obtain fat-soluble fraction; suspending the fat-soluble part in 90% methanol water solution, extracting with petroleum ether of equal volume for 3 times, mixing the extractive solutions, and concentrating under reduced pressure to obtain petroleum ether layer crude extract; then, diluting the 90% methanol aqueous solution into 60% methanol aqueous solution, extracting with equal volume of dichloromethane for 3 times, mixing the extracts, and concentrating under reduced pressure to obtain a dichloromethane layer crude extract;
secondly, separating and purifying:
subjecting the dichloromethane layer crude extract to reduced pressure liquid column chromatography, gradient eluting with petroleum ether and ethyl acetate=1:0, 50:1, 25:1, 10:1,5:1,0:1 as solvents, and eluting with pure methanol; combining similar fractions according to thin layer chromatography characteristics (developer: 10% sulfuric acid-vanillin solution) and LC-MS data to obtain 8 components a-H;
and (3) performing gel column chromatographic separation (Sephadex LH-20) on the component F, wherein the mobile phase is methanol, and finally three components (F1, F2 and F3) are obtained. The F1 fraction was subjected to reversed-phase medium-pressure column chromatography (reversed-phase column YMC ODS-A (50 μm) spherical reversed-phase silicse:Sup>A gel, 300 g), methanol/water as mobile phase, 30 m/min flow rate, 10-100% gradient elution for 10 hours to obtain 21 fractions (F1A-F1U). The F1P fraction was separated by using a high performance liquid chromatograph (Waters 1525/2996, 2998 type) and a reverse chromatographic column (XB ridge C18 semi-prep 250X 10mmL 5 μm), and 50% acetonitrile/water was used for eluting with a flow rate of 2mL/min to prepare the tetrabromospirohexadienyl isoxazoles compound Aerothionin (retention time: 20.9 min) and Homoaerothionin (retention time: 24.5 min) of the present invention.
The marine-derived tetrabromospirohexadienyl isoxazoles can also be isolated by known methods from sponge verogicd Suberea obtained from red sea (Bioactive Secondary Metabolites from the Red Sea Marine Verongid Sponge Suberea Speces. Marine Drugs,13 (4), 1621-1631.).
In the embodiment of the invention, the inhibition effect of tetrabromospirodienyl isoxazole compounds Aerothionin and Homoaerothionin on human acute promyelocytic leukemia NB4 cells, human histiocyte lymphoma U937 cells and human Burkitt's lymphoma Raji cells is verified.
In vitro experiments prove that the tetrabromospirohexdienyl isoxazole compounds Aerothionin and Homoaerothionin have obvious inhibition effects on NB4 cell strains, U937 cell strains and Raji cell strains, wherein the Homoaerothionin has more obvious effects. Further studies have found that homoaerothin can block the cell cycle of NB4, U937 and Raji cells in G0/G1 phase and induce apoptosis. Therefore, the tetrabromospirocyclic hexadienyl isoxazole compounds Aerothionin and Homoaerothionin have remarkable inhibitory activity on leukemia and lymphoma cells.
By adopting the technical scheme, the invention has the following advantages and beneficial effects:
the preparation method of the compound is simple, and the invention researches the effect of the two compounds in blood diseases for the first time. IC of Aerothionin and Homoaerothionin compared to compounds for treating leukemia and lymphoma mentioned in other published literature 50 The values were lower (FIG. 1), the cycle arrest and apoptosis effects were more pronounced (FIGS. 2 and 3), with cycle arrest cells up to about 30% and apoptotic cells up to about 20% at 24 hours after 0.8. Mu.M dosing of Homoaerothionin, showing more pronounced tumor activity. The invention provides a new lead compound for researching and developing new anti-blood tumor drugs, and lays a foundation for reasonably developing and utilizing marine medicinal resources in China.
Drawings
FIG. 1 shows the inhibition of NB4, U937 and Raji cell activities by the compounds of this invention and IC thereof 50 Schematic representation of values. .
FIG. 2 is a schematic representation of the cycle blocking effect of Homoaerothionin on NB4, U937 and Raji cells.
FIG. 3 is a schematic representation of the apoptotic effect of the compound Homoaerothionin on NB4, U937 and Raji cells.
Detailed Description
In order to more clearly illustrate the present invention, the present invention will be further described with reference to preferred embodiments. It is to be understood by persons skilled in the art that the following detailed description is illustrative and not restrictive, and that this invention is not limited to the details given herein.
The sponge (Aplysinopsis sp.) used in the examples of the present invention was harvested from around the southwest sand Yongxing Island (Woody Island) in 2016. Through the identification of the Qingdao ocean institute Li Jin and researchers of China academy of sciences, the specimen (XD 15) is stored in the Shanghai university of transportation medical institute affiliated Renzhi hospital ocean pharmaceutical laboratory.
Specific structures of tetrabromospirodienyl isoxazoles Aerothionin and Homoaerothionin are identified by comparison with literature data (Mar drugs.2020, 18:236.).
Example 1
Preparation of the tetrabromospirohexdienyl isoxazoles Aerothionin and Homoaerothionin of the present invention
1. Preparation of crude extract of dichloromethane layer
Cutting frozen Aplysinopsis sp (wet weight 20 kg) into pieces, percolating with methanol/dichloromethane (v: v 1/1) 30L at room temperature, mixing the extractive solutions, and concentrating under reduced pressure at 45deg.C to obtain total extract.
200.3g of the total extract was dispersed in 15L of water, extracted 4 times with 15L of ethyl acetate, and the extract was concentrated to obtain a fat-soluble fraction (89.5 g). The fat-soluble fraction was suspended in 2L of 90% aqueous methanol, extracted 3 times with an equal volume of petroleum ether, and the extracts were combined and concentrated under reduced pressure to give 29g of a crude petroleum ether layer extract. Then, the aqueous solution of 90% methanol was diluted to 60% aqueous solution of methanol, extracted 3 times with an equal volume of methylene chloride, and the extracts were combined and concentrated under reduced pressure to obtain 49.9g of a crude methylene chloride extract.
2. Separation and purification
1) And (3) separating and purifying: the crude extract of the dichloromethane layer was subjected to liquid column chromatography (VLC) under reduced pressure, using petroleum ether: ethyl acetate=1:0, 50:1, 25:1, 10:1,5:1,0:1 as solvents, and finally eluting with pure methanol. Combining similar fractions according to thin layer chromatography characteristics (developer: 10% sulfuric acid-vanillin solution) and LC-MS data to obtain 8 components a-H;
2) And (3) performing gel column chromatographic separation (Sephadex LH-20) on the component F, wherein the mobile phase is methanol, and finally three components (F1, F2 and F3) are obtained. The F1 fraction was subjected to reversed-phase medium-pressure column chromatography (reversed-phase column YMC ODS-A (50 μm) spherical reversed-phase silicse:Sup>A gel, 300 g), methanol/water as mobile phase, 30 m/min flow rate, 10-100% gradient elution for 10 hours to obtain 21 fractions (F1A-F1U). The F1P fraction was separated by using a high performance liquid chromatograph (Waters 1525/2996, 2998 type) and a reverse chromatographic column (XB ridge C18 semi-prep 250X 10mmL 5 μm), and 50% acetonitrile/water was used for eluting with a flow rate of 2mL/min to prepare the tetrabromospirohexadienyl isoxazoles compound Aerothionin (retention time: 20.9 min) and Homoaerothionin (retention time: 24.5 min) of the present invention.
3. Structural identification
The chemical structure of the tetrabromospirohexdienyl isoxazole compound Aerothionin is shown as a formula (I) through a plurality of modern spectroscopic techniques such as 1D/2D NMR, HRESIMS, IR, UV and the like.
Compound Aerothionin: white bulk crystals, HRESIMS m/z 840.95[ M+Na ]] + (calcd for C 24 H 26 Br 4 N 4 O 8 Na,840.95)； 1 H-NMR(600MHz,DMSO-d 6 )3.91(2H，d，J＝7.8Hz，H-1，H-1')，6.58(2H，s，H-5，H-5')，3.19(2H，d，J＝18.0Hz，H-7a，H-7'a)，3.64(1H，d，J＝18.0Hz，H-7b)，3.60(1H，d，J＝18.0Hz，H-7'b)，3.14(4H，br，m，H 2 -10，H 2 -10')，1.45(4H，br，m，H 2 -11，H 2 -11')，3.63(3H，s，H-12),3.60(3H，s，H-12')，6.39(1H，d，J＝7.8Hz，HO-1),6.58(1H，s，HO-1')，8.51(2H，t，J＝5.6Hz，-NH-). 13 C-NMR(150MHz,DMSO-d 6 )73.6(C-1，C-1')，120.9(C-2，C-2')，147.2(C-3，C-3')，113.1(C-4，C-4')，131.3(C-5，C-5')，90.2(C-6，C-6')，39.4(C-7，C-7')，154.6(C-8，C-8')158.9(C-9，C-9')，38.5(C-10，C-10')，26.4(C-11，C-11')，59.7(C-12，C-12')。
The chemical structure of the tetrabromospirohexdienyl isoxazole compound Homoaerothionin is shown as a formula (II) through a plurality of modern spectroscopic techniques such as 1D/2D NMR, HRESIMS, IR, UV and the like.
The compound Homoaerothionin: white bulk crystals, HRESIMS m/z 855.01[ M+Na ]] + (calcd for C 25 H 28 Br 4 N 4 O 8 Na,855.01)； 1 H-NMR(600MHz,DMSO-d 6 )3.91(2H，d，J＝7.8Hz，H-1，H-1')，6.57(2H，s，H-5，H-5')，3.19(1H，d，J＝18.0Hz，H-7a，H-7'a)，3.64(1H，d，J＝18.0Hz，H-7b)，3.60(1H，d，J＝18.0Hz，H-7'b)，3.12(4H，br，m，H 2 -10，H 2 -10'),1.46(4H，br，m，H 2 -11，H 2 -11')，3.62(3H，s，H-12),3.59(3H，s，H-12')，1.25(2H，br，m，H-13)，6.38(1H，d，J＝7.8Hz，HO-1),6.58(1H，s，HO-1')，8.50(2H，t，J＝5.6Hz，-NH-). 13 C-NMR(150MHz,DMSO-d 6 )73.6(C-1，C-1')，120.9(C-2，C-2')，147.2(C-3，C-3')，113.1(C-4，C-4')，131.3(C-5，C-5')，90.2(C-6，C-6')，39.5(C-7，C-7')，154.6(C-8，C-8')，158.8(C-9，C-9')，38.8(C-10，C-10')，26.6(C-11，C-11'),59.7(C-12，C-12')，23.8(C-13)。
Example 2
In vitro antitumor Activity test of the Compounds of the invention on human leukemia cells and lymphoma cells
1. Experimental cell line:
an in vitro anti-tumor experiment was performed on compound Aerothionin, homoaerothionin prepared in example 1 using tumor cell lines as follows:
human acute promyelocytic leukemia NB4 cells;
human histiocyte lymphoma U937 cells;
human Burkitt's lymphoma Raji cells;
three cells were purchased from Shanghai department of science cell banks;
2. the experimental method comprises the following steps:
(one) cell proliferation-toxicity analysis of the compound by using CTL method:
1. taking cells with good growth state into a 15mL centrifuge tube, uniformly mixing the cells by a pipette and counting,then the culture medium is used for diluting the culture medium to the density of 1 multiplied by 10 5 Single cell suspensions at each mL, cells were seeded in black 96-well plates with a row gun at 100 μl per well.
2. The Aerothionin, homoaerothionin mother liquor prepared in advance was taken and diluted to 100. Mu.M with a medium, and 7 concentrations of 20. Mu.M, 10. Mu.M, 5. Mu.M, 2.5. Mu.M, 1.25. Mu.M, 0.625. Mu.M, and 0.3125. Mu.M were set, respectively.
3. 10. Mu.l of each of the well plates to which Aerothionin, homoaerothionin was added was placed in an incubator to be cultured for 72 hours.
After 4.72h, CTL reagent is added according to the requirement of 100 mu L/hole, then a 96-well plate is placed on a shaking table to shake for 10min, and after the cells are completely cracked, a multifunctional enzyme-labeled instrument with a chemiluminescent detection function is used for detecting the chemiluminescent value of each hole.
5. Cell viability calculation formula: cell viability (%) = (dosing chemiluminescent value-blank chemiluminescent value)/(blank chemiluminescent value-blank method chemiluminescent value) ×100%.
The antitumor activity of Homoaerothionin on NB4, U937 and Raji cells is superior to that of Aerothionin, so that Homoaerothionin is selected for subsequent experiments.
(II) analysis of the effects of compounds on cell cycle arrest by flow cytometry:
1. NB4, U937 and Raji cells with good growth status were gently blown into single cell suspensions.
2. Count cells and count cells at 2X 10 5 Density of individual/mL in 6-well plates, each cell line was divided into 3 groups according to experimental purposes: control, homoaerothionin low concentration group and Homoaerothionin high concentration group.
3. Adding Homoaerothionin into 6-well plate after preparing culture solution into corresponding concentration, and adding CO at 37deg.C 2 Culturing in an incubator for 24 hours.
4. After 24h, each group of cells was collected directly in a centrifuge tube, washed once with PBS, and collected in 6-well plates (cell number at least 1X 10) 6 And (c) a).
Centrifuge at 5.1200rpm for 3min, discard supernatant, add 3ml pbs per tube, wash 2 times.
6. After the last centrifugation, the supernatant was carefully discarded (20. Mu.L of the supernatant was added with a 1mL gun head), 250. Mu.L of PBS was added to gently resuspend the cells, 750. Mu.L of pre-chilled absolute ethanol at-20℃was added dropwise while swirling, and the mixture was stored in a-20℃refrigerator for fixation overnight.
7. The fixed cells were removed, centrifuged at 1600rpm for 5min, and the supernatant was discarded.
5mL of LPBS was added to the 8.15mL centrifuge tube, and the mixture was centrifuged at 1200rpm for 3min, and the supernatant was discarded and washed twice.
9. The washed cell suspension was transferred to a 1.5mL centrifuge tube, 400. Mu.L/RNAse was added to each tube, and the mixture was heated in a 37℃water bath for 30min.
10. And detecting by a flow cytometry.
(III) analysis of apoptosis effects of compounds on cells using flow cytometry:
1. NB4, U937 and Raji cells with good growth state were gently beaten into single cell suspensions.
2. Count cells and count cells at 2X 10 5 Density of individual/mL in 6-well plates, each cell line was divided into 3 groups according to experimental purposes: control, homoaerothionin low concentration group and Homoaerothionin high concentration group.
3. The Homoaerothionin is prepared into corresponding concentration by using culture solution, and then added into a 6-well plate inoculated with cells, and CO is added at 37 DEG C 2 Culturing in an incubator for 24 hours.
4. After 24h, each group of cells was collected directly in a centrifuge tube, washed once with PBS, and collected in 6-well plates (cell number at least 1X 10) 6 And (c) a).
Centrifuge at 5.1200rpm for 3min, discard supernatant, add 3ml pbs to each well, wash 2 times.
6. The control group was divided into 4 groups, which were blank group, single-stained PI group, single-stained annexin v group, PI and annexin v double-stained group, respectively.
7. 100 mu L of 1X AnnexinV Binding solution is added to each tube, after the single-dyeing PI group and the single-dyeing annexin V group are boiled in a water bath kettle at 55 ℃ for 2 minutes, 4 mu L of a dye and a blank group are respectively added to each tube together with a dosing group, and no dye is added.
8. Incubate for 15min at room temperature in the dark and add 400. Mu.L of 1XAnnexinVBinding solution before loading.
9. And detecting by a flow cytometry.
3. Experimental results
FIG. 1 shows the inhibition of NB4, U937 and Raji cell activities by the compounds of this invention and IC thereof 50 Schematic representation of values. The results show that the compounds Aerothionin and Homoaerothionin can inhibit the cell viability of three cell lines in vitro and have certain concentration dependence. Wherein Aerothionin is for NB4 cells 50 The value was 1.673. Mu.M, IC for U937 cells 50 IC for Raji cells with a value of 1.819. Mu.M 50 A value of 2.351. Mu.M; IC of Homoaerothionin for NB4 cells 50 Value 0.8443. Mu.M, IC for U937 cells 50 IC for Raji cells at 0.897. Mu.M 50 The value was 1.133. Mu.M (IC of the control drug 5-fluorouracil to NB 4) 50 The value was 1.09. Mu.M). Therefore, the antitumor activity of Homoaerothionin on NB4, U937 and Raji cells is superior to that of Aerothionin, so that the Homoaerothionin is selected for subsequent experiments.
FIG. 2 is a schematic representation of the cycle blocking effect of Homoaerothionin on NB4, U937 and Raji cells. The results showed that after 0.4. Mu.M and 0.8. Mu.M homoaerothin treatment of NB4 cells for 24h, the ratio of G0/G1 phase cells was increased by 28.30% and 32.44% respectively compared to the control group, which blocked the cell cycle at the G0/G1 phase; after U937 cells were treated with homoaerothin at the same concentration for 24h, the G0/G1 phase cell ratio increased by 9.53% and 22.16% relative to the control group, which also blocked the cell cycle at the G0/G1 phase; after 0.6. Mu.M and 1.2. Mu.M Homoaerothionin treatment of Raji cells for 24h, the G0/G1 phase cell ratio increased by 4.12% and 29.54% compared to the control group, respectively, which also blocked the cell cycle at the G0/G1 phase.
FIG. 3 is a schematic representation of the apoptotic effect of the compound Homoaerothionin on NB4, U937 and Raji cells. The results showed that after 0.4. Mu.M and 0.8. Mu.M homoaerothin treatment of NB4 cells for 24 hours, the apoptosis ratio of the dosing group was increased by 12.7% and 19.1% respectively compared with the control group, and apoptosis was induced; after U937 cells are treated by homoaerothin with the same concentration for 24 hours, the apoptosis proportion of the dosing group is respectively increased by 1.3 percent and 20.1 percent compared with that of the control group, and the apoptosis is also induced; after treatment of Raji cells with Homoaerothionin at 0.6 μm and 1.2 μm for 24h, the apoptosis ratio of the drug-added group was increased by 21% and 45.9% respectively compared with the control group, and apoptosis was induced.
In summary, the compound Aerothionin, homoaerothionin prepared in example 1 has a remarkable inhibitory effect on NB4, U937 and Raji cells, wherein the effect of Homoaerothionin is more remarkable. Further studies have found that homoaerothin can block the cell cycle of NB4, U937 and Raji cells in G0/G1 phase and induce apoptosis. Therefore, the compound has certain in vitro anti-tumor activity on leukemia cells and lymphoma cells.
The foregoing description is only illustrative of the preferred embodiment of the present invention, and is not to be construed as limiting the invention, but is to be construed as limiting the invention to any and all simple modifications, equivalent variations and adaptations of the embodiments described above, which are within the scope of the invention, may be made by those skilled in the art without departing from the scope of the invention.
Claims (1)
1. The application of the tetrabromospirocyclic hexadienyl isoxazole compound from the ocean in preparing the medicine for treating the blood tumor is characterized in that the structure of the tetrabromospirocyclic hexadienyl isoxazole compound from the ocean is shown as follows:
the hematological neoplasm is selected from leukemia or lymphoma.
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| CN1717382A (en) * | 2002-12-23 | 2006-01-04 | 科学与工业研究委员会 | Process for preparing 2,4,4,6-tetrabomo-2,5-cyclohexadienone |
| CN103936734A (en) * | 2014-04-30 | 2014-07-23 | 中国人民解放军第二军医大学 | Aaptamine alkaloid compound in sponge from Paracel Islands and anti-tumor application of alkaloid compound |
| CN107903295A (en) * | 2017-11-15 | 2018-04-13 | 上海交通大学医学院附属仁济医院 | A kind of 4 methylene steroids class compounds and its anticancer usage |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1717382A (en) * | 2002-12-23 | 2006-01-04 | 科学与工业研究委员会 | Process for preparing 2,4,4,6-tetrabomo-2,5-cyclohexadienone |
| CN103936734A (en) * | 2014-04-30 | 2014-07-23 | 中国人民解放军第二军医大学 | Aaptamine alkaloid compound in sponge from Paracel Islands and anti-tumor application of alkaloid compound |
| CN107903295A (en) * | 2017-11-15 | 2018-04-13 | 上海交通大学医学院附属仁济医院 | A kind of 4 methylene steroids class compounds and its anticancer usage |
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