CN108261414A - A kind of pharmaceutical composition for treating lung cancer - Google Patents
A kind of pharmaceutical composition for treating lung cancer Download PDFInfo
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- CN108261414A CN108261414A CN201810028516.5A CN201810028516A CN108261414A CN 108261414 A CN108261414 A CN 108261414A CN 201810028516 A CN201810028516 A CN 201810028516A CN 108261414 A CN108261414 A CN 108261414A
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- bcl
- inhibitor
- fluorescence probe
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- lung cancer
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- 0 CCOC(CNc1c(cccc2C(N(CCc3cc(N=C*4)c4cc3)C3*)=[U])c2c3cc1)=O Chemical compound CCOC(CNc1c(cccc2C(N(CCc3cc(N=C*4)c4cc3)C3*)=[U])c2c3cc1)=O 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/473—Quinolines; Isoquinolines ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/472—Non-condensed isoquinolines, e.g. papaverine
- A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a kind of pharmaceutical compositions for treating lung cancer.The pharmaceutical composition contains the upper Bcl xl inhibitor A 1331852 of effective dose and fluorescence probe NA 2a for the treatment of.In the pharmaceutical composition, fluorescence probe NA 2a and Bcl xl inhibitor A 1331852 acts synergistically, cell permeability is opened by fluorescence probe NA 2a, under the premise of not destroying the function of Bcl xl inhibitor A 1331852 and ensureing cell integrity, Bcl xl inhibitor A 1331852 is helped to enter in cell and plays a role to reach significantly more treatment lung cancer effect.Vitro Experimental Results show that, for A549 cell strains, the inhibiting rate of pharmaceutical composition of the present invention improves 20 30% compared with single use Bcl xl inhibitor A 1331852, and more than 60% is improved compared with single use fluorescence probe NA 2a.
Description
Technical field
The present invention relates to a kind of pharmaceutical compositions for treating lung cancer, belong to pharmaceutical technology field.
Background technology
Cancer is the number one killer of serious threat human health, and incidence is big, and lethality is high.Studies have shown that causes to swell
Knurl occurs and drug resistant most important the reason is that the high expression of Bcl-xl genes and albumen in people's cell makes body normal
Removing aberrant gene, it is suppressed that Apoptosis, and apoptosis is by the autonomous orderly death of intracellular controlling gene.Existing research
Show that Apoptosis plays negative regulation during tumor development, the proliferation of tumour cell can be inhibited.Bcl-xl with
Bak formed heterodimer in Bcl-xl ratio, determine cell receive apoptotic signal after survival whether.If Bcl-xl tables
Decline up to level, then can not balance the effect for promoting apoptogene Bak, cell can be made to move towards apoptosis.
Bcl-xl inhibitor can inhibit anti-apoptotic functions of the Bcl-xl in cell, be withered by repairing the normal of tumour cell
Approach is died, overcomes resistance of the anti-apoptotic proteins to apoptosis.But certain inhibitor are poor there are structural stability, permeability of cell membrane,
The deficiencies of selectivity is not ideal enough.
One kind that the fluorescence probe NA-2a of structure shown in following formula (I)s is developed before being the applicant has mitochondria target
To the fluorescence probe of effect, which, which has mitochondria, is directly targeted effect but to cell without obvious inhibiting effect, tool
Body is see the patent of invention for being disclosed as CN106977499A.Bcl-xl inhibitor A-1331852 (shown in structure such as following formula (II))
It is a kind of effective, selectivity Bcl-xl inhibitor, may be made in treating cancer, immune and autoimmune disease
With;
It has had not yet to see and has been used in combination to treat lung cancer by above-mentioned fluorescence probe and Bcl-xl inhibitor A-1331852
Relevant report.
Invention content
The technical problem to be solved in the present invention is to provide a kind of pharmaceutical composition for treating lung cancer, in the pharmaceutical composition
Two component synergistic effects, make its therapeutic effect to lung cancer be significantly better than the effect of single Bcl-xl inhibitor A-1331852
The function and effect of effect and single fluorescence probe NA-2a.
The pharmaceutical composition for the treatment of lung cancer of the present invention, the Bcl-xl inhibitor A- containing the upper effective dose for the treatment of
1331852 and following formula (I)s shown in structure fluorescence probe NA-2a;
" effective dose in treatment " refers to the amount of Bcl-xl inhibitor A-1331852 contained in pharmaceutical composition
The activity of lung cancer tumor strain can be effectively inhibited, achievees the effect that treat lung cancer.The difference of administration object, the effective dose is not yet
Together, it can be specifically determined according to the common knowledge and the prior art of those skilled in the art.
The pharmaceutical composition of co-action treatment lung cancer of the present invention, is preferably inhibited by single formulation Bcl-xl
Agent A-1331852 and single formulation fluorescence probe NA-2a (fluorescence probe NA-2a is made into a preparation) compositions.It is described
Single formulation Bcl-xl inhibitor A-1331852 directly can be obtained commercially, and single formulation fluorescence probe NA-2a is then
Fluorescence probe NA-2a can be prepared into single formulation by existing conventional techniques.
It, can be by single formulation Bcl-xl inhibitor A-1331852 and single formulation fluorescence probe in specific medication
NA-2a takes simultaneously, can also first take single formulation Bcl-xl inhibitor A-1331852 and take single formulation fluorescence probe again
NA-2a can also first take single formulation fluorescence probe NA-2a and take single formulation Bcl-xl inhibitor A-1331852 again.It is adopting
During with successively taking single formulation Bcl-xl inhibitor A-1331852 and single formulation fluorescence probe NA-2a, preferably formerly take
With taking another preparation again after a preparation 12h.
Fluorescence probe NA-2a the present invention also provides structure shown in following formula (I)s is in enhancing Bcl-xl inhibitor A-
Application in the therapeutic effect of 1331852 pairs of lung cancer.
Compared with prior art, the fluorescence probe NA-2a and Bcl-xl inhibitor A- in pharmaceutical composition of the present invention
1331852 synergistic effects, open cell permeability by fluorescence probe NA-2a, are not destroying Bcl-xl inhibitor A-
1331852 function and under the premise of ensureing cell integrity, helps Bcl-xl inhibitor A-1331852 to enter in cell and plays
Effect treats lung cancer effect to reach significantly more.The Vitro Experimental Results of the applicant show for A549 lung carcinoma cells
Strain, using pharmaceutical composition of the present invention to the inhibiting rate of cell strain growth compared with single use Bcl-xl inhibitor A-
1331852 improve 20-30%, and more than 60% is improved compared with single use fluorescence probe NA-2a.
Specific embodiment
With reference to specific embodiment, the present invention is described in further detail, to more fully understand present disclosure, but
The present invention is not limited to following embodiments.
Embodiment 1:It is prepared by fluorescence probe NA-2a
1) bromo- 1, the 8- naphthalic anhydrides of 4- are weighed to be dissolved in 150mL ethyl alcohol, stir and add in 3,4- (methylenedioxy) phenyl ethylamines
(molar ratio of the bromo- 1,8- naphthalic anhydrides of 4- and 3,4- (methylenedioxy) phenyl ethylamines is 1:1.2), 80 DEG C of reaction temperature, react into
Journey carries out tracking and monitoring using thin-layer chromatography.After reaction, reaction system is cooled to room temperature, filters and retains filter cake, made
With ethanol rinse filter cake, yellow solid NA-1a is obtained, yield is about 90.47%;1H NMR(500MHz,DMSO-d6)δ:8.53
(ddd, J=9.5,7.9,1.0Hz, 2H), 8.31 (d, J=7.9Hz, 1H), 8.20 (d, J=7.9Hz, 1H), 7.99-7.96
(m, 1H), 6.85 (d, J=1.6Hz, 1H), 6.80 (s, 1H), 6.69 (dd, J=7.9,1.7Hz, 1H), 5.97 (s, 2H),
4.20-4.15 (m, 2H), 2.84 (t, J=7.5Hz, 2H);13C NMR(126MHz,DMSO-d6)δ:162.86,162.82,
147.36,145.78,132.78,132.54,131.72,131.50,131.11,129.90,129.30,128.94,128.36,
122.79,122.01,121.61,109.09,108.33,100.82,41.39,33.19.
2) NA-1a is weighed to be dissolved in dimethyl sulfoxide (DMSO), add in glycine ethyl ester and triethylamine (NA-1a, glycine ethyl ester and
The molar ratio of triethylamine is 1:1.5:2), 135 DEG C of reaction temperature, reaction process carry out tracking and monitoring using thin-layer chromatography.Reaction
After, reaction system is cooled to room temperature, and is poured into ice water, there is yellow solid precipitation, is made to be extracted with ethyl acetate three times, be collected
Merge ester layer and with anhydrous MgSO4It is dry, solvent is removed under reduced pressure, gained crude product carries out silica gel column chromatography separating purification (VPetroleum ether:
VEthyl acetate=20:1~5:1) bright yellow solid 2.9g, yield 65%, are obtained.
Nuclear magnetic resonance spectroscopy, carbon-13 nmr spectra, Electrospray Ionization Mass Spectrometry, specific wave spectrum are carried out to gained bright yellow solid
Characteristic is as follows:
(1) nuclear magnetic resonance spectroscopy:
1H NMR(400MHz,DMSO-d6)δ:8.66 (d, J=8.4Hz, 1H), 8.46 (d, J=7.2Hz, 1H), 8.26
(d, J=8.5Hz, 1H), 8.14 (s, 1H), 7.74 (t, J=7.8Hz, 1H), 6.90-6.75 (m, 2H), 6.67 (dd, J=
10.7,9.0Hz, 2H), 5.97 (s, 2H), 4.29 (d, J=5.5Hz, 2H), 4.17 (q, J=7.1Hz, 4H), 2.90-2.74
(m,2H),1.23(s,3H)。
(2) carbon-13 nmr spectra:
13C NMR(101MHz,DMSO-d6)δ:170.38,164.07,163.26,150.81,147.72,146.10,
134.38,133.18,131.25,130.11,129.68,128.86,125.23,122.45,121.93,120.68,109.44,
109.31,108.66,104.88,101.16,61.26,40.63,40.42,40.21,40.00,39.79,39.58,39.37,
33.84,14.59。
(3) electrospray ionization mass spectrum:ESI-MSm/z:445.14[M-H]-
Accordingly, it can be determined that above-mentioned bright yellow solid product is 4- (carbethoxyl group methylamino)-N- (3,4- (methylenedioxy) benzene
Ethyl) -1,8-naphthalimide, shown in chemical structural formula such as following formula (I):
Embodiment 2:Fluorescence probe NA-2a and Bcl-xl inhibitor A-1331852 drug combinations are to lung cancer A549 cell strain
The influence of proliferation
Human lung cancer cell A549's cell strain is selected in this experiment.Cell strain culture used is in calf serum containing 10wt%, 100U/
ML penicillin, 100U/mL streptomysins 1640 culture medium in, put 37 DEG C of 5%CO containing volumetric concentration2It is cultivated in incubator.Used
NA-2a is prepared by 1 the method for above-described embodiment, is purified gained, purity >=95%.Bcl-xl inhibitor A- used
1331852 are purchased from Selleck.cn.Match during experiment using DMSO as NA-2a active compound of the solvent with 2mM and by solvent of DMSO
The Bcl-xl inhibitor A-1331852 of 1mM are added in after being diluted to a certain concentration with culture medium in 96 orifice plates, experiment packet
Situation is:
Experimental group, it is specific as follows including 2 groups:
Test 1 group:That is 2a (12h)+xl groups first handle 12h using fluorescence probe NA-2a, reuse Bcl-xl inhibitor
A-1331852 handles 48h;
Test 2 groups:That is xl (12h)+2a groups first handle 12h using Bcl-xl inhibitor A-1331852, reuse fluorescence
Probe NA-2a handles 48h;
Blank group:That is CON groups, in addition to probe and Bcl-xl inhibitor A-1331852 is not added with, other conditions are and experimental group
It is identical;
Compare 1 group:That is 2a (60h) group, without using Bcl-xl inhibitor A-1331852 processing, using only fluorescence probe NA-
2a handles 60h under equal experiment condition;
Compare 2 groups:That is 2a (48h) group, without using Bcl-xl inhibitor A-1331852 processing, using only fluorescence probe NA-
2a handles 48h under equal experiment condition;
Compare 3 groups:That is xl (60h) without fluorescence probe NA-2a processing, exists using only Bcl-xl inhibitor A-1331852
60h is handled under equal experiment condition;
Compare 4 groups:That is xl (48h) without fluorescence probe NA-2a processing, exists using only Bcl-xl inhibitor A-1331852
48h is handled under equal experiment condition.
(1) dosing for the first time
The lung cell A549 in growth period of taking the logarithm is inoculated in 96 orifice plates, after trypsin digestion, with small containing 10%
The culture solution of cow's serum is configured to the cell suspension of a concentration of 5000/mL, is inoculated in 96 well culture plates with every 180 μ L of hole,
Make cell density to be measured to 1000~10000/hole (the sterile PBS of edge hole is filled);5%CO2, 37 DEG C are incubated for 24 hours, until thin
Born of the same parents' individual layer is paved with bottom hole, carries out dosing for the first time.2a (12h)+xl is organized and 2a (60h) groups add in 20 μ L NA-2a dilutions, makes it
Final concentration of 5 μm of ol/L in culture solution, xl (12h)+2a are organized and xl (60h) groups add in 20 μ L Bcl-xl inhibitor A-
1331852 inhibitor dilutions make its final concentration of 10 μm of ol/L in culture solution, and other groups are supplied respective volume culture
Liquid, in 5%CO2, 37 DEG C of incubation 12h, 5 multiple holes of setting.
(2) it is administered again
After first administration, it is administered again.During administration, 2a (12h)+xl groups and xl (48h) groups add in 20 μ L
Bcl-xl inhibitor A-1331852 dilutions make its final concentration of 10 μm of ol/L in culture solution;Xl (12h)+2a groups and 2a
(48h) group adds in 20 μ L NA-2a dilutions, makes its final concentration of 5 μm of ol/L in culture solution;Other groups are supplied corresponding body
Product culture solution, in 5%CO2, 37 DEG C of incubation 48h.
(3) viability examination
After being administered again, the MTT solution (5mg/mL PBS, i.e. 0.5%MTT) of 10 μ L is added in per hole, continues to cultivate
4h;Culture is terminated, carefully sucks culture solution in hole, 100 μ LDMSO are added in per hole and fully dissolve first a ceremonial jade-ladle, used in libation precipitation, oscillator mixing
Afterwards, it is 570nm with wavelength in microplate reader, reference wavelength measures the OD value in each hole for 630nm;It is calculated using following formula each
Group is to the inhibiting rate of cell strain growth, and result is as described in Table 1:
Embodiment 3:Fluorescence probe NA-2a and Bcl-xl inhibitor A-1331852 drug combinations are to lung cancer cell line NCI-
The influence of H460 cell Proliferations
Embodiment 2 is repeated, unlike, used cell strain is lung cancer cell line NCI-H460.
Each group to the inhibiting rate of cell strain growth as described in Table 1.
Embodiment 4:Fluorescence probe NA-2a and Bcl-xl inhibitor A-1331852 drug combinations are to lung cancer cell line H1299
The influence of cell Proliferation
Embodiment 2 is repeated, unlike, used cell strain is lung cancer cell line H1299.
Each group to the inhibiting rate of cell strain growth as described in Table 1.
Embodiment 5:Fluorescence probe NA-2a and Bcl-xl inhibitor A-1331852 drug combinations are to lung cancer cell line HCC-
The influence of 827 cell Proliferations
Embodiment 2 is repeated, unlike, used cell strain is lung cancer cell line HCC-827.
Each group to the inhibiting rate of cell strain growth as described in Table 1.
Table 1:
As shown in Table 1, in lung cancer cell line, the cell viability of 2a (12h)+xl groups and xl (12h)+2a groups is less than CON
Group, less than xl (60h) and xl (48h) group, less than 2a (60h) groups and 2a (48h) group.As it can be seen that in the help of light probe NA-2a
Under, Bcl-xl inhibitor A-1331852 is significantly increased to the inhibiting rate of cell.
In conclusion pharmaceutical composition of the present invention can enhance the therapeutic effect to lung cancer, show significant
Pharmacology acts synergistically, and is expected to be used for the probe in the drug combination of other inhibitor, being expected to be used for the probe and institute
State drug combination of the inhibitor in other tumor cell lines.
Claims (1)
1. a kind of pharmaceutical composition for treating lung cancer, it is characterised in that:Bcl-xl inhibitor A- containing the upper effective dose for the treatment of
1331852 and following formula (I)s shown in structure fluorescence probe NA-2a;
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Citations (5)
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CN103987711A (en) * | 2011-10-14 | 2014-08-13 | 艾伯维公司 | 8-carbamoyl-2-(2,3-di substituted pyrid-6-yl)-1,2,3,4-tetrahydroisoquinoline derivatives as apoptosis-inducing agents for the treatment of cancer and immune and autoimmune diseases |
WO2016131100A1 (en) * | 2015-02-18 | 2016-08-25 | The Walter And Eliza Hall Institute Of Medical Research | Methods of treating infectious diseases |
CN106770611A (en) * | 2016-12-22 | 2017-05-31 | 广西师范大学 | One kind enters mitochondrial method for cell in-situ detection micromolecular compound |
CN106977499A (en) * | 2017-03-27 | 2017-07-25 | 广西师范大学 | A kind of fluorescence probe and its synthetic method and application that effect is directly targeted with mitochondria |
WO2017172826A1 (en) * | 2016-03-28 | 2017-10-05 | Presage Biosciences, Inc. | Pharmaceutical combinations for the treatment of cancer |
-
2018
- 2018-01-11 CN CN201810028516.5A patent/CN108261414B/en not_active Expired - Fee Related
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
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CN103987711A (en) * | 2011-10-14 | 2014-08-13 | 艾伯维公司 | 8-carbamoyl-2-(2,3-di substituted pyrid-6-yl)-1,2,3,4-tetrahydroisoquinoline derivatives as apoptosis-inducing agents for the treatment of cancer and immune and autoimmune diseases |
WO2016131100A1 (en) * | 2015-02-18 | 2016-08-25 | The Walter And Eliza Hall Institute Of Medical Research | Methods of treating infectious diseases |
WO2017172826A1 (en) * | 2016-03-28 | 2017-10-05 | Presage Biosciences, Inc. | Pharmaceutical combinations for the treatment of cancer |
CN106770611A (en) * | 2016-12-22 | 2017-05-31 | 广西师范大学 | One kind enters mitochondrial method for cell in-situ detection micromolecular compound |
CN106977499A (en) * | 2017-03-27 | 2017-07-25 | 广西师范大学 | A kind of fluorescence probe and its synthetic method and application that effect is directly targeted with mitochondria |
Non-Patent Citations (2)
Title |
---|
M MILANI ET AL: "DRP-1 is required for BH3 mimetic-mediated mitochondrial fragmentation and apoptosis", 《CELL DEATH AND DISEASE》 * |
吴亦明: "1,8-萘二甲酰亚胺衍生物NA-17对肝癌细胞株HepG2的体外抗肿瘤作用研究", 《广西师范大学学报(自然科学版)》 * |
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