CN107281180A - Application of the 8- alkyl berberine salts in prevention and treatment lung-cancer medicament is prepared - Google Patents
Application of the 8- alkyl berberine salts in prevention and treatment lung-cancer medicament is prepared Download PDFInfo
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Abstract
The invention discloses application of 8 alkyl berberine salts in prevention and treatment lung-cancer medicament is prepared, the molecular structural formula of 8 alkyl berberine salt is：Wherein, X=F‑、Cl‑、Br‑Or I‑, R1=CnH2n+1, n=12~22, such compound have preferable anti-lung cancer effect, especially alkyl chain carbon number be 16~22 when, its anti-lung cancer effect is significantly better than berberine salt, available for prepare prevent and treat lung-cancer medicament.
Description
Technical field
The invention belongs to field of medicaments, and in particular to 8- alkyl berberine salts are in prevention and treatment lung-cancer medicament is prepared
Using.
Background technology
Jamaicin (Berberine) is also known as berberine, is one of main active of the coptis, is a kind of quaternary amine ionic
Morphinane alkaloid.Jamaicin has the pharmacological action such as antibacterial, anti-inflammatory, antipyretic, hypoglycemic, reducing blood lipid, anticancer, faces
It is the most frequently used on bed to treat bacillary dysentery and enterogastritis.Research finds that Berberine hydrochloride and its some structural derivatives have
There are a variety of pharmacological activity such as antibacterial, anti-inflammatory, antitumor, hypoglycemic and reducing blood lipid, therefore, Berberine hydrochloride pharmacology is made
With and structural modification research turn into study hotspot.
As Authorization Notice No. discloses the synthesis side of 8- octyl berberine hydrochlorides for CN100494193C patent document
Method and application, antibacterial activity, reducing blood lipid and the hypoglycemic activity of the 8- octyl berberine hydrochlorides that the patented method is obtained
Apparently higher than berberine salt；Authorization Notice No. discloses a class chain alkyl barberry for CN101104618B patent document
Alkali salt derivative and synthetic method, the long chain alkyl berberine salt derivative have obvious reducing blood lipid and hypoglycemic activity；
Publication No. CN103127102A patent document discloses 8- the third dicyan jamaicins answering in antineoplastic is prepared
With there is the compound preferable tumor suppression to imitate to liver cancer cells, leukaemia, lung adenocarcinoma cell and pancreatic cancer cell
Fruit is substantially；Publication No. CN102225961A patent document disclose the coupling cholic acid new derivatives of jamaicin 9 and
Its preparation method, the invention passes through jamaicin and chlolic acid derivatives in the case where fully keeping the antineoplastic pharmacological activity of jamaicin
Berberinc derivate of the reaction generation with hepatic targeting；Publication No. CN104208061A patent document is disclosed
The medical usage of 9-O-R- berberinc derivates, the compound not only can effectively suppress the propagation of glioma cell, moreover it is possible to
Suppress migration and the invasive ability of cell, while Mitochondrially targeted delivery system can also be used as.
So far, there is not yet report of the long-chain 8- alkyl berberine salts in terms of anti-lung cancer.
The content of the invention
It is an object of the invention to provide application of the long-chain 8- alkyl berberine salts in prevention and treatment lung-cancer medicament is prepared,
Such compound anti-lung cancer activity increases with the increase of long alkyl chains, when carbon number is 12~22, its anti-lung cancer activity
Apparently higher than berberine salt.
Purposes of the 8- alkyl berberine salts that the present invention is provided in prevention and treatment lung-cancer medicament is prepared, wherein, 8- alkyl
The molecular structural formula of berberine salt is as follows：
In formula, X is F-、Cl-、Br-Or I-；
R1For CnH2n+1, n=12~22.
Applicants have found that, after jamaicin enters in vivo, " liver " and " spleen " are mainly distributed on, lung is distributed in
Seldom, (such as 8- octyl groups are small compared with short 8- alkyl berberine salts for other coptis alkaloids and long alkyl chains for the quantity in portion
Bark of a cork tree alkali salt) etc. be also mainly distributed on the organ such as " liver " and " spleen ", therefore they are used in treatment PUD D especially
Be anti-lung cancer medicine in terms of prospect it is bad.
And found through substantial amounts of research, (long alkyl chains are more than 12 for the longer 8- alkyl berberine salts of long alkyl chains
After, such as 8- cetyls berberine salt) enter in vivo after, the overwhelming majority enters lung, has obvious lung to target
Property.
Because the 8- alkyl berberine salts obtained by being modified through chain alkyl have antibacterial activity, with reference to its lung's targeting,
Applicant considers further to be applied to 8- cetyls berberine salt to prepare in the drug research for treating PUD D then.
But found through many experiments, although 8- cetyl berberine salts have lung's targeting, do not ensure that to lung
Portion's disease is effective：Such as in treating pulmonery tuberculosis experiment, although 8- cetyls berberine salt has treating pulmonery tuberculosis bacterium in vitro
Effect, still, living animal experiment has been found that 8- cetyls berberine salt to " pulmonary tuberculosis " of experiment mice but
It is invalid.
And in further research experiment, applicant has been surprisingly found that 8- cetyls berberine salt is external and condition of living body
Under good inhibiting effect is respectively provided with to lung carcinoma cell, compared to Berberine hydrochloride salt, 8- cetyl berberine salts it is anti-
Lung cancer activity is greatly improved, by further study show that, carbon number has and 8- for 12~22 8- alkyl berberine salts
The similar anti-lung cancer effect for being significantly higher than low carbon number 8- alkyl berberine salts of cetyl berberine salt, especially carbon number
For 16~22 when, its anti-lung cancer effect is especially pronounced.
Therefore, preferably, the 8- alkyl berberine salts are 8- cetyls berberine salt, 8- octadecyl jamaicins
Salt, 8- eicosyls berberine salt or 8- docosyl berberine salts.
Further, the survival dose of 8- alkyl berberine salts of the invention is significantly less than the survival dose of other berberine salts, institute
The day dosage for stating 8- alkyl berberine salts is 0.01-1.0g/ people, and preferably day dosage is 0.05-0.2g/ people.Condition of living body
Under, the berberine salt of the anti-lung cancer activities of the 8- cetyl berberine salts of 0.1g/ days people apparently higher than 1g/ days people.Its
In, in the present invention, day dosage and the conversion relation of mouse dose be：Day dosage=mouse dose × people's weight ÷ 9.01,
Wherein, people is calculated by 60kg again, and 9.01 be mouse and the conversion coefficient of people.
In the present invention, the synthetic method of long-chain 8- alkyl berberine salts is as follows：
(1) using anhydrous tetrahydro furan, ether or dioxane as reaction dissolvent, under nitrogen protection with magnesium chips and halo
Alkane in molar ratio 1.2:1 prepares corresponding grignard reagent, and the consumption of solvent and alkyl halide adds 50mL for 0.1mol alkyl halides
Solvent；
(2) anhydrous tetrahydro furan, ether or dioxane are added in Berberine hydrochloride, Berberine hydrochloride suspension is obtained
Afterwards, ice bath is carried out under nitrogen protection, less than 10 DEG C are cooled to, and the mol ratio of Berberine hydrochloride salt and alkyl halide is 1:2,
The consumption of solvent and Berberine hydrochloride salt is 0.1mol Berberine hydrochlorides salt addition 50mL solvents；
(3) under nitrogen protection and ice bath, grignard reagent is added in Berberine hydrochloride salt suspension, stirred simultaneously, plus
Ice bath is removed after complete, is heated to reflux finishing its reaction；
(4) separation obtains supernatant, is concentrated in vacuo into after solid and uses methanol crystallization, obtains 8- alkyl dihydroberberine halogen
Hydrochlorate intermediate；
(5) 8- alkyl dihydroberberine halate intermediates are aoxidized in acetic acid with halogen, obtains 8- alkyl berberines
Halate product, 8- alkyl dihydroberberine halate intermediate is 1 with halogen mol ratio:1.5；
Products therefrom can differentiate whether be pure material, thin-layer chromatography condition using thin-layer chromatography：Silica G making sheet, expansion
Agent is benzene：Ethyl acetate：Isopropanol：Methanol：Ammoniacal liquor=6:3:1.5:1.5:0.5；Agents useful for same is that analysis is pure.
Sample after purification determines IR spectrograms (KBr tablettings) using Perkin Elmer one types infrared spectrophotometer；
UV analyses determine ultraviolet spectra using Hitachi U-1800 types ultraviolet specrophotometer；1H NMR and13NMR points of C
Analysis is using the hydrogen spectrum and carbon spectrum of the type nmr determination compounds of Bruker 300, and solvent is DMSO-d6,1H NMR
TMS is designated as in determining.
Using the above method, structural modification, the 8- tetradecanes of acquisition are carried out to Berberine hydrochloride salt with chloro n-tetradecane
The structural characterization structure of base berberine hydrochloride is as follows：
Yellow powdery solid, is dissolved in methanol, Rf=0.76, and yield is 65.6%.MP=173~174 DEG C；UV(CH3OH)
λmax：348(0.295),266(0.333)nm；1HNMR(DMSO-d6)δ：0.86(t,3H,-CH3),1.31(m,8H,
-(CH2)4-),1.58(m,2H,-CH2-),1.77(m,2H,Ar-CH2-),3.15(t,2H,5-CH2),3.75(t,2H,
Ar-CH2-),4.03,4.06(each s,6H,-OCH3),4.81(d,2H,6-CH2),6.17(s,2H,-OCH2O-),7.11(s,
1H,4-CH),7.73(s,1H,1-CH),8.02(d,1H,11-CH),8.19(d,1H,12-CH),8.80(s,1H,13-CH)；13CNMR(DMSO-d6)δ：13.80,21.93,26.53,27.78,28.48,28.53,29.20,31.10,32.15,49.52,
56.94,61.45,101.85,105.65,107.54,120.07,121.08,121.28,124.60,125.07,130.63,132.52,
137.67,145.51,147.49,149.48,152.37,160.96.IR(KBr)v:3435,3036,3007,2953,2921,
2852,1630,1617,1602,1550,1509,1485,1466cm-1。
The following is the structural characterization result of Berberine hydrochloride salt：
Rf=0.43, UV (CH3OH)λmax:348(0.284),266(0.322)nm；1HNMR(DMSO-d6)δ:3.21
(t,2H,5-CH2),4.07,4.09(each s,6H,-OCH3),4.93(d,2H,6-CH2),6.12(s,2H,-OCH2O-),
7.091(s,1H,4-CH),7.80(s,1H,1-CH),8.00(d,1H,11-CH),8.21(d,1H,12-CH),8.94(s,
1H,13-CH),9.89(s,1H,8-CH)；13CNMR(DMSO-d6)δ：26.65,49.63,57.08,61.57,101.10,
105.82,107.54,120.29,121.19,121.41,124.68,125.25,130.78,132.67,137.83,145.57,
147.63,149.66,152.44,160.17.IR(KBr)v:3413,3017,3000,2946,2909,2846,1634,1619,
1601,1567,1509,1480,1458cm-1。
The structural characterization number of Berberine hydrochloride salt and 8- myristyl berberine hydrochlorides is contrasted it has been found that hydrochloric acid after modification
In berberine salt molecule, in addition to 8 proton peaks disappear, newly occurs the corresponding peak of alkyl in addition, the site for showing modification is
8- alkyl berberine hydrochlorides.
Above-mentioned as shown by data, obtained compound is 8- myristyl berberine hydrochlorides really.Using same method,
8- dodecyls berberine hydrochloride, 8- cetyls berberine hydrochloride, 8- octadecyl jamaicin hydrochloric acid can be synthesized
Salt, 8- eicosyls berberine hydrochloride, 8- docosyl berberine hydrochlorides etc..
The compounds of this invention can be administered by modes such as oral, injection or external applications in the form of compositions.For oral
When, conventional solid pharmaceutical preparation can be made into, liquid preparation such as water oil is made in such as tablet, pulvis, granula, capsule
Suspending agent or syrup etc.；During for drug administration by injection, injection solution or oil-suspending agent etc. can be made into；Can for external application
So that emplastrum or liniment is made.Any of the above formulation can be prepared according to the conventional production process of pharmaceutical field.Chemical combination of the present invention
The amount of application of thing can be according to route of administration, the age of patient, body weight, the change such as type and the order of severity for treating disease.
The beneficial effects of the invention are as follows：The invention provides the new application of long-chain 8- alkyl berberine salts, such compound
With preferable anti-lung cancer effect, especially alkyl chain carbon number be 12~22 when, it is small that its anti-lung cancer effect is significantly better than hydrochloric acid
Bark of a cork tree alkali salt, lung-cancer medicament is prevented and treated available for preparing, and its live body anti-lung cancer activity is higher than jamaicin more than 100 times,
Dosage is significantly less than other berberine salts.
Embodiment
Below by specific embodiment, technical scheme is described further.
If not raw material of the present invention and equipment are refered in particular to, it is commercially available or commonly used in the art, embodiment
In method, be the conventional method of this area unless otherwise instructed.
Embodiment 1：8- dodecyl berberine hydrochlorides
Its preparation is as follows：
1. all reaction glass apparatus, are dried, dried magnesium chips 0.12mol is weighed and is placed in 250mL three-neck flasks
In, using anhydrous tetrahydro furan 60mL as reaction dissolvent, 0.1mol chloro n-dodecane is added under nitrogen protection,
Prepare corresponding RMgBr.
2. the drying hydrochloric acid berberine salt for, weighing 0.05mol is placed in 500mL three-neck flasks, adds 25mL anhydrous
Tetrahydrofuran, make after hydrochloric acid berberine salt suspension under nitrogen protection ice bath to 10 DEG C.
3., the RMgBr of preparation is slowly added into Berberine hydrochloride salt suspension under nitrogen protection and ice bath, simultaneously
Stirring, removes ice bath, makes to return to room temperature after adding, be heated to reflux reaction after 2h and finish.
4., reaction solution is centrifuged, taken after supernatant, tetrahydrofuran extraction is added, it is repeated multiple times, monitored with thin-layer method
The extraction situation of reaction product, untill raw material point very little.Centrifuged supernatant, which is concentrated in vacuo into after solid, uses methanol crystallization,
Crystal is 8- dodecyl dihydroberberine hydrochlorides.
5. 0.015mol Cl, are taken2Dissolve in 10mL glacial acetic acid, weigh 0.01mol 8- dodecyl dihydroberberine salt
Hydrochlorate is dissolved in after 100mL glacial acetic acid, and two liquid are mixed, 1h is heated to reflux.
6., reaction solution cooled and filtered, precipitates the Na with 10%2S2O5Solution is washed, last water washing and precipitating, and precipitation is used
Methanol crystallization, produces 8- dodecyl berberine hydrochlorides.
Embodiment 2：8- myristyl jamaicin bromates
Its preparation process is as follows：
1. all reaction glass apparatus, are dried, dried magnesium chips 0.12mol is weighed and is placed in 250mL three-neck flasks
In, using absolute ether 60mL as reaction dissolvent, 0.1mol bromo n-tetradecane is added under nitrogen protection, is prepared
Corresponding RMgBr.
2. the drying hydrochloric acid berberine salt for, weighing 0.05mol is placed in 500mL three-neck flasks, adds 25mL anhydrous
Ether, make after hydrochloric acid berberine salt suspension under nitrogen protection ice bath to 0 DEG C.
3., the RMgBr of preparation is slowly added into Berberine hydrochloride salt suspension under nitrogen protection and ice bath, simultaneously
Stirring, removes ice bath, makes to return to room temperature after adding, be heated to reflux reaction after 2h and finish.
4., reaction solution is centrifuged, taken after supernatant, extracted by ether is added, it is repeated multiple times, monitored and reacted with thin-layer method
The extraction situation of product, untill raw material point very little.Centrifuged supernatant, which is concentrated in vacuo into after solid, uses methanol crystallization, crystal
As 8- myristyls dihydroberberine bromate.
5. 0.015mol Br, are measured with pipette2Dissolve in 10mL glacial acetic acid, weigh 0.01mol 8- myristyls two
Hydrogen jamaicin bromate is dissolved in the mixing of two liquid after 100mL glacial acetic acid, is heated to reflux 1h.
6., reaction solution cooled and filtered, precipitates the Na with 10%2S2O5Solution is washed, last water washing and precipitating, and precipitation is used
Methanol crystallization, produces 8- myristyl jamaicin bromates.
Embodiment 3：8- cetyl jamaicin iodates
Its preparation process is as follows：
1. all reaction glass apparatus, are dried, dried magnesium chips 0.12mol is weighed and is placed in 250mL three-neck flasks
In, using dioxane 60mL as reaction dissolvent, 0.1mol bromo hexadecane is added under nitrogen protection, is prepared
Corresponding RMgBr.
2. the drying hydrochloric acid berberine salt for, weighing 0.05mol is placed in 500mL three-neck flasks, adds 25mL dioxies
Six rings, make after hydrochloric acid berberine salt suspension under nitrogen protection ice bath to 0 DEG C.
3., the RMgBr of preparation is slowly added into Berberine hydrochloride salt suspension under nitrogen protection and ice bath, simultaneously
Stirring, removes ice bath, makes to return to room temperature after adding, be heated to reflux reaction after 2h and finish.
4., reaction solution is centrifuged, taken after supernatant, dioxane extraction is added, it is repeated multiple times, monitored with thin-layer method
The extraction situation of reaction product, untill raw material point very little.Centrifuged supernatant, which is concentrated in vacuo into after solid, uses methanol crystallization,
Crystal is 8- cetyl dihydroberberine iodates.
5. 0.015mol I, are measured with pipette2Dissolve in 10mL glacial acetic acid, weigh 0.01mol 8- cetyl dihydros
Jamaicin iodate is dissolved in the mixing of two liquid after 100mL glacial acetic acid, is heated to reflux 1h.
6., reaction solution cooled and filtered, precipitates the Na with 10%2S2O5Solution is washed, last water washing and precipitating, and precipitation is used
Methanol crystallization, produces 8- cetyl jamaicin iodates.
Embodiment 4：8- docosyl jamaicin fluorate
Its preparation process is as follows：
1. all reaction glass apparatus, are dried, dried magnesium chips 0.12mol is weighed and is placed in 250mL three-neck flasks
In, using absolute ether 60mL as reaction dissolvent, 0.10mol bromo n-docosane, system are added under nitrogen protection
Standby corresponding RMgBr.
2. the drying hydrochloric acid berberine salt for, weighing 0.05mol is placed in 500mL three-neck flasks, adds 25mL anhydrous
Ether, make after hydrochloric acid berberine salt suspension under nitrogen protection ice bath to 0 DEG C.
3., the RMgBr of preparation is slowly added into Berberine hydrochloride salt suspension under nitrogen protection and ice bath, simultaneously
Stirring, removes ice bath, makes to return to room temperature after adding, be heated to reflux reaction after 2h and finish.
4., reaction solution is centrifuged, taken after supernatant, extracted by ether is added, it is repeated multiple times, monitored and reacted with thin-layer method
The extraction situation of product, untill raw material point very little.Centrifuged supernatant, which is concentrated in vacuo into after solid, uses methanol crystallization, crystal
As 8- docosyls dihydroberberine bromate.
5. 0.015mol F, are measured with pipette2Dissolve in 10mL glacial acetic acid, weigh 0.01mol 8- docosyls two
Hydrogen jamaicin fluorate is dissolved in the mixing of two liquid after 100mL glacial acetic acid, is heated to reflux 1h.
6., reaction solution cooled and filtered, precipitates the Na with 10%2S2O5Solution is washed, last water washing and precipitating, and precipitation is used
Methanol crystallization, i.e. 8- docosyls jamaicin fluorate.
Embodiment 5：Prepare 8- eicosyl berberine salt anti-tumor drug tablets
10 grams of 8- eicosyls berberine salts (medicine) are taken, 70 grams of pelletiod lactose (auxiliary material), magnesium stearate is added
15 grams of (auxiliary material), 5 grams of microcrystalline cellulose (auxiliary material), is suppressed into 0.5 gram of a piece of tablet, i.e., after being well mixed
Every pastille 50mg, orally, you can be used as anti-tumor drug.
Embodiment 6：Prepare 8- dodecyl berberine salt anti-tumor drug tablets：
10 grams of 8- dodecyls berberine salts (medicine) are taken, 80 grams of pelletiod lactose (auxiliary material), stearic acid is added
5 grams of magnesium (auxiliary material), 5 grams of microcrystalline cellulose (auxiliary material), 0.5 gram of a piece of tablet is suppressed into after being well mixed,
I.e. every pastille 50mg, orally, you can be used as anti-tumor drug.
Embodiment 7：Prepare 8- myristyl berberine salt anti-tumor drug capsules：
Take 10 grams of 8- myristyls berberine salts (medicine), add 80 grams of starch (diluent and disintegrant), micro-
Divide 10 grams of silica gel (glidant), be ground into powder after being well mixed, encapsulated, 0.25 gram one, i.e., every capsule
Pastille 25mg, orally, you can be used as anti-tumor drug.
Embodiment 8：Prepare 8- cetyl berberine salt anti-tumor drug capsules：
10 grams of 8- cetyls berberine salts (medicine) are taken, 40 grams of dextrin (diluent), CMS is added
40 grams of sodium (disintegrant), 10 grams of talcum powder (glidant), be well mixed, be ground into powder, be a granulated into particle or
Micropill, it is encapsulated, 0.25 gram one, i.e., every capsule medicated 25mg, orally, you can be used as anti-tumor drug.
Embodiment 9：The external anti-lung cancer effect of Berberine hydrochloride salt and 8- alkyl berberine salts
Test method：Lung carcinoma cell (A549) is conventionally cultivated, and is then seeded into 96 orifice plates, the addition 1 per hole
×106Individual cell, culture 24 hours after, per hole add various concentrations 8- alkyl berberine salts (0,0.1,0.2,0.4,
0.8th, 1.6,3.2,6.4,12.8,25.6mg/L), continue to cultivate 24 hours, cell survival amount is determined using mtt assay,
Its MTT concentration (concentration of complete inhibition cell growth) is calculated according to cell survival amount, 1 is the results are shown in Table.
The Berberine hydrochloride salt of table 1 and the external anti-lung cancer experimental result of 8- alkyl berberine salts
It can see from table, the external anti-lung cancer activity of 8- alkyl berberine salts is significantly better than Berberine hydrochloride salt.With
The alkyl chain carbon number increase of 8- alkyl berberine salts, anti tumor activity in vitro increased, but be more or less the same；From external
Antitumor activity sees that 8- octyls berberine salt and the alkyl berberine salts of 8- ten are best；With the further increasing of alkyl chain
Plus, external anti-lung cancer activity has a declining tendency.
Embodiment 10：The anti-lung cancer effect of Berberine hydrochloride salt and 8- alkyl berberine salts
(1) zoopery：Nude mice 120 (every 15~20g), is fed with basal feed observation 5 under experimental situation
After it, experimental animal is randomly divided into 12 groups, every group 10, is respectively：Normal group, model group, medicine group；
In the well-grown lung carcinoma cell of mouse forelimb single subcutaneous injection culture while administration, after 5 days, record gross tumor volume becomes
Change, after 20 days, take the lung of experimental animal, the situation of observation lung cancer lung transfer.
(2) anti-lung cancer experimental result is shown in Table 2
Anti-lung cancer experimental result (the tumor volume change/mm of the Berberine hydrochloride salt of table 2 and 8- alkyl berberine salts3)
It can see from table, with the alkyl chain carbon number increase of 8- alkyl berberine salts, tumour growth volume diminishes,
Show the increased activity of its anti-lung cancer, when alkyl chain carbon number is less than 12, its anti-lung cancer activity is poor；Work as alkyl chain carbon
When number is 12, significant change occurs for its anti-lung cancer activity, greatly enhances than before；When alkyl chain carbon number is 16, its
Anti-lung cancer activity reaches of a relatively high level, and increases in alkyl chain carbon number from 16 during 22, its anti-lung cancer
Activity is held essentially constant；It is also possible to find out, alkyl chain carbon number is the anti-of 12~22 8- alkyl berberine salts
Lung cancer activity is significantly higher than Berberine hydrochloride salt.
Lung's testing result shows that model group lung carcinoma cell is largely shifted to lung；Berberine hydrochloride salt group experimental animal
Lung cancer there occurs substantial amounts of transfer；As long alkyl chains increase, the quantity monotonic decreasing that lung carcinoma cell is shifted to lung,
To after 8- dodecyl jamaicins, the lung of experimental animal does not find tumour, shows that 8- alkyl berberines can suppress
Lung carcinoma cell is shifted to lung.
Embodiment 11：The anti-lung cancer dose-dependence of Berberine hydrochloride salt and 8- cetyl berberine salts compares
(1) zoopery：Nude mice 80 (every 15~20g), is fed with basal feed observation 5 days under experimental situation
Afterwards, experimental animal is randomly divided into 8 groups, every group 10, is respectively：Normal group, model group, medicine group；Give
In the well-grown lung carcinoma cell of mouse forelimb single subcutaneous injection culture while medicine, after 5 days, tumor volume change is recorded,
After 20 days, blood sampling detection blood serum tumor markers (CYFRA211) concentration.
(2) anti-lung cancer experimental result is shown in Table 3 and table 4
Anti-lung cancer experimental result (the tumor volume change/mm of the Berberine hydrochloride salt of table 3 and 8- cetyl berberine salts3)
It can see from table 3, even if the concentration of jamaicin reaches 1000mg/Kg, its live body anti-lung cancer activity is also paid no attention to
Think, then high dose has been difficult to be administered；And the anti-lung cancer activity of 8- cetyl berberine salts is preferably, during 10mg/Kg
There is preferable effect, still, after concentration is more than 100mg/Kg, effect increase is not obvious.Further it was found that,
The anti-lung cancer activity of cetyl berberine salt is better than 100mg/Kg jamaicin, i.e. cetyl barberry during 1mg/Kg
The live body anti-lung cancer activity of alkali salt is higher than jamaicin more than 100 times.
The influence experimental result of the Berberine hydrochloride salt of table 4 and 8- cetyls berberine salt to lung cancer marker concentration
CYFRA211 is to react the index whether lung cancer occurs transfer and transition probability.It can see from table 4, salt
Sour berberine salt group animal blood serum CYFRA211 concentration does not change, identical with model group, although showing hydrochloric acid barberry
Alkali salt has the effect for suppressing lung cancer growth, but does not suppress the effect of lung cancer metastasis；8- cetyl berberine salt groups
The CYFRA211 concentration of animal blood serum is remarkably decreased, in good dose-dependence, shows 8- cetyl barberries
Alkali salt not only has the effect for suppressing lung cancer growth, and with the effect for suppressing lung cancer metastasis.
Embodiment 12：The anti-liver cancer efficacy of Berberine hydrochloride salt and 8- alkyl berberine salts
(1) zoopery：Nude mice 130 (every 15~20g), is fed with basal feed observation 5 under experimental situation
After it, experimental animal is randomly divided into 13 groups, every group 10, is respectively：Normal group, model group, medicine group；
In the well-grown liver cancer cells of mouse forelimb single subcutaneous injection culture while administration, after 5 days, record gross tumor volume becomes
Change, after 20 days, take the lung of experimental animal, observe situation of the liver cancer to hepatic metastasis.
(2) anti-liver cancer and anti-experimental result is shown in Table 2
Anti-liver cancer and anti-experimental result (the tumor volume change/mm of the Berberine hydrochloride salt of table 5 and 8- alkyl berberine salts3)
It can see from table, Berberine hydrochloride salt anti-liver cancer efficacy is preferable；With the alkyl chain of 8- alkyl berberine salts
Length increase, the activity of anti-liver cancer and anti-does not have significant changes, after 8- alkyl berberine salt length is more than 16, anti-liver
Cancer activity has a declining tendency on the contrary.
Liver testing result shows, the trend of the oriented hepatic metastasis of model group liver cancer；The Berberine hydrochloride salt group of high dose is real
The liver for testing animal does not find liver cancer；Other each group experimental animals find the trend for having liver cancer growth, but and model group
Compare, the transfer of liver cancer has declined, show that 8- alkyl berberine salts have certain resisting liver cancer activity, but anti-liver cancer and anti-
Activity does not change with the increase of 8- alkyl berberine salt long alkyl chains.
Claims (6)
- Purposes of the 1.8- alkyl berberine salts in prevention and treatment lung-cancer medicament is prepared, the molecule of the 8- alkyl berberine salts Structural formula is as follows：Wherein, X=F-、Cl-、Br-Or I-；R1=CnH2n+1, n=12~22.
- 2. purposes according to claim 1, it is characterised in that the 8- alkyl berberine salts are 8- dodecyl barberries Alkali salt, 8- myristyls berberine salt, 8- cetyls berberine salt, 8- octadecyls berberine salt, 8- eicosyls Berberine salt or 8- docosyl berberine salts.
- 3. purposes according to claim 1 or 2, it is characterised in that the day dosage of the 8- alkyl berberines is 0.01-1.0g/ people.
- 4. purposes according to claim 3, it is characterised in that the day dosage of the 8- alkyl berberines is 0.05-0.2g/ People.
- 5. a kind of medicine for preventing and treating lung cancer, it is characterised in that the 8- alkyl berberine salts comprising treatment effective dose, With one or more pharmaceutically acceptable drug excipients.
- 6. the medicine of prevention and treatment lung cancer according to claim 1, it is characterised in that 8- alkyl berberine salts are 8- Dodecyl berberine salt, 8- myristyls berberine salt, 8- cetyls berberine salt, 8- octadecyls berberine salt, 8- eicosyls berberine salt or 8- docosyl berberine salts.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2019196955A1 (en) * | 2018-04-13 | 2019-10-17 | 中国医学科学院药物研究所 | Hydrophilic berberine derivative with r10 and r11 connected and application thereof in preparation of drugs |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20070298132A1 (en) * | 2002-05-03 | 2007-12-27 | Pharmchem Inc. | Berberine as a selective lung cancer agent |
| CN101787029A (en) * | 2010-03-05 | 2010-07-28 | 西南大学 | Long-chain alkyl coptisine halate derivative, synthesis method and application |
| CN102225961A (en) * | 2011-04-21 | 2011-10-26 | 东北林业大学 | Novel berberine 9-position coupled cholic acid derivative and preparation method thereof |
| CN102659777A (en) * | 2012-05-07 | 2012-09-12 | 雷海民 | Antitumor medicament |
| CN103127102A (en) * | 2011-11-22 | 2013-06-05 | 复旦大学 | Application of 8-propyl dicyan berberine in preparation of antitumor drug |
| CN103372210A (en) * | 2012-04-19 | 2013-10-30 | 上海迪亚凯特生物医药科技有限公司 | Application of berberine combined chemotherapeutic medicament in antitumor therapy |
| CN104208061A (en) * | 2013-06-04 | 2014-12-17 | 中山大学 | Medical application of berberine derivative |
-
2016
- 2016-04-05 CN CN201610204121.7A patent/CN107281180B/en not_active Expired - Fee Related
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20070298132A1 (en) * | 2002-05-03 | 2007-12-27 | Pharmchem Inc. | Berberine as a selective lung cancer agent |
| CN101787029A (en) * | 2010-03-05 | 2010-07-28 | 西南大学 | Long-chain alkyl coptisine halate derivative, synthesis method and application |
| CN102225961A (en) * | 2011-04-21 | 2011-10-26 | 东北林业大学 | Novel berberine 9-position coupled cholic acid derivative and preparation method thereof |
| CN103127102A (en) * | 2011-11-22 | 2013-06-05 | 复旦大学 | Application of 8-propyl dicyan berberine in preparation of antitumor drug |
| CN103372210A (en) * | 2012-04-19 | 2013-10-30 | 上海迪亚凯特生物医药科技有限公司 | Application of berberine combined chemotherapeutic medicament in antitumor therapy |
| CN102659777A (en) * | 2012-05-07 | 2012-09-12 | 雷海民 | Antitumor medicament |
| CN104208061A (en) * | 2013-06-04 | 2014-12-17 | 中山大学 | Medical application of berberine derivative |
Non-Patent Citations (3)
| Title |
|---|
| 丁阳平等: "8-烷基-13-溴代盐酸小檗碱合成及对人肝癌细胞株增殖的影响", 《中草药》 * |
| 庞婕等: "8-烷基小檗碱对焦虑模型小鼠行为学及脑组织神经递质的影响", 《中草药》 * |
| 金鑫等: "小檗碱的结构改造及其药理活性的研究进展", 《药学实践杂志》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2019196955A1 (en) * | 2018-04-13 | 2019-10-17 | 中国医学科学院药物研究所 | Hydrophilic berberine derivative with r10 and r11 connected and application thereof in preparation of drugs |
| CN110372689A (en) * | 2018-04-13 | 2019-10-25 | 中国医学科学院药物研究所 | R9With R10The hydrophily berberine type derivative of connection and its application for preparing drug |
| CN110372690A (en) * | 2018-04-13 | 2019-10-25 | 中国医学科学院药物研究所 | R10With R11The hydrophily berberine type derivative of connection and its application for preparing drug |
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