CN102659742A - Application of genistein derivative in preparing medicament for treating learning and memory disorder - Google Patents
Application of genistein derivative in preparing medicament for treating learning and memory disorder Download PDFInfo
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- 150000002273 genistein derivatives Chemical class 0.000 title abstract 2
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Abstract
The invention belongs to the field of chemical pharmaceutical technology, and in particular relates to application of a genistein derivative 4', 5'-dyhydroxy-7-[4-(N, N-diethylamino) butoxy] isoflavone in preparing a medicament for treating learning and memory disorder. 4', 5'-dyhydroxy-7-[4-(N, N-diethylamino) butoxy] isoflavone has the effect of promoting macrophage chemotactic fator (MCF)-7 cell proliferation and the action effect is in a bell jar type. The latent time of female castrated mice (oophorectomy is performed) in a water maze experiment is shortened and the error time of the mice is greatly decreased in a Y maze experiment. The fact indicates that 4', 5'-dyhydroxy-7-[4-(N, N-diethylamino) butoxy] isoflavone can effectively improve learning and memory capability. The improvement of learning and memory is consistent with the enhancement of phosphorylation of calcium-calmodulin dependent protein kinase (CaMk) II. 4', 5'-dyhydroxy-7-[4-(N, N-diethylamino) butoxy] isoflavone has good effects of improving learning and memory and can be used for preparing the medicament for improving learning and memory.
Description
One, technical field
The invention belongs to technical field of pharmaceutical chemistry, be specifically related to genistein verivate 4', the application of 5'-dihydroxyl-7-[4-(N, N-diethylin) butoxy] NOVASOY 400 in preparation treatment learning memory disorder medicine.
Two, background technology
Along with the aging of population and the increase of stress, the study cognitive disorder becomes serious social concern.Oestrogenic hormon and phytoestrogen have outstanding role (Barbara BS.Estrogen and cognitive aging in women.TRENDS in Pharmacological Sciences.2002 aspect the learning and memory improving; 23 (11): 527-534.; Craig MC and Murphy DG.Oestrogen, Cognition and the Maturing Female Brain.Journal of Neuroendocrinology 2006; 19:1-6).Except that climacteric and climacteric women; Someone took low dose of oestrogenic hormon once for male sex's dysmnesia patient; Successfully improved its learning and memory function (Sex steroids modify working memory.Janowsky JS; Chavez B, Orwoll E.J Cogn Neurosci.2000; 12 (3): 407-14).Because of oestrogenic hormon extensively acts on ER α and ER β; The bad meeting of dosage control causes relevant tumour (the Horwitz KB of oestrogenic hormon; Koseki Y, McGuire WL.Estrogen control of progesterone receptor in human breast cancer:role of estradiol and antiestrogen.Endocrinology.1978; 103 (5): 1742-51).For increasing the specificity of oestrogenic hormon to target spot; As much as possible reduce untoward reaction, the phytoestrogen genistein is carried out structure of modification, obtain genistein verivate 4' first; 5'-dihydroxyl-7-[4-(N, N-diethylin) butoxy] NOVASOY 400 (being called for short GS 14).4', 5'-dihydroxyl-7-[4-(N, N-diethylin) butoxy] NOVASOY 400 has stronger bonding force to ER β, can improve learning and memory better and reduce untoward reaction, improves the report that does not still have this class formation in the medicine of learning and memory aspect at present.
Three, summary of the invention
The problem that the present invention need solve is research phytoestrogen genistein verivate 4', and 5'-dihydroxyl-7-[4-(N, N-diethylin) butoxy] NOVASOY 400 improves the application in the learning and memory medicine in preparation.
4' according to the invention, the structural formula of 5'-dihydroxyl-7-[4-(N, N-diethylin) butoxy] NOVASOY 400 is following:
The present invention finds; 4', 5'-dihydroxyl-7-[4-(N, N-diethylin) butoxy] NOVASOY 400 can promote to rely on the propagation of the human breast cancer cell strain MCF-7 of oestrogenic hormon growth to a certain extent; This propagation can be suppressed by the antagonist ICI182670 of ERs; 4' is described, 5'-dihydroxyl-7-[4-(N, N-diethylin) butoxy] NOVASOY 400 still has estrogen activity.When giving female castration mouse (row ovariectomy) 4', behind 5' dihydroxyl-7-[4-(N, N-diethylin) butoxy] NOVASOY 400, in water maze laboratory, significantly shorten the latent period of mouse; In the Y maze experiment, the errors number of mouse significantly reduces.4' is described, 5'-dihydroxyl-7-[4-(N, N-diethylin) butoxy] NOVASOY 400 can effectively improve ability of learning and memory.
The improvement of this learning and memory is corresponding to the enhancing of CaMKII phosphorylation.
The invention has the beneficial effects as follows genistein verivate 4' according to the invention, 5'-dihydroxyl-7-[4-(N, N-diethylin) butoxy] NOVASOY 400 has the good effect that improves learning and memory, can be used for preparing the medicine that improves learning and memory.In the medicine that improves learning and memory of listing, do not see the report of this structure as yet, at present so this mechanical development is to improve the learning and memory medicine important meaning and far-reaching influence will be arranged.The invention provides a kind of good effect, technology new drug simple, with low cost, filled up the blank of this type of medicine.
Four, description of drawings
Fig. 1 .4', 5'-dihydroxyl-7-[4-(N, N-diethylin) butoxy] NOVASOY 400 (GS14) has increased the expression of mouse brain cortex CaMKII and pCaMKII.Sham: sham operated rats; OVX: ovariectomy group; GSL:GS 14 low dosages (1mg/kg); GSH:GS 14 high dosages (5mg/kg).X=Mean±SD，n=10。
##P<0.01vs?Sham；
*P<0.05,
**P<0.01vs?OVX。
Five, embodiment
1.4', the synthetic and evaluation of 5'-dihydroxyl-7-[4-(N, N-diethylin) butoxy] NOVASOY 400
(application number: 201010573851.7 Tan Ren are auspicious, Shi Dahua, Wu Junhua, dinner will strong, Zhang Lina, Wang Yurong to see patent.Title: " 4', 5'-dihydroxyl-7-[4-(N, N-diethylin) butoxy] NOVASOY 400." date of application: on December 6th, 2010).
Embodiment 1:4', 5'-dihydroxyl-7-[4-(N, N-diethylin) butoxy] NOVASOY 400 and preparation thereof
Preparation genistein verivate 4', 5'-dihydroxyl-7-[4-(N, N-diethylin) butoxy] NOVASOY 400 may further comprise the steps:
1. 4', the preparation of 5'-dihydroxyl-7-[4-(N, N-diethylin) butoxy] NOVASOY 400
Genistein (0.27g, 1mmol), 1, (5.4g, 25mmol), (0.07g 0.5mmol) is dissolved in the dry DMF of 60ml K2CO3 the 4-dibromobutane, 40 ℃ of following ultrasonic reaction 1.5h.After reaction is accomplished, with the mixture cool to room temperature.Behind the filtering insolubles, the filtrate decompression distillation obtains faint yellow solid, and recrystallization obtains light yellow needle-like crystal in the acetone, productive rate 86%, fusing point 130-131 ℃.
1H?NMR(DMSO-d
6):1.83（m，2H），1.94（m，2H），3.60（t，J=6.2Hz，2H），4.12（t，J=6.4Hz，2H），6.40（d，J=2.0Hz，1H），6.65（d，J=2.0Hz，1H），6.80（d，J=8.5Hz，1H），7.38（d，J=8.5Hz，2H），8.4（s，1H），9.65（s，1H),12.95(s,1H).ESI-MSC
19H
17BrO
5[M+H]
+405.Calcd forC
19H
17BrO
5:C,56.31;H,4.23.Found:C,56.28;H,4.27.
2. 4', the preparation of 5'-dihydroxyl-7-[4-(N, N-diethylin) butoxy] NOVASOY 400
With compound 4', 5'-dihydroxyl-7-4-bromine butoxy) (0.40g 1mmol) is dissolved in the 5ml dry DMF NOVASOY 400, slowly drips diethylamine (0.37g; 5mmol), 80 ℃-90 ℃ are stirred down 1h, and reaction product is slowly in the impouring 100ml mixture of ice and water, hold over night; Leach solid, acetone recrystallization, product are 4', 5'-dihydroxyl-7-[4-(N; The N-diethylin) butoxy] NOVASOY 400, productive rate 82%, fusing point 170-171 ℃.
1H?NMR(DMSO-d
6):0.94（t，J=7.2Hz,6H），1.52（m，2H），1.72（m，2H），2.4（m，2H），3.33（t，J=7.0Hz，4H），4.1（t，J=6.5Hz，2H），6.39（d，J=2.0Hz，1H），6.64（d，J=2.0Hz，1H），6.82（d，J=8.5Hz，2H），7.39（d，J=8.5Hz,2H），8.40(s,1H)，9.60(s,1H),12.93(s,1H).ESI-MS C
23H
27NO
5[M+H]
+398.Anal.Calc.for?C
23H
27NO
5:C,?69.50;H,6.85;N,3.52.Found:C,69.60;H,6.79;N,3.58.
2,4', the estrogen-like effects of 5'-dihydroxyl-7-[4-(N, N-diethylin) butoxy] NOVASOY 400
MCF-7 inoculates 96 orifice plates with the density of 4500 cells/well, changes the substratum (no phenol red DMEM contains 10% foetal calf serum through VISOSE/active carbon filtration) of no estrogen behind the 24h into.Continue to cultivate 48h, the oestrogenic hormon in the cell is fallen in completely consumed.After changing substratum, add 10 respectively
-10～10
-5The 4' of M, 5'-dihydroxyl-7-[4-(N, N-diethylin) butoxy] NOVASOY 400, or add 10
-9Behind the ERs suppressor factor ICI182680 of M, add 10 respectively again
-10～10
-5The 4' of M, 5'-dihydroxyl-7-[4-(N, N-diethylin) butoxy] NOVASOY 400.After cultivating 6d, discard substratum, every hole adds 0.1ml MTT (5mg/ml is dissolved in PBS).After cultivating 4h, inhale and remove the nutrient solution in the hole, every hole adds the DMSO 99.8MIN. of 100 μ l, surveys absorbancy with ELIASA at the 550nm wavelength, detects cytoactive.Theelin,dihydro-is as shown in table 1 to the active influence of MCF-7.17 beta estradiols can promote the propagation of MCF-7 cell, if the proliferation rate of the MCF-7 cell that will hatch altogether with 17 beta estradiols is set at 100%, give ERs suppressor factor ICI182680 after, the proliferation rate of MCF-7 cell drops to 35% ± 6%.
The relative proliferation rate of table 1.MCF-7 cell (%, n=6)
Subsequently, investigated 4', 5'-dihydroxyl-7-[4-(N, N-diethylin) butoxy] NOVASOY 400 (GS14) and ICI182670 (10
-9M) to the influence of MCF-7 cell proliferation rate, the result sees table 2.10
-9M ~ 10
-5The GS14 of M all can increase the propagation of MCF-7 cell, and GS14 is the bell jar type to the propagation of MCF-7 cell, explains that GS14 has estrogen-like effects.In GS14 concentration is 10
-9During M, maximum to the proliferation rate of MCF-7 cell, be 109% ± 14%.If give 10 in advance
-9The ICI182670 of M, cell proliferation rate significantly reduces, and has further verified the estrogen-like effects of GS14.
The 4' of table 2. gradient concentration, 5'-dihydroxyl-7-[4-(N, N-diethylin) butoxy] NOVASOY 400 (GS14) and ICI182670 (10
-9M) to the influence (%) of MCF-7 cell proliferation rate
3,4', 5'-dihydroxyl-7-[4-(N, N-diethylin) butoxy] NOVASOY 400 is to the improvement effect of learning and memory
1. the foundation of estrogen deficiency memory dysfunction model
Get the ICR mouse in 6 ~ 8 ages in week, be divided into negative control group, oophorectomize group, 17 β Theelin,dihydro-groups, 4' at random, 5'-dihydroxyl-7-[4-(N, N-diethylin) butoxy] NOVASOY 400 (1mg/kg and 5mg/kg) group, 10 every group.After the intraperitoneal anesthesia, the row ovariectomy.Sham operated rats is only done the incision suture operation, does not extract ovary.Postoperative is subcutaneous respectively 17 β Theelin,dihydro-(0.1mg/kg), the 4' of giving after one week, 5'-dihydroxyl-7-[4-(N, N-diethylin) butoxy] NOVASOY 400 (1mg/kg and 5mg/kg) group.Give compound 6 weeks.After 6 weeks, treat that mouse is finished study of behaviour experiment such as water maze and Y labyrinth after, get blood, detect estradiol content in the mice serum; Get the uterus, survey the body of uterus anharmonic ratio.
Visible from table 3, the mouse uterine weight of row oophorectomize postoperative significantly reduces, and estradiol content also drops to (289 ± 38) pg/ml from (412 ± 26) pg/ml of sham operated rats in the serum.It is thus clear that ovariectomy causes mouse body inner estrogen level significantly to reduce.
Estradiol content (pg/ml) in uterus/weight ratio (%) of the capable oophorectomize postoperative of table 3. mouse and the serum
2. water maze laboratory is observed 4', and 5'-dihydroxyl-7-[4-(N, N-diethylin) butoxy] NOVASOY 400 is to the improvement of spatial memory
At diameter 1.5m, in the circular swimming pool of high 0.5m (in have place the black platform of 1.5cm under water), the training mouse seeks the black platform.Through the time that mouse is gone up on the stage smoothly, investigate the improvement of compound to learning and memory.The movement locus of camera record mouse.First day: after at first letting mouse carry out 30s freestyle swimming, be placed on rest 10s on the platform.Subsequently, let mouse freestyle swimming.If mouse do not find platform in 60s, then place it on the platform behind the rest 10s, let it leave platform.Each training of every day at upper and lower noon was once trained 4 days continuously.Each training is 15min at interval, writes down latent period, if can not find in the 60s.Official testing in the 5th day.Test 3 times, average, the result sees table 4.
Water maze laboratory is the classics experiment of observing mouse spatial memory ability.The ICR mouse of sham-operation can be found the platform in the water quickly after training.And mouse row oophorectomize postoperative, the time of going up on the stage obviously prolongs, average latency time is 44 ± 17s, have in addition can not find platform at the appointed time.It is thus clear that estrogenic minimizing can cause mouse spatial memory ability to reduce.After giving estrin treatment, the time of finding platform can obviously be shortened.4', the treatment of 5'-dihydroxyl-7-[4-(N, N-diethylin) butoxy] NOVASOY 400 (GS14) also can reduce the time (seeing table 4) that the oophorectomize mouse is found platform in dose-dependently ground.4' is described, 5'-dihydroxyl-7-[4-(N, N-diethylin) butoxy] NOVASOY 400 can improve the spatial cognition ability of row oophorectomize postoperative mouse.
The latent period of mouse (s) in table 4. water maze laboratory
3. the Y maze experiment is observed 4', and 5'-dihydroxyl-7-[4-(N, N-diethylin) butoxy] NOVASOY 400 is to the improvement of short-term memory
At the bottom of forming the case in Y labyrinth by isometric I, II, III arm and three's junction region.Every brachium 30cm, wide 5cm, high 12cm.Diameter 0.2cm is laid in every arm bottom, long 14cm, and the conductive thin layer copper sheet of spacing 1cm, the stimulus signal lamp of a 15w is respectively adorned on the top.When the SL of respective arms was bright, this arm no power was the safety zone, and two arms and the junction region of not having light in addition all switched on and become non-safety zone (electric shock district).When beginning experiment, (arm that rat begins to belong to) adapts to 3min in the starting area to let rat, and the random transition stud switch is observed Zoological Society and fled from the electric shock district and advance the response capacity like the safety zone with the position of conversion safety zone with the electric shock district then.Mouse runs away to the safety zone for correct when electricity irritation does not begin as yet.Mouse is remembered the bright safety zone that is of SL through after training through study.1d trains mouse, morning and afternoon each 1 time.2d stimulates 10 times altogether, writes down correct per-cent, judges the improvement of compound to learning and memory with this.
As shown in table 5, give the 4' of 1mg/kg or 5mg/kg, behind 5'-dihydroxyl-7-[4-(N, N-diethylin) butoxy] NOVASOY 400, accuracy rises to 63% ± 10% and 73% ± 13% from 21% ± 8% respectively.It is thus clear that, 4', 5'-dihydroxyl-7-[4-(N, N-diethylin) butoxy] NOVASOY 400 has the good effect that improves short-term memory.
The correct judgment rate of table 5.Y labyrinth examination mouse (%, n=10)
4. 4', 5'-dihydroxyl-7-[4-(N, N-diethylin) butoxy] NOVASOY 400 is to the influence of learning and memory GAP-associated protein GAP CaMKII and pCaMKII
Finish the mouse of study of behaviour test and put to death, get brain, after cerebral tissue is washed with ice-cold PBS; [contain 50mmol/L Tris-HCl (pH 8.0), 50mmol/L KCl, 5mmol/L DTT with lysate; 1mmol/L EDTA, 0.1%SDS, 0.5%Triton X-100 and proteinase inhibitor cocktail (Roche; Indianapolis, Indiana)] the homogenate cracking.After putting on ice 30min, the centrifugal 10min of 12000rpm.Supernatant is ordered albumen with the BCA method, and total protein is transferred to pvdf membrane after being separated by 12% SDS-polyacrylamide gel.The sealing of 5% skimmed milk, the CaMKII of anti-mouse and pCaMKII one anti-4 ℃ of incubated overnight.After film cleans with the PBS that contains 0.1%Tween20, two anti-2h of incubated at room HRP mark.PBS cleans the back with the colour developing of ECL luminescent solution, X exposure.The result sees accompanying drawing 1.
The phosphorylation level of CaMKII and CaMKII (pCaMKII) plays a crucial role in learning and memory.Mouse row oophorectomize postoperative; The phosphorylation level of CaMKII and CaMKII significantly reduces, 17 β Theelin,dihydro-and 4', 5'-dihydroxyl-7-[4-(N; The N-diethylin) butoxy] NOVASOY 400 can significantly increase the phosphorylation level (Fig. 1) of CaMKII and CaMKII; Further specify 4', 5'-dihydroxyl-7-[4-(N, N-diethylin) butoxy] NOVASOY 400 has the improvement effect of learning and memory.
Claims (3)
1. genistein verivate 4', 5'-dihydroxyl-7-[4-(N, N-diethylin) butoxy] NOVASOY 400 structural formula is:
2. the said genistein verivate of claim 1 4', the application of 5'-dihydroxyl-7-[4-(N, N-diethylin) butoxy] NOVASOY 400 in preparation treatment learning memory disorder disease medicament.
3. according to the said genistein verivate of claim 2 4'; 5'-dihydroxyl-7-[4-(N; The N-diethylin) butoxy] application of NOVASOY 400 in preparation treatment learning memory disorder disease medicament; It is characterized in that being used to improving the dysmnesia that estrogen deficiency causes or be used for climacteric, climacteric women, the learning memory disorder that the women of ovary or hysterectomy causes.
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| CN104262313A (en) * | 2014-09-25 | 2015-01-07 | 山东理工大学 | Preparation method of genistein derivative containing phenylpiperazine and antibacterial activity of genistein derivative containing phenylpiperazine |
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| CN104311519B (en) * | 2014-09-23 | 2018-12-18 | 山东理工大学 | Functional food factor preparation and its application with mucosal lesion protective effect |
| CN104193717A (en) * | 2014-09-25 | 2014-12-10 | 山东理工大学 | Preparation method and application of phenylpiperazine-containing genistein derivative |
| CN104262313A (en) * | 2014-09-25 | 2015-01-07 | 山东理工大学 | Preparation method of genistein derivative containing phenylpiperazine and antibacterial activity of genistein derivative containing phenylpiperazine |
| CN104193717B (en) * | 2014-09-25 | 2018-02-02 | 山东理工大学 | The preparation method and applications of genistein derivative containing phenylpiperazine |
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