CN103450194B - Tetrahydro-beta-carbolinyl-3-formyl aliphatic chain amines, and preparation, nano structure, immunosuppression action and application thereof - Google Patents
Tetrahydro-beta-carbolinyl-3-formyl aliphatic chain amines, and preparation, nano structure, immunosuppression action and application thereof Download PDFInfo
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- CN103450194B CN103450194B CN201210183030.1A CN201210183030A CN103450194B CN 103450194 B CN103450194 B CN 103450194B CN 201210183030 A CN201210183030 A CN 201210183030A CN 103450194 B CN103450194 B CN 103450194B
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- 0 [*+]C([C@](C1)NC(CO)(CO)c2c1c(cccc1)c1[n]2)=O Chemical compound [*+]C([C@](C1)NC(CO)(CO)c2c1c(cccc1)c1[n]2)=O 0.000 description 1
Abstract
The invention relates to 6 aliphatic chain amine modified carbolinyl carboxylic acid analogs disclosed as general formula I, wherein n is equal to 6, 8, 10, 12, 14 or 16. The invention also relates to a preparation method of the 6 aliphatic chain amine modified carbolinyl carboxylic acid analogs disclosed as general formula I. The invention further relates to a nano structure of the 6 aliphatic chain amine modified carbolinyl carboxylic acid analogs disclosed as general formula I. By researching the inhibiting action of the saturated fatty chain amine modified carbolinyl carboxylic acid analogs on the spleen lymphocyte mitogen breeder reaction and the survival time after transplanting the mouse postotic cardiac muscle, the invention further relates to excellent immunosuppression action of the 6 aliphatic chain amine modified carbolinyl carboxylic acid analogs disclosed as general formula I. The 6 aliphatic chain amine modified carbolinyl carboxylic acid analogs with immunosuppressive activity disclosed as general formula I have wide application prospects in preparing immunosuppressive drugs.
Description
Technical field
The present invention relates to 6 kinds of general formula I and there is the amine-modified carboline carboxylate analogue of the aliphatic chain of immunosuppressive activity, n=6,8,10,12,14 or 16 in formula.The invention still further relates to their preparation method.The invention further relates to their nanostructure.The present invention to the restraining effect of splenic lymphocyte mitogen proliferative response and to the survival time after myocardium transplantation after mouse ear, relate to their outstanding immunosuppressive action by the amine-modified carboline carboxylate analogue of saturated aliphatic chain described in research further.The carboline carboxylate analogue amine-modified at 6 kinds that prepare immunosuppressive drug formula of I aliphatic chains with immunosuppressive activity is with a wide range of applications.The invention belongs to biomedicine field.
Background technology
Before thousands of year, people just once imagine the organ-tissue of replacing pathology with normal organ-tissue, but the transplanting before 20th century is except corneal transplantation, and major part is failed.Until the forties in 20th century, the dermatoplastic experimental model of Britain surgeon Mdewaar utilizer rabbit, demonstrating the rejection occurred in organ transplantation is for the first time a kind of immune response in essence, thus has established the basis of transplantation immunology.After the eighties, effective immunosuppressor, as the discovery of cyclosporin A and FK506 etc. and application, makes the survival time of transplant organ extend further, but many effective immunosuppressor have toxicity widely, therefore, the immunosuppressor of development of new is the study hotspot of the world of medicine always.
2-amino-[2-(4-octyl phenyl) ethyl]-1,3-propylene diamine hydrochloride (being called for short FTY720) is a kind of neotype immunosuppressant deriving from Cordyceps sinensis.Contriver recognizes, belongs to carboline carboxylate from structure FTY720.The experience that contriver studies according to long campaigns carboline carboxylate, recognizes that it is different from ciclosporin A, tacrolimus and rapamycin, should have immunosuppressive effect obvious, the features such as toxic side effect is low.So contriver recognizes that FTY720 is the outstanding guide structure of immunosuppressor further.
In studying for a long period of time, contriver also recognizes and can form nanostructure with the amine-modified carboline carboxylate of saturated aliphatic chain.Nanostructure can improve the curative effect of adorned carboline carboxylate.According to these understanding, inventors herein propose the present invention.
Summary of the invention
First content of the present invention is to provide 6 kinds of 3S-1,1-dihydroxymethyls-2,3,4,9-tetrahydro-beta-carboline-3-formyl saturated fatty streptamine of general formula I representative, n=6,8,10,12,14 or 16 in formula.
Second content of the present invention is to provide the preparation method of 6 kinds of 3S-1,1-dihydroxymethyls-2,3,4,9-tetrahydro-beta-carboline-3-formyl saturated fatty streptamine of general formula I representative, and concrete comprises the following steps:
(1) under water and the vitriol oil exist, tryptophane and 1,3-Dihydroxyacetone generate 3S-1,1-dihydroxymethyl-2,3,4,9-tetrahydro-beta-carboline-3-carboxylic acid;
(2) dicyclohexyl carbonyl diimine, N-hydroxy benzo triazole, methylene dichloride exist under by 3S-1,1-dihydroxymethyl-2,3,4,9-tetrahydro-beta-carboline-3-carboxylic acid and the condensation of saturated fatty amine, generate 3S-1,1-dihydroxymethyl-2,3,4,9-tetrahydro-beta-carboline-3-formyl saturated fatty streptamine.
3rd content of the present invention is the nanostructure of 6 kinds of 3S-1,1-dihydroxymethyls-2,3,4, the 9-tetrahydro-beta-carboline-3-formyl saturated fatty streptamine measuring general formula I representative.
The present invention solve the 4th content be, evaluate general formula I representative 6 kinds of 3S-1,1-dihydroxymethyls-2,3,4,9-tetrahydro-beta-carboline-3-formyl saturated fatty streptamine to the restraining effect of mouse spleen lymphocyte to the proliferative response of mitogen.
The 5th content that the present invention solves is, evaluates 6 kinds of 3S-1,1-dihydroxymethyls-2,3,4,9-tetrahydro-beta-carboline-3-formyl saturated fatty streptamine of general formula I representative to the impact of mouse ear rear myocardium tissue transplanting survival time.
Accompanying drawing explanation
The synthetic route .i of 6 kinds of 3S-1,1-dihydroxymethyls-2,3,4,9-tetrahydro-beta-carboline-3-formyl fat streptamine of Fig. 1 general formula I) water, the vitriol oil; Ii) CH
2cl
2, DCC, HOBt and NMM; N=16. in n=14,2f in n=12,2e in n=10,2d in n=8,2c in n=6,2b in 2a
The transmission electron microscope photo of Figure 22 a.
The transmission electron microscope photo of Figure 32 b.
The transmission electron microscope photo of Figure 42 c.
The transmission electron microscope photo of Figure 52 d.
The transmission electron microscope photo of Figure 62 e.
The transmission electron microscope photo of Figure 72 f.
Breviary term
Embodiment
In order to set forth the present invention further, provide a series of embodiment below.These embodiments are illustrative completely, and they are only used for being specifically described the present invention, not should be understood to limitation of the present invention.
Embodiment 1 prepares 3S-1,1-dihydroxymethyl-2,3,4,9-tetrahydro-beta-carboline-3-carboxylic acid (1)
By L-Trp 6.12g (30mmol), be added in 100mL water, slowly drip the vitriol oil in ice-water bath and all dissolve to tryptophane, add 3.24g (36mmol) 1,3-Dihydroxyacetone.After 24h, reaction solution becomes muddy, can be observed solid matter and has separated out, and filtration under diminished pressure also repeatedly obtains 5.73g (69%) title compound with distilled water cleaning.ESI-MS(m/e)：275[M-H]
-
Embodiment 2 prepares N-(3S-1,1-dihydroxymethyl-2,3,4,9-tetrahydro-beta-carboline-3-formyl)-NHC
8h
17(2a)
By 1.38g (5.0mmol) 3S-1,1-dihydroxymethyl-2,3,4,9-tetrahydro-beta-carboline-3-carboxylic acid and 1.29g (6.0mmol) CH
3(CH
2)
6cH
2nH
2be dissolved in 20ml methylene dichloride, ultrasonic dissolution assisting.In the solution obtained, 0.75g (5.0mmol) N-hydroxy benzo triazole (HOBt) and 1.55g (4.50mmol) dicyclohexylcarbodiimide (DCC) is added under ice bath.With N-methylmorpholine (NMM) under ice bath, adjust pH 8-9.1h is stirred under ice bath, then stirring at room temperature 12h, TLC (dichloro/methyl alcohol=20: 1) show product dot generation.Filtering dicyclohexylurea (DCU) (DCU), filtrate adds 50ml methylene dichloride.The solution obtained uses saturated NaHCO successively
3the aqueous solution is washed, the saturated NaCl aqueous solution is washed, 5%KHSO
4the aqueous solution is washed and is washed with the saturated NaCl aqueous solution.Organic phase anhydrous Na
2sO
4drying, filtration, filtrate reduced in volume are to dry.Gained compound is through through silica gel column chromatography, (sherwood oil: acetone=5: 1) purifying obtains 0.31g (16%) title compound is colorless gum.ESI-MS(m/e)386[M-H]
-.Mp 129-130℃.
1H-NMR(DMSO-d
6，500MHz)：δ/ppm＝10.59(s，1H)，8.03(t，J＝5.0Hz，1H)，7.38(d，J＝10.0Hz，1H)，7.32(d，J＝10.0Hz，1H)，7.02(dd，J＝10.0Hz，J＝5.0Hz，1H)，6.94(dd，J＝5.0Hz，J＝10.0Hz，1H)，4.72-4.66(m，2H)，3.85(d，J＝5.0Hz，1H)，3.64(d，J＝5.0Hz，1H)，3.59-3.54(m，3H)，3.15-3.11(m，2H)，2.89-2.86(m，1H)，1.53-1.39(m，2H)，1.38-1.18(m，10H)，0.90(dd，J＝10.0Hz，J＝5.0Hz，3H).
Embodiment 3 prepares N-(3S-1,1-dihydroxymethyl-2,3,4,9-tetrahydro-beta-carboline-3-formyl)-NHC
10h
21(2b)
According to the method for embodiment 2 by 1.38g (5.0mmol) 3S-1,1-dihydroxymethyl-2,3,4,9-tetrahydro-beta-carboline-3-carboxylic acid and 1.17g (7.5mmol) CH
3(CH
2)
8cH
2nH
2obtained 0.32g (15%) title compound is colorless gum.ESI-MS(m/e)：415[M-H]
-.Mp 127-129℃.
1H-NMR(DMSO-d
6，300MHz)：δ/ppm＝10.58(s，1H)，8.02(s，1H)，7.38(d，J＝6.0Hz，1H)，7.32(d，J＝3.0Hz，1H)，7.01(dd，J＝6.0Hz，J＝3.0Hz，1H)，6.93(dd，J＝3.0Hz，J＝6.0Hz，1H)，4.72-4.62(m，2H)，3.86-3.83(m，1H)，3.64-3.62(m，1H)，3.58-3.53(m，3H)，3.14-3.10(m，2H)，2.88-2.84(m，1H)，1.52-1.39(m，2H)，1.38-1.18(m，14H)，0.87(t，J＝3.0Hz，3H).
Embodiment 4 prepares N-(3S-1,1-dihydroxymethyl-2,3,4,9-tetrahydro-beta-carboline-3-formyl)-NHC
12h
25(2c)
According to the method for embodiment 2 by 1.38g (5.0mmol) 3S-1,1-dihydroxymethyl-2,3,4,9-tetrahydro-beta-carboline-3-carboxylic acid and 1.85g (10.0mmol) CH
3(CH
2)
10cH
2nH
2obtained 0.22g (10%) title compound is colorless gum.ESI-MS(m/e)：444[M+H]
+.Mp 135-137℃.
1H-NMR(CDCl
3，300MHz)：δ/ppm＝8.85(s，1H)，7.49(d，J＝11.4Hz，1H)，7.32(s，1H)，7.18-7.10(m，2H)，6.93(t，J＝3.0Hz，1H)，4.01-3.65(m，6H)，3.30-3.10(m，4H)，2.85-2.65(m，2H)，1.58-1.39(m，3H)，1.38-1.14(m，15H)，0.90(d，J＝6.6Hz，3H).
Embodiment 5 prepares N-(3S-1,1-dihydroxymethyl-2,3,4,9-tetrahydro-beta-carboline-3-formyl)-NHC
14h
29(2d)
According to the method for embodiment 2 by 1.66g (6.00mmol) 3S-1,1-dihydroxymethyl-2,3,4,9-tetrahydro-beta-carboline-3-carboxylic acid and 2.56g (12.00mmol) CH
3(CH
2)
12cH
2nH
2obtained, gained compound is through through silica gel column chromatography (sherwood oil: acetone=5: 1) purifying obtains 0.30g (10.5%) colorless gum.ESI-MS(m/e)：470[M-H]
-.Mp 137-138℃.
1H-NMR(DMSO-d
6，300MHz)：δ/ppm＝10.57(s，1H)，8.01(t，J＝5.4Hz，1H)，7.38-7.30(m，2H)，7.01(t，J＝6.9Hz，1H)，6.92(t，J＝4.8Hz，1H)，4.79-4.52(m，1H)，3.89-3.81(m，1H)，3.69-3.59(m，1H)，3.40-3.28(m，1H)，3.16-3.08(m，2H)，2.92-2.80(m，1H)，1.52-1.39(m，2H)，1.38-1.20(m，22H)，0.87(t，J＝6.0Hz，3H).
Embodiment 6 prepares N-(3S-1,1-dihydroxymethyl-2,3,4,9-tetrahydro-beta-carboline-3-formyl)-NHC
16h
33(2e)
According to the method for embodiment 2 by 1.10g (4.0mmol) 3S-1,1-dihydroxymethyl-2,3,4,9-tetrahydro-beta-carboline-3-carboxylic acid and 1.93g (8.0mmol) CH
3(CH
2)
14cH
2nH
2obtained 0.16g (8%) title compound is colorless gum.ESI-MS(m/e)：500[M+H]
+.Mp 126-128℃.
1H-NMR(DMSO-d
6，300MHz)：δ/ppm＝10.56(s，1H)，8.00(t，J＝5.4Hz，1H)，7.41-7.22(m，2H)，7.01(t，J＝7.2Hz，1H)，6.92(t，J＝7.2Hz，1H)，4.76-4.57(m，2H)，3.91-3.79(m，1H)，3.69-3.50(m，4H)，3.19-3.08(m，2H)，2.92-2.81(m，1H)，1.52-1.39(m，2H)，1.38-1.20(m，26H)，0.85(m，J＝6.6Hz，3H).
Embodiment 7 prepares N-(3S-1,1-dihydroxymethyl-2,3,4,9-tetrahydro-beta-carboline-3-formyl)-NHC
18h
37(2f)
According to the method for embodiment 2 by 1.38g (5.0mmol) 3S-1,1-dihydroxymethyl-2,3,4,9-tetrahydro-beta-carboline-3-carboxylic acid and 2.69g (10.0mmol) CH
3(CH
2)
16cH
2nH
2obtained 0.17g (6%) title compound is colorless gum.ESI-MS(m/e)：526[M-H]
-.Mp 136-138℃.
1H-NMR(DMSO-d
6，300MHz)：δ/ppm＝10.57(s，1H)，8.00(t，J＝5.4Hz，1H)，7.41-7.29(m，2H)，7.01(t，J＝7.2Hz，1H)，6.92(t，J＝7.5Hz，1H)，4.74-4.59(m，2H)，3.90-3.79(m，1H)，3.68-3.50(m，4H)，3.18-3.08(m，2H)，2.92-2.81(m，1H)，1.52-1.39(m，2H)，1.38-1.20(m，30H)，0.85(t，J＝6.0Hz，3H).
The restraining effect that experimental example 13S-1,1-dihydroxymethyl-2,3,4,9-tetrahydro-beta-carboline-3-formyl saturated fatty streptamine 2a-f breeds mouse spleen lymphocyte mitogen
De-neck puts to death mouse, asepticly gets spleen, grinds, wash twice with HANK ' S liquid with 200 order steel meshes and piston, under 1500 revs/min of conditions centrifugal 10 minutes, is made into splenocyte 5 × 10 after counting with complete RPMI-1640 nutrient solution
6the cell suspension of/mL, adds 100 μ L cell suspensions (every empty containing 5 × 10 in 96 well culture plates
5individual cell).Every hole adds 20 μ L canavalines, and final concentration is 5 μ g/mL, if mitogen is lipopolysaccharides, then lipopolysaccharides final concentration is 20 μ g/mL.This 96 well culture plate is placed in the CO that volume fraction is 0.05
24h is cultivated for 37 DEG C in the incubator of saturated humidity.After 4h by the concentration gradient preset add to be measured, through the 2a-f (1 × 10 of sterilising treatment
-4, 8 × 10
-5, 5 × 10
-5, 2 × 10
-5, 1 × 10
-5, 8 × 10
-6, 5 × 10
-6, 1 × 10
-6), the multiple hole of each concentration 3, control group adds the solvent of isopyknic sample dissolution.Establish not containing compound control hole with only containing the cell blank hole with amount nutrient solution no mitogen simultaneously.Each hole is all repeated 3 times (n=3).Use mtt assay detection compound to the restraining effect of splenic lymphocyte after cultivating 48h.
The compound of different concns is calculated to the restraining effect of spleen lymphocyte proliferation according to formula " inhibiting rate=(D contrasts-D pastille)/D contrasts × 100% ", concentration according to cell relative survival rate and compound draws cell growth curve, utilize this growth curve try to achieve half inhibiting rate (
dxiC50).Result lists table 1 and table 2 in, and result shows that 3S-1,1-dihydroxymethyl-2,3,4,9-tetrahydro-beta-carboline-3-formyl saturated fatty streptamine 2a-f of the present invention has clear and definite restraining effect to mice spleen lymphocytes proliferation.
Table 1 2a-f is to the restraining effect of the proliferation of mouse T lymphocytes that canavaline is induced
The restraining effect that table 2 2a-f breeds lipopolysaccharide-induced mouse B cell
Experimental example 23S-1,1-dihydroxymethyl-2,3,4,9-tetrahydro-beta-carboline-3-formyl saturated fatty streptamine 2a-f is on the impact of mouse ear rear myocardium tissue transplanting survival
Recipient mice is through 10% urethane (10 milligrams/10 grams body weight) intraperitoneal injection of anesthesia.1% bromogeramine tincture auricle partly sterilised, shaves hair, holds eye scissors 1/3 place's work one and auricle median perpendicular place before auricle dorsal part center line and makes the otch of a 3-4 millimeters long, do not damage auricle vein.Hold tweezers to have sharp ears direction blunt separation subcutis, make it into a tube chamber.New life is placed in trash ice 75% alcohol skin degerming after a minute for mouse, cuts open chest and win heart.Heart is placed in PBS liquid and beats 1-2 time with blood more than the emptying chambers of the heart.During transplanting, become basic etc. large 2 half with blade longitudinally cuing open for the heart, myofiber becomes an inclined-plane.Cardiac muscular tissue is transplanted and inserts in acceptor mouse ear chamber, skin incision is sewed up a pin.(isolated time of cardiac muscular tissue is no more than 2 minutes), with finger flicking local, makes graft be adjacent to the surrounding tissue by mouse.Post-transplantation administration on the same day.2a-f intraperitoneal injection every day 0.2mL, dosage is 1 μm of ol/kg, successive administration 15 days.Positive control cyclosporin A intraperitoneal injection every day 0.2mL, dosage is 2.5 μm of ol/kg, successive administration 15 days.Blank physiological saline intraperitoneal injection every day 0.2mL, gives 15 days continuously.Within postoperative 6th day, play the electrocardiosignal recording heart transplantation muscular tissue every day.During test ectocardia electrograph, positive and negative electrode is placed in heart transplant both sides respectively, and earthing pole is connected to mouse hind leg.Within postoperative 15 days, terminate to observe, add up prolonged Survival of Rat Cardiac.Result lists table 3 in, and result shows that 3S-1,1-dihydroxymethyl-2,3,4,9-tetrahydro-beta-carboline-3-formyl saturated fatty streptamine 2a-f of the present invention effectively can extend the mouse ear rear myocardium tissue transplanting survival time.Result lists table 3 in.Result shows, the 2a-f of 1 μm of ol/kg dosage treats cyclosporine A therapy mouse heart transplant that mouse heart transplant survives mean time and 2.5 μm of ol/kg dosage and survives and do not have significant difference mean time.They have identical curative effect.
Table 3 mouse ear rear myocardium tissue transplantation experiments evaluation result
N=12; A) P < 0.05 is compared with physiological saline, variant;
Experimental example 3 various dose 2b is on the impact of mouse ear rear myocardium tissue transplanting survival
By the method for embodiment 2, choose the dose-effect relationship of 10.0 μm of ol/kg, 1.0 μm of ol/kg and 0.01 μm of ol/kg Three doses investigation 2b.Result shows, mouse ear rear myocardium tissue survival time of 2b is by show dose dependency (table 4).
The dose-effect relationship of table 42b
N=12, a) compares P < 0.05 with 0.01 μm of ol/kg group; B) P < 0.05 is compared with 0.01 μm of ol/kg and 1.0 μm ol/kg group; C) P > 0.05. is compared with physiological saline
The autonomous dress performance evaluation of embodiment 112a-f
2a-f being made into concentration is 1 × 10
-12the ethanolic soln of mg/mL, then drops on copper mesh by this solution, observes the form of nanometer ball after the dry solvent that volatilizees under JEM-1230 transmission electron microscope.Mensuration shows, the nanostructure of 2a-f formation rule.
Claims (4)
1. the carboline carboxylate analogue that 6 kinds of the general formula I aliphatic chains with immunosuppressive activity are amine-modified, n=6,8,10,12,14 or 16 in formula
2. prepare a method for the amine-modified carboline carboxylate analogue of the aliphatic chain of claim 1, it is characterized in that following steps:
(1) under water and the vitriol oil exist, tryptophane and 1,3-Dihydroxyacetone generate 3S-1,1-dihydroxymethyl-2,3,4,9-tetrahydro-beta-carboline-3-carboxylic acid;
(2) dicyclohexyl carbonyl diimine, N-hydroxy benzo triazole, methylene dichloride exist under by 3S-1,1-dihydroxymethyl-2,3,4,9-tetrahydro-beta-carboline-3-carboxylic acid and the condensation of saturated fatty amine, generate 3S-1,1-dihydroxymethyl-2,3,4,9-tetrahydro-beta-carboline-3-formyl saturated fatty amine.
3. the nanostructure of the carboline carboxylate analogue that the aliphatic chain of claim 1 is amine-modified.
4. the purposes of the carboline carboxylate analogue that the aliphatic chain of claim 1 is amine-modified in preparation immunosuppressor.
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| CN108976283B (en) * | 2017-05-30 | 2021-12-03 | 首都医科大学 | 1, 1-dihydroxymethyl-tetrahydro-beta-carboline-3-formyl-GLDV, and synthesis, activity and application thereof |
| CN109134603B (en) * | 2017-06-13 | 2022-04-22 | 首都医科大学 | 1, 1-dihydroxymethyl-tetrahydro-beta-carboline-3-formyl-GYIGSR, and synthesis, activity and application thereof |
| CN109134604B (en) * | 2017-06-16 | 2022-04-22 | 首都医科大学 | 1, 1-dihydroxymethyl-tetrahydro-beta-carboline-3-formyl-GRGDF, and synthesis, activity and application thereof |
| CN109134607B (en) * | 2017-06-16 | 2022-02-08 | 首都医科大学 | 1, 1-dihydroxymethyl-tetrahydro-beta-carboline-3-formyl-GRGDS, synthesis, activity and application thereof |
| CN109134606B (en) * | 2017-06-16 | 2022-02-08 | 首都医科大学 | 1, 1-dihydroxymethyl-tetrahydro-beta-carboline-3-formyl-GRGDV, synthesis, activity and application thereof |
| CN109134605B (en) * | 2017-06-16 | 2022-04-22 | 首都医科大学 | 1, 1-dihydroxymethyl-tetrahydro-beta-carboline-3-formyl-GYIGSK, and synthesis, activity and application thereof |
| CN109111502B (en) * | 2017-06-23 | 2022-04-22 | 首都医科大学 | 1, 1-dihydroxymethyl-tetrahydro-beta-carboline-3-formyl-GGPRP, and synthesis, activity and application thereof |
| CN111793067B (en) * | 2019-04-07 | 2023-04-07 | 首都医科大学 | Synthesis, activity and application of dihydroxymethyl tetrahydrocarboline-3-formyl-The |
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