CN107602557B - A kind of nitrogen mustards rutaecarpin derivative and its preparation method and application - Google Patents
A kind of nitrogen mustards rutaecarpin derivative and its preparation method and application Download PDFInfo
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- CN107602557B CN107602557B CN201710849627.8A CN201710849627A CN107602557B CN 107602557 B CN107602557 B CN 107602557B CN 201710849627 A CN201710849627 A CN 201710849627A CN 107602557 B CN107602557 B CN 107602557B
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Abstract
The present invention relates to natural drug and field of medicinal chemistry, a kind of nitrogen mustards rutaecarpin derivative and its preparation method and application.The preparation method and its application in preparation of anti-tumor drugs of DNA alkylating agent melphalan derivative are introduced in the site N-13 of rutaecarpin more particularly to these.Rutaecarpin split melphalan derivative of the present invention and its pharmaceutically acceptable salt structure are as shown in general formula I, wherein n, m, p are as described in claims and specification.
Description
Technical field
The present invention relates to natural drug and field of medicinal chemistry, a kind of nitrogen mustards rutaecarpin derivative and preparation method thereof
And purposes, and in particular to the derivative that the site N-13 of rutaecarpin is modified is related to these in the site N-13 by DNA alkanisation
Rutaecarpin derivative that agent melphalan derivative replaces and preparation method thereof and application in preparation of anti-tumor drugs.
Background technique
Rutaecarpin (evodiamine) is isolated indoles quinoline from Rutaceae Evodia (Euodia) plant
Oxazolone Alkaloid compound.Rutaecarpin is a kind of faint yellow acicular crystal, not soluble in water, is soluble in methylene chloride, chloroform,
Dissolve in the organic solvents such as methanol, ethyl acetate.There is inhibiting effect to kinds of tumor cells.Rutaecarpin has antitumor thin
Born of the same parents' proliferation, the formation and invasion for inhibiting tumour cell micro-pipe, inducing apoptosis of tumour cell and necrosis, enhance cell autophagy, are good
Good topoisomerase enzyme inhibitor.Studies have shown that rutaecarpin is to cervical cancer cell, human leukemia cell, liver cancer cells, black
Plain oncocyte, stomach cancer cell, colon cancer cell etc. have certain inhibiting effect, and pharmacology activity research is also very deep, right
The research of rutaecarpin Anticancer Effect and Mechanism has gradually become a hot spot.Its mechanism of action may be to inhibit PI3K/Akt/
Caspase, Fas-L/NF- κ B signal access etc..With going deep into rutaecarpin pharmacological research, rutaecarpin is caused
The great interest of domestic and international scientist, has carried out the synthetic work to rutaecarpin derivative.Purpose is to obtain active more preferable, poison
The antitumor candidate compound that property is lower, property is more stable.It is separated, compared with the report in terms of mechanism of action with extracting, about Wu
Report in terms of fruit of medicinal cornel alkali structural modification such as synthesizes at the pharmaceutical chemistry with transformation, derivative is less.
Chlormethine series pharmaceuticals, also referred to as DNA alkylating agent, belong to cytotoxic drug, and mechanism of action is to be formed in vivo
The height reactive intermediate of electron deficient or other compounds with active electrophilic groups, and then occur with large biological molecule
Covalent Irreversible binding makes DNA molecular loss of activity or is broken.This kind of drug is clinically widely used, but it
Toxic side effect is bigger, lacks specificity to cytosis, and with the generation of tumor drug resistance in recent years, therapeutic effect is not
Therefore ideal is chemically modified chlormethine series pharmaceuticals, improving its curative effect has critically important value.
Summary of the invention
The technical problem to be solved by the present invention is to find the good rutaecarpin split melphalan derivative of anti-tumor activity,
That is nitrogen mustards rutaecarpin derivative, and further provide for the pharmaceutical composition comprising the derivative, i.e. the nitrogen mustards Wu
Fruit of medicinal cornel alkali derivant or combinations thereof object has anti-tumor activity.
In order to solve the above technical problems, the invention provides the following technical scheme:
General formula I is shown nitrogen mustards rutaecarpin derivative and its pharmaceutically acceptable salt:
Wherein, n is the integer of 1-12；M is the integer of 1-6；P is the integer of 1-12.
Preferably, n is the integer of 1-6；M is the integer of 1-4；P is the integer of 1-6.
It is highly preferred that n is 2,3 or 6；M is 1 or 2；P is 2.
The derivative of general formula I of the present invention can be prepared with following method:
Rutaecarpin 1 reacts under the conditions of NaH/DMF with bromhydrin, obtains rutaecarpin hydroxy derivatives 2.
The heating of melphalan 3 and methanol react to obtain melphalan methyl esters 4, then 4 under conditions of DMAP catalysis with dicarboxylic anhydride
React to obtain melphalan methyl esters carboxylic acid derivates 5.
Rutaecarpin intermediate 2 and melphalan methyl esters carboxylic acid derivates 5 react at room temperature under the conditions of EDCI/DMAP obtains mesh
Mark compound 6.
The present invention, using principle of hybridization, selects the preferable melphalan of activity derivative using rutaecarpin as lead compound
It is connected on the position 13-N of its molecular structure by object by linking group, has been designed and synthesized the rutaecarpin that general formula is I and has been spelled
Close melphalan derivative.Compound after split has preferable pharmaceutical active.
Specific embodiment
Embodiment 1
Rutaecarpin intermediate 2 (n 2, m 1) is taken, 65mg, 0.19mmol are dissolved in methylene chloride (15ml), successively
Melphalan methyl esters butyric acid (85mg, 0.19mmol), EDCI (120mg, 0.60mmol), DMAP (6mg, 0.05mmol), room is added
Temperature is stirred to react, and TCL monitors reaction process, terminates reaction afterwards for 24 hours.Reaction solution is poured into 20ml mixture of ice and water, dichloromethane
Alkane extracts (30ml × 3), and the washing of saturated common salt aqueous solution, anhydrous sodium sulfate is dry, recycles methylene chloride, obtains crude product 6a,
Through silicagel column (petroleum ether: ethyl acetate=2:1), separation obtains yellow oily, yield 24%.HRMS(ESI,M+H)m/z
calcd for C39H43Cl2N5O6H:748.2663,found:748.2684.1H NMR(CDCl3,400MHz),δ(ppm)8.17
(1H, d, J=7.7Hz, Ar-H), 7.63 (1H, d, J=7.8Hz, Ar-H), 7.55 (1H, m, Ar-H), 7.49 (1H, m, Ar-
), H 7.33 (1H, d, J=7.4Hz, Ar-H), 7.28 (1H, d, J=7.4Hz, Ar-H), 7.23 (1H, m, Ar-H), 7.20 (1H,
D, J=7.7Hz, Ar-H), 6.99 (2H, d, J=8.0Hz, Ar-H), 6.62 (2H, d, J=8.0Hz, Ar-H), 6.04 (1H, s,
NCH),6.00(1H,m,-NH),4.48-4.78(4H,m,-CH2),4.43(1H,m,-CH),3.75(3H,s,-COOCH3),
3.71(4H,m,NCH2CH2Cl),3.63(4H,m,NCH2CH2Cl),2.10-3.25(10H,m,-CH2),2.43(3H,s,
NCH3)；13C NMR(CDCl3,100MHz)δ(ppm)172.43,172.12,170.64,164.59,150.88,145.09,
137.72,133.07,131.00,130.66,129.04(×2),128.91,125.89,124.86,124.55,124.23,
123.45,123.02,120.03,119.14,112.29(×2),109.89,68.09,65.64,63.24,60.47,53.60
(×2),52.39,42.43,40.43(×2),36.74,30.46,29.76,29.13,20.40.
Embodiment 2
Compound 6b is prepared into referring to the synthetic method of embodiment 1.Yellow oily, yield 75%.HR-MS(ESI,M+H)
m/z:calcd for C40H45Cl2N5O6H:762.2820,found:762.2811.1H NMR(CDCl3,400MHz),δ(ppm)
8.11 (1H, d, J=7.8Hz, Ar-H), 7.60 (1H, d, J=7.8Hz, Ar-H), 7.48 (1H, m, Ar-H), 7.40 (1H, m,
), Ar-H 7.30 (1H, m, Ar-H), 7.21 (2H, m, Ar-H), 7.16 (1H, m, Ar-H), 6.97 (2H, d, J=8.2Hz, Ar-
), H 6.60 (2H, d, J=8.2Hz, Ar-H), 6.00 (1H, m, NCH), 5.96 (1H, m ,-NH), 4.80 (1H, m ,-CH),
4.05-4.54(4H,m,-CH2),3.72(3H,d,-COOCH3),3.68(4H,m,NCH2CH2Cl),3.60(4H,m,
NCH2CH2Cl),2.47-3.20(6H,m,-CH2),2.39(3H,s,NCH3),1.65-2.36(6H,m,-CH2)；13C NMR
(CDCl3,100MHz)δ(ppm)172.72,172.16,170.74,164.66,150.99,145.12,137.25,133.07,
133.04,130.70(×2),129.04,128.40,125.90,124.49,124.44,123.29,122.92,119.85,
119.19,113.46,112.31(×2),109.70,68.06,62.12,62.09,53.63(×2),52.43,40.75,
40.71(×2),40.45,39.39,36.80,30.59,29.24,29.05,20.44.
Embodiment 3
Compound 6c is prepared into referring to the synthetic method of embodiment 1.Yellow oily, yield 64%.HR-MS(ESI,M+H)
m/z:calcd for C43H51Cl2N5O7H:820.3238,found:820.3239.1H NMR(CDCl3,400MHz),δ(ppm)
8.11 (1H, d, J=7.8Hz, Ar-H), 7.60 (1H, d, J=7.8Hz, Ar-H), 7.47 (1H, m, Ar-H), 7.42 (1H, m,
Ar-H),7.29(1H,m,Ar-H),7.22(1H,m,Ar-H),7.19(1H,m,Ar-H),7.15(1H,m,Ar-H),6.97
(2H, d, J=8.5Hz, Ar-H), 6.59 (2H, d, J=8.5Hz, Ar-H), 6.17 (1H, m ,-NH), 5.99 (1H, s, NCH),
4.55(1H,m,-CH),4.28(2H,m,-CH2),4.06(2H,m,-CH2),3.73(3H,s,-COOCH3),3.69(4H,m,
NCH2CH2Cl),3.60(4H,m,NCH2CH2Cl),2.90-3.37(6H,m,-CH2),2.49-2.63(4H,m,-CH2),2.39
(3H,s,NCH3),1.45-2.05(8H,m,-CH2)；13C NMR(CDCl3,100MHz)δ(ppm)172.78,172.23,
171.00,164.75,151.07,145.30,137.37,133.00,131.04,130.71(×2),129.01,128.97,
125.86,124.71,124.21,123.16,122.72,119.70,119.09,113.16,112.17(×2),109.95,
67.96,67.64,67.38,65.70,61.92,53.59(×2),53.43,52.43,40.70,40.53(×2),39.24,
36.83,32.05,30.90,29.83,29.05,20.52.
Embodiment 4
Compound 6d is prepared into referring to the synthetic method of embodiment 1.Yellow oily, yield 45%.HR-MS(ESI,M+Na)
m/z:calcd for C43H51Cl2N5O6Na:826.3109,found:826.3109.1H NMR(CDCl3,400MHz),δ
(ppm) 8.13 (1H, d, J=7.8Hz, Ar-H), 7.60 (1H, d, J=7.8Hz, Ar-H), 7.50 (1H, m, Ar-H), 7.38
(1H,m,Ar-H),7.29(1H,m,Ar-H),7.22(1H,m,Ar-H),7.18(1H,m,Ar-H),7.15(1H,m,Ar-H),
6.96 (2H, d, J=8.5Hz, Ar-H), 6.59 (2H, d, J=8.5Hz, Ar-H), 6.08 (1H, m ,-NH), 5.97 (1H, s,
NCH),4.80(1H,m,-CH),4.35(1H,m,-CH2),4.17(1H,m,-CH2),4.05(4H,m,-CH2),3.72(3H,
s,-COOCH3),3.68(4H,m,NCH2CH2Cl),3.60(4H,m,NCH2CH2Cl),3.19(1H,m,-CH2),2.90(1H,
m,-CH2),2.59(2H,m,-CH2),2.47(2H,m,-CH2),2.40(3H,s,NCH3),1.37-1.83(10H,m,-CH2)
；13C NMR(CDCl3,100MHz)δ(ppm)172.89,172.16,170.94,164.66,151.00,145.21,137.23,
133.03,130.68(×2),129.06,128.37,125.79,124.71,124.30,124.20,123.16,122.68,
119.62,119.10,113.14,112.16(×2),109.86,68.15,64.68,64.45,53.56(×2),52.39,
43.93,40.48(×2),39.41,36.80,30.73,30.17,29.80,29.32,28.58,26.93,25.79,20.47.
Pharmacological testing
Experimental facilities and reagent
Experimental method
Cell inhibitory activity experimental method
Cell is in 37 DEG C, 5%CO2Routine culture in the incubator of saturated humidity.Culture solution is containing 10% heat inactivation tire ox
The RPMI1640 cell culture medium of serum, penicillin 100U/mL and streptomysin 100U/mL.48h replaces culture solution, and cell is adherent
Afterwards, it is passed on 0.25% trypsin digestion.Experiment is in logarithmic growth phase with cell, and trypan exclusion stain shows that cell is living
Power > 95%.
It takes in good condition one bottle of cell of logarithmic growth phase, digestive juice (0.125% trypsase+0.01% is added
EDTA it) digests, counts 2~4 × 104Cell suspension inoculation is made on 96 orifice plates in cell/mL, and constant temperature CO is set in 100 holes μ L/2Training
It supports and is cultivated 24 hours in case.Liquid is changed, test medicine is added, 100 holes μ L/ are cultivated 72 hours.CCK-8 is added in 96 orifice plates, 50
The hole μ L/ is incubated for 4 hours in incubator.Supernatant is sucked, adds DMSO, 200 holes μ L/ are shaken 10 minutes on plate shaker.It is tested
Object investigates 3 concentration (0.25 μM, 0.5 μM, 1 μM), with enzyme linked immunological monitor in the extinction that wavelength is the every hole of measurement at 450nm
Degree, calculates separately the cell inhibitory rate under each concentration.
Inhibiting rate calculation method:
Susceptibility hole is with respect to the absolute absolute OD value of OD value ﹣ blank control wells in OD value=susceptibility hole
Experimental result
IC of 1 embodiment of table to 4 kinds of human cancer cells strains and a kind of normal human cells' antiproliferative activity50It is worth (μM)
Pharmacological testing proves that rutaecarpin derivative of the invention has better antitumor action, can be used for into one
Step prepares anti-tumor drug.
Claims (8)
1. nitrogen mustards rutaecarpin derivative and its pharmaceutically acceptable salt shown in general formula I:
Wherein, n is the integer of 1-6；M is the integer of 1-4；P is the integer of 1-6.
2. nitrogen mustards rutaecarpin derivative and its pharmaceutically acceptable salt shown in general formula I described in claim 1: its
In, n 2,3 or 6；M is 1 or 2；P is 2.
3. nitrogen mustards rutaecarpin derivative and its pharmaceutically acceptable salt shown in general formula I described in claim 1, choosing
From:
4. a kind of pharmaceutical composition, wherein shown in general formula I described in the claim 1-3 any one containing therapeutically effective amount
Nitrogen mustards rutaecarpin derivative and its pharmaceutically acceptable salt and pharmaceutically acceptable carrier.
5. nitrogen mustards rutaecarpin derivative shown in general formula I as described in claim 1 and its pharmaceutically acceptable salt
Preparation method, it is characterised in that:
Rutaecarpin 1 reacts under the conditions of NaH/DMF with bromhydrin, obtains rutaecarpin hydroxy derivatives 2；
The heating of melphalan 3 and methanol react to obtain melphalan methyl esters 4, then 4 under conditions of DMAP catalysis with diacid anhydride reactant
Obtain melphalan methyl esters carboxylic acid derivates 5；
Rutaecarpin intermediate 2 and melphalan methyl esters carboxylic acid derivates 5 react at room temperature under the conditions of EDCI/DMAP obtains targeted
Close object 6；
6. nitrogen mustards rutaecarpin derivative shown in general formula I described in claim 1-3 any one and its can pharmaceutically connect
Application of the salt received in the drug of preparation treatment tumor disease.
7. application of the pharmaceutical composition as claimed in claim 4 in the drug of preparation treatment tumor disease.
8. application as claimed in claims 6 or 7, which is characterized in that the tumour is colon cancer, liver cancer or leukaemia.
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| CN108467394B (en) * | 2018-04-02 | 2019-08-30 | 沈阳药科大学 | A kind of alpha-lipoic acid class H2S donor and rutaecarpin splicing object and its preparation method and application |
| CN108191866B (en) * | 2018-04-02 | 2019-07-26 | 沈阳药科大学 | A kind of ADT-OH class H2S donor and rutaecarpin splicing object and its preparation method and application |
| CN113416189B (en) * | 2021-07-14 | 2023-09-12 | 沈阳药科大学 | Beta-carbopol Lin Dangai derivative, preparation method and anti-tumor application |
| CN113563331B (en) * | 2021-07-14 | 2023-04-18 | 沈阳药科大学 | Nitrogen mustard beta-carbopol derivative and preparation method and application thereof |
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| CN101787025A (en) * | 2010-03-04 | 2010-07-28 | 中国人民解放军第二军医大学 | Substituted-evodiamine anti-tumor and antifungal compounds and preparation method thereof |
| CN105524061A (en) * | 2015-12-15 | 2016-04-27 | 中国人民解放军第二军医大学 | Multi-targeted antitumor active evodiamine derivative and preparation and application thereof |
| CN105622607A (en) * | 2016-01-12 | 2016-06-01 | 沈阳药科大学 | Furazan NO donor type evodiamine derivatives with anti-tumor activity |
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|---|---|---|---|---|
| CN101787025A (en) * | 2010-03-04 | 2010-07-28 | 中国人民解放军第二军医大学 | Substituted-evodiamine anti-tumor and antifungal compounds and preparation method thereof |
| CN105524061A (en) * | 2015-12-15 | 2016-04-27 | 中国人民解放军第二军医大学 | Multi-targeted antitumor active evodiamine derivative and preparation and application thereof |
| CN105622607A (en) * | 2016-01-12 | 2016-06-01 | 沈阳药科大学 | Furazan NO donor type evodiamine derivatives with anti-tumor activity |
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