CN110028480A - 4,7- position split melphalan class nitrogen mustard derivatives of brefeldin A and its preparation method and application - Google Patents
4,7- position split melphalan class nitrogen mustard derivatives of brefeldin A and its preparation method and application Download PDFInfo
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- CN110028480A CN110028480A CN201810042469.XA CN201810042469A CN110028480A CN 110028480 A CN110028480 A CN 110028480A CN 201810042469 A CN201810042469 A CN 201810042469A CN 110028480 A CN110028480 A CN 110028480A
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- brefeldin
- melphalan
- pharmaceutically acceptable
- general formula
- acceptable salt
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D313/00—Heterocyclic compounds containing rings of more than six members having one oxygen atom as the only ring hetero atom
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Abstract
The present invention relates to natural drug and field of medicinal chemistry, the preparation methods and purposes of 4, the 7- position split melphalan class nitrogen mustard derivatives of brefeldin A.The preparation method and its application in preparation of anti-tumor drugs of DNA alkylating agent melphalan derivative are introduced in the site 4-OH and 7-OH of brefeldin A more particularly to these.4, the 7- position split melphalan class nitrogen mustard derivatives and its pharmaceutically acceptable salt structure of brefeldin A of the present invention are as shown in general formula I, wherein n is as described in claims and specification.
Description
Technical field
The invention belongs to natural drug and field of medicinal chemistry, are related to 4, the 7- position split melphalan of brefeldin A
Class nitrogen mustard derivatives and its preparation method and application, and in particular to the site 4-OH and 7-OH of brefeldin A is modified
Derivative, be related to these and spread out in the site 4-OH and 7-OH by the brefeldin A that DNA alkylating agent melphalan derivative replaces
Biology and preparation method thereof and application in preparation of anti-tumor drugs.
Background technique
Brefeldin A (brefeldin A, BFA) is that a kind of cometabolism of Saccharomyces (Ascomycetes) produces
Object belongs to macrolide type antibiotic, also referred to as decumbin or ascochitine.It in 1958, by Singleton et al. from
It is isolated in the fermentation liquid of Penicillium decumbens.Brefeldin A, crystal are in prismatic, and white does not dissolve in
Petroleum ether, chloroform, water are soluble in ethyl acetate, acetone and methanol.It is anti-swollen that pharmacological research shows that brefeldin A has
The pharmacological activity such as tumor, antiviral, antimycotic, anti-nematode and antimitotic, wherein anti-tumor activity is especially pronounced.NCI's grinds
Study carefully and shows that the brefeldin A property of can choose inhibits and kills human tumor cells.Macrolide antibiotic brefeldin A
The number of ways such as cell Proliferation can be inhibited to inhibit simultaneously with induced various types of tumors apoptosis as a kind of er stress agent
Tumour cell is killed, including human cervical carcinoma cell, prostate gland cancer cell, chronic lymphocytic leukemia cell and follicular lymphoma
Cell etc. has inhibiting effect to kinds of tumor cells.Research shows that brefeldin A by activation mitochondria and it is dead by
Body approach and the cell invasion for inhibiting focal adhesion kinase to adjust come apoptosis-induced.For example, brefeldin A can be by swashing
Apoptosis occurs for the mitochondrial pathways living and capase-8, Bid dependent form access induction ovarian cancer cell.Brefeldin A withers
Dying effect may be to be adjusted by the generation of active oxygen and the consumption of glutathione, and this adjusting will lead to apoptosis correlation
The activation of caspase approach.In addition, brefeldin A can inhibit sticking for the OVCAR-3 cell induced by fetal calf serum
And transfer.This effect is completed by the activation for the intracellular Related Component for inhibiting focal adhesion kinase to rely on.Mine-laying is luxuriant and rich with fragrance
Moral rhzomorph A leads to the apoptosis for activating induction er stress to adjust of caspase-3,6 by the mitochondrial pathways.With right
Brefeldin A pharmacological research gos deep into, and brefeldin A causes the great interest of domestic and international scientist, opens
The synthetic work to brefeldin A derivative is opened up.Purpose is that acquisition activity is more preferable, toxicity is lower, property is more stable
Antitumor candidate compound.It is separated, compared with the report in terms of mechanism of action with extracting, about brefeldin A structural modification
Report in terms of the pharmaceutical chemistry such as synthesizing 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 anti-tumor activity, good brefeldin A split melphalan spreads out
Biology, i.e. 4, the 7- position split melphalan class nitrogen mustard derivatives of brefeldin A, and further provide for comprising the derivative
Pharmaceutical composition, 4,7- position split melphalan class nitrogen mustard derivatives of the brefeldin A or combinations thereof object have anti-
Tumor promotion.
In order to solve the above technical problems, the invention provides the following technical scheme:
General formula I is the 4,7- position split melphalan class nitrogen mustard derivatives of shown brefeldin A and its can pharmaceutically connect
The salt received:
Wherein, n is the integer of 1-12.
Preferably, n is the integer of 1-6.
It is highly preferred that n is 2.
The derivative of general formula I of the present invention can be prepared with following method:
Melphalan (2) and methanol are in SOCl2Under the conditions of existing, heating reflux reaction obtains melphalan methyl esters (3), then
(3) melphalan methyl esters carboxylic acid derivates (4) are obtained with diacid anhydride reactant under conditions of DMAP is catalyzed.
Brefeldin A (1) and 2 equivalent melphalan methyl esters carboxylic acid derivates (4) room temperatures under the conditions of EDCI/DMAP are anti-
It should obtain compound (5).
The present invention also provides a kind of pharmaceutical compositions, 4, the 7- position split comprising brefeldin A shown in general formula I
Melphalan class nitrogen mustard derivatives and its pharmaceutically acceptable salt and pharmaceutically acceptable excipient.
4,7- position split melphalan class nitrogen mustard derivatives of brefeldin A of the invention and its pharmaceutically acceptable
Salt or its pharmaceutical composition can be prepared into clinically acceptable preparation with clinically acceptable carrier, and the preparation is
Tablet, granule, capsule etc..
The present invention, using principle of hybridization, selects the preferable melphalan of activity using brefeldin A as lead compound
It is connected on the position 4-OH and 7-OH of its molecular structure by derivative by linking group, and having designed and synthesized general formula is I's
Brefeldin A split melphalan derivative.Compound after split has preferable pharmaceutical active.
Specific embodiment
Embodiment 1
Brefeldin A 1 (32mg, 0.08mmol) is taken, is dissolved in methylene chloride (2.5ml), sequentially adds melphalan
Reaction, TCL prison is stirred at room temperature in the DMAP of methyl esters butyric acid (68mg, 0.16mmol), EDCI (29mg, 0.15mmol) and catalytic amount
Reaction process is surveyed, terminates reaction afterwards for 24 hours.Reaction solution is poured into 20ml mixture of ice and water, methylene chloride extracts (30ml × 3),
The washing of saturated common salt aqueous solution, anhydrous sodium sulfate is dry, recycles methylene chloride, through silicagel column (petroleum ether: ethyl acetate=2:
1) it, separates, obtains yellow oil 5-1, yield 24%.HR-MS(ESI,M+H)m/z:calcd for C43H51Cl2N5O7H:
1081.3661,found 1081.3552.1H NMR(400MHz,DMSO-d6): δ (ppm) 7.23 (1H, dd, J=15.8,
3.1Hz,C3- H), 7.03 (4H, d, J=8.5Hz, Ar-H), 6.64 (4H, d, J=8.4Hz, Ar-H), 5.75 (1H, m, C11-
), H 5.64 (1H, dd, J=15.8,1.5Hz, C2-H),5.17-5.24(2H,m,C4,C10-H),4.98(1H,m,C7-H),4.73
(1H,m,C15-H),4.33-4.40(2H,m,-NH),3.69(16H,m,-NCH2CH2Cl),3.57-3.58(6H,s,-OCH3),
0.74-2.89(29H,m,-COCH2CH2CO-,-ArCH2CHNCO-,C5,2C6,2C8,C9,2C12,2C13,2C14-H,CH3).13C
NMR(100MHz,DMSO-d6):δ(ppm)172.6,172.6,172.2,171.7,171.3,171.3,165.4,148.6,
145.4,145.4,136.4,131.1,130.6,130.6,130.6,130.6,125.6,125.6,117.7,112.1,
112.1,112.1,112.1,76.3,75.2,71.6,54.4,54.4,52.6,52.6,52.6,52.6,52.2,52.2,
49.6,43.0,41.6,41.6,41.6,41.6,41.6,41.6,37.8,36.4,36.4,33.9,31.8,30.0,30.0,
29.5,29.2,21.1.
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 5 kinds of human cancer cells strains and a kind of normal liver cell strain antiproliferative activity50It is worth (μM)
Pharmacological testing proves that brefeldin A derivative of the invention is much smaller than tumour to the toxicity of normal cell strain
Cell strain has selectivity, can be further used for preparing anti-tumor drug.
Claims (9)
1. 4,7- position split melphalan class nitrogen mustard derivatives of brefeldin A shown in general formula I and its pharmaceutically acceptable
Salt:
Wherein, n is the integer of 1-12.
2. the 4,7- position split melphalan class nitrogen mustard derivatives of brefeldin A shown in general formula I described in claim 1 and
Its pharmaceutically acceptable salt:
Wherein, n is the integer of 1-6.
3. the 4,7- position split melphalan class mustargen of brefeldin A shown in general formula I of any of claims 1 or 2 is derivative
Object and its pharmaceutically acceptable salt:
Wherein, 2 n, i.e.,
4. a kind of pharmaceutical composition, wherein shown in general formula I described in the claim 1-3 any one containing therapeutically effective amount
The 4,7- position split melphalan class nitrogen mustard derivatives and its pharmaceutically acceptable salt of brefeldin A and pharmaceutically acceptable
Carrier.
5. a kind of pharmaceutical preparation, which is characterized in that include the phenanthrene of mine-laying shown in general formula I described in claim 1-3 any one
The 4,7- position split melphalan class nitrogen mustard derivatives and its pharmaceutically acceptable salt of moral rhzomorph A or medicine as claimed in claim 4
Compositions.
6. the 4,7- position split melphalan class nitrogen mustard derivatives of brefeldin A shown in general formula I as described in claim 1
And its preparation method of pharmaceutically acceptable salt, it is characterised in that:
Melphalan (2) and methanol are in SOCl2Under the conditions of existing, heating reflux reaction obtains melphalan methyl esters (3), and then (3) exist
Melphalan methyl esters carboxylic acid derivates (4) are obtained with diacid anhydride reactant under conditions of DMAP catalysis;
Brefeldin A (1) and 2 equivalent melphalan methyl esters carboxylic acid derivates (4) react at room temperature under the conditions of EDCI/DMAP
To compound (5);
7. the 4,7- position split melphalan class nitrogen of brefeldin A shown in general formula I described in claim 1-3 any one
The application of mustard derivative and its pharmaceutically acceptable salt in the drug of preparation treatment tumor disease.
8. pharmaceutical preparation described in pharmaceutical composition as claimed in claim 4 or claim 5 is in preparation treatment tumor disease
Application in drug.
9. application as claimed in claim 7 or 8, which is characterized in that the tumour is leukaemia, prostate cancer or liver cancer.
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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CN116535380A (en) * | 2023-05-15 | 2023-08-04 | 沈阳药科大学 | Isothiocyanate derivative of brefeldin A, preparation method and application thereof |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
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CN103788053A (en) * | 2012-10-30 | 2014-05-14 | 浙江工业大学 | Brefeldin A ester derivatives and their preparation method and use |
CN106928209A (en) * | 2017-03-10 | 2017-07-07 | 沈阳药科大学 | Brefeldin A derivative and its production and use |
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Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
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CN103788053A (en) * | 2012-10-30 | 2014-05-14 | 浙江工业大学 | Brefeldin A ester derivatives and their preparation method and use |
CN106928209A (en) * | 2017-03-10 | 2017-07-07 | 沈阳药科大学 | Brefeldin A derivative and its production and use |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN116535380A (en) * | 2023-05-15 | 2023-08-04 | 沈阳药科大学 | Isothiocyanate derivative of brefeldin A, preparation method and application thereof |
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