CN106928213B - Double furazan NO donor substitutive derivatives in the position 4,7- of brefeldin A and its preparation method and application - Google Patents
Double furazan NO donor substitutive derivatives in the position 4,7- of brefeldin A and its preparation method and application Download PDFInfo
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Abstract
The present invention relates to field of medicinal chemistry, are related to the derivative that the position 4,7- of brefeldin A is modified simultaneously.Brefeldin A derivative replaced more particularly to 4,7- furazan class NO donors and preparation method thereof and purposes in the preparation of antitumor drugs.The brefeldin A derivative is as shown in general formula I or II, wherein m, n are respectively the integer of 1-8.
Description
Technical field
The present invention relates to field of medicinal chemistry, are related to the derivative that brefeldin A -4,7 is modified.Specifically relate to
And brefeldin A derivative for replacing of 4,7- double furazan NO donors and preparation method thereof and in the preparation of antitumor drugs
Purposes.
Background technique
Brefeldin A (brefeldin A) is a kind of macrolide antibiotics, for the first time from Penicillium
It is isolated in decumbens.It has extensive biological characteristics, including antitumor, antiviral, antimycotic and anti-have
Mitotic activity etc..The detection data of American National tumor research institute (NCI) shows that brefeldin A is thin to 60 kinds of tumours
The average GI of born of the same parents system50For 40nM.The decomposition of the mechanism of action and golgiosome of brefeldin A has close ties, Gorky
The reversible decomposition of body leads to the interruption of protein transport, and then the redistribution of Golgi apparatus protein matter is caused to enter endoplasmic reticulum.Though
It is the potentiality of tumor chemotherapeutic drug that so it, which has exploitation, but lower water-soluble, poor bioavilability and in animal
The neurotoxicity generated in research all limits brefeldin in the application of field of medicaments.Therefore, a kind of holding life is developed
The brefeldin A derivative of object activity, raising treatment characteristic and low toxicity is always the hot spot in pharmaceutical developments field.
Effect of the NO in tumorigenesis and death has become one of the hot spot of oncobiology research.NO donor
Type anti-tumor drug generally refers to NO donor and is combined by linking group and existing anti-tumor drug (or active group).Furazan
Nitrogen oxides is a kind of important NO donor, and not inducing and generating tolerance is its advantage.
The present invention is using brefeldin A as lead compound, and using principle of hybridization, selection can generate higher concentration NO
Furoxan-based NO donors are connected on 4 and 7 of its molecular structure as NO donor, by it by linking group, are designed and are closed
The NO donator type brefeldin A derivative for being I and II at general formula.
Summary of the invention
It is derivative the technical problem to be solved by the present invention is to find the good NO donator type brefeldin A of anti-tumor activity
Object, and further provide for the pharmaceutical composition of a kind for the treatment of tumour using the derivative as active constituent and Other diseases or illness
Object.
In order to solve the above technical problems, the invention provides the following technical scheme:
The donator type brefeldin A derivative of furazan NO shown in general formula I or II or its pharmaceutically acceptable salt:
Wherein, m, n are respectively the integer of 1-8.
Preferably, m, n are respectively the integer of 1-4；
It is highly preferred that m, n are respectively 2 or 3.
Compound of the present invention is preferably following compound:
The derivative of general formula I or II of the present invention can be prepared with following method:
Benzenethiol (2) is reacted to obtain to benzene sulphur acetic acid (3) under alkaline condition with monoxone, then through 30%H2O2Oxidation life
At benzene sulfonyl acetic acid (4).Compound 4 is in smoke HNO3In the presence of heating cyclization at 3,4- dibenzenesulfonyl furoxan-based NO donors
(5).The 4- position benzenesulfonyl of compound 5 is replaced by ethylene glycol or propylene glycol generates list benzenesulfonyl furoxan-based NO donors class NO confession
Body compound 6a and 6b.Again with succinic anhydride, glutaric anhydride or phthalic anhydride through DMAP, triethylamine is urged by compound 6a or 6b
Change reaction and obtains NO donor 7a-f.Brefeldin A and excessive furazan NO donor 7a-f are contracted under the conditions of EDCI/DMAP
Target compound 8a-f is closed to obtain, (petroleum ether: ethyl acetate is that 1:1 to 10:1) obtains monomeric compound to column chromatography.
Specific embodiment
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 180 holes μ L/2Training
It supports and is cultivated 24 hours in case.Liquid is changed, test medicine is added, 20 holes μ L/ are cultivated 72 hours.MTT is added in 96 orifice plates, 20 μ L/
Hole is incubated for 4 hours in incubator.Supernatant is sucked, adds DMSO, 150 holes μ L/ are shaken 10 minutes on plate shaker.Exempted from enzyme-linked
Epidemic disease monitor calculates separately the cell inhibitory rate under each concentration in the absorbance that wavelength is the every hole of measurement at 570nm.
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 3 kinds of human cancer cell's strain antiproliferative activities50It is worth (nM)
Pharmacological testing proves, part brefeldin A derivative of the invention has better antitumor action, can be with
For further preparing anti-tumor drug.
Embodiment 1
By 60g NaOH and 480mL H2The solution that O is made into pours into reaction flask, takes benzenethiol (75mL, 0.63mol), and
Monoxone (78g, 0.825mol) is added afterwards, there are a large amount of white precipitates to be precipitated in reaction solution.6N HCl is added, obtains white solid benzene
Sulphur acetic acid (3).3 (20g, 0.12mol) are dissolved in 90mL glacial acetic acid, 24.3mL 30%H is added2O2, it is stirred at room temperature.Wait react
Completely, smoke HNO is added348mL.Temperature reaction after 4h, there is white needle-like crystals precipitation, filters, dry 3,4- hexichol sulphur
Acyl group furoxan-based NO donors (5).Ethylene glycol (0.56mL, 10mmol) and 5 (1g, 2.7mmol) are dissolved in 10mL THF, instilled
30%NaOH aqueous solution (0.5mL, 3mmol) reacts 2h.It is poured into 20mL H2In O, extracted with EtOAc (3 × 20mL), organic layer
After merging plus saturated common salt washing is primary, with anhydrous sodium sulfate drying, filtering, filtrate concentration, recrystallization, obtains white solid chemical combination
Object 6a.Compound 6a (202mg, 0.71mmol) is dissolved in 10mL methylene chloride, addition succinic anhydride (111mg,
1.11mmol).The DMAP of catalytic amount is sequentially added, 1h is stirred at room temperature in triethylamine 0.3mL.To after reaction, anhydrous sodium sulfate
Dry, filtering, filtrate concentration, silica gel column chromatography (petroleum ether: ethyl acetate=1:1) obtain white powdery solids 7a.It will change
It closes object 7a to be dissolved in 10mL anhydrous methylene chloride, be added brefeldin A (81mg, 0.29mmol), EDCI (112mg,
0.58mmol), the DMAP of catalytic amount, is stirred at room temperature 12h.TLC monitoring reaction stops when fully reacting or when not going on
Reaction.Organic phase is washed with saturated common salt, then, filtering dry with anhydrous sodium sulfate, concentration, silica gel column chromatography (petroleum ether: acetic acid
Ethyl ester=2:1), obtain white powdery solids 8a, 70.9%:mp.60-65 DEG C of yield；1H-NMR(400MHz,DMSO-d6)δ
7.72~8.02 (10H, m, Ar-H), 7.22 (1H, dd, J=15.84Hz and 3.12Hz, C3-H),5.75(1H,m,C11-
), H 5.64 (1H, dd, J=15.74Hz and 1.88Hz, C2- H), 5.27 (1H, d, J=9.64Hz, C10-H),5.18(1H,
Dd, J=15.04Hz and 9.64Hz, C4-H),5.00(1H,m,C7-H),4.72(1H,m,C15- H), 4.37~4.60 (8H,
T, J=4.41Hz, 2OCH2 CH2 ), O 2.55~2.76 (8H, m, 2COCH2 CH2 ), CO 0.72~2.54 (15H, m, C5,2C6,
2C8,C9,2C12,2C13,2C14-H,CH3 )；13C-NMR(400MHz,DMSO-d6)δ171.87,171.83,171.39,170.93,
164.87,158.68,158.68,148.02,137.22,137.20,136.11,136.09,135.76,130.66,129.97,
129.97,129.97,129.97,128.33,128.33,128.33,128.33,117.24,110.46,110.44,76.09,
75.06,71.25,69.21,69.21,61.59,61.46,49.14,49.14,42.43,40.06,37.38,33.38,
31.29,28.78,28.57,28.47,26.26,20.56；HR-MS(ESI,M+Na)m/z:calcd for C44H48N4O20S2:
1039.2196,found 1039.2197。
Embodiment 2
Referring to the synthetic method of embodiment 1.Yellow oil, yield 13.4%；1H-NMR(400MHz,DMSO-d6)δ
7.72~8.02 (10H, m, Ar-H), 7.23 (1H, dd, J=15.70Hz and 3.29Hz, C3-H),5.73(1H,m,C11-
), H 5.60 (1H, dd, J=15.80Hz and 1.69Hz, C2-H),5.28(1H,m,C10- H), 5.16 (1H, dd, J=
15.14Hz and 9.75Hz,C4-H),5.01(1H,m,C7-H),4.73(1H,m,C15- H), 4.43~4.62 (8H, m,
2OCH2 CH2 ), O 2.39~2.63 (8H, m, 2COCH2 CH2CH2 ), CO 0.73~2.34 (19H, m, C5,2C6,2C8,C9,2C12,
2C13,2C14-H,2COCH2CH2 CH2CO,CH3 )；13C-NMR(400MHz,DMSO-d6)δ172.83,172.29,172.05,
171.56,164.86,158.69,158.69,148.34,137.21,136.13,136.13,136.10,135.78,130.68,
129.97,129.97,129.97,129.97,128.31,128.31,128.31,128.31,117.13,110.46,110.46,
75.76,74.74,71.26,69.33,69.33,61.28,61.24,51.28,42.43,42.40,37.43,33.40,
32.71,32.66,32.40,32.28,31.27,26.26,20.57,19.82,19.77；HR-MS(ESI,M+Na)m/z:
calcd for C46H52N4O20S2:1067.2509,found 1067.2510。
Embodiment 3
Referring to the synthetic method of embodiment 1.Yellow oil, yield 8.7%；1H-NMR(400MHz,DMSO-d6)δ7.71
~8.01 (10H, m, Ar-H), 7.22 (1H, dd, J=15.86Hz and 3.25Hz, C3-H),5.74(1H,m,C11-H),
5.63 (1H, dd, J=15.80Hz and 1.67Hz, C2-H),5.25(1H,m,C10- H), 5.18 (1H, dd, J=15.04Hz
and 9.74Hz,C4-H),4.94(1H,m,C7-H),4.71(1H,m,C15- H), 4.15~4.45 (8H, t, J=6.13Hz,
2OCH2 CH2CH2 ), O 2.52~2.70 (8H, m, 2COCH2 CH2 ), CO 0.72~2.52 (19H, m, C5,2C6,2C8,C9,2C12,
2C13,2C14-H,2OCH2CH2 CH2O,CH3 )；13C-NMR(400MHz,DMSO-d6)δ172.36,172.36,171.83,
171.40,165.26,159.15,159.15,148.45,137.53,137.50,136.50,136.50,136.16,131.03,
130.37,130.37,130.37,130.37,128.72,128.72,128.72,128.72,117.60,110.88,110.88,
76.43,75.42,71.62,68.62,68.56,60.90,60.73,49.57,42.80,40.42,37.78,33.76,
31.67,29.22,28.98,28.90,28.90,27.75,27.75,26.64,20.93；HR-MS(ESI,M+Na)m/z:
calcd for C46H52N4O20S2:1067.2509,found 1067.2456。
Embodiment 4
Referring to the synthetic method of embodiment 1.Yellow oil, yield 19.3%；1H-NMR(400MHz,DMSO-d6)δ
7.70~7.99 (10H, m, Ar-H), 7.21 (1H, dd, J=15.79Hz and 3.33Hz, C3-H),5.72(1H,m,C11-
), H 5.56 (1H, dd, J=15.86Hz and 1.80Hz, C2-H),5.26(1H,m,C10- H), 5.15 (1H, dd, J=
15.22Hzand 9.77Hz,C4-H),4.99(1H,m,C7-H),4.69(1H,m,C15- H), 4.10~4.44 (8H, m,
2OCH2 CH2CH2 ), O 2.30~2.48 (8H, m, 2COCH2 CH2CH2 ), CO 0.70~2.65 (23H, m, C5,2C6,2C8,C9,
2C12,2C13,2C14-H,2OCH2CH2 CH2O,2COCH2CH2 CH2CO,CH3 )；13C-NMR(400MHz,DMSO-d6)δ172.79,
172.76,172.37,171.92,165.21,159.15,159.15,148.68,137.56,137.56,136.49,136.49,
136.13,131.07,130.36,130.36,130.36,130.36,128.70,128.70,128.70,128.70,117.52,
110.86,110.86,76.15,75.13,71.62,68.60,68.60,60.60,60.57,55.27,49.60,42.82,
37.80,33.77,33.10,32.81,32.81,32.70,31.67,27.75,27.75,26.63,20.93,20.21,
20.21；HR-MS(ESI,M+Na)m/z:calcd for C48H56N4O20S2:1095.2822,found 1095.2771。
Embodiment 5
Referring to the synthetic method of embodiment 1.White powdery solids, 27.3%:mp.50-54 DEG C of yield；1H-NMR
(400MHz,DMSO-d6) δ 7.51~7.92 (18H, m, Ar-H), 7.25 (1H, dd, J=15.83Hz and 3.49Hz, C3-
H),5.75(1H,m,C11- H), 5.58 (1H, dd, J=15.84Hz and 1.59Hz, C2-H),5.51(1H,m,C10-H),
5.24(1H,m,C4- H), 5.16 (1H, dd, J=14.98Hz and 9.81Hz, C7-H),4.71(1H,m,C15-H),4.63
(8H,m,2OCH2 CH2 ), O 0.73~2.32 (15H, m, C5,2C6,2C8,C9,2C12,2C13,2C14-H,CH3 )；13C-NMR
(400MHz,DMSO-d6)δ167.05,167.02,166.54,165.79,165.10,159.06,159.02,147.84,
137.54,137.54,136.36,136.29,135.90,132.45,132.32,132.20,132.01,131.92,131.81,
131.54,131.26,131.06,130.17 130.17,130.09,130.09,129.37,129.33,129.29,129.15,
128.62,128.62,128.56,128.56,117.96,110.82,110.74,77.83,76.91,71.68,69.41,
69.31,62.99,62.92,49.73,42.99,40.43,37.77,33.81,31.67,26.49,20.87；HR-MS(ESI,M
+Na)m/z:calcd for C52H48N4O20S2:1135.2196,found 1135.2176。
Embodiment 6
Referring to the synthetic method of embodiment 1.Yellow oil, yield 8.4%；1H-NMR(400MHz,DMSO-d6)δ7.69
~7.99 (18H, m, Ar-H), 7.28 (1H, dd, J=15.84Hz and 3.60Hz, C3-H),5.77(1H,m,C11-H),
5.69 (1H, dd, J=15.82Hz and 1.67Hz, C2-H),5.50(1H,m,C10-H),5.21(2H,m,C4-H,C7-H),
4.74(1H,m,C15- H), 4.34~4.44 (8H, m, 2OCH2 CH2CH2 ), O 0.74~2.32 (19H, m, C5,2C6,2C8,C9,
2C12,2C13,2C14-H,2OCH2CH2 CH2O,CH3 )；13C-NMR(400MHz,DMSO-d6)δ167.36,167.25,166.63,
165.77,165.16,159.16,159.14,147.91,137.50,137.49,136.48,136.48,135.95,132.49,
132.34,132.09,131.97,131.97,131.91,131.79,131.26,130.66,130.33,130.33,130.33,
130.33,129.34,129.20,129.11,129.04,128.70,128.70,128.70,128.70,118.06,110.89,
110.89,76.90,71.71,71.52,68.53,67.78,62.11,61.87,49.83,43.01,40.44,40.44,
38.45,30.17,28.74,27.58,23.62,22.77；HR-MS(ESI,M+Na)m/z:calcd for C54H52N4O20S2:
1163.2509,found 1163.2464。
Claims (8)
1. brefeldin A derivative or its pharmaceutically acceptable salt as shown in general formula I or II:
Wherein, m, n are respectively the integer of 1-4.
2. brefeldin A derivative or its pharmaceutically acceptable salt described in general formula I or II described in claim 1:
Wherein, m, n are respectively 2 or 3.
3. brefeldin A derivative of any of claims 1 or 2 or its pharmaceutically acceptable salt, are selected from:
4. a kind of pharmaceutical composition, wherein derivative described in the claim 1-3 any one containing therapeutically effective amount or its
Pharmaceutically acceptable salt and pharmaceutically acceptable carrier.
5. the preparation method of brefeldin A derivative as claimed in claim 3 or its pharmaceutically acceptable salt, special
Sign is, benzenethiol 2 is reacted to obtain to benzene sulphur acetic acid 3 under alkaline condition with monoxone, then through 30%H2O2Oxidation generates benzene sulphur
Ethyl acetoacetic acid 4, compound 4 is in smoke HNO3In the presence of heating cyclization at 3,4- dibenzenesulfonyl furoxan-based NO donors 5, compound 5
4- position benzenesulfonyl the single benzenesulfonyl furoxan-based NO donors class NO compound donator 6a of generation is replaced by ethylene glycol or propylene glycol
And 6b, compound 6a or 6b, again with succinic anhydride, glutaric anhydride or phthalic anhydride through DMAP, triethylamine catalysis reaction obtains
Brefeldin A and excessive furazan NO donor 7a-f are condensed to obtain targeted by NO donor 7a-f under the conditions of EDCI/DMAP
Close object 8a-f, silica gel column chromatography condition petroleum ether: ethyl acetate is 1:1 to 10:1；
6. derivative described in claim 1-3 any one or its pharmaceutically acceptable salt are in preparation treatment tumor disease
Purposes in drug.
7. purposes of the pharmaceutical composition as claimed in claim 4 in the drug of preparation treatment tumour.
8. purposes as claimed in claims 6 or 7, which is characterized in that the tumour is liver cancer, colon cancer or prostate cancer.
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