CN108997319A - Thiocarbamoyl imidazole alkanone derivative and its synthetic method and application - Google Patents
Thiocarbamoyl imidazole alkanone derivative and its synthetic method and application Download PDFInfo
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- CN108997319A CN108997319A CN201810679395.0A CN201810679395A CN108997319A CN 108997319 A CN108997319 A CN 108997319A CN 201810679395 A CN201810679395 A CN 201810679395A CN 108997319 A CN108997319 A CN 108997319A
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- 0 CCC(C**)C(C(*)**(C)C1)C1C(*)CCCC(C*1)[C@@](*)C2(C)C3C(C(C)C)C1C23 Chemical compound CCC(C**)C(C(*)**(C)C1)C1C(*)CCCC(C*1)[C@@](*)C2(C)C3C(C(C)C)C1C23 0.000 description 3
- DYYVBNICRVQWKJ-HTDLUWEMSA-N C[C@@H](CCCC1)[C@@]1(C)N(C(C(C1(c2cc3ccccc3[nH]2)C#N)C2=CCCC(C3)C23Cl)=S)C1=N Chemical compound C[C@@H](CCCC1)[C@@]1(C)N(C(C(C1(c2cc3ccccc3[nH]2)C#N)C2=CCCC(C3)C23Cl)=S)C1=N DYYVBNICRVQWKJ-HTDLUWEMSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- A61P35/00—Antineoplastic agents
Abstract
Thiocarbamoyl imidazole alkanone derivative and its synthetic method and application, the structural formula of the thiocarbamoyl imidazole alkanone derivative is as shown in following formula 11, its by substitution 2-mercaptobenzothiazole, aromatic aldehyde, isonitrile and malononitrile in acetonitrile solution binaphthol-Chao Geer alkali amine Shiff base derivative catalysis under, at room temperature stirring obtained by.Thiocarbamoyl imidazole alkanone derivative of the invention is to triple negative breast cancer (MDA-MB-231), breast cancer (MCF-7), human lung cancer (A549) cell strain has preferable inhibitory effect, and it is lower to the toxicity of normal human cell, it has broad application prospects in terms of preparing anti-lung cancer of new generation and Breast Cancer-Specific drug.
Description
Technical field
The invention belongs to chemical synthesis and biomedicine fields, and in particular to thiocarbamoyl imidazole alkanone derivative and its synthesis side
Method and application.
Background technique
Cancer, especially some malignant tumours are scientist's unassailable difficult points long.Currently, chemotherapy is treating cancer master
One of effective measures wanted.But clinically the quantity of alternative chemotherapeutics is very limited, consequently found that new can be with
Chemotherapeutics for clinical use is the hot spot in current cancer research.
Wherein, three positive breast cancers are that people wish one of malignant tumour captured in a hurry, have investigation to show: although in cream
Accounted in gland cancer it is smaller, but three positive breast cancers have lump is larger, biological behaviour is poor, pathology more be divided into III level, armpit leaching
It fawns on transfer, often have the pathological characters such as nerve or vascular infiltration, high tumor load and high proliferation index.And three positive breast cancer phase
More early to negative breast cancer relapse and metastasis, overall survival and disease-free survival rate are lower.Therefore, the targeting of three positive breast cancers is developed
Drug reduces its recurrence and metastatic rate and has great importance, and Chao Geer alkali derivant and thiocarbamoyl imidazole alkanone analog derivative are
The lead drug skeleton of great potential.
Benzimidazole is the bioisostere of natural nucleotide, is played an important role in biological field.As
A kind of typical alkaloid, thiocarbamoyl imidazole alkanone analog derivative have high bioactivity, unique pharmaceutical activity and reason
Change property, plays huge effect in fields such as medicine, material, chemical industry, pesticides, therefore, thiocarbamoyl imidazole alkanone analog derivative
It is the emphasis of people's research.
Summary of the invention
Inventor has developed a kind of synthetic method of thiocarbamoyl imidazole alkanone derivative by lot of experiments, and designs conjunction
At a variety of thiocarbamoyl imidazole alkanone derivatives.Experiment in vitro shows a variety of thiocarbamoyl imidazole alkanone derivatives of the invention to tumour
Cell strain has preferable inhibitory effect, has potential application prospect in terms of preparing anti-tumor drug.
Specifically, structural formula is as shown in following formula 11 the present invention provides a kind of thiocarbamoyl imidazole alkanone derivative:
Wherein,
It is the substitution 2- mercapto as shown in formula 7 the present invention also provides the synthetic method of above-mentioned thiocarbamoyl imidazole alkanone derivative
Aromatic aldehyde shown in base benzothiazole, formula 8, the compound for catalysis shown in formula 6a in acetonitrile solution of isonitrile and malononitrile shown in formula 9
Under, at room temperature obtained by stirring.
Wherein,
Further, aromatic aldehyde shown in 2-mercaptobenzothiazole, formula 8, isonitrile and malononitrile shown in formula 9 are replaced shown in formula 7
Molar ratio is 1:1:1:1:1.
Further, the volume ratio of acetonitrile and water is 3:1 in acetonitrile solution.
The present invention also provides above-mentioned thiocarbamoyl imidazole alkanone derivative application in preparations of anti-tumor drugs.
Compared with prior art, beneficial effects of the present invention: reaction condition needed for synthesis technology of the present invention is mild, reaction when
Between it is short, yield is high, have wide industrialization/scale application prospect；Thiocarbamoyl imidazole alkanone derivative of the invention is to three yin
Property breast cancer (MDA-MB-231), breast cancer (MCF-7), human lung cancer (A549) cell strain have preferable inhibitory effect, have
Anticancer activity, and it is lower to the toxicity of normal human cell, in terms of preparing anti-lung cancer of new generation and Breast Cancer-Specific drug
It has broad application prospects.
Specific embodiment:
The synthesis of 1 amino-contained Chao Geer alkali derivant of embodiment
Compound 1 (10mmol), N- bromo-succinimide are sequentially added in clean 100mL round-bottomed flask
(20mmol), azodiisobutyronitrile (20mol%) and acetonitrile solution 20mL are heated to reflux 12h (TLC tracking), after fully reacting,
It filters, mother liquor is spin-dried for, and chromatographs (V through columnPetroleum ether:VEthyl acetate=5:1) purify to obtain product 2, yield 81%.
The synthesis of 2 binaphthalene Fen-Chao Geer alkali amine Shiff base derivative of embodiment
Compound 1 (2mmol) and 4 (1mmol) are successively added into dry pressure pipe (10mL), are heated to reflux 12h
(TLC tracking) after fully reacting, filters, recrystallizes to obtain product 6a.
Compound 2 (2mmol) and 4 (1mmol) are successively added into dry pressure pipe (10mL), are heated to reflux 12h
(TLC tracking) after fully reacting, filters, recrystallizes to obtain product 6b.
Compound 3 (2mmol) and 4 (1mmol) are successively added into dry pressure pipe (10mL), are heated to reflux 12h
(TLC tracking) after fully reacting, filters, recrystallizes to obtain product 6c.
Compound 1 (1mmol) and 5 (1mmol) are successively added into dry pressure pipe (10mL), are heated to reflux 12h
(TLC tracking) after fully reacting, filters, recrystallizes to obtain product 6d.
Compound 2 (1mmol) and 5 (1mmol) are successively added into dry pressure pipe (10mL), are heated to reflux 12h
(TLC tracking) after fully reacting, filters, recrystallizes to obtain product 6e.
Compound 3 (1mmol) and 5 (1mmol) are successively added into dry pressure pipe (10mL), are heated to reflux 12h
(TLC tracking) after fully reacting, filters, recrystallizes to obtain product 6f.
The synthesis of 3 thiocarbamoyl imidazole alkanone analog derivative of embodiment
Sequentially added in clean 10mL round-bottomed flask 7 (0.2mmol), aromatic aldehyde 8 (0.2mmol), isonitrile 9 (0.2mmol),
Catalyst 6a (10mmol%) and acetonitrile solution (V in malononitrile 10 (0.2mmol), embodiment 2Acetonitrile: VWater=3:1) 2mL,
12h is stirred at room temperature.(TLC tracking) after complete reaction, through anhydrous Na2SO4Dry, vacuum distillation, column chromatographic purifying obtains target
Product (VPetroleum ether: VEthyl acetate=5:1).
4 product structure of embodiment characterization
3,3 '-bis- ((E)-((9- amino -2,8- dimethyl -6H, 12H-5,11- methylene dibenzo [b, f] [1,5] two
Nitrogen virtue oct-3-yl) imino group) methyl)-[1,1 '-dinaphthalene] -2,2 '-glycol (6a)
(100MHz,CDCl3)δ196.84,162.19,154.62,146.79,143.91,138.58,135.53,134.71,
130.74,129.98,129.05,128.76,127.75,126.67,124.97,123.59,121.46,119.55,117.19,
113.64,110.30,66.94,58.25,17.69,16.84.HRMS(ESI)m/z:calcd for C56H50N8O2[M-H]+:
865.3978；found:865.3952.
3,3 '-bis- ((E)-((bromo- 2,8- dimethyl -6H-, 12H-5,11- methylene dibenzo of 9- amino -4,10- two
[b, f] [1,5] diazocine-pyridin-3-yl) imino group) methyl-[1,1 '-dinaphthyl] -2,2 '-glycol (6b)
201.83.,163.45,152.67,150.69,146.81,141.48,137.83,134.59,132.73,128.89,
128.11,126.55,124.52,124.78,120.31,118.63,112.58,111.38,71.54,69.38,
19.54.HRMS(ESI)m/z:calcd for C56H46Br4N8O2[M-H]+:1177.0399；found:1177.0356.
3,3 '-bis- ((E)-((8- amino -4,10- dimethyl 6H, 12H-5,11- methylene dibenzo [b, f] [1,5] two
Nitrogen virtue octyl- 2- yl) imino group) methyl)-[1,1'- dinaphthalene] -2,2 '-glycol (6c)
MHz,CDCl3),δ161.11,154.53,142.50,135.53,133.99,129.04,128.66,127.76,124.79,
123.49,121.37,116.75,116.52,110.20,67.80,55.32,55.13,17.31,17.11.HRMS(ESI)m/
z:calcd forC56H50N8O2[M-H]+:865.3978；found:865.3934.
(E) -3- (((9- amino -2,8- dimethyl -6H, 12H-5,11- methylene dibenzo [b, f] [1,5] phenodiazine virtue
Oct-3-yl) imino group) methyl)-[1,1 '-dinaphthalene] -2,2 '-glycol (6d)
4.31 (d, J=8.2Hz, 2H), 4.18 (d, J=8.0Hz, 2H), 2.15 (s, 3H), 2.04 (s, 3H)13C NMR(100MHz,
CDCl3),δ161.74,155.39,151.66,146.48,135.64,133.63,130.18,129.12,128.93,
128.32,127.84,126.50,124.85,124.02,123.20,121.28,117.76,66.89,58.34,
17.70.HRMS(ESI)m/z:calcd for C38H32N4O2[M-H]+:575.2447；found:575.2485.
(E) -3- (((bromo- 2,8- dimethyl -6H-, the 12H-5,11- methylene dibenzo [b, f] of 9- amino -4,10- two
[1,5] diazocine -3- base) imino group) methyl)-[1,1 '-dinaphthyl] -2,2 '-glycol (6e)
2H), 4.55 (d, J=10.4Hz, 2H), 4.26 (d, J=8.0Hz, 2H), 2.57 (s, 3H), 2.38 (s, 3H)13C NMR
(100MHz,CDCl3),δ162.83,158.63,153.75,148.63,138.69,135.76,132.14,129.35,
128.37,127.89,126.76,125.61,123.53,122.19,119.85,65.98,60.46,24.83.20.84HRMS
(ESI)m/z:calcd for C38H30Br2N4O2[M-H]+:731.0657；found:731.0632
(E) -3- (((8- amino -4,10- dimethyl 6H, 12H-5,11- methylene dibenzo [b, f] [1,5] phenodiazine virtue
Octyl- 2- yl) imino group) methyl)-[1,1 '-dinaphthalene] -2,2 '-glycol (6f)
CDCl3),δ160.71,155.49,151.42,143.30,135.33,134.33,133.51,130.16,129.35,
129.10,128.33,127.81,126.61,124.77,124.08,123.33,121.91,121.35,117.77,117.18,
114.37,113.87,55.12,17.27.HRMS(ESI)m/z:calcd for C38H32N4O2[M+H]+:575.2447；
found:575.2461.
3- (1H- benzo [d] imidazoles -2- base) -1- cyclohexyl -2- imino group -4- phenyl -5- thioxo-pyrrolidine -3- formonitrile HCN
(11a)
CDCl3)δ204.12,175.35,156.61,132.81,128.69,120.57,113.26,67.81,59.93,58.55,
37.67,25.87,24.78.HRMS(ESI)m/z calcd for C24H23N5S[M-H]+:412.1596；found:
412.1591.
3- (1H- benzo [d] imidazoles -2- base) -4- (4- bromophenyl) -1- cyclohexyl -2- imino group -5- thioxo-pyrrolidine -
3- formonitrile HCN (11b)
1H), 7.51 (d, J=8.1Hz, 3H), 7.32 (d, J=2.2Hz, 2H), 7.16 (d, J=6.6Hz, 2H), 5.46 (s, 1H),
5.03 (s, 1H), 2.07 (s, 1H), 1.96-1.78 (m, 5H), 1.69 (t, J=6Hz, 2H), 1.30-1.12 (m, 3H)13C
NMR(100MHz,CDCl3),δ203.44,161.47,144.20,135.05,131.99,130.58,123.64,115.04,
26.93,25.90,25.72,25.08.HRMS(ESI)m/z calcd for C24H22BrN5S[M-H]+:490.0701；
found:490.0699.
3- (1H- benzo [d] imidazoles -2- base) -1- cyclohexyl -2- imino group -5- thio -4- (p-methylphenyl) pyrrolidines -
3- formonitrile HCN (11c)
MHz,CDCl3),δ204.58,161.74,145.33,139.19,133.12,129.99,128.38,123.38,115.31,
26.93,25.84,25.56,25.04,21.25.HRMS(ESI)m/z calcd for C25H25N5S[M-H]+:426.1752；
found:426.1747.
The thio pyrroles of 3- (1H- benzo [d] imidazoles -2- base) -1- cyclohexyl -2- imino group -4- (4- methoxyphenyl) -5-
Alkane -3- formonitrile HCN (11d)
(100MHz,CDCl3),δ203.26,160.86,153.63,141.07,132.55,126.49,124.57,121.45,
117.47,28.76,26.46,25.17,25.09,21.36.HRMS(ESI)m/z calcd for C25H25N5OS[M-H]+:
442.1702；found:442.1698.
3- (1H- benzo [d] imidazoles -2- base) -4- (2- bromophenyl) -1- cyclohexyl -2- imino group -5- thioxo-pyrrolidine -
3- formonitrile HCN (11e)
128.23,125.91,114.44,63.87,58.74,26.61,25.97,25.78,25.12.HRMS(ESI)m/z calcd
for C24H22BrN5S[M-H]+:490.0701；found:490.0698.
3- (1H- benzo [d] imidazoles -2- base) -4- (3- bromophenyl) -1- cyclohexyl -2- imino group -5- thioxo-pyrrolidine -
3- formonitrile HCN (11f)
130.58,123.64,115.04,60.80,58.00,34.73,26.93,25.72,23.08.HRMS(ESI)m/z calcd
for C24H22BrN5S[M-H]+:490.0701；found:490.0703.
3- (1H- benzo [d] imidazoles -2- base) -4- (2- chlorphenyl) -1- cyclohexyl -2- imino group -5- thioxo-pyrrolidine -
3- formonitrile HCN (11g)
127.67,126.47,125.33,115.62,64.92,57.68,30.21,25.17,24.63,23.24.HRMS(ESI)m/z
calcd for C24H22ClN5S[M-H]+:446.1206；found:446.1206.
3- (1H- benzo [d] imidazoles -2- base) -4- (3- chlorphenyl) -1- cyclohexyl -2- imino group -5- thioxo-pyrrolidine -
3- formonitrile HCN (11h)
169.78,164.70,163.52,145.12,129.31,120.35,116.34,115.63,61.98,59.34,29.62,
23.77,23.29,19.72.HRMS(ESI)m/z calcd for C24H22ClN5S[M-H]+:446.1206；found:
446.1205.
3- (1H- benzo [d] imidazoles -2- base) -1- cyclohexyl -4- (4- fluorophenyl) -2- imino group -5- thioxo-pyrrolidine -
3- formonitrile HCN (11i)
1.25-1.20(m,2H).13C NMR(100MHz,CDCl3),δ203.44,171.41,163.80,161.39,144.84,
130.50,116.16,115.08,60.46,27.43,25.88,24.83,20.91,13.71.HRMS(ESI)m/z calcd
for C24H22FN5S[M-H]+:430.1502；found:430.1499.
The thio pyrrole of 1- cyclohexyl -3- (5,6- dimethyl -1H- benzo [d] imidazoles -2- base) -2- imino group -4- phenyl -5-
Cough up alkane -3- formonitrile HCN (11j)
115.29,113.01,66.04,57.96,25.90,25.75,24.87,20.14.HRMS(ESI)m/z calcd for
C26H27N5S[M-H]+:440.1909；found:440.1906.
4- (4- chlorphenyl) -1- cyclohexyl -3- (5,6- dimethyl -1H- benzo [d] imidazoles -2- base) -2- imino group -5-
Thioxo-pyrrolidine -3- formonitrile HCN (11k)
127.75,113.99,24.85,24.74,24.04,19.39.HRMS(ESI)m/z calcd for C26H26ClN5S[M-H]+:
474.1519；found:474.1509.
4- (3- chlorphenyl) -1- cyclohexyl -3- (5,6- dimethyl -1H- benzo [d] imidazoles -2- base) -2- imino group -5-
Thioxo-pyrrolidine -3- formonitrile HCN (11l)
137.62,134.95,130.44,129.46,129.12,126.96,114.99,57.96,31.92,29.36,26.90,
25.88,25.72,25.04.HRMS(ESI)m/z calcd for C26H26ClN5S[M-H]+:474.1519；found:
474.1516.
4- (2- chlorphenyl) -1- cyclohexyl -3- (5,6- dimethyl -1H- benzo [d] imidazoles -2- base) -2- imino group -5-
Thioxo-pyrrolidine -3- formonitrile HCN (11m)
52.31,26.93,26.00,25.79,25.12,20.38.HRMS(ESI)m/z calcd for C26H26ClN5S[M-H]+:
474.1519；found:474.1518.
1- cyclohexyl -3- (5,6- dimethyl -1H- benzo [d] imidazoles -2- base) -2- imino group -4- (4- methoxybenzene
Base) -5- thioxo-pyrrolidine -3- formonitrile HCN (11n)
114.44,108.37,55.19,26.93,25.92,25.80,24.99,20.39.HRMS(ESI)m/z calcd for
C27H29N5OS[M-H]+:470.2015；found:470.2013.
1- cyclohexyl -4- (2,3- Dimethoxyphenyl) -3- (5,6- dimethyl -1H- benzo [d] imidazoles -2- base) -2- is sub-
Amino -5- thioxo-pyrrolidine -3- formonitrile HCN (11o)
129.29,126.72,108.72,58.18,55.72,50.39,29.48,27.12,25.89,25.68,25.17,
20.37.HRMS(ESI)m/z calcd for C28H31N5O2S[M-H]+:500.2120；found:500.2104.
1- cyclohexyl -3- (5,6- dimethyl -1H- benzo [d] imidazoles -2- base) -2- imino group -4- (4- nitrobenzophenone) -
5- thioxo-pyrrolidine -3- formonitrile HCN (11p)
169.39,164.28,163.57,150.13,133.68,115.35,114.58,60.64,52.89,26.47,25.45,
24.67,21.48,.HRMS(ESI)m/z calcd for C26H26N6O2S[M-H]+:485.1760；found:485.1758.
1- cyclohexyl -3- (5,6- dimethyl -1H- benzo [d] imidazoles -2- base) thio -4- of -2- imino group -5- is (to toluene
Base) pyrrolidines -3- formonitrile HCN (11q)
161.75,144.20,138.67,132.77,129.79,128.61,115.31,65.80,60.71,25.93,25.69,
25.11,22.66,21.19,20.44.HRMS(ESI)m/z calcd for C27H29N5S[M-H]+:454.2065；found:
454.2062.
4- (4- bromophenyl) -1- cyclohexyl -3- (5,6- dimethyl -1H- benzo [d] imidazoles -2- base) -2- imino group -5-
Thioxo-pyrrolidine -3- formonitrile HCN (11r)
31.92,29.70,29.35,26.98,25.90,25.74,25.07,22.68,20.44,14.06.HRMS(ESI)m/z
calcd for C26H26BrN5S[M-H]+:518.1014；found:518.1013.
4- (2- bromophenyl) -1- cyclohexyl -3- (5,6- dimethyl -1H- benzo [d] imidazoles -2- base) -2- imino group -5-
Thioxo-pyrrolidine -3- formonitrile HCN (11s)
114.72,58.53,29.64,26.58,26.00,24.64,20.16.HRMS(ESI)m/z calcd for C26H26BrN5S
[M-H]+:518.1014；found:518.1011.
1- cyclohexyl -3- (5,6- dimethyl -1H- benzo [d] imidazoles -2- base) -4- (4- fluorophenyl) -2- imino group -5-
Thioxo-pyrrolidine -3- formonitrile HCN (11t)
116.43,112.41,53.79,51.22 25.47,25.32,23.19,22.53,21.37.HRMS(ESI)m/z calcd
for C26H26FN5S[M-H]+:460.1971；found:460.1967.
1- hexyl -3- (chloro- 1H- benzo [d] imidazoles -2- base of 5,6- bis-) thio -4- of -2- imino group -5- (p-methylphenyl)
Pyrrolidines -3- formonitrile HCN (11u)
58.09,52.56,31.63,25.66,25.07,21.30.HRMS(ESI)m/z calcd for C24H23Cl2N5S[M-H]+:
494.0973；found:494.0972.
4- (4- chlorphenyl) -1- cyclohexyl -3- (chloro- 1H- benzo [d] imidazoles -2- base of 5,6- bis-) -2- imino group -5- sulphur
For pyrrolidines -3- formonitrile HCN (11v)
131.11,129.19,128.12,102.76,102.49,56.32,29.73,25.97,25.56,25.01.HRMS(ESI)m/z
calcd for C24H20Cl3N5S[M-H]+:514.0427；found:514.0419.
4- (4- bromophenyl) -1- cyclohexyl -3- (chloro- 1H- benzo [d] imidazoles -2- base of 5,6- bis-) -2- imino group -5- sulphur
For pyrrolidines -3- formonitrile HCN (11w)
112.77,60.79,28.22,25.43,24.90,20.77,14.09.HRMS(ESI)m/z calcd for
C24H19BrCl2N5S[M-H]+:557.9922；found:557.9916.
3- (1H- benzo [d] imidazoles -2- base) -4- (the bromo- 4- methoxyphenyl of 2-) -1- cyclohexyl -2- imino group -5- sulphur
For pyrrolidines -3- formonitrile HCN (11x)
161.77,144.98,130.82,116.44,116.16,115.05,60.54,25.91,25.78,25.10,21.12,
14.20.HRMS(ESI)m/z calcd for C25H24BrN5OS[M-H]+:464.0545；found:520.0807.
The thio pyrroles of 3- (1H- benzo [d] imidazoles -2- base) -4- (2- bromophenyl) -1- (tert-butyl) -2- imino group -5-
Alkane -3- formonitrile HCN (11y)
126.13,114.72,64.68,60.62,54.01,28.24.HRMS(ESI)m/z calcd for C22H20BrN5S[M-H]+:
464.0545；found:464.0549.
4- (2- bromophenyl) -1- (tert-butyl) -3- (5,6- dimethyl -1H- benzo [d] imidazoles -2- base) -2- imino group -
5- thioxo-pyrrolidine -3- formonitrile HCN (11z)
HRMS(ESI)m/z calcd for C24H23BrN5S[M-H]+:491.0779；found:491.0785.
4- (the bromo- 4- methoxyphenyl of 2-) -1- cyclohexyl -3- (5,6- dimethyl -1H- benzo [d] imidazoles -2- base) -2-
Imino group -5- thioxo-pyrrolidine -3- formonitrile HCN (11aa)
1.72 (s, 2H), 1.49-1.33 (m, 2H), 1.24 (d, J=13.0Hz, 1H)13C NMR(100MHz,CDCl3)δ160.35,
144.42,129.44,126.42,118.32,114.55,55.59,26.00,25.80,25.12,20.43.HRMS(ESI)m/z
calcd for C27H28BrN5OS[M-H]+:548.1120；found:548.1126.
5 antitumor cytolytic activity of embodiment
Using compound 1, the compound 2 in mtt assay difference testing example 1, compound 11a, 11b in embodiment 3,
11c、11d、11f、11g、11h、11i、11g、11k、11l、11m、11n、11o、11p、11q、11r、11s、11t、11u、11v、
11w, 11x, 11y, 11z, 11aa are to human lung carcinoma cell (A549), three positive breast cancer cells of people (MCF-7), three negative breast of people
The inhibiting effect of cancer cell (MDA-MB-231) and normal human bronchial epithelial cell (HBE).
Testing procedure is as follows:
1. being inoculated in the tumor cell line to be tried for recovery of thawing in the DMEM culture medium containing 10% newborn bovine serum, it is placed in
37 DEG C, 5% CO2Secondary culture in saturated humidity incubator, logarithmic growth phase cell is for testing；
2. logarithmic growth phase tumour cell to be tried is made 1 × 104/ mL single cell suspension, is inoculated in 96 orifice plates, every hole
100uL sets 37 DEG C, 5%CO2Under the conditions of cultivate for 24 hours, it is adherent to cell；
3. removing original fluid, the medium treatment cell of the untested compound of 5ug/mL concentration is added, separately sets blank pair
According to group；Culture plate is set 37 DEG C, 5%CO2Cell incubator routine culture is for 24 hours；
4. before experiment terminates 4h, the MTT solution 20uL of 5mg/mL is added in every hole, prepared with PBS, pH=7.4,0.22um
Membrane filtration degerming terminates culture, inhales and abandons culture supernatant in hole.Every hole adds the hole DCM 100uL/, vibrates 10min at room temperature；
5. measuring each hole absorbance value on enzyme linked immunological monitor, wavelength 490nm is selected, is repeated 3 times；
6. calculating the inhibiting rate of each compound on tumor cell, wherein the calculation formula of inhibiting rate are as follows:
Inhibiting rate %=[1- (dosing cell OD- blank group OD)/(control cell OD- blank group OD)] × 100%.
Calculated result is as shown in table 1:
The inhibiting rate of table 1 compound on tumor and normal cell straina(IC50, unit μ g/mL)
aIC50"-" is labeled as more than or equal to 50 μ g/mL
By data in table 1 it is found that 1,2 couples of MCF-7 of Chao Geer alkali derivant, MDA-MB-231 cell strain have preferable inhibition
Effect, and to normal cell nontoxicity, there is the application prospect for preparing anti-tumor drug.The suppression of 11 cell proliferation of compound
It is very strong to make use.Wherein, the anti-tumor activity of the thiocarbamoyl imidazole alkanone derivative containing halogen group, which is higher than, contains methyl, methoxy
The electron-donating groups such as base, compound 11c, 11e, 11m, 11k, 11s, 11u, 11v, 11w to MCF-7 cell strain inhibiting effect compared with
By force；11g, 11m, 11s have good inhibiting effect to MDA-MB-231 cell strain；11c, 11e, 11f, 11g, 11u, 11v, 11w
It is stronger to A549 cell strain inhibiting effect.In addition to compound 11s, the series compound is very big to the toxicity of normal cell, because
This, needs to modify its structure further to be developed into anti-tumor drug.
The IC of 11c, 11k and 11m to MCF-750Nanogram level is reached, and has been it respectively to normal cell IC5049.7,
9.1 and 65.5 times；11x to 231 IC50Also nanogram level has been reached, has been it to normal cell IC502.8 times, preparing new one
For having broad application prospects on the specific drug of anti-lung cancer and breast cancer.
Claims (5)
1. thiocarbamoyl imidazole alkanone derivative, it is characterized in that, structural formula is as shown in following formula 11:
Wherein,
。
2. the synthetic method of thiocarbamoyl imidazole alkanone derivative described in claim 1, which is characterized in that replace 2- mercapto shown in formula 7
Aromatic aldehyde shown in base benzothiazole, formula 8, the compound for catalysis shown in formula 6a in acetonitrile solution of isonitrile and malononitrile shown in formula 9
Under, it stirs at room temperature, obtains the thiocarbamoyl imidazole alkanone derivative,
Wherein,
。
3. synthetic method according to claim 2, which is characterized in that replace 2-mercaptobenzothiazole, institute shown in the formula 7
The molar ratio for stating isonitrile shown in aromatic aldehyde shown in formula 8, the formula 9 and the malononitrile is 1:1:1:1:1.
4. synthetic method according to claim 2, which is characterized in that the volume ratio of acetonitrile and water in the acetonitrile solution
For 3:1.
5. thiocarbamoyl imidazole alkanone derivative application in preparation of anti-tumor drugs described in claim 2.
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| CN110627798A (en) * | 2019-10-24 | 2019-12-31 | 江苏师范大学 | Tr star gers base-Schiff base derivatives and preparation method and application thereof |
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