CN107163011B - 3- (3,4,5- trimethoxybenzoyl)-benzofurans Antitubulin and its preparation method and application - Google Patents
3- (3,4,5- trimethoxybenzoyl)-benzofurans Antitubulin and its preparation method and application Download PDFInfo
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- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
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Abstract
The invention discloses a kind of 3- (3,4,5- trimethoxybenzoyl)-benzofurans Antitubulins and its preparation method and application；3- (3,4,5- trimethoxybenzoyl)-benzofuran compounds mechanism of action in the present invention is similar to colchicin, is able to suppress tubulin polymerization；3- (3 in the present invention, 4,5- trimethoxybenzoyl)-benzofuran compounds are to human lung cancer cell A549, gastric carcinoma cells MGC-803, human liver cancer cell HepG2, human colon cancer cell HCT-116, human cervical carcinoma cell HeLa, human breast cancer cell line Bcap-37 have very strong proliferation inhibition activity.
Description
Technical field
The present invention relates to field of pharmaceutical chemistry technology, specially a kind of 3- (3,4,5- trimethoxybenzoyl)-benzo furan
Class of muttering Antitubulin and its preparation method and application.The present invention also relates to the intermediate compounds for preparing target compound
Object.
Background technique
Tubulin is a kind of protein families for containing multiple members, including seven kinds of micro-pipe eggs of α, β, γ, δ, ε, ζ, η
It is white.Wherein, alpha-tubulin and 'beta '-tubulin are the main components for constituting micro-pipe.Micro-pipe be eukaryocyte main skeleton at
Point, it plays a key effect during maintaining cellular morphology, protein transport, signal transduction and mitosis, therefore, it has become
One effective target spot for the treatment of cancer.And the micro-pipe targeted drug of tubulin is acted on, become and carries out more grind in recent years
The effective antitumour drug studied carefully.Known tubulin inhibitor passes through at least four binding sites and tubulin phase interaction
With being laulimalide, taxol/Epothilones, vincaleukoblastinum and colchicin site respectively.Be used successfully to cancer
The purple sweater alcohols of clinical treatment is compared with vinca, colchicin (colchicine) although itself be compounds effective,
But it is limited under active drug concentration by the toxicity of its normal tissue, is only approved for familial Mediterranean, fever
It is treated with acute gout.The study found that acting on the inhibitor in colchicin site by preventing new vascular generation or destruction
The existing vascular system of tumour prevents microtubule polymerization, and tumoricidal skeleton makes to swell to block the blood supply of tumour
Oncocyte apoptosis due to a lack of nutrition.In addition, due to colchicin site shared small volume, and corresponding suppression in tubulin
The structure of preparation is relatively simple, and the research of such Antitubulin becomes a new direction.
Many Antitubulins are based on obtained from natural products.Combretastatin family is Pettit small
The native compound that group is separated from South African plants Combretum caffrum.Combretastatin A-4(CA-4)
It is known with the potent natural Antitubulin for inhibiting tubulin activity and cytotoxicity.Research has shown that, CA-4
Inhibit polymerizeing for tubulin by competing the binding site on tubulin with colchicin to reach.Although CA-4 has wide
The anti tumor activity in vitro of spectrum, but due to poorly water-soluble, bioavilability is low, and its is cis- in storage and internal metabolic process
Active configuration is easy alienation into inactive anti-configuration, limits its extensive use clinically.Until 90 years 20th century
Generation, the phosphatization of CA-4 greatly improve these properties, made it into deeper into clinical test.
Summary of the invention
It is an object of the present invention to provide a kind of 3- (3,4,5- trimethoxybenzoyl)-benzofurans tubulins
Inhibitor, using the colchicin binding site in tubulin as target.
It is a further object to provide a kind of midbody compounds for preparing above compound.
The present invention also provides 3- (3,4,5- trimethoxybenzoyl)-benzofurans with good anti-tumor activity are micro-
Tubulin inhibitor.
To achieve the above object, the present invention adopts the following technical solutions:
The present invention provides a kind of 3- (3,4,5- trimethoxybenzoyl)-benzofurans Antitubulin, tool
There is structure shown in general formula I:
Wherein: R1It is H, F, Cl, Br, OH, CH3,OCH3,NO2,OCH2CH3Or OCH (CH3)2,R2It is CH3, OCH3,
OCH2CH3Or OCH (CH3)2, and R1When for H, R2It is not OCH3.Preferred R1For H or F, R2For OCH3Or OCH2CH3.It is more excellent
Choosing, R1For H, while R2For OCH2CH3；Or R1For F, while R2For OCH3。
The present invention also provides a kind of preparation method of above-mentioned Antitubulin, chemical equation is as follows:
Specific step is as follows:
(1) in the presence of catalyst silver trifluoroacetate, elemental iodine is dissolved in organic solvent, is protected from light at room temperature, with
Substituted benzene phenolic compound shown in formula 1 reacts iodinated product shown in acquisition formula 2；
(2) iodinated product shown in formula 2 is subjected under the action of acetic anhydride and organic base acetylation, obtained shown in formula 3
Acetylate；
(3) by acetylate shown in formula 3 in alkali, Pd (PPh3)2Cl2Under the action of CuI, with 4-R2Substituted benzene second
Sonogashira coupling reaction occurs for alkynes, inert atmosphere protection, at a temperature of 95~105 DEG C lower reaction 5~7 hours 4 institute of formula
The coupled product shown；
(4) under alkaline condition, coupled product shown in formula 4 is dissolved in methanol, benzo furan shown in formula 5 can be obtained by being heated to reflux
Class of muttering compound；
(5) benzofuran compounds shown in formula 5 are dissolved in anhydrous methylene chloride, under anhydrous stannic chloride effect,
With 3, friedel-crafts acylation occurs for 4,5- trimethoxy-benzoyl chlorides, obtains 3- (3,4, the 5- trimethoxies of structure shown in general formula I
Base benzoyl)-benzofurans Antitubulin.
In above-mentioned steps (2), organic base is pyridine；In step (3), the alkali used is triethylamine；It is used in step (4)
Alkali be potassium carbonate.
In above-mentioned steps (3), acetylate shown in formula 3,4-R2Substitutedphenylethynyl, alkali, Pd (PPh3)2Cl2With CuI's
Molar ratio is 1:1.3:2:0.05:0.05.
In above-mentioned steps (5), benzofuran compounds shown in formula 5,3,4,5- trimethoxy-benzoyl chlorides and anhydrous four
The molar ratio of stannic chloride is 1:1.2:1.
The present invention further provides one kind to be used to prepare 3- (3,4,5- trimethoxybenzoyl)-benzofurans micro-pipe egg
The midbody compound of white inhibitor, with structure as shown in Equation 4:
Wherein: R1It is H, F, Cl, Br, OH, CH3,OCH3,NO2,OCH2CH3Or OCH (CH3)2,R2It is CH3, OCH3,
OCH2CH3Or OCH (CH3)2, and R1When for H, R2It is not OCH3.Preferably, R1For H or F, R2For OCH3Or OCH2CH3。
The present invention furthermore provides above-mentioned 3- (3,4,5- trimethoxybenzoyl)-benzofurans tubulin suppression
Purposes of the preparation in terms of preparation lung cancer, gastric cancer, liver cancer, colon cancer, cervical carcinoma and breast cancer medicines.
Compared to the prior art, the beneficial effects of the present invention are:
3- (3,4,5- trimethoxybenzoyl)-benzofurans Antitubulin that the present invention synthesizes has outstanding
Tubulin inhibitory activity, mechanism of action is similar to colchicin, is able to suppress tubulin polymerization.
3- (3,4,5- trimethoxybenzoyl)-benzofurans Antitubulin that the present invention synthesizes, to people's lung
Cancer cell A549, gastric carcinoma cells MGC-803, human liver cancer cell HepG2, human colon cancer cell HCT-116, human cervical carcinoma cell
HeLa, human breast cancer cell line Bcap-37 have very strong proliferation inhibition activity.
Specific embodiment
The present invention is further illustrated in conjunction with the embodiments, it should which explanation, following the description is merely to explain this
Invention, is not defined its content.
Nuclear magnetic resonance1H NMR,13C NMR,19F NMR by Brooker AVANCE type III 500MHz nmr determination,
Use deuterated CDCl3Or deuterated DMSO makees solvent, TMS is internal standard, and chemical shift δ unit is ppm, and the unit of coupling constant J is
Hz.High resolution mass spectrum is measured by Bruker solari X 70FT-MS.
Present invention is generally directed to 3- (3,4,5- trimethoxybenzoyl)-benzofurans Antitubulins to be set
Meter and synthesis.First with Computer-Aided Drug Design, pass through model foundation, molecular docking, molecular dynamics simulation means
The analog result of noval chemical compound is obtained, wherein most reference value is the chemical combination obtained with the methods of molecular dynamics simulation
The gibbs Conjugated free energy of object and tubulin compound.For Combretastatin A-4, Conjugated free energy
Predicted value is -37.57 ± 2.62kcalmol-1(document: Med.Chem.Commun., 2014,5,766-782), it is ginseng with it
It examines, designs the smaller noval chemical compound of Conjugated free energy in the embodiment of the present invention: structural formula 1 and structural formula 2 its Conjugated free energy
It as a result is respectively -43.45, -42.03kcalmol-1.The result of Conjugated free energy is smaller, then illustrates that the activity of compound may
It is higher.
Embodiment 1: the preparation of 1 compound of structural formula
(1) in the round-bottomed flask that 250mL is wrapped up with tinfoil, I2(5.1g, 20.0mmol) is dissolved in chloroform (150mL), and stirs
It mixes more than 1.5 hours.In addition, 1 (R of Formula1=H) round-bottomed flask that wrap up with tinfoil of (20.0mmol) merging 250mL, addition
Silver trifluoroacetate AgOTFA (4.5g, 20.0mmol).Chloroformic solution is slowly added to the flask of tinfoil package for (about 2-3 hours)
In, reaction is stirred 24 hours at room temperature to be terminated.Filtering, and with chloroform residue.Then with saturation Na2S2O3Solution, saturation
NaHCO3Solution, saturated salt solution extraction, gained organic phase anhydrous Na2SO4It is dry.Filtering carries out column chromatography after reduced pressure
Separation (uses CH2Cl2Make eluant, eluent, column chromatography is protected from light).Obtain product, the iodo- 5- metoxyphenol (formula 2, R of 2-1=H).White is solid
Body, yield 52.87%.1H NMR(500MHz,CDCl3) δ=7.49 (d, J=9.0Hz, 1H), 6.60 (d, J=2.5Hz, 1H),
6.34 (dd, J=6.0,2.5Hz, 1H), 5.31 (s, 1H), 3.77 (s, 3H)
(2) 2 (R of Formula for obtaining step (1)1=H) (7.46mmol) be dissolved in anhydrous CH2Cl2, add pyridine
(1.2g, 14.92mmol) dropwise adds acetic anhydride (1.54g, 14.92mmol) at 0 DEG C, and then it is small to be protected from light stirring 4 for room temperature
When, reaction terminates.Pour into CH2Cl2, add saturation NaHCO3Solution adds saline solution to extract.Organic phase anhydrous Na2SO4It is dry.Subtract
After pressure concentration, column chromatography for separation is carried out with pet-ether/EtOAc.Obtain product, the iodo- 5- methoxyacetic acid phenyl ester of 2- (formula 3,
R1=H).Colourless liquid, yield 78.55%.1H NMR(500MHz,CDCl3) δ=7.66 (d, J=9.0Hz, 1H), 6.69 (d,
J=3.0Hz, 1H), 6.60 (dd, J=6.0,2.5Hz, 1H), 3.77 (s, 3H), 2.36 (s, 3H)
(3)N2By 3 (R of Formula obtained by step (2) under atmosphere1=H) (5.0mmol) be dissolved in DMF (10mL), then plus
Enter 4- ethoxybenzene acetylene (950mg, 6.5mmol), triethylamine (1.02g, 10.0mmol) and catalyst CuI (50mg,
0.25mmol) and Pd (PPh3)2Cl2(175mg,0.25mmol).100 DEG C are heated to, is reacted 6 hours.TLC tracking reaction.Terminate
Afterwards, system is slowly cooled to room temperature, and is extracted with EtOAc and water.Merge organic phase, anhydrous Na2SO4It dries, filters, is concentrated under reduced pressure
Column chromatography for separation is carried out with pet-ether/EtOAc afterwards, obtains product: 2- ((4- ethoxyl phenenyl) acetenyl) -5- methoxyl group
Phenylacetate (formula 4, R1=H, R2=OCH2CH3)。
Yellow solid, yield 46.08%.1H NMR(500MHz,CDCl3) δ=7.46 (d, J=8.5Hz, 1H), 7.40
(d, J=8.5Hz, 2H), 6.85 (d, J=8.5Hz, 2H), 6.78 (dd, J=6.0,2.5Hz, 1H), 6.67 (d, J=2.5Hz,
1H), 4.05 (q, J=7.0Hz, 2H), 3.82 (s, 3H), 2.36 (s, 3H), 1.42 (t, J=7.0Hz, 3H)13C NMR
(125MHz,CDCl3) δ=168.77,160.28,159.02,152.58,133.40,132.84,115.23,114.54,
112.01,109.89,108.26,92.87,82.84,63.53,55.56,20.89,14.76.ESI-HRMS(m/z):
calculated for C19H18O4(M+H)+,311.12386,found:311.12381.
(4) 4 (R of Formula for obtaining step (3)1=H) (1.6mmol) be dissolved in methanol (10mL), after being uniformly dissolved,
Add anhydrous K2CO3(553mg, 4.0mmol) is heated to 60 DEG C, is stirred at reflux 16 hours.After reaction, excessive methanol depressurizes
Revolving removes, and obtains yellow solid.With EtOAc dissolved solid, and extracted with water, anhydrous Na2SO4Dry gained organic phase.Filtering,
It is concentrated under reduced pressure, then obtains yellow solid.Product, 2- (4- ethoxybenzene can be obtained by carrying out column chromatography with pet ether:EtOAc=30:1
Base) -6- Methoxvbenzofuran (formula 5, R1=H, R2=OCH2CH3)。
White solid, yield 40.25%.1H NMR(500MHz,CDCl3) δ=7.73 (d, J=9.0Hz, 2H), 7.41
(d, J=8.0Hz, 1H), 7.06 (s, 1H), 6.96 (d, J=9.0Hz, 2H), 6.86 (dd, J=6.0,2.5Hz, 1H), 6.80
(s, 1H), 4.09 (q, J=7.0Hz, 2H), 3.87 (s, 3H), 1.45 (t, J=7.0Hz, 3H)13C NMR(125MHz,
CDCl3) δ=159.03,157.70,155.68,155.39,125.93,123.47,122.88,120.64,114.77,
111.67,99.42,95.94,63.55,55.75,14.85.ESI-HRMS(m/z):calculated for C17H16O3(M
+H)+,268.10994,found:268.10936.
(5) 5 (R of Formula for obtaining step (4)1=H, R2=OCH2CH3) (50mg) be dissolved in anhydrous CH2Cl2(2mL)
In, it is added 3,4,5- trimethoxy-benzoyl chloride (1.2eq), anhydrous SnCl then is added dropwise at 0 DEG C4(1.0eq).In room temperature
Lower reaction 3 hours, TLC tracking.It at the end of reaction, is quenched, is stirred for 1 hour with rubble ice.Organic phase is isolated, is used in combination
CH2Cl2Aqueous phase extracted.Use anhydrous Na2SO4Dry combineds organic phase, filtering, reduced pressure, with pet-ether/EtOAc into
Row column chromatographic isolation and purification can obtain target product, 2- (4- ethoxyl phenenyl) -3- (3,4,5- trimethoxybenzoyl) -6- first
Oxygroup benzofuran (structural formula 1, R1=H, R2=OCH2CH3)。
Greenish yellow solid, yield 70.76%.1H NMR(500MHz,CDCl3) δ=7.55-7.53 (m, 3H), 7.12 (s,
2H), 7.08 (d, J=2.0Hz, 1H), 6.91 (dd, J=6.5,2.0Hz, 1H), 6.79 (d, J=9.0Hz, 2H), 4.00 (q, J
=7.0Hz, 2H), 3.88 (s, 3H), 3.86 (s, 3H), 3.69 (s, 6H), 1.39 (t, J=7.0Hz, 3H)13C NMR
(125MHz,CDCl3) δ=190.90,159.99,158.50,157.34,154.69,152.86,142.39,132.68,
129.84,122.21,121.99,121.70,114.54,114.35,112.60,107.42,95.65,63.55,60.93,
56.10,55.76,14.66.ESI-HRMS(m/z):calculated for C27H26O7(M+H)+,463.17121,found:
463.17670.
Embodiment 2: the preparation of 2 compound of structural formula
(1) phenol raw material is 1 (R of formula1=F), step is the same as the step (1) in embodiment 1.It is fluoro- to obtain the iodo- 4- of product 2-
5- metoxyphenol (formula 2, R1=F).
White solid, yield 39.92%.1H NMR(500MHz,CDCl3) δ=7.31 (d, J=10Hz, 1H), 6.67 (d,
J=7.5Hz, 1H), 5.13-5.12 (m, 1H), 3.85 (s, 3H)19F NMR(470MHz,CDCl3) δ=- 143.08.13C NMR
(125MHz,CDCl3) δ=151.73 (d, J=2.5Hz), 149.2,146.82 (d, J=240.6Hz), 123.70 (d, J=
22.5Hz), 100.30,70.97 (d, J=7.5Hz), 56.27.ESI-HRMS (m/z): calculated for C7H6FIO2(M
+H)+,268.94301,found:268.94769.
(2) step is the same as the step (2) in embodiment 1.Obtain the fluoro- 5- methoxyacetic acid phenyl ester (formula 3, R of the iodo- 4- of product 2-1
=F).
White crystal, yield 81.28%.1H NMR(500MHz,CDCl3) δ=7.47 (d, J=10Hz, 1H), 6.74 (d,
J=7.5Hz, 1H), 3.85 (s, 3H), 2.35 (s, 3H)19F NMR(470MHz,CDCl3) δ=- 135.80.13C NMR
(125MHz,CDCl3) δ=168.57,150.05 (d, J=247.5Hz), 148.50 (d, J=11.3Hz), 147.60 (d, J=
2.5Hz), 125.22 (d, J=21.3Hz), 108.28,99.99,56.43,21.15.ESI-HRMS (m/z): calculated
for C9H8FIO3(M+H)+,310.95357,found:310.95754.
(3) step is the same as the step (3) in embodiment 1.Obtain product 2- ((4- methoxyphenyl) acetenyl) fluoro- 5- of -4-
Methoxyacetic acid phenyl ester (formula 4, R1=F, R2=OCH3)。
Yellow solid, yield 32.80%.1H NMR(500MHz,CDCl3) δ=7.43 (d, J=9.0Hz, 2H), 7.27
(d, J=11.5Hz, 1H), 6.89 (d, J=8.5Hz, 2H), 6.75 (d, J=7.5Hz, 1H), 3.90 (s, 3H), 3.84 (s,
3H),2.37(s,3H).19F NMR(470MHz,CDCl3) δ=- 137.90.13C NMR(125Hz,CDCl3) δ=168.81,
159.88,149.6 (d, J=243.8Hz), 148.24 (d, J=12.5Hz), 147.99 (d, J=3.8Hz), 132.94,
119.00 (d, J=21.3Hz), 114.91,114.09,109.59 (d, J=10Hz), 107.86,93.63,81.94,56.38,
55.31,20.77.ESI-HRMS(m/z):calculated for C18H15FO4(M+Na)+,337.09544,found:
337.08508.
(4) obtained yellow solid n-hexane is post-processed, EtOAc elution, remaining step is the same as the step in embodiment 1
(4), the fluoro- 6- Methoxvbenzofuran (formula 5, R of product 2- (4- methoxyphenyl) -5- can be obtained1=F, R2=OCH3)
White solid, yield 25.25%.1δ=7.79 (d, J=9.0Hz, 2H) H NMR (500MHz, DMSO), 7.49
(d, J=7.0Hz, 1H), 7.45 (d, J=11.0Hz, 1H), 7.17 (s, 1H), 7.06 (d, J=8.5Hz, 2H), 3.90 (s,
3H),3.82(s,3H).19F NMR (470MHz, DMSO) δ=- 140.21.13δ=160.05 C NMR (125MHz, DMSO),
(156.03,150.84,149.80 d, J=236.3Hz), 145.83 (d, J=13.8Hz), 126.29,122.96,121.40
(d, J=10.0Hz), 115.00,107.03 (d, J=22.5Hz), 100.68,97.60,56.93,55.74.ESI-HRMS (m/
z):calculated for C16H13FO3(M+H)+,273.08823,found:273.09217.
(5) step obtains target product 2- (4- methoxyphenyl) -3- (3,4,5- tri- with the step (5) in embodiment 1
Methoxybenzoyl) the fluoro- 6- Methoxvbenzofuran (structural formula 2, R of -5-1=F, R2=OCH3)。
Greenish yellow solid, yield 70.07%.1H NMR(500MHz,CDCl3) δ=7.50 (d, J=8.5Hz, 2H), 7.38
(d, J=10.5Hz, 1H), 7.14 (d, J=6.5Hz, 1H), 7.08 (s, 2H), 6.79 (d, J=8.5Hz, 2H), 3.94 (s,
3H),3.85(s,3H),3.76(s,3H),3.68(s,6H).19F NMR(470MHz,CDCl3) δ=- 138.74.13C NMR
(125MHz,CDCl3) δ=190.41,160.76,158.10,152.91,150.58 (d, J=240Hz), 149.85,146.81
(d, J=13.8Hz), 142.60,132.39,129.92,122.14,120.79 (d, J=8.8Hz), 114.74 (d, J=
3.8Hz),113.90,107.60,107.42,96.29,60.93,56.61,56.12,55.32.ESI-HRMS(m/z):
calculated for C26H23FO7(M+H)+,467.14614,found:467.15066.
Embodiment 3: antiproliferative experiment
1. experimental method
Live cell fraction is taken to be tested up to 90% or more cell.Cell inhibitory effect test uses EnoGeneCellTM
Counting Kit-8 (CCK-8) cell viability detection kit.Cell dissociation counts, concentration is made as 1 × 105/mL's
Cell suspension, 100 μ L cell suspensions (1 × 104, every hole cell) is added in every hole in 96 orifice plates；96 orifice plates are placed in 37 DEG C, and 5%
CO2It is cultivated 24 hours in incubator；The culture medium of the 100 corresponding drug containing of μ L is added in every hole, while setting up negative control group, molten
Matchmaker's control group, positive controls, every group of 5 multiple holes；96 orifice plates are placed in 37 DEG C, 5%CO2After being cultivated 72 hours in incubator；Every hole
10 μ L CCK-8 solution are added, culture plate is incubated for 4 hours in incubator, measure the OD value at 450nm, meter with microplate reader
Structural formula 1, structural formula 2 and CA-4 positive control are calculated to human lung cancer cell A549, human colon cancer cell HCT-116, people's uterine neck
Cancer cell HeLa, human liver cancer cell HepG2, gastric carcinoma cells MGC-803, the isocellular inhibiting rate of human breast cancer cell line Bcap-37
And IC50Value.
2. experimental result
The inhibition of 1 the compounds of this invention of table and positive control CA-4 (Combretastatin A-4) to different tumour cells
Activity
In the anti-tumor activity of the compounds of this invention structural formula 1, structural formula 2 and positive control CA-4 to 6 kinds of cancer cells,
Structural formula of compound 1 is shown except HepG2 is extracellular, with the comparable inhibitory activity of positive control CA-4.The inhibition of structural formula 1
Activity is active 12.2 times of CA-4, is more than an order of magnitude.Structural formula of compound 2, in the inhibitory activity of A549, HeLa cell
It is upper suitable with CA-4, it is poor in the inhibitory activity ratio CA-4 of HCT-116, MGC-803 and MCF-7 cell, only in HepG2 cell
It is active 3.8 times of CA-4 in inhibitory activity.Structural formula 1 is to the inhibitory activity of six kinds of cancer cells all than the activity of structural formula 2
It is good.Except HepG2 is extracellular, structural formula 1 is 2 active 5 times of structural formula more to the inhibitory activity of remaining 5 kinds of cancer cell.It says
It is bright that the beneficial effects of the present invention are the 3- of preparation (3,4,5- trimethoxybenzoyl)-benzofurans Antitubulins
There is potent proliferation inhibition activity to cancer cell.
Embodiment 4: tubulin polymerization experiment
1. experimental method
Inhibit tubulin polymerization activity test by Jinan Hua Wei Pharmaceutical Technology Co., Ltd using pig brain tubulin into
The test of row inhibitory activity.
2. experimental result
2 the compounds of this invention of table and positive control CA-4 are to tubulin inhibitory activity
The tubulin inhibitory activity of the compounds of this invention structural formula 1 is 0.86 μM as can be seen from Table 2, with positive reference
The activity (0.88 μM) of CA-4 is suitable.The tubulin activity of structural formula of compound 2 has then been more than 200 μM.Illustrate of the invention
It is outstanding that beneficial effect is that 3- (3,4,5- the trimethoxybenzoyl)-benzofurans Antitubulin prepared has
Tubulin inhibitory activity.
Claims (7)
1. a kind of 3- (3,4,5- trimethoxybenzoyl)-benzofurans Antitubulin, which is characterized in that it has
Structure shown in general formula I:
Wherein: R1For H or F, R2For OCH3Or OCH2CH3, and R1When for H, R2It is not OCH3。
2. Antitubulin according to claim 1, which is characterized in that R1For H, while R2For OCH2CH3；Or R1
For F, while R2For OCH3。
3. a kind of preparation method of Antitubulin according to claim 1, which is characterized in that its chemical reaction side
Formula is as follows:
Specific step is as follows:
(1) in the presence of catalyst silver trifluoroacetate, elemental iodine is dissolved in organic solvent, is protected from light at room temperature, with 1 institute of formula
Show iodinated product shown in substituted benzene phenolic compound reaction acquisition formula 2；
(2) iodinated product shown in formula 2 is subjected under the action of acetic anhydride and organic base acetylation, obtains acetyl shown in formula 3
Change product；
(3) by acetylate shown in formula 3 in alkali, Pd (PPh3)2Cl2Under the action of CuI, with 4-R2Substitutedphenylethynyl occurs
Sonogashira coupling reaction, inert atmosphere protection react at a temperature of 95~105 DEG C 5~7 hours to be coupled shown in formula 4
Product；
(4) under alkaline condition, coupled product shown in formula 4 is dissolved in methanol, benzofurans shown in formula 5 can be obtained by being heated to reflux
Compound；
(5) benzofuran compounds shown in formula 5 are dissolved in anhydrous methylene chloride, under tin tetrachloride effect, with 3,4,5-
Friedel-crafts acylation occurs for trimethoxy-benzoyl chloride, obtains 3- (3,4, the 5- trimethoxy-benzene first of structure shown in general formula I
Acyl)-benzofurans Antitubulin；
In step (3), the alkali used is triethylamine；In step (4), alkali used is potassium carbonate.
4. preparation method according to claim 3, which is characterized in that in step (2), organic base is pyridine.
5. preparation method according to claim 3, which is characterized in that in step (3), acetylate shown in formula 3,4-R2
Substitutedphenylethynyl, alkali, Pd (PPh3)2Cl2Molar ratio with CuI is 1:1.3:2:0.05:0.05.
6. preparation method according to claim 3, which is characterized in that in step (5), benzofurans chemical combination shown in formula 5
The molar ratio of object, 3,4,5- trimethoxy-benzoyl chloride and tin tetrachloride is 1:1.2:1.
7. a kind of 3- as described in claim 1 (3,4,5- trimethoxybenzoyl)-benzofurans Antitubulin
Purposes in terms of preparation lung cancer, gastric cancer, liver cancer, colon cancer, cervical carcinoma and breast cancer medicines.
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| CN108675992B (en) * | 2018-06-20 | 2020-11-27 | 浙江药苑生物科技有限公司 | Antineoplastic medicine acting on tubulin |
| CN110872299B (en) * | 2019-11-19 | 2022-09-30 | 广州中医药大学(广州中医药研究院) | P-benzoquinone-bis-triazole core skeleton derivative and preparation method and application thereof |
| CN111233734B (en) * | 2019-12-06 | 2023-09-19 | 济宁医学院 | Aryloxy maleimide compound and preparation method thereof |
| CN112250688B (en) * | 2020-10-15 | 2022-11-04 | 天津科技大学 | 7-azabenzofuran derivatives and application thereof in antitumor drugs |
| CN112724110B (en) * | 2021-01-13 | 2021-10-26 | 广州安岩仁医药科技有限公司 | Synthesis method of VEGFR inhibitor furoquintinib and benzofuran intermediate thereof |
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