CN107163011A - 3 (3,4,5 trimethoxybenzoyl) benzofurans Antitubulins and its production and use - Google Patents
3 (3,4,5 trimethoxybenzoyl) benzofurans Antitubulins and its production and use 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 production and use；3 (3,4,5 trimethoxybenzoyl) benzofuran compounds mechanism of action in the present invention are similar to colchicin, can suppress tubulin polymerization；3 (3 in the present invention, 4,5 trimethoxybenzoyls) 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 MCF 7 has 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 production and use.The present invention also relates to prepare the intermediate compound of target compound
Thing.
Background technology
Tubulin is the protein families that a class contains multiple members, including seven kinds of micro-pipe eggs of α, β, γ, δ, ε, ζ, η
In vain.Wherein, alpha-tubulin and 'beta '-tubulin are the main components for constituting micro-pipe.Micro-pipe be eukaryotic main skeleton into
Point, played a key effect during cellular morphology, protein transport, signal transduction and mitosis is maintained, therefore become
The effective target spot of one for the treatment of cancer.And the micro-pipe targeted drug of tubulin is acted on, as carrying out more grind in recent years
The effective antitumour medicine 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.With being used successfully to cancer
The yew alcohols of clinical treatment is compared with vinca, colchicin (colchicine) although itself be compounds effective,
But limited under active drug concentration by the toxicity of its normal tissue, be only approved for familial Mediterranean, fever
With acute gout treatment.Research is found, acts 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, so as to block the blood supply of tumour, makes to swell
Oncocyte apoptosis due to a lack of nutrition.Further, since colchicin site shared small volume in tubulin, and corresponding suppression
The structure of preparation is relatively simple, and the research of such Antitubulin turns into 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 the known natural Antitubulin with potent suppression tubulin activity and cytotoxicity.Research has shown that, CA-4
Polymerizeing for suppression tubulin is reached by competing the binding site on tubulin with colchicin.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
The easy alienation of active configuration limits its extensive use clinically into inactive anti-configuration.Until 90 years 20th century
Generation, CA-4 phosphatization greatly improves these properties, made it into deeper into clinical test.
The content of the invention
It is an object of the present invention to provide a kind of 3- (3,4,5- trimethoxybenzoyls)-benzofurans tubulin
Inhibitor, using the colchicin binding site in tubulin as target.
It is a further object to provide a kind of midbody compound for preparing above-claimed cpd.
It is micro- that the present invention also provides 3- (3,4,5- trimethoxybenzoyls)-benzofurans with good antitumor activity
Tubulin inhibitor.
To achieve the above object, the present invention uses following technical proposals：
The present invention provides a kind of 3- (3,4,5- trimethoxybenzoyl)-benzofurans Antitubulin, and it has
There is structure shown in 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 R1During for H, R2It is not OCH3.It is preferred that R1For H or F, R2For OCH3, or 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, and its chemical equation is as follows：
Comprise the following steps that：
(1) in the presence of catalyst silver trifluoroacetate, elemental iodine is dissolved in organic solvent, at room temperature lucifuge, with
Iodinated product shown in the reaction acquisition of substituted benzene phenolic compound shown in formula 1 formula 2；
(2) iodinated product shown in formula 2 is subjected to acetylation in the presence of acetic anhydride and organic base, obtained shown in formula 3
Acetylate；
(3) by the acetylate shown in formula 3 in alkali, Pd (PPh3)2Cl2In the presence of CuI, with 4-R2Substituted benzene second
Sonogashira coupling reactions occur for alkynes, inert atmosphere protection, at a temperature of 95~105 DEG C lower reaction 5~7 hours the institute of formula 4
The coupled product shown；
(4) under alkalescence condition, the coupled product shown in formula 4 is dissolved in methanol, is heated to reflux obtaining benzo furan shown in formula 5
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 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, 4-R shown in formula 32Substitutedphenylethynyl, alkali, Pd (PPh3)2Cl2With CuI's
Molar ratio is 1:1.3:2:0.05:0.05.
In above-mentioned steps (5), benzofuran compounds, 3 shown in formula 5,4,5- trimethoxy-benzoyl chlorides and anhydrous four
The molar ratio of stannic chloride is 1:1.2:1.
It is used to prepare 3- (3,4,5- trimethoxybenzoyls)-benzofurans micro-pipe egg the present invention further provides one kind
The midbody compound of white inhibitor, it has 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 R1During for H, R2It is not OCH3.It is preferred that, R1For H or F, R2For OCH3, or OCH2CH3。
The present invention furthermore provides above-mentioned 3- (3,4,5- trimethoxybenzoyls)-benzofurans tubulin suppression
Purposes of the preparation in terms of lung cancer, stomach cancer, liver cancer, colon cancer, cervical carcinoma and breast cancer medicines are prepared.
Compared to the prior art, the beneficial effects of the present invention are：
3- (3,4,5- trimethoxybenzoyls)-benzofurans Antitubulin that the present invention is synthesized has outstanding
Tubulin inhibitory activity, mechanism of action is similar to colchicin, can suppress tubulin polymerization.
3- (3,4,5- trimethoxybenzoyl)-benzofurans Antitubulin that the present invention is synthesized, 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 has very strong proliferation inhibition activity.
Embodiment
The present invention is further illustrated in conjunction with the embodiments, it should explanation, and the description below is merely to explain this
Invention, is not defined to its content.
Nuclear magnetic resonance1H NMR,13C NMR,19F NMR by Brooker AVANCE type III 500MHz nmr determinations,
Use deuterated CDCl3Or deuterated DMSO makees solvent, TMS is internal standard, and chemical shift δ units are ppm, and coupling constant J unit is
Hz.High resolution mass spectrum is determined by Bruker solari X 70FT-MS.
Set present invention is generally directed to 3- (3,4,5- trimethoxybenzoyls)-benzofurans Antitubulin
Meter and synthesis.First with Computer-Aided Drug Design, set up by model, 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 methods such as molecular dynamics simulations
The gibbs Conjugated free energy of thing and tubulin compound.For Combretastatin A-4, its Conjugated free energy
Predicted value is -37.57 ± 2.62kcalmol-1(document：Med.Chem.Commun., 2014,5,766-782), using it as ginseng
Examine, the smaller noval chemical compound of Conjugated free energy is designed in the embodiment of the present invention：Structural formula 1 and structural formula 2 its Conjugated free energy
As a result it 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 the compound of structural formula 1
(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
Mix more than 1.5 hours.In addition, (the R of Formula 11=H) (20.0mmol) insert the round-bottomed flask that 250mL is wrapped up with tinfoil, add
Silver trifluoroacetate AgOTFA (4.5g, 20.0mmol).Chloroformic solution is added to the flask of tinfoil parcel for slow (about 2-3 hours)
In, stirring terminates for 24 hours at room temperature for reaction.Filtering, and use chloroform residue.Then saturation Na is used2S2O3Solution, saturation
NaHCO3Solution, saturated aqueous common salt extraction, gained organic phase anhydrous Na2SO4Dry.Filtering, column chromatography is carried out after being concentrated under reduced pressure
Separation (uses CH2Cl2Make eluant, eluent, column chromatography lucifuge).Obtain product, the iodo- 5- metoxyphenols (formulas 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),
(s, the 3H) of 6.34 (dd, J=6.0,2.5Hz, 1H), 5.31 (s, 1H), 3.77
(2) (the R of Formula 2 for obtaining step (1)1=H) (7.46mmol) be dissolved in anhydrous CH2Cl2, plus pyridine
(1.2g, 14.92mmol), dropwise adds acetic anhydride (1.54g, 14.92mmol) at 0 DEG C, and then the stirring 4 of room temperature lucifuge is small
When, reaction terminates.Pour into CH2Cl2, plus saturation NaHCO3Solution, plus saline solution extraction.Organic phase anhydrous Na2SO4Dry.Subtract
After pressure concentration, column chromatography for separation is carried out with pet-ether/EtOAc.Obtain product, the iodo- 5- methoxyacetic acids phenyl esters 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 (the R of Formula 3 obtained by step (2) under atmosphere1=H) (5.0mmol) be dissolved in DMF (10mL), Ran Houjia
Enter 4- ethoxybenzenes acetylene (950mg, 6.5mmol), triethylamine (1.02g, 10.0mmol), and catalyst CuI (50mg,
0.25mmol) with Pd (PPh3)2Cl2(175mg,0.25mmol).100 DEG C are heated to, is reacted 6 hours.TLC tracking reactions.Terminate
Afterwards, system is slowly cooled to room temperature, and is extracted with EtOAc and water.Merge organic phase, anhydrous Na2SO4Dry, filtering is concentrated under reduced pressure
Column chromatography for separation is carried out with pet-ether/EtOAc afterwards, product is obtained：2- ((4- ethoxyl phenenyls) acetenyl) -5- methoxyl groups
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), (t, J=7.0Hz, the 3H) of 4.05 (q, J=7.0Hz, 2H), 3.82 (s, 3H), 2.36 (s, 3H), 1.4213C 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) (the R of Formula 4 for obtaining step (3)1=H) (1.6mmol) be dissolved in methanol (10mL), after being uniformly dissolved,
Plus anhydrous K2CO3(553mg, 4.0mmol), is heated to 60 DEG C, is stirred at reflux 16 hours.After reaction terminates, excessive methanol decompression
Revolving is removed, and obtains yellow solid.EtOAc dissolved solids are used, and are extracted with water, anhydrous Na2SO4Dry gained organic phase.Filtering,
It is concentrated under reduced pressure, then obtains yellow solid.Use pet ether:EtOAc=30:1 progress column chromatography can obtain product, 2- (4- ethoxybenzenes
Base) -6- Methoxvbenzofurans (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) (the R of Formula 5 for obtaining step (4)1=H, R2=OCH2CH3) (50mg) be dissolved in anhydrous CH2Cl2(2mL)
In, 3,4,5- trimethoxy-benzoyl chlorides (1.2eq) are added, anhydrous SnCl then is added dropwise at 0 DEG C4(1.0eq).In room temperature
Lower reaction 3 hours, TLC tracking.At the end of reaction, it is quenched, is stirred for 1 hour with rubble ice.Organic phase is isolated, is used in combination
CH2Cl2Aqueous phase extracted.Use anhydrous Na2SO4The organic phase merged is dried, filtering is concentrated under reduced pressure, entered with pet-ether/EtOAc
Row column chromatographic isolation and purification, can obtain target product, 2- (4- ethoxyl phenenyls) -3- (3,4,5- trimethoxybenzoyl) -6- first
Epoxide 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 the compound of structural formula 2
(1) phenol raw material is the (R of formula 11=F), the step (1) in step be the same as Example 1.Obtain the iodo- 4- of product 2- fluoro-
5- metoxyphenols (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 (2) in step be the same as Example 1.Obtain the fluoro- 5- methoxyacetic acids phenyl ester (formulas 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 (3) in step be the same as Example 1.Obtain product 2- ((4- methoxyphenyls) 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,
(d, J=243.8Hz), 159.88,149.6 148.24 (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) step in obtained yellow solid n-hexane, EtOAc elutions, remaining step be the same as Example 1 is post-processed
(4) the fluoro- 6- Methoxvbenzofurans (formulas 5, R of product 2- (4- methoxyphenyls) -5- can, be obtained1=F, R2=OCH3)
White solid, yield 25.25%.1H NMR (500MHz, DMSO) δ=7.79 (d, J=9.0Hz, 2H), 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=- 140.21.13C NMR (125MHz, DMSO) δ=160.05,
(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 (5) in step be the same as Example 1, obtains target product 2- (4- methoxyphenyls) -3- (3,4,5- tri-
Methoxybenzoyl) the fluoro- 6- Methoxvbenzofurans (structural formulas 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 is tested
1. experimental method
Live cell fraction is taken to be tested up to more than 90% cell.Cell inhibitory effect experiment uses EnoGeneCellTM
Counting Kit-8 (CCK-8) cell viability detection kit.Cell dissociation, count, concentration is made for 1 × 105/mL
100 μ L cell suspensions are added in cell suspension, 96 orifice plates per hole (per 1 × 104, hole cell)；96 orifice plates are placed in 37 DEG C, 5%
CO2Cultivated 24 hours in incubator；The culture medium of the 100 corresponding drug containing of μ L is added per hole, while negative control group is set up, it is 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；Per hole
10 μ L CCK-8 solution are added, culture plate is incubated 4 hours in incubator, the OD values at 450nm, meter are determined with ELIASA
Structural formula 1, structural formula 2 and CA-4 positive controls 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 suppression of the compounds of this invention of table 1 and positive control CA-4 (Combretastatin A-4) to different tumour cells
Activity
In the antitumor 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, the inhibitory activity suitable with positive control CA-4.The suppression of structural formula 1
Activity is 12.2 times of CA-4 activity, 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 cells
It is 3.8 times of CA-4 activity in inhibitory activity.The inhibitory activity of six kinds of cancer cells of structural formula 1 pair all will than the activity of structural formula 2
It is good.Except HepG2 is extracellular, structural formula 1 is more than 5 times of the activity of structural formula 2 to the inhibitory activity of remaining 5 kinds of cancer cell.Say
It is bright that the beneficial effects of the present invention are the 3- of preparation (3,4,5- trimethoxybenzoyls)-benzofurans Antitubulin
There is potent proliferation inhibition activity to cancer cell.
Embodiment 4：Tubulin polymerization is tested
1. experimental method
Suppress tubulin polymerization activity test by Jinan Hua Wei Pharmaceutical Technology Co., Ltd using pig brain tubulin to be entered
Row inhibitory activity is tested.
2. experimental result
The compounds of this invention of table 2 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
CA-4 activity (0.88 μM) is quite.The tubulin activity of structural formula of compound 2 has then exceeded 200 μM.Illustrate the present invention's
It is outstanding that beneficial effect is that 3- (3,4,5- the trimethoxybenzoyls)-benzofurans Antitubulin prepared has
Tubulin inhibitory activity.
Claims (10)
1. a kind of 3- (3,4,5- trimethoxybenzoyl)-benzofurans Antitubulin, it is characterised in that it has
Structure shown in 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 R1During for H, R2It is not OCH3。
2. Antitubulin according to claim 1, it is characterised in that R1For H or F, R2For OCH3Or
OCH2CH3。
3. Antitubulin according to claim 1, it is characterised in that R1For H, while R2For OCH2CH3；Or R1
For F, while R2For OCH3。
4. a kind of preparation method of Antitubulin according to claim 1, it is characterised in that its chemical reaction side
Formula is as follows：
Comprise the following steps that：
(1) in the presence of catalyst silver trifluoroacetate, elemental iodine is dissolved in organic solvent, at room temperature lucifuge, with the institute of formula 1
Show iodinated product shown in substituted benzene phenolic compound reaction acquisition formula 2；
(2) iodinated product shown in formula 2 is subjected to acetylation in the presence of acetic anhydride and organic base, obtains the acetyl shown in formula 3
Change product；
(3) by the acetylate shown in formula 3 in alkali, Pd (PPh3)2Cl2In the presence of CuI, with 4-R2Substitutedphenylethynyl occurs
Sonogashira coupling reactions, inert atmosphere protection, at a temperature of 95~105 DEG C reaction 5~7 hours coupling shown in formula 4
Product；
(4) under alkalescence condition, the coupled product shown in formula 4 is dissolved in methanol, is heated to reflux that benzofurans shown in formula 5 can be obtained
Compound；
(5) benzofuran compounds shown in formula 5 are dissolved in anhydrous methylene chloride, under anhydrous stannic chloride effect, and 3,
Friedel-crafts acylation occurs for 4,5- trimethoxy-benzoyl chlorides, obtains 3- (3,4, the 5- trimethoxy-benzenes of structure shown in formula I
Formyl)-benzofurans Antitubulin.
5. preparation method according to claim 4, it is characterised in that in step (2), organic base is pyridine；Step (3)
In, the alkali used is triethylamine；In step (4), alkali used is potassium carbonate.
6. preparation method according to claim 4, it is characterised in that in step (3), acetylate, 4-R shown in formula 32
Substitutedphenylethynyl, alkali, Pd (PPh3)2Cl2Molar ratio with CuI is 1:1.3:2:0.05:0.05.
7. preparation method according to claim 4, it is characterised in that in step (5), benzofurans chemical combination shown in formula 5
The molar ratio of thing, 3,4,5- trimethoxy-benzoyl chlorides and anhydrous stannic chloride is 1:1.2:1.
8. one kind is used for the intermediate for preparing 3- (3,4,5- trimethoxybenzoyls)-benzofurans Antitubulin
Compound, it is characterised in that its is 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 R1During for H, R2It is not OCH3。
9. midbody compound according to claim 8, it is characterised in that R1For H or F, R2For OCH3Or OCH2CH3。
10. a kind of 3- as claimed in claim 1 (3,4,5- trimethoxybenzoyls)-benzofurans Antitubulin
Purposes in terms of lung cancer, stomach cancer, liver cancer, colon cancer, cervical carcinoma and breast cancer medicines are prepared.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108675992A (en) * | 2018-06-20 | 2018-10-19 | 桑文军 | A kind of antitumor drug acting on tubulin |
| CN108864053A (en) * | 2018-06-20 | 2018-11-23 | 桑文军 | A kind of novel tubulin inhibitor and its application in anti-tumor drug |
| CN110872299A (en) * | 2019-11-19 | 2020-03-10 | 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 |
| CN111233734A (en) * | 2019-12-06 | 2020-06-05 | 济宁医学院 | Aryloxy maleimide compound and preparation method thereof |
| CN112250688A (en) * | 2020-10-15 | 2021-01-22 | 天津科技大学 | 7-azabenzofuran derivatives and application thereof in antitumor drugs |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998039323A1 (en) * | 1997-03-06 | 1998-09-11 | Baylor University | Anti-mitotic agents which inhibit tubulin polymerization |
| WO2005019184A1 (en) * | 2003-08-20 | 2005-03-03 | Eli Lilly And Company | Compounds, methods and formulations for the oral delivery of a glucagon like peptide (glp)-1 compound or an melanocortin 4 receptor (mc4) agonist peptide |
| CN101981029A (en) * | 2008-03-26 | 2011-02-23 | 株式会社钟根堂 | Benzophenone thiazole derivatives useful for inhibiting formation of microtubule and method for producing the same |
-
2017
- 2017-05-27 CN CN201710388643.1A patent/CN107163011B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998039323A1 (en) * | 1997-03-06 | 1998-09-11 | Baylor University | Anti-mitotic agents which inhibit tubulin polymerization |
| WO2005019184A1 (en) * | 2003-08-20 | 2005-03-03 | Eli Lilly And Company | Compounds, methods and formulations for the oral delivery of a glucagon like peptide (glp)-1 compound or an melanocortin 4 receptor (mc4) agonist peptide |
| CN101981029A (en) * | 2008-03-26 | 2011-02-23 | 株式会社钟根堂 | Benzophenone thiazole derivatives useful for inhibiting formation of microtubule and method for producing the same |
Non-Patent Citations (3)
| Title |
|---|
| ARATA YAJIMA ET AL: "Asymmetric synthesis of abietane diterpenoids via B-alkyl Suzuki–Miyaura coupling. Formal total asymmetric synthesis of 12-deoxyroyleanone and cryptoquinone", 《TETRAHEDRON》 * |
| XIZHEN JIANG ET AL: "Synthesis and antimicrobial evaluation of new benzofuran derivatives", 《EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY》 * |
| 全阳平: "微管蛋白抑制剂 Combretastatin A-4类似物分子模型、合成和生物活性研究", 《上海应用技术大学硕士学位论文》 * |
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| CN108864053A (en) * | 2018-06-20 | 2018-11-23 | 桑文军 | A kind of novel tubulin inhibitor and its application in anti-tumor drug |
| 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 |
| CN108864053B (en) * | 2018-06-20 | 2020-12-01 | 浙江药苑生物科技有限公司 | Tubulin inhibitor and application thereof in antitumor drugs |
| CN110872299A (en) * | 2019-11-19 | 2020-03-10 | 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 |
| 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 |
| CN111233734A (en) * | 2019-12-06 | 2020-06-05 | 济宁医学院 | Aryloxy maleimide compound and preparation method thereof |
| CN111233734B (en) * | 2019-12-06 | 2023-09-19 | 济宁医学院 | Aryloxy maleimide compound and preparation method thereof |
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| CN112250688B (en) * | 2020-10-15 | 2022-11-04 | 天津科技大学 | 7-azabenzofuran derivatives and application thereof in antitumor drugs |
| CN112724110A (en) * | 2021-01-13 | 2021-04-30 | 广州安岩仁医药科技有限公司 | Synthesis method of VEGFR inhibitor furoquintinib and benzofuran intermediate thereof |
| 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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