CN107089963B - With inhibition active cumarin esterification derivative of RXR alpha transcriptional and its preparation method and application - Google Patents
With inhibition active cumarin esterification derivative of RXR alpha transcriptional and its preparation method and application Download PDFInfo
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- CN107089963B CN107089963B CN201710307609.7A CN201710307609A CN107089963B CN 107089963 B CN107089963 B CN 107089963B CN 201710307609 A CN201710307609 A CN 201710307609A CN 107089963 B CN107089963 B CN 107089963B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/06—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2
- C07D311/08—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring
- C07D311/16—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring substituted in position 7
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
The invention discloses having to inhibit active cumarin esterification derivative of RXR alpha transcriptional and its preparation method and application, the cumarin esterification derivative is 4- chloromethyl-umbelliferone esterification derivative shown in following general formula.The present invention discloses such 4- chloromethyl-umbelliferone esterification derivative preparation methods, make catalyst using anhydrous bismuth chloride and prepares 4- chloromethyl-umbelliferone under solvent-free conditions, separately by the way that different side-chain acids are prepared into corresponding acyl chlorides, then reacts and respective compound is prepared with the 4- chloromethyl-umbelliferone.4- chloromethyl-umbelliferone esterification derivative of the invention has certain active effect of inhibition RXR alpha transcriptional, provides thinking by the drug of target spot of RXR α to develop.
Description
Technical field
The invention belongs to field of medicinal chemistry, and in particular to have and the active cumarin esterification of RXR alpha transcriptional is inhibited to derive
Object and its preparation method and application.
Background technique
Retinol X receptor (Retinoid X Receptor, RXR) belongs to on-steroidal hormone receptor superfamily, be core by
A unique member with multiple biological function, mediates the life of many hormones, vitamin A and other medicines in body family
Object function.RXR takes part in body from embryonic development to orga- nogenesis and the physiological regulating control of the various metabolism of adult waited
Journey.It has also been found that, RXR can carry out caryoplasm shuttle under different ligands regulation, execute different biological functions, such as thin in recent years
Born of the same parents' apoptosis, proliferation and differentiation etc..According to the difference of the promoter and cut mode that utilize, RXR includes three kinds of hypotypes.Three hypotypes
Expressive site be very different.Wherein RXR α expressed in abundance in liver,kidney,spleen, placenta, epidermis and various viscera tissues.By
The function controlling of key signal molecule in many nuclear receptors and growth and apoptotic signal Signal Transduction Pathways, the gene are participated in RXR
It is considered as the important member for most having development prospect in nuclear receptor superfamily.The key point that RXR α is developed as tumour medicine
Sub- target spot, expression and the function for changing it will affect the growth of tumour cell.Coumarin kind compound has extensive biology living
Property, and such compound is still rare as the research report of nuclear receptor inhibitor.Also there has been no living with RXR alpha transcriptional at present
The relevant report of the cumarin esterification derivative of property.
Summary of the invention
It is an object of the invention in place of overcome the deficiencies in the prior art, provide to have to inhibit the active perfume (or spice) of RXR alpha transcriptional
Legumin esterification derivative and its preparation method and application.
The technical solution adopted by the present invention to solve the technical problems first is that:
One kind, which has, inhibits the active cumarin esterification derivative of RXR alpha transcriptional, and the cumarin esterification derivative is following
4- chloromethyl-umbelliferone esterification derivative shown in general formula (I):
Wherein, R is Sorbic acylAcyl groupNicotinoyl basePhenylpropyl alcohol
Acyl groupBenzene oxygen acetyl groupFuranylcarbonylOr phenylacetyl group
I.e. above-mentioned 4- chloromethyl-umbelliferone esterification derivative be following structural formula compound represented K1, K2,
K3, K4, K5, K6, K7:
The R base and physical property of 1 compound K 1 of table, K2, K3, K4, K5, K6, K7
The technical solution adopted by the present invention to solve the technical problems second is that:
It is above-mentioned that there is the preparation method for inhibiting the active cumarin esterification derivative of RXR alpha transcriptional, comprising:
1) resorcinol and 4- chloroacetyl acetacetic ester are mixed according to the ratio of molar ratio 1:1.1~1.3, is added anhydrous
Bismuth chloride is as catalyst, wherein the amount of anhydrous bismuth chloride is the 4.5~5.5% of resorcinol；Under solvent-free conditions 60~
70 DEG C are stirred to react 4~6h, after reaction, according to the volume ratio of 4- chloroacetyl acetacetic ester and 45~55% ethanol waters
45~55% ethanol waters are added for the ratio of 1:1.8~4, continuation is recrystallized in 60~70 DEG C of 8~12min of stirring,
It being cooled to room temperature, is separated by solid-liquid separation, solid portion is washed to neutrality, and it is dry, obtain the 4- chloromethyl -7- hydroxyl as shown in formula (II)
Cumarin；
2) at -2~5 DEG C, using the anhydrous methylene chloride for having instilled 1~2 drop DMF as solvent, it is molten that organic acid is dissolved in this
In agent, acylating reagent is added, wherein the molar ratio of organic acid and acylating reagent is 1:1.5~2.5, places 25 at -2~5 DEG C
It is gradually brought to room temperature after~35min, is stirred to react 2~4h under room temperature (for example, 0~25 DEG C), removes after reaction not anti-
The acylating reagent answered, shown in obtained product such as formula (III)；Product is added after being dissolved with anhydrous methylene chloride extremely contains step 1)
In the methylene chloride mixed liquor of obtained 4- chloromethyl-umbelliferone and acid binding agent, wherein 4- chloromethyl -7- hydroxyl tonka-bean
The molar ratio of element and acid binding agent is 1:1.1~1.3；2~4h is reacted at room temperature under alkaline condition；After reaction, reaction is adjusted
Liquid pH value to neutrality, methylene chloride extraction, organic phase is successively used saturated sodium bicarbonate solution, saturated common salt water washing, is then done
It is dry, it filters, concentration obtains crude product；Crude product purifies on silica gel chromatographic column, with petroleum ether-acetic acid of 1~7:1 of volume ratio
Ethyl ester mixed liquor is eluant, eluent, obtains final product；The organic acid be sorbic acid, caproic acid, niacin, benzenpropanoic acid, phenoxy acetic acid,
K1, K2, K3, K4, K5, K6, K7 are respectively obtained when furancarboxylic acid, phenylacetic acid.
In one embodiment: the acid binding agent is triethylamine.
In one embodiment: the acylating reagent is oxalyl chloride or thionyl chloride.
The reaction equation of above-mentioned preparation method is shown below:
The technical solution adopted by the present invention to solve the technical problems third is that:
It is above-mentioned that there is the inhibition active cumarin esterification derivative of RXR alpha transcriptional to inhibit the active medicine of RXR alpha transcriptional in preparation
Purposes on object and/or inhibitor.
It is above-mentioned that there is the inhibition active cumarin esterification derivative of RXR alpha transcriptional to prepare the purposes on anti-tumor drug.
In one embodiment: it is described it is antitumor be by inhibiting RXR alpha transcriptional activity to realize.
The technical program compared with the background art, it has the following advantages:
1. the present invention provides a kind of structures and its system for having and inhibiting the active cumarin esterification derivative of RXR alpha transcriptional
Preparation Method.
2. present invention BiCl34- chloromethyl-umbelliferone is synthesized as catalyst, is synthesized compared to conventional method,
Although yield is slightly lower, have it is cheap and easy to get, the reaction time is short, convenient post-treatment, it is low in the pollution of the environment the advantages that.
3. the compound of the present invention has certain active effect of inhibition RXR alpha transcriptional, to develop using RXR α as target spot
Drug provides thinking.
Detailed description of the invention
Present invention will be further explained below with reference to the attached drawings and examples.
Fig. 1 is 1~K7 of compound K obtained in embodiment to RXR alpha transcriptional activity activator effect caused by 9-cis-RA
Inhibiting effect is as a result, wherein ordinate is the relative luciferase activity of 9-cis-RA.
Specific embodiment
The contents of the present invention are illustrated below by embodiment:
Embodiment 1: preparation 4- chloromethyl-umbelliferone
By resorcinol (5.5g, 0.05mol), 4- chloroacetyl acetacetic ester (9.9g, 0.06mol), anhydrous bismuth chloride
(0.8g, 2.5mmol) is mixed in 100mL round-bottomed flask, and 65 DEG C of heating stirrings react 5h under solvent-free conditions, and reaction terminates
Afterwards, 50% ethanol water 16mL is added, continues to be cooled to room temperature in 65 DEG C of heating stirring 10min, filter, solid portion water
It is washed till neutrality, dries, obtains white solid 7.45g, as 4- chloromethyl-umbelliferone, yield 70%.
4- chloromethyl-umbelliferone NMR data:
1H NMR(400MHz,DMSO-d6):δ4.95(s,2H,CH2), Cl 6.42 (s, 1H, 3-H), 6.76 (d, 1H, J=
2.4Hz, 8-H), 6.83,6.85 (dd, 1H, J=2.4Hz, J=8.7Hz, 6-H), 7.67 (d, 1H, J=8.7Hz, 5-H),
10.66(s,1H,OH)ppm
Embodiment 2: preparation 4- chloromethyl -7- sorb acyl-oxygen butylcoumariii (compound K 1)
At 0 DEG C, sorbic acid (0.224g, 2.0mmol) is placed in two neck round-bottom flask of 25mL, 2 drop DMF is instilled, adds
Enter 10mL anhydrous methylene chloride (CH2Cl2) dissolution, oxalyl chloride (0.2mL, 4.0mmol) is added with disposable syringe；Two necks circle
One mouth of bottom flask is stoppered with rubber stopper, and another mouth connects device for absorbing tail gas；Room temperature, room are gradually brought to after ice bath 30min
2h is stirred to react under temperature, after reaction, vacuum distillation removes unreacted oxalyl chloride to dry；Product 2mL CH2Cl2Dissolution
Afterwards, it is extracted to be added into 10mL with syringe and contains 4- chloromethyl-umbelliferone (0.315g, 1.5mmol) and three
The CH of ethamine (0.208g, 1.8mmol)2Cl2In mixed liquor, 3h is reacted at room temperature；After reaction, reaction solution is adjusted with 1M HCl
PH value is extracted three times with 15mL methylene chloride to neutrality, merges organic phase, washed with saturated sodium bicarbonate solution, then with full
Twice with brine It, organic phase is dried, filtered with anhydrous magnesium sulfate, and concentration obtains crude product；Crude product is in silica gel chromatograph
It is purified on column, using the petroleum ether-ethyl acetate mixed liquor of volume ratio 7:1 as eluant, eluent, obtains final product white solid
0.338g, as 4- chloromethyl -7- sorb acyl-oxygen butylcoumariii (compound K 1), yield 74%.
The NMR data of compound K 1:
1H NMR(400MHz,DMSO-d6): δ 1.87 (d, 3H, J=4.5Hz, 6'-CH3), 5.04 (s, 2H, CH2Cl),
6.11 (d, 1H, J=15.3Hz, 2'-H), 6.36-6.46 (m, 2H, 3', 4'-CHCH), 6.68 (s, 1H, 3-H), 7.26,7.28
(dd, 1H, J=2.2Hz, J=8.7Hz, 6-H), 7.37 (d, 1H, J=2.2Hz, 8-H), 7.44-7.50 (m, 1H, 5'-H),
7.90 (d, 1H, J=8.7Hz, 5-H) ppm
Embodiment 3: preparation 4- chloromethyl -7- hexylyloxy cumarin (compound K 2)
At 0 DEG C, caproic acid (0.232g, 2.0mmol) is placed in two neck round-bottom flask of 25mL, 2 drop DMF is instilled, is added
10mL CH2Cl2Oxalyl chloride (0.2mL, 4.0mmol) is added with disposable syringe in dissolution；One mouth of two neck round-bottom flasks is used
Rubber stopper stoppers, and another mouth connects device for absorbing tail gas；It is gradually brought to room temperature after ice bath 30min, is stirred to react 2h at room temperature, instead
After answering, vacuum distillation removes unreacted oxalyl chloride to dry；Product 2mL CH2Cl2After dissolution, being extracted with syringe will
It is added to 10mL containing 4- chloromethyl-umbelliferone (0.315g, 1.5mmol) and triethylamine (0.208g,
CH 1.8mmol)2Cl2In mixed liquor, 3h is reacted at room temperature；After reaction, reacting liquid pH value is adjusted to neutrality with 1M HCl, use
15mL methylene chloride extracts three times, merges organic phase, is washed with saturated sodium bicarbonate solution, then uses saturated common salt water washing two
Secondary, organic phase is dried, filtered with anhydrous magnesium sulfate, and concentration obtains crude product；Crude product purifies on silica gel chromatographic column, with body
Petroleum ether-ethyl acetate mixed liquor of the product than 7:1 is eluant, eluent, obtains final product white solid 0.337g, as 4- chloromethane
Base -7- hexylyloxy cumarin (compound K 2), yield 73%.
The NMR data of compound K 2:
1H NMR(400MHz,DMSO-d6): δ 0.90 (t, 3H, J=7.0Hz, 6'-CH3),1.29-1.39(m,4H,4',
5'-CH2CH2), 1.63-1.70 (m, 2H, 3'-H), 2.62 (t, 2H, J=7.5Hz, 2'-H), 5.04 (s, 2H, CH2Cl),6.68
(s, 1H, 3-H), 7.21,7.23 (dd, 1H, J=2.2Hz, J=8.7Hz, 6-H), 7.31 (d, 1H, J=2.2Hz, 8-H),
7.90 (d, 1H, J=8.7Hz, 5-H) ppm
Embodiment 4: preparation 4- chloromethyl -7- nicotinylsalicylic oxygen cumarin (compound K 3)
At 0 DEG C, niacin (0.246g, 2.0mmol) is placed in two neck round-bottom flask of 25mL, 2 drop DMF is instilled, is added
10mL CH2Cl2Oxalyl chloride (0.2mL, 4.0mmol) is added with disposable syringe in dissolution；One mouth of two neck round-bottom flasks is used
Rubber stopper stoppers, and another mouth connects device for absorbing tail gas；It is gradually brought to room temperature after ice bath 30min, is stirred to react 2h at room temperature, instead
After answering, vacuum distillation removes unreacted oxalyl chloride to dry；Product 2mL CH2Cl2After dissolution, being extracted with syringe will
It is added to 10mL containing 4- chloromethyl-umbelliferone (0.315g, 1.5mmol) and triethylamine (0.208g,
CH 1.8mmol)2Cl2In mixed liquor, 3h is reacted at room temperature；After reaction, reacting liquid pH value is adjusted to neutrality with 1M HCl, use
15mL methylene chloride extracts three times, merges organic phase, is washed with saturated sodium bicarbonate solution, then uses saturated common salt water washing two
Secondary, organic phase is dried, filtered with anhydrous magnesium sulfate, and concentration obtains crude product；Crude product purifies on silica gel chromatographic column, with body
Petroleum ether-ethyl acetate mixed liquor of the product than 1:1 is eluant, eluent, obtains final product white solid 0.340g, as 4- chloromethane
Base -7- nicotinylsalicylic oxygen cumarin (compound K 3), yield 72%.
The NMR data of compound K 3:
1H NMR(400MHz,DMSO-d6):δ5.07(s,2H,CH2Cl),6.72(s,1H,3-H),7.45,7.47(dd,
1H, J=2.2Hz, J=8.7Hz, 6-H), 7.57 (d, 1H, J=2.2Hz, 8-H), 7.66-7.69 (m, 1H, 5'-H), 7.98
(d, 1H, J=8.7Hz, 5-H), 8.49-8.52 (m, 1H, 4'-H), 8.92,8.93 (dd, 1H, J=1.5Hz, J=4.8Hz,
6'-H), 9.29 (d, 1H, J=1.5Hz, 2'-H) ppm
Embodiment 5: preparation 4- chloromethyl -7- phenylpropyl alcohol acyl-oxygen butylcoumariii (compound K 4)
At 0 DEG C, benzenpropanoic acid (0.300g, 2mmol) is placed in two neck round-bottom flask of 25mL, 2 drop DMF is instilled, is added
10mL CH2Cl2Oxalyl chloride (0.2mL, 4.0mmol) is added with disposable syringe in dissolution；One mouth of two neck round-bottom flasks is used
Rubber stopper stoppers, and another mouth connects device for absorbing tail gas；It is gradually brought to room temperature after ice bath 30min, is stirred to react 2h at room temperature, instead
After answering, vacuum distillation removes unreacted oxalyl chloride to dry；Product 2mL CH2Cl2After dissolution, being extracted with syringe will
It is added to 10mL containing 4- chloromethyl-umbelliferone (0.315g, 1.5mmol) and triethylamine (0.208g,
CH 1.8mmol)2Cl2In mixed liquor, 3h is reacted at room temperature；After reaction, reacting liquid pH value is adjusted to neutrality with 1M HCl, use
15mL methylene chloride extracts three times, merges organic phase, is washed with saturated sodium bicarbonate solution, then uses saturated common salt water washing two
Secondary, organic phase is dried, filtered with anhydrous magnesium sulfate, and concentration obtains crude product；Crude product purifies on silica gel chromatographic column, with body
Petroleum ether-ethyl acetate mixed liquor of the product than 5:1 is eluant, eluent, obtains final product light yellow solid 0.420g, as 4- chlorine
Methyl -7- phenylpropyl alcohol acyl-oxygen butylcoumariii (compound K 4), yield 82%.
The NMR data of compound K 4:
1H NMR(400MHz,DMSO-d6):δ2.94-3.03(m,4H,CH2CH2),5.04(s,2H,CH2Cl),6.68(s,
1H, 3-H), 7.14,7.16 (dd, 1H, J=2.2Hz, J=8.7Hz, 6-H), 7.23 (d, 1H, J=2.2Hz, 8-H), 7.22-
7.26 (m, 2H, aromatic, 8-H), 7.30-7.35 (m, 4H, aromatic), 7.89 (d, 1H, J=8.7Hz, 5-H) ppm
Embodiment 6: preparation 4- chloromethyl -7- benzene oxygen acetoxy cumarin (compound K 5)
At 0 DEG C, phenoxy acetic acid (0.304g, 2mmol) is placed in two neck round-bottom flask of 25mL, 2 drop DMF is instilled, adds
Enter 10mL CH2Cl2Oxalyl chloride (0.2mL, 4.0mmol) is added with disposable syringe in dissolution；One mouth of two neck round-bottom flasks
It is stoppered with rubber stopper, another mouth connects device for absorbing tail gas；It is gradually brought to room temperature after ice bath 30min, is stirred to react 2h at room temperature,
After reaction, vacuum distillation removes unreacted oxalyl chloride to dry；Product 2mL CH2Cl2After dissolution, extracted with syringe
Be added into 10mL containing 4- chloromethyl-umbelliferone (0.315g, 1.5mmol) and triethylamine (0.208g,
CH 1.8mmol)2Cl2In mixed liquor, 3h is reacted at room temperature；After reaction, reacting liquid pH value is adjusted to neutrality with 1M HCl, use
15mL methylene chloride extracts three times, merges organic phase, is washed with saturated sodium bicarbonate solution, then uses saturated common salt water washing two
Secondary, organic phase is dried, filtered with anhydrous magnesium sulfate, and concentration obtains crude product；Crude product purifies on silica gel chromatographic column, with body
Petroleum ether-ethyl acetate mixed liquor of the product than 6:1 is eluant, eluent, obtains final product light yellow solid 0.413g, as 4- chlorine
Methyl -7- benzene oxygen acetoxy cumarin (compound K 5), yield 80%.
The NMR data of compound K 5:
1H NMR(400MHz,DMSO-d6):δ5.04(s,2H,CH2Cl),5.13(s,2H,2’-H),6.70(s,1H,3-
), H 7.00-7.07 (m, 3H, aromatic), 7.29,7.32 (dd, 1H, J=2.24Hz, J=8.72Hz, 6-H), 7.32-
7.36 (m, 2H, aromatic), 7.40 (d, 1H, J=2.24Hz, 8-H), 7.94 (d, 1H, J=8.72Hz) ppm
Embodiment 7: preparation 4- chloromethyl -7- furoyl oxygroup cumarin (compound K 6)
At 0 DEG C, furancarboxylic acid (0.224g, 2mmol) is placed in two neck round-bottom flask of 25mL, 2 drop DMF is instilled, adds
Enter 10mL CH2Cl2Oxalyl chloride (0.2mL, 4.0mmol) is added with disposable syringe in dissolution；One mouth of two neck round-bottom flasks
It is stoppered with rubber stopper, another mouth connects device for absorbing tail gas；It is gradually brought to room temperature after ice bath 30min, is stirred to react 2h at room temperature,
After reaction, vacuum distillation removes unreacted oxalyl chloride to dry；Product 2mL CH2Cl2After dissolution, extracted with syringe
Be added into 10mL containing 4- chloromethyl-umbelliferone (0.315g, 1.5mmol) and triethylamine (0.208g,
CH 1.8mmol)2Cl2In mixed liquor, 3h is reacted at room temperature；After reaction, reacting liquid pH value is adjusted to neutrality with 1M HCl, use
15mL methylene chloride extracts three times, merges organic phase, is washed with saturated sodium bicarbonate solution, then uses saturated common salt water washing two
Secondary, organic phase is dried, filtered with anhydrous magnesium sulfate, and concentration obtains crude product；Crude product purifies on silica gel chromatographic column, with body
Petroleum ether-ethyl acetate mixed liquor of the product than 5:1 is eluant, eluent, obtains final product light yellow solid 0.356g, as 4- chlorine
Methyl -7- furoyl oxygroup cumarin (compound K 6), yield 78%.
The NMR data of compound K 6:
1H NMR(400MHz,DMSO-d6):δ5.07(s,2H,CH2Cl),6.71(s,1H,3-H),6.83,6.84(dd,
- the H of 1H, J=1.7Hz, J=3.5Hz, 4 '), 7.39,7.41 (dd, 1H, J=2.24Hz, J=8.7Hz, 6-H), 7.52 (d, 1H,
J=2.2Hz, 8-H), the 7.64 (- H of d, 1H, J=3.5Hz, 3 '), 7.95 (d, 1H, J=8.7Hz, 5-H), 8.15 (d, 1H, J=
1.7Hz,5’-H)ppm
Embodiment 8: preparation 4- chloromethyl -7- phenylacetyl oxygroup cumarin (compound K 7)
At 0 DEG C, phenylacetic acid (0.272g, 2mmol) is placed in two neck round-bottom flask of 25mL, 2 drop DMF is instilled, is added
10mL CH2Cl2Oxalyl chloride (0.2mL, 4.0mmol) is added with disposable syringe in dissolution；One mouth of two neck round-bottom flasks is used
Rubber stopper stoppers, and another mouth connects device for absorbing tail gas；It is gradually brought to room temperature after ice bath 30min, is stirred to react 2h at room temperature, instead
After answering, vacuum distillation removes unreacted oxalyl chloride to dry；Product 2mL CH2Cl2After dissolution, being extracted with syringe will
It is added to 10mL containing 4- chloromethyl-umbelliferone (0.315g, 1.5mmol) and triethylamine (0.208g,
CH 1.8mmol)2Cl2In mixed liquor, 3h is reacted at room temperature；After reaction, reacting liquid pH value is adjusted to neutrality with 1M HCl, use
15mL methylene chloride extracts three times, merges organic phase, is washed with saturated sodium bicarbonate solution, then uses saturated common salt water washing two
Secondary, organic phase is dried, filtered with anhydrous magnesium sulfate, and concentration obtains crude product；Crude product purifies on silica gel chromatographic column, with body
Petroleum ether-ethyl acetate mixed liquor of the product than 6:1 is eluant, eluent, obtains final product light yellow solid 0.394g, as 4- chlorine
Methyl -7- phenylacetyl oxygroup cumarin (compound K 7), yield 80%.
The NMR data of compound K 7:
1H NMR(400MHz,CDCl3):δ3.92(s,2H,2'-H),4.64(s,2H,CH2Cl),6.64(s,1H,3-H),
7.09-7.11 (dd, 1H, J=2.24Hz, J=8.70Hz, 6-H), 7.16 (d, 1H, J=2.24Hz, 8-H), 7.33-7.43
(m, 5H, aromatic), 7.66 (d, 1H, J=8.70Hz, 5-H) ppm
Above-described embodiment can realize the technical effect of following experimental examples:
Experimental example: 1~K7 of compound K tests the active inhibiting effect of RXR alpha transcriptional:
Luciferase reporter gene technology: Luciferase Reporter System is with fluorescein (luciferin) bottom of for
Object detects a kind of active reporting system of firefly luciferase (fireflyluciferase).Luciferase can be catalyzed
Luciferin is oxidized to oxyluciferin, during luciferin oxidation, can issue bioluminescence
(bioluminescence).It may then pass through fluor tester and be also referred to as Chemiluminescence Apparatus (luminometer) or liquid flashing determining
The bioluminescence discharged in instrument measurement luciferin oxidation process.Fluorescein and luciferase this bioluminescence system, can be with
Expression that is extremely sensitive, efficiently detecting gene.It is detect transcription factor and target gene promoter region DNA interaction one
Kind detection method.
The means that luciferase reporter gene is used among this experimental example, are transferred to the relevant luciferase of RXR α in the cell
The system of reporter gene, by the way that each compound is total with 9-cis-RA (activator that 9-cis-RA is classical RXR α) respectively
Cell 12h is handled, then detects whether these compounds can inhibit RXR alpha transcriptional caused by 9-cis-RA living by luminous intensity
Property activation effect.So that it is determined that whether compound is able to suppress the transcriptional activity of RXR α.
Specifically, cell is used 1~K7 of compound K (20 μM) with RA (0.1 μM) coprocessing 12h, to collect thin respectively in advance
Born of the same parents, with luciferase reporter gene Activity determination RXR alpha transcriptional activity.The uciferase activity of 9-cis-RA is as blank control.
As a result data are indicated, * * * p < 0.001 by mean+SD (n=3) mode treatment with the ratio of experimental group and blank control group.
Experimental result is as shown in Figure 1.
Experimental result can further be illustrated by table 2:
Inhibiting effect of the 2 1~K7 of compound K of table to RXR alpha transcriptional activity activator effect caused by 9-cis-RA
Above-mentioned experimental result is shown: 1~K7 of compound K has RXR alpha transcriptional activity activator effect caused by 9-cis-RA
Inhibiting effect, and inhibiting rate reaches 30% or more, compound K 5 is to RXR alpha transcriptional activity activator effect caused by 9-cis-RA
Inhibitory effect it is best, inhibiting rate reaches 45.31%.
By above-mentioned experiment it is found that the compound of the present invention has certain active effect of inhibition RXR alpha transcriptional, for exploitation
Thinking is provided by the drug of target spot of RXR α.
The above is only the preferred embodiment of the present invention, the range implemented of the present invention that therefore, it cannot be limited according to, i.e., according to
Equivalent changes and modifications made by the invention patent range and description, should still be within the scope of the present invention.
Claims (7)
- Inhibit the active cumarin esterification derivative of RXR alpha transcriptional 1. having, it is characterised in that: the cumarin esterification derivative For the chloromethyl of 4- shown in following structural formula-umbelliferone esterification derivative K1, K2, K3, K4, K5, K6, K7:
- 2. a kind of preparation method with the inhibition active cumarin esterification derivative of RXR alpha transcriptional described in claim 1, It is characterized in that: including:1) resorcinol and 4- chloroacetyl acetacetic ester are mixed according to the ratio of molar ratio 1:1.1~1.3, anhydrous chlorination is added Bismuth is as catalyst, wherein the amount of anhydrous bismuth chloride is the 4.5~5.5% of resorcinol；60~70 DEG C under solvent-free conditions It is stirred to react 4~6h, is 1 according to the volume ratio of 4- chloroacetyl acetacetic ester and 45~55% ethanol waters after reaction: 45~55% ethanol waters are added in 1.8~4 ratio, continue to be cooled to room temperature, solid-liquid in 60~70 DEG C of 8~12min of stirring Separation, solid portion are washed to neutrality, dry, obtain 4- chloromethyl-umbelliferone；2) at -2~5 DEG C, using the anhydrous methylene chloride for having instilled 1~2 drop DMF as solvent, organic acid is dissolved in the solvent, Be added acylating reagent, wherein the molar ratio of organic acid and acylating reagent be 1:1.5~2.5, at -2~5 DEG C place 25~ It is gradually brought to room temperature after 35min, is stirred to react 2~4h at room temperature, removes unreacted acylating reagent after reaction；Product It is added after being dissolved with anhydrous methylene chloride to the 4- chloromethyl-umbelliferone and acid binding agent dichloro obtained containing step 1) In methane blended liquid, wherein the molar ratio of 4- chloromethyl-umbelliferone and acid binding agent is 1:1.1~1.3；Room temperature reaction 2 ~4h；After reaction, reacting liquid pH value is adjusted to neutrality, and methylene chloride extracts, and organic phase successively uses saturated sodium bicarbonate molten Liquid, saturated common salt water washing, then dry, filter, and concentration obtains crude product；Crude product purifies on silica gel chromatographic column, with body Petroleum ether-ethyl acetate mixed liquor of the product than 1~7:1 is eluant, eluent, obtains final product；The organic acid be sorbic acid, oneself K1, K2, K3, K4, K5, K6, K7 are respectively obtained when acid, niacin, benzenpropanoic acid, phenoxy acetic acid, furancarboxylic acid, phenylacetic acid.
- 3. a kind of preparation method with the inhibition active cumarin esterification derivative of RXR alpha transcriptional as claimed in claim 2, Be characterized in that: the acid binding agent is triethylamine.
- 4. a kind of preparation method with the inhibition active cumarin esterification derivative of RXR alpha transcriptional as claimed in claim 2, Be characterized in that: the acylating reagent is oxalyl chloride or thionyl chloride.
- 5. one kind is described in claim 1 there is the inhibition active cumarin esterification derivative of RXR alpha transcriptional to inhibit RXR α in preparation The drug of transcriptional activity and/or the purposes on inhibitor.
- 6. one kind is described in claim 1 there is the inhibition active cumarin esterification derivative of RXR alpha transcriptional to prepare antineoplastic Purposes on object.
- 7. purposes according to claim 6, it is characterised in that: it is described it is antitumor be by inhibit RXR alpha transcriptional activity come reality It is existing.
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