CN109705133B - Selective estrogen receptor regulator compounds containing phenylselenium group and application thereof in anti-breast cancer drugs - Google Patents
Selective estrogen receptor regulator compounds containing phenylselenium group and application thereof in anti-breast cancer drugs Download PDFInfo
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Abstract
The invention discloses a selective estrogen receptor modulator compound containing a phenylselenium group and application thereof in anti-breast cancer drugs. 3- (4-hydroxyphenyl) -4- (4-phenylseleno) phenyl-furan and styrene sulfonic acid derivatives are used as raw materials, a catalyst is not needed, the reaction is carried out for 8 hours at 90 ℃, and the selective estrogen receptor modulator containing the phenylseleno group is prepared in one step.
Description
Technical Field
The invention belongs to the field of selective estrogen receptor modulators, and particularly relates to a selective estrogen receptor modulator compound containing a phenylselenium group and application thereof in anti-breast cancer drugs.
Background
Breast cancer (Breastcancer) is a kind of cancer which is originated from breast tissue, most commonly mammary duct or mammary lobule, and is one of the common malignant tumors of women worldwide, the incidence rate of breast cancer is the first of the female malignant tumors, and the body and mind health of women is seriously harmed. Currently, hormone replacement therapy, i.e., the treatment of alleviating menopausal symptoms by supplementing postmenopausal women with estrogen deficiency with estrogen and progestin, is mainly used clinically. Most of the commonly used therapeutic drugs take ER as a target, but the long-term use of Selective Estrogen Receptor Modulators (SERMs) drugs, such as tamoxifen, can generate drug resistance and increase the risk of endometrial cancer.
The Estrogen Receptor (ER) belongs to a member of nuclear receptor superfamily and is a ligand-dependent transcription factor, the known Estrogen receptor has α and β subtypes, ER α and ER β have different organ and tissue distribution patterns in human bodies, ER α mainly promotes the proliferation of cells, so ER α is regarded as an important target spot for treating breast cancer, selenium is a trace element essential to human bodies and has wide physiological effects such as anti-inflammation, antioxidation, neuroprotection and the like.
In 2005, the inventors designed and synthesized a compound (shown in formula 1) based on an oxido-diheptene structure, and the molecule has a special three-dimensional structure, can better act with a binding site on an estrogen receptor, can effectively block the combination of estradiol and the estrogen receptor, inhibits the proliferation of cancer cells, and has a certain anti-inflammatory effect.
However, the drug resistance problem in the current clinical treatment of breast cancer drugs is more prominent, so that the search for anti-tumor compounds with better activity and higher safety is urgent.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a selective estrogen receptor modulator compound containing a phenylselenium group, and in consideration of the important role of the selenium-containing compound in tumor prevention and treatment, on the basis of the latest research progress of ER ligands and the earlier stage work of the subject group, the phenylselenium group is introduced into the molecular structure of the oxido bicycloheptene SERMs (OBHS) of the formula 1, so that the two are organically combined into one molecule, and the anti-breast cancer medicine with better anti-cancer activity is obtained.
The invention also aims to provide a synthesis method of the selective estrogen receptor modulator compound containing the phenylselenium group, which takes 3- (4-hydroxyphenyl) -4- (4-phenylseleno) phenyl-furan and styrene sulfonic acid derivatives as raw materials, does not need a catalyst, and reacts for 8 hours at 90 ℃ to prepare the selective estrogen receptor modulator containing the phenylselenium group in one step.
The invention further aims to provide application of the selective estrogen receptor modulator compound containing the phenylselenium group in preparing anti-breast cancer drugs.
In order to achieve the purpose, the invention adopts the following technical scheme:
in a first aspect, selective estrogen receptor modulator compounds containing a phenylselenium group and pharmaceutically acceptable salts thereof are provided, and have a structure shown in the following formula I or formula II:
wherein the content of the first and second substances,
r is 4-OCH3, 4-CH3, 4-Cl, 4-OH, 4-CF3, 4-Br, 3-OCH3, 3-CH3, 3-Cl, 3-OH, 3-CF3, 3-Br, or,
Preferably, the selective estrogen receptor modulator containing a phenylselenium group compound is:
5- (4-hydroxyphenyl) -6- (4-phenylselenophenyl) -7-oxobicyclo [2.2.1] -5-heptene-3-sulfonic acid- (4-methoxyphenyl) ester (13 a);
5- (4-hydroxyphenyl) -6- (4-phenylselenophenyl) -7-oxobicyclo [2.2.1] -5-heptene-2-sulfonic acid- (4-methoxyphenyl) ester (13 b);
5- (4-hydroxyphenyl) -6- (4-phenylselenophenyl) -7-oxobicyclo [2.2.1] -5-heptene-3-sulfonic acid- (4-chlorophenyl) ester (13 c);
5- (4-hydroxyphenyl) -6- (4-phenylselenophenyl) -7-oxobicyclo [2.2.1] -5-heptene-2-sulfonic acid- (4-chlorophenyl) ester (13 d);
5- (4-hydroxyphenyl) -6- (4-phenylselenophenyl) -7-oxobicyclo [2.2.1] -5-heptene-3-sulfonic acid- (4-bromophenyl) ester (13 e);
5- (4-hydroxyphenyl) -6- (4-phenylselenophenyl) -7-oxobicyclo [2.2.1] -5-heptene-2-sulfonic acid- (4-bromophenyl) ester (13 f);
5- (4-hydroxyphenyl) -6- (4-phenylselenophenyl) -7-oxobicyclo [2.2.1] -5-heptene-3-sulfonic acid- (4-methylphenyl) ester (13 g);
5- (4-hydroxyphenyl) -6- (4-phenylselenophenyl) -7-oxabicyclo [2.2.1] -5-heptene-2-sulfonic acid- (4-methylphenyl) ester (13 h);
5- (4-hydroxyphenyl) -6- (4-phenylselenophenyl) -7-oxobicyclo [2.2.1] -5-heptene-3-sulfonic acid- (4-hydroxyphenyl) ester (13 i);
5- (4-hydroxyphenyl) -6- (4-phenylselenophenyl) -7-oxobicyclo [2.2.1] -5-heptene-3-sulfonic acid- (4-trifluoromethylphenyl) ester (13 j);
5- (4-hydroxyphenyl) -6- (4-phenylselenophenyl) -7-oxobicyclo [2.2.1] -5-heptene-2-sulfonic acid- (4-trifluoromethylphenyl) ester (13 k);
5- (4-hydroxyphenyl) -6- (4-phenylselenophenyl) -7-oxobicyclo [2.2.1] -5-heptene-2-sulfonic acid- (3-methoxyphenyl) ester (13 l);
5- (4-hydroxyphenyl) -6- (4-phenylselenophenyl) -7-oxobicyclo [2.2.1] -5-heptene-2-sulfonic acid- (3-methylphenyl) ester (13 m);
5- (4-hydroxyphenyl) -6- (4-phenylselenophenyl) -7-oxabicyclo [2.2.1] -5-heptene-2-sulfonic acid- (3-methoxyphenyl) ester (13 n);
5- (4-hydroxyphenyl) -6- (4-phenylselenophenyl) -7-oxabicyclo [2.2.1] -5-heptene-2-sulfonic acid- (3-chlorophenyl) ester (13 o);
5- (4-hydroxyphenyl) -6- (4-phenylselenophenyl) -7-oxobicyclo [2.2.1] -5-heptene-3-sulfonic acid- (3-hydroxyphenyl) ester (13 p);
5- (4-hydroxyphenyl) -6- (4-phenylselenophenyl) -7-oxabicyclo [2.2.1] -5-heptene-2-sulfonic acid- (3-bromophenyl) ester (13 q);
5- (4-hydroxyphenyl) -6- (4-phenylselenophenyl) -7-oxobicyclo [2.2.1] -5-heptene-3-sulfonic acid- (1-naphthol) ester (13 r);
5- (4-hydroxyphenyl) -6- (4-phenylselenophenyl) -7-oxobicyclo [2.2.1] -5-heptene-2-sulfonic acid- (1-naphthol) -ester (13 s);
5, 6-bis (4-hydroxyphenyl) -7-oxobicyclo [2.2.1] -5-heptene-2-sulfonic acid- (4-phenylselenophenyl) ester (22 a);
5, 6-bis (4-hydroxyphenyl) -7-oxobicyclo [2.2.1] -5-heptene-2-sulfonic acid- (3-phenylselenophenyl) ester (22 b); or a pharmaceutically acceptable salt of the above compound.
In a second aspect, a preparation method of the above selective estrogen receptor modulator compounds containing phenylselenium groups is provided, which comprises the following specific steps:
(1) synthesis of 3- (4-hydroxyphenyl) -4- (4-phenylselenophenyl) furan Compound 10:
reaction reagents and conditions (a) NBS, p-TsOH, CHCl3,rt,12h；(b)Et3N,CH3CN,rt,12h；(c)NaH,DMSO,rt,3h；(d)BBr3,CH2Cl2,0 ℃,10h；(e)DIBAl-H,THF,-78℃,12h.(f)Bis(pinacolato)diboron,Pd(dppf)Cl2,DMSO,rt,12h；(g)NaIO4,NH4Cl, Actone:H2O＝1:1,0℃to rt,12h；(h)PhSeSePh,CuI,O2,DMSO,100℃,28h.
a. Synthesis of p-methoxy bromoacetophenone compound 2
Weighing 1equiv p-methoxyacetophenone 1, 0.2equiv p-toluenesulfonic acid and 1.2equiv N-bromosuccinimide (NBS) in a round-bottom flask with the diameter of 150m L, adding 50m L of chloroform, reacting at room temperature for 12 hours, monitoring the completion of the reaction by T L C, adding water for quenching, extracting by 3 × 20m L of dichloromethane, drying an organic layer with anhydrous sodium sulfate, performing desolventization under reduced pressure, and purifying by a silica gel column to obtain a yellow solid p-methoxybromoacetophenone compound 2;
b. synthesis of 2- (4-methoxyphenyl) -2-carbonylethyl-2- (4-bromophenyl) acetate Compound 4
Weighing 1equiv compound 2 and 1equiv p-bromophenylacetic acid 3 in a 50m L round-bottom flask, adding 25m L of anhydrous acetonitrile, slowly dropwise adding 1equiv anhydrous triethylamine, continuing to react for 8 hours at room temperature, monitoring the completion of the reaction by T L C, adding water to quench after the reaction is finished, extracting with 3 × 15m L ethyl acetate, drying an organic layer with anhydrous sodium sulfate, filtering, performing decompression and desolventization, and purifying by column chromatography to obtain a yellow powdery solid compound 4;
c. synthesis of 3- (4-bromophenyl) -4- (4-methoxyphenyl) furan-2-one Compound 5
Baking a 50m L two-mouth bottle and magnetons at 105 ℃ for 15min, then, immediately heating, performing anhydrous and anaerobic operation, weighing 1equiv compound 4 under the protection of argon, adding into the bottle, adding 10m L of anhydrous dimethyl sulfoxide, slowly adding 2equiv 60% NaH, reacting at 25 ℃ for 3h, monitoring the reaction completion by T L C, adding 5m L2N hydrochloric acid to quench the reaction, extracting with 3 × 15m L ethyl acetate, drying an organic layer of anhydrous sodium sulfate, performing desolventization under reduced pressure to obtain a crude product, and purifying by a silica gel column (petroleum ether/ethyl acetate is 9:1) to obtain a yellow solid compound 5;
d. synthesis of 3- (4-bromophenyl) -4- (4-hydroxyphenyl) furan-2-one Compound 6
Baking 100m L single-neck bottle and magneton at 105 deg.C for 15min, immediately heating, anhydrous and oxygen-free, under the protection of argon, weighing 1equiv compound 5, adding 20m L anhydrous dichloromethane, and adding 3equiv BBr under ice bath3After 12h of reaction, 20m L of water is added to quench the reaction, the mixture is extracted by 3 × 15m L of ethyl acetate, washed by 15m L of saturated sodium bicarbonate solution, an organic layer is dried by anhydrous sodium sulfate and desolventized under reduced pressure to obtain a crude product, and the crude product is purified by a silica gel column (petroleum ether/ethyl acetate: 7:3) to obtain a white solid compound 6;
e. synthesis of 3- (4-bromophenyl) -4- (4-hydroxyphenyl) furan compound 7
Baking a 100m L single-neck bottle and magnetons at 105 ℃ for 15min, then, immediately heating, carrying out anhydrous and anaerobic operation, weighing 1equiv compound 6 in the solution under the protection of argon, adding 4equiv diisobutylaluminum hydride (DIBAL-H) at-78 ℃ for reaction for 12H, adding 4% sulfuric acid for quenching reaction, extracting with 3 × 25m L ethyl acetate, washing with 30m L saturated sodium chloride solution, drying an organic layer with anhydrous sodium sulfate, carrying out decompression and desolventizing to obtain a crude product, and carrying out silica gel column purification (petroleum ether/ethyl acetate is 6:1) to obtain a white powdery solid compound 7;
f. synthesis of 3- (4-boronate phenyl) -4- (4-hydroxyphenyl) -furan 8
Baking 100m L single-neck bottle and magneton at 105 deg.C for 15min, heating, anhydrous and oxygen-free, and weighing 1equiv compound 7, 1.1equiv diboronic acid ester, 3equiv KOAc, and 0.05 equiv Pd (dppf) under the protection of argonCl2Adding 1, 4-dioxane 20m L as a solvent, reacting at 90 ℃ for 12h, adding 20m L of water for quenching after the reaction is finished, extracting with 3 × 25m L of ethyl acetate, washing with 30m L of saturated sodium chloride solution, drying an organic layer of anhydrous sodium sulfate, decompressing and desolventizing to obtain a crude product, and purifying by a silica gel column (petroleum ether/ethyl acetate is 10:1) to obtain a white powdery solid compound 8;
g. 9 Synthesis of 3- (4-boranophenyl) -4- (4-hydroxyphenyl) furan Compound
Weighing 1equiv of compound 8, 3.5equiv CH in a single-mouth bottle of 100m L and magneton3COONH4To this, 40m L Acetone H was added2O1: 1 as solvent, adding 3.5equiv NaIO in batches under ice bath4Then moving to normal temperature, reacting for 12h, adding 20m L water to quench and react, extracting with 3 × 15m L ethyl acetate, washing with 15m L saturated sodium bicarbonate solution, drying an organic layer with anhydrous sodium sulfate, decompressing and desolventizing to obtain a crude product, and purifying by a silica gel column (petroleum ether/ethyl acetate is 4:1) to obtain a light yellow solid compound 9;
h. synthesis of 3- (4-phenylselenophenyl) -4- (4-hydroxyphenyl) furan compound 10
Weighing 1equiv of compound 9, 0.5equiv of diphenyl diselenide and 0.2equiv of CuI in a single-neck bottle of 100m L, adding dimethyl sulfoxide 20m L as a solvent, reacting for 28h at 100 ℃, adding 20m of L water after the reaction is finished, extracting with 3 × 25m of L ethyl acetate, washing with 30m of L saturated sodium chloride solution, drying an organic layer of anhydrous sodium sulfate, and performing decompression and desolventization to obtain a crude product, and purifying by a silica gel column (petroleum ether/ethyl acetate is 10:1) to obtain a white powdery solid compound 10;
(2)3,4 bis (4-hydroxyphenyl) -furan compound 18:
reaction reagents and conditions (a) NBS, p-TsOH, CHCl3,rt,12h；(b)Et3N,CH3CN,rt,12h；(c)NaH,DMSO, rt,3h；(d)BBr3,CH2Cl2,0℃,10h；(e)DIBAl-H,THF,-78℃,12h.
a. Synthesis of 2- (4-methoxyphenyl) -2-carbonylethyl-2- (4-methoxyphenyl) acetate compound 15
Weighing 1.0eq of compound 2 and 1.0eq of p-methoxyphenylacetic acid 14 (purchased from Aladdin, Cat. S115483) in a round-bottomed flask of 50m L, adding 25m L of anhydrous acetonitrile, slowly adding 1.0eq anhydrous triethylamine dropwise, continuing to react for 2h at room temperature, monitoring the reaction completion by T L C, evaporating to remove acetonitrile and triethylamine after the reaction is finished, adding ethyl acetate to dissolve, washing with 5.0eq 2N dilute hydrochloric acid, 2 × 30m L saturated sodium bicarbonate and 30m L saturated sodium chloride, drying an organic layer with anhydrous sodium sulfate, filtering to obtain a crude product, and purifying to obtain a yellow solid compound 15;
b. synthesis of 3, 4-bis (4-methoxy-phenyl) furan-2-one Compound 16
Baking a 25m L two-mouth bottle and magnetons at 105 ℃ for 15min, heating, performing anhydrous and anaerobic operation, weighing 1equiv of a compound 15 under the protection of argon, adding 10m L of anhydrous dimethyl sulfoxide, slowly dropwise adding 2equiv 80% NaH, reacting at 25 ℃ for 2h, monitoring the reaction completion by T L C, adding 5m L2N of hydrochloric acid to quench the reaction, extracting with 3 × 25m L ethyl acetate, drying an organic layer of anhydrous sodium sulfate, performing desolventization under reduced pressure to obtain a crude product, and purifying by a silica gel column (petroleum ether/ethyl acetate is 9:1) to obtain a compound 16;
c. synthesis of 3, 4-bis (4-hydroxy-phenylfuran) -2-one Compound 17
Baking 100m L single-neck bottle and magneton at 105 deg.C for 15min, weighing 1equiv of compound 16 under protection of argon gas, adding 25m L dichloromethane, and adding 6equiv BBr at-20 deg.C3After 12h of reaction, adding 10m L of water to quench the reaction, extracting with 3 × 20m L of ethyl acetate, washing with 15m L of saturated sodium bicarbonate solution, drying the organic layer with anhydrous sodium sulfate, and removing the solvent under reduced pressure to obtain a crude product, and purifying with a silica gel column (petroleum ether/ethyl acetate: 7:3) to obtain a compound 17;
d. synthesis of 3, 4-bis (4-hydroxy-phenyl) furan compound 18
Baking a 50M L single-mouth bottle and magnetons at 105 ℃ for 15min, then, immediately heating, carrying out anhydrous and anaerobic operation, weighing 1equiv compound 17 under the protection of argon, adding 4equiv diisobutylaluminum hydride (1M DIBAL-H) at-78 ℃ for reaction for 12H, adding 4% sulfuric acid for quenching reaction, extracting with 3 × 25M L ethyl acetate, washing with 30M L saturated sodium chloride solution, drying an organic layer with anhydrous sodium sulfate, carrying out decompression and desolventization to obtain a crude product, and purifying (petroleum ether/ethyl acetate is 6:4) to obtain a compound 18;
(3) synthesis of the vinyl sulfonate dienophile Compound 12a-u
Reaction reagents and conditions: (i) TEA, DCM,0 ℃ for 12h
Wherein the content of the first and second substances,
r is 4-OCH3、4-CH3、4-Cl、4-OH、4-CF3、4-Br、3-OCH3、3-CH3、 3-Cl、3-OH、3-CF3、3-Br、
a. General procedure for the Synthesis of Compound 12
Taking a 100m L single-mouth bottle, baking magnetons at 105 ℃ for 15min, heating, carrying out anhydrous and anaerobic operation, weighing 1equiv of corresponding compound 11 under the protection of argon, dissolving in anhydrous dichloromethane, slowly adding 1.2equiv of 2-chloroethanesulfonyl chloride at 0 ℃, reacting for 10min, slowly dropwise adding anhydrous triethylamine, reacting at room temperature for 12h, carrying out decompression and desolventizing to obtain a crude product, and purifying by using a silica gel column (petroleum ether/ethyl acetate is 12: 1-3: 2) to obtain an ethylene sulfonate dienophile 12;
(4) synthesis of phenylseleno sulfonate dienophile derivatives
Reaction reagent and conditions (a) NaBH4,MeOH,40℃,24h；(b)2-Chloroethanesulfonylchloride,TEA,CH3CN,rt,12h；
a. General method for synthesizing phenylselenophenol compound 20
Baking 100m L single-neck bottle with magneton at 105 deg.C for 15min, heating, anhydrous and oxygen-free, dissolving 1equiv of corresponding compound diphenyl diselenide in anhydrous methanol under protection of argon, and adding 3equiv NaBH at 0 deg.C4Reacting for 1h, slowly dropwise adding 2equiv of corresponding phenol compound, reacting for 24h at 40 ℃, slowly adding water under an ice-water bath to quench, extracting with 3 × 25m L ethyl acetate, washing with 30m L saturated sodium chloride solution, drying an organic layer with anhydrous sodium sulfate, decompressing and desolventizing to obtain a crude product, and purifying by a silica gel column (petroleum ether/ethyl acetate is 1:2) to obtain a colorless oily compound 20;
b. general procedure for the Synthesis of sulfonate dienophile derivative Compound 21
Taking a 100m L single-mouth bottle, baking magnetons at 105 ℃ for 15min, heating, carrying out anhydrous and anaerobic operation, weighing 1equiv of corresponding compound 20 under the protection of argon, dissolving in anhydrous dichloromethane, slowly adding 1.2equiv of 2-chloroethanesulfonyl chloride at 0 ℃, reacting for 10min, slowly dropwise adding anhydrous triethylamine, reacting at room temperature for 12h, carrying out decompression and desolventizing to obtain a crude product, and purifying by using a silica gel column (petroleum ether/ethyl acetate is 12: 1-3: 2) to obtain a sulfonic acid ester dienophile 21;
(5) synthesis of target Compounds 13a-13u,22a,22b
Taking a 25m L double-mouth bottle, baking magnetons at 105 ℃ for 15min, then, under the conditions of heat and no water and oxygen, dissolving a synthesized furan compound 10 or a 3, 4-bis (4-hydroxyphenyl) furan compound 18, a vinylsulfonate dienophile and a phenylselenyl-containing derivative thereof in tetrahydrofuran under the protection of argon, and reacting at 90 ℃ for 8h to prepare the selective estrogen receptor regulator containing a phenylselenyl group in one step, wherein the reaction formulas are shown as the following I and II:
I:
the reaction reagent and the conditions are (a) THF at 90 ℃ for 8 h;
wherein the content of the first and second substances,
r is 4-OCH3、4-CH3、4-Cl、4-OH、4-CF3、4-Br、3-OCH3、3-CH3、 3-Cl、3-OH、3-CF3、3-Br、
II:
The reaction reagent and the conditions are (a) THF at 90 ℃ for 8 h;
wherein 22 a-4-SePh and 22 b-3-SePh.
The above formula I or II of the present invention can form a pharmaceutically acceptable salt thereof with an acid, which may include inorganic or organic acids, such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, propionic acid, trifluoroacetic acid, maleic acid, tartaric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and the like, according to some conventional methods in the art to which the present invention pertains. The medicament of the present invention may be a medicament in which the compound itself is mixed with a pharmaceutically acceptable diluent, adjuvant and/or carrier, or a medicament in which a composition of the compound of the present invention or a pharmaceutically acceptable salt, solvate, optical isomer or polymorph thereof as one of the active ingredients is mixed with a pharmaceutically acceptable diluent, adjuvant and/or carrier.
The medicine of the invention can be prepared into various pharmaceutically acceptable dosage forms such as tablets, capsules, oral liquid, injections, granules or various sustained and controlled release preparations and the like by adding conventional auxiliary materials and adopting a conventional process.
The carriers for the medicaments of the invention are of the usual type available in the pharmaceutical field and include: binders, lubricants, disintegrants, cosolvents, diluents, stabilizers, suspending agents or matrices, and the like.
In a third aspect, the application of the selective estrogen receptor modulator compound containing the phenylselenium group and the pharmaceutically acceptable salt thereof in preparing anti-breast cancer drugs is provided.
In a fourth aspect, a pharmaceutical composition for treating breast cancer is provided, which comprises the above selective estrogen receptor modulator compound containing a phenylselenium group and one or more pharmaceutically acceptable auxiliary agents.
In a fifth aspect, an application of the anti-breast cancer pharmaceutical composition in preparing an anti-breast cancer medicament is provided.
Compared with the prior art, the invention has the beneficial effects that:
the selective estrogen receptor regulator containing the phenylselenium group is prepared by taking 3- (4-hydroxyphenyl) -4- (4-phenylseleno) phenyl-furan and styrene sulfonate derivatives as raw materials, reacting for 8 hours at 90 ℃ without a catalyst, and reacting in one step to obtain the selective estrogen receptor regulator containing the phenylseleno group, wherein the selective estrogen receptor regulator has a different action mode from the existing anti-breast cancer medicament tamoxifen, the basic side chain of tamoxifen replaces the original position of a helix 12 in an estrogen receptor, so that the helix 12 cannot be normally closed, and a ligand binding region cannot recruit a transcription coactivator and cannot start a gene regulation function.
Detailed Description
Further features and advantages of the present invention will be understood from the following detailed description. The examples provided are merely illustrative of the method of the present invention and do not limit the remainder of the disclosure in any way.
[ example 1] Synthesis of 3- (4-hydroxyphenyl) -4- (4-phenylselenophenyl) furan Compound 10
1. Synthesis of p-methoxy bromoacetophenone compound 2
P-methoxyacetophenone 1(6.998g,46.6mmol), p-toluenesulfonic acid (1.617g,9.3mmol) and N-bromosuccinimide (NBS,10.049g,55.9mmol) were weighed into a round bottom flask with the volume of 150m L, chloroform with the volume of 50m L was added, after 12 hours of reaction at room temperature, T L C was monitored for completion of the reaction, water was added for quenching, dichloromethane was extracted (3 × 20m L), the organic layer was dried over anhydrous sodium sulfate, desolventized under reduced pressure, and purified by silica gel column to obtain 6.404 g (yield 60%) of a yellow solid.
2. Synthesis of 2- (4-methoxyphenyl) -2-carbonylethyl-2- (4-bromophenyl) acetate Compound 4
Compound 2(1.5896g,6.94mmol) and p-bromophenylacetic acid 3(1.492g,6.94mmol) are weighed into a round bottom flask with the volume of 50m L, 25m L of anhydrous acetonitrile is added, anhydrous triethylamine (702.3mg, 6.94mmol) is slowly added dropwise, after reaction is continued for 8 hours at room temperature, T L C monitors that the reaction is complete, water is added for quenching after the reaction is finished, ethyl acetate is extracted (3 × 15m L), an organic layer is dried by anhydrous sodium sulfate, filtration and decompression desolventization are carried out, and 1.99g (yield 79%) of yellow powdery solid is obtained after column chromatography purification.1H NMR(400MHz, Acetone-d6)7.97–7.92(m,2H),7.51(d,J＝8.4Hz,2H),7.33(d,J＝8.5Hz,2H), 7.01(d,J＝9.0Hz,2H),5.43(s,2H),3.86(s,3H),3.81(s,2H)。
3. Synthesis of 3- (4-bromophenyl) -4- (4-methoxyphenyl) furan-2-one Compound 5
Baking a 50m L two-neck bottle and magneton at 105 ℃ for 15min, then heating, carrying out anhydrous and oxygen-free operation, weighing compound 4(1.022g and 2.8mmol) under the protection of argon, adding into the bottle, adding 10m L of anhydrous dimethyl sulfoxide, slowly adding 60% NaH (224mg and 5.6mmol), reacting at 25 ℃ for 3h, monitoring the reaction completion by T L C, adding 5m L2N hydrochloric acid to quench the reaction, extracting with ethyl acetate (3 × 15m L), drying an organic layer of anhydrous sodium sulfate, carrying out decompression and desolventization to obtain a crude product, and purifying with a silica gel column (petroleum ether/ethyl acetate 9:1) to obtain 611mg (yield 63%) of yellow solid compound 5.1H NMR(400MHz,CDCl3)7.50 (d,J＝8.2Hz,2H),7.31(d,J＝8.4Hz,2H),7.27(d,J＝8.9Hz,2H),6.85(d,J＝8.8 Hz,2H),5.13(s,2H),3.81(s,3H)。
4. Synthesis of 3- (4-bromophenyl) -4- (4-hydroxyphenyl) furan-2-one Compound 6
Placing 100m L single-mouth bottle and magneton at 105 deg.CBaking for 15min, weighing compound 5(1.998g,5.81mmol) under argon protection, adding 20m L anhydrous dichloromethane, adding BBr under ice bath3(1.9m L, 20.33mmol) was reacted for 12h, then 20m L was added to quench the reaction with water, extracted with ethyl acetate (3 × 15m L), washed with a saturated solution of sodium bicarbonate (15m L), the organic layer was dried over anhydrous sodium sulfate and desolventized under reduced pressure to give the crude product which was purified on silica gel column (petroleum ether/ethyl acetate 7:3) to give 1.716g (92% yield) of compound 6 as a white solid.1H NMR(400MHz,Acetone-d6)9.11(s, 1H),7.65–7.58(m,2H),7.41–7.35(m,2H),7.35–7.29(m,2H),6.89–6.82(m,2H),5.27(s,2H)。
5. Synthesis of 3- (4-bromophenyl) -4- (4-hydroxyphenyl) furan compound 7
After a 100M L one-neck flask and magneton are roasted at 105 ℃ for 15min, and then the mixture is heated and oxygen-free, compound 6(1.012g,3.07mmol) is weighed into the mixture under the protection of argon, diisobutylaluminum hydride (1M DIBAl-H,12M L, 12.12mmol) is added at-78 ℃ for reaction for 12H, 4% sulfuric acid is added for quenching reaction, ethyl acetate (3 × 25M L) is used for extraction, a saturated sodium chloride (30M L) solution is used for washing, an organic layer is dried by anhydrous sodium sulfate, and decompression and desolventization are carried out to obtain a crude product, and the crude product is purified by a silica gel column (petroleum ether/ethyl acetate 6:1) to obtain 967.6 mg (yield 77%) of white powdery compound 7.1H NMR(400MHz,Acetone-d6)8.58 (s,1H),7.72(d,J＝1.8Hz,1H),7.63(d,J＝1.8Hz,1H),7.45–7.41(m,2H),7.22– 7.15(m,2H),7.11–7.03(m,2H),6.88–6.80(m,2H)。
6. Synthesis of 3- (4-boronate phenyl) -4- (4-hydroxyphenyl) -furan 8
Baking 100m L single-neck bottle and magneton at 105 deg.C for 15min, weighing compound 7(0.542g,1.63mmol), diboron ester (0.455g,1.79 mmol), KOAc (0.480g,4.89mmol), Pd (dppf) Cl under protection of argon2(0.059g,0.081mmol) is added with 1, 4-dioxane 20m L as solvent, the mixture reacts for 12 hours under the condition of 90 ℃,20 m L water is added for quenching after the reaction is finished, the mixture is extracted by ethyl acetate (3 × 25m L), saturated sodium chloride (30m L) solution is washed, an organic layer is dried by anhydrous sodium sulfate, and decompression desolventization is carried out to obtain a crude product, silicon and oxygen are added into the crude productGel column purification (petroleum ether/ethyl acetate 10:1) afforded 289mg (63% yield) of compound 8 as a white powder.
7.9 Synthesis of 3- (4-boranophenyl) -4- (4-hydroxyphenyl) furan Compound
In a 100m L single-neck flask, magneton, compound 8(2.00g,4.52mmol), CH were weighed3COONH4(3.20g,15.02mmol) to which 40m L Acetone H was added2Adding NaIO in batches under ice bath by taking O as a solvent and taking 1:1 as a solvent4(1.16g,15.02mmol), then brought to normal temperature, reacted for 12h, quenched with 20m L water, extracted with ethyl acetate (3 × 15m L), washed with saturated sodium bicarbonate (15m L) solution, dried over anhydrous sodium sulfate of the organic layer, and desolventized under reduced pressure to give the crude product which was purified on silica gel column (petroleum ether/ethyl acetate 4:1) to give 1.407g (91% yield) of compound 9 as a pale yellow solid.
8. Synthesis of 3- (4-phenylselenophenyl) -4- (4-hydroxyphenyl) furan compound 10
Compound 9(1.41g,5.034mmol), diphenyl diselenide (0.780g,2.517mmol) and CuI (0.19g,1.01mmol) are weighed in a single-neck bottle of 100m L, dimethyl sulfoxide 20m L is added as a solvent, reaction is carried out at 100 ℃ for 28h, 20m L water is added after the reaction is finished, the reaction product is quenched, ethyl acetate (3 × 25m L) is used for extraction, a saturated sodium chloride (30m L) solution is washed, an organic layer is dried by anhydrous sodium sulfate, reduced pressure desolventization is carried out, a crude product is obtained, and silica gel column purification (petroleum ether/ethyl acetate 10:1) is carried out to obtain 1.709g (yield 86%) of white powdery solid compound 10.
Example 2 Synthesis of 3, 4-bis (4-hydroxyphenyl) -furan Compound 18
1. Synthesis of 2- (4-methoxyphenyl) -2-carbonylethyl-2- (4-methoxyphenyl) acetate 15
α -bromo-p-methoxyacetophenone 2(6.36g,27.76mmol) and p-methoxyphenylacetic acid 14(4.612g,20.82mmol) were weighed into a round-bottomed flask of 150m L, acetonitrile of 50m L was added, triethylamine (2.809g,27.26mmol) was added, the mixture was reacted at room temperature for 12 hours, the reaction was monitored by T L C for completion, the solvent was removed under reduced pressure, ethyl acetate (50m L) was added for dissolution, the mixture was washed with dilute hydrochloric acid (2N, 60m L), and the organic layer was washed with anhydrous Na2SO4Drying, removing solvent under reduced pressure to obtain crude productPurification by column chromatography (20: 1 petroleum ether/ethyl acetate) gave 8.289g (95% yield) of compound 15.
2. Synthesis of 3, 4-bis (4-methoxy-phenyl) furan-2-one Compound 16
After baking a 25m L two-necked flask and magneton at 105 ℃ for 15min, weighing compound 15(786.2mg,2.5mmol) under the protection of argon, adding 10m L of anhydrous dimethyl sulfoxide, slowly dropwise adding 80% NaH (150.1mg,5.0mmol), reacting at 25 ℃ for 2h, monitoring the reaction completion by T L C, adding 5m L2N hydrochloric acid to quench the reaction, extracting with ethyl acetate (3 × 25m L), drying the organic layer with anhydrous sodium sulfate, and removing the solution under reduced pressure to obtain a crude product, wherein 475.9mg (64.3% yield) of compound 16 is obtained by silica gel column purification (petroleum ether/ethyl acetate 9: 1).
3. Synthesis of 3, 4-bis (4-hydroxy-phenylfuran) -2-one Compound 17
Baking 100m L single-neck bottle and magneton at 105 deg.C for 15min, weighing compound 16(1.345g,4.56mmol) under argon protection, adding 25m L dichloromethane, adding BBr at-20 deg.C3(2.6m L, 27.33mmol) after 12h reaction, 10m L was added to quench the reaction with water, extracted with ethyl acetate (3 × 20m L), washed with saturated sodium bicarbonate (15m L) solution, the organic layer was dried over anhydrous sodium sulfate and desolventized under reduced pressure to give the crude product which was purified on silica gel column (petroleum ether/ethyl acetate 7:3) to give 1.06g (86.7% yield) of compound 17.
4. Synthesis of 3, 4-bis (4-hydroxy-phenyl) furan compound 18
After baking a 50M L single-neck flask and magnetons at 105 ℃ for 15min, weighing compound 17(560mg,1.98mmol) under the protection of argon, adding diisobutylaluminum hydride (1M DIBAL-H,8M L, 7.93mmol) at-78 ℃ for reaction for 12H, adding 4% sulfuric acid for quenching reaction, extracting with ethyl acetate (3 × 25M L), washing with saturated sodium chloride (30M L) solution, drying an organic layer with anhydrous sodium sulfate, and desolventizing under reduced pressure to obtain a crude product, and purifying with a silica gel column (petroleum ether/ethyl acetate ═ 6:4) to obtain 203.1mg (yield 40.7%) of compound 18.1H NMR(400MHz,CDCl3):7.41(s,2H),6.94(d,J＝8.4 Hz,2H),6.87(d,J＝8.8Hz,2H)。
Example 3 Synthesis of an ethylene sulfonate dienophile Compound 12a-u
General procedure for the Synthesis of Compound 12
Taking a 100m L single-mouth bottle, baking magnetons at 105 ℃ for 15min, heating, carrying out anhydrous and anaerobic operation, weighing corresponding compound 11 under the protection of argon, dissolving in anhydrous dichloromethane, slowly adding 2-chloroethanesulfonyl chloride (1.2equiv.) at 0 ℃, reacting for 10min, slowly dropwise adding anhydrous triethylamine, reacting at room temperature for 12h, carrying out decompression and desolventizing to obtain a crude product, and purifying by using a silica gel column (petroleum ether/ethyl acetate is 12: 1-3: 2) to obtain the ethylene sulfonate dienophile 12 (the yield is 61-93%).
Example 4 Synthesis of Phenylselenosulfonate dienophile derivatives
1. General method for synthesizing phenylselenophenol compound 20
Baking 100m L single-neck bottle at 105 deg.C for 15min, heating, anhydrous and oxygen-free, weighing corresponding compound diphenyl diselenide under protection of argon gas, dissolving in anhydrous methanol, and adding NaBH at 0 deg.C4(3equiv.) after reaction for 1h, the corresponding phenol compound (2equiv) was slowly added dropwise, after reaction for 24h at 40 ℃, water was slowly added under an ice-water bath to quench, extraction was performed with ethyl acetate (3 × 25m L), washing was performed with a saturated sodium chloride (30m L) solution, the organic layer was dried over anhydrous sodium sulfate, and desolventization was performed under reduced pressure to obtain a crude product, which was purified by a silica gel column (petroleum ether/ethyl acetate 1:2) to obtain compound 20 as a colorless oil (yield 83%).
2. General procedure for the Synthesis of sulfonate dienophile derivative Compound 21
Taking a 100m L single-mouth bottle, baking magnetons at 105 ℃ for 15min, then, immediately heating, carrying out anhydrous and anaerobic operation, weighing corresponding compound 20 under the protection of argon, dissolving in anhydrous dichloromethane, slowly adding 2-chloroethanesulfonyl chloride (1.2equiv.) at 0 ℃, reacting for 10min, slowly dropwise adding anhydrous triethylamine, reacting at room temperature for 12h, carrying out decompression and desolventizing to obtain a crude product, and purifying by using a silica gel column (petroleum ether/ethyl acetate is 12: 1-3: 2) to obtain the sulfonic acid ester dienophile 21 (the yield is 61-93%).
Example 5 preparation of compounds 13a and 13 b:
weighing 10(100mg,0.255mmol) of 3- (4- (phenylseleno) phenyl) -4- (4-hydroxyphenyl) furan compound and 65.56mg,0.306mmol of ethylene 4-methoxyphenyl sulfonate in a 25m L two-opening round-bottom bottle, adding 4m L anhydrous tetrahydrofuran for dissolution, slowly heating to 90 ℃, reacting for 8h, detecting that the reaction is complete by T L C, adding water for quenching, extracting by ethyl acetate, taking an organic layer, drying by anhydrous sodium sulfate, performing decompression and desolventization, separating and purifying by column chromatography, wherein the ratio of an eluent to the ethyl acetate is 6:1, obtaining 63.4mg of brown yellow solid 13a, the yield is 41%,1H NMR(400MHz,Acetone-d6)8.88(s,1H), 7.59-7.46 (m,2H), 7.41-7.34 (m,5H), 7.32-7.19 (m,4H), 7.17-7.12 (m,2H),6.86(dd, J ═ 11.7,8.9Hz,4H),5.68(d, J ═ 1.2Hz,1H), 5.46(dd, J ═ 4.2,1.2Hz,1H),3.78(s,3H),3.70(dd, J ═ 8.3,4.6Hz,1H), 2.47-2.38 (m,1H), 2.33(dd, J ═ 12.1,8.3Hz, 1H); 57.2mg of a brown solid 13b are simultaneously obtained, in a yield of 37%,1H NMR(400MHz,Acetone-d6)8.81(s,1H),7.56(dd,J＝6.6,2.9Hz,2H),7.37(dd,J＝6.4,2.8 Hz,4H),7.32–7.27(m,3H),7.23(d,J＝8.6Hz,2H),7.19(d,J＝9.1Hz,2H),6.92–6.86(m, 2H),6.82–6.76(m,2H),5.66(d,J＝1.2Hz,1H),5.47(dd,J＝4.5,1.2Hz,1H),3.84(dd,J＝8.4, 4.4Hz,1H),3.79(d,J＝5.8Hz,3H),2.38(s,1H),2.23(dd,J＝12.2,8.4Hz,1H).
[ example 6 ] preparation of Compounds 13c and 13d
Weighing 3- (4- (phenylseleno) phenyl) -4- (4-hydroxyphenyl) furan compound 10(100mg,0.255mmol) and ethylene 4-chlorophenylsulfonate (66.91mg,0.306mmol) in a 25m L round-bottomed bottle, adding 4m L anhydrous tetrahydrofuran for dissolution, slowly heating to 90 ℃, reacting for 8h, detecting that the reaction is complete at T L C, adding water for quenching, extracting with ethyl acetate, taking an organic layer, drying with anhydrous sodium sulfate, removing the solvent under reduced pressure, separating and purifying by column chromatography, wherein the eluent ratio is petroleum ether and ethyl acetate5:1, 62.2mg of a body brown solid 13c are obtained, yield 40%,1h NMR (400MHz, Chloroform-d)7.53(dd, J ═ 6.5,3.1Hz,2H), 7.40-7.27 (m,7H), 7.23-7.09 (m,6H), 6.82-6.72 (m,2H),5.98(s,1H),5.69(d, J ═ 1.2Hz,1H), 5.40(dd, J ═ 4.3,1.2Hz,1H),3.56(dd, J ═ 8.4,4.5Hz,1H),2.57(dt, J ═ 12.2,4.5Hz,1H),2.19(dd, J ═ 12.3,8.4Hz, 1H); 60.7mg of a pale yellow solid 13d are simultaneously obtained, with a yield of 49%,1H NMR(400MHz,Chloroform-d)7.56(dd,J＝6.5,3.0Hz, 2H),7.38–7.26(m,8H),7.15(dd,J＝8.3,4.9Hz,6H),6.76(d,J＝8.3Hz,2H),6.09 (s,1H),5.69(s,1H),5.42(d,J＝4.3Hz,1H),3.61(dd,J＝8.4,4.4Hz,1H),2.54(dt, J＝12.3,4.6Hz,1H),2.14(dd,J＝12.3,8.4Hz,1H).
example 7 preparation of compounds 13e and 13 f:
weighing 10(100mg,0.255mmol) of 3- (4- (phenylseleno) phenyl) -4- (4-hydroxyphenyl) furan compound and 80.51mg,0.306mmol of ethylene 4-bromophenyl sulfonate in a 25m L two-opening round-bottomed bottle, adding 4m L anhydrous tetrahydrofuran for dissolution, slowly heating to 90 ℃, reacting for 8h, detecting that the reaction is complete by T L C, adding water for quenching, extracting by ethyl acetate, taking an organic layer, drying by anhydrous sodium sulfate, performing decompression and desolventization, separating and purifying by column chromatography, wherein the ratio of an eluent to the ethyl acetate is 5:1, obtaining 73.37mg of dark brown solid 13e, the yield is 44%,1h NMR (400MHz, Chloroform-d)7.55(dd, J ═ 6.6,3.0Hz,2H), 7.50-7.43 (m,2H), 7.37-7.30 (m,5H),7.18(dd, J ═ 10.8,8.2Hz,4H), 7.13-7.07 (m,2H), 6.81(d, J ═ 8.3Hz,2H),5.71(s,1H),5.43(d, J ═ 4.3Hz,1H),3.58(dd, J ═ 8.4,4.5Hz,1H), 2.59(dt, J ═ 12.2,4.4Hz,1H),2.21(dd, J ═ 12.2,8.4Hz, 1H); 68.37mg of a yellowish brown solid 13f are obtained in the meantime, with a yield of 41%,1H NMR(400MHz,Chloroform-d) 7.61–7.44(m,5H),7.38–7.25(m,6H),7.21–7.10(m,4H),6.80(dd,J＝8.2,5.1 Hz,2H),5.77–5.58(m,1H),5.40(dd,J＝16.3,4.5Hz,1H),3.63(dd,J＝8.4,4.4 Hz,1H),2.57(dq,J＝12.4,4.6Hz,1H),2.16(dd,J＝12.3,8.4Hz,1H).
example 8 preparation of compound 13g and 13 h:
weighing 10(100mg,0.255mmol) of 3- (4- (phenylseleno) phenyl) -4- (4-hydroxyphenyl) furan compound and 60.66mg,0.306mmol of ethylene 4-methylphenyl sulfonate in a 25m L round-bottomed bottle, adding 4m L anhydrous tetrahydrofuran for dissolution, slowly heating to 90 ℃, reacting for 8 hours, detecting that the reaction is complete at T L C, adding water for quenching, extracting with ethyl acetate, taking an organic layer, drying with anhydrous sodium sulfate, carrying out decompression and desolventization, carrying out column chromatography separation and purification, wherein the eluent ratio of petroleum ether to ethyl acetate is 6:1, obtaining 13g of 63.14mg of earthy yellow solid, the yield is 42%,1h NMR (400MHz, Chloroform-d)7.55(dd, J ═ 6.5,3.0Hz,2H),7.34 (p, J ═ 5.4,4.5Hz,5H), 7.24-7.03 (m,8H),6.81(d, J ═ 8.6Hz,2H),5.73(d, J ═ 5.4 Hz,1H),5.42(d, J ═ 4.3Hz,1H),3.58(dd, J ═ 8.4,4.4Hz,1H),2.60(dt, J ═ 12.2, 4.6Hz,1H),2.34(s,3H),2.19(dd, J ═ 12.2,8.4, 1H); at the same time, 68.13mg of a light brown solid was obtained in a yield of 40% for 13h,1H NMR(400MHz,Chloroform-d)7.58(dt,J＝7.3, 3.9Hz,2H),7.39–7.30(m,5H),7.20–7.10(m,8H),6.79(d,J＝8.3Hz,2H),5.71 (s,1H),5.43(d,J＝4.4Hz,1H).
example 9 preparation of compound 13 i:
weighing 10(100mg,0.255mmol) of 3- (4- (phenylseleno) phenyl) -4- (4-hydroxyphenyl) furan compound and 61.26mg,0.306mmol of ethylene 4-hydroxyphenyl sulfonate in 25m L round-bottomed bottles, adding 4m L anhydrous tetrahydrofuran for dissolution, slowly heating to 90 ℃, reacting for 8h, detecting that the reaction is complete at T L C, adding water for quenching, extracting with ethyl acetate, taking an organic layer, drying with anhydrous sodium sulfate, carrying out decompression and desolventization, carrying out column chromatography separation and purification, wherein the eluent ratio of petroleum ether to ethyl acetate is 3:1, obtaining 84.47mg of light gray solid 13i respectively, the yield is 56%,1H NMR(400MHz,Acetone-d6)8.80(s,1H),8.71(s,1H),7.62–7.51 (m,2H),7.46–7.35(m,5H),7.35–7.25(m,4H),7.10–7.02(m,2H),6.91–6.82 (m,2H),6.82–6.74(m,2H),5.69(d,J＝1.2Hz,1H),5.47(dd,J＝4.3,1.2Hz,1H), 3.71(dd,J＝8.3,4.6Hz,1H),2.43(dt,J＝12.1,4.5Hz,1H),2.34(dd,J＝12.1,8.3Hz,1H)。
example 10 preparation of compounds 13j and 13 k:
weighing 10(100mg,0.255mmol) of 3- (4- (phenylseleno) phenyl) -4- (4-hydroxyphenyl) furan compound and 77.17mg,0.306mmol of ethylene 4-trifluoromethylphenyl sulfonate in a 25m L round-bottomed bottle, adding 4m L anhydrous tetrahydrofuran for dissolution, slowly heating to 90 ℃, reacting for 8h, detecting that the reaction is complete at T L C, adding water for quenching, extracting with ethyl acetate, taking an organic layer, drying with anhydrous sodium sulfate, performing decompression and desolventization, separating and purifying by column chromatography, wherein the eluent ratio of petroleum ether to ethyl acetate is 5:1, obtaining 68.92mg of dark brown solid 13j, the yield is 42%,1h NMR (400MHz, Chloroform-d)7.65(d, J ═ 8.4Hz,2H),7.56 (dd, J ═ 6.5,2.9Hz,2H), 7.43-7.30 (m,7H), 7.24-7.12 (m,4H),6.81(d, J ═ 8.5Hz, 2H),5.74(s,1H),5.44(d, J ═ 4.2Hz,1H),3.62(dd, J ═ 8.4,4.4Hz,1H),2.61(dt, J ═ 12.2,4.5Hz,1H),2.24(dd, J ═ 12.3,8.5Hz, 1H); 64.0mg of 13k are simultaneously obtained as a dark gray solid in a yield of 39%,1H NMR(400MHz,Chloroform-d)7.66(d,J＝8.4Hz, 2H),7.58(dd,J＝7.0,2.8Hz,2H),7.48–7.30(m,7H),7.25–7.13(m,4H),6.80(d, J＝8.2Hz,2H),5.73(s,1H),5.46(d,J＝4.4Hz,1H),3.67(dd,J＝8.4,4.4Hz,1H), 2.59(dt,J＝12.4,4.5Hz,1H),2.19(dd,J＝12.3,8.4Hz,1H).
example 11 preparation of compound 13 l:
weighing 3- (4- (phenylseleno) phenyl) -4- (4-hydroxyphenyl) furan compound 10(100mg,0.255mmol) and ethylene 3-methoxyphenyl sulfonate (65.56mg,0.306mmol), placing in a 25m L two-mouth round-bottom bottle, adding 4m L anhydrous tetrahydrofuran for dissolution, slowly heating to 90 ℃, and reactingAnd (3) detecting that the reaction is complete by T L C, adding water for quenching, extracting by ethyl acetate, taking an organic layer, drying by anhydrous sodium sulfate, performing decompression and desolventizing, and performing column chromatography separation and purification, wherein the eluent ratio is petroleum ether and ethyl acetate is 6:1, so that 94.19mg of light yellow solid 13l is obtained, and the yield is 61%.1H NMR(400MHz,Chloroform-d)7.55(dd,J＝6.5,3.0Hz,2H),7.39 –7.27(m,5H),7.18(t,J＝9.0Hz,4H),6.81(ddd,J＝12.8,8.5,5.5Hz,6H),5.74(d, J＝7.6Hz,1H),5.42(d,J＝4.3Hz,1H),3.78(s,3H),3.60(dd,J＝8.4,4.5Hz,1H), 2.61(dt,J＝12.3,4.4Hz,1H),2.20(dd,J＝12.3,8.3Hz,1H).
Example 12 preparation of compound 13 m:
weighing 10(100mg,0.255mmol) of a 3- (4- (phenylseleno) phenyl) -4- (4-hydroxyphenyl) furan compound and 60.66mg,0.306mmol of ethylene 3-methylphenyl sulfonate in a 25m L round-bottomed bottle, adding 4m L anhydrous tetrahydrofuran for dissolution, slowly heating to 90 ℃, reacting for 8 hours, detecting that the reaction is complete at T L C, adding water for quenching, extracting with ethyl acetate, taking an organic layer, drying with anhydrous sodium sulfate, performing decompression and desolventization, and performing column chromatography separation and purification, wherein the eluent ratio of petroleum ether to ethyl acetate is 6:1, so that 102.23mg of pale yellow solid 13m is obtained, and the yield is 68%.1H NMR(400MHz,Chloroform-d)7.62–7.50(m,3H),7.43–7.25(m, 5H),7.19–7.13(m,3H),7.14–6.94(m,4H),6.81(dd,J＝9.0,6.6Hz,2H),5.78– 5.63(m,1H),5.53–5.39(m,1H),3.62(ddd,J＝12.5,8.4,4.5Hz,1H),2.58(dq,J＝ 12.2,3.9,3.4Hz,1H),2.36–2.29(m,3H),2.15(dd,J＝12.2,8.5Hz,1H).
Example 13 preparation of compound 13 n:
weighing 3- (4- (phenylseleno) phenyl) -4- (4-hydroxyphenyl) furan compound 10(100mg,0.255mmol) and ethylene 3-trifluoromethylphenylsulfonate (77.17mg,0.306mmol), placing in a 25m L two-neck round-bottom bottle, adding 4m L anhydrous tetrahydrofuran to assist dissolution, and slowly addingHeating to 90 ℃, reacting for 8h, detecting complete reaction by T L C, adding water for quenching, extracting by ethyl acetate, taking an organic layer, drying by anhydrous sodium sulfate, decompressing, desolventizing, and separating and purifying by column chromatography, wherein the eluent ratio is petroleum ether and ethyl acetate is 5:1, so that 101.74mg of dark brown solid 13n is obtained, and the yield is 62%.1H NMR(400MHz,Chloroform-d)7.64–7.50(m,6H),7.35(dt, J＝5.2,2.8Hz,5H),7.19(dd,J＝8.5,2.6Hz,4H),6.86–6.77(m,2H),5.75(s,1H), 5.46(d,J＝4.4Hz,1H),3.71(dd,J＝8.3,4.4Hz,1H),2.60(dt,J＝12.3,4.5Hz,1H), 2.20(dd,J＝12.3,8.4Hz,1H).
Example 14 preparation of compound 13 o:
weighing 3- (4- (phenylselenyl) phenyl) -4- (4-hydroxyphenyl) furan compound 10(100mg,0.255mmol) and ethylene 3-chlorophenylsulfonate (66.91mg,0.306mmol) in a 25m L round-bottomed bottle, adding 4m L anhydrous tetrahydrofuran for assisting dissolution, slowly raising the temperature to 90 ℃, reacting for 8 hours, detecting that the reaction is complete by T L C, adding water for quenching, extracting by ethyl acetate, taking an organic layer, drying by anhydrous sodium sulfate, performing decompression and desolvation, and performing column chromatography separation and purification, wherein the eluent ratio of petroleum ether to ethyl acetate is 5:1, so as to obtain 105.77mg of dark brown solid 13o with the yield of 68%.1H NMR(400MHz,Chloroform-d)7.66–7.51(m,3H),7.32(ddd,J＝19.0,6.8,2.8Hz,8H),7.18(dd,J＝8.4,3.5Hz,4H),6.80(d,J＝8.4Hz,2H),5.72(s, 1H),5.44(d,J＝4.4Hz,1H),3.66(dd,J＝8.4,4.4Hz,1H),2.58(dt,J＝12.4,4.5Hz, 1H),2.18(dd,J＝12.4,8.4Hz,1H).
Example 15 preparation of compound 13 p:
weighing 3- (4- (phenylseleno) phenyl) -4- (4-hydroxyphenyl) furan compound 10(100mg,0.255mmol) and ethylene 3-hydroxyphenyl sulfonate (61.26mg,0.306mmol), placing in a 25m L round-bottomed bottle, adding 4m L anhydrous tetrahydrofuran for dissolution, slowly heating to 90 ℃, reacting for 8h, and detecting the completion of the reaction by T L CQuenching with water, extracting with ethyl acetate, collecting organic layer, and drying with anhydrous sodium sulfate. The mixture was desolventized under reduced pressure and purified by column chromatography using petroleum ether and ethyl acetate at a ratio of 3:1 to give 82.96mg of 13p as a light brown solid in 55% yield.1H NMR(400MHz,Acetone-d6)8.92(s,1H),8.80(s,1H),7.55(dd,J ＝6.6,3.0Hz,2H),7.45–7.34(m,5H),7.32(d,J＝8.3Hz,2H),7.29–7.21(m,2H), 7.18(t,J＝8.5Hz,1H),6.91–6.77(m,4H),6.75–6.67(m,1H),5.70(d,J＝1.2Hz,1H),5.48(dd,J＝4.3,1.2Hz,1H),3.78(dd,J＝8.3,4.5Hz,1H),2.46(dt,J＝12.2, 4.5Hz,1H),2.35(dd,J＝12.2,8.3Hz,1H).
Example 16 preparation of compound 13 q:
weighing 10(100mg,0.255mmol) of a 3- (4- (phenylseleno) phenyl) -4- (4-hydroxyphenyl) furan compound and 80.51mg,0.306mmol of ethylene 3-bromophenyl sulfonate in a 25m L two-opening round-bottom bottle, adding 4m L anhydrous tetrahydrofuran for dissolution assistance, slowly heating to 90 ℃, reacting for 8h, detecting that the reaction is complete by T L C, adding water for quenching, extracting by ethyl acetate, taking an organic layer, drying by anhydrous sodium sulfate, performing decompression and desolventization, separating and purifying by column chromatography, wherein the ratio of an eluent to the ethyl acetate is petroleum ether and 5:1, and respectively obtaining 106.80mg of light gray solid 13q with the yield of 64%.1H NMR(400MHz,Chloroform-d)7.57(dt,J＝6.8,2.3Hz,2H), 7.45(dd,J＝6.8,1.9Hz,2H),7.40–7.30(m,5H),7.30–7.15(m,6H),6.85–6.75 (m,2H),5.72(d,J＝1.2Hz,1H),5.45(dd,J＝4.4,1.2Hz,1H),3.65(dd,J＝8.4,4.4 Hz,1H),2.58(dt,J＝12.3,4.5Hz,1H),2.18(dd,J＝12.3,8.4Hz,1H).
Example 17 preparation of compounds 13r and 13 s:
3- (4- (phenylseleno) phenyl) -4- (4-hydroxyphenyl) furan compound 10(100mg,0.255mmol) and ethylene 1-naphthol sulfonate (71.68mg,0.306mmol) were weighed into a 25m L two-necked flask, and 4m L was addedDissolving with anhydrous tetrahydrofuran, slowly heating to 90 deg.C, reacting for 8 hr, detecting with T L C to complete reaction, adding water, quenching, extracting with ethyl acetate, collecting organic layer, drying with anhydrous sodium sulfate, desolventizing under reduced pressure, separating and purifying by column chromatography to obtain 65.40mg light gray solid 13r with yield of 41%,1h NMR (400MHz, Chloroform-d) 8.17-8.04 (m,1H), 7.90-7.80 (m,1H),7.76 (d, J ═ 8.2Hz,1H), 7.61-7.44 (m,6H),7.31(d, J ═ 9.0Hz,5H),7.14(dd, J ═ 8.2,5.7Hz,4H), 6.72(d, J ═ 8.4Hz,2H),6.09(s,1H),5.82(s,1H),5.44(d, J ═ 4.3Hz,1H),3.77(dd, J ═ 8.4,4.4Hz,1H), 2.71(dt, J ═ 12.3,4.5, 1H),2.23(dd, J ═ 8.4, 4Hz, 1H); 62.22mg of a dark gray solid were simultaneously obtained in a yield of 39%,1H NMR(400MHz,Chloroform-d)8.18–8.08(m, 1H),7.89–7.82(m,1H),7.77(d,J＝8.2Hz,1H),7.59–7.46(m,6H),7.32(dd,J＝5.1,1.8Hz, 3H),7.24(s,2H),7.13(dd,J＝15.2,8.3Hz,4H),6.81–6.70(m,2H),5.79(s,1H),5.44(d,J＝ 4.3Hz,1H).
example 18 preparation of compound 22 a:
weighing 18(100mg,0.396mmol) of a 3, 4-dihydroxyphenyl furan compound and 161.50mg,0.476mmol of ethylene 4-phenylselenopulfonate, placing the mixture in a 25m L round-bottomed bottle, adding 5m L anhydrous tetrahydrofuran for dissolving, slowly heating to 90 ℃, reacting for 8 hours, detecting that the reaction is complete by T L C, adding water for quenching, extracting by ethyl acetate, taking an organic layer, drying by anhydrous sodium sulfate, carrying out decompression and desolventization, carrying out column chromatography separation and purification, wherein the eluent ratio is petroleum ether and ethyl acetate is 3:1, and 168.65mg of yellow solid 22a is obtained, and the yield is 72%.1H NMR (400MHz,Acetone-d6)8.67(s,2H),7.53(dd,J＝6.5,3.1Hz,2H),7.50–7.45(m, 2H),7.41–7.35(m,3H),7.24(dd,J＝8.7,3.0Hz,6H),6.82(t,J＝8.6Hz,4H),5.65 (d,J＝1.2Hz,1H),5.45(d,J＝4.3Hz,1H),3.81(dd,J＝8.3,4.5Hz,1H),2.42(dt,J ＝12.1,4.4Hz,1H),2.29(dd,J＝12.1,8.3Hz,1H).
Example 19 preparation of compound 22 b:
weighing 18(100mg,0.396mmol) of the 3, 4-dihydroxyphenyl furan compound and 161.50mg,0.476mmol of the ethylene 3-phenylselenopropane sulfonate, placing the materials in a 25m L round-bottomed bottle, adding 5m L anhydrous tetrahydrofuran for dissolving, slowly heating to 90 ℃, reacting for 8 hours, detecting that the reaction is complete by T L C, adding water for quenching, extracting by ethyl acetate, taking an organic layer, drying by anhydrous sodium sulfate, performing decompression and desolventization, separating and purifying by column chromatography, wherein the eluent ratio is petroleum ether and ethyl acetate is 3:1, and 163.97mg of dark brown solid 22b is obtained, and the yield is 70%.1H NMR (400MHz,Acetone-d6)9.21(d,J＝4.9Hz,2H),7.18–7.02(m,2H),6.89(ddd,J＝ 10.4,4.7,2.8Hz,6H),6.73(dq,J＝5.1,3.2,2.8Hz,5H),6.34–6.30(m,4H),5.19(d, J＝1.2Hz,1H),4.96(d,J＝4.3Hz,1H),3.58(q,J＝7.1Hz,1H),3.37(dd,J＝8.3,4.3Hz,1H),1.80(dt,J＝12.1,4.5Hz,1H).
[ example 20 ] relative affinity assay of Compounds
The affinity of the target compound to ER α and ER β was determined by fluorescence polarization, the affinity of the compound being endogenous E2Relative value of affinity, set E2The value of affinity to the receptor, RBA, was 100%. in a 384 well plate, 20 μ L of 0.8 μ M ER α or ER β protein, 150nM fluorescent ligand and 2.4 μ g bovine immunoglobulin in potassium phosphate buffer were added, followed by 20 μ L of the target compound solution, with a compound concentration gradient of 3.16 × 10-4M,1×10-4M,3.16×10-5M,1×10-5M,3.16×10-6M,1×10-6M, 3.16×10-7M,1×10-7M,3.16×10-8M,1×10-8M,3.16×10-9And M. Placing the plate at room temperature in a dark place for 2 hours, reading the plate on an enzyme labeling instrument, selecting a wavelength at 485nm as a main wavelength and a wavelength at 528nm as a reference wavelength, analyzing an experimental result, and determining the receptor affinity RBA (RBA) as a test substance K according to a formulaiEstradiol Ki× 100 RBA values were calculated for each compound.
From the results in table 1, it was found that these conjugates of PhSe-OBHS all exhibited better ER affinity and most ER α selectivity, with compounds 13m and 13n having the highest relative binding capacity with RBA values of 6.62% and 6.39%, respectively, and with ER α/ER β having the highest selectivity of 20.79(13d), and that the substituents at the 4-position of the benzene ring of benzenesulfonate had a greater effect on affinity, and the bulkier naphthalene compounds (13r,13s) had significantly lower affinity than the other compounds, indicating that it is likely that the receptor would not bind well with bulkier groups.
TABLE 1 relative affinities of PhSe-OBHS conjugates for ER α and ER β
[ example 21 ] antitumor Activity test of Compound
MCF-7 cells are cultured in a DMEM liquid culture medium containing 10% fetal calf serum, when the cell density reaches 80% -90%, the cells are digested, and a cell suspension is paved into a 96-well cell culture plate by using a phenol red-free DMEM culture medium containing 10% CS, after the cells are completely attached to the wall, original culture solution is discarded, 100 mu L of fresh compound solution prepared by the DMEM liquid culture medium containing 10% CS is added into each well, and the compound concentration gradient is 1 × 10-6M,5×10-5M,1×10-5M,5×10-4M,1×10-4M. after 3 days of drug treatment, the plates were removed and 20. mu. L5 mg/m L MTT medium was added to each well and placed at 37 ℃ in 5% CO2Incubating for 4 hours in an incubator, absorbing liquid in each hole, adding 100 mu L dimethyl sulfoxide (DMSO) into each hole, placing on a micro stirrer, shaking for 10-15 minutes to fully dissolve crystals, reading a plate on an enzyme-linked immunosorbent assay (ELISA) instrument, selecting a wavelength at 490nm as a dominant wavelength and a wavelength at 630nm as a reference wavelength, analyzing an experiment result, and calculating IC (integrated circuit)50。
TABLE 2 antitumor Activity results (IC) of PhSe-OBHS conjugates50,μM)
Discussion of the results:
according to the results of biological activity tests, the conjugates of PhSe-OBHS all showed better ER affinity and most of ER α selectivity, wherein the relative binding force of compounds 13m and 13n is the highest, and the RBA value is 6.62% and 6.39%, respectively, in vitro cell inhibition experiments, all compounds except compound 22a showed stronger anti-breast cancer activity than 4OHT, and when the substituents are the same, the compound with the para-position substituent showed stronger anti-breast cancer activity, wherein the best activity is compound 13i, and IC of the compound is IC α502.08. mu.M is achieved, probably because para-hydroxyl can be used as a hydrogen bond donor, and simultaneously, the polarity and charge distribution of the molecule can be effectively changed, so that the biological activity of the molecule is improved. The results prove that the introduction of the benzene selenium group can improve the anticancer activity of the compound, and provide a certain basis for the subsequent optimization design of OBHS series breast cancer resistant small molecular compounds.
Claims (5)
1. A selective estrogen receptor modulator containing a phenylselenium group is characterized by having a structure shown in the following formula I or formula II:
wherein the content of the first and second substances,
r is 4-OCH3, 4-CH3, 4-Cl, 4-OH, 4-CF3, 4-Br, 3-OCH3, 3-CH3, 3-Cl, 3-OH, 3-CF3, 3-Br, or,
2. The selective estrogen receptor modulator containing a phenylselenium group according to claim 1, which is in particular:
5- (4-hydroxyphenyl) -6- (4-phenylselenophenyl) -7-oxobicyclo [2.2.1] -5-heptene-3-sulfonic acid- (4-methoxyphenyl) ester (13 a);
5- (4-hydroxyphenyl) -6- (4-phenylselenophenyl) -7-oxobicyclo [2.2.1] -5-heptene-2-sulfonic acid- (4-methoxyphenyl) ester (13 b);
5- (4-hydroxyphenyl) -6- (4-phenylselenophenyl) -7-oxobicyclo [2.2.1] -5-heptene-3-sulfonic acid- (4-chlorophenyl) ester (13 c);
5- (4-hydroxyphenyl) -6- (4-phenylselenophenyl) -7-oxobicyclo [2.2.1] -5-heptene-2-sulfonic acid- (4-chlorophenyl) ester (13 d);
5- (4-hydroxyphenyl) -6- (4-phenylselenophenyl) -7-oxobicyclo [2.2.1] -5-heptene-3-sulfonic acid- (4-bromophenyl) ester (13 e);
5- (4-hydroxyphenyl) -6- (4-phenylselenophenyl) -7-oxobicyclo [2.2.1] -5-heptene-2-sulfonic acid- (4-bromophenyl) ester (13 f);
5- (4-hydroxyphenyl) -6- (4-phenylselenophenyl) -7-oxobicyclo [2.2.1] -5-heptene-3-sulfonic acid- (4-methylphenyl) ester (13 g);
5- (4-hydroxyphenyl) -6- (4-phenylselenophenyl) -7-oxabicyclo [2.2.1] -5-heptene-2-sulfonic acid- (4-methylphenyl) ester (13 h);
5- (4-hydroxyphenyl) -6- (4-phenylselenophenyl) -7-oxobicyclo [2.2.1] -5-heptene-3-sulfonic acid- (4-hydroxyphenyl) ester (13 i);
5- (4-hydroxyphenyl) -6- (4-phenylselenophenyl) -7-oxobicyclo [2.2.1] -5-heptene-3-sulfonic acid- (4-trifluoromethylphenyl) ester (13 j);
5- (4-hydroxyphenyl) -6- (4-phenylselenophenyl) -7-oxobicyclo [2.2.1] -5-heptene-2-sulfonic acid- (4-trifluoromethylphenyl) ester (13 k);
5- (4-hydroxyphenyl) -6- (4-phenylselenophenyl) -7-oxobicyclo [2.2.1] -5-heptene-2-sulfonic acid- (3-methoxyphenyl) ester (13 l);
5- (4-hydroxyphenyl) -6- (4-phenylselenophenyl) -7-oxobicyclo [2.2.1] -5-heptene-2-sulfonic acid- (3-methylphenyl) ester (13 m);
5- (4-hydroxyphenyl) -6- (4-phenylselenophenyl) -7-oxabicyclo [2.2.1] -5-heptene-2-sulfonic acid- (3-methoxyphenyl) ester (13 n);
5- (4-hydroxyphenyl) -6- (4-phenylselenophenyl) -7-oxabicyclo [2.2.1] -5-heptene-2-sulfonic acid- (3-chlorophenyl) ester (13 o);
5- (4-hydroxyphenyl) -6- (4-phenylselenophenyl) -7-oxobicyclo [2.2.1] -5-heptene-3-sulfonic acid- (3-hydroxyphenyl) ester (13 p);
5- (4-hydroxyphenyl) -6- (4-phenylselenophenyl) -7-oxabicyclo [2.2.1] -5-heptene-2-sulfonic acid- (3-bromophenyl) ester (13 q);
5- (4-hydroxyphenyl) -6- (4-phenylselenophenyl) -7-oxobicyclo [2.2.1] -5-heptene-3-sulfonic acid- (1-naphthol) ester (13 r);
5- (4-hydroxyphenyl) -6- (4-phenylselenophenyl) -7-oxobicyclo [2.2.1] -5-heptene-2-sulfonic acid- (1-naphthol) -ester (13 s);
5, 6-bis (4-hydroxyphenyl) -7-oxobicyclo [2.2.1] -5-heptene-2-sulfonic acid- (4-phenylselenophenyl) ester (22 a);
5, 6-bis (4-hydroxyphenyl) -7-oxido-bicyclo [2.2.1] -5-heptene-2-sulfonic acid- (3-phenylselenophenyl) ester (22 b).
3. Use of a selective estrogen receptor modulator containing a phenylselenium group of claim 1 or 2 in the manufacture of a medicament for the treatment of breast cancer.
4. A pharmaceutical composition for treating breast cancer, comprising the phenylselenium-containing selective estrogen receptor modulator of claim 1 or 2 and one or more pharmaceutically acceptable auxiliary agents.
5. The use of the anti-breast cancer pharmaceutical composition of claim 4 in the preparation of an anti-breast cancer medicament.
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