CN111018686A - 6-benzylidene-2-aryl ethynyl cyclohexenone derivative and preparation method and medical application thereof - Google Patents

6-benzylidene-2-aryl ethynyl cyclohexenone derivative and preparation method and medical application thereof Download PDF

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CN111018686A
CN111018686A CN201911132955.1A CN201911132955A CN111018686A CN 111018686 A CN111018686 A CN 111018686A CN 201911132955 A CN201911132955 A CN 201911132955A CN 111018686 A CN111018686 A CN 111018686A
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凌勇
缪捷飞
凌长春
刘昕
李洋阳
钱建强
孟迟
谢旭东
吴红梅
张逸蓉
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Abstract

The invention discloses a 6-benzylidene-2-arylethynyl cyclohexenone derivative, a pharmaceutically acceptable salt thereof, a preparation method, a medicinal composition containing the derivative and medicinal application thereof, in particular application in preparing medicaments for treating malignant tumors. The compound has certain tumor selectivity, can obviously inhibit tumor proliferation, and has weak inhibition effect on normal cells. The compound can obviously inhibit the activity of the TrxR target spot and induce the increase of the ROS level in tumor cells, thereby promoting the antitumor activity of the compound.

Description

6-benzylidene-2-aryl ethynyl cyclohexenone derivative and preparation method and medical application thereof
Technical Field
The invention relates to the field of medicines, in particular to 6-benzylidene-2-arylethynylcyclohexenone derivatives and pharmaceutically acceptable salts thereof, a preparation method thereof, a medicinal composition containing the derivatives and medicinal application thereof, and especially application thereof in preparing medicaments for treating malignant tumors.
Background
Tumors are second only to cardiovascular diseases the second leading cause of death in humans. Although various anti-tumor drugs can be clinically used, the existing drugs can not meet the treatment requirements due to factors such as complexity of tumor etiology, drug resistance of tumors, toxic and side effects of the anti-tumor drugs and the like. Therefore, the search for a novel antitumor drug with high drug effect, strong targeting property and small toxic and side effects is of great significance.
α -unsaturated ketone can interact with nucleophilic groups of biomacromolecules with high tumor expression (such as sulfydryl of cysteine residues), regulate proliferation in tumor cells and transfer various signal paths to play an anti-tumor role.
Disclosure of Invention
According to the invention, in order to further improve the antitumor activity and enzyme inhibition activity of the benzyl subunit cyclohexenone derivative, an aryl acetylene group is introduced at a proper position on the basis of activity α -unsaturated ketone according to the structure-activity relationship of PL and the derivative thereof to form a brand-new cyclohexenone dominant skeleton, and a series of novel 6-benzyl subunit-2-aryl ethynyl cyclohexenone derivatives with tumor cell ROS level induction and target TrxR targeting are designed and synthesized.
The invention aims to provide a novel 6-benzylidene-2-aryl ethynyl cyclohexenone derivative, and a preparation method and medical application thereof.
The specific technical scheme of the invention is as follows:
a6-benzylidene-2-arylethynylcyclohexenone derivative having the following general formula I:
Figure BDA0002278541030000021
wherein, R and R 'are the same or different and respectively represent one or more substituent groups on the corresponding substituted benzene ring, and are selected from one or more of H, halogen group, hydroxyl, amino, nitro, alkyl, halogenated alkyl, alkoxy, halogenated alkoxy and alkylamino, and when R or R' represent a plurality of substituent groups, all the substituent groups are the same or different.
Preferably, R and R 'are the same or different and respectively represent one or more substituents on the corresponding substituted benzene ring, and are selected from one or more of H, halogen group, hydroxyl, amine group, nitro, C1-C6 alkyl, C1-C6 halogenated alkyl, C1-C6 alkoxy, C1-C6 halogenated alkoxy and C1-C6 alkylamino, and when R or R' represent a plurality of substituents, all the substituents are the same or different.
Preferably, R and R 'are the same or different and each represents one or more substituents on the corresponding substituted benzene ring, and is selected from one or more of H, F, Cl, Br, I, hydroxyl, amino, nitro, methyl, ethyl, propyl, isopropyl, trifluoromethyl, pentafluoroethyl, trichloromethyl, tribromomethyl, methoxy, ethoxy, trifluoromethoxy, trichloromethoxy, tribromomethoxy, methylamino, ethylamino and methylethylamino, and when R or R' represent multiple substituents, each substituent is the same or different.
Preferably, R 'represents one or more substituents on the phenyl ring selected from H, F, Cl, Br, and when R' represents a plurality of substituents, each substituent may be the same or different.
Preferably, R represents one or more substituents on a benzene ring and is selected from one or more of H, a halogen group, nitro, methyl, trifluoromethyl, methoxy, trifluoromethoxy and methylamino; r' represents a halogen group.
The code numbers of the preferred compounds of the general structural formula I and the corresponding structures are shown in Table 1:
table 1 partial compound symbols of general formula i and corresponding structures
Figure BDA0002278541030000022
Figure BDA0002278541030000031
Another object of the present invention is to provide a method for preparing a derivative of 6-benzylidene-2-arylethynylcyclohexenone according to the general formula I of the present invention, which comprises the following steps:
(1) r-substituted benzaldehydes are reacted with cyclohexen-2-ones by Adol condensation (preferably on TiCl)4And PPh3Under the catalysis of) to obtain a compound 3, wherein R represents one or more substituent groups on a benzene ring and is selected from one or more of H, halogen groups, hydroxyl, amino, nitro, alkyl, halogenated alkyl, alkoxy, halogenated alkoxy and alkylamino, and when R represents a plurality of substituent groups, all the substituent groups are the same or different;
Figure BDA0002278541030000032
(2) compound 3 is reacted with elemental iodine (preferably CCl)4Py ═ 1:1 in a mixed solvent) to give compound 4;
Figure BDA0002278541030000033
(3) compound 4 is reacted with R' substituted phenylacetylene by Sonogashira coupling reaction (preferably in Pd (PPh)3)4And N, N-Diisopropylethylamine (DIPEA) to obtain a 6-benzylidene-2-arylethynylcyclohexenone derivative, wherein R 'represents one or more substituents on a benzene ring and is selected from one or more of H, a halogen group, hydroxyl, amino, nitro, alkyl, haloalkyl, alkoxy, haloalkoxy and alkylamino, and when R' represents a plurality of substituents, all the substituents are the same or different;
Figure BDA0002278541030000041
the specific synthetic route is as follows:
Figure BDA0002278541030000042
preferably, R represents one or more substituents on a benzene ring and is selected from one or more of H, a halogen group, nitro, methyl, trifluoromethyl, methoxy, trifluoromethoxy and methylamino; r' represents a halogen group.
The invention also aims to provide a pharmaceutical composition which comprises the 6-benzylidene-2-arylethynylcyclohexenone derivative or pharmaceutically acceptable salt thereof. Furthermore, the compound can be composed of a therapeutically effective dose of the compound of the general formula I or the pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or auxiliary material.
The invention also aims to provide application of the 6-benzylidene-2-arylethynylcyclohexenone derivative or pharmaceutically acceptable salt thereof in preparation of drugs with thioredoxin oxidoreductase inhibitory activity. The drug having thioredoxin oxidoreductase inhibitory activity is a drug for preventing and/or treating cancer. The cancer is liver cancer, prostatic cancer, colon cancer, gastric cancer or lung cancer, etc.
The compounds of the invention may be formulated for administration either alone or in combination with one or more pharmaceutically acceptable carriers. For example, solvents, diluents, and the like, may be administered in oral dosage forms such as tablets, capsules, dispersible powders, granules, and the like. The various dosage forms of the pharmaceutical compositions of the present invention may be prepared according to methods well known in the pharmaceutical art. Such pharmaceutical formulations may contain, for example, from 0.05% to 90% by weight of the active ingredient, more usually between about 15% and 60% by weight of the active ingredient, in combination with a carrier. The dosage of the compound can be 0.005-5000 mg/kg/day, and the dosage can be beyond the dosage range according to the severity of diseases or different dosage forms.
The compounds of the invention may be used in combination with other antineoplastic agents, for example alkylating agents (such as cyclophosphamide or cisplatin), antimetabolites (such as 5-fluorouracil or hydroxyurea), topoisomerase inhibitors (such as camptothecin), mitotic inhibitors (such as paclitaxel or vinblastine), DNA intercalating agents (such as doxorubicin), and in addition in combination with radiotherapy. These other antineoplastic agents or radiation therapy may be administered simultaneously or at different times than the compounds of the present invention. These combination therapies may produce a synergistic effect that helps improve the therapeutic effect.
The invention has the advantages that:
according to the structure-activity relationship of a natural product piperlongumine and a derivative thereof, on the basis of an active fragment α -unsaturated ketone, an arylacetylene group is introduced at a proper position by utilizing the framework transition and splicing principle of an active structure to form a brand-new cyclohexenone dominant framework, and a series of novel 6-benzyl subunit-2-arylethynyl cyclohexenone derivatives with the functions of inducing the ROS level of tumor cells and targeting TrxR are designed and synthesized.
Detailed Description
To further illustrate the present invention, a series of examples are given below, which are purely illustrative and are intended to be a detailed description of the invention only and should not be understood as limiting the invention.
Example 1(E) -6-styrylidene-2- ((2-fluorophenyl) ethynyl) cyclohex-2-enone (I)1) Preparation of
(E) -6-styrylidene-cyclohex-2-enone (3a)
The starting cyclohexen-2-one (0.95g,10.0mmol) was dissolved in 15ml of anhydrous dichloromethane and 200mg of TiCl was added at-50 deg.C4And PPh3(2.62g,10.0mmol), benzaldehyde (2.12g,20.0mmol) was added after 15min, and the reaction was allowed to proceed overnight at room temperature. After the reaction is completed, 10% K is added2CO3The solution was treated for 10min, the organic layer was collected, concentrated in vacuo and purified by column chromatography to give 1.69g of solid 3a, yield: 79 percent. MS (ESI) M/z 185[ M + H ]]+.
(E) -2-iodo-6-styrylidene-cyclohex-2-enone (4a)
Compound 3a (0.37g,2.0mmol) was dissolved in 16ml CCl4And pyridine 1:1 at room temperatureAdd iodine (1.01g,4.0mmol) and stir for 3h in the dark. After the reaction was complete, 80ml of saturated NH were added4The mixture was extracted with ethyl acetate (3X 40ml), and the organic layer was washed with saturated sodium thiosulfate and then with anhydrous MgSO4After drying, concentration and purification by column chromatography, the solid product 4a 0.76g is obtained, yield: 95 percent. MS (ESI) M/z 311[ M + H ]]+.
(E) -6-styrenyl-2- ((2-fluorophenyl) ethynyl) cyclohex-2-enone (I)1)
Compound 4a (0.62g,2mmol) and 2-fluorophenylacetylene (0.72g, 6mmol) were dissolved in 15ml of anhydrous 1, 4-dioxane, and Pd (PPh) was added under nitrogen atmosphere3)4(0.23g,0.2mmol), CuI (76.18mg,0.4mmol) and DIPEA (1.05ml, 6mmol), and stirred at room temperature for 10 min. After the reaction was complete, 80ml of saturated NH were added4The Cl solution, the mixture was extracted with dichloromethane (3X 40ml) and the organic layer was MgSO4Drying, concentrating, and purifying by column chromatography to obtain target compound I10.52g, yield: 60 percent. MS (ESI) M/z 303[ M + H ]]+.1H NMR(400MHz,DMSO-d6)δ7.48-7.53(m,2H,Ar-H,ArCH),7.35-7.43(m,6H,Ar-H),7.15-7.19(m,2H,Ar-H),6.43(m,1H,C＝CH),2.97(m,2H,CH2),2.43(m,2H,CH2)。
Example 2(E) -6- (4-Fluorostyrenyl) -2- ((2-fluorophenyl) ethynyl) cyclohex-2-enone (I)2) Preparation of
(E) -6- (4-fluorophenylethenylene) -cyclohex-2-enone (3b)
Referring to the preparation method of compound 3a, benzaldehyde was replaced with 4-fluorobenzaldehyde to obtain solid compound 3b in yield: 75 percent. MS (ESI) M/z 203[ M + H ]]+.
(E) -2-iodo-6- (4-fluorophenylenevinyl) -cyclohex-2-enone (4b)
Referring to the preparation method of compound 4a, solid compound 4b was obtained in yield: 95 percent. MS (ESI) M/z 329[ M + H ]]+.
(E) -6- (4-fluorophenylethenylidene) -2- ((2-fluorophenyl) ethynyl) cyclohex-2-enone (I)2)
Reference Compound I1The preparation method comprises the step of reacting 4b instead of 4a with 2-fluorobenzeneacetyleneTo obtain the target compound I2The yield is as follows: 65 percent. MS (ESI) M/z 321[ M + H ]]+.1H NMR(400MHz,DMSO-d6)δ7.69(d,J＝8.4Hz,2H,Ar-H),7.51-7.55(m,2H,ArCH),7.38-7.41(m,3H,Ar-H),7.14-7.16(m,2H,Ar-H),6.41(m,1H,C＝CH),2.95(m,2H,CH2),2.42(m,2H,CH2)。
Example 3(E) -6- (2-methyl-4-methoxy-styrenyl) -2- ((4-fluorophenyl) ethynyl) cyclohex-2-enone (I)3) Preparation of
(E) -6- (2-methyl-4-methoxy-styrylidene) -cyclohex-2-enone (3c)
Referring to the preparation method of compound 3a, benzaldehyde was replaced with 2-methyl-4-methoxybenzaldehyde to obtain solid compound 3c in yield: 68 percent. MS (ESI) M/z 229[ M + H ]]+.
(E) -2-iodo-6- (2-methyl-4-methoxy-styrylidene) -cyclohex-2-enone (4c)
Referring to the preparation method of compound 4a, solid compound 4c was obtained in yield: 95 percent. MS (ESI) M/z 355[ M + H]+(E) -6- (2-methyl-4-methoxy-styrylidene) -2- ((4-fluorophenyl) ethynyl) cyclohex-2-enone (I)3)
Reference Compound I1The preparation method comprises the step of reacting 4c instead of 4a with 4-fluorophenylacetylene to obtain a target compound I3The yield is as follows: 62 percent. MS (ESI) M/z 347[ M + H]+.1H NMR(400MHz,DMSO-d6)δ7.55(s,1H,ArCH),7.46(d,J＝8.4Hz,2H,Ar-H),7.10-7.16(m,3H,Ar-H),6.73(m,1H,Ar-H),6.69(m,1H,Ar-H),6.30(m,1H,CH＝),3.78(s,3H,OCH3),2.84(m,2H,CH2),2.35(m,2H,CH2),2.28(s,3H,Ar-CH3).
Example 4(E) -6- (3-Nitro-4-methoxyphenylethenylene) -2- ((2-chlorophenyl) ethynyl) -cyclohex-2-enone (I)4) Preparation of
(E) -6- (3-nitro-4-methoxyphenylethenylidene) -cyclohex-2-enone (3d)
Referring to the preparation method of compound 3a, benzaldehyde was replaced with 3-nitro-4-methoxybenzaldehyde to obtain solid compound 3d in yield: 76 percent. MS (ESI) M/z 260[ M + H ]]+.
(E) -2-iodo-6- (3-nitro-4-methoxyphenylethenylene) -cyclohex-2-enone (4d)
Referring to the preparation method of compound 4a, solid compound 4d was obtained in yield: 95 percent. MS (ESI) M/z 386[ M + H ]]+.
(E) -6- (3-nitro-4-methoxystyrylidene) -2- ((2-chlorophenyl) ethynyl) -cyclohex-2-enone (I)4)
Reference Compound I1The preparation method comprises the step of reacting 4d instead of 4a with 2-chlorophenylacetylene to obtain a target compound I4The yield is as follows: 58 percent. MS (ESI) M/z 394[ M + H ]]+.1H NMR(400MHz,DMSO-d6)δ7.78(d,J＝2.1Hz,1H,Ar-H),7.41-7.49(m,3H,Ar-H,ArCH),7.31-7.33(m,2H,Ar-H),7.25(m,1H,Ar-H),7.11(d,J＝8.7Hz,1H,Ar-H),6.36(m,1H,CH＝),3.89(s,3H,OCH3),2.92(m,2H,CH2),2.37(m,2H,CH2)。
Example 5(E) -6- (3-Methoxyphenylethenylene) -2- ((2-bromophenyl) ethynyl) cyclohex-2-enone (I)5) Preparation of
(E) -6- (3-Methoxyphenylethenylene) -cyclohex-2-enone (3e)
Referring to the preparation method of compound 3a, benzaldehyde was replaced with 3-methoxybenzaldehyde to obtain solid compound 3e in yield: 70 percent. MS (ESI) M/z 215[ M + H ]]+.
(E) -2-iodo-6- (3-methoxyphenylethenylidene) -cyclohex-2-enone (4e)
Referring to the preparation method of compound 4a, solid compound 4e was obtained in yield: 95 percent. MS (ESI) M/z 341[ M + H ]]+.
(E) -6- (3-Methoxyphenylethenyl) -2- ((2-bromophenyl) ethynyl) cyclohex-2-enone (I)5)
Reference Compound I1The preparation method comprises the step of reacting 4e instead of 4a with 2-bromophenylacetylene to obtain a target compound I5The yield is as follows: and 55 percent. MS (ESI) M/z 393[ M + H ]]+.1H NMR(400MHz,DMSO-d6)δ7.51(s,1H,ArCH),7.40-7.45(m,2H,Ar-H),7.33(m,1H,Ar-H),7.26(m,1H,Ar-H),7.13(m,1H,Ar-H),7.02(m,1H,Ar-H),6.81(m,1H,Ar-H),6.39(m,1H,CH＝C),3.77(s,3H,OCH3),2.96(m,2H,CH2),2.37(m,2H,CH2)；
Example 6(E) -6- (3-trifluoromethylphenylethenyl) -2- ((2, 4-difluorophenyl) ethynyl) cyclohex-2-enone (I)6) Preparation of
(E) -6- (3-trifluoromethylphenylvinylidene) -cyclohex-2-enone (3f)
Referring to the preparation method of compound 3a, benzaldehyde was replaced with 3-trifluoromethylbenzaldehyde to obtain solid compound 3f in yield: 72 percent. MS (ESI) M/z 253[ M + H ]]+.
(E) -2-iodo-6- (3-trifluoromethylphenylvinylene) -cyclohex-2-enone (4f)
Referring to the preparation method of compound 4a, solid compound 4f was obtained in yield: 95 percent. MS (ESI) M/z 379[ M + H]+.
(E) -6- (3-trifluoromethylphenylethenyl) -2- ((2, 4-difluorophenyl) ethynyl) cyclohex-2-enone (I)6)
Reference Compound I1The preparation method comprises the step of reacting 4f instead of 4a with 2, 4-difluorophenylacetylene to obtain a target compound I6The yield is as follows: 58 percent. MS (ESI) M/z 389[ M + H ]]+.1H NMR(400MHz,DMSO-d6)δ7.57(s,1H,CH＝),7.43-7.46(m,3H,Ar-H),7.19(d,J＝8.0Hz,2H,Ar-H),7.01(m,1H,Ar-H),6.71(s,1H,Ar-H),6.49(m,1H,C＝CH),3.00(m,2H,CH2),2.45(m,2H,CH2)。
Example 7(E) -6- (4- (dimethylamino) styrylidene) -2- ((2-fluorophenyl) ethynyl) cyclohex-2-enone (I)7) Preparation of
(E) -6- (4- (dimethylamino) phenylethenyl) -cyclohex-2-enone (3g)
Referring to the preparation method of compound 3a, benzaldehyde was replaced with 4-dimethylaminobenzaldehyde to obtain 3g of a solid compound in yield: 70 percent. MS (ESI) M/z 228[ M + H ]]+.
(E) -2-iodo-6- (4- (dimethylamino) phenylethenyl) -cyclohex-2-enone (4g)
Referring to the preparation method of compound 4a, solid compound 4g was obtained in yield: 95 percent. MS (ESI) M/z 354[ M + H ]]+(E) -6- (4- (dimethylamino) phenylethene2- ((2-fluorophenyl) ethynyl) cyclohex-2-enone (I)7)
Reference Compound I1The preparation method comprises the step of reacting 4g of the substituted 4a with 2-fluorobenzeneacetylene to obtain a target compound I7The yield is as follows: 60 percent. MS (ESI) M/z 346[ M + H ]]+.
Example 8(E) -6- (4-trifluoromethoxy-phenylethenylidene) -2- ((2-fluorophenyl) ethynyl) cyclohex-2-enone (I)8) Preparation of
(E) -6- (4-trifluoromethoxy-phenylethenylidene) -cyclohex-2-enone (3h)
Referring to the preparation method of compound 3a, benzaldehyde was replaced with 4-trifluoromethoxybenzaldehyde to obtain a solid compound 3h, yield: 65 percent. MS (ESI) M/z 269[ M + H]+.
(E) -2-iodo-6- (4-trifluoromethoxy-phenylethenylidene) -cyclohex-2-enone (4h)
Referring to the preparation of compound 4a, solid compound 4h was obtained in yield: 95 percent. MS (ESI) M/z 395[ M + H ]]+.
(E) -6- (4-trifluoromethoxy-phenylethenyl) -2- ((2-fluorophenyl) ethynyl) cyclohex-2-enone (I)8)
Reference Compound I1The preparation method comprises the step of reacting 4h instead of 4a with 2-fluorobenzeneacetylene to obtain a target compound I8The yield is as follows: 67%. MS (ESI) M/z 387[ M + H ]]+.1H NMR(400MHz,DMSO-d6)δ7.52-7.55(m,2H,Ar-H,CH＝),7.46(m,1H,Ar-H),7.37(m,1H,Ar-H),7.31(d,J＝8.0Hz,2H,Ar-H),7.15(d,J＝8.0Hz,2H,Ar-H),7.03(m,1H,Ar-H),6.43(m,1H,C＝CH),2.93-2.99(m,2H,CH2),2.38-2.43(m,2H,CH2)。
Example 9(E) -6- (4-trifluoromethoxy-phenylethenyl) -2- ((2-chlorophenyl) ethynyl) cyclohex-2-enone (I)9) Preparation of
Reference Compound I1The preparation method comprises the step of reacting 4h instead of 4a with 2-chlorophenylacetylene to obtain a target compound I9The yield is as follows: 67%. MS (ESI) M/z 403[ M + H]+.1H NMR(400MHz,DMSO-d6)δ7.57(s,1H,CH＝),7.47(m,1H,Ar-H),7.31-7.35(m,4H,Ar-H),7.16(d,J＝8.0Hz,2H,Ar-H),7.05(m,1H,Ar-H),6.48(m,1H,C＝CH),2.98(m,2H,CH2),2.41(m,2H,CH2)。
Example 10(E) -6- (3, 4-Dimethoxyphenylethenylene) -2- ((4-fluorophenyl) ethynyl) cyclohex-2-enone (I)10) Preparation of
(E) -6- (3, 4-Dimethoxyphenylethenylidene) -cyclohex-2-enone (3i)
Referring to the preparation method of compound 3a, benzaldehyde was substituted with 3, 4-dimethoxybenzaldehyde to obtain solid compound 3i in yield: 80 percent. MS (ESI) M/z 245[ M + H ]]+.
(E) -2-iodo-6- (3, 4-dimethoxystyrylidene) -cyclohex-2-enone (4i)
Referring to the preparation method of compound 4a, solid compound 4i was obtained in yield: 95 percent. MS (ESI) M/z 371[ M + H ]]+.
(E) -6- (3, 4-Dimethoxyphenylethenylidene) -2- ((4-fluorophenyl) ethynyl) cyclohex-2-enone (I)10)
Reference Compound I1The preparation method comprises the step of reacting 4I instead of 4a with 4-fluorophenylacetylene to obtain a target compound I10The yield is as follows: 62 percent. MS (ESI) M/z 363[ M + H]+.1HNMR(400MHz,DMSO-d6)δ7.47-7.51(m,3H,Ar-H),7.27(m,1H,CH＝),7.16(d,J＝8.0Hz,2H,Ar-H),6.97(m,2H,Ar-H),6.43(m,1H,C＝CH),3.95(m,3H,OCH3),3.81(m,3H,OCH3),3.01(m,2H,CH2),2.39(m,2H,CH2).
Example 11(E) -6- (3,4, 5-trimethoxyphenylethenyl) -2- ((2-fluorophenyl) ethynyl) cyclohex-2-enone (I)11) Preparation of
(E) -6- (3,4, 5-trimethoxyphenylethenylidene) -cyclohex-2-enone (3j)
Referring to the preparation method of compound 3a, benzaldehyde was substituted with 3,4, 5-trimethoxybenzaldehyde to obtain solid compound 3j in yield: 75 percent. MS (ESI) M/z 275[ M + H ]]+.
(E) -2-iodo-6- (3,4, 5-trimethoxyphenylvinylene) -cyclohex-2-enone (4j)
Referring to the preparation method of compound 4a, solid compound 4j was obtained in yield: 95 percent. MS (ESI) m/z 401[M+H]+.
(E) -6- (3,4, 5-trimethoxyphenylethenyl) -2- ((2-fluorophenyl) ethynyl) cyclohex-2-enone (I)11)
Reference Compound I1The preparation method comprises the step of reacting 4j instead of 4a with 2-fluorobenzeneacetylene to obtain a target compound I11The yield is as follows: 60 percent. MS (ESI) M/z 393[ M + H ]]+.1H NMR(400MHz,CDCl3)δ7.57(m,1H,Ar-H),7.47(d,J＝1.6Hz,1H,Ar-H),7.38(m,1H,CH＝),7.19(m,1H,Ar-H),7.07(m,1H,Ar-H),7.01(m,1H,CH＝C),6.54(m,2H,Ar-H),3.82(s,3H,OCH3),3.81(s,6H,2×OCH3),3.02(m,2H,CH2),2.49(m,2H,CH2)。
Example 12(E) -6- (3,4, 5-trimethoxyphenylethenyl) -2- ((4-fluorophenyl) ethynyl) cyclohex-2-enone (I)12) Preparation of
Reference Compound I1The preparation method comprises the step of reacting 4j instead of 4a with 4-fluorophenylacetylene to obtain a target compound I12The yield is as follows: 62 percent. MS (ESI) M/z 393[ M + H ]]+.1H NMR(400MHz,CDCl3)δ7.48(m,2H,Ar-H),7.36(s,1H,CH＝C),7.00-7.08(m,3H,Ar-H,CH＝),6.58(s,2H,Ar-H),3.86(s,3H,OCH3),3.85(s,6H,OCH3),3.05(m,2H,CH2),2.52(m,2H,CH2)。
Example 13(E) -6- (3,4, 5-trimethoxyphenylethenyl) -2- ((2-bromophenyl) ethynyl) cyclohex-2-enone (I)13) Preparation of
Reference Compound I1The preparation method comprises the step of reacting 4j instead of 4a with 2-bromophenylacetylene to obtain a target compound I13The yield is as follows: and 55 percent. MS (ESI) M/z 453[ M + H ]]+.1H NMR(400MHz,CDCl3)δ7.59(s,1H,Ar-H),7.48(m,1H,Ar-H),7.40(m,1H,CH＝),7.23(m,1H,Ar-H),7.03(m,2H,Ar-H,CH＝C),6.57(s,2H,Ar-H),3.84(s,3H,OCH3),3.82(s,6H,2×OCH3),3.05(m,2H,CH2),2.51(m,2H,CH2)。
Example 14(E) -6- (3,4, 5-trimethoxyphenylethenyl) -2- ((2, 4-difluorophenyl) ethynyl) cyclohex-2-enone (I)14) Preparation of
Reference Compound I1The preparation method comprises the step of reacting 4j instead of 4a with 2, 4-difluorophenylacetylene to obtain a target compound I14The yield is as follows: 60 percent. MS (ESI) M/z 411[ M + H ]]+.
EXAMPLE 15 measurement of tumor cell and Normal cell proliferation inhibition Rate of Compound of the present invention by MTT method
The anti-proliferative activity of the compound on 4 human cancer cell lines was evaluated by MTT in vitro anti-tumor assay. Piperlonguminine (PL) was used as a positive control. Human cancer cell line: human liver cancer cell HepG2, human lung cancer cell H1975, human stomach cancer cell HGC-27, human prostate cancer cell DU145, human normal cell: human gastric mucosal epithelial cells GES-1.
The experimental method is as follows: taking a bottle of cells in exponential growth phase, adding 0.25% trypsin for digestion to make adherent cells fall off, and preparing the solution containing 2 × 10 cells per ml4～4×104A suspension of individual cells. Inoculating the cell suspension on a 96-well plate, placing 180 μ L of the cell suspension in each well, and placing in a constant temperature CO2The culture was carried out in an incubator for 24 hours. Changing the solution, adding the test compound I1-I14(Compound dissolved in DMSO 20 u M PBS, test compounds concentration 20 u L, culture 72 hours, MTT added 96 hole plate, each hole 20 u L, incubator for 4 hours reaction, supernatant, adding DMSO, each hole 150 u L, shaking for 5 minutes on the shaking table, using enzyme linked immunosorbent assay at 570nm wavelength to determine each hole absorbance, calculation of cell inhibition rate, pharmacological test results as shown in Table 2, the results show the invention of compound I1-Ⅰ14Under the concentration of 20 mu mol/L, the compound has different degrees of inhibition effects on the proliferation of a plurality of human tumor cells, most of the compounds have stronger inhibition effects on a plurality of cancer cells and are superior to positive control medicine PL, particularly, the compounds have better inhibition effects on prostate cancer cells, and the activity is obviously superior to that of the positive control medicine PL.
TABLE 2 inhibition of some human tumor cells and normal cells by the compounds of the invention (% 20. mu.M)
Figure BDA0002278541030000101
ND, not detected.
Furthermore, the compounds I of the invention1-Ⅰ14The proliferation inhibitory activity on normal cells of the stomach was also investigated. Experimental results show that the inhibitory activity of most of the compounds of the invention on normal gastric cells is obviously weaker than that on tumor cells. Therefore, the compound of the invention can selectively inhibit the growth of tumor cells under a certain concentration, and has small damage to normal cells.
EXAMPLE 16 study of TrxR inhibitory Activity of Compounds of the present invention
The effect of the test drug (10 μ M) on TrxR activity was assessed by the TrxR activity test kit (BioVision, Milpitas, CA, USA). The test cell line HGC27 was dissolved in 1 Xbuffer solution in a centrifuge tube, then subjected to ice-bath for 20 minutes, and then centrifuged at 10000 Xg 4 ℃ for 15 minutes. The supernatant was transferred to a new centrifuge tube and the protein concentration was calculated by the Bio-Rad protein assay. The samples were diluted with buffer to 2X working concentration. Loading and testing were performed with reference to kit instructions. Absorbance was measured at 412nm wavelength every 20 seconds for 5 minutes after shaking using a BioTek Synergy HT multimode microplate reader before reading.
The results are shown in Table 3 and show that Compound I1-Ⅰ14The compound I has obvious inhibitory activity to TrxR under the concentration of 10 mu M, and most compounds show stronger or equivalent inhibitory activity to positive control drug PL, which indicates that the compound I of the invention1-Ⅰ14Has better TrxR inhibition activity, and is consistent with the display of antitumor activity.
TABLE 3 Compounds I of the invention1-Ⅰ14In vitro inhibition rate of TrxR (10. mu.M)
Figure BDA0002278541030000111
ND, not detected.
Example 17 intracellular ROS level determination
ROS-Glo Hydrogen peroxide assay (Promega, Sout)hampton, UK) by direct probing for H in cells2O2Levels measure ROS changes. Cells were seeded into 96-well cell culture plates and incubated with test drug (20 μ M) for 24 hours. Adding hydrogen peroxide substrate solution to each well and CO at constant temperature2Incubate at 37 ℃ for 6 hours. After incubation, ROS-Glo probe was added to each well and incubated for 20 minutes at room temperature. Fluorescence was detected by a BioTek Synergy HT multimodal microplate reader.
Selecting compounds of the invention of the general formula I4～I9、I11～I12To represent, it was tested for ROS levels in tumor cells at a concentration of 20 μ M. The ROS change of human gastric cancer HGC27 cells after the drug is added is measured by using DCFH-DA as a fluorescent probe, and the ROS level in the cells can be quantitatively reflected from the change of the fluorescence intensity. The results show that the compounds I of the invention4～I9、I11～I12The ROS expression level in HGC27 cells can be obviously improved at 20 mu M, is 4.2-9.5 times of that of a control group, and is better than that of positive control drug PL (3.7 times of that of the control group).
TABLE 3 Compounds I of the invention4～I9、I11～I12ROS expression level in tumor cells at 20. mu.M concentration (ROS level in control group is 1 unit)
Figure BDA0002278541030000121

Claims (10)

1. A6-benzylidene-2-arylethynylcyclohexenone derivative having the following general formula I:
Figure FDA0002278541020000011
wherein, R and R 'are the same or different and respectively represent one or more substituent groups on the corresponding substituted benzene ring, and are selected from one or more of H, halogen group, hydroxyl, amino, nitro, alkyl, halogenated alkyl, alkoxy, halogenated alkoxy and alkylamino, and when R or R' represent a plurality of substituent groups, all the substituent groups are the same or different.
2. The 6-benzylidene-2-arylethynylcyclohexenone derivative of claim 1, wherein:
wherein, R and R 'are the same or different and respectively represent one or more substituents on the corresponding substituted benzene ring, and are selected from one or more of H, halogen group, hydroxyl, amino, nitro, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy and C1-C6 alkylamino, and when R or R' represent a plurality of substituents, all the substituents are the same or different.
3. The 6-benzylidene-2-arylethynylcyclohexenone derivative of claim 2, wherein:
wherein, R and R 'are the same or different and respectively represent one or more substituents on the corresponding substituted benzene ring, and are selected from one or more of H, F, Cl, Br, I, hydroxyl, amino, nitro, methyl, ethyl, propyl, isopropyl, trifluoromethyl, pentafluoroethyl, trichloromethyl, tribromomethyl, methoxy, ethoxy, trifluoromethoxy, trichloromethoxy, tribromomethoxy, methylamino, ethylamino and methylethylamino, and when R or R' represent a plurality of substituents, all the substituents are the same or different.
4. The 6-benzylidene-2-arylethynylcyclohexenone derivative of claim 3, wherein:
r 'represents one or more substituent groups on the benzene ring, and is selected from H, F, Cl and Br, and when R' represents a plurality of substituent groups, each substituent group is the same or different.
5. The 6-benzylidene-2-arylethynylcyclohexenone derivative of claim 4, wherein: r and R' in the structure of formula I are selected from the following combinations:
R＝H，R’＝2’-F；
or R ═ 4-F, R ═ 2' -F;
or R is 2-CH3-4-OCH3，R’＝4’-F；
Or R ═ 3-NO2-4-OCH3，R’＝2’-Cl；
Or R is 3-OCH3，R’＝2’-Br；
Or R-3-CF3，R’＝2’,4’-di-F；
Or R is 4-N (CH)3)2，R’＝2’-F；
Or R-4-OCF3，R’＝2’-F；
Or R-4-OCF3，R’＝2’-Cl；
Or R ═ 3,4-di-OCH3，R’＝4’-F；
Or R is 3,4,5-tri-OCH3，R’＝2’-F；
Or R is 3,4,5-tri-OCH3，R’＝4’-F；
Or R is 3,4,5-tri-OCH3，R’＝2’-Br；
Or R is 3,4,5-tri-OCH3，R’＝2’,4’-di-F。
6. The process for the preparation of 6-benzylidene-2-arylethynylcyclohexenone derivative according to any one of claims 1 to 5, wherein: the method comprises the following steps:
(1) r-substituted benzaldehyde and cyclohexene-2-ketone are subjected to an Adol condensation reaction to obtain a compound 3, wherein R represents one or more substituents on a benzene ring and is selected from one or more of H, a halogen group, hydroxyl, amino, nitro, alkyl, halogenated alkyl, alkoxy, halogenated alkoxy and alkylamino, and when R represents a plurality of substituents, all the substituents are the same or different;
Figure FDA0002278541020000021
(2) reacting the compound 3 with an iodine simple substance to obtain a compound 4;
Figure FDA0002278541020000022
(3) performing Sonogashira coupling reaction on a compound 4 and R ' substituted phenylacetylene to obtain the 6-benzylidene-2-arylethynyl cyclohexenone derivative disclosed by any one of claims 1-5, wherein R ' represents one or more substituents on a benzene ring, and is selected from one or more of H, a halogen group, hydroxyl, amino, nitro, alkyl, halogenated alkyl, alkoxy, halogenated alkoxy and alkylamino, and when R ' represents a plurality of substituents, all the substituents are the same or different;
Figure FDA0002278541020000023
7. a pharmaceutical composition characterized by comprising the 6-benzylidene-2-arylethynylcyclohexenone derivative according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof.
8. Use of the 6-benzylidene-2-arylethynylcyclohexenone derivative according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof for the preparation of a medicament having thioredoxin oxidoreductase inhibitory activity.
9. The use according to claim 8, characterized in that the medicament having thioredoxin oxidoreductase inhibitory activity is a medicament for the prevention and/or treatment of cancer.
10. Use according to claim 9, characterized in that the cancer is liver cancer, prostate cancer, colon cancer, stomach cancer or lung cancer.
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021098319A1 (en) * 2019-11-19 2021-05-27 南通大学 6-benzylidene-2-aryl ethynyl cyclohexenone derivatives, and preparation method therefor and medical use thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105263893A (en) * 2013-02-20 2016-01-20 国鼎生物科技股份有限公司 Cyclohexenone compositions and process for making thereof
WO2016011130A1 (en) * 2014-07-17 2016-01-21 National Taiwan University Compositions and methods for the preparation of 4-oxy-2-cyclohexenone and 6-oxy-2-cyclohexenone compounds
CN106673988A (en) * 2016-12-05 2017-05-17 南通大学 Benzyl cyclohexenone derivative and preparation method and medical application thereof

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SE1350211A1 (en) * 2012-02-23 2013-08-24 Golden Biotechnology Corp Methods and compositions for the treatment of cancer metastases
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Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105263893A (en) * 2013-02-20 2016-01-20 国鼎生物科技股份有限公司 Cyclohexenone compositions and process for making thereof
WO2016011130A1 (en) * 2014-07-17 2016-01-21 National Taiwan University Compositions and methods for the preparation of 4-oxy-2-cyclohexenone and 6-oxy-2-cyclohexenone compounds
CN106673988A (en) * 2016-12-05 2017-05-17 南通大学 Benzyl cyclohexenone derivative and preparation method and medical application thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
XIAOZE BAO等: "C60 steric bulk of cinchona alkaloid enables an enantioselective Michael addition/annulation sequence toward pyranopyrazoles", 《CHEM. COMMUN.》 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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