CN110002987A - Phenyl acrol cyclohexenone derivates and preparation method and purposes - Google Patents

Phenyl acrol cyclohexenone derivates and preparation method and purposes Download PDF

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CN110002987A
CN110002987A CN201910223740.4A CN201910223740A CN110002987A CN 110002987 A CN110002987 A CN 110002987A CN 201910223740 A CN201910223740 A CN 201910223740A CN 110002987 A CN110002987 A CN 110002987A
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acrol
phenyl
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cancer
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CN110002987B (en
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凌勇
杨圣菊
张延安
刘季
凌长春
李洋阳
刘思群
贾启新
明古旭
吴红梅
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Nantong University
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    • C07C225/22—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
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    • C07C255/40—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by doubly-bound oxygen atoms
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    • C07C49/657—Unsaturated compounds containing a keto groups being part of a ring containing six-membered aromatic rings
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    • C07C49/687—Unsaturated compounds containing a keto groups being part of a ring containing halogen
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    • C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
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    • C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
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    • C07C69/12—Acetic acid esters
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    • C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated

Abstract

The invention discloses a kind of phenyl acrol cyclohexenone derivates, have structure shown in general formula I:

Description

Phenyl acrol cyclohexenone derivates and preparation method and purposes
Technical field
The present invention relates to biomedicine fields, and in particular to a kind of phenyl acrol cyclohexenone derivates and preparation side Method and the Pharmaceutical composition containing these derivatives and the drug medical usage with TrxR inhibitory activity, are especially making Application in standby anti-tumor drug.
Background technique
The report of the World Health Organization (WHO) shows that malignant tumour already becomes global one of major disease, and just It is No.1 " killer's disease " quickly to become the world, seriously threatens human health and life.It is counted according to WHO, in the late three decades, the world Before cancer morbidity increasing velocity is average annual 3-5% and expects the year two thousand twenty, world's cancer morbidity will increase than 2008 50%, i.e., it every year will newly-increased 15,000,000 cancer patients.Moreover, global Cancer death is died number and is also rapidly being risen, and has become At global first fatal disease.And the year two thousand thirty is expected, global cancer mortality case is up to 13,200,000.Cancer has become entirely The challenge and problem of ball, the fight with cancer shoulder heavy responsibilities.
Active oxygen (ROS) is molecular oxygen by the active oxygen metabolism product of chemical property generated after one-electron reduction and its spreads out The general name of biology.ROS can be divided into radical type and non-free base class, and wherein radical type mainly includes superoxide anion (O2 -)、 Hydroxy radical (HO) etc., non-free base class ROS mainly have hydrogen peroxide (H2O2), ozone (O3), peroxy-nitrate etc..Normally giving birth to Under the conditions of reason, a variety of ROS remove system and are present in into the cell, such as superoxide dismutase (SOD1, SOD2, SOD3), paddy Guang Sweet peptide peroxidase, catalase (CAT) and glutathione (GSH), glutaredoxin, anti-oxidant albumen (peroxiredoxins) and thioredoxin etc., the generation of internal ROS and elimination can be made to reach dynamic equilibrium, can allows cell Unaffected (Trachootham D, Alexandre J, the Huang P.Nature Reviews Drug of every normal function Discovery,2009,8,579-591).It is reported that ROS level increases in a variety of cancer cells, for example, thin from chronic lymphatic The leukaemia cell separated in born of the same parents' leukaemia or hairy cell leukemia blood sample of patient ROS yield compared with normal lymphocytes Increase (Zhou Y, Hileman E O, Plunkett W, et al.Blood, 2003,101,4098-4104).In entity tumor Oxidation Damage Products such as O-DNA base, lipid peroxide etc. is horizontal to be increased.
Studies have shown that intracellular ROS level reaches threshold value, series reaction will be caused and lead to cell death.It compares In normal cell, tumour cell has higher ROS level (Fruehauf J P, Meyskens F L.Clinical Cancer Research,2007,13,789-794).Induction ROS is generated or is inhibited antioxidant system to increase in tumour cell ROS level be considered as a kind of effective antitumour strategy.2011, Raj etc. had found that piperlongumine can be by raising tumour ROS in cell, does not influence the ROS of normal cell, thus achieve the purpose that selectivity kill tumour cell (Raj L, Ide T, Gurkar AU,et al.Nature 2011,475,231-234).Studies have shown that piperlongumine adjusts sulphur hydrogen reduction through targeting Protease (TrxR) adjusts the dynamic equilibrium of redox and active oxygen, and the GSH level in tumour cell is caused to decline, GSSG level rises, and the ROS concentration for eventually leading to tumour cell increases, and makes its apoptosis or necrosis.
Really at present it has been found that piperlongumine has good anti-tumor activity, but itself is lacked there is also some Point limits its clinical application.Firstly, the activity of piperlongumine is high not enough, specific mechanism of action not yet illustrates completely；Its It is secondary, it is limited from the piperlongumine raw material of plant extract, and the consumption of herb resource needed for producing is quite big；Additionally by artificial synthesized Piperlongumine, preparation process is complicated, needs expensive metallic catalyst, and reaction yield is low.Therefore, it is necessary to fructus piperis longi acyl Amine carries out structure derivatization and structure optimization, and then filters out that targeting is strong, high-efficiency low-toxicity, the antitumor chemical combination being readily synthesized Object.
Summary of the invention
The present invention takes into account bioactivity, druggability, three aspects of synthesis difficulty or ease, design according to the design feature of piperlongumine The novel phenyl acrol cyclohexenone derivates with TrxR inhibitory activity have been synthesized, it is bis- to retain PL active site C2-C3 Key and C7-C8 double bond not only all have significant inhibitory activity to a variety of source of people tumour cells and cells of resistant tumors, but also right Normal cell damage is smaller, the property of can choose ground killing tumor cell.Primary Study mechanism shows that the compounds of this invention can press down TrxR enzymatic activity processed improves tumour cell ROS level, causes tumour cell membrane damage, inducing apoptosis of tumour cell promotes invention The anti-tumor activity of compound.
Specific technical solution of the present invention is as follows:
A kind of phenyl acrol cyclohexenone derivates have structure shown in general formula I:
Wherein, R represents one or more substituent groups on phenyl ring, is selected from H, hydroxyl, halogen group, amino, nitro, C1-C6 Alkyl, the alkoxy of C1-C6, the alkylamino radical of C1-C6, the acyloxy of C1-C6, C1-C6 one of methoxyl group ethers or It is several；X represents the alkyl of H, halogen group, CN or C1-C6.Preferably, the R represents H, Br, NO2、OCH3、F、CH3、Cl、N (CH3)2、OH、O(CH2)2OCH3、O(CH2)2O(CH2)2OCH3Or one or more of OAc.
Preferably, the R is one or more of 2,3,4 in the position of substitution of phenyl ring.
Preferably, the R represents H, 4-F, 4-Cl, 4-Br, 2-NO2、4-NO2、3-OH、2-OCH3、4-OCH3、4-CH3、3- CH3、4-N(CH3)2、4-OH-3-OCH3、4-OAc-3-OCH3、3-O(CH2)2OCH3、3-OCH3-4-O(CH2)2OCH3、3-OCH3- 4-O(CH2)2O(CH2)2OCH3, X represents H, Cl, Br, CN, CH3。
Above-mentioned general formula structure compound preferred structure is as shown in table 1:
1 general formula of table, I part of compounds code name and its corresponding structure
I1: (E) -6- ((E) -3- cinnamyl) hexamethylene -2- ketenes；
I2: (E) -6- ((E) -3- (4- bromophenyl)-acrol) hexamethylene -2- ketenes；
I3: (E) -6- ((E) -3- (2- nitrobenzophenone) acrol) hexamethylene -2- ketenes；
I4: (E) -6- ((E) -3- (4- nitrobenzophenone) acrol) hexamethylene -2- ketenes；
I5: (E) -6- ((E) -3- (3- hydroxy phenyl) acrol) hexamethylene -2- ketenes；
I6: (E) -6- ((E) -3- (2- methoxyphenyl) acrol) hexamethylene -2- ketenes；
I7: (E) -6- ((E) -3- (4- methoxyphenyl) acrol) hexamethylene -2- ketenes；
I8: (E) -6- ((E) -3- (4- fluorophenyl) acrol) hexamethylene -2- ketenes；
I9: (E) -6- ((E) -3- (4- aminomethyl phenyl) acrol) hexamethylene -2- ketenes；
I10: (E) -6- ((E) -3- (4- chlorphenyl) acrol) hexamethylene -2- ketenes；
I11: (E) -6- ((E) -3- (4- dimethylamino phenyl) acrol) hexamethylene -2- ketenes；
I12: (E) -6- ((E) -3- (4- hydroxy 3-methoxybenzene base) acrol) hexamethylene -2- ketenes；
I13: (E) -6- ((E) -3- (3- (2- methoxy ethoxy) phenyl) acrol) hexamethylene -2- ketenes；
I14: (E) -6- ((E) -3- (3- methoxyl group -4- (2- methoxy ethoxy) phenyl) acrol) hexamethylene -2- alkene Ketone；
I15: (E) -6- ((E) -3- (3- methoxyl group -4- (2- (2- methoxy ethoxy) ethyoxyl) phenyl) acrol) Hexamethylene -2- ketenes；
I16: (E) -6- ((E) -3- (3- methoxyl group -4- acetylphenyl) acrol) hexamethylene -2- ketenes；
I17: (E) -6- (the chloro- 3- phenyl of (Z) -2-) acrol) hexamethylene -2- ketenes；
I18: (E) -6- (the bromo- 3- phenyl of (Z) -2-) acrol) hexamethylene -2- ketenes；
I19: (E) -6- ((Z) -2- cyano -3- phenyl) acrol) hexamethylene -2- ketenes.
I20: (E) -6- ((Z) -2- methyl -3- phenyl) acrol) hexamethylene -2- ketenes.
It is as follows another object of the present invention is to provide the preparation method of compound described in general formula I of the present invention:
Adol condensation reaction preparation is occurred under catalyst for substituted or non-substituted cinnamic acid and cyclohexene -2- ketone It obtains, the substituted or non-substituted cinnamic acid structural formula are as follows:R represents one or more on phenyl ring Substituent group, selected from H, hydroxyl, halogen group, amino, nitro, the alkyl of C1-C6, the alkoxy of C1-C6, C1-C6 alkylamino radical, One or more of the acyloxy of C1-C6, methoxyl group ethers of C1-C6；X represents the alkane of H, halogen group, CN or C1-C6 Base.Preferably, the R represents H, Br, NO2、OCH3、F、CH3、Cl、N(CH3)2、OH、O(CH2)2OCH3、O(CH2)2O(CH2)2OCH3Or one or more of OAc.
Preferably, the R is one or more of 2,3,4 in the position of substitution of phenyl ring.
Preferably, the R represents H, 4-F, 4-Cl, 4-Br, 2-NO2、4-NO2、3-OH、2-OCH3、4-OCH3、4-CH3、3- CH3、4-N(CH3)2、4-OH-3-OCH3、4-OAc-3-OCH3、3-O(CH2)2OCH3、3-OCH3-4-O(CH2)2OCH3、3-OCH3- 4-O(CH2)2O(CH2)2OCH3, X represents H, Cl, Br, CN, CH3。
Preferably, the catalyst is selected from triphenyl phosphorus, TiCl4, trimethyl silane imidazoles (TMSI), in magnesium bisulfate It is one or more of.
Cyclohexene -2- ketone and triphenyl phosphorus, are specially dissolved in anhydrous methylene chloride by one specific preparation method, TiCl is added under the conditions of -40 to -78 DEG C4Dichloromethane solution, be slowly added dropwise methylene chloride dissolution cinnamic acid solution, drop After adding, reacting recovery is to 0-30 DEG C, and appropriate 10%K is added in the reaction was continued 10-12h2CO3Solution makes the pH=8- of reaction solution 10, reaction obtains phenyl acrol cyclohexenone derivates.
Synthetic route is as follows:
Another object of the present invention is to provide cyclonene analog derivatives of the present invention to have TrxR suppression in preparation Make the application in active drug.The drug with TrxR inhibitory activity becomes the drug for the treatment of and/or pre- anti-cancer, excellent Choosing, the cancer is selected from liver cancer, colon cancer, gastric cancer, breast cancer or cervical carcinoma.
The compounds of this invention can combine individually or with one or more kinds of pharmaceutically acceptable carriers preparation is made For administration.For example, solvent, diluent etc., can be used for oral administered dosage form, such as capsule, dispersible powder, tablet, Granula etc..The various dosage forms of pharmaceutical composition of the present invention can be prepared according to method well known in pharmaceutical field.These medicines With in preparation can containing the active constituent of such as 0.05%~90% weight combined with carrier, more common about 15%~60% Between weight active constituent.The compounds of this invention dosage can be 0.005~5000mg/kg/ days, can also be serious according to disease The different dosages of degree or dosage form exceed this dosage range.
The compounds of this invention can individually be self-assembled into nanoparticle improve activity, or with other anti-tumor drugs such as alkanisation Agent (such as cyclophosphamide or Chlorambucil), antimetabolite (such as 5 FU 5 fluorouracil or hydroxycarbamide), topoisomerase enzyme inhibitor are (such as Camptothecine), mitotic inhibitor (such as taxol or vincaleukoblastinum), DNA inserting agent (such as adriamycin) combine self-assembled nanometer grain Improve activity, in addition it can with radiotherapy use in conjunction.These other anti-tumor drugs or radiotherapy can be with this hairs Bright compound simultaneously or given in different time.These combination therapies can produce synergistic effect to help to improve treatment effect Fruit.
Design feature, structure-activity relationship and the Pharmacophore Model of present invention combination anti-tumor drug piperlongumine, in fructus piperis longi acyl On the basis of amine, using bioisostere theory, using the cinnamic acid of different substituents as raw material, so that design, which synthesizes, to be had The novel phenyl acrol cyclonene analog derivative of TrxR inhibitory activity simplifies its synthetic route, is convenient for mass production, grinds Study carefully its inhibiting effect to TrxR target spot and malignant cell, find such compound not only to kinds of tumor cells (including Liver cancer, breast cancer, gastric cancer, colon cancer, cervical carcinoma etc.) it is proliferated the inhibitory effect all with strong and selectivity, and can TrxR enzymatic activity is significantly inhibited, in addition, the compounds of this invention is smaller to normal cell damage under a certain concentration, and can be induced Tumour cell ROS expression, collaboration promote apoptosis of tumor cells or necrosis.
Specific embodiment
In order to which the present invention is furture elucidated, a series of embodiments are given below, these embodiments be entirely it is illustrative, it Only be used to the present invention specifically describe, be not construed as limitation of the present invention.
Embodiment 1 (E) -6- ((E) -3- cinnamyl) hexamethylene -2- ketenes (I1) preparation
Cyclohexene -2- ketone (0.48g, 5.0mmol) and triphenyl phosphorus (1.31g, 5.0mmol) are dissolved in the anhydrous dichloro of 50ml In methane, then 5ml 1mol/L TiCl is added under the conditions of -50 DEG C4Dichloromethane solution, it is slow with constant pressure funnel after 15min Slow cinnamic acid (1.32g, 10.0mmol) solution 30ml that methylene chloride dissolution is added dropwise, after half an hour is added dropwise, reacting recovery To room temperature, appropriate 10%K is added in the reaction was continued about 12h, TLC monitoring after fully reacting2CO3After solution continues stir about 5min, Make the pH=9 of reaction solution, then extracted with methylene chloride (50ml × 2), cleans two be obtained by extraction with saturated salt solution (50mL) Chloromethanes layer collects dichloromethane layer, and anhydrous sodium sulfate is dry, concentration, column chromatographic purifying (EA:PE=1:3 is as eluant, eluent), Obtain yellow solid product 0.90g, yield 86%.I1Spectral data are as follows: ESI-MS (m/z): 211 [M+H]+；1H NMR (DMSO-d6,400MHz):δ7.46(m,2H,Ar-H),7.32(m,3H,Ar-H),7.12(m,1H,CH),6.96(m,3H, ), CH 6.19 (d, 1H, J=16.8Hz, CH), 2.88 (m, 2H, CH2),2.44(m,2H,CH2)。13C NMR(CDCl3, 100MHz):δ188.18,141.07,140.25,135.63,134.28,133.77,131.06,131.02,128.73, 128.57,128.31,127.16,125.02,25.45,21.00。
(E) -6- ((E) -3- (4- bromophenyl)-acrol) hexamethylene -2- ketenes (I2) preparation
Referring to I1Synthetic method, by the bromo- cinnamic acid of 4- (2.22g, 10.0mmol) substitute cinnamic acid (1.32g, 10.0mmol), it is reacted with cyclohexene -2- ketone (0.48g, 5.0mmol), obtains yellow solid product 1.20g, yield: 83%.I2 Spectral data are as follows: ESI-MS (m/z): 289 [M+H]+；1H NMR(DMSO-d6,400MHz):δ(CDCl3,400MHz)7.46(m, 2H, Ar-H), 7.34 (m, 2H, Ar-H), 7.28 (d, 1H, J=18.4Hz, CH), 7.07 (m, 1H, CH), 7.01 (m, 1H, CH), 6.87(m,1H,CH),6.22(m,1H,CH),2.91(m,2H,CH2),2.48(m,2H,CH2)。13C NMR(CDCl3, 100MHz):δ188.15,149.06,138.62,135.62,133.81,131.22,131.02,128.51,128.39, 123.69,123.56,122.65,25.59,25.20。
(E) -6- ((E) -3- (2- nitrobenzophenone) acrol) hexamethylene -2- ketenes (I3) preparation
Referring to I1Synthetic method, by 2- nitro-cinnamic acid (1.81g, 10.0mmol) substitution cinnamic acid (1.32g, 10.0mmol), it is reacted with cyclohexene -2- ketone (0.48g, 5.0mmol), obtains yellow solid product 1.10g, yield: 86%.I3 Spectral data are as follows: ESI-MS (m/z): 256 [M+H]+；1H NMR(CDCl3,400MHz):δ7.98(m,1H,CH),7.72(m, 1H, Ar-H), 7.61 (m, 1H, Ar-H), 7.45 (m, 1H, Ar-H), 7.42 (m, 1H, CH), 7.31 (d, 1H, J=16.8Hz, CH),7.06(m,1H,CH),7.05(m,1H,CH),6.25(m,1H,CH),2.93(m,2H,CH2),2.50(m,2H,CH2)。13C NMR(CDCl3,100MHz):δ181.98,149.46,161.76,147.99,136.11,134.35,133.22, 133.05,132.35,131.02,128.84,128.37,127.69,124.85,25.54,25.43。
(E) -6- ((E) -3- (4- nitrobenzophenone) acrol) hexamethylene -2- ketenes (I4) preparation
Referring to I1Synthetic method, by 4- nitro-cinnamic acid (1.81g, 10.0mmol) substitution cinnamic acid (1.32g, 10.0mmol), it is reacted with cyclohexene -2- ketone (0.48g, 5.0mmol), obtains yellow solid product 0.84g, yield: 66%.I4 Spectral data are as follows: ESI-MS (m/z): 256 [M+H]+；1H NMR(CDCl3,400MHz):δ8.18(m,2H,Ar-H),7.58(m, 2H, Ar-H), 7.20 (m, 2H, CH), 7.03 (m, 1H, CH), 6.94 (d, 1H, J=15.7Hz, CH), 6.21 (m, 1H, CH), 2.91(m,2H,CH2),2.49(m,2H,CH2)。13C NMR(CDCl3,100MHz):δ187.86,149.49,142.91, 136.99,136.57,132.80,130.98,127.37,127.13,124.11,25.56,25.40。
(E) -6- ((E) -3- (3- hydroxy phenyl) acrol) hexamethylene -2- ketenes (I5) preparation
Referring to I1Synthetic method, by 3- hydroxyl-cinnamic acid (1.48g, 10.0mmol) substitution cinnamic acid (1.32g, 10.0mmol), it is reacted with cyclohexene -2- ketone (0.48g, 5.0mmol), obtains yellow solid product 0.91g, yield: 80%.I5 Spectral data are as follows: ESI-MS (m/z): 227 [M+H]+。
(E) -6- ((E) -3- (2- methoxyphenyl) acrol) hexamethylene -2- ketenes (I6) preparation
Referring to I1Synthetic method, by 2- methoxy-cinnamic aldehyde (1.69g, 10.0mmol) substitute cinnamic acid (1.32g, 10.0mmol), it is reacted with cyclohexene -2- ketone (0.48g, 5.0mmol), obtains yellow solid product 0.97g, yield: 81%.I6 Spectral data are as follows: ESI-MS (m/z): 241 [M+H]+；1H NMR(DMSO-d6,400MHz):δ7.53(m,1H,CH),7.35(m, 1H,Ar-H),7.32(m,1H,CH),7.27(m,1H,Ar-H),7.12(m,1H,CH),7.00(m,1H,CH),6.98(m,1H, ), Ar-H 6.91 (m, 1H, Ar-H), 6.21 (d, 1H, J=18.4Hz, CH), 3.86 (s, 3H, CH3),2.91(m,2H,CH2), 2.47(m,2H,CH2)。13C NMR(CDCl3,100MHz):δ188.42,157.37,149.14,148.97,135.65, 133.07,131.16,129.90,127.32,125.69,123.80,120.82,111.01,55.43,25.43,25.22。
(E) -6- ((E) -3- (4- methoxyphenyl) acrol) hexamethylene -2- ketenes (I7) preparation
Referring to I1Synthetic method, by 4- methoxy-cinnamic aldehyde (1.67g, 10.0mmol) substitute cinnamic acid (1.32g, 10.0mmol), it is reacted with cyclohexene -2- ketone (0.48g, 5.0mmol), obtains yellow solid product 0.98g, yield: 82%.I7 Spectral data are as follows: ESI-MS (m/z): 241 [M+H]+；1H NMR(CDCl3,400MHz):δ7.44(m,2H,Ar-H),7.30(m, 1H,CH),7.0(m,1H,CH),6.94(m,4H,Ar-H,CH),6.21(m,1H,CH),7.80(m,3H,CH3),2.90(m, 2H,CH2),2.47(m,2H,CH2)。13C NMR(CDCl3,100MHz):δ188.41,160.20,149.19,140.22, 135.03,132.59,131.21,129.50,128.58,121.07,114.33,55.51,25.39,18.55。
(E) -6- ((E) -3- (4- fluorophenyl) acrol) hexamethylene -2- ketenes (I8) preparation
Referring to I1Synthetic method, by the fluoro- cinnamic acid of 4- (1.58g, 10.0mmol) substitute cinnamic acid (1.32g, 10.0mmol), it is reacted with cyclohexene -2- ketone (0.48g, 5.0mmol), obtains yellow solid product 0.95g, yield: 83%.I8 Spectral data are as follows: ESI-MS (m/z): 229 [M+H]+；1H NMR(DMSO-d6,400MHz):δ7.46(m,2H,Ar-H),7.28 (m,1H,CH),7.04(m,2H,Ar-H),6.96(m,1H,CH),6.94(m,1H,CH),6.91(m,1H,CH),6.21(m, 1H,CH),2.91(m,2H,CH2),2.48(m,2H,CH2)。13C NMR(CDCl3,100MHz):δ188.18,164.22, 161.76,148.95,138.85,134.20,132.96,131.02,131.25,128.68,122.69,116.08,115.60, 25.50,25.32。
(E) -6- ((E) -3- (4- aminomethyl phenyl) acrol) hexamethylene -2- ketenes (I9) preparation
Referring to I1Synthetic method, by 4- methyl-cinnamic acid (1.46g, 10.0mmol) substitution cinnamic acid (1.32g, 10.0mmol), it is reacted with cyclohexene -2- ketone (0.48g, 5.0mmol), obtains yellow solid product 0.90g, yield: 80%.I9 Spectral data are as follows: ESI-MS (m/z): 225 [M+H]+；1H NMR(DMSO-d6,400MHz):δ7.54(m,2H,Ar-H),7.22 (m, 3H, Ar-H, CH), 7.14 (m, 2H, CH), 7.03 (d, 1H, J=15.3Hz, CH), 6.10 (m, 1H, CH), 2.92 (m, 2H, CH2),2.44(m,2H,CH2),2.32(s,3H,CH3)。13C NMR(DMSO-d6,101MHz):δ187.63,151.05, 140.41,138.89,134.34,134.27,134.12,130.63,129.77,127.67,123.10,25.47,25.24, 21.40。
(E) -6- ((E) -3- (4- chlorphenyl) acrol) hexamethylene -2- ketenes (I10) preparation
Referring to I1Synthetic method, by the chloro- cinnamic acid of 4- (1.66g, 10.0mmol) substitute cinnamic acid (1.32g, 10.0mmol), it is reacted with cyclohexene -2- ketone (0.48g, 5.0mmol), obtains yellow solid product 1.06g, yield: 87%.I10 Spectral data are as follows: ESI-MS (m/z): 256 [M+H]+；1H NMR(DMSO-d6,400MHz):δ7.68(m,2H,Ar-H),7.44 (m,2H,Ar-H),7.35(m,1H,CH),7.15(m,3H,CH),6.11(m,1H,CH),2.94(m,2H,CH2),2.45(m, 2H,CH2)。13C NMR(CDCl3,100MHz):δ187.67,151.32,138.78,135.96,135.49,133.55, 133.48,130.57,129.33,129.23,124.91,25.50,25.32。
(E) -6- ((E) -3- (4- dimethylamino phenyl) acrol) hexamethylene -2- ketenes (I11) preparation
Referring to I1Synthetic method, by 4- dimethylamino-cinnamic acid (1.75g, 10.0mmol) substitution cinnamic acid (1.32g, 10.0mmol), it is reacted with cyclohexene -2- ketone (0.48g, 5.0mmol), obtains red solid product 0.97g, yield: 77%.I11 Spectral data are as follows: ESI-MS (m/z): 254 [M+H]+；1H NMR(CDCl3,400MHz):δ7.38(m,1H,CH),7.33(m, 2H,Ar-H),6.97(m,1H,CH),6.88(m,1H,CH),6.68(m,2H,Ar-H),6.19(m,1H,CH),3.00(s,6H, CH3),2.89(m,2H,CH2),2.45(m,2H,CH2)。13C NMR(CDCl3,101MHz):δ188.24,150.85,148.49, 141.34,135.87,131.30,128.55,124.90,118.79,112.11,40.26,25.33,25.10。
(E) -6- ((E) -3- (4- hydroxy 3-methoxybenzene base) acrol) hexamethylene -2- ketenes (I12) preparation
Referring to I1Synthetic method, 4- hydroxy-3-methoxy-cinnamic acid (1.78g, 10.0mmol) is substituted into cinnamic acid (1.32g, 10.0mmol) reacts with cyclohexene -2- ketone (0.48g, 5.0mmol), obtains yellow solid product 1.13g, yield: 88%.I12Spectral data are as follows: ESI-MS (m/z): 257 [M+H]+；1H NMR(DMSO-d6,400MHz):δ7.30(m,1H,CH), 7.01(m,3H,Ar-H),6.90(m,3H,CH),6.21(m,1H,CH),5.93(s,1H,OH),3.94(s,3H,CH3),2.90 (m,2H,CH2),2.48(m,2H,CH2)。13C NMR(CDCl3,101MHz):δ188.24,150.85,148.49,141.34, 135.87,131.30,128.55,124.90,118.79,112.11,40.26,25.33,25.10。
(E) -6- ((E) -3- (3- (2- methoxy ethoxy) phenyl) acrol) hexamethylene -2- ketenes (I13) preparation
Referring to I1Synthetic method, by 3- (2- methoxy ethoxy)-cinnamic acid (2.06g, 10.0mmol) substitute cortex cinnamomi Aldehyde (1.32g, 10.0mmol) reacts with cyclohexene -2- ketone (0.48g, 5.0mmol), obtains yellow solid product 1.08g, receives Rate: 76%.I13Spectral data are as follows: ESI-MS (m/z): 285 [M+H]+。
(E) -6- ((E) -3- (3- methoxyl group -4- (2- methoxy ethoxy) phenyl) acrol) hexamethylene -2- ketenes (I14) preparation
Referring to I1Synthetic method, by 3- methoxyl group -4- (2- methoxy ethoxy)-cinnamic acid (2.36g, 10.0mmol) It substitutes cinnamic acid (1.32g, 10.0mmol), is reacted with cyclohexene -2- ketone (0.48g, 5.0mmol), obtain yellow solid product 1.10g, yield: 70%.I14Spectral data are as follows: ESI-MS (m/z): 315 [M+H]+。
(E) -6- ((E) -3- (3- methoxyl group -4- (2- (2- methoxy ethoxy) ethyoxyl) phenyl) acrol) ring Hex- 2- ketenes (I15) preparation
Referring to I1Synthetic method, by 3- methoxyl group -4- (2- (2- methoxy ethoxy) ethyoxyl-cinnamic acid (2.80g, Cinnamic acid (1.32g, 10.0mmol) 10.0mmol) is substituted, is reacted with cyclohexene -2- ketone (0.48g, 5.0mmol), obtains yellow Solid product 1.27g, yield: 71%.I15Spectral data are as follows: ESI-MS (m/z): 359 [M+H]+。
(E) -6- ((E) -3- (3- methoxyl group -4- acetylphenyl) acrol) hexamethylene -2- ketenes (I16) preparation
Referring to I1Synthetic method, 3- methoxyl group -4- acetyl group-cinnamic acid (2.20g, 10.0mmol) is substituted into cinnamic acid (1.32g, 10.0mmol) reacts with cyclohexene -2- ketone (0.48g, 5.0mmol), obtains yellow solid product 1.16g, yield: 78%.I16Spectral data are as follows: ESI-MS (m/z): 299 [M+H]+；1H NMR(CDCl3,400MHz):δ7.23(m,1H,CH), 7.03 (m, 1H, CH), 6.96 (m, 4H, Ar-H, CH), 6.84 (d, J=15.3Hz, 1H, CH), 6.16 (m, 1H, CH), 3.82 (s,3H,CH3),2.86(m,1H,CH2),2.42(m,1H,CH2),2.26(s,3H,CH3)。13C NMR(CDCl3,101MHz):δ 188.06,168.83,151.23,149.14,140.14,139.48,135.67,134.01,133.97,131.01,123.25, 123.03,119.69,110.66,55.88,25.34,25.30。
(E) -6- (the chloro- 3- phenyl of (Z) -2-) acrol) hexamethylene -2- ketenes (I17) preparation
Referring to I1Synthetic method, by alpha-chloro cinnamic acid (1.66g, 10.0mmol) substitute cinnamic acid (1.32g, 10.0mmol), it is reacted with cyclohexene -2- ketone (0.48g, 5.0mmol), obtains yellow solid product 0.98g, yield: 80%.I17 Spectral data are as follows: ESI-MS (m/z): 245 [M+H]+。
(E) -6- (the bromo- 3- phenyl of (Z) -2-) acrol) hexamethylene -2- ketenes (I18) preparation
Referring to I1Synthetic method, by alpha-bromo-cinnamaldehyde (2.11g, 10.0mmol) substitute cinnamic acid (1.32g, 10.0mmol), it is reacted with cyclohexene -2- ketone (0.48g, 5.0mmol), obtains yellow solid product 1.18g, yield: 82%.I18 Spectral data are as follows: ESI-MS (m/z): 289 [M+H]+；1H NMR(CDCl3,400MHz):δ7.66(m,2H,Ar-H),7.36(m, 3H,Ar-H),7.20(m,1H,CH),7.03(m,1H,CH),6.91(s,1H,CH),6.20(m,1H,CH),3.03(m,2H, CH2),2.45(m,2H,CH2)。
(E) -6- ((Z) -2- cyano -3- phenyl) acrol) hexamethylene -2- ketenes (I19) preparation
Referring to I1Synthetic method, by alpha-cyano cinnamic acid (1.57g, 10.0mmol) substitute cinnamic acid (1.32g, 10.0mmol), it is reacted with cyclohexene -2- ketone (0.48g, 5.0mmol), obtains yellow solid product 0.75g, yield: 64%.I19 Spectral data are as follows: ESI-MS (m/z): 236 [M+H]+；1H NMR(CDCl3,400MHz):δ7.38(m,7H,Ar-H),7.03(m, 1H,CH),6.64(s,1H,CH),3.02(m,2H,CH2),2.42(m,2H,CH2)。
(E) -6- ((Z) -2- methyl -3- phenyl) acrol) hexamethylene -2- ketenes (I20) preparation
Referring to I1Synthetic method, by α-methylcinnamaldehyde (1.46g, 10.0mmol) substitute cinnamic acid (1.32g, 10.0mmol), it is reacted with cyclohexene -2- ketone (0.48g, 5.0mmol), obtains yellow solid product 0.87g, yield: 78%.I20 Spectral data are as follows: ESI-MS (m/z): 224 [M+H]+；1H NMR(CDCl3,400MHz):δ7.32(m,4H,Ar-H),7.23(m, 1H,Ar-H),7.16(s,1H,CH),6.99(m,1H,CH),6.61(s,1H,CH),6.18(m,1H,CH),2.99(m,2H, CH2),2.40(m,2H,CH2),2.09(s,3H,CH3)。13C NMR(CDCl3,101MHz):δ189.00,149.09,139.72, 136.96,134.59,133.93,133.51,130.84,129.23,128.21,127.17,26.71,25.71,18.57。
Embodiment 2 measures research using tumour cell and normal cell proliferation inhibiting rate of the mtt assay to the compounds of this invention
The compounds of this invention is had rated to 4 kinds of people's cancers using tetramethyl nitrogen azoles indigo plant colorimetric method (MTT) antitumor activity in vitro The antiproliferative activity of cell strain.Positive control drug is used as using piplartine (PL).Man―machine systems: liver cancer cells SMMC7721, colon cancer cell HCT116, stomach cancer cell HGC-27, human cervical carcinoma cell Hela, human normal cell line: people's stomach lining Epithelial cell GES-1.
Experimental method is as follows: taking in exponential phase of growth in good condition one bottle of cell, 0.25% trypsase is added and disappears Change, attached cell is made to fall off, is made every milliliter containing 2 × 104~4 × 104The suspension of a cell.Take cell suspension inoculation in 96 holes On plate, every 180 μ L of hole sets constant temperature CO2It is cultivated 24 hours in incubator.Liquid is changed, test-compound I is added1-I20(compound is used Diluted after DMSO dissolution with PBS, Test compound concentrations are 12.5 μM), every 20 μ L of hole is cultivated 72 hours.96 holes are added in MTT In plate, every 20 μ L of hole reacts 4 hours in incubator.It sucks supernatant, is added DMSO, every 150 μ L of hole shakes 5 on plate shaker Minute.With enzyme-linked immunosorbent assay instrument in the trap that wavelength is the every hole of measurement at 570nm, cell inhibitory rate is calculated.Experimental result As shown in table 2.
Cell inhibitory rate=(negative control group OD value-tested material group OD value)/negative control group OD value × 100%.
Compound of the present invention is tested by a series of tumour cell antiproliferative activities, the Pharmacological experiment result shows that (see Table 2), find the compounds of this invention I1-I20It is stronger to the effect of most of Cytostatic to tumor cell under 12.5 μM of concentration, especially The inhibitory activity of its part of compounds is significantly better than positive control drug piplartine (PL).However, the compounds of this invention I1~I20 Tumour cell is significantly lower than to the cell toxicant of people's normal gastric mucosa cell GES-1 under same concentrations, illustrates the compounds of this invention Not only there is significant anti-tumor activity to tumour cell, but also lower to normal cell toxicity, there is certain tumour cell Selectivity.
Inhibiting rate % (12.5 μM) of the part of compounds of the present invention of table 2 to human tumor cells and normal cell
ND: it does not detect
The measurement of 3 intracellular ROS level of embodiment
ROS-Glo hydrogen peroxide method of testing (Promega, Southampton, UK) passes through H in direct detection cell2O2Water Flat measurement ROS changes.It is cultivated 24 hours in cell inoculation to 96 porocyte culture plates and with (0.01~12.5 μM) of test medicine. Every hole is added hydrogen peroxide substrate solution and in constant temperature CO237 DEG C of incubator are incubated for 6 hours.After incubation, each hole is added ROS-Glo detection liquid is incubated for 20 minutes at room temperature.Fluorescence is detected by BioTek Synergy HT multi-mode microplate reader.
Select I in compound of Formula I of the present invention4~I8、I11~I15、I18、I19To represent, to it in tumour cell ROS level is tested.DCFH-DA is used to determine human cervical carcinoma Hela cell after drug-treated is added as fluorescence probe ROS situation of change, from the variation of fluorescence intensity can the intracellular ROS of quantitative response it is horizontal.The result shows that the compounds of this invention I4~I8、I11~I15、I18、I19The ROS content that can be obviously improved in Hela cell at 12.5 μM, be control group 3.7~ 8.9 times, it is better than positive control drug PL (3.2 times of control group).
4 the compounds of this invention of embodiment is to TrxR inhibitory activity research
Test medicine (12.5 μM) to TrxR activity influence by TrxR active testing box (BioVision, Milpitas, CA, USA) assessment.Briefly, then cell strain exists with ice bath 20 minutes after the dissolution of 1x buffer liquid in centrifuge tube It is centrifuged 15 minutes at 4 DEG C of 10000 × g.Supernatant is transferred in new centrifuge tube, and protein concentration passes through Bio-Rad albumen test Method calculates.Sample is diluted to 2X working concentration with buffer liquid.Every part of two hole of preparation of samples (containing and be free of inhibitor) and a formula Three parts.Reaction buffer and the reaction buffer of inhibitor is added to be prepared according to specification.BioTek is used before reading Absorbance was measured under 412nm wavelength every 20 seconds in 5 minutes after the concussion of Synergy HT multi-mode microplate reader.
The experimental results showed that chemical compounds I1~I20There is remarkable inhibiting activity to TrxR under 12.5 μM of concentration, inhibit Activity data is shown in Table 3, and majority of compounds all shows more stronger than positive control drug piplartine or comparable inhibitory activity, mentions Show that phenyl acrol cyclohexenone derivates of the invention have preferable TrxR inhibitory activity, shows antitumor work with it Property is consistent.
The external TrxR inhibiting rate % of the part of compounds of the present invention of table 3 (12.5 μM)

Claims (11)

1. a kind of phenyl acrol cyclohexenone derivates, have structure shown in general formula I:
Wherein, R represents the alkanamine of H, hydroxyl, halogen group, amino, nitro, the alkyl of C1-C6, the alkoxy of C1-C6, C1-C6 One or more of base, the acyloxy of C1-C6, methoxyl group ethers of C1-C6；X represents H, halogen group, CN or C1-C6's Alkyl.
2. phenyl acrol cyclohexenone derivates according to claim 1, it is characterised in that the R represent H, F, Cl、Br、NO2、OCH3、CH3、N(CH3)2、OH、O(CH2)2OCH3、O(CH2) 2O(CH2)2OCH3、OAc。
3. phenyl acrol cyclohexenone derivates according to claim 1, it is characterised in that the R takes phenyl ring Subrogate and is set to one or more of 2,3,4.
4. phenyl acrol cyclohexenone derivates according to claim 1, it is characterised in that the R represent H, 4-F, 4-Cl、4-Br、2-NO2、4-NO2、3-OH、2-OCH3、4-OCH3、4-CH3、3-CH3、4-N(CH3)2、4-OH-3-OCH3、4- OAc-3-OCH3、3-O(CH2)2OCH3、3-OCH3-4-O(CH2)2OCH3、3-OCH3-4-O(CH2)2O(CH2)2OCH3, X represent H, Cl、Br、CN、CH3。
5. phenyl acrol cyclohexenone derivates according to claim 1, it is characterised in that phenyl Asia allyl Cyclohexene ketone derivatives are selected from as follows:
R represents H, 4-F, 4-Cl, 4-Br, 2-NO2、4-NO2、3-OH、2-OCH3、4-OCH3、4-CH3、3-CH3、4-N(CH3)2、4- OH-3-OCH3、4-OAc-3-OCH3、3-O(CH2)2OCH3、3-OCH3-4-O(CH2)2OCH3、3-OCH3-4-O(CH2)2O(CH2)2OCH3, X represents H；
Alternatively, R represents H, X represents Cl, Br, CN or CH3。
6. the preparation method of any one of -5 phenyl acrol cyclohexenone derivates, feature exist according to claim 1 It is prepared in cyclohexene -2- ketone Adol condensation reaction is occurred under catalyst for substituted or non-substituted cinnamic acid, The substituted or non-substituted cinnamic acid structural formula are as follows:
R represent H, hydroxyl, halogen group, amino, nitro, the alkyl of C1-C6, the alkoxy of C1-C6, C1-C6 alkylamino radical, One or more of the acyloxy of C1-C6, methoxyl group ethers of C1-C6；X represents the alkane of H, halogen group, CN or C1-C6 Base.
7. preparation method according to claim 6, it is characterised in that the catalyst is selected from triphenyl phosphorus, TiCl4, front three One or more of base silane imidazoles, magnesium bisulfate.
8. preparation method according to claim 6, it is characterised in that the preparation method be specially by cyclohexene -2- ketone and Triphenyl phosphorus is dissolved in anhydrous methylene chloride, and TiCl is added under the conditions of -40 to -78 DEG C4Dichloromethane solution, be slowly added dropwise The cinnamic acid solution of methylene chloride dissolution, after being added dropwise, reacting recovery is to 0-30 DEG C, the reaction was continued 10-12h, is added in right amount 10%K2CO3Solution makes the pH=8-10 of reaction solution, obtains phenyl acrol cyclohexenone derivates.
9. any one of -5 phenyl acrol cyclohexenone derivates are preparing TrxR inhibitory activity according to claim 1 Application in drug.
10. application according to claim 9, it is characterised in that the drug with TrxR inhibitory activity be treatment and/ Or the drug of pre- anti-cancer.
11. application according to claim 10, it is characterised in that the cancer is selected from liver cancer, colon cancer, gastric cancer, breast cancer Or cervical carcinoma.
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