CN110002987B - Phenylallylidene cyclohexenone derivative, preparation method and application thereof - Google Patents
Phenylallylidene cyclohexenone derivative, preparation method and application thereof Download PDFInfo
- Publication number
- CN110002987B CN110002987B CN201910223740.4A CN201910223740A CN110002987B CN 110002987 B CN110002987 B CN 110002987B CN 201910223740 A CN201910223740 A CN 201910223740A CN 110002987 B CN110002987 B CN 110002987B
- Authority
- CN
- China
- Prior art keywords
- och
- cancer
- cinnamaldehyde
- allylidene
- derivative
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
- C07C205/45—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by at least one doubly—bound oxygen atom, not being part of a —CHO group
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C225/00—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
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
- C07C255/32—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
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
- C07C49/657—Unsaturated compounds containing a keto groups being part of a ring containing six-membered aromatic rings
- C07C49/683—Unsaturated compounds containing a keto groups being part of a ring containing six-membered aromatic rings having unsaturation outside the aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
- C07C49/687—Unsaturated compounds containing a keto groups being part of a ring containing halogen
- C07C49/697—Unsaturated compounds containing a keto groups being part of a ring containing halogen containing six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
- C07C49/703—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups
- C07C49/747—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups containing six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
- C07C49/753—Unsaturated compounds containing a keto groups being part of a ring containing ether groups, groups, groups, or groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/02—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen
- C07C69/12—Acetic acid esters
- C07C69/14—Acetic acid esters of monohydroxylic compounds
- C07C69/145—Acetic acid esters of monohydroxylic compounds of unsaturated alcohols
- C07C69/157—Acetic acid esters of monohydroxylic compounds of unsaturated alcohols containing six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention discloses a phenyl allylidene cyclohexenone derivative which has a structure shown in a general formula I:
Description
Technical Field
The invention relates to the field of biomedicine, in particular to a phenyl allyl idene cyclohexenone derivative, a preparation method thereof, a medicinal composition containing the derivative and medicinal application of a medicament with TrxR (TrxR) inhibitory activity, and especially application in preparation of antitumor medicaments.
Background
The World Health Organization (WHO) report shows that malignant tumors have long become one of the major diseases worldwide and are rapidly becoming the world's first killer disease' seriously threatening human health and life. According to WHO statistics, the increasing rate of the world cancer incidence rate is 3-5% every year in recent thirty years, and the world cancer incidence rate is expected to increase by 50% compared with that in 2008 by 2020, namely 1500 ten thousand cancer patients are newly added every year. Moreover, the number of cancer deaths worldwide is also rapidly increasing, and has become the first death disease worldwide. And it is expected that by 2030, worldwide cancer death cases will reach 1320 thousands. Cancer has become a global challenge and problem, and the struggle with cancer is great and far away.
Reactive Oxygen Species (ROS) are a general term for chemically active oxygen metabolites and derivatives thereof, which are generated by reduction of molecular oxygen by a single electron. ROS can be divided into free and non-free radicals, where the radical is mainlyTo contain a superoxide anion (O)2 -) Hydroxyl radical (HO.), etc., the non-radical ROS is mainly hydrogen peroxide (H)2O2) Ozone (O)3) Peroxynitrate salts, and the like. Under normal physiological conditions, various ROS scavenging systems exist in cells, such as superoxide dismutase (SOD1, SOD2, SOD3), glutathione peroxidase, Catalase (CAT), Glutathione (GSH), glutaredoxin, antioxidant proteins (peroxiredoxins), thioredoxin, etc., which enable the generation and elimination of ROS in vivo to reach a dynamic balance, and enable the normal functions of cells to be unaffected (Trachootham D, Alexandre J, Huang p. nature drugs, 2009,8, 579-. ROS levels have been reported to be elevated in a variety of cancer cells, for example, leukemic cells isolated from blood samples from patients with chronic lymphocytic leukemia or hairy cell leukemia have increased ROS production compared to normal lymphocytes (Zhou Y, Hileman E O, Plunkett W, et al blood,2003,101, 4098-. Levels of oxidative damage products such as oxidized DNA bases, lipid peroxides, etc., are increased in solid tumors.
Studies have shown that cellular ROS levels reaching a threshold trigger a series of reactions leading to cell death. Tumor cells have higher ROS levels than normal cells (Fruehauf J P, systems F l. clinical cancer Research,2007,13, 789-. Induction of ROS production or inhibition of the antioxidant system to increase ROS levels in tumor cells is considered an effective anti-tumor strategy. 2011, Raj, etc. found that piperlongumine can selectively kill tumor cells by up-regulating ROS in tumor cells without affecting ROS in normal cells (Raj L, Ide T, Gurkar AU, et al, Nature 2011,475, 231-. Research shows that piperlongumine regulates dynamic balance of redox action and active oxygen through target regulation of thioredoxin (TrxR), so that GSH level in tumor cells is reduced, GSSG level is increased, ROS concentration of the tumor cells is increased, and the tumor cells are subjected to apoptosis or necrosis.
Indeed, piperlongumine has been found to have good anti-tumor activity, but it has some disadvantages, which limit its clinical application. Firstly, the activity of the piperlongumine is not high enough, and the specific action mechanism is not completely clarified; secondly, the raw material of the piperlongumine extracted from the plants is limited, and the consumption of the medicinal material resources required by the production is quite large; in addition, the artificially synthesized piperlongumine has a complex preparation process, needs an expensive metal catalyst and has low reaction yield. Therefore, structural derivatization and structural optimization of piperlongumine are necessary, and an anti-tumor compound which is strong in targeting property, high in efficiency, low in toxicity and easy to synthesize is further screened out.
Disclosure of Invention
According to the structural characteristics of the piperlongumine, the biological activity, the pharmaceutical property and the synthesis difficulty are considered, the novel phenylallylidene cyclohexenone derivative with the TrxR inhibitory activity is designed and synthesized, the C2-C3 double bond and the C7-C8 double bond of a PL active site are reserved, the obvious inhibitory activity is realized on various human-derived tumor cells and drug-resistant tumor cells, the damage to normal cells is small, and the tumor cells can be selectively killed. The preliminary research mechanism shows that the compound can inhibit the activity of TrxR enzyme, improve the ROS level of tumor cells, cause the damage of tumor cell membranes, induce the apoptosis of the tumor cells and promote the antitumor activity of the compound.
The specific technical scheme of the invention is as follows:
a kind of phenyl allyl cyclohexenone derivative has a structure shown in a general formula I:
wherein, R represents one or more substituents on a benzene ring and is one or more selected from H, hydroxyl, halogen group, amino, nitro, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, C1-C6 acyloxy and C1-C6 methoxy ether; x represents H, a halogen group, CN or C1-C6 alkyl. Preferably, R represents H, Br, NO2、OCH3、F、CH3、Cl、N(CH3)2、OH、O(CH2)2OCH3、O(CH2)2O(CH2)2OCH3Or OAcOr several of them.
Preferably, the substitution position of the R on the benzene ring is one or more of 2, 3 and 4 positions.
Preferably, 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)2OCH3X represents H, Cl, Br, CN, CH3。
The preferred structure of the compound of the above general structure is shown in table 1:
table 1 partial compound symbols of general formula i and corresponding structures
I1: (E) -6- ((E) -3-phenylallyl) cyclohex-2-enone;
I2: (E) -6- ((E) -3- (4-bromophenyl) -allylidene) cyclohex-2-enone;
I3: (E) -6- ((E) -3- (2-nitrophenyl) allylidene) cyclohex-2-enone;
I4: (E) -6- ((E) -3- (4-nitrophenyl) allylidene) cyclohex-2-enone;
I5: (E) -6- ((E) -3- (3-hydroxyphenyl) allylene) cyclohex-2-enone;
I6: (E) -6- ((E) -3- (2-methoxyphenyl) allylidene) cyclohex-2-enone;
I7: (E) -6- ((E) -3- (4-methoxyphenyl) allylidene) cyclohex-2-enone;
I8: (E) -6- ((E) -3- (4-fluorophenyl) ylideneAllyl) cyclohex-2-enone;
I9: (E) -6- ((E) -3- (4-methylphenyl) allylidene) cyclohex-2-enone;
I10: (E) -6- ((E) -3- (4-chlorophenyl) allylidene) cyclohex-2-enone;
I11: (E) -6- ((E) -3- (4-dimethylaminophenyl) allylene) cyclohex-2-enone;
I12: (E) -6- ((E) -3- (4-hydroxy-3-methoxyphenyl) allylidene) cyclohex-2-enone;
I13: (E) -6- ((E) -3- (3- (2-methoxyethoxy) phenyl) allylidene) cyclohex-2-enone;
I14: (E) -6- ((E) -3- (3-methoxy-4- (2-methoxyethoxy) phenyl) allylidene) cyclohex-2-enone;
I15: (E) -6- ((E) -3- (3-methoxy-4- (2- (2-methoxyethoxy) ethoxy) phenyl) allylidene) cyclohex-2-enone;
I16: (E) -6- ((E) -3- (3-methoxy-4-acetylphenyl) allylidene) cyclohex-2-enone;
I17: (E) -6- ((Z) -2-chloro-3-phenyl) allylidene) cyclohex-2-enone;
I18: (E) -6- ((Z) -2-bromo-3-phenyl) allylidene) cyclohex-2-enone;
I19: (E) -6- ((Z) -2-cyano-3-phenyl) allylidene) cyclohex-2-enone.
I20: (E) -6- ((Z) -2-methyl-3-phenyl) allylidene) cyclohex-2-enone.
Another object of the present invention is to provide a process for the preparation of the compounds of the general formula I according to the invention, as follows: the cinnamyl aldehyde is prepared by carrying out Adol condensation reaction on substituted or unsubstituted cinnamyl aldehyde and cyclohexene-2-ketone under the catalysis of a catalyst, wherein the structural formula of the substituted or unsubstituted cinnamyl aldehyde is as follows:
r represents one or more substituents on a benzene ring and is selected from H, hydroxyl, halogen group, amino, nitro, C1-C6 alkyl, C1-C6 alkoxy,One or more of alkylamino of C1-C6, acyloxy of C1-C6 and methoxy ether of C1-C6; x represents H, a halogen group, CN or C1-C6 alkyl. Preferably, R represents H, Br, NO2、OCH3、F、CH3、Cl、N(CH3)2、OH、O(CH2)2OCH3、O(CH2)2O(CH2)2OCH3Or OAc.
Preferably, the substitution position of the R on the benzene ring is one or more of 2, 3 and 4 positions.
Preferably, 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)2OCH3X represents H, Cl, Br, CN, CH3。
Preferably, the catalyst is selected from triphenylphosphine, TiCl4One or more of Trimethylsilylimidazole (TMSI) and magnesium bisulfate.
A specific preparation method, which is to dissolve cyclohexene-2-ketone and triphenylphosphine in anhydrous dichloromethane, and add TiCl at the temperature of between 40 ℃ below zero and 78 DEG C4Slowly dropwise adding a cinnamyl aldehyde solution dissolved by dichloromethane, after dropwise adding, recovering the reaction to 0-30 ℃, continuing the reaction for 10-12h, and adding a proper amount of 10% K2CO3The reaction solution was brought to a pH of 8 to 10 to obtain a phenylallylenylcyclohexenone derivative.
The synthetic route is as follows:
the invention also aims to provide application of the cyclohexenone derivative in preparing a medicament with TrxR inhibitory activity. The medicament with the TrxR inhibition activity becomes a medicament for treating and/or preventing cancers, preferably, the cancers are selected from liver cancer, colon cancer, gastric cancer, breast cancer or cervical cancer.
The compounds of the invention can be formulated for administration either alone or in combination with one or more pharmaceutically acceptable carriers. For example, solvents, diluents, etc., and can be used in oral administration forms such as capsules, dispersible powders, tablets, granules, etc. 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 can be self-assembled into nanoparticles alone to improve activity, or in combination with other antineoplastic agents such as alkylating agents (e.g., cyclophosphamide or chlorambucil), antimetabolites (e.g., 5-fluorouracil or hydroxyurea), topoisomerase inhibitors (e.g., camptothecin), mitotic inhibitors (e.g., paclitaxel or vinblastine), DNA intercalators (e.g., doxorubicin) to improve activity, or in combination with radiation therapy. 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 combines the structural characteristics, structure-activity relationship and pharmacophore model of the antitumor drug piperlongumine, on the basis of the piperlongumine, by utilizing the theory of bioelectronics isostere and taking cinnamaldehyde with different substituents as raw materials, thereby designing and synthesizing a novel phenyl allylidene cyclohexenone derivative with TrxR inhibitory activity, simplifying the synthetic route thereof, facilitating mass production, researching the inhibitory action of the derivative on TrxR target spots and malignant tumor cells, finding that the compound not only has strong and selective inhibitory effect on the proliferation of various tumor cells (including liver cancer, breast cancer, gastric cancer, colon cancer, cervical cancer and the like), but also can obviously inhibit the activity of the TrxR enzyme.
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- ((E) -3-phenylallyl) cyclohex-2-enone (I)1) Preparation of
Cyclohexen-2-one (0.48g,5.0mmol) and triphenylphosphine (1.31g,5.0mmol) were dissolved in 50ml of anhydrous dichloromethane and 5ml of 1mol/L TiCl was added at-50 deg.C4After 15min, slowly adding 30ml of cinnamaldehyde (1.32g,10.0mmol) solution dissolved in dichloromethane dropwise into a constant pressure funnel, after half an hour of dropwise addition, returning the reaction to room temperature, continuing the reaction for about 12h, monitoring by TLC, and adding a proper amount of 10% K after the reaction is completed2CO3After the solution was further stirred for about 5 minutes, the reaction solution was adjusted to pH 9, extracted with dichloromethane (50mL × 2), the dichloromethane layer obtained by the extraction was washed with saturated brine (50mL), collected, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (EA: PE ═ 1:3 as an eluent) to obtain 0.90g of a yellow solid product with a yield of 86%. I1The spectrogram data is as follows: ESI-MS (M/z):211[ M + H]+；1H NMR(DMSO-d6,400MHz):7.46(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):188.18,141.07,140.25,135.63,134.28,133.77,131.06,131.02,128.73,128.57,128.31,127.16,125.02,25.45,21.00。
(E) -6- ((E) -3- (4-bromophenyl) -allylidene) cyclohex-2-enone (I)2) Preparation of
Reference I1The synthesis of (4-bromo-cinnamaldehyde) (2.22g,10.0mmol) instead of cinnamaldehyde (1.32g,10.0mmol) was reacted with cyclohexen-2-one (0.48g,5.0mmol) to give the product as a yellow solid, 1.20g, yield: 83 percent. I is2The spectrogram data is as follows: ESI-MS (M/z):289[ M + H]+；1H NMR(DMSO-d6,400MHz):(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):188.15,149.06,138.62,135.62,133.81,131.22,131.02,128.51,128.39,123.69,123.56,122.65,25.59,25.20。
(E) -6- ((E) -3- (2-nitrophenyl) allylidene) cyclohex-2-enone (I)3) Preparation of
Reference I1The synthesis of (1.81g,10.0mmol) of 2-nitro-cinnamaldehyde instead of cinnamaldehyde (1.32g,10.0mmol) was reacted with cyclohexene-2-one (0.48g,5.0mmol) to give the product as a yellow solid, 1.10g, yield: 86 percent. I is3The spectrogram data is as follows: ESI-MS (M/z) 256[ M + H]+；1H NMR(CDCl3,400MHz):7.98(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):181.98,149.46,161.76,147.99,136.11,134.35,133.22,133.05,132.35,131.02,128.84,128.37,127.69,124.85,25.54,25.43。
(E) -6- ((E) -3- (4-nitrophenyl) allylidene) cyclohex-2-enone (I)4) Preparation of
Reference I1By reacting 4-nitro-cinnamaldehyde (1.81g,10.0mmol) instead of cinnamaldehyde (1.32g,10.0mmol) with cyclohexen-2-one (0.48g,5.0mmol), 0.84g of a yellow solid product was obtained, yield: 66 percent. I is4The spectrogram data is as follows: ESI-MS (M/z) 256[ M + H]+；1H NMR(CDCl3,400MHz):8.18(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):187.86,149.49,142.91,136.99,136.57,132.80,130.98,127.37,127.13,124.11,25.56,25.40。
(E) -6- ((E) -3- (3-hydroxyphenyl) allylidene) cyclohex-2-enone (I)5) Preparation of
Reference I1The synthesis of (3-hydroxy-cinnamaldehyde) (1.48g,10.0mmol) instead of cinnamaldehyde (1.32g,10.0mmol) was reacted with cyclohexen-2-one (0.48g,5.0mmol) to give the product as a yellow solid, 0.91g, yield: 80 percent. I is5The spectrogram data is as follows: ESI-MS (M/z):227[ M + H]+。
(E) -6- ((E) -3- (2-methoxyphenyl) allylidene) cyclohex-2-enone (I)6) Preparation of
Reference I1The synthesis of (1.69g,10.0mmol) of 2-methoxy-cinnamaldehyde instead of cinnamaldehyde (1.32g,10.0mmol) was reacted with cyclohexene-2-one (0.48g,5.0mmol) to give the product as a yellow solid, 0.97g, yield: 81 percent. I is6The spectrogram data is as follows: ESI-MS (M/z):241[ M + H]+；1H NMR(DMSO-d6,400MHz):7.53(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):188.42,157.37,149.14,148.97,135.65,133.07,131.16,129.90,127.32,125.69,123.80,120.82,111.01,55.43,25.43,25.22。
(E) -6- ((E) -3- (4-methoxyphenyl) allylidene) cyclohex-2-enone (I)7) Preparation of
Reference I1The synthesis of (4-methoxy-cinnamaldehyde) (1.67g,10.0mmol) instead of cinnamaldehyde (1.32g,10.0mmol) was reacted with cyclohexen-2-one (0.48g,5.0mmol) to give 0.98g of a yellow solid product, yield: 82 percent. I is7The spectrogram data is as follows: ESI-MS (M/z):241[ M + H]+；1H NMR(CDCl3,400MHz):7.44(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):188.41,160.20,149.19,140.22,135.03,132.59,131.21,129.50,128.58,121.07,114.33,55.51,25.39,18.55。
(E) -6- ((E) -3- (4-fluorophenyl) allylidene) cyclohex-2-enone (I)8) Preparation of
Reference I1The synthesis of (1.58g,10.0mmol) of 4-fluoro-cinnamaldehyde instead of cinnamaldehyde (1.32g,10.0mmol) was reacted with cyclohexen-2-one (0.48g,5.0mmol) to give 0.95g of yellow solid product, yield: 83 percent. I is8The spectrogram data is as follows: ESI-MS (M/z):229[ M + H]+；1H NMR(DMSO-d6,400MHz):7.46(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):188.18,164.22,161.76,148.95,138.85,134.20,132.96,131.02,131.25,128.68,122.69,116.08,115.60,25.50,25.32。
(E) -6- ((E) -3- (4-methylphenyl) allylidene) cyclohex-2-enone (I)9) Preparation of
Reference I1The synthesis of (4-methyl-cinnamaldehyde) (1.46g, 10.0mmol) instead of cinnamaldehyde (1.32g,10.0mmol) was reacted with cyclohexen-2-one (0.48g,5.0mmol) to give the product as a yellow solid, 0.90g, yield: 80 percent. I is9The spectrogram data is as follows: ESI-MS (M/z) 225[ M + H]+；1H NMR(DMSO-d6,400MHz):7.54(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):187.63,151.05,140.41,138.89,134.34,134.27,134.12,130.63,129.77,127.67,123.10,25.47,25.24,21.40。
(E) -6- ((E) -3- (4-chlorophenyl) allylidene) cyclohex-2-enone (I)10) Preparation of
Reference I1The synthesis method of (1.66g,10.0mmol) of 4-chloro-cinnamaldehyde instead of cinnamaldehyde (1.32g,10.0mmol) is reacted with cyclohexene-2-one (0.48g,5.0mmol) to obtain 1.06g of yellow solid product, and the yellow solid product is collectedRate: 87 percent. I is10The spectrogram data is as follows: ESI-MS (M/z) 256[ M + H]+；1H NMR(DMSO-d6,400MHz):7.68(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):187.67,151.32,138.78,135.96,135.49,133.55,133.48,130.57,129.33,129.23,124.91,25.50,25.32。
(E) -6- ((E) -3- (4-dimethylaminophenyl) allylidene) cyclohex-2-enone (I)11) Preparation of
Reference I1The synthesis of (1.75g, 10.0mmol) of 4-dimethylamino-cinnamaldehyde instead of cinnamaldehyde (1.32g,10.0mmol) was reacted with cyclohexen-2-one (0.48g,5.0mmol) to give 0.97g of a red solid product, yield: 77 percent. I is11The spectrogram data is as follows: ESI-MS (M/z) 254[ M + H]+；1H NMR(CDCl3,400MHz):7.38(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):188.24,150.85,148.49,141.34,135.87,131.30,128.55,124.90,118.79,112.11,40.26,25.33,25.10。
(E) -6- ((E) -3- (4-hydroxy-3-methoxyphenyl) allylidene) cyclohex-2-enone (I)12) Preparation of
Reference I1The synthesis of (1.78g, 10.0mmol) of 4-hydroxy-3-methoxy-cinnamaldehyde (1.32g,10.0mmol) was reacted with cyclohexen-2-one (0.48g,5.0mmol) to give the product as a yellow solid, 1.13g, yield: 88 percent. I is12The spectrogram data is as follows: ESI-MS (M/z):257[ M + H]+；1H NMR(DMSO-d6,400MHz):7.30(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):188.24,150.85,148.49,141.34,135.87,131.30,128.55,124.90,118.79,112.11,40.26,25.33,25.10。
(E) -6- ((E) -3- (3- (2-methoxyethoxy) phenyl) allylidene) cyclohex-2-oneAlkenones (I)13) Preparation of
Reference I1The synthesis of (3- (2-methoxyethoxy) -cinnamaldehyde (2.06g,10.0mmol) instead of cinnamaldehyde (1.32g,10.0mmol) was reacted with cyclohexen-2-one (0.48g,5.0mmol) to give the product 1.08g as a yellow solid in yield: 76 percent. I is13The spectrogram data is as follows: ESI-MS (M/z):285[ M + H]+。
(E) -6- ((E) -3- (3-methoxy-4- (2-methoxyethoxy) phenyl) allylidene) cyclohex-2-enone (I)14) Preparation of
Reference I1The synthesis of (3-methoxy-4- (2-methoxyethoxy) -cinnamaldehyde (2.36g, 10.0mmol) instead of cinnamaldehyde (1.32g,10.0mmol) was reacted with cyclohexen-2-one (0.48g,5.0mmol) to give the product 1.10g as a yellow solid in yield: 70 percent. I is14The spectrogram data is as follows: ESI-MS (M/z) 315[ M + H ]]+。
(E) -6- ((E) -3- (3-methoxy-4- (2- (2-methoxyethoxy) ethoxy) phenyl) allylidene) cyclohex-2-enone (I)15) Preparation of
Reference I1The synthesis method of (1) is to react 3-methoxy-4- (2- (2-methoxyethoxy) ethoxy-cinnamaldehyde (2.80g, 10.0mmol) instead of cinnamaldehyde (1.32g,10.0mmol) with cyclohexene-2-one (0.48g,5.0mmol) to obtain 1.27g of a yellow solid product with a yield of 71%. I15The spectrogram data is as follows: ESI-MS (M/z):359[ M + H]+。
(E) -6- ((E) -3- (3-methoxy-4-acetylphenyl) allylidene) cyclohex-2-enone (I)16) Preparation of
Reference I1The synthesis of (1.16 g, yield, 1.0 mmol) of 3-methoxy-4-acetyl-cinnamaldehyde (2.20g, 10.0mmol) was reacted with cyclohexen-2-one (0.48g,5.0mmol) instead of cinnamaldehyde (1.32g,10.0mmol) to give the product as a yellow solid: 78 percent. I is16The spectrogram data is as follows: ESI-MS (M/z):299[ M + H]+；1H NMR(CDCl3,400MHz):7.23(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):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- ((Z) -2-chloro-3-phenyl) allylidene) cyclohex-2-enone (I)17) Preparation of
Reference I1The synthesis method of (1.66g,10.0mmol) α -chlorocinnamaldehyde (instead of cinnamaldehyde) (1.32g,10.0mmol) was reacted with cyclohexene-2-one (0.48g,5.0mmol) to give 0.98g yellow solid product, yield: 80%. I17The spectrogram data is as follows: ESI-MS (M/z):245[ M + H]+。
(E) -6- ((Z) -2-bromo-3-phenyl) allylidene) cyclohex-2-enone (I)18) Preparation of
Reference I1The synthesis method of (1) is to react α -bromo-cinnamaldehyde (2.11g, 10.0mmol) instead of cinnamaldehyde (1.32g,10.0mmol) with cyclohexene-2-one (0.48g,5.0mmol) to obtain 1.18g of yellow solid product with 82% yield18The spectrogram data is as follows: ESI-MS (M/z):289[ M + H]+；1H NMR(CDCl3,400MHz):7.66(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) allylidene) cyclohex-2-enone (I)19) Preparation of reference I1The synthesis of (1.57g, 10.0mmol) α -cyanocinnamaldehyde was reacted with cyclohexene-2-one (0.48g,5.0mmol) instead of cinnamaldehyde (1.32g,10.0mmol) to give 0.75g yellow solid product in 64% yield19The spectrogram data is as follows: ESI-MS (M/z) 236[ M + H ]]+；1H NMR(CDCl3,400MHz):7.38(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) allylidene) cyclohex-2-enone (I)20) Preparation of
Reference I1The synthesis method of (1.46g, 10.0mmol) α -methyl cinnamaldehyde was reacted with cyclohexene-2-one (0.48g,5.0mmol) instead of cinnamaldehyde (1.32g,10.0mmol) to give 0.87g yellow solid product with yield of 78%. I20The spectrogram data is as follows: ESI-MS (M/z):224[ M + H]+；1H NMR(CDCl3,400MHz):7.32(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):189.00,149.09,139.72,136.96,134.59,133.93,133.51,130.84,129.23,128.21,127.17,26.71,25.71,18.57。
EXAMPLE 2 assay of the inhibition rates of tumor cell proliferation and Normal cell proliferation of the Compound of the present invention by MTT method
The anti-proliferation activity of the compound on 4 human cancer cell lines is evaluated by adopting a tetramethyl triazole blue colorimetric Method (MTT) in-vitro anti-tumor test. Piperlonguminine (PL) was used as a positive control. Human cancer cell line: liver cancer cell SMMC7721, colon cancer cell HCT116, stomach cancer cell HGC-27, human cervical carcinoma cell Hela, human normal cell: human gastric mucosal epithelial cells GES-1.
The experimental method comprises collecting a bottle of cells in exponential growth phase, adding 0.25% trypsin for digestion to make adherent cells shed to obtain a solution containing 2 × 10/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-I20(compounds dissolved in DMSO and diluted in PBS, test compound concentration of 12.5 u M), each hole 20L, cultured for 72 hours. MTT was added to a 96-well plate at 20. mu.L per well and reacted in an incubator for 4 hours. The supernatant was aspirated, DMSO was added, 150. mu.L per well, and shaken on a plate shaker for 5 minutes. The absorbance of each well was measured at a wavelength of 570nm using an enzyme linked immunosorbent assay to calculate the cell inhibition rate. The results of the experiment are shown in table 2.
The cell inhibition rate (negative control OD value-test substance OD value)/negative control OD value × 100%.
A series of tumor cell antiproliferative activity tests prove that the compound I of the invention is found through pharmacological experiment results (shown in table 2)1-I20At a concentration of 12.5. mu.M, for largeThe proliferation inhibition effect of part of tumor cells is stronger, and especially the inhibition activity of part of compounds is obviously better than that of a positive control medicament Piperlongumine (PL). However, the compounds I of the invention1～I20The cytotoxicity of human normal gastric mucosal GES-1 is obviously lower than that of tumor cells under the same concentration, which shows that the compound of the invention not only has obvious anti-tumor activity to the tumor cells, but also has lower toxicity to the normal cells and certain tumor cell selectivity.
TABLE 2 inhibition of some of the compounds of the invention on human tumor and normal cells% (12.5. mu.M)
ND: not detected
Example 3 intracellular ROS level determination
ROS-Glo Hydrogen peroxide assay (Promega, Southampton, UK) by direct probing for H in cells2O2Levels measure ROS changes. Cells were seeded into 96-well cell culture plates and cultured with test drugs (0.01-12.5. mu.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～I8、I11～I15、I18、I19For representation, ROS levels in tumor cells were tested. The change of ROS of human cervical carcinoma Hela 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 fluorescence intensity. The results show that the compounds I of the invention4～I8、I11～I15、I18、I19Can obviously promote Hela cells in 12.5 mu MThe ROS content of the compound is 3.7-8.9 times of that of the control group, and is better than that of the positive control drug PL (3.2 times of that of the control group).
EXAMPLE 4 study of TrxR inhibitory Activity of Compounds of the present invention
The effect of the test drug (12.5 μ M) on TrxR activity was assessed by the TrxR activity test kit (BioVision, Milpitas, CA, USA). Briefly, the cell lines were lysed in a centrifuge tube with 1 Xbuffer solution and then centrifuged at 10000 Xg for 15 minutes in an ice bath for 20 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. Two wells (with and without inhibitor) were prepared for each sample and triplicate. The reaction buffer and the reaction buffer with the inhibitor added were prepared according to the instructions. The absorbance was measured at 412nm wavelength every 20 seconds for 5 minutes after shaking using a BioTekSynergy HT multimode microplate reader before reading.
The experimental results show that the compound I1～Ⅰ20The compounds have obvious inhibitory activity to TrxR under the concentration of 12.5 mu M, the inhibitory activity data are shown in Table 3, most compounds show stronger or equivalent inhibitory activity to that of a positive control medicament piperlongumine, and the fact that the phenyl allylidene cyclohexenone derivative has better TrxR inhibitory activity is shown to be consistent with that of the phenyl allylidene cyclohexenone derivative which shows the antitumor activity.
TABLE 3 inhibition of TrxR in vitro by partial compounds of the invention (12.5. mu.M)
Claims (11)
1. A kind of phenyl allyl cyclohexenone derivative has a structure shown in a general formula I:
wherein R represents one or more of H, hydroxyl, halogen group, amino, nitro, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, C1-C6 acyloxy and C1-C6 methoxy ether; x represents H, a halogen group, CN or C1-C6 alkyl.
2. Phenylallylenecyclohexenone derivative according to claim 1, characterized in that said R represents H, F, Cl, Br, NO2、OCH3、CH3、N(CH3)2、OH、O(CH2)2OCH3、O(CH2)2O(CH2)2OCH3、OAc。
3. The phenylallylenylcyclohexenone derivative according to claim 1, wherein said R is one or more of the 2-, 3-, 4-positions in the substitution position of the benzene ring.
4. Phenylallylenecyclohexenone derivative according to claim 1, characterized in that said 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)2OCH3X represents H, Cl, Br, CN, CH3。
5. Phenylallylenecyclohexenone derivative according to claim 1, characterized in that it is selected from the following:
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)2OCH3X represents H;
or R represents H, X represents Cl, Br, CN or CH3。
6. The method for preparing phenylallylenecyclohexenone derivative according to claim 1, wherein said substituted or unsubstituted cinnamaldehyde is prepared by Adol condensation reaction with cyclohexene-2-one under catalysis of catalyst, and said substituted or unsubstituted cinnamaldehyde has the structural formula:
r represents one or more of H, hydroxyl, halogen group, amino, nitro, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, C1-C6 acyloxy and C1-C6 methoxy ether; x represents H, a halogen group, CN or C1-C6 alkyl.
7. The method according to claim 6, wherein the catalyst is selected from triphenylphosphine and TiCl4。
8. The method according to claim 6, wherein the cyclohexen-2-one and triphenylphosphine are dissolved in anhydrous dichloromethane, and TiCl is added at-40 to-78 ℃4Slowly dropwise adding a substituted or unsubstituted cinnamaldehyde solution dissolved by dichloromethane, after dropwise adding, recovering the reaction to 0-30 ℃, continuing the reaction for 10-12h, and adding a proper amount of 10% K2CO3The reaction solution was adjusted to pH =8-10 to obtain a phenylallylenylcyclohexenone derivative.
9. Use of a phenylallylenylcyclohexenone derivative according to any one of claims 1 to 5 for the preparation of a medicament having TrxR inhibitory activity.
10. Use according to claim 9, characterized in that the medicament having TrxR inhibitory activity is a medicament for the treatment and/or prevention of cancer.
11. Use according to claim 10, characterized in that said cancer is selected from liver cancer, colon cancer, stomach cancer, breast cancer or cervical cancer.
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910223740.4A CN110002987B (en) | 2019-03-22 | 2019-03-22 | Phenylallylidene cyclohexenone derivative, preparation method and application thereof |
| PCT/CN2020/076878 WO2020192348A1 (en) | 2019-03-22 | 2020-02-27 | Phenyl allylidene cyclohexenone derivatives and preparation method and use |
| AU2020213346A AU2020213346B2 (en) | 2019-03-22 | 2020-02-27 | Phenylallyl cyclohexenone derivatives and their preparation method and application |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910223740.4A CN110002987B (en) | 2019-03-22 | 2019-03-22 | Phenylallylidene cyclohexenone derivative, preparation method and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN110002987A CN110002987A (en) | 2019-07-12 |
| CN110002987B true CN110002987B (en) | 2020-09-15 |
Family
ID=67167849
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910223740.4A Active CN110002987B (en) | 2019-03-22 | 2019-03-22 | Phenylallylidene cyclohexenone derivative, preparation method and application thereof |
Country Status (3)
| Country | Link |
|---|---|
| CN (1) | CN110002987B (en) |
| AU (1) | AU2020213346B2 (en) |
| WO (1) | WO2020192348A1 (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110002987B (en) * | 2019-03-22 | 2020-09-15 | 南通大学 | Phenylallylidene cyclohexenone derivative, preparation method and application thereof |
| CN113336631B (en) * | 2021-06-10 | 2022-12-02 | 南开大学 | Application of artificial synthesis palladium nano-enzyme catalysis compound containing phenolic hydroxyl group connection |
| CN114904012B (en) * | 2021-07-22 | 2023-12-15 | 四川大学华西医院 | Active oxygen self-supplementing amphiphilic block copolymer-drug conjugate, preparation method and application thereof |
| CN115974768B (en) * | 2023-01-06 | 2024-09-27 | 贵州大学 | Preparation method and application of piperlonguminine derivatives containing diaryl urea structure |
| CN116375672B (en) * | 2023-02-21 | 2024-06-25 | 广州医科大学 | Coumarin acrolein derivative, preparation method thereof and application thereof in preparation of antitumor drugs |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BR112012004701A2 (en) * | 2009-09-02 | 2018-06-12 | Canthera Therapeutics Inc | cancer treatment compounds and compositions |
| US10071087B2 (en) * | 2014-07-22 | 2018-09-11 | Bioventures, Llc | Compositions and methods for selectively depleting senescent cells |
| CN110002987B (en) * | 2019-03-22 | 2020-09-15 | 南通大学 | Phenylallylidene cyclohexenone derivative, preparation method and application thereof |
-
2019
- 2019-03-22 CN CN201910223740.4A patent/CN110002987B/en active Active
-
2020
- 2020-02-27 AU AU2020213346A patent/AU2020213346B2/en not_active Ceased
- 2020-02-27 WO PCT/CN2020/076878 patent/WO2020192348A1/en active Application Filing
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 (2)
| Title |
|---|
| Iron Catalyzed Highly Enantioselective Epoxidation of Cyclic Aliphatic Enones with Aqueous H2O2;Olaf Cussó等;《J. Am. Chem. Soc.》;20160122;第138卷;第2732-2738,S8页 * |
| 荜茇明碱对人乳腺癌MDA-MB-231细胞放射增敏作用;姚建新等;《介入放射学杂志》;20141231;第23卷(第2期);第147-152页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN110002987A (en) | 2019-07-12 |
| WO2020192348A1 (en) | 2020-10-01 |
| AU2020213346B2 (en) | 2020-12-17 |
| AU2020213346A1 (en) | 2020-10-08 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN110002987B (en) | Phenylallylidene cyclohexenone derivative, preparation method and application thereof | |
| Bhale et al. | Synthesis of extended conjugated indolyl chalcones as potent anti-breast cancer, anti-inflammatory and antioxidant agents | |
| Zhu et al. | Design, synthesis, and evaluation of chalcone analogues incorporate α, β-Unsaturated ketone functionality as anti-lung cancer agents via evoking ROS to induce pyroptosis | |
| Ratković et al. | Synthesis, characterization, electrochemical studies and antitumor activity of some new chalcone analogues containing ferrocenyl pyrazole moiety | |
| US9145381B2 (en) | Derivative of [(3-hydroxy-4-pyron-2-yl)-methyl]-amine and use thereof as anti-neoplastic drugs | |
| EP2497775A1 (en) | Ferrocene-based compounds and their use as ROS regulating prodrugs | |
| CA2294278C (en) | Chalcones having antiproliferative activity | |
| KR101674145B1 (en) | Decursinol-carbamate derivatives, and pharmaceutical composition containing the same for preventing or treating cancer | |
| CN104151391B (en) | A kind of oleanolic acid derivate with antitumor action and its production and use | |
| WO2018068665A1 (en) | Microtubule protein inhibitor | |
| Ranjbari et al. | Molecular docking, synthesis and evaluation of the antimicrobial, antiproliferative, and antioxidant properties of β-lactam bisindoles | |
| CN113444069B (en) | 2-aryl-4- (1H-pyrazol-3-yl) pyridine LSD1/HDAC double-target inhibitor | |
| CN106673988A (en) | Benzyl cyclohexenone derivative and preparation method and medical application thereof | |
| US9682931B2 (en) | Aryloyl(oxy or amino)pentafluorosulfanylbenzene compound, pharmaceutically acceptable salt thereof, and prodrugs thereof | |
| CN107573318A (en) | A kind of new gossypol Schiff bases derivative and its synthetic method for having antitumor activity | |
| CN109516926B (en) | Preparation and application of piperlonguminine derivative | |
| KR20150041786A (en) | Combination therapy for the treatment of cancer and immunosuppression | |
| CN111018686B (en) | 6-benzylidene-2-aryl ethynyl cyclohexenone derivative and preparation method and medical application thereof | |
| CN113527195B (en) | 5-aryl nicotinamide LSD1/HDAC double-target inhibitor, preparation method and application thereof | |
| CN103012394B (en) | Rhodanine derivative and preparation method thereof | |
| CN111646937A (en) | Propenone derivative of N-acetyl ciprofloxacin and preparation method and application thereof | |
| CN110183471B (en) | Piperazine derivative, preparation method and application | |
| CN110229112B (en) | Anti-tumor immunoregulation conjugate and preparation method and application thereof | |
| CN110981713B (en) | Preparation method and application of 4-hydroxy emodin | |
| Al-Hazmi | Synthesis, spectroscopic characterizations and cytotoxic activities of some novel 1, 2-bis-(tetrasubstituted-benzylidene) hydrazine analogues |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |