Sesquiterpene lactone derivatives with anti-inflammatory and anticancer activities, preparation method and use thereof

Abstract

The present invention provides a sesquiterpene lactone derivative with anti-inflammatory and anticancer activity, as well as a preparation method and use thereof. Specifically, the present invention provides a compound represented by the following formula I, or a hydrate, solvate, stereoisomer, racemate, or pharmaceutically acceptable salt or prodrug thereof, wherein R1 and R2 are as defined herein. Compound I is an NF-κB inhibitor. Therefore, the compounds of the present invention can be used to treat or prevent NF-κB-mediated diseases, disorders, and conditions, such as cancer and inflammation.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical chemistry, and particularly relates to a sesquiterpene lactone derivative with anti-inflammatory and anti-cancer activities, a preparation method and use thereof. Background Art

[0002] Nuclear factor kappa B (NF-κB) is a protein complex that selectively binds to the B cell kappa-light chain enhancer to regulate the expression of many genes (Sen RB D. Cell, 1986, 46(5):705-716). NF-κB is present in almost all animal cell types and participates in the body's inflammatory and immune responses, regulating apoptosis and stress responses (Ghosh MJM a S. Immunol Today, 1998, 19(2):80-88). Improper regulation of NF-κB is associated with cancer, inflammatory and autoimmune diseases, septic shock, viral infections, and improper immune development.

[0003] The NF-κB family has five members, including NF-κB1 (p50), NF-κB2 (p52), RelA (p65), RelB, and c-Rel (Caamano J, Hunter CA. Clin Microbiol Rev, 2002, 15(3):414-429.). There are three main signal transduction pathways that activate NF-κB: the canonical pathway, the alternative pathway, and the atypical pathway (Karin M, Greten FR. Nat Rev Immunol, 2005, 5(10):749-759.). NF-κB1, RelA, and c-Rel are all activated by the canonical pathway, while NF-κB2 and RelB are activated by the alternative pathway. In addition, there is an atypical pathway induced by factors such as DNA oxidative damage (Vallabhapurapu S, Karin M. Annu Rev Immunol, 2009, 27:693-733.).

[0004] In the classical pathway, when stimulatory factors such as tumor necrosis factor α (TNF-α), interleukin-1, phorbol esters, and lipopolysaccharide (LPS) bind to the relevant receptors, the latter change their conformation, thereby activating IkBα kinase, which can phosphorylate IkBα. Then, under the action of the ubiquitin ligase P-TrCP, it is ubiquitinated and can be recognized and degraded by the 26S proteasome (Schmid JA, Birbach A. Cytokine Growth Factor Rev, 2008, 19(2):157-165.; Perkins ND, Gilmore TD. Cell Death Differ, 2006, 13(5):759-772.). NF-κB is then released from the cytoplasmic NF-κB / IkBα complex, activated, and the nuclear localization domain is exposed, forming a p50 / RelA dimer, which rapidly undergoes nuclear translocation and binds to the NF-κB binding site in the promoter region of the target gene through the p50 subunit, thereby initiating target gene expression.

[0005] In some tumor cells, NF-κB is active due to genetic mutations in the transcription factor encoding NF-κB itself or in genes that control NF-κB activity; in addition, some tumor cells secrete factors that lead to NF-κB activation (Raychaudhuri B, Han Y, Lu T, et al. J Neurooncol, 2007, 85(1):39-47.; Shoichi Nagai KW, Masanori Kurimoto, Akira Takaku, Shunro Endo, Toshiro Kumanishi. Journal of Neurosurgery, 2002, 96(5):909-917.). Blocking NF-κB can cause tumor cells to stop proliferating, die, or become more sensitive to anti-tumor agents (Salem K, Brown CO, Schibler J, et al. Exp Hematol, 2013, 41(2):209-218; Rushworth SA, Bowles KM, Barrera LN, et al. Cell Signal, 2013, 25(1):106-112). Therefore, NF-κB is an active research topic as a target for anti-cancer therapy.

[0006] NF-κB can induce the excessive or sustained expression of a variety of inflammatory target genes, such as cytokines, chemokines, adhesion molecules, immune recognition receptors and some enzymes related to the inflammatory cascade, thereby attracting a large number of inflammatory cells such as neutrophils to infiltrate and accumulate at the site of inflammation, inducing the production of inflammatory effector molecules such as nitric oxide and prostaglandins, and ultimately causing an inflammatory response.

[0007] Currently, inhibitors of the NF-κB signaling pathway are mainly divided into specific inhibitors and nonspecific inhibitors. Specific inhibitors target the IKK complex and the NF-κB dimer, respectively. Since the IKK complex is the main pathway for activating the NF-κB signaling pathway, there are a large number of inhibitors targeting the IKK complex. For example, BAY11-7082, curcumin, and celecoxib can all inhibit the IKK complex (Zanotto-Filho A, Braganhol E, Schroder R, et al. Biochem Pharmacol, 2011, 81(3): 412-424.). However, even inhibitors with high specificity such as BAY11-7082 can regulate other signaling pathways while inhibiting the NF-κB signaling pathway (Lee J, Rhee MH, Kim E, et al. Mediators Inflamm, 2012, 2012: 416036.). There are relatively few inhibitors that directly target NF-κB dimers, such as DHMEQ, which can bind to cysteine ​​residues of NF-κB family proteins to block the binding of dimers to DNA, thereby producing an inhibitory effect (Mizuki Yamamoto RH, Masatoshi Takeiri, Ikuko Kozawa, Kazuo Umezawa. J Med Chem, 2008, 51(18):5780-5788.). Currently, nonspecific inhibitors of the NF-κB pathway are mainly proteasome inhibitors, such as bortezomib (Premkumar DR, Jane EP, Agostino NR, et al. Mol Carcinog, 2013, 52(2):118-133.; Daniel R Premkumar EPJ, Naomi R Agostino, Joseph D Didomenico, Ian F Pollack. Molecular Carcinogenesis, 2013, 52(2):118-133.). They inhibit the activity of the proteasome and thus block the ubiquitination and degradation of IκBα, thereby maintaining its inhibitory effect on NF-κB.

[0008] Therefore, there is still a need for novel compounds that can serve as potent inhibitors of NF-κB and are beneficial for the treatment of cancer or inflammation. Summary of the Invention

[0009] The present invention provides novel sesquiterpene lactone derivatives having the structure shown in Formula I below, or their hydrates, solvates, stereoisomers, racemates, or pharmaceutically acceptable salts or prodrugs:

[0010]

[0011] In formula I, R1 is selected from C 1-4 Alkyl, C 2-4 Alkenyl, C 3-8 Cycloalkyl, aryl and heteroaryl, R2 is selected from C 1-4 Alkyl, C 2-4 Alkenyl, C 3-8 Cycloalkyl, aryl and heteroaryl.

[0012] In one or more embodiments, the compound of formula I is a compound represented by the following formula 1 ((±)-1,10-dehydroxerantholide):

[0013]

[0014] The present invention also relates to a process for preparing the compound of formula I.

[0015] The present invention also provides a pharmaceutical composition comprising as an active ingredient a compound of Formula I or a compound of Formula 1 or a hydrate, solvate, stereoisomer, racemate or a pharmaceutically acceptable salt or prodrug thereof.

[0016] In one or more embodiments, the pharmaceutical composition may further contain one or more pharmaceutically acceptable carriers.

[0017] In one or more embodiments, the pharmaceutical composition may further contain at least one known anticancer drug or a pharmaceutically acceptable salt of the anticancer drug.

[0018] In one or more embodiments, the pharmaceutical composition may further contain at least one known anti-inflammatory drug or a pharmaceutically acceptable salt of the anti-inflammatory drug.

[0019] In one or more embodiments, the pharmaceutical composition is used to treat or prevent a disease that benefits from inhibition of the NF-κB signaling pathway. Preferably, the disease is cancer or inflammation.

[0020] The present invention also provides the use of a compound of Formula I or a compound of Formula 1, or a hydrate, solvate, stereoisomer, racemate, or a pharmaceutically acceptable salt or prodrug thereof, in the preparation of a drug for treating or preventing a disease that benefits from inhibition of the NF-κB signaling pathway, or in the preparation of an NF-κB inhibitor. Preferably, the disease is cancer or inflammation. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 :Chiral HPLC chromatogram of (±)-1,10-dehydro-glaucolide.

[0022] Figure 2:Chiral HPLC chromatogram of (–)-1,10-dehydro-glaucolide.

[0023] Figure 3 :Chiral HPLC chromatogram of (+)-1,10-dehydro-glaucolide.

[0024] Figure 4 :(±)-1,10-Dehydrogenin lactone is cytotoxic to multiple cell lines.

[0025] Figure 5 :(±)-1,10-Dehydrogenin lactone on the apoptosis of MDA-MB-231 cells.

[0026] Figure 6 :Effects of (±)-1,10-dehydrogenated chrysanthellactone on the levels of apoptosis-related proteins in MDA-MB-231 cells.

[0027] Figure 7 :Effects of (±)-1,10-dehydrogenin on the levels of NF-κB pathway-related proteins in MDA-MB-231 cells.

[0028] Figure 8 : Cytotoxicity of chiral isomers of 1,10-dehydro-glaucolide.

[0029] Figure 9 :(+)-1,10-dehydro-glaucolide has an apoptotic effect on MDA-MB-231 cells.

[0030] Figure 10 : A, The effect of (+)-1,10-dehydro-glaucinone in inducing apoptosis of MDA-MB-231 cells is concentration-dependent; B, The effect of (+)-1,10-dehydro-glaucinone in inducing apoptosis of MDA-MB-231 cells is time-dependent.

[0031] Figure 11 :Effect of (+)-1,10-dehydrogenin on NF-κB pathway.

[0032] Figure 12 :Effect of (+)-1,10-dehydrogenin on the intracellular distribution of p65.

[0033] Figure 13 :(±)-1,10-Dehydro-glaucolide affects nitric oxide release (left) and cytotoxicity (right) of mouse macrophage RAW264.7 cells.

[0034] Figure 14: A, Effects of (±)-1,10-dehydro-glaucinone on the NF-κB signaling pathway at different time periods; B, Effects of (±)-1,10-dehydro-glaucinone on the distribution of P65 in the cytoplasm and nucleus.

[0035] Figure 15 :A, Effects of (+)-1,10-dehydro-glaucinone and (-)-1,10-dehydro-glaucinone on the release of nitric oxide from mouse macrophages RAW264.7; B, Effects of (-)-1,10-dehydro-glaucinone on the release of nitric oxide from mouse macrophages RAW264.7; C, Effects of (-)-1,10-dehydro-glaucinone on the cytotoxicity of RAW264.7 cells.

[0036] Figure 16 :A, The inhibitory effect of (-)-1,10-dehydro-glaucinone on the NF-κB signaling pathway in RAW264.7 cells was concentration-dependent; B, The inhibitory effect of (-)-1,10-dehydro-glaucinone on the NF-κB signaling pathway in RAW264.7 cells was time-dependent.

[0037] Figure 17 :A, The effect of (-)-1,10-dehydro-glaucinone on reducing the nuclear translocation of P65 in RAW264.7 cells was concentration-dependent; B, The effect of (-)-1,10-dehydro-glaucinone on reducing the nuclear translocation of P65 in RAW264.7 cells was time-dependent.

[0038] Figure 18 :Effects of (-)-1,10-dehydrogenated chrysanthellactone on iNOS and COX-2. DETAILED DESCRIPTION

[0039] After extensive and in-depth research, the inventors have prepared a class of sesquiterpene lactone derivatives having the structure represented by Formula I and discovered that they possess anti-inflammatory and anti-cancer activities. Specifically, the inventors discovered that compounds of Formula I can significantly inhibit the NF-κB signaling pathway, thereby inducing tumor cell apoptosis or exerting anti-inflammatory activity. Therefore, they are useful for treating and preventing diseases associated with the NF-κB signaling pathway, such as cancer and inflammation. Based on these findings, the inventors have completed the present invention.

[0040] It should be understood that within the scope of the present invention, the above-mentioned various technical features of the present invention and the various technical features specifically described below (such as in the examples) can be combined with each other to form new or preferred technical solutions. The definitions of various groups herein apply to any embodiment described herein. For example, the definitions of substituents of alkyl herein apply to any embodiment described herein, unless the embodiment clearly defines substituents of alkyl.

[0041] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0042] As used herein, the terms "comprising" or "including" may be open, semi-closed or closed. In other words, the terms also include "consisting essentially of" or "consisting of."

[0043] Definitions of standard chemical terms can be found in the references (including Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY 4THED." Vols. A (2000) and B (2001), Plenum Press, New York). Unless otherwise indicated, conventional methods within the skill of the art, such as mass spectrometry, NMR, IR and UV / VIS spectroscopy and pharmacological methods, are used. Unless otherwise specified, the terms used herein in the descriptions of analytical chemistry, synthetic organic chemistry, and pharmaceuticals and medicinal chemistry are known in the art. Standard techniques can be used in chemical synthesis, chemical analysis, pharmaceutical preparation, formulation and delivery, and in the treatment of patients. For example, the manufacturer's instructions for use of the kit can be utilized, or reactions and purifications can be carried out in accordance with methods well known in the art or the description of the present invention. The above techniques and methods can generally be implemented according to conventional methods well known in the art, as described in the various general and more specific references cited and discussed in this specification. In this specification, groups and substituents thereof can be selected by those skilled in the art to provide stable structural moieties and compounds.

[0044] Certain chemical groups defined herein are preceded by a shorthand notation to indicate the total number of carbon atoms present in the group. For example, C 1-4 Alkyl refers to an alkyl group as defined below having a total of 1 to 4 carbon atoms. The total number of carbon atoms in the shorthand notation does not include carbons that may be present in substituents of the group being described.

[0045] In the present invention, as a group or part of other groups, the term "alkyl" refers to a fully saturated straight-chain or branched hydrocarbon group consisting only of carbon atoms and hydrogen atoms, having, for example, 1 to 12 (preferably 1 to 6, more preferably 1 to 4) carbon atoms, and connected to the rest of the molecule by a single bond, such as, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.

[0046] In the present invention, as part of a group or other group, the term "alkenyl" refers to a straight or branched hydrocarbon group containing at least one double bond, consisting only of carbon atoms and hydrogen atoms, having, for example, 2 to 12 (preferably 2 to 6, more preferably 2 to 4) carbon atoms, and connected to the rest of the molecule by a single bond, for example, including but not limited to ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl and 2-butenyl, etc.

[0047] In the present invention, as a group or part of other groups, the term "cycloalkyl" refers to a saturated hydrocarbon group containing an alicyclic structure, consisting only of carbon atoms and hydrogen atoms, having, for example, 3 to 8 (preferably 3 to 6, more preferably 3 to 4) carbon atoms, and connected to the rest of the molecule by a single bond, for example, including but not limited to cyclopropyl, cyclobutyl, etc.

[0048] As used herein, "aryl" refers to a conjugated hydrocarbon ring system containing from 6 to 18 ring atoms, either as an aromatic group or as part of another group, wherein the ring atoms are carbon atoms. Aryl groups can be monocyclic, bicyclic, tricyclic, or higher ring systems. Examples of aryl groups include phenyl, naphthyl, phenanthrenyl, anthracenyl, indenyl, azulenyl, biphenyl, biphenylene, and fluorenyl.

[0049] As used herein, "heteroaryl" refers to a conjugated heterocyclic ring system containing 5 to 16 ring atoms, either as a heteroaryl group or as part of a group, wherein the ring atoms are carbon atoms and 1 to 6 heteroatoms selected from oxygen, nitrogen, and sulfur. A heteroaryl group can be a monocyclic, bicyclic, tricyclic, or multicyclic ring system. Examples of heteroaryl groups include, but are not limited to, thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzimidazolyl, benzopyrazolyl, indolyl, furanyl, pyrrolyl, triazolyl, tetrazolyl, triazinyl, indolizinyl, isoindolyl, indazolyl, isoindazolyl, purinyl, quinolyl, isoquinolyl, naphthazinyl, naphthyridinyl, quinoxalinyl, pteridinyl, carbazolyl, carbolinyl, phenanthridinyl, phenanthrolinyl, acridinyl, phenazinyl, isothiazolyl, benzothiazolyl, benzothiophenyl, oxatriol, oxazolyl, cinnolinyl, quinazolinyl, phenylthio, indolizinyl, o-phenanthroline, isoxazolyl, phenoxazinyl, phenothiazinyl, 4,5,6,7-tetrahydrobenzo[b]thienyl, naphthopyridinyl, [1,2,4]triazolo[4,3-b]pyridazine, [1,2,4]triazolo[4,3-a]pyrazine, [1,2,4]triazolo[4,3-c]pyrimidine, [1,2,4]triazolo[4,3-a]pyridine, imidazo[1,2-a]pyridine, imidazo[1,2-b]pyridazine, imidazo[1,2-a]pyrazine, etc.

[0050] As used herein, the terms "moiety," "moiety," "chemical moiety," "group," and "chemical group" refer to specific segments or functional groups in a molecule. A chemical moiety is generally considered to be a chemical entity embedded in or attached to a molecule.

[0051] "Stereoisomers" refer to compounds composed of the same atoms, bonded by the same bonds, but having different three-dimensional structures. The present invention is intended to encompass various stereoisomers and mixtures thereof.

[0052] The compounds of the present invention, or pharmaceutically acceptable salts thereof, may contain one or more chiral carbon atoms and may therefore give rise to enantiomers, diastereomers, and other stereoisomeric forms. Each chiral carbon atom may be defined as (R)- or (S)- based on stereochemistry. The present invention is intended to include all possible isomers, as well as racemates and optically pure forms thereof. The compounds of the present invention may be prepared using racemates, diastereomers, or enantiomers as starting materials or intermediates. Optically active isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as crystallization and chiral chromatography.

[0053] Some compounds of the present invention may exist as stereoisomers, including optical isomers. The present invention includes all stereoisomers and racemic mixtures of such stereoisomers, as well as individual enantiomers that can be separated according to methods well known to those skilled in the art.

[0054] In the present application, the term "pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0055] "Pharmaceutically acceptable acid addition salts" refer to salts formed with inorganic or organic acids that retain the biological effectiveness of the free base without the side effects. Inorganic acid salts include, but are not limited to, hydrochlorides, hydrobromides, sulfates, nitrates, and phosphates; organic acid salts include, but are not limited to, formates, acetates, 2,2-dichloroacetates, trifluoroacetates, propionates, caproates, caprylates, decanoates, undecylenates, glycolates, gluconates, lactates, sebacates, adipates, glutarates, malonates, oxalates, maleates, succinates, fumarates, tartrates, citrates, palmitates, stearates, oleates, cinnamates, laurates, malates, glutamate, pyroglutamate, aspartate, benzoates, methanesulfonates, benzenesulfonates, p-toluenesulfonates, alginate, ascorbate, salicylates, 4-aminosalicylates, and naphthalene disulfonates. These salts can be prepared by methods known in the art.

[0056] "Pharmaceutically acceptable base addition salts" refer to salts formed with inorganic or organic bases that retain the biological effectiveness of the free acid without other side effects. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Preferred inorganic salts are ammonium, sodium, potassium, calcium, and magnesium salts. The salt derived from organic base includes but is not limited to following salt: primary amines, secondary amines and tertiary amines, substituted amines, including natural substituted amines, cyclic amines and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins etc. Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine. These salts can be prepared by methods known in the art.

[0057] Examples of prodrugs of the compounds of the invention include simple esters of carboxylic acid-containing compounds (e.g., by reacting with C 1-4 esters of compounds containing hydroxyl groups (for example, by reacting with C 1-4 Carboxylic acid, C 3-6 esters obtained by condensation of diacids or their anhydrides, such as succinic anhydride and fumaric anhydride); imines of compounds containing amino groups (for example, by reacting with C 1-4 (J. Med. Chem. 1999, 42: 3623-3628) and Greenwald et al. (J. Med. Chem. 1999, 42: 3657-3667); acetals or ketal of compounds containing alcohols (e.g., those obtained by condensation with chloromethyl methyl ether or chloromethyl ethyl ether according to methods known in the art).

[0058] The present invention provides a compound represented by Formula I, or a hydrate, solvate, stereoisomer, racemate, or pharmaceutically acceptable salt or prodrug thereof:

[0059]

[0060] In formula I, R1 is selected from C 1-4 Alkyl, C 2-4 Alkenyl, C 3-8 Cycloalkyl, aryl and heteroaryl, R2 is selected from C 1-4 Alkyl, C 2-4Alkenyl, C 3-8 Cycloalkyl, aryl and heteroaryl.

[0061] Preferably, the compound of formula I is a compound represented by the following formula 1:

[0062]

[0063] In the present invention, the compound of formula 1 is named (±)-1,10-dehydroxerantholide.

[0064] The compounds of the present invention can be prepared using the methods provided by the present invention. The present invention provides a method for preparing the compound of formula I of the present invention, comprising the following steps:

[0065] (1) reacting a compound of formula VII with a compound of formula VIII in the presence of a metallic copper catalyst to obtain a compound of formula IX;

[0066]

[0067] (2) reacting the compound of formula IX with a cyanide source reagent in the presence of a metal palladium catalyst to obtain a compound of formula X;

[0068]

[0069] (3) reacting the compound of formula X with a bromination reagent to obtain a compound of formula IV;

[0070]

[0071] (4) oxidizing the hydroxyl group of the compound of formula VI to an aldehyde group to obtain a compound of formula V;

[0072]

[0073] (5) reacting the compound of formula IV with the compound of formula V to obtain the compound of formula III;

[0074]

[0075] (6) reacting the compound of formula III in the presence of an acid to obtain a compound of formula II;

[0076]

[0077] (7) reacting the compound of formula II in the presence of a metal catalyst in a CO atmosphere to obtain the compound of formula I;

[0078]

[0079] In Formula I to Formula X, R1 and R2 are as described in any embodiment of the compound of Formula I.

[0080] The reaction in step (1) can be carried out in tetrahydrofuran (THF), usually at a low temperature (e.g., -40±5°C) for a period of time, and then at room temperature for a period of time. Metallic copper catalysts that can be used in step (1) include, but are not limited to, cuprous bromide dimethyl sulfide and cuprous cyanide.

[0081] The reaction of step (2) can be carried out in N,N-dimethylformamide (DMF), and the reaction is usually carried out under heating (e.g., 80±5° C.). The cyanide source reagent is a reagent that can provide a cyanide group, including cyanide, such as zinc cyanide and sodium cyanide. The metal palladium catalyst can be a palladium catalyst that can be used in the art to replace the halogen such as iodine in the reactant with a cyanide group, including but not limited to tetrakis(triphenylphosphine)palladium.

[0082] The reaction of step (3) can be carried out in dichloromethane, and the reaction is usually carried out at a low temperature (e.g., -78 ± 5 ° C). The brominating agent is usually a reagent containing bromine, including but not limited to N-bromosuccinimide, phosphine tribromide and carbon tetrabromide. When using different brominating agents, it may be necessary to use a suitable catalyst together. The catalyst is usually triphenylphosphine. For example, when the brominating agent is N-bromosuccinimide or carbon tetrabromide, the reaction needs to be carried out in the presence of triphenylphosphine.

[0083] The reaction in step (4) can be carried out in dichloromethane, and the reaction temperature is usually room temperature. The hydroxyl group can be oxidized to an aldehyde group using an oxidizing agent conventional in the art. Suitable oxidizing agents include, but are not limited to, pyridinium chlorochromate, Desmartin, oxalyl chloride / DMSO / triethylamine, and the like.

[0084] The reaction of step (5) can be carried out in a mixed solvent of THF and water, and the reaction temperature is usually room temperature. The reaction of step (5) can be carried out in the presence of indium, zinc, SnCl2 or CrCl2.

[0085] The reaction in step (6) can be carried out in toluene, usually under heating (e.g., 60±5° C.). An organic acid or inorganic acid known in the art can be used to provide an acidic environment. Suitable acids include, but are not limited to, hydrochloric acid, sulfuric acid, and camphorsulfonic acid.

[0086] The reaction of step (7) can be carried out in toluene, and the reaction is usually carried out under heating (eg, 110±5° C.). The metal catalyst can be tetracarbonyl dirhodium dichloride, octacarbonyl dicobalt, etc.

[0087] In particular, compound 1 (compound of formula 1) can be prepared as shown in the reaction example in reaction scheme 1: diiodide compound 7 and propyne magnesium bromide 8 are reacted in THF in the presence of cuprous bromide dimethyl sulfide at low temperature (e.g., -40±5°C) and then at room temperature to obtain cis-allyl alcohol 9; cis-allyl alcohol 9 and zinc cyanide are reacted in DMF in the presence of tetrakis(triphenylphosphine)palladium under heating (e.g., 80±5°C) to obtain alkenyl nitrile 10; alkenyl nitrile 10 and N-bromosuccinimide are reacted in dichloromethane in the presence of PPh3. The reaction is carried out in alkane at low temperature (e.g., -78±5°C) to obtain allyl bromide 4; allenol 6 and PCC are reacted in dichloromethane at room temperature to obtain compound 5; compound 4 and compound 5 are reacted in the presence of indium powder in a mixed solvent of THF and water at room temperature to obtain compound 3; compound 3 and camphorsulfonic acid are reacted in toluene with heating (e.g., 60±5°C) to obtain compound 2; compound 2 and [Rh(CO)2Cl]2 are reacted in toluene under CO atmosphere with heating (e.g., 110±5°C) to obtain compound 1.

[0088] Reaction Scheme 1

[0089]

[0090] The chiral product of compound 1 can be obtained by chiral column separation (CHIRALPAK AS-H column, MeOH, 1.0 mL / min) of compound 1. The peak compound at 2.92 min is (–)-1,10-dehydro-glaucinone (compound (–)-1), [α]26D=–294 (c=1.0 in CHCl3); the peak compound at 3.51 min is (+)-1,10-dehydro-glaucinone (compound (+)-1), [α]26D=+245 (c=1.0 in CHCl3).

[0091]

[0092] An important aspect of the present invention is the discovery that compounds of Formula I of the present invention (including Compound 1 as described herein) are NF-κB inhibitors. Therefore, compounds of Formula I of the present invention (including Compound 1 as described herein) or hydrates, solvates, stereoisomers, racemates, or pharmaceutically acceptable salts or prodrugs thereof can be used to treat diseases, disorders, and conditions mediated by NF-κB, or to prepare medicaments for treating diseases, disorders, and conditions mediated by NF-κB, or to prepare NF-κB inhibitors. As used herein, diseases, disorders, and conditions mediated by NF-κB refer to diseases, disorders, and conditions that benefit from inhibition of the NF-κB signaling pathway.

[0093] The present invention also includes a method for treating or preventing NF-κB-mediated diseases, which comprises administering to a subject an effective amount of a compound of Formula I of the present invention (including Compound 1 described herein) or a hydrate, solvate, stereoisomer, racemate or a pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition containing an effective amount of a compound of Formula I of the present invention (including Compound 1 described herein) or a hydrate, solvate, stereoisomer, racemate or a pharmaceutically acceptable salt or prodrug thereof.

[0094] In the present invention, NF-κB mediated diseases, disorders and conditions include, but are not limited to, cancer and inflammation. Cancer can be a solid tumor or a blood tumor, including, but not limited to, liver cancer, melanoma, Hodgkin's disease, non-Hodgkin's lymphoma, acute lymphoblastic leukemia, chronic lymphoblastic leukemia, multiple myeloma, neuroblastoma, breast cancer (such as triple-negative breast cancer), ovarian cancer, lung cancer, Wilms' tumor, cervical cancer, testicular cancer, soft tissue sarcoma, primary macroglobulinemia, bladder cancer, chronic myeloid leukemia, primary brain cancer, malignant melanoma, small cell lung cancer, gastric cancer, In some embodiments, the present invention relates to a group of cancers that are classified as comprising cancer, colon cancer, malignant pancreatic insulinoma, malignant carcinoid cancer, choriocarcinoma, mycosis fungoides, head and neck cancer, osteogenic sarcoma, pancreatic cancer, acute myeloid leukemia, hairy cell leukemia, rhabdomyosarcoma, Kaposi's sarcoma, genitourinary tumors, thyroid cancer, esophageal cancer, malignant hypercalcemia, cervical hyperplasia, renal cell carcinoma, endometrial cancer, polycythemia vera, essential thrombocythemia, adrenocortical carcinoma, skin cancer and prostate cancer. In some embodiments, the cancer is breast cancer, such as triple-negative breast cancer. Inflammation includes but is not limited to rheumatoid arthritis, atherosclerosis, chronic inflammatory demyelinating polyneuritis, multiple sclerosis, polyneuritis, asthma, inflammatory bowel disease, Helicobacter pylori-associated gastritis, sepsis, glomerulonephritis, psoriasis, myocardial reperfusion injury and systemic inflammatory response syndrome. In some embodiments, the inflammation is macrophage-associated inflammation. In a particularly preferred embodiment, the compound is (-)-1,10-dehydro-glaucinolactone represented by the formula (-)-1 or (+)-1,10-dehydro-glaucinolactone represented by the formula (+)-1, or a racemate formed by the two, and the disease is breast cancer, more preferably triple-negative breast cancer; or the compound is (-)-1,10-dehydro-glaucinolactone represented by the formula (-)-1, and the disease is inflammation, especially macrophage-related inflammation.

[0095] When practicing the treatment method of the present invention, an effective amount of a pharmaceutical preparation is administered to a patient with one or more of these symptoms. The pharmaceutical preparation contains an effective therapeutic concentration of a compound of formula I of the present invention (including compound 1 as described herein) or a hydrate, solvate, stereoisomer, racemate or a pharmaceutically acceptable salt or prodrug thereof, formulated for oral, intravenous, local or external administration, for the treatment of cancer, inflammation and other diseases. The dosage is an amount that effectively improves or eliminates one or more symptoms. For the treatment of a specific disease, an effective amount is an amount that is sufficient to improve or alleviate in some way the symptoms associated with the disease. Such a dosage can be administered as a single dose or can be administered according to an effective treatment regimen. The dosage may cure the disease, but administration is generally intended to improve the symptoms of the disease. Repeated administration is generally required to achieve the desired symptom improvement.

[0096] In another embodiment, a pharmaceutical composition is provided, which contains a compound of formula I of the present invention (including compound 1 described herein) as an NF-κB inhibitor, or a hydrate, solvate, stereoisomer, racemate or a pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable carrier.

[0097] As used herein, a "pharmaceutical composition" refers to a formulation of a compound of the present invention and a medium generally accepted in the art for delivering a biologically active compound to a mammal (e.g., a human). The medium includes a pharmaceutically acceptable carrier. The purpose of a pharmaceutical composition is to facilitate administration to an organism, thereby facilitating the absorption of the active ingredient and thereby exerting its biological activity. A pharmaceutical composition typically contains an effective amount of a compound of the present invention (e.g., 0.01-100 mg of the compound of the present invention).

[0098] As used herein, the term "pharmaceutically acceptable" or "pharmaceutically usable" refers to a substance (such as a carrier or diluent) that does not affect the biological activity or properties of the compounds of the present invention and is relatively non-toxic, that is, the substance can be administered to a subject without causing an adverse biological response or interacting in an adverse manner with any components contained in the composition.

[0099] As used herein, the terms "effective amount," "therapeutically effective amount," or "pharmaceutically effective amount" refer to an amount of at least one agent or compound sufficient, upon administration, to provide some relief to some degree from one or more symptoms of the disease or condition being treated. This can result in a reduction and / or alleviation of signs, symptoms, or causes of disease, or any other desired change in a biological system. For example, an "effective amount" for therapeutic purposes is the amount of a composition comprising a compound disclosed herein required to provide a clinically significant alleviation of symptoms.

[0100] Another embodiment of the present invention relates to a pharmaceutical composition that is effective for treating cancer, wherein the compound of formula I of the present invention (including compound 1 as described herein) or a hydrate, solvate, stereoisomer, racemate or a pharmaceutically acceptable salt or prodrug thereof, which is an NF-κB inhibitor, is used in combination with at least one known anticancer drug or a pharmaceutically acceptable salt of an anticancer drug, in particular, in combination with at least one of the following drugs: anticancer drugs related to DNA damage and repair mechanisms, including PARP inhibitors Olaparib, Niraparib, Rucaparib and Talazoparib; HDAC inhibitors, including Vorinostat, Romidepsin, Panobinostat and Beliscine; Others; Anticancer drugs related to cell division checkpoints, including Chk1 / 2 inhibitors, CDK4 / 6 inhibitors such as palbociclib, ATR inhibitors; Other known anticancer drugs that can be used for anticancer combination therapy, including but not limited to alkylating agents such as busulfan, melphalan, chlorambucil, cyclophosphamide, ifosfamide, temozolomide, bendamustine, cisplatin, mitomycin C, bleomycin and carboplatin; Topoisomerase I inhibitors, such as camptothecin, irinotecan and topotecan; Topoisomerase II inhibitors, such as doxorubicin, epirubicin, aclarubicin, mitoxantrone, methylhydroxyellipticine and mingtopop; RNA / DNA anti-metabolites, such as 5-azacytidine, gemcitabine, 5-fluorouracil and methotrexate; DNA antimetabolites such as 5-fluoro-2′-deoxyuridine, fludarabine, nelarabine, cytarabine, pralatrexate, pemetrexed, hydroxyurea, and thioguanine; antimitotic agents such as colchicine, vinblastine, vincristine, vinorelbine, paclitaxel, ixabepilone, cabazitaxel, and docetaxel; antibodies such as the monoclonal antibodies panitumumab, nelarabine, nivolumab, pembrolizumab, ramucirumab, bevacizumab, pertuzumab, trastuzumab, cetuximab, obinutuzumab, ofatumumab, rituximab, alemtuzumab, ibritumomab tiuxetan, tositumomab, brentuximab, daratumumab, elotuzumab, T- DM1, Ofatumumab, Dinutuximab, Blinatumomab, Ipilimumab, Avastin, Herceptin, and Rituximab; kinase inhibitors such as Imatinib, Gefitinib, Erlotinib, Osimertinib, Afatinib, Ceritinib, Alectinib, Crizotinib, Erlotinib, Lapatinib, Sorafenib, Regorafenib, Vemurafenib, Dabrafenib, Aflibercept, Sunitinib, Nilotinib, Dasatinib, Bosutinib, Pratinib, Ibrutinib, Cabozantinib, Lenvatinib, Vandetanib, Trametinib, Cobimetinib, Axitinib, Temsirolimus, Idelalisib, Pazopanib, Tecansitinib, and Everolimus;Other known anticancer drugs that can be used in combination anticancer therapy include tamoxifen, letrozole, fulvestrant, mitoguanidine, octreotide, retinoic acid, arsenic, zoledronic acid, bortezomib, carfilzomib, ixazomib, vismodegib, sonidegi, denosumab, thalidomide, lenalidomide, venetoclax, aldesleukin (recombinant human interleukin-2), and sipueucel-T (prostate cancer therapeutic vaccine).

[0101] Another embodiment of the present invention relates to a pharmaceutical composition effective for treating inflammation, comprising a compound of Formula I of the present invention (including Compound 1 as described herein), or a hydrate, solvate, stereoisomer, racemate, or pharmaceutically acceptable salt or prodrug thereof, as an NF-κB inhibitor, in combination with at least one known anti-inflammatory drug or a pharmaceutically acceptable salt thereof. Examples of such anti-inflammatory drugs include aspirin and ibuprofen.

[0102] When practicing the methods of the present invention, the compounds of the present invention and at least one known anticancer or anti-inflammatory agent can be administered together as a single pharmaceutical composition. Alternatively, the compounds of the present invention and at least one known anticancer or anti-inflammatory agent can be administered separately. In one embodiment, the compounds of the present invention and at least one known anticancer or anti-inflammatory agent are administered approximately simultaneously, i.e., all agents are administered simultaneously or sequentially, as long as therapeutic blood concentrations of the compounds are achieved simultaneously. In another embodiment, the compounds of the present invention and at least one known anticancer or anti-inflammatory agent are administered according to separate dosage regimens, as long as therapeutic blood concentrations of the compounds are achieved.

[0103] Another embodiment of the present invention relates to a pharmaceutical composition that is effective in inhibiting tumors, comprising a compound of Formula I of the present invention (including Compound 1 as described herein), or a hydrate, solvate, stereoisomer, racemate, or pharmaceutically acceptable salt or prodrug thereof, as an NF-κB inhibitor, in combination with radiation therapy. In this embodiment, the compound of the present invention and the radiation therapy may be administered at the same time or at different times.

[0104] The pharmaceutical compositions of the present invention include pharmaceutical formulations containing all of the compounds of the present invention in an amount effective to achieve their intended purpose. While individual needs vary, those skilled in the art can determine the optimal dosage of each component of the pharmaceutical formulation. Generally, the compounds, or pharmaceutically acceptable salts thereof, are administered orally to mammals daily in an amount of about 0.0025 to 50 mg / kg body weight. However, an oral dosage of about 0.01 to 10 mg / kg is preferred. If a known anticancer drug is also administered, its dosage should be effective to achieve its intended purpose. The optimal dosages of these known anticancer drugs are well known to those skilled in the art.

[0105] The unit oral dose may comprise about 0.01 to 50 mg, preferably about 0.1 to 10 mg, of a compound of this invention. The unit dose may be administered once or multiple times, in one or more tablets per day, each tablet containing about 0.1 to 50 mg, conveniently about 0.25 to 10 mg, of a compound of this invention or a solvate thereof.

[0106] The compounds of the present invention can be administered as raw pharmaceuticals. They can also be administered as part of a suitable pharmaceutical formulation containing a pharmaceutically acceptable carrier (including excipients and adjuvants). These pharmaceutically acceptable carriers facilitate processing of the compound into pharmaceutical formulations for pharmaceutical use. Preferred pharmaceutical formulations, particularly those for oral administration and preferred modes of administration, such as tablets, lozenges, and capsules, as well as solutions suitable for injection or oral administration, contain from about 0.01% to 99%, preferably from about 0.25% to 75%, of the active compound and excipients.

[0107] The present invention also encompasses the non-toxic pharmaceutically acceptable salts of the compounds of this invention. Acid addition salts are formed by mixing a solution of a non-toxic pharmaceutically acceptable acid with a solution of the compound of this invention. Examples of such acids are hydrochloric acid, fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid, and oxalic acid. Base addition salts are formed by mixing a solution of a non-toxic pharmaceutically acceptable base with a solution of the compound of this invention. Examples of such bases are sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, tris(hydroxymethyl)aminomethane, and N-methylglucamine.

[0108] The pharmaceutical preparations of the present invention can be administered to any mammal, provided they can obtain the therapeutic effect of the compounds of the present invention. The most important of these mammals is human, although the present invention is not intended to be so limited.

[0109] The pharmaceutical preparations of the present invention may be administered by any route to achieve their intended purpose. For example, they may be administered parenterally, subcutaneously, intravenously, intramuscularly, intraperitoneally, transdermally, orally, intrathecally, intracranially, nasally, or topically. Alternatively or concurrently, they may be administered orally. The dosage will be determined based on the patient's age, health, and weight, the type of concurrent treatment, the frequency of treatment, and the desired therapeutic benefit.

[0110] The pharmaceutical preparations of the present invention can be manufactured in known manners. For example, they can be manufactured by conventional mixing, granulation, tableting, dissolution, or freeze-drying processes. For oral preparations, solid excipients and the active compound can be combined and the mixture can be optionally ground. After adding appropriate amounts of adjuvants, if desired or necessary, the granular mixture can be processed to obtain tablets or lozenge cores.

[0111] Suitable excipients are, in particular, fillers, for example, sugars such as lactose or sucrose, mannitol or sorbitol; cellulose preparations and / or calcium phosphates, for example, tricalcium phosphate or calcium hydrogen phosphate; and binders, for example, starch pastes, including corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone. If necessary, disintegrants such as the starches mentioned above, as well as carboxymethyl starch, cross-linked polyvinylpyrrolidone, agar, or alginic acid or salts thereof, such as sodium alginate, can be added. Auxiliary agents are, in particular, flow regulators and lubricants, for example, silica, talc, stearic acid or salts thereof, such as magnesium stearate or calcium stearate, and / or polyethylene glycol. If necessary, the tablet cores can be provided with a suitable coating that is resistant to gastric juices. For this purpose, concentrated sugar solutions can be used. This solution may contain gum arabic, talc, polyvinyl pyrrolidone, polyethylene glycol and / or titanium dioxide, a lacquer solution and a suitable organic solvent or solvent mixture. To prepare a coating resistant to gastric juices, a suitable cellulose solution may be used, for example, cellulose acetate phthalate or hydroxypropyl methylcellulose phthalate. Dyes or pigments may be added to the coating of the tablet or lozenge core, for example, for identification or to characterize the combination of active ingredient doses.

[0112] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention only and are not intended to limit the scope of the invention. The experimental methods in the following examples, for which specific conditions are not specified, are generally based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0113] Example

[0114] General Notes

[0115] All reagents used were of commercial quality, and solvents were dried and purified according to standard methods. NMR data were provided by Agilent 500 and Bruker AV-400. 1 The unit of H NMR chemical shift is ppm. The solvent peak in the CDCl3 spectrum is 7.26 ppm. The unit of coupling constant is Hz. The abbreviations for nuclear magnetic splitting are as follows: s = singlet, br = broad singlet, d = doublet, t = triplet, q = quartet, m = multiplet. 13C NMR chemical shifts are in ppm, and the solvent peak in the CDCl3 carbon spectrum is 77.16 ppm. Mass spectra were measured using Finnigan FTMS-2000, HP 5989A, and Finnigan 4021 instruments, respectively. High-resolution mass spectra were measured using Bruker APEXIII 7.0 Tesla ESI-FT and IonSpec 4.7 Tesla FT mass spectrometers, respectively. Infrared (IR) spectra were measured using ThermoScientific Nicolet 380 and FTS-185 infrared spectrometers, and optical rotation was determined using a Jasco P-1030 polarimeter.

[0116] Example 1

[0117] Synthesis of Compound 1 ((±)-1,10-Dehydrogenated Glecholide)

[0118]

[0119] 1) Synthesis of cis-allyl alcohol 9: Diiodide compound 7 (20.0 g, 61.7 mmol, 1.0 equivalent) was added to a 1.0 L eggplant-shaped flask, protected by argon, and dissolved in 100 mL of dry THF. A solution of cuprous bromide dimethyl sulfide (25.4 g, 123 mmol, 2.0 equivalent) was added, and the mixture was cooled to -40°C. A solution of propyne magnesium bromide 8 in THF (185 mmol, 370 mL, 3.0 equivalent) was added to the reaction system. The reaction mixture was stirred at -40°C for 30 minutes, then warmed to room temperature and stirred for 12 hours. After the reaction was completed, it was filtered through celite, and the filter cake was washed with EtOAc (200 mL). The filtrate was washed twice with saturated brine (200 mL). The organic phase was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography with PE / EtOAc (20:1→10:1) as eluent to obtain cis-allyl alcohol 9 (11.4 g, 78%) as a colorless oil. f =0.33 (silica, EtOAc: petroleum ether 1:4); IR (film): ν max =3332,2915,2854,1646,1422,1262,1084,1003cm -1 ; 1 H NMR (400MHz, CDCl3): δ=6.08-5.91(m,1H),4.29-4.22(m,2H),3.09-2.95(m,2H),1.86(s,1H),1.78(t,J=2.6Hz,3H)ppm; 13CNMR (101MHz, CDCl3): δ = 131.8, 109.0, 77.1, 75.2, 71.4, 26.4, 3.7ppm; HRMS (m / z): [M] + calcdfor C7H9OI + 235.9698,found 235.9699.

[0120]

[0121] 2) Synthesis of alkenyl nitrile 10: Cis-allyl alcohol 9 (10.0 g, 42.4 mmol, 1.0 eq) was added to a 250 mL eggplant flask. The argon atmosphere was replaced, and zinc cyanide (20.0 g, 170 mmol, 4.0 eq) and Pd(PPh3)4 (4.90 g, 4.24 mmol, 0.1 eq) were added and dissolved in 100 mL of DMF. The reaction system was heated to 80°C and stirred for 1 h. After the reaction was completed, the mixture was filtered through celite, and the filter cake was washed with EtOAc (100 mL). The filtrate was washed twice with saturated brine (100 mL). The organic phase was concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography using PE / EtOAc (15:1→8:1) as the eluent to obtain alkenyl nitrile 10 (4.80 g, 84%) as a colorless oil. f =0.42 (silica, EtOAc: petroleum ether 1:2); IR (film): ν max =3192,1654,1447,1367,880,864,846cm -1 ; 1 H NMR (400MHz, CDCl3): δ=6.44(m,1H),4.34–4.20(m,2H),3.30–3.18(m,2H),1.82(t,J=6.5Hz,1H),1.79(t,J=2.6Hz,3H)ppm; 13 C NMR (101MHz, CDCl3): δ = 143.5, 115.8, 115.7, 78.3, 73.4, 62.6, 2.22, 3.5ppm; HRMS (m / z): [M] + calcd for C8H8NO + 134.0606,found 134.0610.

[0122]

[0123] 3) Synthesis of Allyl Bromide 4: Compound 10 (4.50 g, 33.3 mmol, 1.0 equivalent) was added to a 250 mL eggplant flask. The argon atmosphere was replaced and 60 mL of dichloromethane was added to dissolve the compound. The system was cooled to -78°C and PPh3 (10.5 g, 40.0 mmol, 1.2 equivalent) and NBS (6.51 g, 36.6 mmol, 1.1 equivalent) were added in sequence. After the addition, the reaction system was slowly heated from -78°C to -30°C and stirred for 1 hour. After the reaction was completed, the mixture was concentrated to remove most of the dichloromethane and purified by silica gel column chromatography using PE / EtOAc (30:1→15:1) as the eluent to obtain allyl bromide 4 (6.10 g, 93%) as a colorless oil. f =0.37 (silica, EtOAc: petroleum ether 1:7); IR (film): ν max =2226,1532,1430,1218,772,669cm -1 ; 1 H NMR (400MHz, CDCl3): δ = 6.47 (t, J = 7.2Hz, 1H), 4.00 (s, 2H), 3.35–3.16 (m, 2H), 1.79 (t, J = 2.5Hz, 3H) ppm; 13 C NMR (101MHz, CDCl3): δ = 146.3, 115.0, 113.6, 78.9, 72.7, 29.9, 21.7, 3.6ppm; HRMS (m / z): [M] + calcd for C8H8NBr + 196.9840, found 196.9845.

[0124]

[0125] 4) Synthesis of Compound 5: Allenol (5.00 g, 51.0 mmol, 1.0 equivalent) was added to a 250 mL eggplant-shaped flask, and the argon atmosphere was replaced. 50 mL of dichloromethane was added to dissolve the mixture. PCC (22.0 g, 102 mmol, 2.0 equivalent) and diatomaceous earth (22.0 g) were added separately. The reaction mixture was stirred at room temperature for 2 h. After the reaction was completed, it was directly and rapidly filtered through a short silica gel column using anhydrous ether as the elution column. The organic phase was concentrated at low temperature to obtain a crude product of Compound 5 (4.3 g). This compound is unstable and not suitable for storage and was used directly in the next reaction.

[0126]

[0127] 5) Preparation of compound 3: Compound 4 (4.00 g, 20.2 mmol, 1.0 equiv), 5 (4.3 g) and indium powder (4.65 g, 40.4 mmol, 2.0 equiv) were added to a 250 mL eggplant flask, the argon atmosphere was replaced, and a THF / H2O (100 mL, 1:1) mixed solution was added. The reaction mixture was vigorously stirred at room temperature for 16 h. After the reaction was completed, 100 mL of EtOAc was added to dilute the mixture and washed sequentially with water (50 mL) and saturated brine (50 mL). The organic phase was dried over anhydrous Na2SO4, filtered through a fritted funnel, and concentrated under reduced pressure to give the crude product, which was purified by silica gel column chromatography with PE / EtOAc (20:1→10:1) as the eluent to give compound 3 (2.48 g, 57%) and its diastereomer 3a (1.22 g, 28%).

[0128] Compound 3: colorless oil; R f =0.40 (silica, EtOAc: petroleum ether 1:4); IR (film): ν max =3478,2919,2223,1959,1679,1434,1205,1181cm -1 ; 1 H NMR (400MHz, CDCl3): δ = 6.06 (s, 1H), 5.86 (s, 1H), 4.79–4.66 (m, 2H), 4.11–3.94 (m, 1H) ),2.64–2.38(m,3H),2.22–2.03(m,3H),1.82–1.75(m,3H),1.73(t,J=3.1Hz,3H)ppm; 13 C NMR (101MHz, CDCl3): δ = 206.4, 133.8, 122.7, 118.3, 95.1, 78.5, 75.5, 75.5, 69.7, 49.3, 39.3, 20.8, 19.1, 3.6ppm; HRMS (m / z): [M] + calcd for C 14 H 17 NO + 215.1310, found 215.1308.

[0129] Compound 3a: colorless oil; R f =0.43 (silica, EtOAc: petroleum ether 1:4); IR (film): ν max =3489,2917,1546,1424,1318,938,771,728cm -1 ; 1H NMR (400MHz, CDCl3): δ=6.03(s,1H),5.89(s,1H),4.85–4.65(m,2H),4.00–3.80(m,1H),2.76–2.61(m,1H) ,2.53–2.37(m,2H),2.25–2.14(m,2H),2.09-2.00(m,1H),1.77(t,J=2.3Hz,3H),1.73(t,J=3.1Hz,3H)ppm; 13 CNMR (101MHz, CDCl3): δ = 206.3, 133.3, 123.2, 117.6, 95.2, 78.4, 75.6, 75.5, 69.8, 49.9, 39.4, 19.7, 18.9, 3.5ppm; HRMS (m / z): [M] + calcd for C 14 H 17 NO + 215.1310, found 215.1303.

[0130]

[0131] 6) Synthesis of Compound 2: Compound 3 (2.00 g, 9.30 mmol, 1.0 equivalent) was added to a 100 mL eggplant flask, the argon atmosphere was replaced, 50 mL of toluene was added to dissolve, and camphorsulfonic acid (2.37 g, 10.2 mmol, 1.1 equivalent) was added. The reaction mixture was stirred at 60°C for 12 h. After the reaction was completed, it was directly concentrated and purified by column chromatography with PE / EtOAc (30:1→20:1) as the eluent to obtain compound 2 (1.65 g, 82%) as a colorless oil. f =0.35 (silica, EtOAc: petroleum ether 1:6); IR (film): ν max =2917,1962,1765,1433,1265,1126,991,852cm -1 ; 1 H NMR (400MHz, CDCl3): δ = 6.32 (d, J = 2.7Hz, 1H), 5.73 (d, J = 2.3Hz, 1H), 4.76–4.58 (m, 2H), 4.52–4.37 (m, 1H) ,2.99–2.80(m,1H),2.48–2.41(m,2H),2.41–2.26(m,2H),1.77(t,J=2.5Hz,3H),1.74(t,J=3.2Hz,3H)ppm; 13C NMR (101MHz, CDCl3): δ = 207.2, 169.9, 137.9, 123.3, 93.7, 80.9, 78.5, 75.1, 74.8, 43.3, 39.5, 23.5, 19.3, 3.5ppm; HRMS (m / z): [M+Na] + calcd for C 14 H 16 O2Na + 239.1043,found239.1047.

[0132]

[0133] 7) Synthesis of (±)-1,10-dehydro-glaucinolactone: Compound 2 (1.00 g, 4.63 mmol, 1.0 equivalent) was added to a 50 mL eggplant-shaped flask, dissolved with 10 mL of toluene, and [Rh(CO)2Cl]2 (180 mg, 0.463 mmol, 0.1 equivalent) was added. The system was switched to a CO atmosphere, heated to 110 ° C, and stirred for 2 h. After the reaction was completed, the mixture was concentrated under pressure to remove toluene and directly purified by silica gel column chromatography with PE / EtOAc (10:1→6:1) as the eluent to obtain (±)-1,10-dehydro-glaucinolactone (757 mg, 67%) as a colorless oil. f =0.38 (silica, EtOAc: petroleum ether 1:1); IR (film): ν max =1761,1684,1581,1535,1418,1342,1002cm -1 ; 1 H NMR (400MHz, CDCl3): δ = 6.35 (d, J = 3.4Hz, 1H), 5.69 (d, J = 3.1Hz, 1H), 4.46–4.13 (m, 1H), 3.29 (dd, J = 1 8.3,3.4Hz,1H)3.13–2.90(m,4H),2.73–2.56(m,1H),2.55–2.40(m,1H),1.92(s,3H),1.83(s,3H)ppm; 13 C NMR (101MHz, CDCl3): δ = 203.1, 169.6, 160.8, 141.6, 139.1, 131.5, 128.1, 121.4, 80.9, 43.1, 42.9, 41.9, 31.1, 24.3, 8.9ppm; HRMS (m / z): [M+Na] + calcd for C 15 H 16 O3Na +267.0992,found 267.0996.

[0134]

[0135] Example 2

[0136] Separation of chiral products (–)-1,10-dehydro-glaucinone and (+)-1,10-dehydro-glaucinone

[0137]

[0138] The chiral product (–)-1,10-dehydroxerantholide was obtained from (±)-1,10-dehydroxerantholide by chiral column separation (CHIRALPAK AS-H column, MeOH, 1.0 mL / min). The peak compound at 2.92 min was (–)-1,10-dehydroxerantholide. (c = 1.0 in CHCl3).

[0139] The chiral product (+)-1,10-dehydroxerantholide was obtained from (±)-1,10-dehydroxerantholide by chiral column separation (CHIRALPAK AS-H column, MeOH, 1.0 mL / min). The peak compound at 3.51 min was (+)-1,10-dehydroxerantholide. (c=1.0 in CHCl3).

[0140] The chiral HPLC chromatograms of (±)-1,10-dehydroglaucinolide, (–)-1,10-dehydroglaucinolide and (+)-1,10-dehydroglaucinolide are shown in Figure 1. Figure 1-3 shown.

[0141] Example 3

[0142] Cytotoxicity of (±)-1,10-dehydro-glaucolide on various cell lines

[0143] Cytotoxicity screening was performed on various cell lines including MDA-MB-231 (human triple-negative breast cancer cells), MCF7 (human Luminal A breast cancer cells), L-02 (human normal liver cells), SMMC-7721 (human liver cancer cells), HepG2 (human liver cancer cells) and U251 (human glioma cells). The corresponding cells were seeded in 96-well culture plates. After the cells adhered to the wall, the corresponding concentrations of compounds were added to the culture plates. At the same time, the same amount of DMSO as the drug-dosed group was added to the control group. After continued culture in the incubator for 24 hours, CCK8 cytotoxicity detection reagent was added to the 96-well culture plates. After incubation in the incubator for 1-2 hours, the absorbance at a wavelength of 450nm was detected using a microplate reader and the obtained experimental results were processed to obtain the cytotoxicity of the compound (±)-1,10-dehydro-glaucocyanin against multiple tumor cells. The results are shown as follows. Figure 4 As shown. Figure 4 It can be seen that (±)-1,10-dehydro-glaucocyanin has certain cytotoxicity to different types of tumor cells, and is significantly cytotoxic to MDA-MB-231 cells. When the concentration is above 15 micromolar, the cell viability can be reduced to below 50% compared with the control.

[0144] Example 4

[0145] Effects of (±)-1,10-dehydrogenin on apoptosis of MDA-MB-231 cells

[0146] Inoculate an appropriate amount of cells in a 6-well plate and culture overnight. Then add the corresponding concentration of (±)-1,10-dehydro-glaucin or an equal amount of DMSO to each well. After culturing in an incubator for 24 hours, digest the cells with EDTA-free trypsin and collect the cells. After washing the collected cells twice with PBS, resuspend the cells with staining buffer. Add an equal amount of PI and FITC-labeled Annexin V staining solution to each sample. After incubation at 37°C for 20 minutes, detect the samples using a flow cytometer and process the data. The effects of different concentrations of (±)-1,10-dehydro-glaucin on the apoptosis of MDA-MB-231 cells at 24 hours were detected. The results are shown in Figure 2. Figure 5 As shown in the figure, it was found that (±)-1,10-dehydro-glaucinone gradually induced obvious apoptosis in MDA-MB-231 cells with increasing concentrations. At the same time, cells seeded in 6-well plates were treated with different concentrations of (±)-1,10-dehydro-glaucinone. After incubation for 24 hours, the cells were lysed using RIPA cell lysis buffer and samples were prepared. The samples were detected by Western Blot. The experimental results are shown in the figure. Figure 6As shown in the figure, the experimental results also showed that after treatment with (±)-1,10-dehydro-glaucocyanin, the level of intracellular anti-apoptotic protein Bcl-2 decreased, while the apoptosis marker protein cleaved-PARP increased significantly, indicating that (±)-1,10-dehydro-glaucocyanin caused cell death by inducing apoptosis in MDA-MB-231 cells.

[0147] Example 5

[0148] Effects of (±)-1,10-dehydrogenin on the levels of NF-κB pathway-related proteins in MDA-MB-231 cells

[0149] Western Blot experiments were performed to examine the effect of the compound (±)-1,10-dehydro-glaucinone on the levels of NF-κB pathway-related proteins in MDA-MB-231 cells. Cells seeded in 6-well plates were treated with different concentrations of (±)-1,10-dehydro-glaucinone for 4 hours. 5 ng / mL of TNFα was added to the corresponding wells and incubated in an incubator for 15 minutes. After incubation, the cells were lysed using RIPA to prepare samples. Figure 7 As shown in the results, when stimulated with 5 ng / mL TNF-α, the NF-κB signaling pathway was activated, which was manifested by the degradation of IκBα and the decrease in protein level, while the protein levels of pho-IκBα and pho-p65 increased; when different concentrations of (±)-1,10-dehydro-glaucocyanin were added, it was found that with the increase of concentration, the level of IκBα protein increased, while the protein levels of pho-IκBα and pho-p65 decreased, indicating that (±)-1,10-dehydro-glaucocyanin can significantly inhibit the NF-κB signaling pathway.

[0150] In summary, through preliminary studies on the anti-cancer mechanism of the sesquiterpene lactone derivative (±)-1,10-dehydro-glaucinone, it was found that (±)-1,10-dehydro-glaucinone had a significant pro-apoptotic effect on triple-negative breast cancer MDA-MB-231 cells; at the same time, (±)-1,10-dehydro-glaucinone could significantly inhibit the NF-κB signaling pathway in a concentration-dependent manner. Therefore, (±)-1,10-dehydro-glaucinone may induce tumor cell apoptosis by inhibiting the NF-κB pathway.

[0151] Example 6

[0152] Antitumor activity of chiral isomers of 1,10-dehydro-glaucinolide

[0153] The compound (±)-1,10-dehydro-glaucinolide was chirally resolved to obtain two chiral molecules of 1,10-dehydro-glaucinolide: (–)-1,10-dehydro-glaucinolide and (+)-1,10-dehydro-glaucinolide. The cytotoxicity of the two chiral molecules against MDA-MB-231 cells at multiple concentration gradients was tested using the aforementioned cytotoxicity assay. The inhibition rate curve was fitted using data processing software and the IC was calculated. 50 .like Figure 8 As shown in the results, both chiral molecules were cytotoxic to triple-negative breast cancer cells MDA-MB-231, and the cytotoxicity of (–)-1,10-dehydro-glaucinone was stronger than that of (+)-1,10-dehydro-glaucinone. 50 The value was 5.442 μM, (+)-1,10-dehydro-glaucolide IC 50 The value is 8.191 μM.

[0154] The apoptosis-inducing effect of (+)-1,10-dehydrogenated chrysanthellactone on MDA-MB-231 cells was detected by the aforementioned method. Figure 9 shown. Figure 9 The results showed that (+)-1,10-dehydro-glaucocyanin had a significant pro-apoptotic effect.

[0155] Western Blot analysis of (+)-1,10-dehydrogenated chrysanthellactone was performed using the aforementioned method. Figure 10 Western blot results also showed that (+)-1,10-dehydro-glaucocyanin induced apoptosis in MDA-MB-231 cells in a concentration-dependent and time-dependent manner.

[0156] In addition, the aforementioned method was used to detect the effect of (+)-1,10-dehydrogenated chrysanthellactone on the NF-κB pathway. Figure 11 It was found that (+)-1,10-dehydro-glaucinone has a significant inhibitory effect on the NF-κB signaling pathway in cells. After tumor necrosis factor TNFα activates the NF-κB pathway, (+)-1,10-dehydro-glaucinone can inhibit the phosphorylation of IκBα activated by TNFα, increase IκBα, and reduce the level of phosphorylated p65, playing a role in inhibiting the NF-κB pathway. The effect is concentration-dependent.

[0157] In order to further confirm the inhibitory effect of (+)-1,10-dehydrogenated chrysanthellol on the NF-κB signaling pathway, a nuclear-cytoplasmic fractionation experiment was performed to detect the nuclear entry of the NF-κB marker protein p65. The results are as follows: Figure 12As shown in the figure. Under the stimulation of TNFα, NF-κB is activated through the classical pathway, and the levels of nuclear p65 and phosphorylated p65 increase. However, after treatment with (+)-1,10-dehydro-glaucinone, the levels of nuclear p65 and phosphorylated p65 decrease, further demonstrating the inhibitory effect of (+)-1,10-dehydro-glaucinone on the NF-κB signaling pathway in MDA-MB-231 cells.

[0158] The above experimental results show that the compound (+)-1,10-dehydro-glaucocyanin has obvious anti-tumor activity against triple-negative breast cancer cells MDA-MB-231, and has a significant inhibitory effect on the activation of the NF-κB pathway in triple-negative breast cancer cells MDA-MB-231.

[0159] Example 7

[0160] Study on the anti-inflammatory activity of (±)-1,10-dehydrogenin

[0161] The effect of (±)-1,10-dehydrogenated chrysanthellactone on the release of nitric oxide in mouse macrophage RAW264.7 cells was examined. Figure 13 (Left figure) It was found that LPS stimulation alone can effectively increase the release of nitric oxide in mouse macrophage RAW264.7 cells compared with the control group. After adding (±)-1,10-dehydro-glaucinone, it can effectively inhibit the release of NO in LPS-induced macrophage RAW264.7 cells as the concentration increases. There is a significant inhibitory effect at 1μM and 2μM. At the same time, the cytotoxicity of (±)-1,10-dehydro-glaucinone on RAW264.7 macrophages was detected. The results are as follows Figure 13 As shown in the figure (right), it was found that the toxicity was weak at low concentrations and no significant toxicity was found, indicating that the reduction in NO release was not caused by cell death, indicating that (±)-1,10-dehydro-glaucolide has certain anti-inflammatory activity.

[0162] Example 8

[0163] Study on the anti-inflammatory mechanism of (±)-1,10-dehydro-glaucolide

[0164] Based on the discovery that (±)-1,10-dehydro-glaucocyanin has anti-inflammatory activity, we investigated its anti-inflammatory mechanism. There are many signaling pathways involved in inflammatory cells, such as the NF-κB signaling pathway, so we tested some key proteins in this pathway.

[0165] like Figure 14As shown in (A), the effects of (±)-1,10-dehydro-glaucinolide on the NF-κB signaling pathway were examined over different time periods. Upon LPS stimulation, IκBα protein levels were significantly decreased, while Pho-IκBα protein levels were significantly increased. This indicates that NF-κB is released and translocated from the cytoplasm to the nucleus to function. IκB phosphorylation is manifested by increased Pho-P65 protein levels, indicating activation of the NF-κB signaling pathway. Following the addition of (±)-1,10-dehydro-glaucinolide, IκBα protein levels increased over time, while Pho-IκBα protein levels decreased, demonstrating that the compound effectively inhibits the NF-κB signaling pathway in a time-dependent manner.

[0166] At the same time, nuclear-cytoplasmic separation experiments were carried out to detect the effect of (±)-1,10-dehydro-glaucocyanin on the distribution of P65 in the cytoplasm and nucleus. Figure 14 As shown in (B). Upon LPS stimulation, IκB dissociated from the NF-κB complex and underwent degradation. Released NF-κB translocated to the nucleus. Addition of (±)-1,10-dehydro-glaucinolide inhibited the nuclear import of P65, showing a time- and concentration-dependent gradient. Nuclear-cytoplasmic fractionation further confirmed that (±)-1,10-dehydro-glaucinolide significantly inhibited NF-κB pathway activation in RAW264.7 cells. Therefore, (±)-1,10-dehydro-glaucinolide may exert its anti-inflammatory activity by inhibiting the NF-κB pathway.

[0167] Example 9

[0168] Study on the anti-inflammatory activity and mechanism of chiral isomers of 1,10-dehydro-glaucinolide

[0169] It was found that (±)-1,10-dehydro-glaucinone has good anti-inflammatory activity. The anti-inflammatory activities of its two chiral isomers (-)-1,10-dehydro-glaucinone and (+)-1,10-dehydro-glaucinone were further tested. The results are as follows: Figure 15 The effects of (-)-1,10-dehydro-glaucinone and (+)-1,10-dehydro-glaucinone on NO release were detected in RAW264.7 cells using a nitric oxide detection kit. The results are shown in Figure 2. Figure 15As shown in (A and B). It can be found that under LPS induction, the amount of NO released increased significantly, and both (-)-1,10-dehydro-glaucinone and (+)-1,10-dehydro-glaucinone can effectively inhibit the release of NO at low concentrations, indicating that both have good anti-inflammatory activity. Because (-)-1,10-dehydro-glaucinone was found to have better anti-inflammatory activity in this experiment, (-)-1,10-dehydro-glaucinone was subsequently selected to further explore its anti-inflammatory mechanism. The CCK8 method was used to detect the cytotoxicity of (-)-1,10-dehydro-glaucinone to RAW264.7 cells, as shown in Figure 5. Figure 15 As shown in (C), (-)-1,10-dehydro-glaucocyanin was not toxic to RAW264.7 at a concentration of 5 μM, so its anti-inflammatory mechanism was subsequently studied at a concentration of 5 μM.

[0170] The NF-κB pathway is closely related to the occurrence of inflammation. The effect of (-)-1,10-dehydrogenated chrysanthellactone on this pathway was detected. The results are as follows Figure 16 As shown. From the concentration gradient of (-)-1,10-dehydro-glaucocyanin ( Figure 16 , A) and time gradient ( Figure 16 Western Blot analysis was performed on (B) and it was found that (-)-1,10-dehydro-glaucocyanin could inhibit the NF-κB pathway in a concentration- and time-dependent manner. Nuclear-cytoplasmic fractionation experiments were further used to detect the nuclear entry of P65. The results are shown in Figure 2. Figure 17 As shown. When the NF-κB pathway is activated, IκBα releases the inhibition of P65 and the nuclear entry of P65 increases. (-)-1,10-Dehydro-glaucolide can be expressed in a concentration gradient ( Figure 17 , A) and time gradient ( Figure 17 , B) It depends on the reduction of P65 nuclear import, further indicating its inhibition of NF-κB pathway.

[0171] iNOS and COX2 are inflammatory proteins. Literature has shown that activation of the NF-κB pathway can increase the transcription and expression of related inflammatory factors such as iNOS and COX2. Therefore, Western Blot was used to detect the effect of (-)-1,10-dehydro-glaucocyanin on these two proteins after LPS induction in RAW264.7 cells. The results are as follows: Figure 18 LPS can increase the expression of iNOS and COX2. As the duration of (-)-1,10-dehydro-glaucolide increases, the protein levels of iNOS and COX2 can be gradually inhibited, further demonstrating its anti-inflammatory effect.

[0172] Although the present invention has been fully described, it will be understood by those skilled in the art that the same implementation can be carried out within a wide range of and equivalent conditions, formulations, and other parameters without affecting the scope of the present invention or any embodiment thereof. All patents, patent applications, and publications cited herein are incorporated herein by reference in their entirety.

Claims

1. A compound of formula I, or a hydrate, solvate, racemate or pharmaceutically acceptable salt thereof: In formula I, R1 is C 1-4 Alkyl, R2 is C 1-4 alkyl.

2. The compound according to claim 1, or a hydrate, solvate, racemate or pharmaceutically acceptable salt thereof, characterized in that: R1 is a methyl group, and R2 is a methyl group.

3. The compound according to claim 1, or a hydrate, solvate, racemate or pharmaceutically acceptable salt thereof, characterized in that: The compound of formula I is (-)-1,10-dehydro-glaucinolactone represented by the following formula (-)-1 or (+)-1,10-dehydro-glaucinolactone represented by the following formula (+)-1, or a racemate formed by the following formulas (-)-1 and (+)-1: 。 4. A method for preparing the compound according to any one of claims 1 to 3, characterized in that The method comprises the following steps: (1) reacting a compound of formula VII with a compound of formula VIII in the presence of a metallic copper catalyst to produce a compound of formula IX; (2) reacting the compound of formula IX with a cyanide source reagent in the presence of a metal palladium catalyst to obtain a compound of formula X; (3) reacting the compound of formula X with a brominating agent in the presence of a brominating agent to obtain a compound of formula IV; (4) oxidizing the hydroxyl group of the compound of formula VI to an aldehyde group to obtain a compound of formula V; (5) reacting the compound of formula IV with the compound of formula V to obtain the compound of formula III; (6) reacting the compound of formula III under acidic conditions to obtain the compound of formula II; (7) reacting the compound of formula II in the presence of a metal catalyst in a CO atmosphere to obtain the compound of formula I; In Formula I to Formula X, R1 and R2 are as described in any one of claims 1 to 3.

5. The method according to claim 4, wherein Step (1) is carried out in tetrahydrofuran.

6. The method according to claim 4, wherein The metallic copper catalyst used in step (1) is selected from cuprous bromide dimethyl sulfide and cuprous cyanide.

7. The method according to claim 4, wherein The reaction of step (2) is carried out in N,N-dimethylformamide.

8. The method according to claim 4, wherein In step (2), the reaction is at 80 ± 5 o C is carried out.

9. The method according to claim 4, wherein In step (2), the cyanide source reagent is selected from zinc cyanide and sodium cyanide.

10. The method according to claim 4, wherein In step (2), the metal palladium catalyst is tetrakis(triphenylphosphine)palladium.

11. The method according to claim 4, wherein The reaction in step (3) is carried out in dichloromethane.

12. The method according to claim 4, wherein In step (3), the reaction is at −78 ± 5 o C is carried out.

13. The method according to claim 4, wherein In step (3), the bromination reagent is selected from N-bromosuccinimide, phosphine tribromide and carbon tetrabromide.

14. The method according to claim 4, wherein In step (3), the bromination reagent is N-bromosuccinimide or carbon tetrabromide, and the reaction is carried out in the presence of triphenylphosphine.

15. The method according to claim 4, wherein The reaction of step (4) is carried out in dichloromethane.

16. The method according to claim 4, wherein In step (4), the oxidizing agent for oxidizing the hydroxyl group to the aldehyde group is selected from pyridinium chlorochromate, Dess-Martin, oxalyl chloride / DMSO / triethylamine.

17. The method according to claim 4, wherein Step (5) is carried out in a mixed solvent of THF and water.

18. The method according to claim 4, wherein The reaction of step (5) is carried out in the presence of indium, zinc, SnCl2 or CrCl2.

19. The method according to claim 4, wherein The reaction of step (6) is carried out in toluene.

20. The method according to claim 4, wherein Step (6) at 60 ± 5 o C is carried out.

21. The method according to claim 4, wherein In step (6), the acid is selected from hydrochloric acid, sulfuric acid and camphorsulfonic acid.

22. The method according to claim 4, wherein The reaction of step (7) is carried out in toluene.

23. The method of claim 4, wherein: The reaction of step (7) is carried out at 110 ± 5 o C is carried out.

24. The method according to claim 4, wherein In step (7), the metal catalyst is selected from tetracarbonyl dirhodium dichloride and octacarbonyl dicobalt.

25. A pharmaceutical composition comprising the compound according to any one of claims 1 to 3, or a hydrate, solvate, racemate or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

26. The pharmaceutical composition according to claim 25, wherein The pharmaceutical composition further contains at least one known anticancer drug, or a pharmaceutically acceptable salt of the anticancer drug.

27. The pharmaceutical composition according to claim 26, wherein The anticancer drug is selected from the group consisting of busulfan, melphalan, chlorambucil, cyclophosphamide, ifosfamide, temozolomide, bendamustine, cisplatin, mitomycin C, bleomycin, carboplatin, camptothecin, irinotecan, topotecan, doxorubicin, epirubicin, aclarubicin, mitoxantrone, methylhydroxyellipticine, etoposide, 5-azacytidine, gemcitabine, 5-fluorouracil, methotrexate, 5-fluoro-2'-deoxyuridine, fludarabine, nelarabine, cytarabine, alanosine, pralatrexate, pemetrexed, hydroxyurea, thioguanine, colchicine, vinblastine, vincristine, vinorelbine, paclitaxel, Ixabepilone, cabazitaxel, docetaxel, monoclonal antibody, imatinib, gefitinib, erlotinib, lapatinib, sorafenib, sunitinib, nilotinib, dasatinib, pazopanib, tebuconazole, everolimus, vorinostat, romidifenapyr, tamoxifen, letrozole, fulvestrant, mitoguanzone, octreotide, retinoic acid, arsenic, zoledronic acid, bortezomib, thalidomide, lenalidomide, venetoclax, aldesleukin, sipueucel-T, palbociclib, olaparib, niraparib, rucaparib, and talazoparib.

28. The pharmaceutical composition according to claim 27, wherein The monoclonal antibody is selected from panitumumab, Ofatumumab, Avastin, Herceptin and Rituximab.

29. The pharmaceutical composition according to claim 25, wherein The pharmaceutical composition further contains at least one known anti-inflammatory drug or a pharmaceutically acceptable salt of the anti-inflammatory drug.

30. The pharmaceutical composition according to claim 29, wherein The anti-inflammatory drug is selected from aspirin and ibuprofen.

31. Use of the compound according to any one of claims 1 to 3, or a hydrate, solvate, racemate or pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating or preventing a disease that benefits from inhibition of NF-κB, or in the preparation of an NF-κB inhibitor.

32. The use according to claim 31, wherein The disease is cancer or inflammation.

33. The use according to claim 32, wherein The cancer is triple-negative breast cancer; The inflammation is rheumatoid arthritis, rheumatoid arthritis, atherosclerosis, chronic inflammatory demyelinating polyneuritis, multiple sclerosis, polyneuritis, asthma, inflammatory bowel disease, Helicobacter pylori-related gastritis, sepsis, glomerulonephritis, psoriasis, myocardial reperfusion injury or systemic inflammatory response syndrome.

34. The use according to claim 31, wherein The compound is (-)-1,10-dehydro-glaucinolactone represented by the formula (-)-1 or (+)-1,10-dehydro-glaucinolactone represented by the formula (+)-1, or a racemate formed by the two, and the disease is triple-negative breast cancer; or The compound is (-)-1,10-dehydro-glaucolide represented by the formula (-)-1, and the disease is inflammation.

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