CN109400479B - Bicyclic unsaturated ketone derivative with antibacterial and antitumor activities and preparation method thereof - Google Patents
Bicyclic unsaturated ketone derivative with antibacterial and antitumor activities and preparation method thereof Download PDFInfo
- Publication number
- CN109400479B CN109400479B CN201811384079.7A CN201811384079A CN109400479B CN 109400479 B CN109400479 B CN 109400479B CN 201811384079 A CN201811384079 A CN 201811384079A CN 109400479 B CN109400479 B CN 109400479B
- Authority
- CN
- China
- Prior art keywords
- compound
- antibacterial
- unsaturated ketone
- bicyclic unsaturated
- antitumor activities
- 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
- 125000002619 bicyclic group Chemical group 0.000 title claims abstract description 22
- 150000002576 ketones Chemical class 0.000 title claims abstract description 22
- 230000000259 anti-tumor effect Effects 0.000 title claims abstract description 20
- 230000000844 anti-bacterial effect Effects 0.000 title claims abstract description 18
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- 150000001875 compounds Chemical class 0.000 claims abstract description 27
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims abstract description 21
- 229940126214 compound 3 Drugs 0.000 claims abstract description 9
- 229940125782 compound 2 Drugs 0.000 claims abstract description 7
- 229940125898 compound 5 Drugs 0.000 claims abstract description 7
- 230000017531 blood circulation Effects 0.000 claims abstract description 4
- 230000001737 promoting effect Effects 0.000 claims abstract description 4
- CIHOLLKRGTVIJN-UHFFFAOYSA-N tert‐butyl hydroperoxide Chemical compound CC(C)(C)OO CIHOLLKRGTVIJN-UHFFFAOYSA-N 0.000 claims abstract description 4
- 229910000404 tripotassium phosphate Inorganic materials 0.000 claims abstract description 4
- 238000010438 heat treatment Methods 0.000 claims abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract 4
- 229910018162 SeO2 Inorganic materials 0.000 claims abstract 2
- 238000006243 chemical reaction Methods 0.000 claims description 14
- 239000012074 organic phase Substances 0.000 claims description 12
- 238000010898 silica gel chromatography Methods 0.000 claims description 9
- 239000003814 drug Substances 0.000 claims description 8
- 238000001914 filtration Methods 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 7
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 6
- 239000007832 Na2SO4 Substances 0.000 claims description 6
- 239000008346 aqueous phase Substances 0.000 claims description 6
- 238000001035 drying Methods 0.000 claims description 6
- 229910052938 sodium sulfate Inorganic materials 0.000 claims description 6
- 239000000243 solution Substances 0.000 claims description 5
- 229940079593 drug Drugs 0.000 claims description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 3
- 239000007864 aqueous solution Substances 0.000 claims description 3
- 229910052786 argon Inorganic materials 0.000 claims description 3
- 229940125904 compound 1 Drugs 0.000 claims description 3
- RNHDAKUGFHSZEV-UHFFFAOYSA-N 1,4-dioxane;hydrate Chemical compound O.C1COCCO1 RNHDAKUGFHSZEV-UHFFFAOYSA-N 0.000 claims description 2
- 239000008280 blood Substances 0.000 claims description 2
- 210000004369 blood Anatomy 0.000 claims description 2
- 239000012295 chemical reaction liquid Substances 0.000 claims description 2
- 229920006395 saturated elastomer Polymers 0.000 claims description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical group CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims 2
- 125000005605 benzo group Chemical group 0.000 claims 2
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims 2
- TZIHFWKZFHZASV-UHFFFAOYSA-N methyl formate Chemical group COC=O TZIHFWKZFHZASV-UHFFFAOYSA-N 0.000 claims 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 2
- 230000003110 anti-inflammatory effect Effects 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 7
- 206010028980 Neoplasm Diseases 0.000 abstract description 4
- ONVABDHFQKWOSV-UHFFFAOYSA-N 16-Phyllocladene Natural products C1CC(C2)C(=C)CC32CCC2C(C)(C)CCCC2(C)C31 ONVABDHFQKWOSV-UHFFFAOYSA-N 0.000 abstract description 3
- 206010061218 Inflammation Diseases 0.000 abstract description 3
- UYNPPIDGSVPVSW-UHFFFAOYSA-N ent-kaurane Natural products CC1(O)CC23CCC4C(CCCC4(C)C(=O)O)C2C=CC1C3 UYNPPIDGSVPVSW-UHFFFAOYSA-N 0.000 abstract description 3
- 230000004054 inflammatory process Effects 0.000 abstract description 3
- 239000000463 material Substances 0.000 abstract description 3
- 231100000331 toxic Toxicity 0.000 abstract description 3
- 230000002588 toxic effect Effects 0.000 abstract description 3
- 241000894006 Bacteria Species 0.000 abstract description 2
- 230000003467 diminishing effect Effects 0.000 abstract description 2
- -1 ent-kaurane diterpenoid compound Chemical class 0.000 abstract description 2
- 239000000126 substance Substances 0.000 abstract description 2
- 208000007536 Thrombosis Diseases 0.000 abstract 1
- 238000005556 structure-activity relationship Methods 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 28
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 7
- 238000005160 1H NMR spectroscopy Methods 0.000 description 7
- 241001183967 Isodon Species 0.000 description 6
- 210000004027 cell Anatomy 0.000 description 6
- 229930014626 natural product Natural products 0.000 description 5
- 125000003545 alkoxy group Chemical group 0.000 description 4
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 4
- 206010009944 Colon cancer Diseases 0.000 description 3
- 229960004316 cisplatin Drugs 0.000 description 3
- RTIKCEKESDRWAE-UHFFFAOYSA-N eriocalyxin B Natural products C=C1C(=O)C23CC1CCC2C12C(=O)C=CC(C)(C)C1C(O)C3(O)OC2 RTIKCEKESDRWAE-UHFFFAOYSA-N 0.000 description 3
- RTIKCEKESDRWAE-UJVKWQRCSA-N eriocalyxin b Chemical compound C([C@@H]1C[C@@]23C(C1=C)=O)C[C@H]2[C@]12C(=O)C=CC(C)(C)[C@H]1[C@H](O)[C@@]3(O)OC2 RTIKCEKESDRWAE-UJVKWQRCSA-N 0.000 description 3
- 239000000178 monomer Substances 0.000 description 3
- 241000196324 Embryophyta Species 0.000 description 2
- 241001365031 Isodon japonicus Species 0.000 description 2
- 241001646826 Isodon rubescens Species 0.000 description 2
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 2
- 208000029742 colonic neoplasm Diseases 0.000 description 2
- 239000000287 crude extract Substances 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 210000004881 tumor cell Anatomy 0.000 description 2
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 1
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- MQOJPNKACWKUGI-CDKPERABSA-N Enmein Chemical compound C1C[C@H]2[C@@]34CO[C@@H](O)[C@@H]3C(C)(C)[C@@H](O)C[C@@H]4OC(=O)[C@]22C(=O)C(=C)[C@H]1C2 MQOJPNKACWKUGI-CDKPERABSA-N 0.000 description 1
- MQOJPNKACWKUGI-UHFFFAOYSA-N Eumein Natural products C1CC2C34COC(O)C3C(C)(C)C(O)CC4OC(=O)C22C(=O)C(=C)C1C2 MQOJPNKACWKUGI-UHFFFAOYSA-N 0.000 description 1
- 241000554447 Isodon eriocalyx Species 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 229940125773 compound 10 Drugs 0.000 description 1
- 229940125797 compound 12 Drugs 0.000 description 1
- 230000009982 effect on human Effects 0.000 description 1
- IVZWRQBQDVHDNG-KUIXFMFUSA-N ent-kaurane Chemical compound C([C@@]1(C)[C@@H]2CC3)CCC(C)(C)[C@H]1CC[C@]21C[C@H](C)[C@H]3C1 IVZWRQBQDVHDNG-KUIXFMFUSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 230000005918 in vitro anti-tumor Effects 0.000 description 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 201000005296 lung carcinoma Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
- SDHTXBWLVGWJFT-XKCURVIJSA-N oridonin Chemical compound C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12[C@@H](O)CCC(C)(C)[C@H]1[C@H](O)[C@@]3(O)OC2 SDHTXBWLVGWJFT-XKCURVIJSA-N 0.000 description 1
- CAQAFLRZJHXSIS-UHFFFAOYSA-N oridonin Natural products CC1(C)C=CC(O)C23COC(O)(C(O)C12)C45C(O)C(CCC34)C(=C)C5=O CAQAFLRZJHXSIS-UHFFFAOYSA-N 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicon dioxide Inorganic materials O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 210000002363 skeletal muscle cell Anatomy 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/74—Esters of carboxylic acids having an esterified carboxyl group bound to a carbon atom of a ring other than a six-membered aromatic ring
- C07C69/757—Esters of carboxylic acids having an esterified carboxyl group bound to a carbon atom of a ring other than a six-membered aromatic ring having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
- A61P39/02—Antidotes
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/46—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino or carboxyl groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
- C07C69/78—Benzoic acid esters
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
- C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
- C07D317/60—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Toxicology (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention belongs to the technical field of medical high molecular substances, and discloses a bicyclic unsaturated ketone derivative with antibacterial and antitumor activities and a preparation method thereof, wherein [ RhCl (C) is added into a compound 2 and a compound 12H4)2]2，K3PO4Separating to obtain a compound 3; putting the compound 3 into a round bottom single-mouth bottle, adding dichloromethane, and adding SeO2And t-BuOOH until the compound 3 completely reacts, and separating to obtain a compound 4; and (3) putting the compound 4 into a round-bottom single-mouth bottle, adding ethyl acetate and IBX, and heating to react to obtain a compound 5. The invention analyzes and reforms the structure-activity relationship of the ent-kaurane diterpenoid compound, and finds out the compound with simpler structure and stronger activity; has wide application in clearing away heat and toxic material, promoting blood circulation to disperse blood clots, resisting bacteria, diminishing inflammation, resisting tumor, etc.
Description
Technical Field
The invention belongs to the technical field of medical high molecular substances, and particularly relates to a bicyclic unsaturated ketone derivative with antibacterial and antitumor activities and a preparation method thereof.
Background
Currently, the current state of the art commonly used in the industry is such that:
the Rabdosia drugs have effects of clearing away heat and toxic materials, promoting blood circulation, relieving pain, resisting inflammation, and resisting tumor. At present, all medicines are extracted from rabdosia plants, such as crude extract medicines, namely rabdosia pilifera heat clearing and throat benefiting tablets; the monomer medicine-oridonin (oridonin) is extracted from whole plant of Rabdosia Rubescens (Rabdosia rubescens) of Rabdosia; the enmein is extracted and separated from Isodon japonicus; eriocalyxin B is extracted and separated from leaf of Isodon japonicus (Isodon eriocalyx var. laxiflora). Other methods are structural modification based on natural products.
In summary, the problems of the prior art are as follows:
(1) the crude extract has complicated medicinal components, unreliable quality control and undefined effective components.
(2) The content of the monomer medicine in the plant is low, natural resources are consumed, extraction is difficult, and the large-scale production cost is high.
(3) The enantiomer-kaurane diterpenoid compounds have the advantages of complex structure, long artificial synthesis route, low yield and high cost, and do not meet the requirements of production and application.
The difficulty and significance for solving the technical problems are as follows:
the rabdosia plant is widely released in our country, and the history of use as a medicine is long in folk, but the application of the rabdosia plant is greatly limited based on the problems.
The current realistic solution is to artificially simulate the structure of the ent-kaurane diterpenoid compounds, the synthesis is much simpler than the structure of natural products, and the bioactivity similar to or stronger than that of the natural products is kept, so that the dependence on natural resources can be eliminated, the monomer compounds can be artificially synthesized by a short route and an economic method, and the medicaments with independent intellectual property rights can be obtained.
Disclosure of Invention
Aiming at the problems in the prior art, the invention provides a bicyclic unsaturated ketone derivative with antibacterial and antitumor activities and a preparation method thereof.
The invention is realized by the following steps that the bicyclic unsaturated ketone derivative with antibacterial and antitumor activities has the following structure:
wherein R is1is-H or-OH or-OCH3or-OC2H5or-OCH2Ph OR other alkoxy (-OR) OR F OR Cl OR Br OR I, OR R1＝-OCH2O-or R1＝-NR2；R2Can be-H or alkyl (-R) or aryl (-Ar) or-OH or-OCH3or-OC2H5or-OCH2Ph OR other alkoxy (-OR) OR-NR 2.
Another object of the present invention is to provide a method for preparing bicyclic unsaturated ketone derivatives having antibacterial and antitumor activities, comprising:
taking compound 2 and compound 1 in a round bottom double-mouth bottle, and adding [ RhCl (C)2H4)2]2，K3PO4Changing argon for several times, adding dioxane H2O, heating to 70 ℃ for reaction overnight; after the compound 2 completely reacts, pouring the reaction liquid into a saturated ammonium chloride solution, and separating out an organic phase; extracting the aqueous phase with ethyl acetate, combining the organic phases, anhydrous Na2SO4Drying, filtering, concentrating, and separating by silica gel column chromatography to obtain compound 3;
taking compound 3(1mmol) and adding SeO into a 25mL round bottom single-mouth bottle2(0.9mmol) and t-BuOOH (2mmol), CH was added2Cl2(2mL) was allowed to react overnight at room temperature, and after completion of the reaction by TLC, addedSaturated Na2S2O3Aqueous solution (20mL) and the organic phase separated. The aqueous phase was extracted with ethyl acetate (3X 5mL), and the organic phases were combined, anhydrous Na2SO4Drying, filtering, concentrating, and separating by silica gel column chromatography to obtain compound 4. Dissolving Compound 4 in CH3CO2C2H5To (5mL) was added IBX (1eq.) and the reaction was carried out overnight at 50 ℃. TLC shows that the reaction is complete, and then the mixture is filtered, concentrated and separated by silica gel column chromatography to obtain a compound 5. Compound 5 may derive the structure of compound (I).
Further, the reaction formula for preparing the bicyclic unsaturated ketone derivative with antibacterial and antitumor activities comprises:
1.
2.
the invention also aims to provide a medicament which is prepared from the bicyclic unsaturated ketone derivative with antibacterial and antitumor activities and has the functions of clearing away heat and toxic materials, promoting blood circulation by removing blood stasis, resisting bacteria, diminishing inflammation and resisting tumors.
In summary, the advantages and positive effects of the invention are:
the invention mainly synthesizes the compound with the bicyclic unsaturated ketone structure through three steps of reactions. The synthesis method can smoothly react to obtain corresponding products no matter the electron donating effect group or the electron withdrawing effect group, and the total yield is 45-62%. Meanwhile, an in vitro antitumor activity experiment is carried out on the bicyclic unsaturated ketone structural compound with the structural formula (I). The compounds 6-12 were screened for anti-tumor activity in vitro by MTT method against HepG2 (human hepatoma cell), NSCLC-H292 (human lung carcinoma cell), SNU-1040 (human colon carcinoma cell) cancer cell line, and rat skeletal muscle cell (normal cell L6) was used as control, and natural products Eriocalyxin B and cisplatin were used as positive control, and the results showed (see Table 1): the bicyclic unsaturated ketone structural compound has wide antitumor activity in vitro and has obvious inhibition effect on human liver cancer, human lung cancer and human colon cancer. The synthesized compound 6-12 has stronger activity than that of a contrast-natural product eriocalyxin B and weaker activity than that of cisplatin. But the selectivity of the synthesized compound on normal cells and human colon cancer tumor cells is stronger than that of the contrast-cisplatin.
Table 1: the inhibition rate of the compound 6-12 on the growth of tumor cells%
In summary, compared with the complex structure of the ent-kaurane natural product, the compound with simpler structure and stronger activity is found in the invention.
Drawings
FIG. 1 is a flow chart of the preparation method of bicyclic unsaturated ketone derivatives with antibacterial and antitumor activities according to the embodiment of the present invention.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
The invention is further described below with reference to specific assays.
The embodiment of the invention provides a bicyclic unsaturated ketone derivative with antibacterial and antitumor activities, which has the following structure:
wherein R is1is-H or-OH or-OCH3or-OC2H5or-OCH2Ph OR other alkoxy (-OR) OR F OR Cl OR Br OR I, OR R1＝-OCH2O-or R1＝-NR2；R2Can be-H or alkyl (-R) or aryl(-Ar) or-OH or-OCH3or-OC2H5or-OCH2Ph OR other alkoxy (-OR) OR-NR 2.
Referring to fig. 1, a method for preparing a bicyclic unsaturated ketone derivative with antibacterial and antitumor activities according to an embodiment of the present invention includes:
s101 taking compound 2(1mmol) and compound 1(5mmol) in a 25mL round bottom double-mouth bottle, adding [ RhCl (C)2H4)2]2(0.015mmol)，K3PO4(1.1mmol), argon was exchanged three times and dioxane: H was added23mL of O (2:1 vol.) was heated to 70 ℃ and reacted overnight. TLC showed that Compound 2 had reacted to completion, the reaction was poured into 10mL of saturated ammonium chloride solution and the organic phase was separated. The aqueous phase was extracted with ethyl acetate (3X 5mL), and the organic phases were combined, anhydrous Na2SO4Drying, filtering, concentrating, and separating by silica gel column chromatography to obtain compound 3.
S102 taking compound 3(1mmol) and adding SeO into a 25mL round bottom single-mouth bottle2(0.9mmol) and t-BuOOH (2mmol), CH was added2Cl2(2mL) was allowed to react overnight at room temperature, and after completion of the reaction by TLC, saturated Na was added2S2O3Aqueous solution (20mL) and the organic phase separated. The aqueous phase was extracted with ethyl acetate (3X 5mL), and the organic phases were combined, anhydrous Na2SO4Drying, filtering, concentrating, and separating by silica gel column chromatography to obtain compound 4. Dissolving Compound 4 in CH3CO2C2H5To (5mL) was added IBX (1eq.) and the reaction was carried out overnight at 50 ℃. TLC shows that the reaction is complete, and then the mixture is filtered, concentrated and separated by silica gel column chromatography to obtain a compound 5. Compound 5 may derive the structure of compound (I).
The invention is further described below with reference to specific assays.
The preparation method of the bicyclic unsaturated ketone derivative with antibacterial and antitumor activities provided by the embodiment of the invention comprises the following steps:
1.
2.
the application of the invention is further described below with reference to specific examples.
According to the preparation method, 8 representative compounds are synthesized, and the structure is as follows:
the relevant test data are as follows:
compound 6:1H-NMR(300MHz,CDCl3):δ＝8.17(1H,d),7.31-7.76(6H,m),6.29(1H,s),5.66(1H,s),4.81(1H,d),3.84(1H,t),3.66(2H,q),3.04(2H,m),2.63(2H,m),1.25(3H,t)ppm；13C-NMR(75.5MHz,CDCl3):δ＝206.14,198.62,167.95,143.08,137.46,134.04,131.26,128.87,128.45,126.15,125.90,124.99,124.72,123.70,120.55,61.29,54.33,42.64,38.54,31.93,29.69,13.37ppm；IR(KBr):υmax＝2960.21，2924.82，2871.42，1715.20，1598.60，1511.65，1463.07cm-1；MS(EI):m/z:371；MS(HR-ESI):m/z:calcd for C22H20O4Na:371.1259；found:371.1263[M+Na]+.
compound 7:1H-NMR(300MHz,CDCl3):δ＝6.82-6.76(4H,m),6.18(1H,s),5.60(1H,s),4.14(2H,q),3.88(1H,t),3.73-3.67(4H,m),3.00(1H,t),2.73-2.58(4H,m),1.60(1H,s),1.11(3H,t)ppm；13C-NMR(75.5MHz,CDCl3):δ＝206.32,197.98,171.18,167.61,166.56,145.23,142.86,129.77,129.68,128.95,120.69,62.09,61.82,60.41,54.65,52.23,44.14,40.80,30.91,14.06ppm；IR(KBr):υmax＝2934.74,2836.14,1752.68,1717.64,1639.05,1611.39,1588.53,1500.40cm-1；MS(+ESI):m/z:381；MS(HR-ESI):m/z:calcd for C20H22O6Na:381.1314；found:381.1314[M+Na]+.
compound 8:1H-NMR(300MHz,CDCl3):δ＝7.09(2H,d),6.78(2H,d),6.19(1H,s),5.59(1H,s),4.50(1H,m),4.13(2H,q),4.01(1H,t),3.77(1H,d),2.91-2.89(1H,dd),2.61-2.51(3H,m),1.27(6H,d),1.22(3H,t)ppm；13C-NMR(75.5MHz,CDCl3):δ＝207.11,199.8,168.21,157.40,143.29,131.88,129.94,120.04,115.64,69.83,62.71,61.59,54.81,43.82,41.30,30.93,22.00,21.97,14.09ppm；IR(KBr):υmax＝2977.02,2932.66,1752.18,1716.83,1639.91,1609.04,1577.61,1542.22,1509.92cm-1；MS(ESI):m/z:379；MS(HR-ESI):m/z:calcd for C21H24O5Na:379.1521；found:379.1514[M+Na]+.
compound 9:1H-NMR(300MHz,CDCl3):δ＝7.26(4H,m),7.06-6.94(10H,m),6.28(1H,s),5.61(1H,s),4.12(2H,q),3.72(2H,m),2.74-2.68(3H,m),2.49(1H,d),1.11(3H,t)ppm；3C-NMR(75.5MHz,CDCl3):δ＝206.76,198.36,167.98,147.42,143.34,133.56,129.55,129.31,124.61,123.24,122.87,120.00,62.61,61.58,54.76,44.04,41.18,31.01,14.14ppm；IR(KBr):υmax＝3059.29,3036.04,2978.39,2926.85,2853.18,1753.25,1717.43,1639.73,1588.09,1509.38cm-1；MS(EI):m/z:488；MS(HR-ESI):m/z:calcd for C30H27NO4Na:488.1838；found:488.1846[M+Na]+.
compound 10:1H-NMR(300MHz,CDCl3):δ＝7.23-7.20(5H,m),7.06-6.98(9H,m),6.19(1H,s),5.60(1H,s),4.25-4.22(2H,m),4.16(1H,d),3.76(1H,d),2.94-2.88(1H,dd),2.66-2.55(3H,m),1.27(3H,t)ppm；13C-NMR(75.5MHz,CDCl3):δ＝204.63,197.41,169.41,147.58,147.19,143.50,129.24,124.59,123.01,122.78,120.23,61.37,60.46,53.42,47.08,43.12,39.66,13.96ppm；IR(KBr):υmax＝3059.20,3035.85,2979.04,2935.72,2904.89,1721.58,1639.44,1587.71,1509.29cm-1；MS(EI):m/z:488；MS(HR-ESI):m/z:calcd for C30H27NO4Na:488.1838；found:488.1846[M+Na]+
compound 11:1H-NMR(300MHz,CDCl3):δ＝6.73-6.70(3H,m),6.32(1H,s),5.96(2H,s),5.65(1H,s),4.14(2H,q),3.75(1H,d),2.70(1H,dd),2.50-2.25(4H,m),1.18(3H,t)ppm；13C-NMR(75.5MHz,CDCl3):δ＝206.82,198.28,167.91,147.81,147.15,143.17,133.81,122.15,120.19,109.33,108.21,101.22,62.60,61.70,54.74,44.21,41.28,30.93,14.12ppm；IR(KBr):υmax＝2959.27,2919.93,2851.16,1751.93,1716.35,1639.93,1609.71,1503.82cm-1；MS(EI):m/z:365；MS(HR-ESI):m/z:calcd for C19H18O6Na:365.1001；found:365.1006[M+Na]+.
compound 12:1H-NMR(300MHz,CDCl3):δ＝6.74-6.67(3H,m),6.22(1H,s),5.96(2H,s),5.60(1H,s),4.22(2H,q),3.99(1H,d),2.87(1H,dd),2.57-2.53(4H,m),1.24(3H,t)ppm；13C-NMR(75.5MHz,CDCl3):δ＝204.44,197.40,169.26,147.52,147.04,143.38,132.64,121.86,120.43,108.57,101.09,61.43,60.45,53.38,47.16,43.23,39.53,13.95ppm；IR(KBr):υmax＝2958.70,2923.35,2852.44,1721.95,1639.22,1548.68,1505.38cm-1；MS(EI):m/z:365；MS(HR-ESI):m/z:calcd for C19H18O6Na:365.1001；found:365.1006[M+Na]+.
the above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents and improvements made within the spirit and principle of the present invention are intended to be included within the scope of the present invention.
Claims (3)
1. A method for preparing a bicyclic unsaturated ketone derivative having antibacterial and antitumor activities, comprising:
taking compound 2 and compound 1 in a round bottom double-mouth bottle, and adding [ RhCl (C)2H4)2]2，K3PO4Changing argon for several times, adding dioxane H2O, heating to 70 ℃ for reaction overnight; after the compound 2 completely reacts, pouring the reaction liquid into a saturated ammonium chloride solution, and separating out an organic phase; extracting the aqueous phase with ethyl acetate, combining the organic phases, anhydrous Na2SO4Drying, filtering, and concentratingSeparating with silica gel column chromatography to obtain compound 3;
taking the compound 3 into a 25mL round bottom single-mouth bottle, adding SeO2And t-BuOOH, adding CH2Cl2Reacting at room temperature overnight, and adding saturated Na after TLC shows that the reaction is complete2S2O3Separating out an organic phase from the aqueous solution;
extracting the aqueous phase with ethyl acetate, combining the organic phases, anhydrous Na2SO4Drying, filtering, concentrating, and separating by silica gel column chromatography to obtain compound 4;
dissolving Compound 4 in CH3CO2C2H5Adding IBX, and reacting at 50 ℃ overnight; after TLC shows that the reaction is complete, filtering, concentrating, and separating by silica gel column chromatography to obtain a compound 5;
structure of compound (I) derived from compound 5
Wherein R is1Is methyl formate group, isopropyl ether group, -N-Ph2Or R1Condensed with the adjacent benzene ring is of the following benzo structure:
R2is ethoxy.
2. The method for preparing bicyclic unsaturated ketone derivatives having antibacterial and antitumor activities according to claim 1, wherein said bicyclic unsaturated ketone derivatives having antibacterial and antitumor activities are prepared according to the reaction formula comprising:
a bicyclic unsaturated ketone derivative having the structure:
wherein R is1Is methyl formate group, isopropyl ether group, -N-Ph2Or R1Condensed with the adjacent benzene ring is of the following benzo structure:
R2is ethoxy.
3. Use of the bicyclic unsaturated ketone derivative prepared by the preparation method of the bicyclic unsaturated ketone derivative with antibacterial and antitumor activities of claim 2 in the preparation of drugs with heat-clearing and detoxifying, blood circulation promoting and blood stasis removing, antibacterial, anti-inflammatory and antitumor activities.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811384079.7A CN109400479B (en) | 2018-11-20 | 2018-11-20 | Bicyclic unsaturated ketone derivative with antibacterial and antitumor activities and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811384079.7A CN109400479B (en) | 2018-11-20 | 2018-11-20 | Bicyclic unsaturated ketone derivative with antibacterial and antitumor activities and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN109400479A CN109400479A (en) | 2019-03-01 |
| CN109400479B true CN109400479B (en) | 2021-07-30 |
Family
ID=65474052
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201811384079.7A Active CN109400479B (en) | 2018-11-20 | 2018-11-20 | Bicyclic unsaturated ketone derivative with antibacterial and antitumor activities and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN109400479B (en) |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS57167938A (en) * | 1981-04-07 | 1982-10-16 | Taiho Yakuhin Kogyo Kk | Novel diterpenoid |
| JPS59162931A (en) * | 1983-03-08 | 1984-09-13 | Wakunaga Seiyaku Kk | Dissolving aid |
| JPH0769886A (en) * | 1993-09-03 | 1995-03-14 | Lotte Co Ltd | Anticariogenic antiperiodontic agent and oral cavity composition containing the agent |
| CN1566061A (en) * | 2003-06-30 | 2005-01-19 | 桂明玉 | Novel natural drug effective region of rabdosiaexcisa total diterpene |
| CN101307059A (en) * | 2008-07-01 | 2008-11-19 | 中国科学院昆明植物研究所 | Eriocalyxin B derivates, preparation method thereof and applications in antineoplastic drugs |
| CN101851271A (en) * | 2009-03-31 | 2010-10-06 | 苏州金昊药业开发有限公司 | Glaucocalyxin D derivative, preparation method and application thereof |
| CN101993359A (en) * | 2009-08-14 | 2011-03-30 | 上海金昊药业开发有限公司 | Fatty acid derivative of glaucocalyxin A, as well as preparation method and applications thereof |
-
2018
- 2018-11-20 CN CN201811384079.7A patent/CN109400479B/en active Active
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS57167938A (en) * | 1981-04-07 | 1982-10-16 | Taiho Yakuhin Kogyo Kk | Novel diterpenoid |
| JPS59162931A (en) * | 1983-03-08 | 1984-09-13 | Wakunaga Seiyaku Kk | Dissolving aid |
| JPH0769886A (en) * | 1993-09-03 | 1995-03-14 | Lotte Co Ltd | Anticariogenic antiperiodontic agent and oral cavity composition containing the agent |
| CN1566061A (en) * | 2003-06-30 | 2005-01-19 | 桂明玉 | Novel natural drug effective region of rabdosiaexcisa total diterpene |
| CN101307059A (en) * | 2008-07-01 | 2008-11-19 | 中国科学院昆明植物研究所 | Eriocalyxin B derivates, preparation method thereof and applications in antineoplastic drugs |
| CN101851271A (en) * | 2009-03-31 | 2010-10-06 | 苏州金昊药业开发有限公司 | Glaucocalyxin D derivative, preparation method and application thereof |
| CN101993359A (en) * | 2009-08-14 | 2011-03-30 | 上海金昊药业开发有限公司 | Fatty acid derivative of glaucocalyxin A, as well as preparation method and applications thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN109400479A (en) | 2019-03-01 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN106632383B (en) | Curcuma zedoary 01 derivatives and preparation method thereof and the application in antitumor drug | |
| CN104107179B (en) | The application in preparing anti-acute gout medicine of the diethylamine derivative of Cleistanone Cleistanone | |
| CN103641827A (en) | Purrocoline derivative and synthetic method and application thereof | |
| CN109400479B (en) | Bicyclic unsaturated ketone derivative with antibacterial and antitumor activities and preparation method thereof | |
| CN102382164B (en) | Toad lactam compound as well as preparation method and application thereof | |
| CN103467556B (en) | A kind of preparation method of phytosterol cinnamate | |
| CN103772277A (en) | Hydroxychloroquine linolenate and synthesis method thereof | |
| CN110511233B (en) | Thiazolo [2,3-b ] oxazolone compound and preparation method and application thereof | |
| CN104288160A (en) | Application of O-(piperazinyl) ethyl derivative of cleistanone to preparation of medicine for resisting acute gout | |
| CN105085267A (en) | Synthetic method for salvianolic acid A | |
| CN108864130B (en) | Enmein derivative and preparation method and application thereof | |
| CN103864874B (en) | Phellinus monomer component ergot sterone and preparation method thereof with in the application of preparing in antineoplastic | |
| CN105343043A (en) | Composition and application thereof in drug for resisting acute gout | |
| CN104825470A (en) | Application of cleistanone O-(benzimidazolyl) ethyl derivative in preparation of drugs for treating acute gout | |
| CN106588614B (en) | A kind of preparation method and applications of diphenylmethyl alkanes compound | |
| CN115785040B (en) | Chiral synthesis method of active natural products curcumene and iso Ji Mafu lactone | |
| CN105287579A (en) | Composition and application thereof to acute gout resistant medicines | |
| CN105193789A (en) | Composition and application thereof in anti-acute gout drugs | |
| CN115197236B (en) | Linear type glabra A analogue and preparation and application thereof | |
| CN112851535B (en) | Synthesis and application of novel 4,4' - (((polyhalogenated phenyl) azadiyl) bis (methylene)) dibenzoic acid | |
| CN107445859B (en) | Fluorine-containing gossypol derivative with anti-tumor activity and preparation method and application thereof | |
| CN115594715B (en) | Targeted mitochondria chalcone derivative and application thereof | |
| CN106667980A (en) | Application of composition of derivatives of Harrisotone A in resisting acute gout | |
| CN104666311A (en) | Application of O-(triazolyl) ethyl derivative of Cleistanone in preparation of medicine resistant to acute gout | |
| CN105287590A (en) | Composition and application of composition in medicine for resisting acute gout |
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 | ||
| OL01 | Intention to license declared | ||
| OL01 | Intention to license declared |