CN112574198A - Indolated derivative of tetrahydro-beta-carboline and preparation and application thereof - Google Patents
Indolated derivative of tetrahydro-beta-carboline and preparation and application thereof Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 24
- CFTOTSJVQRFXOF-UHFFFAOYSA-N 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole Chemical class N1C2=CC=CC=C2C2=C1CNCC2 CFTOTSJVQRFXOF-UHFFFAOYSA-N 0.000 title claims abstract description 18
- 238000006243 chemical reaction Methods 0.000 claims abstract description 33
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 17
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 17
- 239000001301 oxygen Substances 0.000 claims abstract description 17
- ZXLDQJLIBNPEFJ-UHFFFAOYSA-N tetrahydro-beta-carboline Natural products C1CNC(C)C2=C1C1=CC=C(OC)C=C1N2 ZXLDQJLIBNPEFJ-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000003814 drug Substances 0.000 claims abstract description 8
- 150000002475 indoles Chemical class 0.000 claims abstract description 8
- 238000006919 indolization reaction Methods 0.000 claims abstract description 8
- 206010006187 Breast cancer Diseases 0.000 claims abstract description 6
- 208000026310 Breast neoplasm Diseases 0.000 claims abstract description 6
- 206010008342 Cervix carcinoma Diseases 0.000 claims abstract description 5
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims abstract description 5
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims abstract description 5
- 201000010881 cervical cancer Diseases 0.000 claims abstract description 5
- 201000005202 lung cancer Diseases 0.000 claims abstract description 5
- 208000020816 lung neoplasm Diseases 0.000 claims abstract description 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 117
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 45
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 18
- 239000012074 organic phase Substances 0.000 claims description 17
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 claims description 15
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 15
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 12
- ONYNOPPOVKYGRS-UHFFFAOYSA-N 6-methylindole Natural products CC1=CC=C2C=CNC2=C1 ONYNOPPOVKYGRS-UHFFFAOYSA-N 0.000 claims description 9
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 claims description 9
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- 229940054051 antipsychotic indole derivative Drugs 0.000 claims description 4
- 239000003054 catalyst Substances 0.000 claims description 4
- 238000001035 drying Methods 0.000 claims description 4
- 239000002994 raw material Substances 0.000 claims description 4
- ZWKIJOPJWWZLDI-UHFFFAOYSA-N 4-fluoro-1h-indole Chemical compound FC1=CC=CC2=C1C=CN2 ZWKIJOPJWWZLDI-UHFFFAOYSA-N 0.000 claims description 3
- VXWVFZFZYXOBTA-UHFFFAOYSA-N 5-bromo-1h-indole Chemical compound BrC1=CC=C2NC=CC2=C1 VXWVFZFZYXOBTA-UHFFFAOYSA-N 0.000 claims description 3
- MYTGFBZJLDLWQG-UHFFFAOYSA-N 5-chloro-1h-indole Chemical compound ClC1=CC=C2NC=CC2=C1 MYTGFBZJLDLWQG-UHFFFAOYSA-N 0.000 claims description 3
- DWAQDRSOVMLGRQ-UHFFFAOYSA-N 5-methoxyindole Chemical compound COC1=CC=C2NC=CC2=C1 DWAQDRSOVMLGRQ-UHFFFAOYSA-N 0.000 claims description 3
- YPKBCLZFIYBSHK-UHFFFAOYSA-N 5-methylindole Chemical compound CC1=CC=C2NC=CC2=C1 YPKBCLZFIYBSHK-UHFFFAOYSA-N 0.000 claims description 3
- YTYIMDRWPTUAHP-UHFFFAOYSA-N 6-Chloroindole Chemical compound ClC1=CC=C2C=CNC2=C1 YTYIMDRWPTUAHP-UHFFFAOYSA-N 0.000 claims description 3
- MAWGHOPSCKCTPA-UHFFFAOYSA-N 6-bromo-1h-indole Chemical compound BrC1=CC=C2C=CNC2=C1 MAWGHOPSCKCTPA-UHFFFAOYSA-N 0.000 claims description 3
- KGWPHCDTOLQQEP-UHFFFAOYSA-N 7-methylindole Chemical compound CC1=CC=CC2=C1NC=C2 KGWPHCDTOLQQEP-UHFFFAOYSA-N 0.000 claims description 3
- 239000003513 alkali Substances 0.000 claims description 3
- 239000002585 base Substances 0.000 claims description 3
- 238000012544 monitoring process Methods 0.000 claims description 2
- 238000010898 silica gel chromatography Methods 0.000 claims description 2
- 238000003756 stirring Methods 0.000 claims description 2
- 238000000034 method Methods 0.000 claims 6
- 150000001875 compounds Chemical class 0.000 abstract description 37
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 4
- 238000005691 oxidative coupling reaction Methods 0.000 abstract description 3
- -1 tetrahydro-beta-carboline compound Chemical class 0.000 abstract description 3
- JPVYNHNXODAKFH-UHFFFAOYSA-N Cu2+ Chemical compound [Cu+2] JPVYNHNXODAKFH-UHFFFAOYSA-N 0.000 abstract description 2
- 230000000259 anti-tumor effect Effects 0.000 abstract description 2
- 238000006555 catalytic reaction Methods 0.000 abstract description 2
- 229910001431 copper ion Inorganic materials 0.000 abstract description 2
- 230000008878 coupling Effects 0.000 abstract description 2
- 238000010168 coupling process Methods 0.000 abstract description 2
- 238000005859 coupling reaction Methods 0.000 abstract description 2
- 238000007306 functionalization reaction Methods 0.000 abstract description 2
- 235000019439 ethyl acetate Nutrition 0.000 description 50
- 210000004027 cell Anatomy 0.000 description 27
- 239000000243 solution Substances 0.000 description 20
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 13
- 238000005160 1H NMR spectroscopy Methods 0.000 description 13
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 13
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 13
- 239000003480 eluent Substances 0.000 description 13
- 238000002844 melting Methods 0.000 description 13
- 230000008018 melting Effects 0.000 description 13
- 239000000741 silica gel Substances 0.000 description 13
- 229910002027 silica gel Inorganic materials 0.000 description 13
- 239000007787 solid Substances 0.000 description 12
- 239000006285 cell suspension Substances 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 239000001963 growth medium Substances 0.000 description 6
- 230000004083 survival effect Effects 0.000 description 6
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 5
- 238000012258 culturing Methods 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 238000007664 blowing Methods 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 239000008055 phosphate buffer solution Substances 0.000 description 4
- 239000006228 supernatant Substances 0.000 description 4
- 206010028980 Neoplasm Diseases 0.000 description 3
- 238000002835 absorbance Methods 0.000 description 3
- 238000010009 beating Methods 0.000 description 3
- 238000004113 cell culture Methods 0.000 description 3
- 230000003833 cell viability Effects 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 230000003013 cytotoxicity Effects 0.000 description 3
- 231100000135 cytotoxicity Toxicity 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 230000001502 supplementing effect Effects 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- 239000012980 RPMI-1640 medium Substances 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 230000004663 cell proliferation Effects 0.000 description 2
- 210000004881 tumor cell Anatomy 0.000 description 2
- 238000004293 19F NMR spectroscopy Methods 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 229930005303 indole alkaloid Natural products 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 244000045947 parasite Species 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
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- 238000001308 synthesis method Methods 0.000 description 1
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- 238000010257 thawing Methods 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Indole Compounds (AREA)
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Abstract
The invention belongs to the field of medicinal chemistry, and discloses an indolization derivative of tetrahydro-beta-carboline, and a preparation method and application thereof. Coupling the tetrahydro-beta-carboline compound with the indole derivative under the conditions of copper ion catalysis and oxygen, and carrying out terminal functionalization on the tetrahydro-carboline derivative under a mild oxidative coupling condition. The preparation method is simple, the used reagent is a reagent commonly used in a laboratory, the reaction condition is mild, the practicability is strong, the skeleton structure is synthesized for the first time, the antitumor activity is obvious, and the compound can be used for developing medicaments for treating breast cancer, lung cancer, cervical cancer and the like.
Description
Technical Field
The invention belongs to the field of medicinal chemistry, and particularly relates to an indolization derivative of tetrahydro-beta-carboline and a preparation method thereof.
Background
The carboline compounds are indole alkaloids, and the tetrahydrocarboline derivatives are widely distributed in the nature and have various biological activities of resisting tumors, viruses, bacteria, parasites, oxidation, platelet aggregation and the like. The specific skeleton structure of the tetrahydrocarboline derivative determines that the chemical reactivity of the tetrahydrocarboline derivative is difficult to control.
The invention is based on a tetrahydro-beta-carboline structure, and obtains the indolization derivative of the tetrahydro-beta-carboline through oxidative coupling reaction. Coupling the tetrahydro-beta-carboline compound with an indole derivative under the conditions of copper ion catalysis and oxygen, and carrying out terminal functionalization on the tetrahydro-beta-carboline compound through a mild oxidative coupling condition. The preparation method is simple, the used reagents are common laboratory reagents, the reaction conditions are mild, the practicability is high, the relative molecular mass of the synthesized compound is about 500, the skeleton structure is synthesized for the first time, and the cell experiment proves that the compound has good in-vitro anticancer activity, so that the compound obtained by the invention is expected to be used for preparing related cancer treatment medicines.
Disclosure of Invention
The invention aims to provide an indolization derivative of tetrahydro-beta-carboline, a preparation method and application thereof, the preparation method is simple, the experimental conditions are mild, and harsh conditions such as high temperature, high pressure, strong acid and strong base are not required.
In order to achieve the purpose, the invention adopts the following technical scheme:
an indolized derivative of tetrahydro-beta-carboline, which has one of the following structural general formulas:
wherein R is1 Is composed of
、
、
Or
； R2 H, OMe or Cl; r3 H, F, Cl, Br, Me or OMe.
The preparation method of the indolized derivative of the tetrahydro-beta-carboline comprises the following steps:
dissolving raw materials in a proper solvent, adding 4.0 equivalent of indole derivatives, 0.2 equivalent of catalyst and 2.0 equivalent of alkali, stirring and reacting for several hours at room temperature under the condition of oxygen, monitoring the reaction to be complete, extracting by using ethyl acetate and water, collecting an organic phase, drying and spin-drying the obtained organic phase, and separating by silica gel column chromatography to obtain the indolization derivatives of tetrahydro-beta-carboline, wherein the reaction yield is about 50% generally, and the individual yield can reach more than 65%.
The raw materials comprise:
、
、
、
、
、
。
the solvent is N, N-dimethylformamide.
The indole derivatives comprise indole, 4-fluoroindole, 5-chloroindole, 5-bromoindole, 5-methylindole, 7-methylindole, 5-methoxyindole, 6-methylindole, 6-bromoindole and 6-chloroindole.
The catalyst is anhydrous copper chloride.
The base is pyridine.
Use of an indolised derivative of tetrahydro- β -carboline:
the obtained indolization derivative of the tetrahydro-beta-carboline has certain inhibitory activity on MCF-7 cell strains, A549 cell strains and Hela cell strains, and has a prospect for preparing medicaments for resisting breast cancer, lung cancer and cervical cancer.
The invention has the following remarkable advantages:
(1) the synthesis method is simple, mild in reaction conditions, low in energy consumption, strong in practicability, and does not require harsh conditions such as high temperature, high pressure, strong acid and strong alkali; the reaction yield is about 50% generally, and the individual yield can reach more than 65%.
(2) The molecular weight of the designed and synthesized indolization derivative of the tetrahydro-beta-carboline is smaller and is generally about 500, and the compound obtained by the invention is expected to be used for preparing related cancer treatment medicines and provides a new solution and scheme for the synthesis of other similar compounds.
Drawings
FIG. 1 is a schematic diagram of a ball and stick model of compounds FZU-0070-019.
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
In order to make the content of the present invention more comprehensible, the technical solutions of the present invention are further described below with reference to specific embodiments.
The synthetic route is detailed inAngew. Chem. Int. Ed. 2017, 56, 14968–14972；Org. Lett.2018, 20, 5457-5460；Org. Lett.2019, 21, 6160-6163；Org. Lett. 2019, 21, 7475-7477；Org. Lett. 2019, 21, 8884-8887；Adv. Synth. Catal.2019, 361,432-435）。
Example 1 preparation of FZU-0070-019
1.63 g S1 was dissolved in N, N-dimethylformamide and 2.34 g indole, 134 mg anhydrous copper chloride and 805. mu.L pyridine were added. After the reaction was stirred under oxygen at room temperature for 16 hours, the reaction was diluted with 350 mL of ethyl acetate and extracted with 400 mL of water. The organic phase was collected, dried over anhydrous sodium sulfate, spun dry and purified on column silica gel to give compound FZU-0070-019 (1.55 g, 67%). Eluents used were PE/EtOAc = 4:1 to PE/EtOAc = 2: 1.
Physical state: a pale yellow solid. Melting point: 194.1-195.4oC. TLC: Rf= 0.46 (PE/EtOAc = 2:1). 1H NMR (400 MHz, DMSO-d 6) δ 11.01 (s, 1H), 8.00 (d, J = 8.1 Hz, 1H), 7.74 (s, 1H), 7.56 (s, 1H), 7.55 (s, 1H), 7.38 (d, J = 7.9 Hz, 2H), 7.34 (d, J = 8.0 Hz, 1H), 7.09 (d, J = 7.4 Hz, 1H), 7.02 (t, J = 6.4 Hz, 2H), 6.86 (t, J = 7.6 Hz, 1H), 6.64 – 6.55 (m, 2H), 6.14 (s, 1H), 4.36 (s, 1H), 4.06 (d, J= 11.9 Hz, 1H), 3.70 (d, J = 11.0 Hz, 1H), 2.34 (s, 3H), 2.30 (s, 1H), 2.16 (t, J = 11.9 Hz, 1H), 2.03 (d, J = 12.3 Hz, 1H), 1.96 (d, J = 12.1 Hz, 1H). 13C NMR (101 MHz, DMSO-d 6) δ 150.62, 144.26, 136.41, 132.70, 131.15, 130.46, 129.63, 128.76, 127.76, 124.20, 123.97, 123.74, 120.91, 118.11, 117.66, 114.86, 111.25, 110.39, 79.12, 68.34, 56.17, 45.04, 31.39, 21.48. HRMS (ESI): calcd for C26H26N3O3S[M + H]+ m/z 460.1689, found 460.1687.
EXAMPLE 2 preparation of the Compounds FZU-0070-022
326 mg of S1 was dissolved in N, N-dimethylformamide, and 540 mg of 4-fluoroindole, 27 mg of anhydrous copper chloride and 160. mu.L of pyridine were added. After the reaction was stirred under oxygen at room temperature for 23 hours, the reaction was diluted with 200 mL of ethyl acetate and extracted with 250 mL of water. The organic phase was collected, dried over anhydrous sodium sulfate, spun-dried and purified on silica gel column to give compound FZU-0070-022 (233 mg, 50%). Eluents used were PE/EtOAc = 4:1 to PE/EtOAc = 2: 1.
Physical state: a white solid. Melting point: 184.5-186.2oC. TLC: Rf= 0.47 (PE/EtOAc = 2:1). 1H NMR (400 MHz, DMSO-d 6) δ 11.08 (s, 1H), 7.98 (d, J = 6.4 Hz, 1H), 7.73 (s, 1H), 7.56 (s, 1H), 7.54 (s, 1H), 7.38 (s, 1H), 7.36 (s, 1H), 7.10 (t, J = 7.5 Hz, 2H), 7.03 (t, J = 7.4 Hz, 1H), 6.72 (t, J = 9.2 Hz, 1H), 6.61 (s, 1H), 6.60 (s, 1H), 6.14 (s, 1H), 4.44 (s, 1H), 4.05 (d, J = 11.6 Hz, 1H), 3.71 (d, J = 9.4 Hz, 1H), 2.34 (s, 3H), 2.31 (s, 1H), 2.13 (t, J = 11.8 Hz, 1H), 2.00 (d, J = 12.7 Hz, 1H), 1.90 (d, J = 11.7 Hz, 1H) 13C NMR (101 MHz, DMSO-d 6) δ 158.96 (d, J = 233.9 Hz), 150.60, 144.30, 136.11 (d, J = 12.5 Hz), 132.63, 131.04, 130.47, 129.67, 127.76, 125.68, 125.08 (d, J = 9.6 Hz), 124.65 (d, J = 3.3 Hz), 123.76, 117.79, 115.27, 110.48, 106.53 (d, J = 23.5 Hz), 96.89 (d, J = 25.0 Hz), 79.09, 68.16, 56.52, 45.09, 31.20, 21.47 . 19F NMR (376 MHz, DMSO-d 6) δ -123.04 – -123.15 (m). HRMS (ESI): calcd for C26H25FN3O3S[M + H]+ m/z 478.1595, found 478.1596.
Example 3 preparation of the Compounds FZU-0070-023
326 mg of S1 was dissolved in N, N-dimethylformamide, and 606 mg of 5-chloroindole, 27 mg of anhydrous copper chloride and 160. mu.L of pyridine were added. After the reaction was stirred under oxygen at room temperature for 48 hours, the reaction was diluted with 200 mL of ethyl acetate and extracted with 250 mL of water. The organic phase was collected, dried over anhydrous sodium sulfate, spun-dried and purified on column silica gel to give compounds FZU-0070-023 (220 mg, 45%). The eluent used was PE/EtOAc = 3: 1.
Physical state: a pale yellow solid. Melting point: 198.9-201.5oC. TLC: Rf= 0.56 (PE/EtOAc = 2:1). 1H NMR (400 MHz, DMSO-d 6) δ 11.21 (s, 1H), 8.00 (s, 1H), 7.81 (s, 1H), 7.56 (s, 1H), 7.54 (s, 1H), 7.37 (d, J = 7.5 Hz, 2H), 7.34 (s, 1H), 7.09 (d, J = 6.9 Hz, 1H), 7.07 – 6.99 (m, 2H), 6.62 (t, J = 8.8 Hz, 2H), 6.14 (s, 1H), 4.57 (s, 1H), 4.04 (d, J = 11.6 Hz, 1H), 3.71 (d, J = 8.9 Hz, 1H), 2.34 (s, 3H), 2.31 (s, 1H), 2.11 (t, J = 11.0 Hz, 1H), 1.97 (d, J = 13.2 Hz, 1H), 1.87 (d, J = 11.9 Hz, 1H). 13C NMR (101 MHz, DMSO-d 6) δ 150.58, 144.35, 134.82, 132.54, 131.02, 130.49, 130.02, 129.75, 127.77, 125.75, 123.81, 123.15, 122.85, 120.84, 117.89, 115.01, 112.69, 110.57, 79.06, 68.07, 56.18, 45.14, 31.12, 21.48 . HRMS (ESI): calcd for C26H25ClN3O3S[M + H]+ m/z 494.1300, found 494.1299.
EXAMPLE 4 preparation of FZU-0070-024 Compound
326 mg of S1 was dissolved in N, N-dimethylformamide, and 784 mg of 5-bromoindole, 27 mg of anhydrous copper chloride and 160. mu.L of pyridine were added. After the reaction was stirred under oxygen at room temperature for 24 hours, the reaction was diluted with 200 mL of ethyl acetate and extracted with 250 mL of water. The organic phase was collected, dried over anhydrous sodium sulfate, spun-dried and purified on silica gel to give compound FZU-0070-024 (280 mg, 53%). Eluents used were PE/EtOAc = 3:1 to PE/EtOAc = 2: 1.
Physical state: a pale yellow solid. Melting point: 196.3-197.7oC. TLC: Rf= 0.39 (PE/EtOAc = 2:1). 1H NMR (400 MHz, DMSO-d 6)δ 11.23 (s, 1H), 8.15 (s, 1H), 7.79 (s, 1H), 7.56 (s, 1H), 7.54 (s, 1H), 7.39 (s, 1H), 7.37 (s, 1H), 7.32 (d, J = 8.5 Hz, 1H), 7.14 – 7.08 (m, 2H), 7.04 (t, J = 7.5 Hz, 1H), 6.64 (d, J = 6.4 Hz, 1H), 6.61 (d, J = 7.5 Hz, 1H), 6.14 (s, 1H), 4.58 (s, 1H), 4.04 (d, J = 11.8 Hz, 1H), 3.72 (d, J = 9.9 Hz, 1H), 2.34 (s, 3H), 2.31 (s, 1H), 2.11 (t, J = 11.9 Hz, 1H), 1.98 – 1.91 (m, 1H), 1.87 (d, J = 11.8 Hz, 1H). 13C NMR (101 MHz, DMSO-d 6) δ 150.59, 144.36, 135.05, 132.52, 131.02, 130.73, 130.50, 129.75, 127.76, 126.12, 125.58, 123.81, 123.36, 117.91, 114.94, 113.21, 111.06, 110.59, 79.04, 68.08, 56.18, 45.14, 31.12, 21.49. HRMS (ESI): calcd for C26H25BrN3O3S[M + H]+ m/z 538.0795, found 538.0788.
EXAMPLE 5 preparation of FZU-0070-027
326 mg of S1 was dissolved in N, N-dimethylformamide, and 524 mg of 5-methylindole, 27 mg of anhydrous copper chloride and 160. mu.L of pyridine were added. After the reaction was stirred under oxygen at room temperature for 31 hours, the reaction was diluted with 200 mL of ethyl acetate and extracted with 250 mL of water. The organic phase was collected, dried over anhydrous sodium sulfate, spun-dried and purified on column silica gel to give compound FZU-0070-027 (250 mg, 53%). Eluents used were PE/EtOAc = 3:1 to PE/EtOAc = 2: 1.
Physical state: a pale yellow solid. Melting point: 194.8-197.0oC. TLC: Rf= 0.47 (PE/EtOAc = 2:1). 1H NMR (400 MHz, DMSO-d 6) δ 10.88 (s, 1H), 7.78 (s, 1H), 7.69 (s, 1H), 7.57 (s, 1H), 7.55 (s, 1H), 7.38 (s, 1H), 7.37 (s, 1H), 7.23 (d, J = 8.0 Hz, 1H), 7.09 (d, J = 6.8 Hz, 1H), 7.03 (t, J = 7.2 Hz, 1H), 6.86 (d, J = 8.0 Hz, 1H), 6.66 – 6.57 (m, 2H), 6.11 (s, 1H), 4.33 (s, 1H), 4.04 (d, J = 11.6 Hz, 1H), 3.69 (d, J = 9.3 Hz, 1H), 2.34 (s, 3H), 2.30 (s, 3H), 2.24 (d, J = 2.5 Hz, 1H), 2.16 (d, J = 11.5 Hz, 1H), 1.99 (t, J = 14.3 Hz, 2H). 13C NMR (101 MHz, DMSO-d 6) δ 150.63, 144.25, 134.86, 132.67, 131.24, 130.45, 129.62, 128.94, 127.78, 126.21, 124.39, 123.72, 123.41, 122.55, 117.66, 114.25, 110.95, 110.43, 79.12, 68.39, 56.14, 44.99, 31.45, 21.91, 21.48. HRMS (ESI): calcd for C27H28N3O3S[M + H]+ m/z 474.1846, found 474.1844.
EXAMPLE 6 preparation of the Compounds FZU-0070-028
326 mg of S1 was dissolved in N, N-dimethylformamide, and 525 mg of 7-methylindole, 27 mg of anhydrous copper chloride and 160. mu.L of pyridine were added. After the reaction was stirred under oxygen at room temperature for 16 hours, the reaction was diluted with 200 mL of ethyl acetate and extracted with 250 mL of water. The organic phase was collected, dried over anhydrous sodium sulfate, spun-dried and purified on silica gel to give compound FZU-0070-028 (260 mg, 55%). The eluent used was PE/EtOAc = 3: 1.
Physical state: a pale red solid. Melting point: 192.5-194.4oC. TLC: Rf= 0.54 (PE/EtOAc = 5:2). 1H NMR (400 MHz, DMSO-d 6) δ 10.95 (s, 1H), 7.82 (d, J = 7.6 Hz, 1H), 7.74 (s, 1H), 7.56 (s, 1H), 7.54 (s, 1H), 7.38 (s, 1H), 7.36 (s, 1H), 7.08 (d, J = 6.9 Hz, 1H), 7.02 (t, J = 7.5 Hz, 1H), 6.82 (d, J = 6.2 Hz, 1H), 6.77 (t, J = 11.2 Hz, 1H), 6.59 (t, J = 8.8 Hz, 2H), 6.12 (s, 1H), 4.29 (s, 1H), 4.05 (d, J = 11.2 Hz, 1H), 3.69 (d, J = 9.3 Hz, 1H), 2.46 (s, 3H), 2.34 (s, 3H), 2.30 (s, 1H), 2.17 (t, J = 11.2 Hz, 1H), 2.02 (d, J = 11.9 Hz, 1H), 1.97 (d, J = 12.5 Hz, 1H). 13C NMR (101 MHz, DMSO-d 6)δ 150.62, 144.24, 135.89, 132.74, 131.14, 130.45, 129.60, 128.37, 127.75, 124.02, 123.72, 121.58, 121.31, 120.05, 118.31, 117.64, 115.21, 110.38, 79.10, 68.35, 56.17, 45.01, 31.45, 21.48, 17.29. HRMS (ESI): calcd for C27H28N3O3S[M + H]+ m/z 474.1846, found 474.1844.
Example 7 preparation of the Compounds FZU-0070-
326 mg of S1 was dissolved in N, N-dimethylformamide, and 588 mg of 5-methoxyindole, 27 mg of anhydrous copper chloride and 160. mu.L of pyridine were added. After the reaction was stirred under oxygen at room temperature for 24 hours, the reaction was diluted with 200 mL of ethyl acetate and extracted with 250 mL of water. The organic phase was collected, dried over anhydrous sodium sulfate, spun-dried and purified on column silica gel to give compound FZU-0070-. Eluents used were PE/EtOAc = 5:2 to PE/EtOAc = 2: 1.
Physical state: a pale purple solid. Melting point: 186.4-191.2oC. TLC: Rf= 0.31 (PE/EtOAc = 2:1). 1H NMR (400 MHz, DMSO-d 6) δ 10.86 (s, 1H), 7.68 (s, 1H), 7.55 (d, J = 7.5 Hz, 2H), 7.50 (s, 1H), 7.38 (s, 1H), 7.36 (s, 1H), 7.23 (d, J = 8.5 Hz, 1H), 7.08 (d, J = 6.9 Hz, 1H), 7.02 (t, J = 7.4 Hz, 1H), 6.70 (d, J = 8.5 Hz, 1H), 6.62 (d, J = 7.5 Hz, 1H), 6.59 (d, J = 6.9 Hz, 1H), 6.13 (s, 1H), 4.44 (s, 1H), 4.01 (d, J = 11.6 Hz, 1H), 3.69 (s, 1H), 3.66 (s, 3H), 2.34 (s, 3H), 2.29 (s, 1H), 2.21 (t, J = 11.2 Hz, 1H), 2.01 (d, J = 11.5 Hz, 2H). 13C NMR (101 MHz, DMSO-d 6) δ 152.77, 150.63, 144.23, 132.70, 131.88, 131.36, 130.44, 129.62, 128.97, 127.78, 125.13, 123.67, 117.67, 114.57, 111.63, 110.94, 110.38, 106.42, 79.13, 68.52, 55.99, 44.88, 31.58, 21.47. HRMS (ESI): calcd for C27H28N3O4S[M + H]+ m/z 490.1795, found 490.1792.
Example 8 preparation of the Compounds FZU-0070-034
230 mg of S2 were dissolved in N, N-dimethylformamide, and 470 mg of indole, 27 mg of anhydrous copper chloride and 160. mu.L of pyridine were added. After the reaction was stirred under oxygen at room temperature for 18 hours, the reaction was diluted with 200 mL of ethyl acetate and extracted with 250 mL of water. The organic phase was collected, dried over anhydrous sodium sulfate, spun-dried and purified on silica gel to give compound FZU-0070-034 (200 mg, 55%). Eluents used were PE/EtOAc = 3:2 to PE/EtOAc = 1: 1.
Physical state: a white solid. Melting point: 205.1-207.0oC. TLC: Rf= 0.43 (PE/EtOAc = 1:1). 1H NMR (400 MHz, DMSO-d 6)δ 10.89 (s, 1H), 7.72 (d, J = 6.9 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H), 7.25 (s, 1H), 7.10 (d, J = 7.3 Hz, 1H), 7.05 (d, J = 8.0 Hz, 1H), 7.01 (t, J = 7.3 Hz, 1H), 6.86 (t, J = 6.8 Hz, 1H), 6.62 (t, J = 7.7 Hz, 2H), 6.08 (s, 1H), 4.45 (s, 1H), 4.22 (d, J = 13.1 Hz, 1H), 3.66 (d, J = 12.0 Hz, 1H), 3.55 (s, 3H), 3.32 (d, J = 13.6 Hz, 1H), 2.96 (t, J = 10.4 Hz, 1H), 2.11 (q, J = 14.3, 13.4 Hz, 2H). 13C NMR (101 MHz, DMSO-d 6)δ 156.02, 150.75, 137.03, 132.07, 129.31, 127.82, 123.76, 123.74, 123.04, 120.90, 118.36, 117.28, 115.65, 111.48, 109.23, 79.78, 69.81, 52.65, 50.63, 41.21, 33.94. HRMS (ESI): calcd for C21H22N3O3[M + H]+ m/z 364.1656, found 364.1653.
EXAMPLE 9 preparation of Compounds FZU-0070-035
244 mg of S3 was dissolved in N, N-dimethylformamide, and 470 mg of indole, 27 mg of anhydrous copper chloride and 160. mu.L of pyridine were added. After the reaction was stirred under oxygen at room temperature for 21 hours, the reaction was diluted with 200 mL of ethyl acetate and extracted with 250 mL of water. The organic phase was collected, dried over anhydrous sodium sulfate, spun-dried and purified on column silica gel to give compounds FZU-0070-035 (205 mg, 54%). The eluent used was PE/EtOAc = 3: 2.
Physical state: a pale yellow solid. Melting point: 190.2-192.7oC. TLC: Rf= 0.53 (PE/EtOAc = 1:1). 1H NMR (400 MHz, DMSO-d 6)δ 10.89 (s, 1H), 7.74 (s, 1H), 7.31 (d, J = 8.2 Hz, 1H), 7.26 (s, 1H), 7.11 (d, J = 7.2 Hz, 1H), 7.06 (t, J = 7.7 Hz, 1H), 7.01 (t, J = 7.4 Hz, 1H), 6.90 – 6.83 (m, 1H), 6.64 (s, 1H), 6.62 (d, J = 7.6 Hz, 1H), 6.07 (s, 1H), 4.46 (s, 1H), 4.24 (d, J = 13.5 Hz, 1H), 3.94 (d, J = 31.7 Hz, 2H), 3.69 (d, J = 12.6 Hz, 1H), 3.26 (s, 1H), 2.93 (s, 1H), 2.11 (s, 2H), 1.07 (d, J = 59.5 Hz, 3H). 13C NMR (101 MHz, DMSO-d 6)δ 155.52, 150.76, 137.00, 132.10, 129.31, 127.84, 123.79, 123.74, 123.05, 120.90, 118.36, 117.36, 115.53, 111.48, 109.47, 79.78, 69.73, 60.97, 50.74, 41.18, 33.68, 14.93. HRMS (ESI): calcd for C22H24N3O3[M + H]+ m/z 378.1812, found 378.1810.
Example 10 preparation of the Compounds FZU-0070-036
214 mg of S4 was dissolved in N, N-dimethylformamide, and 470 mg of indole, 27 mg of anhydrous copper chloride and 160. mu.L of pyridine were added. After the reaction was stirred under oxygen at room temperature for 16 hours, the reaction was diluted with 200 mL of ethyl acetate and extracted with 250 mL of water. The organic phase was collected, dried over anhydrous sodium sulfate, spun-dried and purified on silica gel to give compound FZU-0070-036 (200 mg, 57%). Eluents used were PE/EtOAc = 1:3 to PE/EtOAc = 1: 4.
Physical state: a white solid. Melting point: 164.8-171.2oC. TLC: Rf= 0.38 (PE/EtOAc =1:4). 1H NMR (400 MHz, DMSO-d 6) δ 10.89 (d, J = 35.0 Hz, 1H), 7.78 – 7.68 (m, 1H), 7.32 (t, J = 7.2 Hz, 1H), 7.27 (s, 1H), 7.14 – 7.08 (m, 1H), 7.08 – 6.97 (m, 2H), 6.95 – 6.81 (m, 1H), 6.68 – 6.58 (m, 2H), 6.10 (d, J = 70.4 Hz, 1H), 4.59 (s, 0.5H), 4.47 – 4.23 (m, 1H), 4.18 (d, J = 13.8 Hz, 0.5H), 3.72 – 3.59 (m, 1H), 3.34 (s, 1H), 3.03 (t, J = 10.8 Hz, 1H), 2.19 (t, J = 9.3 Hz, 1H), 2.14 – 2.05 (m, 1H), 1.96 (s, 1.3H), 1.76 (s, 1.7H). 13C NMR (101 MHz, DMSO-d 6)δ 169.37 (d, J = 11.9 Hz), 150.66 (d, J = 39.9 Hz), 137.02 , 132.19 (d, J = 24.7 Hz), 129.30 (d, J = 8.9 Hz), 127.69 (d, J = 56.3 Hz), 123.99 (d, J = 35.2 Hz), 123.46 (d, J = 31.0 Hz), 122.20 , 120.93 (d, J = 20.3 Hz), 118.46 (d, J = 37.6 Hz), 117.27 (d, J = 15.1 Hz), 115.35 (d, J = 80.3 Hz), 111.55 (d, J = 33.8 Hz), 109.16 (d, J = 14.2 Hz), 79.89 (d, J = 12.8 Hz), 70.03 (d, J = 30.8 Hz), 50.40 (d, J = 383.7 Hz), 43.15 , 34.13 (d, J = 42.4 Hz), 21.83 (d, J = 39.3 Hz). HRMS (ESI): calcd for C21H22N3O2[M + H]+ m/z 348.1710, found 348.1705.
Example 11 preparation of the Compounds FZU-0070-039
356 mg of S5 was dissolved in N, N-dimethylformamide, and 525 mg of 6-methylindole, 27 mg of anhydrous copper chloride and 160. mu.L of pyridine were added. After the reaction was stirred under oxygen at room temperature for 15 hours, the reaction was diluted with 200 mL of ethyl acetate and extracted with 250 mL of water. The organic phase was collected, dried over anhydrous sodium sulfate, spun-dried and purified on silica gel to give compound FZU-0070-039 (240 mg, 48%). Eluents used were PE/EtOAc = 4:1 to PE/EtOAc = 2: 1.
Physical state: a pale yellow solid. Melting point: 202.2-203.1oC. TLC: Rf= 0.40 (PE/EtOAc =2:1). 1H NMR (500 MHz, DMSO-d 6) δ 10.83 (d, J = 2.3 Hz, 1H), 7.86 (d, J = 8.2 Hz, 1H), 7.62 (d, J = 2.5 Hz, 1H), 7.56 – 7.53 (m, 2H), 7.38 – 7.36 (m, 2H), 7.12 – 7.11 (m, 1H), 6.74 (d, J = 2.6 Hz, 1H), 6.71 – 6.68 (m, 1H), 6.65 – 6.62 (m, 1H), 6.55 (d, J = 8.4 Hz, 1H), 5.67 (s, 1H), 4.34 (s, 1H), 4.04 – 4.01 (m, 1H), 3.67 (d, J = 9.3 Hz, 1H), 3.63 (s, 3H), 2.36 (s, 3H), 2.34 (s, 3H), 2.33 – 2.29 (m, 1H), 2.21 – 2.14 (m, 1H), 2.02 – 1.97 (m, 2H).13C NMR (126 MHz, DMSO-d 6) δ 152.56, 144.42, 144.21, 136.78, 132.75, 132.60, 130.42, 129.69, 127.73, 123.57, 123.45, 119.92, 114.99, 114.79, 111.15, 110.95, 109.95, 79.43, 68.66, 55.88, 55.82, 44.89, 31.37, 21.78, 21.44. HRMS (ESI): calcd for C28H30N3O4S[M + H]+ m/z 504.1952, found 504.1968.
EXAMPLE 12 preparation of the Compounds FZU-0070-041
361 mg of S6 was dissolved in N, N-dimethylformamide, and 784 mg of 6-bromoindole, 27 mg of anhydrous copper chloride and 160. mu.L of pyridine were added. After the reaction was stirred under oxygen at room temperature for 12 hours, the reaction was diluted with 200 mL of ethyl acetate and extracted with 250 mL of water. The organic phase was collected, dried over anhydrous sodium sulfate, spun-dried and purified on silica gel to give compound FZU-0070-. Eluents used were PE/EtOAc = 5:1 to PE/EtOAc = 3: 1.
Physical state: light yellow solidAnd (3) a body. Melting point: 200.7-202.1oC. TLC: Rf= 0.45 (PE/EtOAc =3:1). 1H NMR (500 MHz, DMSO-d 6) δ 11.19 (s, 1H), 7.90 (d, J = 8.7 Hz, 1H), 7.75 (d, J = 2.2 Hz, 1H), 7.57 (d, J = 8.0 Hz, 2H), 7.54 (s, 1H), 7.38 (d, J = 8.0 Hz, 2H), 7.14 (s, 1H), 7.06 – 7.03 (m, 1H), 7.01 (d, J = 9.3 Hz, 1H), 6.61 (d, J = 8.3 Hz, 1H), 6.37 (s, 1H), 4.73 (s, 1H), 4.06 (d, J = 11.9 Hz, 1H), 3.70 (d, J = 11.2 Hz, 1H), 2.36 (d, J = 2.9 Hz, 1H), 2.34 (s, 3H), 2.18 (t, J= 11.4 Hz, 1H), 2.00 – 1.95 (m, 1H), 1.93 (d, J = 11.8 Hz, 1H). 13C NMR (126 MHz, DMSO-d 6) δ 149.32, 144.39, 137.30, 133.29, 132.57, 130.52, 129.40, 127.83, 127.78, 125.67, 125.11, 124.00, 121.08, 121.00, 114.96, 113.88, 113.80, 111.68, 79.15, 68.57, 55.93, 45.02, 31.11, 21.50. HRMS (ESI): calcd for C26H24BrClN3O3S[M + H]+ m/z 572.0405, found 572.0420.
Example 13 preparation of FZU-0070-042 Compound
361 mg of S6 was dissolved in N, N-dimethylformamide, and 606 mg of 6-chloroindole, 27 mg of anhydrous copper chloride and 160. mu.L of pyridine were added. After the reaction was stirred under oxygen at room temperature for 12 hours, the reaction was diluted with 200 mL of ethyl acetate and extracted with 250 mL of water. The organic phase was collected, dried over anhydrous sodium sulfate, spun-dried and purified on silica gel to give compound FZU-0070-042 (265 mg, 50%). Eluents used were PE/EtOAc = 5:1 to PE/EtOAc = 3: 1.
Physical state: a white solid. Melting point: 160.1-161.2oC. TLC: Rf= 0.42 (PE/EtOAc =3:1). 1H NMR (500 MHz, DMSO-d 6) δ 11.18 (s, 1H), 7.93 (d, J = 8.7 Hz, 1H), 7.75 (d, J = 2.2 Hz, 1H), 7.57 (d, J = 8.1 Hz, 2H), 7.39 (s, 2H), 7.37 (s, 1H), 7.13 (d, J = 8.0 Hz, 1H), 7.06 – 7.03 (m, 1H), 6.90 – 6.87 (m, 1H), 6.61 (d, J = 8.3 Hz, 1H), 6.37 (s, 1H), 4.73 (s, 1H), 4.05 (d, J = 11.6 Hz, 1H), 3.70 (d, J = 10.6 Hz, 1H), 2.35 (s, 3H), 2.17 (t, J = 11.5 Hz, 1H), 1.99 – 1.94 (m, 1H), 1.93 (d, J = 11.9 Hz, 1H). 13C NMR (126 MHz, DMSO-d 6) δ 149.38, 144.46, 136.83, 133.34, 132.62, 130.58, 129.46, 127.84, 127.63, 125.85, 125.30, 125.24, 124.05, 121.04, 118.59, 114.99, 111.74, 110.88, 79.20, 68.62, 55.99, 45.07, 40.50, 31.16, 21.56. HRMS (ESI): calcd for C26H26N3O3S[M + H]+ m/z528.0910, found 528.0926.
Biological activity test specific examples:
human breast cancer cell line MCF-7 cells, human lung cancer cell line A549 cells and cervical cancer cell line Hela are taken as test cell lines (the cells are purchased from the cell resource center of Shanghai Life sciences institute of Chinese academy of sciences).
Application example 1: inhibition of proliferation and survival of human breast cancer cell line MCF-7
Materials: human breast cancer cell line MCF-7; the tested drugs are: 10 μm; the cell culture method comprises the following steps: taking MCF-7 cells frozen in liquid nitrogen, unfreezing in warm water at 37 ℃, transferring the cell suspension into a 15 mL centrifuge tube, adding 5 mL DMEM complete culture solution, lightly blowing and beating uniformly, placing in a centrifuge, centrifuging at 3000 rpm for 5 min, discarding the supernatant, adding 2 mL DMEM complete culture solution, lightly blowing and beating uniformly, adding the cell suspension into a culture dish, supplementing 6 mL DMEM complete culture solution, placing the culture dish in 5% CO2And cultured in an incubator at 37 ℃. Cytotoxicity experiments: mixing MCF-7 at 2 × 104Inoculating the cells/well into 96-well culture plate, culturing for 24 hr, changing the culture solution to fresh serum culture solution, adding 10 μ M compound, incubating for 72 hr, removing the solution from the wells, washing with PBS for 3 times, adding fresh culture solution 180 μ L, adding 20 μ L MTT solution (5 mg/mL) per well, and continuously culturing at 37 deg.C with 5% CO2(relative humidity 90%) in an incubatorAfter 4 h of incubation, the culture was terminated, the supernatant carefully aspirated off, 150 μ l of LDMSO was added to each well, and the crystals were fully dissolved by shaking in the dark for 10 min. The absorbance (A) at 570 nm was measured with a microplate reader, and calculated according to the following formula: cell viability% = (mean a value of test group/mean a value of blank control group) × 100%.
Application example 2: inhibition of a549 tumor cell proliferation and survival
Materials: lung cancer cell strain a 549; the tested drugs are: 10 μm; the cell culture method comprises the following steps: taking out A549 cells cryopreserved in liquid nitrogen, unfreezing the cells in warm water at 37 ℃, transferring the cell suspension into a 1.5 mL centrifuge tube, placing the centrifuge tube in a centrifuge, centrifuging the centrifuge tube at 2000 rpm for 10 min, removing supernatant, adding 1 mL RPMI 1640 complete culture solution, gently blowing and beating the cell suspension uniformly, adding the cell suspension into a culture dish, supplementing 2 mL RPMI 1640 complete culture solution, placing the culture dish in 5% CO2And cultured in an incubator at 37 ℃. Cytotoxicity experiments: a549 cells at 8X 103Inoculating the density of each cell/well into a 96-well culture plate, culturing for 20 h, sucking and discarding the old culture medium, adding a compound with the concentration of 10 mu m in each well, additionally arranging a solvent control group and a blank control group, incubating for 72h in an incubator, carefully sucking and discarding the culture medium, washing for 3 times by PBS (phosphate buffer solution), adding 90 mu L of serum-free and phenol-red-free 1640 culture medium and 10 mu L of MTT solution (5 mg/mL) into each well, continuing to incubate for 5 h, terminating the culture, carefully sucking and discarding the culture solution in the 96-well plate, adding 150 mu L of DMSO solution into each well, and oscillating for 10 min in a dark place to fully dissolve the purple crystals; the absorbance (A) of each well was measured at a wavelength of 570 nm with a multifunctional microplate reader, and the survival rate of the cells was calculated as follows: cell viability = (test group a value/blank control group a value) × 100%.
Application example 3: inhibition of Hela tumor cell proliferation and survival
Materials: cervical cancer cell line Hela; the tested drugs are: 10 μm; the cell culture method comprises the following steps: taking out Hela cells frozen in liquid nitrogen, thawing in 37 deg.C warm water, transferring cell suspension into 1.5 mL centrifuge tube, placing in centrifuge, centrifuging at 1500 rpm for 5 min, discarding supernatant, adding 1 mL DMEM complete culture solution, and gently blowing and beatingHomogenizing, adding the cell suspension into a culture dish, supplementing 3 mL of DMEM complete culture solution, and placing the culture dish in 5% CO2And cultured in an incubator at 37 ℃. Cytotoxicity experiments: hela cells were cultured at 9X 103Inoculating the density of each cell/well into a 96-well culture plate, after culturing for 24 h, removing the old culture medium by suction, adding 10 mu m of compound into each well, additionally arranging a solvent control group and a blank control group, after incubating for 72h in an incubator, carefully removing the culture medium by suction, washing for 3 times by PBS, adding 90 mu L of serum-free and phenol-red-free 1640 culture medium and 10 mu L of MTT solution (5 mg/mL) into each well, continuing to incubate for 4 h, terminating the culturing, carefully removing the culture solution in the 96-well plate, adding 150 mu L of DMSO solution into each well, and oscillating for 10 min in a dark place to fully dissolve the purple crystals; the absorbance (A) of each well was measured at a wavelength of 570 nm with a multifunctional microplate reader, and the survival rate of the cells was calculated as follows: cell viability = (test group a value/blank control group a value) × 100%.
The activity parameters of the indolized derivatives of tetrahydro- β -carbolines obtained in the above examples are shown in table 1: survival was at a concentration of 10 μ M compound.
TABLE 1 antitumor Activity of the Compounds obtained in some of the examples
The above description is only a preferred embodiment of the present invention, and all equivalent changes and modifications made in accordance with the claims of the present invention should be covered by the present invention.
Claims (8)
1. An indolized derivative of tetrahydro-beta-carboline, characterized in that: has the following structural general formula:
wherein R is1 Is composed of
、
、
Or
； R2 H, OMe or Cl; r3 H, F, Cl, Br, Me or OMe.
2. A process for the preparation of the indolised derivative of tetrahydro- β -carboline according to claim 1 characterized by: dissolving the raw materials in a proper solvent, adding an indole derivative, a catalyst and alkali, stirring and reacting for several hours at room temperature under the condition of oxygen, monitoring the reaction to be complete, extracting by using ethyl acetate and water, collecting an organic phase, drying and spin-drying the obtained organic phase, and separating by silica gel column chromatography to obtain the indolization derivative of the tetrahydro-beta-carboline.
3. The method of claim 2, wherein: the raw materials comprise:
、
、
、
、
、
。
4. the method of claim 2, wherein: the solvent is N, N-dimethylformamide.
5. The method of claim 2, wherein: the indole derivatives comprise indole, 4-fluoroindole, 5-chloroindole, 5-bromoindole, 5-methylindole, 7-methylindole, 5-methoxyindole, 6-methylindole, 6-bromoindole and 6-chloroindole.
6. The method of claim 2, wherein: the catalyst is anhydrous copper chloride.
7. The method of claim 2, wherein: the base is pyridine.
8. Use of an indolised derivative of a tetrahydro- β -carboline according to claim 1 wherein: the indole derivatives of tetrahydro-beta-carboline are applied to the preparation of medicaments for treating breast cancer, lung cancer and cervical cancer.
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Patent Citations (6)
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| CN106883230A (en) * | 2017-02-28 | 2017-06-23 | 福州大学 | 7 aniline benzo pyridine compounds and theirs and its preparation method and application |
| CN107445969A (en) * | 2017-06-16 | 2017-12-08 | 福州大学 | A kind of tricyclic indole derivatives and its preparation and application |
| CN108440550A (en) * | 2018-06-05 | 2018-08-24 | 福州大学 | A kind of isochroman diindyl derivative and preparation method thereof |
| CN108727399A (en) * | 2018-07-03 | 2018-11-02 | 福州大学 | A kind of benzo dioxane indole derivatives and its preparation method and application |
| CN110698474A (en) * | 2019-11-14 | 2020-01-17 | 福州大学 | Alpha-substituted tetrahydro-gamma-carboline compound and preparation method and application thereof |
| CN110835341A (en) * | 2019-11-29 | 2020-02-25 | 福州大学 | Tetrahydrocarboline skeleton-containing oxidative coupling rearrangement product and preparation method and application thereof |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN113045568A (en) * | 2021-03-31 | 2021-06-29 | 福州大学 | Method for preparing gamma-eudiosmin U |
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