CN108727399B - A kind of benzo dioxane indole derivatives and its preparation method and application - Google Patents
A kind of benzo dioxane indole derivatives and its preparation method and application Download PDFInfo
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- CN108727399B CN108727399B CN201810716348.9A CN201810716348A CN108727399B CN 108727399 B CN108727399 B CN 108727399B CN 201810716348 A CN201810716348 A CN 201810716348A CN 108727399 B CN108727399 B CN 108727399B
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- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- MMNKDVQHUZCKDD-UHFFFAOYSA-N C1=CC=C2NC=CC2=C1.C1=CC=C2OCCOC2=C1 Chemical class C1=CC=C2NC=CC2=C1.C1=CC=C2OCCOC2=C1 MMNKDVQHUZCKDD-UHFFFAOYSA-N 0.000 title claims abstract description 15
- 125000001424 substituent group Chemical group 0.000 claims abstract description 10
- TUCNEACPLKLKNU-UHFFFAOYSA-N acetyl Chemical compound C[C]=O TUCNEACPLKLKNU-UHFFFAOYSA-N 0.000 claims abstract description 4
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims abstract description 3
- 239000002246 antineoplastic agent Substances 0.000 claims abstract 2
- 229940041181 antineoplastic drug Drugs 0.000 claims abstract 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 33
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 30
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 22
- YQUVCSBJEUQKSH-UHFFFAOYSA-N 3,4-dihydroxybenzoic acid Chemical group OC(=O)C1=CC=C(O)C(O)=C1 YQUVCSBJEUQKSH-UHFFFAOYSA-N 0.000 claims description 14
- -1 3,4- dihydroxy cyanophenyl Chemical group 0.000 claims description 13
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 11
- DKGAVHZHDRPRBM-UHFFFAOYSA-N tert-butyl alcohol Substances CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 11
- YCIMNLLNPGFGHC-UHFFFAOYSA-N catechol Chemical compound OC1=CC=CC=C1O YCIMNLLNPGFGHC-UHFFFAOYSA-N 0.000 claims description 6
- 239000002994 raw material Substances 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- XJNPNXSISMKQEX-UHFFFAOYSA-N 4-nitrocatechol Chemical compound OC1=CC=C([N+]([O-])=O)C=C1O XJNPNXSISMKQEX-UHFFFAOYSA-N 0.000 claims description 2
- 238000004090 dissolution Methods 0.000 claims description 2
- 239000007800 oxidant agent Substances 0.000 claims 2
- 230000001590 oxidative effect Effects 0.000 claims 2
- 238000000034 method Methods 0.000 abstract description 4
- 239000003795 chemical substances by application Substances 0.000 abstract description 3
- 238000005516 engineering process Methods 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 63
- 150000001875 compounds Chemical class 0.000 description 40
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 32
- 235000019439 ethyl acetate Nutrition 0.000 description 27
- 238000006243 chemical reaction Methods 0.000 description 24
- 210000004027 cell Anatomy 0.000 description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 18
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 10
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 9
- 238000005160 1H NMR spectroscopy Methods 0.000 description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 9
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 9
- 239000003480 eluent Substances 0.000 description 9
- 239000012044 organic layer Substances 0.000 description 9
- 239000012074 organic phase Substances 0.000 description 9
- 238000000746 purification Methods 0.000 description 9
- 239000000741 silica gel Substances 0.000 description 9
- 229910002027 silica gel Inorganic materials 0.000 description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- 229910002092 carbon dioxide Inorganic materials 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- 238000005406 washing Methods 0.000 description 7
- 206010028980 Neoplasm Diseases 0.000 description 6
- 201000011510 cancer Diseases 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 239000012265 solid product Substances 0.000 description 6
- 230000004083 survival effect Effects 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 4
- 239000001569 carbon dioxide Substances 0.000 description 4
- 239000006285 cell suspension Substances 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 239000006228 supernatant Substances 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- CFTOTSJVQRFXOF-UHFFFAOYSA-N 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole Chemical group N1C2=CC=CC=C2C2=C1CNCC2 CFTOTSJVQRFXOF-UHFFFAOYSA-N 0.000 description 3
- 230000001093 anti-cancer Effects 0.000 description 3
- 230000004071 biological effect Effects 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 210000004881 tumor cell Anatomy 0.000 description 3
- 206010006187 Breast cancer Diseases 0.000 description 2
- 208000026310 Breast neoplasm Diseases 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical class CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 239000012980 RPMI-1640 medium Substances 0.000 description 2
- 239000006146 Roswell Park Memorial Institute medium Substances 0.000 description 2
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- 229910052799 carbon Inorganic materials 0.000 description 2
- 238000010609 cell counting kit-8 assay Methods 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
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- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 230000003013 cytotoxicity Effects 0.000 description 2
- 231100000135 cytotoxicity Toxicity 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 229910052742 iron Inorganic materials 0.000 description 2
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- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 230000010355 oscillation Effects 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
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- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 238000012404 In vitro experiment Methods 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- WYTGDNHDOZPMIW-RCBQFDQVSA-N alstonine Chemical compound C1=CC2=C3C=CC=CC3=NC2=C2N1C[C@H]1[C@H](C)OC=C(C(=O)OC)[C@H]1C2 WYTGDNHDOZPMIW-RCBQFDQVSA-N 0.000 description 1
- 230000002141 anti-parasite Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 239000003096 antiparasitic agent Substances 0.000 description 1
- 230000002508 compound effect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 229930005303 indole alkaloid Natural products 0.000 description 1
- 150000002475 indoles Chemical class 0.000 description 1
- 150000002611 lead compounds Chemical class 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
- 238000005691 oxidative coupling reaction Methods 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- IEQIEDJGQAUEQZ-UHFFFAOYSA-N phthalocyanine Chemical compound N1C(N=C2C3=CC=CC=C3C(N=C3C4=CC=CC=C4C(=N4)N3)=N2)=C(C=CC=C2)C2=C1N=C1C2=CC=CC=C2C4=N1 IEQIEDJGQAUEQZ-UHFFFAOYSA-N 0.000 description 1
- 230000036632 reaction speed Effects 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- ZXLDQJLIBNPEFJ-UHFFFAOYSA-N tetrahydro-beta-carboline Natural products C1CNC(C)C2=C1C1=CC=C(OC)C=C1N2 ZXLDQJLIBNPEFJ-UHFFFAOYSA-N 0.000 description 1
- 238000012549 training Methods 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
- C07D491/18—Bridged systems
-
- 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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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to pharmaceutical technology field, a kind of benzo dioxane indole derivatives and preparation method thereof are provided, the benzo dioxane indole derivatives have the following structure general formula:Wherein R1For Ts, CH3OCO、CH3CO、PhSO2、CH3CH2One of OCO substituent group；R2For H or CO2CH3；R3For COOH, NO2, one of PhCO, CN substituent group.This method agents useful for same is laboratory common agents, and operation is simple, time-consuming short, high income, and has preferable bioactivity, is expected to be used for preparing anticancer drug.
Description
Technical field
The invention belongs to pharmaceutical technology fields, and in particular to a kind of benzo dioxane indole derivatives and its preparation side
Method.
Background technique
Carboline class compound is a kind of indole alkaloid, it is distributed widely in nature, is had antitumor, antiviral, anti-
The multiple biological activities such as bacterium, anti parasitic, anti-oxidant, platelet aggregation-against.Tetrahydro-beta-carboline skeleton, which is commonly used for synthesis, to be had respectively
The indoles alkaloid of kind pharmacological activity, as the lead compound of modifying for chemical structure, in vitro experiments have shown that having
The effect of very strong killing tumor cell.The present invention is based on tetrahydro-beta-carboline structures to synthesize its derivative by simple method,
This kind of reaction has many advantages, such as easy to operate, substrate applicability is extensive, and reaction speed is fast and pollution is small.
The present invention obtains a kind of benzo dioxane indole derivatives, preparation method letter by oxidative coupling reaction
Single, reaction condition is mild, and low energy consumption, and high income is practical, and synthesized compound, and quasi-medicated property evaluation is high, and opposite point
Protonatomic mass is 500 or so, and cell experiment proves it with good Anticancer Activity in vitro, and the compound for illustrating that the present invention obtains has
Prestige is used to prepare relevant cancer treatment drugs, while also providing new resolving ideas and side for the synthesis of other similar compounds
Case.
Summary of the invention
The purpose of the present invention is to provide a kind of benzo dioxane indole derivatives and preparation method thereof, gained chemical combination
Object can be good at inhibiting the growth of human lung cancer cell line A549 cell, Breast cancer lines MDA-MB-231, preparation method
Simply, experiment condition is mild, does not require the harsh conditions such as high temperature and pressure, strong acid and strong base, and reaction yield is high.
To achieve the above object, the present invention adopts the following technical scheme:
A kind of benzo dioxane indole derivatives, it is characterised in that: have the following structure general formula:
Wherein R1For Ts, CH3OCO、CH3CO、PhSO2、CH3CH2One of OCO substituent group；R2For H or CO2CH3；R3For
COOH、NO2, one of PhCO, CN substituent group.
Benzo dioxane indole derivatives the preparation method is as follows:
By dissolution of raw material in solvent, catechol and FePC with electron-withdrawing substituent is added, under condition of ice bath
Acetic acid, methanesulfonic acid and tert-Butanol peroxide are added, it is purified that benzo dioxane indole derivatives, reaction yield one can be obtained
As 80% or more, individual yields reachable 95% or more.
Remarkable advantage of the invention is:
(1) synthetic method of the invention is simple, and target product can be obtained by common agents reaction；Experiment condition temperature
With do not require the harsh conditions such as high temperature and pressure, strong acid and strong base；Reaction time is short and high income, reaction yield generally 80% with
On, individual yields reachable 95% or more.
(2) molecular weight of the designed benzo dioxane indole derivatives synthesized is smaller, generally 500 or so, and
Biological activity test show such compound have fine anticancer activity, therefore resulting target product have be used to prepare anticancer
The prospect of drug.
Specific embodiment
In order to make content of the present invention easily facilitate understanding, With reference to embodiment to of the present invention
Technical solution is described further, but the present invention is not limited only to this.
The preparation of 1 compound FZU-0021-221 of embodiment
170mg compound FZU-0038-034 is dissolved in acetonitrile, 154mg 3,4-Dihydroxybenzoic acid and 7mg is added
30mg acetic acid, 5mg methanesulfonic acid and 135mg tertbutanol peroxide is added in FePC under condition of ice bath.The reaction system is at this
It stirs under part after five minutes, is diluted with 20mL ethyl acetate, then extracted with 20mL water, last organic layer saturated common salt water washing
Once.Stripped organic phase is dry with anhydrous sodium sulfate, it filtered, be spin-dried for, with silica gel column purification, eluant, eluent PE/
EtOAc=2:1 obtains 210mg white solid product (compound FZU-0021-221), reaction yield 88%.
Physical state: white solid
TLC:Rf=0.48 (PE/EtOAc=2:1)
1H NMR(400MHz,CDCl3) δ 11.48 (s, 1H), 7.65 (d, J=7.6Hz, 2H), 7.32 (d, J=7.8Hz,
2H), 7.29 (d, J=5.8Hz, 1H), 7.16 (t, J=7.1Hz, 1H), 7.02 (d, J=8.2Hz, 1H), 6.88-6.73 (m,
3H), 5.79 (s, 1H), 5.18 (s, 1H), 4.25 (d, J=13.0Hz, 1H), 3.68 (d, J=12.2Hz, 1H), 2.77 (d, J
=13.0Hz, 1H), 2.64 (d, J=14.6Hz, 1H), 2.44 (s, 3H), 2.38 (d, J=12.1Hz, 1H), 2.04-1.89
(m,1H).
13C NMR(101MHz,CDCl3)δ168.09,150.56,144.90,144.16,134.13,133.48,
130.13,129.01,127.60,127.49,122.59,121.26,120.92,116.66,111.15,106.55,103.17,
48.24,48.05,42.06,34.95,21.69.
The preparation of 2 compound FZU-0025-043 of embodiment
156mg compound FZU-0038-109 is dissolved in acetonitrile, 154mg 3,4-Dihydroxybenzoic acid and 7mg is added
30mg acetic acid, 5mg methanesulfonic acid and 135mg tertbutanol peroxide is added in FePC under condition of ice bath.The reaction system is at this
It after being stirred 15 minutes under part, is diluted, then is extracted with 20mL water, last organic layer saturated common salt water washing with 20mL ethyl acetate
Once.Stripped organic phase is dry with anhydrous sodium sulfate, it filtered, be spin-dried for, with silica gel column purification, eluant, eluent PE/
EtOAc=2:1 obtains 221mg white solid product (compound FZU-0025-043), reaction yield 95%.
Physical state: white solid
Fusing point: 105.8-106.6 DEG C of
TLC:Rf=0.25 (PE/EtOAc=2:1)
1H NMR(400MHz,CDCl3) 7.81 (d, J=7.6Hz, 2H), 7.67-7.62 (m, 1H), 7.59-7.48 (m,
4H), 7.11 (t, J=6.8Hz, 2H), 6.78 (t, J=7.4Hz, 1H), 6.72 (d, J=8.5Hz, 2H), 4.12 (d, J=
13.1Hz, 1H), 3.68 (d, J=12.1Hz, 1H), 2.83 (t, J=12.3Hz, 2H), 2.36 (d, J=14.7Hz, 1H),
2.14–2.04(m,1H).
13C NMR(101MHz,CDCl3)δ171.31,147.99,145.76,140.18,137.12,133.11,
130.05,129.35,128.86,127.37,124.90,122.52,122.43,120.92,119.73,116.44,111.76,
92.49,79.89,47.81,41.49,36.29.
HRMS(ESI):calcd forC24H20N2O6S[M+H]+m/z465.1115,found 465.1092.
The preparation of 3 compound FZU-0038-131 of embodiment
115mg compound FZU-0038-126 is dissolved in acetonitrile, 154mg 3,4-Dihydroxybenzoic acid and 7mg is added
30mg acetic acid, 5mg methanesulfonic acid and 135mg tertbutanol peroxide is added in FePC under condition of ice bath.The reaction system is at this
It stirs under part after five minutes, is diluted with 20mL ethyl acetate, then extracted with 20mL water, last organic layer saturated common salt water washing
Once.Stripped organic phase is dry with anhydrous sodium sulfate, it filtered, be spin-dried for, with silica gel column purification, eluant, eluent PE/
EtOAc=2:1 obtains 115mg white solid product (compound FZU-0038-131), reaction yield 83%.
Physical state: white solid
Fusing point: 184.2-186.2 DEG C
TLC:Rf=0.45 (PE/EtOAc=1:1)
1H NMR(400MHz,CDCl3) δ 7.73 (d, J=1.6Hz, 1H), 7.64-7.52 (m, 1H), 7.23-7.04 (m,
2H), 6.92-6.74 (m, 2H), 6.71 (d, J=7.7Hz, 1H), 4.80 (s, 1H), 4.52 (d, J=14.0Hz, 0.6H),
4.30 (d, J=14.7Hz, 0.4H), 4.13-3.85 (m, 1H), 3.73 (s, 3H), 3.20 (d, J=14.3Hz, 2H), 2.39-
2.25(m,1H),1.94(s,1H).
13C NMR(101MHz,CDCl3)δ171.03,156.54,156.12,148.36,146.21,140.73,
129.81,129.43,124.85,122.65,122.46,120.95,120.64,116.59,111.52,92.64,80.96,
53.13,46.33,45.97,39.68,36.78,36.71,36.01.
HRMS(ESI):calcd forC20H18N2O6[M-H]-m/z 381.1092,found 381.1100.
The preparation of 4 compound FZU-0038-133 of embodiment
107mg compound FZU-0038-016 is dissolved in acetonitrile, 154mg 3,4-Dihydroxybenzoic acid and 7mg is added
30mg acetic acid, 5mg methanesulfonic acid and 135mg tertbutanol peroxide is added in FePC under condition of ice bath.The reaction system is at this
It after being stirred 2 minutes under part, is diluted, then is extracted with 20mL water, last organic layer saturated common salt water washing with 20mL ethyl acetate
Once.Stripped organic phase is dry with anhydrous sodium sulfate, it filtered, be spin-dried for, with silica gel column purification, eluant, eluent EtOAc,
Obtain 154mg faint yellow solid product (compound FZU-0038-133), reaction yield 86%.
Physical state: faint yellow solid
Fusing point: 190.0-191.6 DEG C
TLC:Rf=0.65 (EtOAc)
1H NMR(400MHz,DMSO-d6)δ12.72(s,1H),7.51–7.36(m,2H),7.28–7.15(m,2H),
7.15-7.06 (m, 1H), 6.92-6.82 (m, 1H), 6.76-6.61 (m, 2H), 4.32 (d, J=13.8Hz, 0.4H), 3.99
(d, J=14.6Hz, 0.6H), 3.84 (d, J=13.3Hz, 0.6H), 3.66-3.55 (m, 1H), 3.47 (d, J=12.0Hz,
0.4H), 3.41 (d, J=14.0Hz, 0.45H), 3.16 (t, J=12.1Hz, 0.6H), 2.33 (d, J=11.8Hz, 0.4H),
2.23 (d, J=14.1Hz, 0.6H), 2.15 (s, 1.62H), 2.03 (s, 1.38H), 1.97 (d, J=10.3Hz, 0.4H),
1.83–1.72(m,0.6H).
13C NMR(101MHz,DMSO-d6)δ169.55,169.34,167.04,147.98,147.66,147.56,
141.72,141.43,130.34,130.31,129.16,129.06,124.53,124.46,124.27,122.92,122.86,
119.88,119.61,118.88,118.76,116.96,116.76,111.07,110.90,93.92,93.78,81.73,
81.59,79.62,48.84,43.82,41.56,37.79,35.76,35.03,21.69.
HRMS(ESI):calcd forC17H16N2O2S[M+H]+m/z 367.1288,found 367.1212.
The preparation of 5 compound FZU-0038-150 of embodiment
192mg compound FZU-0038-072 is dissolved in acetonitrile, 154mg 3,4-Dihydroxybenzoic acid and 7mg is added
30mg acetic acid, 5mg methanesulfonic acid and 135mg tertbutanol peroxide is added in FePC under condition of ice bath.The reaction system is at this
It stirs under part after five minutes, is diluted with 20mL ethyl acetate, then extracted with 20mL water, last organic layer saturated common salt water washing
Once.Stripped organic phase is dry with anhydrous sodium sulfate, it filtered, be spin-dried for, with silica gel column purification, eluant, eluent PE/
EtOAc=2:1 obtains 217mg white solid product (compound FZU-0038-150), reaction yield 81%.
Physical state: white solid
Fusing point: 101.8-102.3 DEG C of
TLC:Rf=0.48 (PE/EtOAc=1:1)
1H NMR(400MHz,CDCl3) δ 7.69 (d, J=7.7Hz, 2H), 7.56 (s, 1H), 7.52 (d, J=8.5Hz,
1H), 7.28 (s, 1H), 7.14 (t, J=7.9Hz, 2H), 6.80 (t, J=7.4Hz, 1H), 6.73 (t, J=8.3Hz, 2H),
4.83-4.67 (m, 2H), 4.24 (d, J=14.0Hz, 1H), 3.72-3.56 (m, 4H), 2.89 (d, J=14.4Hz, 1H),
2.39(s,3H),2.28–2.20(m,1H).
13C NMR(101MHz,CDCl3)δ170.83,169.94,147.67,145.90,143.74,139.60,
136.50,130.04,129.60,129.02,127.23,124.98,122.73,122.56,121.05,119.34,116.68,
111.87,91.38,80.13,52.35,51.44,43.17,39.38,21.56.
HRMS(ESI):calcd forC27H24N2O8S[M+H]+m/z 537.1326,found 537.1348.
The preparation of 6 compound FZU-0038-151 of embodiment
122mg compound FZU-0038-050 is dissolved in acetonitrile, 154mg 3,4-Dihydroxybenzoic acid and 7mg is added
30mg acetic acid, 5mg methanesulfonic acid and 135mg tertbutanol peroxide is added in FePC under condition of ice bath.The reaction system is at this
It stirs under part after five minutes, is diluted with 20mL ethyl acetate, then extracted with 20mL water, last organic layer saturated common salt water washing
Once.Stripped organic phase is dry with anhydrous sodium sulfate, it filtered, be spin-dried for, with silica gel column purification, eluant, eluent PE/
EtOAc=2:1 obtains 188mg white solid product (compound FZU-0038-151), reaction yield 95%.
Physical state: white solid
Fusing point: 91.1-92.3 DEG C of
TLC:Rf=0.45 (PE/EtOAc=1:1)
1H NMR(400MHz,CDCl3) δ 7.74 (s, 1H), 7.57 (d, J=8.4Hz, 1H), 7.21-7.05 (m, 2H),
6.87–6.62(m,3H),4.61–4.28(m,1H),4.25–4.10(m,2H),4.00–3.84(m,1H),3.39–3.08(m,
2H), 2.32 (d, J=14.4Hz, 1H), 1.94 (s, 1H), 1.26 (s, 3H)
13C NMR(101MHz,CDCl3)δ171.04,156.02,148.31,146.03,140.72,129.78,
129.50,124.84,122.47,120.64,119.70,116.57,111.50,92.62,80.94,62.03,46.23,
45.75,39.63,36.83,36.01,14.60.
HRMS(ESI):calcd forC21H20N2O6[M+H]+m/z 397.1394,found 397.1408.
The preparation of 7 compound FZU-0038-182 of embodiment
163mg compound FZU-0038-034 is dissolved in acetonitrile, the phthalocyanine of 155mg 4- Nitrocatechol and 7mg is added
30mg acetic acid, 5mg methanesulfonic acid and 135mg tertbutanol peroxide is added in iron under condition of ice bath.The reaction system is with this condition
Stirring after five minutes, is diluted with 20mL ethyl acetate, then is extracted with 20mL water, and last organic layer washed once with saturated salt solution.
Stripped organic phase is dry with anhydrous sodium sulfate, it filtered, be spin-dried for, with silica gel column purification, eluant, eluent PE/EtOAc=
4:1 obtains 265mg yellow oil (compound FZU-0038-182), reaction yield 96%.
Physical state: yellow oil
TLC:Rf=0.61 (PE/EtOAc=2:1)
1H NMR(400MHz,CDCl3) δ 7.79 (s, 1H), 7.68 (t, J=8.1Hz, 3H), 7.30 (d, J=7.6Hz,
2H), 7.12 (d, J=6.9Hz, 2H), 6.80 (t, J=7.2Hz, 1H), 6.73 (t, J=6.7Hz, 2H), 4.97 (s, 1H),
4.09 (d, J=13.1Hz, 1H), 3.64 (d, J=11.6Hz, 1H), 2.93-2.66 (m, 2H), 2.37 (d, J=11.5Hz,
4H), 2.11 (t, J=12.6Hz, 1H)
13C NMR(101MHz,CDCl3)δ148.84,145.68,144.08,141.64,140.29,133.93,
130.33,129.99,128.23,127.44,122.42,121.03,118.38,116.47,113.64,111.81,93.09,
80.32,47.95,41.50,36.02,21.55.
HRMS(ESI):calcd forC24H21N3O6S[M+H]+m/z 480.1224,found 480.1241.
The preparation of 8 compound FZU-0038-184 of embodiment
163mg compound FZU-0038-034 is dissolved in acetonitrile, 135mg 3, the phthalein of 4- dihydroxy cyanophenyl and 7mg is added
30mg acetic acid, 5mg methanesulfonic acid and 135mg tertbutanol peroxide is added in cyanines iron under condition of ice bath.The reaction system is in this condition
Lower stirring after five minutes, is diluted with 20mL ethyl acetate, then is extracted with 20mL water, last organic layer saturated common salt water washing one
It is secondary.Stripped organic phase is dry with anhydrous sodium sulfate, it filtered, be spin-dried for, with silica gel column purification, eluant, eluent PE/EtOAc
=4:1 obtains 246mg yellow oil (compound FZU-0038-1844), reaction yield 95%.
Physical state: yellow oil
TLC:Rf=0.62 (PE/EtOAc=2:1)
1H NMR(400MHz,CDCl3) δ 7.68 (d, J=7.5Hz, 2H), 7.30 (d, J=7.4Hz, 2H), 7.13 (m, J
=16.3,9.9Hz, 3H), 7.05 (d, J=7.8Hz, 1H), 6.80 (t, J=7.1Hz, 1H), 6.72 (d, J=7.6Hz, 2H),
4.86 (s, 1H), 4.04 (d, J=12.9Hz, 1H), 3.61 (d, J=11.5Hz, 1H), 2.91-2.73 (m, 2H), 2.36 (d, J
=30.6Hz, 4H), 2.09 (t, J=12.2Hz, 1H)
13C NMR(101MHz,CDCl3)δ147.15,145.73,144.03,140.88,134.04,130.27,
129.97,128.37,127.43,126.66,122.40,121.35,120.99,118.62,117.46,111.79,104.51,
92.74,80.19,47.97,41.48,35.96,21.56.
The preparation of 9 compound FZU-0038-185 of embodiment
163mg compound FZU-0038-034 is dissolved in acetonitrile, 214mg 3,4- dihydroxy benaophenonel and 7mg is added
FePC, 30mg acetic acid, 5mg methanesulfonic acid and 135mg tertbutanol peroxide are added under condition of ice bath.The reaction system is herein
Under the conditions of stir after five minutes, diluted with 20mL ethyl acetate, then with the extraction of 20mL water, last organic layer washed with saturated common salt
It washs primary.Stripped organic phase is dry with anhydrous sodium sulfate, it filtered, be spin-dried for, with silica gel column purification, eluant, eluent PE/
EtOAc=4:1 obtains 261mg yellow oil (compound FZU-0038-185), reaction yield 96%.
Physical state: yellow oil
TLC:Rf=0.62 (PE/EtOAc=2:1)
1H NMR(400MHz,CDCl3)δ7.72(s,4H),7.60–7.55(m,1H),7.51–7.42(m,3H),7.33
(d, J=7.0Hz, 2H), 7.27 (s, 1H), 7.16 (t, J=6.5Hz, 2H), 6.83 (t, J=6.9Hz, 1H), 6.76 (t, J=
6.4Hz, 2H), 4.90 (s, 1H), 4.10 (d, J=12.9Hz, 1H), 3.67 (d, J=11.9Hz, 1H), 2.96-2.74 (m,
2H), 2.39 (d, J=30.7Hz, 4H), 2.12 (t, J=12.8Hz, 1H)
13C NMR(101MHz,CDCl3)δ195.14,147.07,145.86,143.97,140.32,137.86,
134.02,132.05,131.02,130.04,129.97,129.72,129.01,128.21,127.46,125.21,122.46,
120.86,119.63,116.12,111.76,92.43,79.89,47.93,41.53,36.24,21.56.
HRMS(ESI):calcd forC31H26N2O5S[M+H]+m/z 539.1635,found 539.1659.
10 biological activity test of embodiment
(1) inhibiting effect of the compound to A549 tumor cell proliferation and survival
Material: Non-small cell lung carcinoma cell line A549；
Test medicine: final compound；
Cell culture processes: the A549 cell frozen in liquid nitrogen is taken out, thaws in 37 DEG C of warm water, cell suspension is moved
Enter in 1.5mL centrifuge tube, be placed in a centrifuge, 1500rpm is centrifuged 5min, discards supernatant liquid, and it is complete that 1mL RPMI 1640 is added
Culture solution, gently piping and druming uniformly, cell suspension is added in culture dish, 1640 complete culture solution of 3mL RPMI is added, will cultivate
Ware is placed in 5%CO2, cultivate in 37 DEG C of incubators.
Cytotoxicity experiment: by A549 cell with 2 × 104The density of a cells/well is inoculated into 96 well culture plates, is added
The compound of various concentration places it in 37 DEG C, cultivates 72 hours in 5% carbon dioxide incubator.Culture plate is taken out, every hole adds
Enter 10 μ L CCK-8 reagents, by culture plate continue to be placed in 37 DEG C, in 5% carbon dioxide incubator after being incubated for 3 hours, terminate training
It supports, careful inhale abandons supernatant, and 150 μ L dimethyl sulfoxides are added in every hole, and being protected from light oscillation 10min dissolves crystal sufficiently；With enzyme
The trap OD450 at instrument detection 450nm is marked, and calculates cell survival rate: cell survival rate %=(processing according to following formula
Group OD450/ control group OD450Then) × 100% is handled data using 13.0 software of SPSS, and calculate cancer cell increasing
Half-inhibitory concentration (the IC grown50)。
(2) inhibiting effect of the compound to 231 tumor cell proliferations and survival
Material: Breast cancer lines MDA-MB-231；
Test medicine: final compound；
Cell culture processes: 231 cells frozen in liquid nitrogen are taken out, thaws in 37 DEG C of warm water, cell suspension is moved
Enter in 1.5mL centrifuge tube, be placed in a centrifuge, 1500rpm is centrifuged 5min, discards supernatant liquid, and it is complete that 1mL RPMI 1640 is added
Culture solution, gently piping and druming uniformly, cell suspension is added in culture dish, 1640 complete culture solution of 3mL RPMI is added, will cultivate
Ware is placed in 5%CO2, cultivate in 37 DEG C of incubators.
Cytotoxicity experiment: by 231 cells with 2 × 104The density of a cells/well is inoculated into 96 well culture plates, is added
The compound of various concentration places it in 37 DEG C, cultivates in 5% carbon dioxide incubator.Culture plate is taken out, 10 μ L are added in every hole
CCK-8 reagent, by culture plate continue to be placed in 37 DEG C, in 5% carbon dioxide incubator after being incubated for 3 hours, terminate culture, it is careful to inhale
Supernatant is abandoned, 150 μ L dimethyl sulfoxides are added in every hole, and being protected from light oscillation 10min dissolves crystal sufficiently；It is detected with microplate reader
Trap OD450 at 450nm, and cell survival rate: cell survival rate %=(processing group OD is calculated according to following formula450/
Control group OD450Then) × 100% handles data using 13.0 software of SPSS, and calculates the half of cancer cell multiplication
Inhibition concentration (IC50)。
The reactivity parameter of embodiment 1 to 9 gained final compound of example is as shown in table 1, IC50Value is each compound effects in cancer
Cell corresponds to cancer cell half effective inhibition concentration after 72 hours.
The reactivity parameter of 1. gained compound of table
Seen from table 1, cancer cell can more preferably be inhibited by carrying out modifying obtained derivative to tetrahydro-beta-carboline
Growth.
The foregoing is merely presently preferred embodiments of the present invention, all equivalent changes done according to scope of the present invention patent with
Modification, is all covered by the present invention.
Claims (6)
1. a kind of benzo dioxane indole derivatives, it is characterised in that: have the following structure general formula:
；
Wherein R1For Ts, CH3OCO、CH3CO、PhSO2、CH3CH2One of OCO substituent group；R2For H or CO2CH3；R3For COOH,
NO2, one of PhCO, CN substituent group.
2. a kind of preparation method of the benzo dioxane indole derivatives as described in claims 1, it is characterised in that: will
Dissolution of raw material in solvent, be added the catechol with electron-withdrawing substituent, FePC, the condition of ice bath add acetic acid,
Methanesulfonic acid and oxidant, it is purified to obtain the benzo dioxane indole derivatives；The raw material is, R1For Ts, CH3OCO、CH3CO、PhSO2、CH3CH2One of OCO substituent group, R2For H or CO2CH3。
3. preparation method according to claim 2, it is characterised in that: the solvent is acetonitrile.
4. preparation method according to claim 2, it is characterised in that: the catechol with electron-withdrawing substituent is 3,
4- dihydroxy-benzoic acid, 3,4- dihydroxy cyanophenyl, 4- nitro -1,2- benzenediol, one in (3,4- dihydroxy) phenyl ketone
Kind.
5. preparation method according to claim 2, it is characterised in that: the oxidant is tert-Butanol peroxide.
6. a kind of benzo dioxane indole derivatives as described in claim 1 are preparing the application on anticancer drug.
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