CN105017129B - A kind of indole alkaloid and its application - Google Patents
A kind of indole alkaloid and its application Download PDFInfo
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- CN105017129B CN105017129B CN201510386719.8A CN201510386719A CN105017129B CN 105017129 B CN105017129 B CN 105017129B CN 201510386719 A CN201510386719 A CN 201510386719A CN 105017129 B CN105017129 B CN 105017129B
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- cancer
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- indole alkaloid
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- 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 title claims abstract description 8
- 229930005303 indole alkaloid Natural products 0.000 title claims abstract description 8
- 206010017758 gastric cancer Diseases 0.000 claims abstract description 10
- 208000005718 Stomach Neoplasms Diseases 0.000 claims abstract description 9
- 201000011549 stomach cancer Diseases 0.000 claims abstract description 9
- 206010006187 Breast cancer Diseases 0.000 claims abstract description 6
- 208000026310 Breast neoplasm Diseases 0.000 claims abstract description 6
- 201000007270 liver cancer Diseases 0.000 claims abstract description 6
- 208000014018 liver neoplasm Diseases 0.000 claims abstract description 6
- 206010028980 Neoplasm Diseases 0.000 claims description 21
- 150000001875 compounds Chemical class 0.000 abstract description 25
- 239000003814 drug Substances 0.000 abstract description 15
- 230000000259 anti-tumor effect Effects 0.000 abstract description 7
- 230000000694 effects Effects 0.000 abstract description 5
- 238000005516 engineering process Methods 0.000 abstract description 2
- 231100001231 less toxic Toxicity 0.000 abstract description 2
- 201000011510 cancer Diseases 0.000 description 19
- 229910052739 hydrogen Inorganic materials 0.000 description 12
- 239000001257 hydrogen Substances 0.000 description 12
- 240000005523 Peganum harmala Species 0.000 description 10
- 229910052799 carbon Inorganic materials 0.000 description 10
- 210000004027 cell Anatomy 0.000 description 10
- 229940079593 drug Drugs 0.000 description 9
- 239000012634 fragment Substances 0.000 description 9
- 210000004881 tumor cell Anatomy 0.000 description 9
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 7
- 230000006907 apoptotic process Effects 0.000 description 7
- -1 hydroxypropyl Chemical group 0.000 description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 6
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 6
- 235000005126 Peganum harmala Nutrition 0.000 description 6
- 238000011160 research Methods 0.000 description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 5
- 230000036541 health Effects 0.000 description 5
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- 230000004663 cell proliferation Effects 0.000 description 4
- 208000029742 colonic neoplasm Diseases 0.000 description 4
- 230000034994 death Effects 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 206010009944 Colon cancer Diseases 0.000 description 3
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 230000009471 action Effects 0.000 description 3
- 229930013930 alkaloid Natural products 0.000 description 3
- 238000003745 diagnosis Methods 0.000 description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 241000196324 Embryophyta Species 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 241000159204 Peganum Species 0.000 description 2
- 241000159213 Zygophyllaceae Species 0.000 description 2
- 150000003797 alkaloid derivatives Chemical class 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 230000000118 anti-neoplastic effect Effects 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 238000002512 chemotherapy Methods 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 238000003919 heteronuclear multiple bond coherence Methods 0.000 description 2
- 238000001052 heteronuclear multiple bond coherence spectrum Methods 0.000 description 2
- 238000005570 heteronuclear single quantum coherence Methods 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 150000002611 lead compounds Chemical class 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 231100000614 poison Toxicity 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 238000001959 radiotherapy Methods 0.000 description 2
- 210000002435 tendon Anatomy 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical group CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 1
- 201000004569 Blindness Diseases 0.000 description 1
- 0 C*(C)(CC1=CC(OP)=CCC=C1C1)C1=O Chemical compound C*(C)(CC1=CC(OP)=CCC=C1C1)C1=O 0.000 description 1
- 241000282836 Camelus dromedarius Species 0.000 description 1
- 208000017897 Carcinoma of esophagus Diseases 0.000 description 1
- 206010010071 Coma Diseases 0.000 description 1
- 206010011224 Cough Diseases 0.000 description 1
- 208000000461 Esophageal Neoplasms Diseases 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 206010019233 Headaches Diseases 0.000 description 1
- 206010019468 Hemiplegia Diseases 0.000 description 1
- JPNXWNDFHKYHFY-UHFFFAOYSA-N N-[2-(3-hydroxy-6-methoxy-2-oxo-1H-indol-3-yl)ethyl]acetamide Chemical compound OC1(C(NC2=CC(=CC=C12)OC)=O)CCNC(C)=O JPNXWNDFHKYHFY-UHFFFAOYSA-N 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 235000016408 Podocarpus macrophyllus Nutrition 0.000 description 1
- 206010036790 Productive cough Diseases 0.000 description 1
- 229920005654 Sephadex Polymers 0.000 description 1
- 239000012507 Sephadex™ Substances 0.000 description 1
- 244000162450 Taxus cuspidata Species 0.000 description 1
- 235000009065 Taxus cuspidata Nutrition 0.000 description 1
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 description 1
- DHZBEENLJMYSHQ-XCVPVQRUSA-N cantharidin Chemical compound C([C@@H]1O2)C[C@@H]2[C@]2(C)[C@@]1(C)C(=O)OC2=O DHZBEENLJMYSHQ-XCVPVQRUSA-N 0.000 description 1
- 229940095758 cantharidin Drugs 0.000 description 1
- 229930008397 cantharidin Natural products 0.000 description 1
- DHZBEENLJMYSHQ-UHFFFAOYSA-N cantharidine Natural products O1C2CCC1C1(C)C2(C)C(=O)OC1=O DHZBEENLJMYSHQ-UHFFFAOYSA-N 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 201000010897 colon adenocarcinoma Diseases 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000004043 dyeing Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 208000010749 gastric carcinoma Diseases 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- 208000024348 heart neoplasm Diseases 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000000990 heteronuclear single quantum coherence spectrum Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- XELZGAJCZANUQH-UHFFFAOYSA-N methyl 1-acetylthieno[3,2-c]pyrazole-5-carboxylate Chemical compound CC(=O)N1N=CC2=C1C=C(C(=O)OC)S2 XELZGAJCZANUQH-UHFFFAOYSA-N 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- SNVLJLYUUXKWOJ-UHFFFAOYSA-N methylidenecarbene Chemical compound C=[C] SNVLJLYUUXKWOJ-UHFFFAOYSA-N 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Substances [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 1
- 239000002574 poison Substances 0.000 description 1
- 230000007096 poisonous effect Effects 0.000 description 1
- 238000010837 poor prognosis Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 208000024794 sputum Diseases 0.000 description 1
- 210000003802 sputum Anatomy 0.000 description 1
- 201000000498 stomach carcinoma Diseases 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000009897 systematic effect Effects 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 208000019553 vascular disease Diseases 0.000 description 1
- 229960003048 vinblastine Drugs 0.000 description 1
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/32—Oxygen atoms
- C07D209/38—Oxygen atoms in positions 2 and 3, e.g. isatin
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a kind of indole alkaloid and its application, belong to pharmaceutical technology field.The general structure of indole alkaloid is
Description
Technical field
The present invention relates to a kind of noval chemical compound and its application.
Background technology
Tumour be human organ tissue cell under the external and interior long term in adverse factor caused one kind
Neoformation using cell hyperproliferation as main feature, it can medically be divided into benign tumour and the major class of malignant tumour two.It is benign
Tumour is smaller to Health Impact, and then serious threat the health of the mankind to malignant tumour (also known as cancer).Defended according to the world
Raw tissue and the recent statistics data of American Cancer Society, cancer have turned into the primary cause of disease of human death, the whole world in 2008
12,700,000 new diagnosis cases of cancers and 7,600,000 cancer mortality cases (account for all death tolls 13%) are there are about, and about
70% cancer mortality case occurs in middle and low income country.The year two thousand thirty is expected, the diagnosis of cancer year and death will respectively
Up to 21,400,000 and 13,200,000.
According to Cancer in China foundation data, China's mortality of malignant tumors belongs to world's higher level, and in lasting
Growth trend.Third National coroner's inquest in 2006 shows that China's mortality of malignant tumors adds than the mid-1970s
83.1%, add 22.5% than the initial stage nineties.Cranial vascular disease and malignant tumour are China's front two causes of death, respectively
Account for the 22.4% and 22.3% of dead sum.Malignant tumour not only has a strong impact on China human mortality health, and turns into medical expense
An important factor for rise.Further, since advanced malignant tumor patient outcomes are still dissatisfied, its poor prognosis often involves
Kith and kin and family, influence social stability.
Although the World Health Organization, national governments and scientific research institution are in tumor prevention with having put into substantial amounts of people in treatment
Power, material resources, in-depth study work is carried out, has been achieved in terms of the diagnosis of tumour, operation, radiation and chemotherapy very big
Progress, but up to the present, many malignant tumours still lack effective treatment means.Found using various means effective
Antineoplastic, have become the hot subject of life science in world wide.At present clinically for oncotherapy
Chemical synthetic drug, most of mechanisms of action are directed to the nucleic acid metabolism of tumour cell, using DNA as action target spot, although for
Oncotherapy serves highly important, but while tumor cell proliferation is suppressed, is also brought to patient's normal structure organ
Great damage, has had a strong impact on the life quality of tumor patient, it is not to die from chronic consumption to decline to cause many tumour patients
Exhaust, but die from the Side effect of Radiotherapy chemotherapy.Therefore, it is still to work as prodrug to continually look for development of new antineoplastic
One of Main way of thing research.
Chinese medicine and natural drug have a long history in terms of human health, disease preventing and treating is ensured, world's medicinal industry
Development practice prove that Chinese medicine, natural drug are always the important sources of innovation drug research.Many natural drugs have poison secondary
Act on the advantages that relatively small, action principle is unique, it has also become the important object of anti-cancer agent research and development, from crude drug
The antitumor lead compound of high-efficiency low-toxicity is found in thing as one of focus on research direction of Natural Medicine Chemistry.Japanese yew
The treatment that alcohol, camptothecine, vinblastine, cantharidin etc. are widely used in malignant tumour is exactly some of successful examples.It is modern
My god, the important victory that antitumor lead compound is still innovation drug research is found from traditional Chinese medicine and natural drug
Footpath.
Harmel (Peganum harmala) is zygophyllaceae (Zygophyllaceae) Peganum (Peganum) plant,
A kind of drought-enduring, cold-resistant, alkaline-resisting, barren-resistant herbaceous plant, Uighur " this awns of Ah's underground heat ", be distributed mainly on Xinjiang,
Gansu, Ningxia, desert or the Semi-desert Area in Qinghai and the Inner Mongol.Harmel, which is the Uygur nationality, the Mongols is among the people is in use for a long time
Medicinal material, medicinal part is mature seed.Harmel is mild-natured, bitter, pungent, poisonous, have firm tendon and vessel, it is supporing yang it is warm it is cloudy, eliminate
The function such as gas of sticky body fluid, dissipation cold-dampness, cures mainly that tendon and vessel weakness, osteoarthrosis pain, coughing with a lot of sputum, hemiplegia be forgetful, coma headache
Deng.Harmel is mainly used in treating the malignant tumours such as stomach cancer, liver cancer, colon cancer, breast cancer on modern clinic.Clinically, white horse with a black mane
The fluffy total alkali preparation of camel reaches 85.7%, and conduct to the effective percentage of the malignant tumours such as cancer of the esophagus, stomach cancer, cardiac cancer, colon cancer
Preparation is in Duo Jia affiliated hospitals of Chinese Medical Sciences University and Xinjiang multiple hospitals application in institute.
Main active is alkaloids in seed of peganum harmala, and modern pharmacological research shows that harmel alkaloid has
Significant antitumor activity.But the complicated component of harmel alkaloid, people can not determine specifically which kind of composition has anti-
The tumor promotion either coefficient result of Multiple components, this causes its application to have certain blindness, and easily occurring need not
The side effect wanted.
The content of the invention
It is an object of the invention to provide a kind of new indole alkaloid and its application.
Inventor separates from seed of peganum harmala by studying for a long period of time and identifies 1 new Benzazole compoundsThe compound has good antitumor work to stomach cancer
With, while liver cancer and breast cancer tool are had certain effect, the compound has the advantages of efficient, less toxic, will turn into the market
New anti-gastric cancer medicament.
Brief description of the drawings
Fig. 1 is the compounds of this invention1H-NMR collection of illustrative plates；
Fig. 2 is the compounds of this invention13C-NMR collection of illustrative plates；
Fig. 3 is the HSQC collection of illustrative plates of the compounds of this invention；
Fig. 4 is the HMBC collection of illustrative plates of the compounds of this invention.
Embodiment
Extraction and identification：
10Kg seed of peganum harmala is taken, with 70% methanol heating and refluxing extraction 3 times after crushing, 2 hours every time, merges extraction
Liquid, with solvent is recovered under reduced pressure after filtered through gauze, total medicinal extract is obtained, total medicinal extract is suspended with 4L water, hydrochloric acid is added and is adjusted to pH
1.0, it is extracted twice with isometric chloroform, removes oil-soluble impurities, pH is adjusted to 7.0 by water layer with ammoniacal liquor, is used successively in equal volume
Chloroform, extracting n-butyl alcohol three times, take organic layer, and be concentrated under reduced pressure recycling design respectively, obtain chloroform layer medicinal extract 220g.
200 grams of n-butyl alcohol extract is taken, by using silica gel column chromatography and hydroxypropyl sephadex (Sephadex LH-
20) separation method such as column chromatography, isolated the compounds of this invention.
Structural Identification：
Use13C-NMR and1H-NMR carries out Structural Identification to the compound that purification obtains,13C-NMR and1H-NMR spectrum difference
As illustrated in fig. 1 and 2, Fig. 3 is the HSQC collection of illustrative plates of compound；Fig. 4 is the HMBC collection of illustrative plates of compound..
1H-NMR(500Hz,DMSO-d6) in, δH10.24 (1H, s), 7.73 (1H, t, J=5.3Hz) 5.86 (1H, s)
It is 3 active hydrogen signals, wherein δH10.24 (1H, s) are the NH of Benzazole compounds 1, and there are 3 hydrogen, δ in fragrant areaH7.16
(1H, d, J=8.2Hz), 6.52 (1H, dd, J=8.2,2.3Hz) and 6.37 (1H, d, J=2.3Hz) form one typically
ABX spin coupling systems, high field region have 1 methoxyl group hydrogen signal δH3.73 (3H, s), the hydrogen signal δ of 2 methyleneH2.88
The hydrogen signal δ of (2H, m), 1.86 (2H, m) and a methylH 1.71(3H,s)。
13C-NMR(125Hz,DMSO-d6) and hsqc spectrum in as can be seen that the compound have 13 carbon signals, including 1
Individual quaternary carbon δC74.1 (C-3), 1 methoxyl group carbon atom δC55.3,2 methylene carbon δC37.3,33.8,1 methyl carbon
Atom δC22.6 and 8 sp2Hydbridized carbon atoms, wherein δC179.5 and 168.9 be two carbonyl carbons, and remaining 6 are then phenyl ring
Carbon signal.
13In C-NMR, δC96.6 and 160.2 and1ABX systems in H-NMR spectrums understand there is one in the compound
Fragment A.In HMBC spectrums, δC74.1 and δC179.5 all with δH10.24 (1H, s), the 5.86 long-range phases of (1H, s) two active hydrogen
Close, therefore fragment B can be obtained, and δH10.24 (NH) at the same also with the δ on phenyl ringC123.6,142.9 two long-range phases of carbon
Close, δC74.1 with the δ on phenyl ringH7.16 (1H, d, J=8.2Hz) are long-range related, thus may determine that fragment A and fragment B connects
Connect to form fragment C.In HMBC spectrums, δHThe methyl hydrogen and δ at 1.71 (3H, s) placesC168.9 carbonyl carbons are remotely related, and δC168.9
And and δHThe active hydrogen at 7.73 (1H, t, J=5.3Hz) places is remotely related, illustrates an acetamide group in the compound be present.
δHThe active hydrogen at 7.73 (1H, t, J=5.3Hz) places and methylene δC33.8 is long-range related, can obtain fragment D, fragment D accordingly
In methylene hydrogen δH1.86 (2H, m) and δC74.1,123.6,179.5 three carbon signals are remotely related, quaternary carbon δC74.1 with two
Individual methylene hydrogen has long-range correlation, summary 1D and 2D data, and fragment C and fragment D are to pass through δC74.1 and δC37.3 two carbon
It is connected.In summary information, the structure for determining compound are
Systematic naming method is 3-Hydroxy-3- (N-acetyl-2-aminoethyl) -6-methoxyindol-2-one.
Table 1：Hydrogen and the carbon signal ownership (DMSO-d6) of compound
After its structural formula is known, it can also be synthesized to obtain the claimed compound of the present invention according to prior art,
Or on the basis of the compound that extraction obtains, carry out corresponding modification and obtain the compound of the present invention, such as formulaCompound, in formula, R1、R2Stand alone as C1~C4's
Alkyl.
Inhibition test：
Test compoundTo the body of 6 knurl strains of human body
The experiment of outer antitumor activity, this 5 knurl strains include gastric carcinoma cells SGC7901, BGC-803, human liver cancer cell HepG2, Hep-3B,
Human breast cancer cell line Bcap-37, Human colon adenocarcinoma cell line Caco-2.
(1) tumor cell proliferation (mtt assay) is suppressed
By tumor cell inoculation in 96 orifice plates, sample to be tested is added after cultivating 24h, is surveyed after being further cultured for 48h with mtt assay
Inhibiting rate of the random sample product to tumor cell proliferation.Cell proliferation inhibition rate according to the following formula, and with CalcuSyn software meters
Calculate the half-inhibition concentration (IC of tested sample50), IC50<20 μ g/mL composition will be considered as active sample；
(2) inducing apoptosis of tumour cell
By tumour cell with 2 × 105Individual/mL density is inoculated in 6 orifice plates, per hole 3mL.Sample is added after culture 24h, then
24h is cultivated, cell is collected, is washed 1 time with PBS, 1000 × g centrifugation 5min, cell, room temperature are resuspended with the paraformaldehydes of 1mL 3.7%
Fixed 1h, 1000 × g centrifugation 5min, supernatant discarding, are washed 1 time with PBS, cell are resuspended in 100 μ L PBS, takes cell suspension
10 μ L, add 33258,37 DEG C of 2 μ L 1mmol/L Hoechst dyeing 15min, observing apoptosis corpusculum under fluorescence microscope.
(3) experimental result：It is shown in Table 2 and table 3
Inhibitory action of the compounds of this invention of table 2 to different tumour cells
The compounds of this invention of table 3 is in 2 μM of concentration to the apoptosis-induced effect of different tumour cells
Note：Notable apoptosis-induced (++), general apoptosis-induced (+), does not find apoptosis (-).
Test result indicates that：Noval chemical compound of the present invention has significant antitumor action, particularly to cancer, including but not
Being limited to stomach cancer, liver cancer, breast cancer and colon cancer has good therapeutic action, and significantly induced tumor apoptosis can make
With experimental data shows, in-vitro multiplication inhibitory action of the compounds of this invention to human stomach cancer cell line SGC7901 and BGC-803
It is better than positive drug cis-platinum.
Formula is(in formula, R1、R2Stand alone as C1
~C4 alkyl) compound can dissociate or be metabolized in vivo and produce identical active molecule, it is same have it is significant anti-
Function of tumor.
Claims (3)
1. a kind of indole alkaloid, its structural formula are。
2. application of the indole alkaloid in tumor is prepared, wherein, the structural formula such as claim 1 of indole alkaloid
It is described.
3. application according to claim 2, it is characterised in that：Tumour is selected from stomach cancer, liver cancer, breast cancer.
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