CN105017129A - Indole alkaloid and application thereof - Google Patents
Indole alkaloid and application thereof Download PDFInfo
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- CN105017129A CN105017129A CN201510386719.8A CN201510386719A CN105017129A CN 105017129 A CN105017129 A CN 105017129A CN 201510386719 A CN201510386719 A CN 201510386719A CN 105017129 A CN105017129 A CN 105017129A
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- cancer
- 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 13
- 229930005303 indole alkaloid Natural products 0.000 title claims abstract description 13
- 239000003814 drug Substances 0.000 claims abstract description 16
- 208000005718 Stomach Neoplasms Diseases 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
- 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 20
- 201000000498 stomach carcinoma Diseases 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 27
- 229940079593 drug Drugs 0.000 abstract description 10
- 230000000259 anti-tumor effect Effects 0.000 abstract description 9
- 239000002246 antineoplastic agent Substances 0.000 abstract description 4
- 206010017758 gastric cancer Diseases 0.000 abstract description 4
- 229940041181 antineoplastic drug Drugs 0.000 abstract description 3
- 230000008901 benefit Effects 0.000 abstract description 3
- 231100000053 low toxicity Toxicity 0.000 abstract description 3
- 201000011549 stomach cancer Diseases 0.000 abstract description 3
- 201000011510 cancer Diseases 0.000 description 20
- 229910052739 hydrogen Inorganic materials 0.000 description 11
- 239000001257 hydrogen Substances 0.000 description 11
- 229910052799 carbon Inorganic materials 0.000 description 10
- 210000004027 cell Anatomy 0.000 description 10
- 210000004881 tumor cell Anatomy 0.000 description 10
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 8
- 238000005481 NMR spectroscopy Methods 0.000 description 7
- 239000012634 fragment Substances 0.000 description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- 235000005126 Peganum harmala Nutrition 0.000 description 6
- 230000006907 apoptotic process Effects 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 230000036541 health Effects 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
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 5
- 238000000605 extraction Methods 0.000 description 5
- 240000005523 Peganum harmala Species 0.000 description 4
- 230000034994 death Effects 0.000 description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 229930013930 alkaloid Natural products 0.000 description 3
- -1 hydroxypropyl Chemical group 0.000 description 3
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- 206010009944 Colon cancer Diseases 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- 241000196324 Embryophyta Species 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical class C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 2
- 241000159204 Peganum Species 0.000 description 2
- 241000159213 Zygophyllaceae Species 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 150000003797 alkaloid derivatives Chemical class 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 230000004663 cell proliferation Effects 0.000 description 2
- 238000002512 chemotherapy Methods 0.000 description 2
- 201000010989 colorectal carcinoma Diseases 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 238000003745 diagnosis Methods 0.000 description 2
- VILAVOFMIJHSJA-UHFFFAOYSA-N dicarbon monoxide Chemical compound [C]=C=O VILAVOFMIJHSJA-UHFFFAOYSA-N 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- RERZNCLIYCABFS-UHFFFAOYSA-N harmaline Chemical compound C1CN=C(C)C2=C1C1=CC=C(OC)C=C1N2 RERZNCLIYCABFS-UHFFFAOYSA-N 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
- 230000001939 inductive effect 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
- 230000004060 metabolic process Effects 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 210000003205 muscle Anatomy 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 230000008520 organization Effects 0.000 description 2
- 238000001959 radiotherapy Methods 0.000 description 2
- 230000000452 restraining effect Effects 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical group CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 1
- 201000004569 Blindness 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
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 1
- 206010019233 Headaches Diseases 0.000 description 1
- 206010019468 Hemiplegia Diseases 0.000 description 1
- LPGWZGMPDKDHEP-HLTPFJCJSA-N Leurosine Chemical compound C([C@]1([C@@H]2O1)CC)N(CCC=1C3=CC=CC=C3NC=11)C[C@H]2C[C@]1(C(=O)OC)C1=CC([C@]23[C@H]([C@@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC LPGWZGMPDKDHEP-HLTPFJCJSA-N 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
- 229930012538 Paclitaxel Natural products 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- 206010036790 Productive cough Diseases 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 230000001640 apoptogenic effect Effects 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 230000015572 biosynthetic process Effects 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
- 239000006285 cell suspension Substances 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 201000010897 colon adenocarcinoma Diseases 0.000 description 1
- 208000029742 colonic neoplasm 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
- 230000006837 decompression Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000004043 dyeing Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 201000004101 esophageal cancer Diseases 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
- 239000000499 gel Substances 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
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 230000010534 mechanism of action 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
- 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
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 229960001592 paclitaxel Drugs 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
- 231100000614 poison Toxicity 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
- 230000005855 radiation Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 230000002829 reductive effect Effects 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
- 208000024794 sputum Diseases 0.000 description 1
- 210000003802 sputum Anatomy 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000009897 systematic effect Effects 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 229960003048 vinblastine Drugs 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
Abstract
The invention discloses indole alkaloid and application thereof and belongs to the technical field of medicines. The structural formula of the indole alkaloid is shown in the description. Experimental data verify that the indole alkaloid has a good anti-tumor effect on gastric cancer and plays a certain role on liver cancer and breast cancer. The compound has the advantages of high efficiency and low toxicity and is to become a novel anti-tumor drug in the market.
Description
Technical field
The present invention relates to a kind of new compound and application thereof.
Background technology
Tumour be that the cell of human organ tissue produces under the external and interior long term at adverse factor a kind of take cell hyperproliferation as the true tumor of principal feature, medically can be divided into innocent tumour and the large class of malignant tumour two.Innocent tumour is less to Health Impact, and malignant tumour (also known as cancer) then serious threat the health of the mankind.According to the recent statistics data of the World Health Organization and American Cancer Society, cancer has become the primary cause of disease of human death, within 2008, about there are 1,270 ten thousand new diagnosing cancer cases and 7,600,000 cancer mortality cases (accounting for 13% of all death tolls) in the whole world, and the cancer mortality case of nearly 70% occurs in middle and low income country.Expect the year two thousand thirty, the diagnosis of cancer year and death will respectively up to 2,140 ten thousand and 1,320 ten thousand.
According to Cancer in China foundation data, China's mortality of malignant tumors belongs to world's higher level, and in sustainable growth trend.Third National coroner's inquest in 2006 shows, and China's mortality of malignant tumors adds 83.1% than the mid-1970s, adds 22.5% than the initial stage nineties.Cerebrovascular disease and malignant tumour are China's front two causes of death, account for 22.4% and 22.3% of dead sum respectively.Malignant tumour not only has a strong impact on China's population health, and becomes the important factor of medical expense rise.In addition, because advanced malignant tumor patient outcomes is still dissatisfied, its poor prognosis often involves kith and kin and family, affects social stability.
Although the World Health Organization, national governments and scientific research institution have dropped into a large amount of human and material resources on tumor prevention with treatment, carry out deep research work, make great progress in the diagnosis of tumour, operation, radiation and chemotherapy, but up to the present, a lot of malignant tumour still lacks effective treatment means.Utilize various means to find effective antitumor drug, become the hot subject of life science in world wide.At present clinically for the chemical synthetic drug of oncotherapy, most of mechanism of action all relates to the nucleic acid metabolism of tumour cell, take DNA as action target spot, although play a part very important for oncotherapy, but while inhibition tumor cell propagation, bring great damage also to patient's healthy tissues organ, had a strong impact on the life quality of tumour patient, cause many tumour patients not to be die from chronic consumption exhaustion, but die from the Side effect of Radiotherapy chemotherapy.Therefore, continuation searching and development of new antitumor drug are still one of Main way of current medical research.
Chinese medicine and natural drug have a long history in guarantee human health, disease preventing and treating, and the development practice of world's medicinal industry proves, Chinese medicine, natural drug are always the important sources of innovation drug research.Many natural drugs have the advantages such as toxic side effect is relatively little, action principle is unique, become the important object of anti-cancer agent research and development, one of antitumor lead compound primary study direction having become Natural Medicine Chemistry finding high-efficiency low-toxicity from natural drug.The treatment that taxol, camptothecine, vincaleucoblastine, Cantharidin etc. are widely used in malignant tumour is exactly the successful examples of some of them.Today, from traditional Chinese medicine and natural drug, find the important shortcut that antitumor lead compound is still innovation drug research.
Herba pegani harmalae (Peganum harmala) is zygophyllaceae (Zygophyllaceae) Peganum (Peganum) plant, it is a kind of drought-enduring, cold-resistant, alkaline-resisting, barren-resistant herbaceous plant, Uighur, " this awns of Ah's underground heat ", is mainly distributed in Xinjiang, Gansu, Ningxia, the desert in Qinghai and the Inner Mongol or Semi-desert Area.Herba pegani harmalae is the Uygur nationality, Mongols's medicinal material used for a long time among the people, and medicinal part is mature seed.Herba pegani harmalae is put down, bitter, pungent, poisonous, has firm muscle arteries and veins, supporing yang warm the moon, eliminates the function such as gas of sticky body fluid, dissipation cold-dampness, cures mainly that muscle weak pulse, osteoarthrosis pain, coughing with a lot of sputum, hemiplegia are forgetful, coma headache etc.Herba pegani harmalae is mainly used in the malignant tumours such as treatment cancer of the stomach, liver cancer, colorectal carcinoma, mammary cancer on modern clinic.Clinically, total alkaloid of harmaline preparation reaches 85.7% to the efficient of malignant tumour such as esophagus cancer, cancer of the stomach, cardiac cancer, colorectal carcinomas, and as preparation in institute in Duo Jia affiliated hospital of Chinese Medical Sciences University and Xinjiang Duo Jia hospital application.
In seed of peganum harmala, main active ingredient is alkaloids, and modern pharmacological research shows, Herba pegani harmalae alkaloid has significant anti-tumor activity.But the alkaloidal complicated component of Herba pegani harmalae, people cannot determine specifically which kind of composition has anti-tumor activity or the coefficient result of Multiple components, and this causes its application to have certain blindness, easily occur unnecessary side effect.
Summary of the invention
The object of the present invention is to provide a kind of novel indole alkaloid and application thereof.
Contriver by studying for a long period of time, the Benzazole compounds that isolation identification 1 is new from seed of peganum harmala
this compound has good antitumor action to cancer of the stomach, has certain effect to liver cancer and mammary cancer tool simultaneously, and this compound has efficiently, the advantage of low toxicity, will become anti-gastric cancer medicament new on market.
Accompanying drawing explanation
Fig. 1 is the compounds of this invention
1h-NMR collection of illustrative plates;
Fig. 2 is the compounds of this invention
13c-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 appraisement:
Get the seed of peganum harmala of 10Kg, pulverize rear 70% methyl alcohol heating and refluxing extraction 3 times, each 2 hours, united extraction liquid, with decompression and solvent recovery after filtered through gauze, obtains total medicinal extract, by total medicinal extract 4L water suspendible, add hydrochloric acid and pH is adjusted to 1.0, with equal-volume chloroform extraction twice, removing oil-soluble impurities, pH is adjusted to 7.0 by water layer ammoniacal liquor, uses isopyknic chloroform successively, n-butanol extraction three times, get organic layer, concentrating under reduced pressure recycling design, obtains chloroform layer medicinal extract 220g respectively.
Get n-butyl alcohol extract 200 grams, by adopting the separation method such as silica gel column chromatography and hydroxypropyl dextrane gel (Sephadex LH-20) column chromatography, being separated and obtaining the compounds of this invention.
Structural Identification:
Use
13c-NMR and
1h-NMR carries out Structural Identification to the compound obtained of purifying,
13c-NMR and
1respectively as illustrated in fig. 1 and 2, Fig. 3 is the HSQC collection of illustrative plates of compound to H-NMR spectrum; Fig. 4 is the HMBC collection of illustrative plates of compound.。
?
1h-NMR (500Hz, DMSO-d
6) in, δ
h10.24 (1H, s), 7.73 (1H, t, J=5.3Hz) 5.86 (1H, s) are 3 reactive hydrogen signals, wherein δ
h10.24 (1H, s) are the NH of Benzazole compounds 1, and there are 3 hydrogen in fragrant district, δ
h7.16 (1H, d, J=8.2Hz), 6.52 (1H, dd, J=8.2,2.3Hz) and 6.37 (1H, d, J=2.3Hz) form a typical ABX spin coupling system, and high field region has 1 methoxyl group hydrogen signal δ
h3.73 (3H, s), the hydrogen signal δ of 2 methylene radical
hthe hydrogen signal δ of 2.88 (2H, m), 1.86 (2H, a m) and methyl
h1.71 (3H, s).
?
13c-NMR (125Hz, DMSO-d
6) and hsqc spectrum in can find out, this compound has 13 carbon signals, comprises 1 quaternary carbon δ
c74.1 (C-3), 1 methoxyl group carbon atom δ
c55.3,2 methylene carbon δ
c37.3,33.8,1 methine carbon atom δ
c22.6 and 8 sp
2hydbridized carbon atoms, wherein δ
c179.5 and 168.9 is two carbonyl carbon, and remaining 6 is then the carbon signal of phenyl ring.
?
13in C-NMR, δ
c96.6 and 160.2 and
1a Segment A is there is in ABX system this compound known in H-NMR spectrum.In HMBC spectrum, δ
c74.1 and δ
c179.5 all with δ
h10.24 (1H, s), 5.86 (1H, s) two reactive hydrogens are long-range relevant, therefore can obtain fragment B, and δ
h10.24 (NH) simultaneously also with the δ on phenyl ring
c123.6,142.9 two carbon are long-range relevant, δ
c74.1 with the δ on phenyl ring
h7.16 (1H, d, J=8.2Hz) are long-range relevant, therefore can determine that Segment A and fragment B are connected to form fragment C.In HMBC spectrum, δ
hthe methyl hydrogen at 1.71 (3H, s) place and δ
c168.9 carbonyl carbon are long-range relevant, and δ
c168.9 again with δ
hthe reactive hydrogen at 7.73 (1H, t, J=5.3Hz) place is long-range relevant, illustrates in this compound to there is an ethanamide group.δ
hthe reactive hydrogen at 7.73 (1H, t, J=5.3Hz) place and methylene radical δ
c33.8 is long-range relevant, can obtain fragment D accordingly, the methylene radical hydrogen δ in fragment D
h1.86 (2H, m) and δ
c74.1,123.6,179.5 three carbon signals are long-range relevant, quaternary carbon δ
c74.1 have long-range relevant to two methylene radical hydrogen, and comprehensive above-mentioned 1D and 2D data, fragment C and fragment D passes through δ
c74.1 and δ
c37.3 two carbon are connected.Comprehensive above information, the structure of deterministic compound is
systematic naming method is 3-Hydroxy-3-(N-acetyl-2-aminoethyl)-6-methoxyindol-2-one.
Table 1: the hydrogen of compound and carbon signal ownership (DMSO-d6)
After knowing its structural formula, also can obtain the claimed compound of the present invention according to prior art synthesis, or on the basis of extracting the compound obtained, carry out corresponding modification and obtain compound of the present invention, as general formula is
compound, in formula, R
1, R
2it is independently the alkyl of C1 ~ C4.
Inhibition test:
Test compounds
to the external antitumor activity experiment of human body 6 knurl strains, these 5 knurl strains comprise 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) inhibition tumor cell propagation (mtt assay)
By tumor cell inoculation in 96 orifice plates, after cultivating 24h, add sample to be tested, then use mtt assay working sample to the inhibiting rate of tumor cell proliferation after cultivating 48h.Cell proliferation inhibition rate by following formulae discovery, and with the half-inhibition concentration (IC of the tested sample of CalcuSyn computed in software
50), IC
50the composition of <20 μ g/mL will be regarded as active sample;
(2) inducing apoptosis of tumour cell
By tumour cell with 2 × 10
5individual/mL density is inoculated in 6 orifice plates, every hole 3mL.Add sample after cultivating 24h, then cultivate 24h, collecting cell, 1 time is washed, the centrifugal 5min of 1000 × g, with 1mL 3.7% paraformaldehyde re-suspended cell with PBS, room temperature fixes 1h, the centrifugal 5min of 1000 × g, supernatant discarded, 1 time is washed with PBS, cell is resuspended in 100 μ L PBS, obtained cell suspension 10 μ L, adds 2 μ L 1mmol/L Hoechst 33258,37 DEG C of dyeing 15min, observing apoptosis corpusculum under fluorescent microscope.
(3) experimental result: in table 2 and table 3
Table 2 the compounds of this invention is to the restraining effect of different tumour cell
The apoptosis-induced effect of table 3 the compounds of this invention when 2 μMs of concentration to different tumour cell
Note: significantly apoptosis-induced (++), generally apoptosis-induced (+), do not find apoptosis (-).
Experimental result shows: new compound of the present invention has significant antitumor action, particularly to cancer, include but not limited to that cancer of the stomach, liver cancer, mammary cancer and colorectal carcinoma have good therapeutic action, and energy significantly inducing tumor cell generation apoptotic effect, experimental data shows, the in-vitro multiplication restraining effect of the compounds of this invention to human stomach cancer cell line SGC7901 and BGC-803 is better than positive drug cis-platinum.
General formula is
(in formula, R
1, R
2the independent alkyl for C1 ~ C4) compound can to dissociate in vivo or metabolism produces the molecule of identical activity, there is significant antitumor action equally.
Claims (6)
1. an indole alkaloid, its general structure is
, in formula, R
1, R
2it is independently the alkyl of C1 ~ C4.
2. indole alkaloid according to claim 1, is characterized in that: R
1, R
2independent is methyl or ethyl.
3. indole alkaloid according to claim 1, is characterized in that: R
1, R
2for methyl.
4. the application of indole alkaloid in preparation treatment tumour Chinese traditional medicine, wherein, the structural formula of indole alkaloid is as described in claims 1 to 3 any one.
5. indole alkaloid is preparing the application be of value in tumour patient functional foodstuff, and wherein, the structural formula of indole alkaloid is as described in claims 1 to 3 any one.
6. the application according to claim 4 or 5, is characterized in that: tumour is selected from cancer of the stomach, liver cancer, mammary cancer.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106045896A (en) * | 2016-06-30 | 2016-10-26 | 山东理工大学 | Isatin hydrazide derivatives and preparation method thereof |
| CN107602438A (en) * | 2017-10-13 | 2018-01-19 | 福州大学 | A kind of arylazo tryptamine derivatives and preparation method thereof |
| CN115772092A (en) * | 2021-09-08 | 2023-03-10 | 广州暨清生物医药科技有限公司 | Amine compound or pharmaceutically acceptable salt thereof, and preparation and application thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008129075A1 (en) * | 2007-04-24 | 2008-10-30 | Topotarget A/S | Substituted 3-(4-hydroxyphenyl)-indolin-2-one-compounds |
| CN103145530A (en) * | 2011-12-06 | 2013-06-12 | 上海来益生物药物研究开发中心有限责任公司 | Compound, and preparation method and application thereof |
-
2015
- 2015-07-02 CN CN201510386719.8A patent/CN105017129B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008129075A1 (en) * | 2007-04-24 | 2008-10-30 | Topotarget A/S | Substituted 3-(4-hydroxyphenyl)-indolin-2-one-compounds |
| CN103145530A (en) * | 2011-12-06 | 2013-06-12 | 上海来益生物药物研究开发中心有限责任公司 | Compound, and preparation method and application thereof |
Non-Patent Citations (9)
| Title |
|---|
| FABIENNE PEYROT,等: "Reactivity of Peroxynitrite with Melatonin as a Function of pH and CO2 Content", 《EUROPEAN JOURNAL OF ORGANIC CHEMISTRY》 * |
| IGOR SEMAK,等: "A Novel Metabolic Pathway of Melatonin: Oxidation by Cytochrome", 《BIOCHEMISTRY》 * |
| METTE K. CHRISTENSEN,等: "Synthesis and Antitumor Effect in Vitro and in Vivo of Substituted 1,3-Dihydroindole-2-ones", 《JOURNAL OF MEDICINAL CHEMISTRY》 * |
| ZHONG-HUA GAO,等: "Four new indole alkaloids from Plantago asiatica", 《NATURAL PRODUCTS AND BIOPROSPECTING》 * |
| 孙梦娅,等: "吲哚酮类衍生物靶向抗肿瘤研究进展", 《广州化工》 * |
| 孙祥军,等: "吲哚类化合物的抗肿瘤作用", 《聊城大学学报(自然科学版)》 * |
| 宫爽,等: "天然药物中生物碱类成分抗肿瘤活性", 《吉林中医药》 * |
| 张屹,等: "吲哚类抗肿瘤药物的研究进展", 《化工中间体》 * |
| 潘启超,等: "骆驼蓬种子——吲哚生物碱的抗肿瘤作用", 《癌症》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106045896A (en) * | 2016-06-30 | 2016-10-26 | 山东理工大学 | Isatin hydrazide derivatives and preparation method thereof |
| CN107602438A (en) * | 2017-10-13 | 2018-01-19 | 福州大学 | A kind of arylazo tryptamine derivatives and preparation method thereof |
| CN115772092A (en) * | 2021-09-08 | 2023-03-10 | 广州暨清生物医药科技有限公司 | Amine compound or pharmaceutically acceptable salt thereof, and preparation and application thereof |
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