CN105418490B - Purposes of the mustargen base piperlongumine class compound in medicine - Google Patents
Purposes of the mustargen base piperlongumine class compound in medicine Download PDFInfo
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- CN105418490B CN105418490B CN201510761363.1A CN201510761363A CN105418490B CN 105418490 B CN105418490 B CN 105418490B CN 201510761363 A CN201510761363 A CN 201510761363A CN 105418490 B CN105418490 B CN 105418490B
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- piperlongumine
- mustargen
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
- C07D211/86—Oxygen atoms
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Abstract
The present invention provides purposes of a kind of mustargen base piperlongumine class compound in medicine.Inhibitory activity research of the present invention by mustargen base piperlongumine class compound to malignant cell, it was demonstrated that such mustargen base piperlongumine class compound has good antitumor activity, and a kind of new selection is provided to prepare antitumor drug.
Description
Technical field
The present invention relates to purposes of the mustargen base piperlongumine class compound in medicine, more particularly to mustargen base piperlongumine
Application of the class compound in treating malignant tumour.
Background technology
Fructus piperis longi is a kind of herbaceous perennial vine plant, and Chinese medicine takes its fruit ear to be used as medicine, cure mainly coldness and pain in the epigastrium, vomiting, diarrhea,
Migraine, controls toothache, coronary heart diseases and angina pectoris at nasosinusitis outside.Piperlongumine (piperlongumine)
It is one of the principle active component being separated to from fructus piperis longi, belongs to alkaloid compound.With the depth studied it
Enter, it has been found that many pharmacotoxicological effects of piperlongumine.There is anti-platelet aggregation, analgesia, antimycotic, anti-blood to inhale for it
Many pharmacological activity such as worm, antianxiety and antidepression.Especially it shows kinds of tumor cells in significant cell toxicant work
With and very small to the toxicity of normal cell under same concentrations, being a kind of great potential has the antitumor of selection virulence
Traditional Chinese medicine monomer（Raj et a1.,2011,Nature 475:231-234）.The compound is in increase in external Research Literature
Gesture is increasingly becoming one of the research hotspot in the field.
Mustargen base class drug is to be applied to clinical anti-tumor alkylating agent, since the advent of the world, to novel mustargen base class earliest
The exploitation of drug is lasting always.In the development process of mustargen base class drug, how to be made by introducing new pharmaceutical carrier
Obtaining the toxicity of drug reduces, is increased to the selectivity of tumour, and to improve therapeutic index, this is the common effort of scientists from all over the world
Direction.So being always a pharmaceutical chemical hot spot to the modification of the structural modification especially carrier part of nitrogen mustards compound
Research field.
To at present for this purpose, yet there are no application of the mustargen base piperlongumine class compound in medicine.
Invention content
The purpose of the present invention is to provide the purposes of a kind of mustargen base piperlongumine class compound, i.e., the use in medicine
On the way, novel drugs are provided for treatment malignant tumour.
The mustargen base piperlongumine class compound refers to following general formula（I）Compound represented：
Wherein,
R1For hydrogen atom, hydroxyl, methyl, methoxyl group, ethyoxyl, fluorine atom, chlorine atom, bromine atom, trifluoromethoxy；
R2For hydrogen atom, hydroxyl, methyl, methoxyl group, ethyoxyl, fluorine atom, chlorine atom, bromine atom, trifluoromethoxy.
Further, the purposes the present invention provides mustargen base piperlongumine class compound in medicine.
Further, the purposes is to treat the purposes of malignant tumour.
The further malignant tumour is cutaneum carcinoma, liver cancer, cancer of the esophagus, gastric cancer, leukemia, oophoroma, prostate
One kind in cancer, lung cancer, colorectal cancer, cancer of pancreas, breast cancer or kidney.
Inventor carries out the inhibitory activity of Several Kinds of Malignancy cell this kind of mustargen base piperlongumine class compound
Further investigation, experimental result finds that such compound can inhibit Several Kinds of Malignancy cell, for the exploitation of such compound at
A kind of new thinking is provided for a kind of new antitumor drug.
Below by way of specific implementation mode, the above of the present invention is described in further detail again.But it should not incite somebody to action
This is not understood as limitation of the present invention.
Specific implementation mode
Embodiment 1：Compound DJBB-1Preparation
Synthetic route is as follows：
The synthetic route of intermediate 1 sees reference document（Liu Wenhu etc., Acta Pharmaceutica Sinica, 2014,49 (2): 217 −
224）.
The synthetic route of intermediate 2 sees reference document（Shoujiao Peng et al, J. Med. Chem. 2015,
58, 5242−5255）.
The synthetic route of compound DJBB-1 sees reference document（Shoujiao Peng et al, J. Med. Chem.
2015, 58, 5242−5255）：
1 10 mmol of raw material, intermediate 2 10 mmol, CH are added in flask2Cl2 10 ml, 10 ml of triethylamine,
It is stirred to react 10 h at room temperature.Saturation NH is then added4Cl solution washs, CH2Cl2 Extraction, saturated common salt water washing, MgSO4It is dry
Dry, concentration.Crude product uses column chromatography to obtain again, yield 65%.
1H NMR (400 MHz, CDCl3)：δ7.89 (d, J = 15.6 Hz,1H), 7.60-7.54 (m, 2H),
7.34 (d, J = 15.6 Hz,1H), 6.94-6.90 (m, 3H), 6.05 (t, J = 9.6 Hz,1H), 4.05
(t, J=6.4 Hz, 2H), 3.85 (t, J=7.6 Hz, 4H), 3.72 (t, J=7.6 Hz, 4H), 2.44 (m,
2H)。
MS-ESI(m/z)：389.08 (M+NaTen)。
Embodiment 2:Compound DJBB-2Preparation
Synthetic route is such as compound DJBB-1.
The yield of compound DJBB-2 is 60%.
1H NMR (400 MHz, CDCl3)：δ7.90 (d, J = 15.6 Hz,1H),7.32 (d, J = 15.6
Hz,1H), 6.96-6.92 (m, 3H), 6.02 (t, J = 9.6 Hz,1H), 4.06 (t, J = 6.4 Hz,2H),
3.89 (s, 6H), 3.86 (t, J=7.6 Hz, 4H), 3.74 (t, J=7.6 Hz, 4H), 2.42 (m, 2H).
MS-ESI(m/z)：449.10 (M+NaTen)。
Embodiment 3:Compound DJBB-3Preparation
Synthetic route is such as compound DJBB-1.
The yield of compound DJBB-3 is 56%.
1H NMR (400 MHz, CDCl3)：δ7.92 (d, J = 15.6 Hz,1H),7.36 (d, J = 15.6
Hz, 1H), 6.96-6.92 (m, 3H), 6.03 (t, J=9.6 Hz, 1H), 4.03 (t, J=6.4 Hz, 2H),
3.82 (t, J=7.6 Hz, 4H), 3.76 (t, J=7.6 Hz, 4H), 2.46 (m, 2H).
MS-ESI(m/z)：425.06 (M+NaTen)。
Embodiment 4:Compound DJBB-4Preparation
Synthetic route is such as compound DJBB-1.
The yield of compound DJBB-4 is 72%.
1H NMR (400 MHz, CDCl3)：δ7.92 (d, J = 15.6 Hz,1H),7.34 (d, J = 15.6
Hz, 1H), 6.93-6.90 (m, 3H), 6.04 (t, J=9.6 Hz, 1H), 4.08 (t, J=6.4 Hz, 2H),
3.86 (t, J=7.6 Hz, 4H), 3.74 (t, J=7.6 Hz, 4H), 2.42 (m, 2H), 2.35 (s, 6H).
MS-ESI(m/z)：417.11 (M+NaTen)。
Embodiment 5：The anti-tumor activity test of the compounds of this invention
Cytostatic to tumor cell experiment is carried out to the compound of the present invention, test method uses conventional mtt assay (such as
Lv Qiujun is edited《Developmental pharmacology research method》, 2007:242-243).
RPMI-1640, DMEM, fetal calf serum, pancreatin etc. are purchased from Gibco BRL companies（Invitrogen
Corporation, USA), thiazole bromide blue tetrazolium (MTT), dromisol (DMSO) they are Sigma companies (USA) product.2- first
The purchase of amide groups thienopyridine derivative is from Specs companies (Holland), and for chemical standard product, when experiment in vitro is prepared with DMSO
At 20mg/mL storing liquids, sets 4 DEG C of refrigerators and be kept in dark place spare, face the used time is diluted to required concentration with complete culture solution.
Cell strain selects human lung carcinoma cell line（A549）, Breast cancer lines (MCF-7), human colon cancer cell strain
(HCT-116) and human hepatoma cell strain (HepG2) ATCC companies of the U.S., are purchased from.
Human lung carcinoma cell line（A549）, Breast cancer lines ((MCF-7) and human colon cancer cell strain (HCT-116) use
RPMI-1640 complete mediums, 5% C0 containing 10% fetal calf serum, 100U/mL penicillin, 100 μ g/mL streptomysins2,37℃
Culture.
Human hepatoma cell strain (HepG2) is with containing 10% fetal calf serum, 100U/mL penicillin, 100 μ g/mL streptomysins
DMEM complete mediums, 5 % C02, 37 DEG C of cultures.
Mtt assay：It is 1-2 × 10 with complete culture solution adjustment cell concentration4/ mL is inoculated in 96 orifice plates, per 200 μ L of hole,
Overnight incubation, next day respectively with the 2- formamido thienopyridine derivatives of various dose (final concentration is respectively 20,5,
1.25,0.31g/ml) processing cell, while setting the not negative control group of drug containing and isometric solvent control group, DMSO are dense
Degree is 0.1%, and each dosage group sets 5 multiple holes, 37 DEG C, 5 % C02Culture.After cultivating 48h, 5mg/mL MTT examinations are added per hole
20 μ L of agent continue to cultivate 2-4h, abandon supernatant, then add DMSO150 μ L, vibrate mixing 15min, are surveyed with microplate reader (λ=570nm)
Determine absorbance (A) value (A values are directly proportional to viable count), takes its average value.
Relative cell proliferation inhibiting rate (%)=(control group inhibiting rate-experimental group inhibiting rate)/control group inhibiting rate × 100%.
Experiment is at least repeated 3 times.Experimental data is indicated with mean ± standard deviation, is handled using 13.0 statistical softwares of SPSS.Measurement data
It is examined using t, P<0.05 is statistically significant for difference.(control group here refers to solvent control group, and solvent control group is without thin
Born of the same parents' inhibited proliferation, therefore be not expressly set out)
Experimental result is shown in Table 1.Wherein, compound refers to the mustargen base piperlongumine class compound prepared in corresponding embodiment
(such as compound DJBB-1 in embodiment 1).
The IC of 14 kinds of tumour cells of compound pair of table50(μM) value
As it can be seen from table 1 the piperlongumine class compound containing mustargen base pharmacophore has good antitumor activity,
Multiple compounds are higher than existing antitumoral compounds piperlongumine.
Claims (3)
1. the purposes of mustargen base piperlongumine class compound in medicine preparation, it is characterised in that the mustargen base piperlongumine
Class compound refers to following general formula（I）Compound represented：
Wherein,
R1For methoxyl group, ethyoxyl, fluorine atom；R2For methoxyl group, ethyoxyl, fluorine atom.
2. purposes according to claim 1, it is characterised in that the purposes in medicine preparation be prepare treatment it is pernicious
Purposes in tumour medicine.
3. according to the purposes described in claim 2, it is characterised in that the malignant tumour is cutaneum carcinoma, liver cancer, esophagus
One kind in cancer, gastric cancer, leukemia, oophoroma, prostate cancer, lung cancer, colorectal cancer, cancer of pancreas, breast cancer or kidney.
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| US20240109855A1 (en) * | 2021-01-14 | 2024-04-04 | B. G. Negev Technologies And Applications Ltd., At Ben-Gurion University | Anti-quorum sensing, anti-biofilm, and inflammation attenuating compounds, compositions, and methods of using same |
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| CN115894407A (en) * | 2022-11-14 | 2023-04-04 | 广东海洋大学 | CIT fluorophore of 1-furan and thienyl-2-alkenyl-1-ketone containing nitrogen mustard and preparation method and application thereof |
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| CN102125552A (en) * | 2010-01-20 | 2011-07-20 | 李绍路 | Use of piperlongumine derivatives in preparation of medicines for treating cancers and medicinal compositions thereof |
| CN102146054A (en) * | 2010-02-10 | 2011-08-10 | 新昌县来益科技开发有限公司 | Piperlongumine derivatives and medicinal composition and application to preparation of medicament for inhibiting tumor growth thereof |
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Effective date of registration: 20201125 Address after: 221000 Quanshan Economic Development Zone, Xuzhou City, Jiangsu Province, No. 6 Tengfei Road, Quanshan Economic Development Zone Management Committee 1-216 Patentee after: JIANGSU TIANMEI ELECTROMECHANICAL TECHNOLOGY Co.,Ltd. Address before: 610041, 26, 1, 2601, 138 Tianfu two street, Chengdu hi tech Zone, Sichuan, China Patentee before: CHENGDU GERUISAISI TECHNOLOGY Co.,Ltd. |
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Effective date of registration: 20210203 Address after: 518000 10N, Taiyangdao building, 2020 Dongmen South Road, Xinnan community, Nanhu street, Luohu District, Shenzhen City, Guangdong Province Patentee after: Guangdong Yongchun Pharmaceutical Group Co.,Ltd. Address before: 221000 Quanshan Economic Development Zone, Xuzhou City, Jiangsu Province, No. 6 Tengfei Road, Quanshan Economic Development Zone Management Committee 1-216 Patentee before: JIANGSU TIANMEI ELECTROMECHANICAL TECHNOLOGY Co.,Ltd. |
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