CN106632328B - A kind of rutaecarpin compound nantokite with anti-tumor activity and its synthetic method - Google Patents
A kind of rutaecarpin compound nantokite with anti-tumor activity and its synthetic method Download PDFInfo
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- CN106632328B CN106632328B CN201610867659.6A CN201610867659A CN106632328B CN 106632328 B CN106632328 B CN 106632328B CN 201610867659 A CN201610867659 A CN 201610867659A CN 106632328 B CN106632328 B CN 106632328B
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- rutaecarpin
- tumor activity
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
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Abstract
The present invention discloses a kind of rutaecarpin compound nantokite with anti-tumor activity and its synthetic method, and structure is as follows,The rutaecarpin compound nantokite significantly inhibits Ovarian Cancer Cells Skov3, shows potential medical value, is expected to as metal anti-tumor drug.Belong to pharmaceutical technology field.
Description
Technical field
The present invention relates to pharmaceutical technology fields, and in particular to a kind of rutaecarpin compound nantokite with anti-tumor activity
And its synthetic method.
Background technique
Ligand selection of the present invention derives from Chinese medicine evodia alkaloid effective component rutaecarpin (Evodiamine), Wu Zhu
Cornel alkali belongs to the classical mother nucleus structure of Indoloquinazoline alkaloid, and such functional structure is easy chelating generation with metal ion and matches
It closes object or exists in the form of alkaloid salt, be expected to play effective component of chinese medicine after complexation of metal ions and the economic benefits and social benefits of metal ion are assisted
Same-action.
Since the successful use of the antitumor Metal Drugs of cis-platinum clinically, the transient metal complexes such as relative platinum
The research of antitumor and anticancer agent also increasingly attracts extensive attention.Copper, as microelement necessary to biology, to aging and cancer and
DNA damage caused by its associated endogenous oxidant plays key effect, and the toxicity of copper is than nonessential microelement such as platinum
Toxicity wants small, thus copper metal complex or copper ion salt compound be expected to similar to cisplatin medicine anti-tumor activity and
Has the characteristics that hypotoxicity.
Currently, having some rutaecarpin derivatives is developed the research as anti-tumor drug.But previous research
The small organic molecule stage is all rested on, and the metal salt of rutaecarpin or complex not yet someone study.Therefore, there is still a need for more
Good alternatives.
Summary of the invention
The present invention provides a kind of rutaecarpin compound nantokite with anti-tumor activity.
A kind of rutaecarpin compound nantokite with anti-tumor activity provided by the invention, structural formula is as follows,
A kind of synthetic method of rutaecarpin compound nantokite with anti-tumor activity are as follows: by rutaecarpin with
CuCl2·2H2Solvent is added by the proportion of amount 1:0.5~1.5 of substance in O, and is put into closed reaction vessel, and heating reaction is extremely
Completely, reaction vessel is taken out to stand and is cooled to room temperature, and take out crystal from container, washed, drying to obtain Wu Zhu
Cornel compound nantokite.
It should be noted that the solvent is acetone, the additive amount of the acetone is every gram of rutaecarpin and CuCl2·
2H210~100mL is added in the mixture of O.
It should be noted that the reaction vessel is the Pyrex heavy-walled glass pipe that length is 15~20cm；A large amount of synthesis
When, then use ptfe autoclave instead.
It should be noted that the heating container is baking oven, reaction temperature control is at 90~110 DEG C, the reaction time 4
~8 days.
It should be noted that the washing is successively washed using petroleum ether, chloroform.
Beneficial effects of the present invention:
The present invention is using rutaecarpin as structure basis, under the conditions of solvent heat, by with CuCl2·2H2It is anti-that complexing occurs for O
Rutaecarpin compound nantokite should be obtained, synthetic method is simple, reaction condition is easily controllable, and reaction raw materials are cheap and easy to get.
Rutaecarpin compound nantokite significantly inhibits Ovarian Cancer Cells Skov3, and IC50 value is 8.02 μ
M shows good potential medical value, is expected to as metal anti-tumor drug.
Detailed description of the invention
Fig. 1 is the infrared spectrum spectrogram of product of the present invention
Fig. 2 is the X-ray single crystal diffraction structure chart of product of the present invention
Specific embodiment
The present invention is described in further details below with reference to specific case, but does not constitute any limitation of the invention,
It is any it is made in interest field do not have a tangible change, still within the scope of protection of the claims of the present invention.
Embodiment 1
It weighs rutaecarpin (0.010g, 0.03mmol), CuCl2·2H2O (0.008g, 0.04mmol) is added to an end seal
In the 15cmPyrex heavy-walled glass pipe closed, 1.8mL acetone is added dropwise, under the high temperature conditions seals open end, mixture mixing is equal
It is put into after even in 100 DEG C of baking oven, there is the generation of yellow rhabdolith after reaction 4 days in glass tube.Glass tube is taken out into rest chamber
Temperature is cooling, and crystal is taken out from glass tube, with petroleum ether, chloroform, is dried to obtain rutaecarpin compound nantokite, yield
It is 85.4%.
Product testing: carrying out infrared spectroscopy, the analysis of X-ray single crystal diffraction to brown solid obtained above respectively,
As shown in Fig. 1~2.
Specific Spectral Characteristic is as follows:
IR spectrum: 3444,1704,1549,1499,1335,1103,813,759cm-1。
1704 be the characteristic absorption peak of C=O, 1549cm-1For the characteristic absorption peak of C=N, 1335cm-1For the feature of C-N
Absorption peak.
X-ray single crystal diffraction structure: X-ray single crystal diffraction is most effective, most accurate structural characterization means, X-ray
The connection type of each atom and spatial position in Accurate Determining rutaecarpin compound nantokite crystallized sample.During structure shows
Heart ion copper ion and chloride binding form [Cu4Cl6]2+Ion cluster, the hydrogen atom on the indole ring N-H of two rutaecarpins
Dehydrogenation forms the rutaecarpin mantoquita of ionic.
Determine that above-mentioned yellow crystals product is rutaecarpin compound nantokite, molecular formula C38H32Cl6Cu4N6O2, molecule
Amount is 1065.7g/mol, and chemical structural formula is as follows:
Application test of the product of the present invention in anti-tumor drug:
It is tested using anti tumor activity in vitro of the rutaecarpin mantoquita to oophoroma Skov3 tumor cell line.
1, cell strain and cell culture
Oophoroma Skov3 tumor cell line is selected in this experiment.
Cell strain culture containing the small ox blood of 10wt%, 100U/mL penicillin, 100U/mL streptomysin RPMI~1640 or
In DMEM culture solution, sets in 37 DEG C of incubators of 5%CO2 containing volumetric concentration and cultivate.Inverted microscope observes cell growth status,
The passage of 0.25% trypsin digestion, logarithmic growth phase cell is for testing.
2, the preparation of untested compound
Rutaecarpin compound nantokite used is product made from the embodiment of the present invention 1, and purity >=95% passes through
RMPI1640 culture medium is successively diluted to five concentration gradients, and respectively 40,20,10,5,2.5 μm of ol/L test 20 μm of ol/L
Inhibiting rate of the rutaecarpin compound nantokite to different tumor cell proliferations under concentration.
3, cell growth inhibition test (mtt assay)
(1) tumour cell of logarithmic growth phase is matched after trypsin digestion with the culture solution containing 10% calf serum
The cell suspension that concentration is 5000/mL is made, is inoculated in 96 well culture plates with every 190 μ L of hole, makes cell density to be measured extremely
1000~10000/hole (edge hole is filled with sterile PBS)；
(2) 5%CO2,37 DEG C are incubated for for 24 hours, until cell monolayer is paved with bottom hole, the drug 10 of a certain concentration gradient is added in every hole
μ L, each concentration gradient set 4 multiple holes；
(3) 5%CO2,37 DEG C are incubated for 48 hours, observe under inverted microscope；
(4) the MTT solution (5mg/mL PBS, i.e. 0.5%MTT) of 10 μ L is added in every hole, continues to cultivate 4h；
(5) culture is terminated, culture solution in hole is carefully sucked, every hole is added 150 μ L DMSO and sufficiently dissolves first a ceremonial jade-ladle, used in libation precipitating, vibration
It swings after device mixes, with wavelength is 570nm in microplate reader, reference wavelength is the OD value that 450nm measures each hole；
(6) it is arranged zeroing hole (culture medium, MTT, DMSO) simultaneously, (the drug dissolution of cell, same concentrations is situated between control wells
Matter, culture solution, MTT, DMSO).
(7) according to the OD value (OD value) measured, to judge living cells quantity, OD value is bigger, and cell activity is stronger.Benefit
With formula:
Calculate the inhibiting rate of compound on tumor cell growth.
The result shows that rutaecarpin compound nantokite there is apparent inhibition to make oophoroma Skov3 tumor cell line
With IC50 value is 8.02 μM, is demonstrated by good potential medical value.On the other hand, metal copper is needed by human micro-
Secondary element, rutaecarpin derive from natural alkaloid, and raw material is natural, is readily synthesized, and have the value of further investigation exploitation.
Embodiment 2
It weighs rutaecarpin (1g, 3mmol), CuCl2·2H2Rutaecarpin, mantoquita are put into 25mL by O (0.8g, 4mmol)
Ptfe autoclave in, be added dropwise acetone 20mL, open end is sealed under the high temperature conditions, mixture is put after mixing
Into 90 DEG C of baking ovens, there is the generation of brown bulk crystals after reaction 4 days in glass tube.Glass tube is taken out and stands room temperature cooling,
Crystal is taken out from glass tube, with petroleum ether, chloroform, is dried to obtain rutaecarpin mantoquita, yield 81.2%.
Product inspection method is the same as embodiment 1.
Embodiment 3
It weighs rutaecarpin (10g, 30mmol), CuCl2·2H2O (8g, 40mmol), rutaecarpin, mantoquita are put into
In the ptfe autoclave of 200mL, the third 180mL is added dropwise, under the high temperature conditions seals open end, mixture is uniformly mixed
It is put into 100 DEG C of baking oven afterwards, there is the generation of brown bulk crystals after reaction 5 days in glass tube.Glass tube is taken out and stands room temperature
It is cooling, crystal is taken out from glass tube, with petroleum ether, chloroform, is dried to obtain rutaecarpin mantoquita, yield is
82.6%.
Product inspection method is the same as embodiment 1.
Embodiment 4
It weighs rutaecarpin (20g, 60mmol), CuCl2·2H2O (8g, 40mmol), rutaecarpin, mantoquita are put into
In the ptfe autoclave of 2000mL, acetone 1800mL is added dropwise, under the high temperature conditions seals open end, mixture mixing
It is put into 100 DEG C of baking oven after uniformly, there is the generation of brown bulk crystals after reaction 4 days in glass tube.Glass tube is taken out and is stood
Room temperature is cooling, and crystal is taken out from glass tube, with petroleum ether, chloroform, is dried to obtain rutaecarpin mantoquita, yield is
80.8%.
Product inspection method is the same as embodiment 1.
Embodiment 5
It weighs rutaecarpin (1g, 3mmol), CuCl2·2H2Rutaecarpin, mantoquita are put into 50mL by O (0.4g, 2mmol)
Ptfe autoclave in, acetone 40mL is added dropwise, mixture is put into after mixing in 110 DEG C of baking oven, after reaction 8 days
There is the generation of brown bulk crystals in glass tube.Glass tube is taken out and stands room temperature cooling, crystal is taken out from glass tube, uses stone
Oily ether, chloroform are dried to obtain rutaecarpin mantoquita, yield 76.3%.
Product inspection method is the same as embodiment 1.
Above-described is only presently preferred embodiments of the present invention, all made within the scope of the spirit and principles in the present invention
What modifications, equivalent substitutions and improvements etc., should all be included in the protection scope of the present invention.
Claims (6)
1. a kind of rutaecarpin compound nantokite with anti-tumor activity, which is characterized in that its structural formula are as follows:
2. a kind of synthetic method of rutaecarpin compound nantokite with anti-tumor activity described in claim 1, feature exist
In by rutaecarpin and CuCl2·2H2Solvent is added by the proportion mixing of amount 1:0.5~1.5 of substance in O, and is put into closed anti-
It answers in container, reaction vessel is taken out to stand and be cooled to room temperature to complete by heating reaction, and takes out crystal from container, is carried out
Washing, drying to obtain evodia rutaecarpa compound nantokite.
3. the synthetic method of rutaecarpin compound nantokite with anti-tumor activity according to claim 2, feature
It is, the solvent is acetone, and additive amount is every gram of rutaecarpin and CuCl2·2H210~100mL is added in the mixture of O.
4. the synthetic method of rutaecarpin compound nantokite with anti-tumor activity according to claim 2, feature
It is, the reaction vessel is the Pyrex heavy-walled glass pipe that length is 15~20cm.
5. the synthetic method of rutaecarpin compound nantokite with anti-tumor activity according to claim 2, feature
It is, at 90~110 DEG C, the reaction time is 4~8 days for reaction temperature control.
6. the synthetic method of rutaecarpin compound nantokite with anti-tumor activity according to claim 2, feature
It is, the washing is successively washed using petroleum ether, chloroform.
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| 吴茱萸碱抗肿瘤活性研究进展;张醇等;《中国新药杂志》;20101231;第19卷(第17期);1558-1562 |
| 天然药物有效成分的金属配合物研究进展;谭明雄等;《林产化学与工业》;20081231;第28卷(第6期);93-99 |
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Application publication date: 20170510 Assignee: Guangxi green recycling new material technology Co.,Ltd. Assignor: Yulin Normal University Contract record no.: X2022450000340 Denomination of invention: A copper salt of evodiamine with anti-tumor activity and its synthesis method Granted publication date: 20190219 License type: Common License Record date: 20221219 |