CN105153148A - Tryptanthrin alkaloid salt, and preparation method and application thereof - Google Patents
Tryptanthrin alkaloid salt, and preparation method and application thereof Download PDFInfo
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- CN105153148A CN105153148A CN201510338986.8A CN201510338986A CN105153148A CN 105153148 A CN105153148 A CN 105153148A CN 201510338986 A CN201510338986 A CN 201510338986A CN 105153148 A CN105153148 A CN 105153148A
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- couroupitine
- tryptanthrin
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- sulfonate
- alkaloid salt
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- BVFCWGJKARXMJW-UHFFFAOYSA-N O=C(c(cc1)cc(/C(/C2=Nc3c4cccc3)=[O]/C35[TlH][IH]C3CC5)c1N2C4=O)N=O Chemical compound O=C(c(cc1)cc(/C(/C2=Nc3c4cccc3)=[O]/C35[TlH][IH]C3CC5)c1N2C4=O)N=O BVFCWGJKARXMJW-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- 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
- C07D471/02—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 two hetero rings
- C07D471/04—Ortho-condensed systems
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- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a tryptanthrin alkaloid salt, and a preparation method and application thereof, belonging to the technical field of medicine. The structural formula of the tryptanthrin alkaloid salt is as shown in a formula I which is described in the specification, and in the formula I, R is Na or K. According to the invention, tryptanthrin is used as a structural basis and undergoes electrophilic substitution reaction with fuming sulphuric acid so as to produce tryptanthrin sulfonate; and the preparation method is simple, has mild reaction conditions and uses cheap and easily available raw materials. Proliferation inhibition activity of the tryptanthrin sulfonate to seven tumor cell strains is investigated in the invention. Investigation results show that the in-vitro antitumor activity of the tryptanthrin sulfonate is selective and the tryptanthrin sulfonate has substantial proliferation inhibition activity to specific tumor cell strains, shows good potential medicinal values and is expected to be used for preparation of a variety of antitumor drugs.
Description
Technical field
The invention belongs to medical art, particularly a kind of couroupitine A alkaloid salt and its preparation method and application.
Background technology
Couroupitine A (Tryptanthrin) is a kind of quinazoline ketones alkaloid, is mainly present in the plants such as acanthaceous indigo, woaded blue, indigo plant, can be used as medicine, and has removing toxic substances, the effect such as antipyretic.Recent study finds that couroupitine A has many pharmacological actions as anti-inflammatory, the effect such as antibacterial, anticancer, but the water-soluble poor of couroupitine A has a strong impact on its widespread use.From structure, couroupitine A belongs to quinazoline ketones alkaloid, there is in molecular structure planarity and electro good phenyl ring, be easy to and electrophilic reagent generation electrophilic substitution reaction, if introduce the hydrophilic radicals such as sulfonic group on phenyl ring, the couroupitine A alkaloid after salify can improve its water-soluble and stability, has easy absorption, alleviate stomach side effect, improve drug effect etc.
Summary of the invention
For solving the shortcomings such as the poorly water-soluble of couroupitine A in prior art, primary and foremost purpose of the present invention is to provide a kind of couroupitine A alkaloid salt.Described couroupitine A alkaloid salt is a kind of new couroupitine A alkaloid salt, can improve water-soluble and stability.
Another object of the present invention is to provide the preparation method of above-mentioned couroupitine A alkaloid salt.Described preparation method is the preparation method of the couroupitine A sulfonate taking couroupitine A as architecture basics.
Another object of the present invention is to provide the application of above-mentioned couroupitine A alkaloid salt.
Object of the present invention is achieved through the following technical solutions: a kind of couroupitine A alkaloid salt, and its structural formula is as shown in the formula shown in I, and wherein R is Na or K:
The preparation method of above-mentioned couroupitine A alkaloid salt, comprises the following steps:
The oleum of couroupitine A and 30% is mixed with the ratio of amount of substance 1:2 ~ 20, to be heated at 80 DEG C to react under condition 1 ~ 2 little of reacting completely, cooling, hold over night, saturated nacl aqueous solution is added in solution, separating out light yellow solid, continuing to add saturated nacl aqueous solution to separating out without solid; Light yellow solid washes with water, washing with acetone, is drying to obtain couroupitine A sulfonate.
In above-mentioned synthetic method,
Preferably, the consumption of described couroupitine A and 30% oleum can be amount of substance ratio is 1:10 ~ 20, and the consumption increasing oleum is beneficial to the transformation efficiency improving couroupitine A, but increases the difficulty of product process.This reaction belongs to electrophilic substitution reaction, reacts under 80 DEG C of conditions, should not carry out under the high temperature conditions.React and can react completely for 2 hours, the reaction situation of carrying out can adopt thin-layer chromatography (TLC) tracing detection to react whether completely, and within the scope of said temperature, reaction is to completely approximately needing 1 ~ 2h.Solution cooling, hold over night after reaction, add saturated nacl aqueous solution and product is separated out from solution, this operation can be carried out at ambient temperature or carry out at 0 ~ 5 DEG C.Described drying adopts vacuum-drying usually, and temperature general control is at 25 ~ 50 DEG C.
The application in antitumor drug prepared by above-mentioned couroupitine A sulfonate.
The advantage had of hinge structure of the present invention and effect are:
The present invention take couroupitine A as architecture basics, and by obtaining couroupitine A sulfonate with oleum generation electrophilic substitution reaction, synthetic method is simple, reaction conditions is gentle, and reaction raw materials is cheap and easy to get.Applicant has also investigated the proliferation inhibition activity of couroupitine A sulfonate to 7 kinds of tumor cell lines, result shows that its anti tumor activity in vitro has certain selectivity, remarkable to the proliferation inhibition activity of specific tumors strain, demonstrate good potential pharmaceutical use, be expected to the preparation for various antitumor drug.
Accompanying drawing explanation
Fig. 1 is the infrared spectra spectrogram of the product that the embodiment of the present invention 1 obtains.
Fig. 2 is the ESI mass spectrum of the product that the embodiment of the present invention 1 obtains.
Fig. 3 is the X-ray single crystal diffraction structure iron of the product that the embodiment of the present invention 1 obtains.
Embodiment
Below in conjunction with embodiment 1 and accompanying drawing, the present invention is described in further detail, but embodiments of the present invention are not limited thereto.
Embodiment 1
Get 0.01g couroupitine A and the mixing of 8mL30% oleum, under agitation, temperature is reacted to complete (TLC tracing detection under 80 DEG C of conditions, 2h), by reaction soln cooling, hold over night after stopped reaction, saturated nacl aqueous solution is added in solution, separate out light yellow solid, continue to add saturated nacl aqueous solution to separate out to without solid, filter, light yellow solid washes with water, washing with acetone, gained solid is vacuum-drying 6h under room temperature condition, obtains tryptamines ketosulfonic acid salt, productive rate 79.6%.
Carry out infrared spectra, ESI Electrospray Ionization Mass Spectrometry, the analysis of X-ray single crystal diffraction respectively to yellow solid product obtained above, result respectively as shown in Figure 1, 2, 3.Concrete spectral characteristic is as follows: IR collection of illustrative plates 1724.0cm
-1and 1682.8cm
-1for the charateristic avsorption band of C=O, 1594.0cm
-1for the charateristic avsorption band of C=N, 1195.6cm
-1for the charateristic avsorption band of C-N.ESI collection of illustrative plates 327.06 loses fragment ion peak after sodium ion for couroupitine A sodium sulfonate.The crystalline structure of couroupitine A sulfonated products shows, sulfonic group, on the 8-position carbon atom of couroupitine A, substitution reaction occurs.
Determine that above-mentioned product as light yellow solid is couroupitine A sulfonate sodium, its molecular formula is C
15h
7n
2o
5sNa, molecular weight is 350.3g/mol, and its chemical structural formula is such as formula II:
The present invention also comprises the application of above-mentioned couroupitine A sulfonate in antitumor drug, applicant carried out couroupitine A sulfonate and tests the anti tumor activity in vitro of 7 kinds of tumor cell lines.
1, cell strain and cell cultures
Stomach cancer cell SCG-7901 is selected in this experiment, kidney cancer cell 786-O, lung carcinoma cell NCI-H460, Colon Carcinoma, breast cancer cell MCF7, liver cancer cell 7721,7 kinds of tumor cell lines such as cervical cancer cell Hela.
All cells strain is all cultivated in RPMI-1640 or the DMEM nutrient solution containing the little ox blood of 10wt%, 100U/mL penicillin, 100U/mL Streptomycin sulphate, puts 37 DEG C containing volumetric concentration 5%CO
2cultivate in incubator.Inverted microscope observation of cell growing state, 0.25% tryptic digestion goes down to posterity, take the logarithm vegetative period cell for experiment.
2, the preparation of testing compound
Couroupitine A sulfonate used is the product that the embodiment of the present invention 1 obtains, its purity >=95%, five concentration gradients are diluted to successively by RMPI1640 substratum, be respectively 40,20,10,5,2.5 μm of ol/L, under testing 10 μm of ol/L concentration, couroupitine A sulfonate is to the inhibiting rate of different tumor cell proliferation.
3, cell growth inhibition test (mtt assay)
(1) tumour cell of taking the logarithm vegetative period, after tryptic digestion, the cell suspension that concentration is 5000/mL is mixed with the nutrient solution containing 10% calf serum, be inoculated in 96 well culture plates with every hole 190 μ L, make cell density to 1000 ~ 10000 to be measured/hole (the aseptic PBS of marginal pore fills);
(2) 5%CO
2, hatch 24h for 37 DEG C, be paved with at the bottom of hole to cell monolayer, every hole adds the medicine 10 μ L of finite concentration gradient, and each concentration gradient establishes 4 multiple holes;
(3) 5%CO
2, hatch 48 hours for 37 DEG C, observe under inverted microscope;
(4) every hole adds the MTT solution (5mg/mLPBS, i.e. 0.5%MTT) of 10 μ L, continues to cultivate 4h;
(5) stop cultivating, carefully suck nutrient solution in hole, every hole adds 150 μ LDMSO and fully dissolves first a ceremonial jade-ladle, used in libation precipitation, and after vibrator mixing, be 570nm at microplate reader wavelength, reference wavelength is the optical density value that 450nm measures each hole;
(6) zeroing hole (substratum, MTT, DMSO) is set simultaneously, control wells (the medicine dissolution medium of cell, same concentrations, nutrient solution, MTT, DMSO).
(7) according to the optical density value (OD value) recorded, judge viable cell quantity, OD value is larger, and cytoactive is stronger.Utilize formula:
Computerized compound is to the inhibiting rate of growth of tumour cell.Its test result is as shown in table 1 below:
Table 1 couroupitine A sulfonate is to the growth inhibition ratio (%) of different tumor cell line
From anti tumor activity in vitro test result, couroupitine A sulfonate shows different proliferation inhibition activities for different tumor cell lines.From primary dcreening operation result, 50% is greater than to four kinds of cell strain inhibiting rates such as 7901,786-o, NCI-H460, MCF-7, wherein, the highest to the inhibiting rate of 7901, reach 73.76%, there is good potential pharmaceutical use.On the other hand, couroupitine A sulfonate has water-soluble preferably, and couroupitine A derives from natural alkaloid, and raw material is natural, be easy to synthesis, has the value of further investigation exploitation.
Above-described embodiment is the present invention's preferably embodiment; but embodiments of the present invention are not restricted to the described embodiments; change, the modification done under other any does not deviate from spirit of the present invention and principle, substitute, combine, simplify; all should be the substitute mode of equivalence, be included within protection scope of the present invention.
Claims (6)
1. a couroupitine A alkaloid salt, is characterized in that: its structural formula is as shown in the formula shown in I, and wherein R is Na or K:
2. the preparation method of couroupitine A alkaloid salt according to claim 1, is characterized in that: comprise the following steps:
The oleum of couroupitine A and 30% is mixed with the ratio of amount of substance 1:2 ~ 20, to be heated at 80 DEG C to react under condition 1 ~ 2 little of reacting completely, cooling, hold over night, saturated nacl aqueous solution is added in solution, separating out light yellow solid, continuing to add saturated nacl aqueous solution to separating out without solid; Light yellow solid washes with water, washing with acetone, is drying to obtain couroupitine A sulfonate.
3. the preparation method of couroupitine A alkaloid salt according to claim 2, is characterized in that: the consumption of described couroupitine A and 30% oleum is that amount of substance is than being 1:10 ~ 20.
4. the preparation method of couroupitine A alkaloid salt according to claim 2, is characterized in that: product is separated out from solution adding saturated nacl aqueous solution, this operation is carried out at ambient temperature or carried out at 0 ~ 5 DEG C.
5. the preparation method of couroupitine A alkaloid salt according to claim 2, is characterized in that: described drying adopts vacuum-drying, and temperature controls at 25 ~ 50 DEG C.
6. the application in antitumor drug prepared by couroupitine A sulfonate according to claim 1.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106317084A (en) * | 2016-08-19 | 2017-01-11 | 玉林师范学院 | Tryptanthrin copper complex with antitumor activity and synthetic method thereof |
| WO2022053964A1 (en) * | 2020-09-11 | 2022-03-17 | Universidade De Coimbra | Water-soluble trypthantrin derivatives for redox flow batteries |
| CN115124531A (en) * | 2022-08-09 | 2022-09-30 | 贵州大学 | 4-azatryptanthrin aromatic thioether derivatives, and preparation method and application thereof |
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| CN1594307A (en) * | 2004-06-25 | 2005-03-16 | 陕西师范大学 | Extraction separation for Nepal irid isoflavone from kudzu, process for preparing sulfonated compounds thereof , and their pharmaceutical uses |
| CN102579452A (en) * | 2012-01-20 | 2012-07-18 | 辽宁思百得医药科技有限公司 | Preparation method of tryptanthrin compound and new application of tryptanthrin compound in preparing indoleamine-2,3-dioxygenase (IDO) inhibitor |
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2015
- 2015-06-18 CN CN201510338986.8A patent/CN105153148A/en active Pending
Patent Citations (2)
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| CN1594307A (en) * | 2004-06-25 | 2005-03-16 | 陕西师范大学 | Extraction separation for Nepal irid isoflavone from kudzu, process for preparing sulfonated compounds thereof , and their pharmaceutical uses |
| CN102579452A (en) * | 2012-01-20 | 2012-07-18 | 辽宁思百得医药科技有限公司 | Preparation method of tryptanthrin compound and new application of tryptanthrin compound in preparing indoleamine-2,3-dioxygenase (IDO) inhibitor |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106317084A (en) * | 2016-08-19 | 2017-01-11 | 玉林师范学院 | Tryptanthrin copper complex with antitumor activity and synthetic method thereof |
| CN106317084B (en) * | 2016-08-19 | 2018-12-21 | 玉林师范学院 | A kind of couroupitine A copper complex with anti-tumor activity and its synthetic method |
| WO2022053964A1 (en) * | 2020-09-11 | 2022-03-17 | Universidade De Coimbra | Water-soluble trypthantrin derivatives for redox flow batteries |
| CN115124531A (en) * | 2022-08-09 | 2022-09-30 | 贵州大学 | 4-azatryptanthrin aromatic thioether derivatives, and preparation method and application thereof |
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Application publication date: 20151216 |