CN114933601A - Tetrandrine derivative and preparation method and application thereof - Google Patents
Tetrandrine derivative and preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses three novel tetrandrine derivatives which are respectively 5-bromo-tetrandrine phosphate, 5-bromo-tetrandrine taurate and 5-bromo-tetrandrine ascorbate; the invention also discloses a preparation method of the compound, which comprises the steps of firstly preparing a 5-bromo-tetrandrine intermediate, and then reacting the intermediate with corresponding acid to generate salt; and their application in preparing antitumor medicine, especially liver cancer and gastric cancer.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a novel tetrandrine derivative, a preparation method of the tetrandrine derivative, and application of the tetrandrine derivative in preparation of antitumor drugs.
Background
Tetrandrine is a bisbenzylisoquinoline alkaloid, is a main active ingredient of the traditional Chinese medicine tetrandrine, has the effects of diminishing inflammation, easing pain, reducing blood pressure, resisting hypoxic pulmonary hypertension, resisting inflammation and the like, and is clinically used for treating diseases such as hypertension, arrhythmia, pulmonary fibrosis and the like. At present, the research reports about tetrandrine at home and abroad mainly focus on the aspects of clinical treatment of silicosis, anti-tumor mechanism, radiotherapy and chemotherapy sensitivity enhancement, reversal of multidrug resistance, extraction and separation and the like. The natural product has good anti-tumor activity, and the modification and reconstruction of the chemical structure of the natural product to obtain the medicine with low toxicity and more remarkable anti-tumor effect is an important way for developing new medicines. The modification of 5-position of tetrandrine has been shown to improve its biological activity, for example, patent application CN103635475A discloses tetrandrine derivatives with 5-position carbon substitution, its preparation method and application, specifically discloses the introduction of-O-CH at 5-position of tetrandrine 2 -、-S-CH 2 -、-N-CH 2 -、-COO-CH 2 And tetrandrine derivatives obtained from such substituents, and the like, and find therapeutic applications in diseases such as leukemia, multiple myeloma, lymphoma, liver cancer, stomach cancer, breast cancer, cholangiocellular carcinoma, pancreatic cancer, lung cancer, colorectal cancer, osteosarcoma, melanoma, human cervical cancer, glioma, nasopharyngeal cancer, laryngeal cancer, esophageal cancer, middle ear tumor, prostate cancer, and the like. Similarly, CN112480140A discloses a C5-substituted tetrandrine derivative and a preparation method thereof, wherein the 5-substituted group is cyano, aldehyde, substituted amino, etc. Therefore, the structural modification of the tetrandrine at present mainly focuses on modifying the 5-position of the tetrandrine to introduce amino, alkynyl and aromatic groups, and improves the anti-tumor and hepatic fibrosis activities to a certain extent.
There is still a need in the art for more novel compounds with better antitumor activity.
Disclosure of Invention
The inventor takes tetrandrine as a lead compound, carries out 5-position bromine substitution at low temperature to generate an intermediate 5-bromotetrandrine, then generates a new compound by the reaction of the intermediate 5-bromotetrandrine and acid, and proves that the anti-tumor activity of the new compound is superior to that of the tetrandrine lead compound through determination by an MTT method, thereby completing the invention.
Accordingly, in one aspect, the present invention provides a tetrandrine derivative selected from any one of 5-bromo-tetrandrine phosphate, 5-bromo-tetrandrine taurate, and 5-bromo-tetrandrine ascorbate.
In another aspect, the present invention provides a pharmaceutical composition comprising 5-bromo-tetrandrine phosphate, 5-bromo-tetrandrine taurate, or 5-bromo-tetrandrine ascorbate as an active compound, and a pharmaceutically acceptable adjuvant.
Further, the adjuvants include diluents, excipients, disintegrants, preservatives, solvents, thickeners, solubilizers, fillers, binders, humectants, absorption enhancers, surfactants, lubricants, stabilizers, flavoring agents, sweeteners, pigments, etc., which are known in the pharmaceutical field.
Further, the pharmaceutical composition is in the form of tablets, capsules, powders, granules, pills, solutions, suspensions, syrups, buccal tablets, sublingual tablets, injections, ointments, suppositories, inhalants and the like.
In another aspect, the present invention provides a method for preparing the tetrandrine derivative, which comprises the following steps:
step 1: dissolving tetrandrine in solvent, slowly adding bromine glacial acetic acid solution in ice bath, adding ice water mixture after reaction, quenching, adjusting pH to neutral or alkalescence, extracting with chloroform, mixing organic phases, drying, and purifying to obtain 5-bromotetrandrine;
and 2, step: dissolving 5-bromotetrandrine and phosphoric acid, taurine or ascorbic acid in solvent, and stirring at room temperature to obtain solid compound.
Further, the solvent used in step 1 is a mixture of trifluoroacetic acid and water, preferably in a ratio of 2:1 to 1: 1.
Further, step 1, purifying 5-bromotetrandrine by chromatography, preferably with chloroform: methanol 20: 1 as eluent.
Further, in the step 2, when the 5-bromotetrandrine reacts with the phosphoric acid, dichloromethane is used as a solvent; when the 5-bromotetrandrine reacts with taurine or ascorbic acid, a mixed solution of ethanol and dichloromethane is used as a solvent, and the ratio of the ethanol to the dichloromethane is preferably 3: 1-5: 1.
In another aspect, the invention provides the use of the tetrandrine derivative in preparing an anti-tumor medicament, wherein the tumor is liver cancer or gastric cancer.
Advantageous effects
In the preparation process of the 5-bromotetrandrine, the glacial acetic acid solution of bromine is used for reaction, and compared with the tribromopyridinium salt selected in the prior art, the reaction conditions are milder and safer, and the reaction time is short; meanwhile, the use of harmful solvents is reduced; and the reaction yield is improved, and the yield of the 5-bromotetrandrine is up to 85 percent.
In addition, MTT method determination proves that the tetrandrine derivative has better inhibition effect on human hepatoma cell strain HepG2 and human gastric cancer cell strain BGC-823 than tetrandrine lead compound, and provides reference for further seeking more effective anti-tumor compound through structure optimization.
Drawings
FIG. 1 is a NMR spectrum of 5-bromo-tetrandrine.
FIG. 2 is a NMR carbon spectrum of 5-bromo-tetrandrine.
FIG. 3 is a NMR spectrum of 5-bromo-tetrandrine phosphate.
FIG. 4 is a NMR carbon spectrum of 5-bromo-tetrandrine phosphate.
FIG. 5 is a NMR chart of 5-bromo-tetrandrine taurate.
FIG. 6 is a NMR carbon spectrum of 5-bromo-tetrandrine taurate.
FIG. 7 is the NMR spectrum of 5-bromo-tetrandrine ascorbate.
FIG. 8 is a NMR carbon spectrum of 5-bromo-tetrandrine ascorbate.
Detailed description of the preferred embodiments
The technical scheme of the invention is explained in detail by combining the specific embodiment; the reagent used in the present invention can be obtained by purchase without specific indication.
Instruments and reagents
Nuclear magnetic resonance apparatus (Bruker AM400 nuclear magnetic resonance apparatus); RAD-680 type microplate reader (Bio-Rad, USA); electronic analytical balance (edm weighing apparatus (wuhan) ltd); a low-temperature cooling liquid circulation pump (zheng zhou great wall science and trade ltd); rotary evaporator (N-1100D-W Tokyo, Japan); a constant temperature magnetic stirrer (Shanghai Spira instruments Co., Ltd., model B11-3); cell culture chambers (Thermo Fisher, usa); inverted biomicroscopes (Leica Microsystems CMS Gmb H).
Tetrandrine (HPLC ≥ 98% fibrate reagent, Inc.); human hepatoma cell line HepG2, human gastric cancer cell line BGC-823 (provided by Shanghai pharmaceutical research institute of Chinese academy of sciences); DMEM medium (Gibco); all other reagents were commercially available analytical grade.
Example 1: synthesis of 5-bromo-tetrandrine
Tetrandrine (compound 1)207mg (about 0.33mmoL) was added to a three-necked flask (25mL) containing trifluoroacetic acid (about 1mL) and water (about 0.5mL), and after completely dissolving it with stirring, under ice-water bath conditions, 0.35mL (1.1mol/L) of a solution of bromine in glacial acetic acid was slowly added and the reaction was continued for 45min, followed by addition of 20mL of ice-water mixture to quench it. Then the pH of the solution was adjusted to neutral or weakly alkaline with ammonia, chloroform was extracted three times, the organic phase was dried over anhydrous sodium sulfate, filtered, and the organic solvent was recovered to give a crude product as a pale yellow oil, which was purified with chloroform: methanol 20: 1 as eluent, to obtain 200mg of 5-bromo-tetrandrine (compound 2), 85% yield.
1 H NMR(400MHz,DMSO)δ,7.16(dd,J＝8.1,2.5Hz,2H),6.92-6.85(m,2H),6.82(dd,J＝8.2,2.3Hz,1H),6.59(d,J＝1.4Hz,1H),6.55(s,1H),6.34(dd,J＝8.4,2.0Hz,1H),6.06(s,1H),5.44(s,1H),3.95-3.93(m,1H),3.92(s,3H),3.48(d,J＝4.8Hz,1H),3.44(s,3H),3.42(s,3H),3.41-3.33(m,2H),3.30(d,J＝5.5Hz,2H),3.24(s,3H),3.07-2.70(m,6H),2.64(s,3H),2.55-2.46(m,1H),2.30(s,3H)；
13 C NMR(100MHz,DMSO)δ153.70,149.32,,148.33,147.01,143.77,136.94,134.68,132.54,130.07,129.83,129.62,128.28,128.00,127.84,126.84,126.69,126.02,122.77,121.87,121.84,120.23,116.05,112.62,111.46,66.20,63.75,61.78,60.59,60.06,56.04,55.62,45.15,44.61,42.54,42.08,37.88,29.60,25.24,21.18。
Example 2: synthesis of 5-bromo-tetrandrine phosphate
Dissolving 5-bromo-tetrandrine (compound 2, 0.1mmol, 70mg) in 2ml dichloromethane, adding 20 μ L1N phosphoric acid aqueous solution (1 equivalent) with a micro-syringe, stirring at room temperature for 12 hours, detecting by TLC that the raw material reaction is finished, evaporating dichloromethane under reduced pressure to obtain solid compound 75.6mg, namely 5-bromo-tetrandrine phosphate (compound 3).
1 H NMR(400MHz,DMSO)δ,7.14(dd,J＝8.1,2.5Hz,2H),6.93-6.86(m,2H),6.85(dd,J＝8.2,2.3Hz,1H),6.57(d,J＝1.4Hz,1H),6.54(s,1H),6.32(dd,J＝8.4,2.0Hz,1H),6.04(s,1H),5.43(s,1H),3.96-3.92(m,1H),3.90(s,3H),3.46(d,J＝4.8Hz,1H),3.43(s,3H),3.42(s,3H),3.40-3.30(m,2H),3.29(d,J＝5.5Hz,2H),3.21(s,3H),3.06-2.72(m,6H),2.65(s,3H),2.55-2.46(m,1H),2.28(s,3H)；
13 C NMR(100MHz,DMSO)δ154.70,148.32,,147.33,145.01,142.77,137.95,134.58,132.34,130.01,129.73,129.52,128.08,128.01,127.83,126.74,126.60,125.02,122.07,121.17,121.74,119.23,115.05,112.02,110.46,65.20,64.75,60.68,60.09,58.06,56.04,54.62,45.13,44.21,42.04,41.08,34.88,28.60,24.24,19.18。
Example 3: synthesis of 5-bromo-tetrandrine taurate
Dissolving 5-bromo-tetrandrine (compound 2, 0.1mmol, 70mg) and taurine (2 equivalent, 0.2mmol, 38mg) in 2ml of a mixed solution (3:1) of ethanol and dichloromethane, stirring at room temperature for 24h to obtain a white solid, and filtering to obtain a yellow solid compound 77.3mg, namely 5-bromo-tetrandrine taurate (compound 4).
1 H NMR(400MHz,DMSO)δ,7.17(dd,J＝8.1,2.5Hz,2H),6.93-6.86(m,2H),6.83(dd,J＝8.2,2.3Hz,1H),6.60(d,J＝1.4Hz,1H),6.58(s,1H),6.44(dd,J＝8.4,2.0Hz,1H),6.06(s,1H),5.54(s,1H),3.96-3.94(m,1H),3.93(s,3H),3.50(d,J＝4.8Hz,1H),3.47(s,3H),3.44(s,3H),3.41-3.33(m,2H),3.29(d,J＝7.1Hz,2H),3.27(d,J＝5.5Hz,2H),3.23(s,3H),3.09(m,2H)3.07-2.70(m,6H),2.69(s,3H),2.55-2.46(m,1H),2.50(s,3H)；
13 C NMR(100MHz,DMSO)δ154.70,148.32,147.33,146.03,144.78,137.96,135.78,133.58,132.02,128.73,128.62,128.08,128.00,127.84,126.74,126.60,124.02,122.07,121.87,121.84,118.23,113.05,112.62,111.06,65.20,62.75,60.78,60.59,60.06,56.04,55.62,50.50,45.15,44.51,42.34,41.08,37.08,34.12,30.60,24.24,23.48。
Example 4: synthesis of 5-bromo-tetrandrine ascorbate
5-bromo-tetrandrine (compound 2, 0.1mmol, 70mg) and ascorbic acid (2 equiv., 0.2mmol, 35mg) were dissolved in 2ml of a mixed solution (3:1) of ethanol and dichloromethane, stirred at room temperature for 24h to form a yellow solid, and filtered to obtain 73.5mg of the yellow solid, which was 5-bromo-tetrandrine ascorbate (compound 5).
1 H NMR(400MHz,DMSO)δ,10.68(s,2H),9.34(s,1H),7.16(dd,J＝8.1,2.5Hz,2H),6.95-6.86(m,2H),6.84(dd,J＝8.2,2.3Hz,1H),6.67(d,J＝1.4Hz,1H),6.53(s,1H),6.31(dd,J＝8.4,2.0Hz,1H),6.07(s,1H),5.49(s,1H),4.82(s,1H),4.22,5.49(m,1H),3.96-3.92(m,1H),3.90(s,3H),3.59(m,2H),3.48(d,J＝4.8Hz,1H),3.42(s,3H),3.42(s,3H),3.41-3.33(m,2H),3.27(d,J＝5.5Hz,2H),3.24(s,3H),3.07-2.71(m,6H),2.65(s,3H),2.54-2.45(m,1H),2.29(s,3H)；
13 C NMR(100MHz,DMSO)δ170.41,156.3,155.60,149.32,,146.33,144.01,141.77,138.95,136.58,131.34,130.01,129.63,129.22,128.08,128.01,127.43,126.14,125.60,125.02,121.57,121.17,120.44,119.23,118.52,114.05,112.02,110.76,77.15,69.63,69.00,65.20,64.75,63.6,62.38,61.09,59.06,55.05,54.62,46.13,45.21,43.04,43.09,35.88,29.41,23.25,21.34。
Experimental example 1: in vitro antitumor Activity Studies
Method
DMSO solutions of the compounds 2 to 5 synthesized in examples 1 to 4 and tetrandrine (control, compound 1) at concentrations of 1000. mu.g/mL, 500. mu.g/mL, 250. mu.g/mL, 125. mu.g/mL, 10. mu.g/mL, and 1. mu.g/mL were prepared, respectively, for use.
The prepared samples and controls were added to flat bottom 96-well plates at 10 μ L per well for two parallel tests. Taking cells (human liver cancer cell line HepG2, human gastric cancer cell line BGC-823) in logarithmic growth phase, pancreatin digesting and washing the cells, suspending the cells in DMEM medium containing 10% serum, and adjusting the cell suspension density to 2 x 10 5 cells/mL. In flat bottom 96 well plates, 90. mu.L of cells were added to each well, 90. mu.L of medium was added to the last well, and 5% CO was added at 37 ℃ 2 Culturing in a cell culture box for 48 h. Mu.l of 5mg/mL MTT solution was added to each well and incubation continued in the incubator for 3-4 h. 100 mul of dissolving solution is added into each hole, and the temperature is kept in the incubator overnight to ensure that the generated formazan crystals are fully dissolved. The 570nm light absorption was measured. Calculating IC of the sample to human hepatoma cell line HepG2 and human gastric cancer cell line BGC-823 50 。
The experiment was repeated 3 times under the same conditions, the final result was expressed as Mean ± SD, and the results of the inhibitory activities of the compounds 1 to 5 on the human hepatoma cell line HepG2 and the human gastric carcinoma cell line BGC-823 are shown in table 1 below.
TABLE 1 IC for inhibition of Hep G2, BGC-823 by compounds 1-5 50 Value (Unit ug/mL)
| Compound (I) | Name(s) | HepG2 | BGC-823 |
| 1 | Tetrandrine | 2.43 | 0.45 |
| 2 | 5-bromo-tetrandrine | — | 0.38 |
| 3 | 5-bromo-tetrandrine phosphate | 1.32 | 0.49 |
| 4 | 5-bromo-tetrandrine taurate | 1.43 | 0.55 |
| 5 | 5-bromo-tetrandrine ascorbate | 2.53 | 0.43 |
The primary screening of 5 samples for in vitro antitumor activity by the MTT method showed that: except that compound 2 had no activity on HepG2 cells, the remaining compounds all had inhibitory effects on HepG2 cells and BGC-823 cells. In particular, the inhibition effect of the compounds 3 and 4 on HepG2 cells is obviously better than that of tetrandrine, and the inhibition effect of the compound 5 on BGC-823 cells is better than that of tetrandrine.
Claims (9)
1. A tetrandrine derivative is selected from any one of 5-bromo-tetrandrine phosphate, 5-bromo-tetrandrine taurate and 5-bromo-tetrandrine ascorbate.
2. A pharmaceutical composition comprising the tetrandrine derivative of claim 1 as an active compound, and a pharmaceutically acceptable adjuvant.
3. The pharmaceutical composition of claim 2, wherein the excipients comprise diluents, excipients, disintegrants, preservatives, solvents, thickeners, solubilizers, fillers, binders, wetting agents, absorption enhancers, surfactants, lubricants, stabilizers, flavoring agents, sweeteners, and pigments known in the pharmaceutical art.
4. The pharmaceutical composition according to claim 2, wherein the pharmaceutical composition is in the form of a tablet, capsule, powder, granule, pill, solution, suspension, syrup, buccal tablet, sublingual tablet, injection, ointment, suppository or inhalant.
5. The method for preparing tetrandrine derivatives according to claim 1, which comprises the steps of:
step 1: dissolving tetrandrine in solvent, slowly adding bromine glacial acetic acid solution in ice bath, adding ice water mixture after reaction to quench reaction, adjusting pH to neutral or weakly alkaline, extracting with chloroform, mixing organic phases, drying, and purifying to obtain 5-bromotetrandrine;
and 2, step: dissolving 5-bromotetrandrine and phosphoric acid, taurine or ascorbic acid in solvent, and stirring at room temperature to obtain solid compound.
6. The process according to claim 5, wherein the solvent used in step 1 is a mixture of trifluoroacetic acid and water, preferably in a ratio of trifluoroacetic acid to water of from 2:1 to 1: 1.
7. The preparation method according to claim 5, wherein the step 1 is performed by purifying 5-bromotetrandrine by using a chromatographic column separation method, preferably using chloroform: methanol 20: 1 as eluent.
8. The preparation method according to claim 5, wherein in the step 2, when the 5-bromotetrandrine is reacted with the phosphoric acid, dichloromethane is used as a solvent; when the 5-bromotetrandrine reacts with taurine or ascorbic acid, a mixed solution of ethanol and dichloromethane is used as a solvent, and the ratio of the ethanol to the dichloromethane is preferably 3: 1-5: 1.
9. The use of the tetrandrine derivative according to claim 1 in preparing an antitumor agent, wherein the tumor is liver cancer or gastric cancer.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102302503A (en) * | 2011-09-09 | 2012-01-04 | 东南大学 | Preparation method for daunorubicin and 5-bromotetrandrine co-carried magnetic ferrosoferric oxide nanoparticles |
| CN103772405A (en) * | 2012-10-25 | 2014-05-07 | 上海医药工业研究院 | Dibenzyl tetrahydroisoquinoline alkaloid as well as preparation method and application thereof |
| CN112480140A (en) * | 2020-12-28 | 2021-03-12 | 杭州医学院 | C5-substituted tetrandrine derivative and preparation method and application thereof |
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- 2022-06-14 CN CN202210670160.1A patent/CN114933601A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102302503A (en) * | 2011-09-09 | 2012-01-04 | 东南大学 | Preparation method for daunorubicin and 5-bromotetrandrine co-carried magnetic ferrosoferric oxide nanoparticles |
| CN103772405A (en) * | 2012-10-25 | 2014-05-07 | 上海医药工业研究院 | Dibenzyl tetrahydroisoquinoline alkaloid as well as preparation method and application thereof |
| CN112480140A (en) * | 2020-12-28 | 2021-03-12 | 杭州医学院 | C5-substituted tetrandrine derivative and preparation method and application thereof |
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