CN114133390A - Harmine derivative and preparation method and application thereof - Google Patents
Harmine derivative and preparation method and application thereof Download PDFInfo
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- CN114133390A CN114133390A CN202111560905.0A CN202111560905A CN114133390A CN 114133390 A CN114133390 A CN 114133390A CN 202111560905 A CN202111560905 A CN 202111560905A CN 114133390 A CN114133390 A CN 114133390A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- BXNJHAXVSOCGBA-UHFFFAOYSA-N Harmine Chemical compound N1=CC=C2C3=CC=C(OC)C=C3NC2=C1C BXNJHAXVSOCGBA-UHFFFAOYSA-N 0.000 claims abstract description 64
- RERZNCLIYCABFS-UHFFFAOYSA-N Harmaline hydrochloride Natural products C1CN=C(C)C2=C1C1=CC=C(OC)C=C1N2 RERZNCLIYCABFS-UHFFFAOYSA-N 0.000 claims abstract description 26
- VJHLDRVYTQNASM-UHFFFAOYSA-N harmine Natural products CC1=CN=CC=2NC3=CC(=CC=C3C=21)OC VJHLDRVYTQNASM-UHFFFAOYSA-N 0.000 claims abstract description 26
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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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a harmine derivative and a preparation method and application thereof, belonging to the field of pharmaceutical chemistry. The invention combines a new NO donor-harmine derivative by modifying the structure of Harmine (HM) and an NO donor. The NO donor-harmine derivative can release a large amount of NO in tumor cells, and the antiproliferative activity selectively in the tumor cells is obviously enhanced along with the increase of the NO release, and the influence on normal cells is small. Compared with the raw material medicine HM and the NO donor, the new compound NO donor-harmine derivative has obviously enhanced anticancer cell proliferation effect.
Description
Technical Field
The invention relates to the field of pharmaceutical chemistry, in particular to a harmine derivative and a preparation method and application thereof.
Background
Harmine (HM), also known as Harmine or hamming, is a beta-carboline alkaloid which is initially isolated from the plant Peganum harmala L, which contains a variety of alkaloids, the main active ingredient being Harmine which has a wide pharmacological action on the cardiovascular system, respiratory system and central nervous system. In addition, harmine has antibacterial, antitumor, analgesic, antiinflammatory, antibacterial, antiviral, and anthelmintic effects. However, the strong neurotoxicity of harmine affects its clinical application.
Nitric oxide donors refer to compounds that release an amount of nitric oxide by enzymatic or non-enzymatic action. Nitric Oxide (NO) plays an important role in various physiological and pathological processes in vivo, such as participation in tumorigenesis and metastasis, maintenance of the dynamic balance of microvessels and macrovessels, participation in nerve signal transduction, and modulation of immune inflammation; in the aspect of tumor resistance, NO promotes tumor angiogenesis at low concentration, and inhibits tumor cells through direct or indirect action at high concentration; NO combines with oxygen free radical to generate a series of active nitrogen, and destroys protein, nucleic acid and other components in tumor cells to play an indirect role. NO donors now found to have antitumor activity include furazan nitroxides, nitrates, azodialenium salts, oximes, guanidines, NO-metal complexes, sydnonimines, hydroxylamines, N-hydroxyureas, S-nitrosothiols, of which furazan nitroxides are an important class of NO donors, have thermal stability, are capable of generating high levels of nitric oxide, and a variety of promising nitric oxide-releasing derivatives based on furazan oxide have been investigated as anticancer candidates. At present, NO relevant research report for combining the harmine derivative and the NO donor is found.
Disclosure of Invention
The invention aims to provide a harmine derivative, a preparation method and application thereof, broadens the variety of the harmine derivative and improves the antitumor activity of the harmine derivative.
In order to achieve the purpose, the invention provides the following scheme:
in one technical scheme of the invention, the structural general formula of the harmine derivative is shown as formula I:
R1is NHC (CH)3)COOCH3、NHC(CH3)2COOCH3Or O (CH)2)nON2SO2Ph, wherein n is 3 or 4.
In the second technical scheme of the invention, the preparation method of the harmine derivative is that R is1Is NHC (CH)3)COOCH3Or NHC (CH)3)2COOCH3The preparation method comprises the following steps: carrying out structural modification on harmine to obtain the harmine derivative;
when R is1Is O (CH)2)nON2SO2Ph, the preparation method comprises the following steps: structurally modifying the harmine to obtain an intermediate product, and combining the intermediate product with a nitric oxide donor to obtain the harmine derivative.
Further, the intermediate product has a structural formula shown in formula II:
further, the NO donor includes furazan nitroxides, azodialenium salts, organic nitrates, metal-NO complexes, sildenone imines, N-hydroxyureas, and hydroxamic acids.
Further, the nitric oxide donor is furazan nitrogen oxides.
In the third technical scheme of the invention, the harmine derivative is applied to the preparation of antitumor drugs.
Further, when R is1Is NHC (CH)3)COOCH3When the anti-tumor drug is a drug for resisting human breast cancer MCF-7.
Further, when R is1Is NHC (CH)3)2COOCH3The anti-tumor drug is a drug for resisting human gastric cancer cells BGC and/or human breast cancer MCF-7.
Further, when R is1Is O (CH)2)nON2SO2At Ph, the antitumor drugs are anti-human liver cancer cell HepG2, anti-human gastric cancer cell BGC, anti-human breast cancer MCF-7 and/or anti-human lung cancer cell A549.
The invention discloses the following technical effects:
(1) the invention takes harmine as raw material, and the harmine is modified in structure and combined with NO donor to form new harmine derivative, so as to improve the anti-tumor effect without neurotoxicity. All channels of structure1H-NMR and MS confirmation. And a series of synthesized harmine derivatives are subjected to preliminary in vitro antitumor activity determination by adopting a CCK-8 method.
(2) The invention synthesizes a new harmine derivative III for the first time6a、Ⅲ6b、Ⅳ3aAnd IV3bThe harmine derivative III is verified by cell experiments6aFor tumor cells MCF-7, III6bHas certain antiproliferative effect on tumor cells BGC, A549 and MCF-7; harmine derivative IV3aAnd IV3bHas certain antiproliferative effect on tumor cells HepG2, BGC, A549 and MCF-7, wherein IV3bThe antitumor activity against HepG2 was best (IC)50=1.79±0.16μM)。
(3) The invention widens the variety of harmine derivatives, and provides a feasible way for improving the antitumor effect of harmine derivatives or NO donors, the harmine derivatives and the NO donors after structure modification are combined to form a new NO donor-harmine derivative, so that a large amount of NO is released in tumor cells, and the high-concentration NO and the harmine derivatives can play a synergistic antitumor role, thereby improving the antitumor effect of the harmine as the raw material drug to a great extent. The harmine derivative prepared by the invention releases NO in normal cells, and has little influence on normal cells.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings needed in the embodiments will be briefly described below, and it is obvious that the drawings in the following description are only some embodiments of the present invention, and it is obvious for those skilled in the art to obtain other drawings without creative efforts.
FIG. 1 shows a harmine derivative IV as NO donor prepared in example 13bThe condition of releasing NO in human hepatoma cells HepG2 and human normal hepatocytes LO 2;
FIG. 2 shows the harmine derivative IV as NO donor prepared in example 13bThe condition of releasing NO in human hepatoma cell HepG2 and human normal hepatocyte LO2 under different concentration conditions;
FIG. 3 shows the harmine derivative IV as NO donor prepared in example 13bThe condition of releasing NO in human hepatoma cell HepG2 and human normal hepatocyte LO2 cells under different reaction times.
Detailed Description
Reference will now be made in detail to various exemplary embodiments of the invention, the detailed description should not be construed as limiting the invention but as a more detailed description of certain aspects, features and embodiments of the invention.
It is to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. Further, for numerical ranges in this disclosure, it is understood that each intervening value, between the upper and lower limit of that range, is also specifically disclosed. Every smaller range between any stated value or intervening value in a stated range and any other stated or intervening value in a stated range is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included or excluded in the range.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although only preferred methods and materials are described herein, any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention. All documents mentioned in this specification are incorporated by reference herein for the purpose of disclosing and describing the methods and/or materials associated with the documents. In case of conflict with any incorporated document, the present specification will control.
It will be apparent to those skilled in the art that various modifications and variations can be made in the specific embodiments of the present disclosure without departing from the scope or spirit of the disclosure. Other embodiments will be apparent to those skilled in the art from consideration of the specification. The description and examples are intended to be illustrative only.
As used herein, the terms "comprising," "including," "having," "containing," and the like are open-ended terms that mean including, but not limited to.
Example 1
NO donor-harmine derivative IV3a、Ⅳ3bThe specific synthetic route is shown as follows:
step 1, adding harmine HM (0.3g, 1.41mmol) and 9mL dimethylformamide DMF into a 50mL three-necked bottle, stirring in an ice bath to be clear under the protection of nitrogen, adding 60% NaH (0.07g, 2.82mmol) and stirring for 0.5h in the ice bath state, dissolving 1-bromo-3-phenylpropane (2.12mmol) into a small amount of DMF (diluting 1-bromo-3-phenylpropane, avoiding too high concentration and violent reaction in the adding process), adding into the three-necked bottle, reacting for 0.5h in the ice bath state, removing the ice bath, stirring for 2h at room temperature, tracking and detecting by TLC, extracting a reaction solution with ethyl acetate and water after complete reaction, concentrating under reduced pressure, purifying by silica gel column chromatography to obtain an off-white solid, namely an intermediate product II1。
Step 4, taking an intermediate product II3Dissolving (0.5g, 1.24mmol) with EA, adding benzyl bromide (2.1g, 12.4mmol), refluxing at 90 deg.C for 12h, detecting by TLC, cooling to precipitate, vacuum filtering, washing with ethyl acetate EA for several times to obtain white solid, and drying to obtain intermediate product II4And directly putting the mixture into the next step without purification.
Step 5, taking an intermediate product II4(0.3g, 0.6mmol), lithium hydroxide (0.07g, 3.0mmol), methanol (3 mL), water (6 mL), Tetrahydrofuran (THF) (9 mL) was added and stirred at room temperature for 2 h. TLC tracking detection, after the reaction is finished, adding dilute hydrochloric acid to regulate pH to 4-5, and spin-drying on a rotary evaporator to obtain an intermediate product II5。
Step 6, taking an intermediate product II5(0.2g, 0.58mmol) was dissolved in 5-6mL of DMF and Et was added3N, TBTU (triethylamine; O-benzotriazole-N, N, N ', N' -tetramethyluronium tetrafluoroborate) was added followed by (0.12g, 0.58mmol) IV2The compound (4- (4-hydroxybutoxy) -3- (phenylsulfonyl) -1,2, 5-oxadiazole 2-oxide, when n-3 is marked as IV2a4- (3-hydroxypropoxy) -3- (benzenesulfonyl) -1,2, 5-oxadiazole 2-oxide, when n ═ 4, is labeled as iv2b) Reacting at room temperature for 3h, and purifying by a column to obtain IV3。
When IV2When n is 3, the NO donor-harmine derivative IV obtained by the reaction3Symbol IV3a: off-white solid, 100mg, yield 70%.1H NMR(600MHz,DMSO-d6)δ8.81(d,J=6.5Hz,1H),8.62(d,J=6.5Hz,1H),8.39(d,J=8.8Hz,1H),8.01-7.97(m,2H),7.90-7.86(m,1H),7.75-7.70(m,2H),7.44-7.38(m,4H),7.23(t,J=7.4Hz,2H),7.19-7.13(m,5H),6.04(s,2H),5.12(s,2H),4.67(d,J=11.1Hz,2H),4.37(t,J=6.1Hz,2H),4.30(t,J=6.2Hz,2H),3.52(s,1H),2.95(s,2H),2.68(t,J=7.8Hz,2H),1.15(s,3H)。
When IV2When n is 4, the NO donor-harmine derivative IV obtained by the reaction3Symbol IV3b: yellow-white solid, 80mg, yield 60%.1H NMR(600MHz,DMSO-d6)δ8.80(s,1H),8.63(s,1H),8.42(s,1H),7.99(s,2H),7.88(d,J=1.5Hz,2H),7.81-7.64(m,2H),7.50-7.31(m,4H),7.31-7.06(m,8H),6.03(s,2H),5.11(s,2H),4.80-4.61(m,2H),4.38(d,J=6.1Hz,2H),4.24(t,J=6.3Hz,2H),3.35(s,2H),2.96(s,3H),2.75-2.62(m,2H),2.50(s,2H),1.89-1.65(m,4H)。
The specific structural formula is as follows:
example 2
Harmine derivative III6aAnd III6bThe specific synthetic route is shown as follows:
the synthesis of intermediate products II 1, II 2, II 3 in steps 1,2, 3 was the same as in example 1.
Step 4, intermediate product II3(0.3g, 0.72mmol) was mixed with lithium hydroxide (0.09g, 3.6mmol), methanol (6 mL), water (12 mL) and THF (18 mL) and stirred at room temperature for 2 h. After the reaction shown by TLC is completed, adding dilute hydrochloric acid to regulate pH to 4-5, and spin-drying on a rotary evaporator to obtain intermediate product III4。
Step 5, taking an intermediate product III4(0.05g, 0.14mmol), dissolved in 3-4mL of DMF, and then 2- (7-azabenzotrisTriazole) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU) (0.1g, 0.27mmol), N, N-Diisopropylethylamine (DIPEA) (0.04g, 0.3mmol), stirring at room temperature for 10min, adding L-amino acid hydrochloride (0.16mmol), continuing to react at room temperature for 30min, tracking and detecting by TLC, extracting the reaction solution with ethyl acetate and water after the reaction is completed, and concentrating under reduced pressure to obtain white solid, namely an intermediate product III5. Purifying by column chromatography to obtain intermediate product III5aAnd III5b. The specific structural formula is as follows:
step 6, respectively taking a compound III5aAnd III5bDissolving (0.3g, 0.54mmol) with ethyl acetate, adding benzyl bromide (1.0g, 5.4mmol), refluxing at 90 deg.C for 12 hr, detecting by TLC, cooling to precipitate, vacuum filtering, washing with ethyl acetate, and drying to obtain white-like solid harmine derivative III6aAnd light yellow solid harmine derivative III6bThe specific structural formula is as follows:
harmine derivative III6a: off-white solid, 100mg, yield 95%.1H NMR(300MHz,DMSO-d6)δ8.80(d,J=6.6Hz,1H),8.67(d,J=12.1Hz,2H),8.43(d,J=8.8Hz,1H),7.40(t,J=7.3Hz,4H),7.19(dt,J=13.2,6.9Hz,9H),6.03(s,2H),4.81(s,2H),4.74-4.61(m,2H),4.48-4.34(m,1H),3.63(s,3H),2.95(s,3H),2.69(t,J=7.6Hz,2H),2.15–2.02(m,2H),1.36(d,J=7.3Hz,2H)。
Harmine derivative III6b: pale yellow solid, 96mg, yield 93%.1HNMR(300MHz,DMSO-d6)δ8.79(d,J=1.9Hz,1H),8.63(d,J=6.5Hz,1H),8.45(dd,J=17.9,9.2Hz,2H),7.47-7.29(m,4H),7.17(q,J=7.5,6.9Hz,8H),6.01(s,2H),4.88(s,2H),4.75-4.59(m,2H),3.64(s,3H),2.94(s,3H),2.68(t,J=7.6Hz,2H),2.13-2.04(m,2H),0.96-0.80(m,6H)。
Experimental example 1
Verification of harmine derivative II4,Ⅱ5,Ⅲ6a,Ⅲ6b,Ⅳ3aAnd IV3bProliferation inhibiting activity on human tumor cells HepG2 (human liver cancer cell), BGC (human gastric cancer cell), A549 (human lung cancer cell), and MCF-7 (human breast cancer cell), and HM and Doxorubicin (DOX) are selected as control.
The method comprises the following specific steps:
the four tumor cells were placed at 37 ℃ and 5% CO2Culturing under the condition, digesting overgrown cells with pancreatin containing EDTA, placing into a 5ml centrifuge tube, and centrifuging at 1200rpm for 5min by a centrifuge. After the centrifugation, the supernatant was decanted off and diluted with 2ml of culture medium. Cells in logarithmic growth phase were grown at 1X 105cells/well were plated in 96-well plates with PBS around, 100. mu.L per well and plated. Putting into an incubator to incubate for 24 h. The method for carrying out gradient dilution on various harmine derivatives comprises the following steps: HM, II 4, II 5 are diluted from high concentration 2-fold gradient to 6.25 μ M at an initial concentration of 200 μ M, i.e. 6 concentration gradients of 200 μ M, 100 μ M, 50 μ M, 25 μ M, 12.5 μ M, 6.25 μ M; the same methods III 6a, III 6b, IV 3a, IV 3b and DOX were performed at an initial concentration of 50. mu.M, diluted from a high concentration 3-fold gradient to 0.21. mu.M, i.e., 50. mu.M, 16.67. mu.M, 5.56. mu.M, 1.85. mu.M, 0.62. mu.M, 0.21. mu.M for 6 concentrations. . Taking out the well-laid 96-well plate from the incubator after 24h, completely sucking out the culture medium in the well, adding the diluted samples into the 96-well plate with the concentration of 3 wells, respectively, wherein each well is 100 mu L, and then placing the 96-well plate into a container with the temperature of 37 ℃ and the concentration of 5% CO2And incubating the incubator for 72 h. Then the culture medium of the 96-well plate is sucked up, CCK-8 reagent (2- (2-methoxy-4-nitrobenzene) -3- (4-nitrobenzene) -5- (2, 4-disulfobenzene) -2H-tetrazole monosodium salt) is added, and then the mixture is put into an incubator to be cultured for 30min for detection. Calculating cell survival rate (%) (A)Sample (I)-ABlank space)/(ANegative of-ABlank space) OD was measured at 450nm with a microplate reader. Results are expressed as mean ± SD, IC is derived from inhibition by GraphPad Prism 6 fitting50. The results are shown in Table 1。
TABLE 1
As can be seen from Table 1, intermediate product II4、Ⅱ5IC for tumor cells HepG250Both are larger, indicating a weaker antiproliferative activity against these two tumor cells. And II4、Ⅱ5、Ⅲ6aShows stronger antiproliferative activity to BGC and MCF than HepG 2. III6bHas good antiproliferative activity (IC) on tumor cells BGC and MCF-750=3.83±0.60μM;IC504.48 ± 0.77 μ M). New NO donor-harmine derivatives IV formed by combining harmine derivatives (intermediate products) with NO donors3aAnd IV3bAlso shows strong antiproliferative activity of human cancer cells, wherein IV3bThe antitumor activity (IC) is strongest50=1.79±0.16μM)。
Experimental example 2
Testing of intermediate products II5NO donor material medicine IV2bNO donor-harmine derivative IV3bAnd JSK (O)2- (2, 4-dinitrophenyl) 1- [ (4-ethoxycarbonyl) piperazin-1-yl]Azo-1-onium-1, 2-diol) in human hepatoma cells HepG2 and human normal hepatocytes LO2, as follows: logarithmic growth phase cells HepG2 and LO2 at 1X 107cells/well were plated in 96 well PBS cells, 100. mu.L of each well was plated at 37 ℃ in 5% CO2And an incubator for 24 h. After the incubation was complete, the medium was removed by pipette and II was added at a concentration of 5. mu.M5、Ⅳ2b、Ⅳ3bAnd JSK added to LO2 and HepG2 cell culture plates, respectively, continuing at 37 ℃ with 5% CO2And incubating in an incubator for 72 h. After the incubation time was completed, the cell culture plate supernatant was removed, the cells were collected, 1.5ml of 5. mu.M DAF-FM DA (Diaminofluorescein-FM diacetate, NO fluorescent probe) was added thereto for 20min, and then the cells were washed 3 times with PBS buffer to remove excess dye. At an excitation/emission frequency of 495/515nAnd (5) measuring the fluorescence intensity by using a flow cytometer under the condition of m, and measuring the level of the NO in the cells. The results are shown in FIG. 1.
As can be seen from FIG. 1, intermediate product II is compared5NO donor drug IV2bAnd positive control drug JS-K, NO donor-harmine derivative IV3bThe NO level is highest in the human liver cancer cell HepG2, the generated effect is strongest, and the NO release amount of the substances is not obviously different in the human normal liver cell, which shows that the NO donor-harmine derivative IV3bThe inhibitor has the strongest effect on human liver cancer cells and less influence on normal liver cells, and the effect is better than that of the positive medicament JS-K.
Experimental example 3
Testing of NO Donor-Harmine derivatives at different concentrations IV3bThe conditions of releasing NO in human hepatoma cell HepG2 and human normal hepatocyte LO2 are as follows: logarithmic growth phase cells HepG2 and LO2 at 1X 107cells/well were plated in 96-well cell culture plates, 100. mu.L of sample was added to each well, plating was completed, and the plates were placed at 37 ℃ in 5% CO2Incubating in an incubator for 24 h. After the incubation was completed, the medium was removed by pipette and IV was added at a concentration of 1, 3, 9. mu.M3bAdd to LO2 and HepG2 cell culture plates, respectively, and continue at 37 ℃ with 5% CO2And incubating in an incubator for 72 h. After the incubation time was complete, the cell culture plate supernatant was removed, the cells were harvested and 1.5ml of 5. mu.M DAF-FM DA was added for 20min, followed by 3 washes with PBS buffer to remove excess dye. Intracellular NO levels were determined by measuring the fluorescence intensity using a flow cytometer at an excitation/emission frequency of 495/515 nm. The results are shown in FIG. 2.
As can be seen from fig. 2, the release of NO is dose-dependent in the different dose groups, with the high dose group acting most significantly. And different concentrations of NO donor-harmine derivative IV3bThe effect on human normal liver cell LO2 is not obvious compared with that in HepG2 cell, which shows that NO donor-harmine derivative IV3bThe effect of releasing NO in the human liver cancer cell HepG2 is strong and the effect on normal liver cells is small.
Experimental example 4
Testing of NO Donor-Harpagine derivative IV3bThe conditions of releasing NO in the human hepatoma cell HepG2 and the human normal hepatocyte LO2 under different reaction times are as follows: logarithmic growth phase cells HepG2 and LO2 at 1X 107cells/well were plated in 96 well PBS cells, 100. mu.L of each well was plated at 37 ℃ in 5% CO2Incubating in an incubator for 24 h. After the incubation was complete, the medium was removed with a pipette and IV was added at a concentration of 1. mu.M3bLO2 and HepG2 cell culture plates were added, and continued at 37 ℃ with 5% CO2Incubate 0h, 8h, 16h, 24h, 48h and 72h in the incubator respectively. After the incubation time was complete, the cell culture plate supernatant was removed, the cells were harvested and 1.5ml of 5. mu.M DAF-FM DA was added for 20min, followed by 3 washes with PBS buffer to remove excess dye. Intracellular NO levels were determined by measuring the fluorescence intensity using a flow cytometer at an excitation/emission frequency of 495/515nm, and the results are shown in fig. 3.
As can be seen from FIG. 3, the NO donor harmine derivative IV3bThe levels of NO release in HepG2 cells were time dependent at 0h, 8h, 16h, 24h, 48h and 72h, with significant differences starting at 16 h. With the effect peaking at 72 h. And at different times NO donor-harmine derivative IV3bHas no time dependence on the action of normal human liver cell LO 2.
Test example 5
Acute toxicity evaluation
Kunming breed mouse (provided by Beijing Hua Biotechnology corporation, license number: SCXK (Jing) 2019-. The solvent used was normal saline, 5% dimethyl sulfoxide (DMSO), and 5% tween 80. After the sample is weighed, adding Tween 80 for dissolving assistance, and then adding physiological saline containing 5% DMSO to the required concentration. Mice were randomized into 3 groups of 5 mice each. The dosages of HM and IV 3b are respectively 150.0mg/kg, 50.0mg/kg and 10.0mg/kg in the high, middle and low groups; the administration was performed 1 time by tail vein injection, and the administration was followed by continuous observation for 7 days. Mice were observed for general condition, activity, feeding, mice death, toxic symptoms and onset and termination of toxic reactions. Mice showed slightly different time to toxic response and death after each test substance was administered. The results are shown in Table 2.
TABLE 2
Mice in the group given the high dose HM (150mg/kg) exhibited convulsions, opisthotonos, rigidity of the body, and total death within 0-5 mm; administration IV3bThe high dose (150mg/kg) group of mice exhibited convulsions, dyspnea and all died gradually within 40 min. Two mice dosed with HM (50mg/kg) died within 30min, and returned to normal after the remaining 30 min. Administration IV3bMedium (50mg/kg) and Low (10mg/kg) dose mice exhibited reduced tremor excitability, but did not die within 7 d. Compared with the raw material medicine HM, the new compound NO donor-harmine derivative obviously reduces the acute toxicity of mice.
The invention verifies the new compound harmine derivative III through the cell level6a、Ⅲ6b、Ⅱ4And II5And a novel compound NO donor-harmine derivative IV3aAnd IV3bCompared with the HM, the series of novel compounds have lower antiproliferative action on normal cells LO2, namely, the toxicity on LO2 is reduced to a certain extent by comparing the HM with the antiproliferative action of the four kinds of cells on HepG2, BGC, A549 and MCF-7. Wherein the new compound NO donor-harmine derivative IV3bThe antiproliferative effect was strongest on HepG2, so we further examined at the cellular level in order to explore the relationship between NO and antiproliferative activity. As shown in figure 1, the positive control drug JS-K, II5,Ⅳ2bCompound IV with the strongest antiproliferative activity compared with the blank group3bThe relative MFI was highest in the liver cancer cell line HepG 2. Thus, the amount of NO released in HepG2 cells correlated with the antiproliferative activity. Under the same conditions, compound IV3b(1.5. mu.M, 72h) significantly increased the relative mean fluorescence of cancer cells HepG2 but not of LO2 cellsIntensity (MFI), indicating that NO is only selectively released in human hepatoma cells HepG2, normal human hepatocytes LO2 were hardly affected. As shown in FIG. 2, compound IV increased with the increase in HepG2 cell concentration3bThe released NO showed a more pronounced concentration dependence than LO2 cells. Also, as shown in FIG. 3, in the reaction with a compound IV3bAfter 72h incubation, NO release was highest in HepG2 cells, whereas the change was not evident in LO2 cells. Compounds IV as described above3bHas certain selectivity in releasing NO to play the antiproliferative effect, namely, has obvious antiproliferative effect in HepG2 cells and has small influence on normal cells LO 2.
The above-described embodiments are merely illustrative of the preferred embodiments of the present invention, and do not limit the scope of the present invention, and various modifications and improvements of the technical solutions of the present invention can be made by those skilled in the art without departing from the spirit of the present invention, and the technical solutions of the present invention are within the scope of the present invention defined by the claims.
Claims (8)
2. The process for the preparation of harmine derivatives according to claim 1, wherein R is the number1Is NHC (CH)3)COOCH3Or NHC (CH)3)2COOCH3The preparation method comprises the following steps: carrying out structural modification on harmine to obtain the harmine derivative;
when R is1Is O (CH)2)nON2SO2Ph, the preparation method comprises the following steps: structurally modifying the harmine to obtain an intermediate product, and combining the intermediate product with a nitric oxide donor to obtain the harmine derivative.
4. a process for the preparation of harmine derivatives according to claim 2, wherein said nitric oxide donors include furazan nitroxides, azodialenium salts, organic nitrates, metal-NO complexes, strepazinones, N-hydroxyureas and hydroxamic acids.
5. The use of harmine derivative according to claim 1 for the preparation of an antitumor agent.
6. The use of harmine derivatives according to claim 5 for the preparation of an antitumor agent, wherein R is R1Is NHC (CH)3)COOCH3When the anti-tumor drug is a drug for resisting human breast cancer MCF-7.
7. The use of harmine derivatives according to claim 5 for the preparation of an antitumor agent, wherein R is R1Is NHC (CH)3)2COOCH3The anti-tumor drug is a drug for resisting human gastric cancer cells BGC and/or human breast cancer MCF-7.
8. A process according to claim 5The application of harmine derivative in preparing antitumor medicine is characterized in that R is1Is O (CH)2)nON2SO2At Ph, the antitumor drugs are anti-human liver cancer cell HepG2, anti-human gastric cancer cell BGC, anti-human breast cancer MCF-7 and/or anti-human lung cancer cell A549.
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