CN116283562A - Isosteviol derivative and application thereof in preparation of antitumor drugs - Google Patents

Isosteviol derivative and application thereof in preparation of antitumor drugs Download PDF

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CN116283562A
CN116283562A CN202310155674.8A CN202310155674A CN116283562A CN 116283562 A CN116283562 A CN 116283562A CN 202310155674 A CN202310155674 A CN 202310155674A CN 116283562 A CN116283562 A CN 116283562A
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isosteviol
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cells
isosteviol derivative
tumor
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郭锐华
李娜
蒋火金
孙晓净
杭思锦
吴文惠
刘宁
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Hunan Yujing Biotechnology Co ltd
Shanghai Ocean University
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Abstract

The invention discloses an isosteviol derivative and application thereof in preparing an anti-tumor medicament, belonging to the field of pharmaceutical chemistry. The isosteviol derivative has a chemical structure shown in 1-8, has the activities of inhibiting mantle cell lymphoma mino and multiple myeloma cells MM.1s, and is used for preparing antitumor drugs; the invention also provides a method for inhibiting proliferation of tumor cells in vitro, which comprises adding the isosteviol derivative into a culture solution of tumor cells. The isosteviol derivative has good anti-tumor activity, the raw materials are cheap and easy to obtain, the reaction condition is mild, the preparation process and the post-treatment are simple, the solvent can be recycled, a research basis and a theoretical basis are provided for new drug screening, and the isosteviol derivative has a good application prospect.

Description

Isosteviol derivative and application thereof in preparation of antitumor drugs
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to an isosteviol derivative and application thereof in preparing antitumor drugs.
Background
According to world health organization data, cancer is a major health problem facing the world, accounting for 13% of all deaths worldwide. Despite the vast number of chemotherapeutics and other therapeutic modalities, such as radiation therapy and surgery, cancer remains one of five causes of death worldwide.
Mantle cell lymphoma is a malignant B cell lymphoma, which has the dual characteristics of rapid progression of invasive lymphoma and incurability of indolent lymphoma, and rapid progression of disease. The chemotherapy effect of mantle cell lymphoma is poor, and development of new targeted drugs for clinical research is urgently needed.
Multiple myeloma, 15% of hematological tumors, is the second most common adult hematological malignancy. Multiple myeloma is diagnosed by more than 10 tens of thousands of patients each year, and the incidence and prevalence is increasing in many areas. Worse still, most patients eventually experience relapse and multi-drug resistance. Therefore, there is an urgent need to design new drugs to expand the treatment.
Natural products are important sources of lead compounds and functional organic molecules of drugs, and screening of lead compounds of drugs from natural products has been an effective approach for the development of new drugs. Although many natural products have certain biological activities, the clinical application of the natural products is limited due to strong toxic and side effects, poor activity or low bioavailability. Therefore, effective structural modification such as introduction of special pharmacophore to natural products to obtain novel derivatives, thereby improving the activity and availability and reducing toxicity is an effective scheme for developing novel natural medicines.
Isosteviol (Isoteviol) is a tetracyclic diterpenoid compound with a behene skeleton, which is obtained by hydrolyzing natural product stevioside under an acidic condition, and researches show that the Isosteviol has wide biological activities such as anti-tumor, bacteriostasis, blood pressure reduction, blood sugar reduction, antioxidation and the like, and the antitumor activity can be enhanced by introducing active groups into molecules through structural modification of the Isosteviol, so that a novel antitumor compound is obtained.
Disclosure of Invention
The first aim of the invention is to provide isosteviol derivatives, which are reasonably structurally modified by selecting isosteviol as a lead compound, so as to obtain a novel compound with anti-tumor activity.
The invention further aims to provide a preparation method of the isosteviol derivative, which uses isosteviol as a raw material, optimizes a reaction substrate, a catalyst, a solvent, a reagent, reaction time, a purification method and the like in specific steps, and has the advantages of convenient operation, higher yield, better selectivity and mild reaction conditions.
It is still another object of the present invention to provide the use of the isosteviol derivative in the preparation of antitumor drugs.
In order to achieve the above purpose, the technical scheme adopted by the invention is as follows:
the isosteviol derivative provided by the invention has the chemical structure as shown in the specification:
Figure BDA0004092255960000021
preferably, the isosteviol derivative has the activity of inhibiting mantle cell lymphoma mino and multiple myeloma cells MM.1s.
The invention also provides a synthesis method of the isosteviol derivative, which comprises the following reaction processes:
Figure BDA0004092255960000022
Figure BDA0004092255960000031
the invention also provides application of the isosteviol derivative in inhibiting the activities of mantle cell lymphoma mino and multiple myeloma cells MM.1s.
The invention also provides application of the isosteviol derivative in preparing antitumor drugs.
Preferably, the anti-tumor drug is an anti-mantle cell lymphoma drug or an anti-multiple myeloma drug.
Preferably, the dosage form of the antitumor drug is at least one preparation form selected from the group consisting of tablets, capsules, granules, drop pills, suspensions, syrups, enteric preparations, emulsion suspensions and injections.
The invention also provides a method for inhibiting proliferation of tumor cells in vitro, which comprises the step of adding the isosteviol derivative into a culture solution of the tumor cells.
Preferably, the tumor cells are lymphoma cells mino or multiple myeloma cells mm.1s.
Preferably, the isosteviol derivative is added at a concentration of 50 μm.
Compared with the prior art, the invention has the following beneficial effects:
1. the isosteviol derivative provided by the invention has good anti-tumor activity, provides a research basis and a theoretical basis for new drug screening, and has good application prospect.
2. The isosteviol derivative has the advantages of simple preparation flow, low-cost and easily-obtained raw materials, mild reaction conditions, simple post-treatment, recyclable solvent and contribution to industrial production.
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FIG. 1 shows the proliferation inhibition effect of the compounds of the series (50 uM) in the examples on the Mino and MM.1s cell lines for 48h treatment.
FIG. 2 shows the proliferation inhibition effect of the series of compounds in the examples on the mino cell line by treatment for 72 hours.
FIG. 3 shows the proliferation inhibition effect of the series of compounds in the examples for 72h on MM.1s cell lines.
Detailed Description
The invention will be further described with reference to specific examples, but the scope of the invention is not limited thereto.
Example 1 preparation of Compound 1
Figure BDA0004092255960000041
NaBH is carried out 4 (47.6 mg,1.256 mmol) was added to an ethanol solution of isosteviol (200 mg, 0.6278 mmol) as a raw material, and left at room temperature for 3 hours. After stirring was completed, the solvent was removed in vacuo. The residue was diluted with saturated aqueous NaCl solution and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica (dichloromethane/methanol=20:1, v/v) to give the product as a white solid. The yield thereof was found to be 82.4%. The spectral data are as follows:
1 H NMR(400MHz,CDCl 3 )δ3.61(s,3H),2.21–2.10(m,1H),1.90–1.72(m,3H),1.71–1.58(m,3H),1.57–1.44(m,3H),1.43–1.29(m,3H),1.29–1.19(m,2H),1.16(s,3H),1.13–1.01(m,2H),0.95(s,3H),0.93–0.79(m,1H),0.65(s,3H).
13 C NMR(100MHz,CDCl 3 )δ185.1,84.0,61.0,59.9,59.2,47.5,46.3,46.0,45.9,45.7,43.9,42.1,42.0,37.7,33.0,28.7,25.7,24.2,22.9,17.1.
example 2 preparation of Compound 2
Figure BDA0004092255960000042
A mixture of compound 1 (100 mg,0.313 mmol) and acetic anhydride (88. Mu.L, 0.939 mmol) in pyridine was stirred at room temperature for 8 hours and then concentrated under reduced pressure. Saturated aqueous NaCl solution was added and the mixture was treated with CH 2 Cl 2 And (5) extracting. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/acetone=5:1) to give compound 2 as a white solid. The yield thereof was found to be 58.6%. The spectral data are as follows:
1 H NMR(400MHz,CD 4 O)δ4.69(t,J＝7.6Hz,1H),3.30–3.27(m,1H),2.16(d,J＝13.6Hz,1H),2.02(s,3H),1.89–1.76(m,3H),1.77–1.67(m,2H),1.67–1.55(m,3H),1.55–1.45(m,1H),1.41–1.29(m,3H),1.29–1.19(m,2H),1.15(s,3H),1.10–0.99(m,3H),0.99–0.90(m,1H),0.88(s,3H),0.79(s,3H).
13 C NMR(100MHz,CD 4 O)δ180.4,172.0,81.9,56.9,55.7,54.6,43.3,42.2,41.4,41.3,40.5,39.9,38.0,37.8,34.4,28.4,24.2,21.6,20.0,19.9,18.8,12.7.
EXAMPLE 3 preparation of Compound 3
Figure BDA0004092255960000051
To a solution of 200mg (0.628 mmol) of isosteviol in EtOH (2 mL) were added hydroxylamine hydrochloride (70 mg,0.942 mmol) and sodium hydrogencarbonate (80.1 mg,0.942 mmol). The mixture was stirred at 60 ℃ for 5h, concentrated under vacuum and the residue extracted with dichloromethane and water. The organic layer was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated in vacuo, and the crude product purified by column chromatography over silica (petroleum ether/acetone=8:1) to give a white powder. The yield thereof was found to be 72.8%. The spectral data are as follows:
1 H NMR(400MHz,CDCl 3 )δ2.97(dd,J＝18.8,3.1Hz,1H),2.15(d,J＝13.2Hz,1H),2.03–1.94(m,1H),1.90–1.69(m,2H),1.68–1.53(m,3H),1.50–1.37(m,4H),1.34–1.27(m,3H),1.24(s,2H),1.22(s,3H),1.08(s,3H),1.03–0.93(m,2H),0.94–0.85(m,1H),0.83(s,3H).
13 C NMR(100MHz,CDCl 3 )δ170.7,57.2,56.3,54.9,44.0,43.7,40.9,40.0,39.5,38.3,37.1,31.6,30.2,29.8,29.1,22.2,21.6,20.5,19.0,13.5.
EXAMPLE 4 preparation of Compound 4
Figure BDA0004092255960000052
200mg of Compound 0 was placed in a 10mL reaction flask, 3mL of acetone was added for dissolution, 117. Mu.L of methyl iodide and 350mg of potassium carbonate were added with stirring, and the mixture was reacted at room temperature for 11 hours. After completion of the TLC detection, the reaction mixture was extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, separated, dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure to give a white solid. Separating by silica gel column chromatography (petroleum ether/ethyl acetate 20:1) to obtain white solid. Yield: 73.3%. The spectral data are as follows:
1 H NMR(400MHz,CDCl 3 )δ3.61(s,2H),3.46(s,3H),2.60(dd,J＝18.6,3.8Hz,1H),2.18–2.12(m,1H),1.84–1.79(m,1H),1.76(d,J＝3.6Hz,1H),1.72–1.63(m,3H),1.62–1.57(m,1H),1.57–1.53(m,1H),1.50(dd,J＝10.0,3.6Hz,1H),1.43–1.36(m,2H),1.36–1.30(m,1H),1.24–1.19(m,1H),1.16(s,4H),1.14–1.07(m,2H),1.01(dd,J＝13.5,4.2Hz,1H),0.95(s,3H),0.88(td,J＝13.1,4.6Hz,1H),0.66(d,J＝0.9Hz,2H).
13 CNMR(101MHz,CDCl 3 )δ222.7,178.0,57.1,54.8,54.4,51.3,50.9,48.8,48.5,43.9,41.6,39.9,39.5,38.0,37.4,28.9,21.8,20.4,19.9,19.0,13.2.
EXAMPLE 5 preparation of Compound 5
Figure BDA0004092255960000061
50mg of Compound 4 was placed in a 10mL reaction flask, dissolved in 1mL of ethanol, followed by 16mg of hydroxylamine hydrochloride and 19mg of sodium hydrogencarbonate, and heated under reflux at 60℃for 6 hours. After completion of the TLC detection, the reaction mixture was extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, separated, dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure to give a white solid. Separating by silica gel column chromatography (petroleum ether/ethyl acetate 8:1) to obtain white solid. Yield: 89.41%. The spectral data are as follows:
1 H NMR(400MHz,CDCl 3 )δ2.93(dd,J＝18.5,3.2Hz,1H),2.19–2.09(m,1H),1.86–1.72(m,2H),1.73–1.62(m,2H),1.62–1.50(m,3H),1.46–1.38(m,3H),1.38–1.33(m,1H),1.25(d,J＝3.6Hz,1H),1.24–1.21(m,2H),1.21–1.17(m,1H),1.15(s,3H),1.07(s,4H),1.06–1.00(m,1H),1.01–0.91(m,1H),0.85(ttd,J＝9.8,4.9,2.6Hz,2H),0.72(s,3H).
13 C NMR(101MHz,CDCl 3 )δ178.1,170.3,57.2,56.3,54.9,51.3,43.9,41.0,40.7,40.0,39.5,38.1,38.1,36.9,29.8,28.8,22.2,21.8,20.5,19.0,13.2.
EXAMPLE 6 preparation of Compound 7
Figure BDA0004092255960000071
EtBr (236. Mu.L, 3.14 mmol) and KOH (105.7 mg,1.88 mmol) were added to a solution of isosteviol (200 mg, 0.627 mmol) dissolved in DMSO, and stirred at room temperature for 5 hours. The mixture was then extracted with ethyl acetate and water, and the organic layer was dried over anhydrous Na 2 SO 4 Dried, filtered and the filtrate evaporated under reduced pressure. The crude extract was subjected to column chromatography using petroleum ether/ethyl acetate (20:1) as eluent to give a white amorphous powder. Yield: 73.1%. The spectral data are as follows:
1 H NMR(400MHz,CDCl 3 )δ4.05(q,J＝7.2Hz,2H),2.59(dd,J＝18.6,3.8Hz,1H),2.13(d,J＝13.5Hz,2H),1.92–1.80(m,2H),1.80–1.75(m,1H),1.73–1.65(m,3H),1.62(dd,J＝6.5,3.7Hz,1H),1.60–1.54(m,1H),1.54–1.49(m,1H),1.48–1.40(m,2H),1.39–1.31(m,2H),1.27(t,J＝7.1Hz,3H),1.23–1.21(m,1H),1.14(s,3H),1.16–1.08(m,2H),0.93(s,3H),0.89–0.81(m,1H),0.67(s,3H).
13 C NMR(100MHz,CDCl 3 )δ223.2,177.5,60.2,57.1,54.7,54.3,48.8,48.5,43.8,41.6,39.9,39.5,38.1,37.9,37.4,29.0,21.8,20.4,19.9,19.0,14.1,13.5
EXAMPLE 7 preparation of Compound 8
Figure BDA0004092255960000072
100mg of Compound 0 was placed in a 10mL reaction flask, 2mL of N, N-Dimethylformamide (DMF) was added for dissolution, 266. Mu.L of 1,4 dibromobutane and 270mg of sodium carbonate were added with stirring, and the reaction was carried out at room temperature for 36 hours. After completion of the TLC detection, the reaction mixture was extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, separated, dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure to give a white solid. Separating by silica gel column chromatography (petroleum ether/acetone 20:1) to obtain white solid. Yield: 48%. The spectral data are as follows:
1 H NMR(400MHz,CDCl 3 )δ4.12–3.96(m,2H),3.42(t,J＝6.5Hz,2H),2.60(dd,J＝18.6,3.8Hz,1H),2.21–2.11(m,1H),2.01–1.91(m,1H),1.95–1.81(m,2H),1.84–1.69(m,4H),1.73–1.64(m,2H),1.68–1.55(m,2H),1.58–1.47(m,1H),1.51–1.36(m,2H),1.39–1.30(m,1H),1.33–1.21(m,3H),1.17(s,3H),1.24–1.07(m,3H),1.06–0.95(m,1H),0.96(s,3H),0.94–0.82(m,1H),0.68(d,J＝0.8Hz,3H).
13 C NMR(101MHz,CDCl 3 )δ222.6,177.4,63.3,57.1,54.8,54.3,48.8,48.5,43.9,41.6,39.9,39.5,38.1,37.4,33.1,29.8,29.6,29.1,27.3,21.8,20.4,19.9,19.0,13.5.
example 8 in vitro inhibition Activity test of cancer cells
1. Cell resuscitation:
(1) Taking out the freezing tube from the liquid nitrogen tank at the temperature of-196 ℃, immediately putting the freezing tube into a water bath kettle at the temperature of 37 ℃ for quick thawing, and simultaneously, continuously and gently shaking the freezing tube to ensure that cells in the freezing tube are thawed within 1 min.
(2) Taking out the frozen tube from the 37 ℃ water bath, sucking out the cell suspension by a pipetting gun, injecting into a 15mL centrifuge tube, adding 3mL culture medium for resuspension, centrifuging for 1000r and 5min, adding into a culture bottle filled with the culture medium, placing the culture bottle in a 37 ℃ incubator for static culture, replacing the culture solution the next day, and continuing to culture. And culturing to a certain concentration for passage.
2. Cell passage:
MM.1s and Mino medium with 10% fetal bovine serum, 100U/mL penicillin and 100. Mu.g/mL streptomycin, RPMI-1640 medium at 37℃and 5% CO by volume 2 Culturing under the condition. The cells were observed daily for growth and passaged when they were grown to about 90% confluence in culture flasks, approximately every 2-4 days, one flask was passaged into three flasks, or one 25cm 2 Passage to a 75cm passage 2 Is provided.
(1) The cell suspension was aspirated into a 15mL centrifuge tube, centrifuged at 1000RPM for 5 minutes, the supernatant discarded, and 2mL of medium was aspirated to resuspend the cells.
(2) Taking two new T25 culture flasks, respectively supplementing 4mL of culture medium, sucking 1mL of resuspended cells, and adding the cells into the T25 culture flasks to complete 1: and 2 passages.
3. Cell cryopreservation:
(1) Taking cells cultured to logarithmic phase, collecting the cells in a centrifuge tube, and centrifuging;
(2) Removing old culture solution, adding 1mL of prepared cell cryopreservation solution, lightly blowing with a straw to make cells uniform, and then sub-packaging into sterile cryopreservation tubes;
(3) And placing the freezing tube into a freezing box, placing the freezing box at-80 ℃, transferring the freezing tube into a liquid nitrogen tank for preservation after 5 hours.
4. Inoculating cells: minu cells and MM.1s cells were counted as seed cells 1X 10 4 Inoculating 100 μl/mL into 96-well culture plate, adding 100 μl/well, and adding CO at 37deg.C 2 Culturing in an incubator for 24 hours;
5. administration: preparing a compound to be tested into a storage with a certain concentration by adding DMSOPreparing solution, preparing 50, 16.67, 5.56, 1.85 and 0.62 mu mol/L solution respectively with RMPI1640 culture medium containing 10% fetal bovine serum, inoculating into 96-well plate, arranging three parallel multiple wells at each concentration, and concentrating at 37deg.C under 5% CO 2 Culturing in an incubator for 48 hours. The control group is treated by DMSO, is not treated by adding medicine, is continuously cultured for 48 hours, and is observed for cell morphology and growth change under an inverted microscope.
6. 10uL of cck8 detection reagent (MCE) is added to each well, the mixture is incubated for 1h at 37 ℃, and an enzyme-labeled instrument detects OD value at a wavelength of 450 nm.
7. And (5) data analysis and processing. The inhibition ratio was calculated according to the following formula: inhibition (%) = (dosing group mean absorbance OD value-blank group mean absorbance OD value)/(control group mean absorbance OD value-blank group mean absorbance OD value) ×100%. Calculation of IC of isosteviol derivatives on mino and mm.1s cells based on cell viability 50 Values.
CCK-8 experiments showed that compounds 5 and 8 inhibited proliferation activity of mino and MM.1s cells significantly more than the starting isosteviol, which had IC for mino and MM.1s cells 50 The values are 17.120, 24.575 mu mol, 15.018 and 35.556 mu mol respectively, which indicate that the compounds 5 and 8 have better inhibition activity on two cancer cell lines, and can be further used for developing new antitumor targeted drugs.
Table 1: inhibition of mino and MM.1s by Compound (50 uM)
mino MM.1s
0 -7.22％ -26.29％
1 -2.11％ -21.01％
2 1.76％ -22.39％
3 12.32％ -11.57％
4 \ \
5 94.01％ 90.82％
6 91.37％ 77.99％
7 19.89％ 12.58％
8 93.66％ 48.30％
The foregoing is merely a preferred embodiment of the present invention, and it should be noted that modifications and additions may be made to those skilled in the art without departing from the method of the present invention, which modifications and additions are also to be considered as within the scope of the present invention.

Claims (9)

1. Isosteviol derivatives having the chemical structure shown below:
Figure FDA0004092255950000011
2. the isosteviol derivative of claim 1, wherein the isosteviol derivative has inhibitory activity against mantle cell lymphoma mino and multiple myeloma cells mm.1s.
3. Use of the isosteviol derivative of claim 1 or 2 for inhibiting the activity of mantle cell lymphoma mino and multiple myeloma cells mm.1s.
4. Use of the isosteviol derivative according to claim 1 or 2 for preparing an antitumor drug.
5. The use according to claim 4, wherein the antineoplastic agent is an anti-mantle cell lymphoma agent or an anti-multiple myeloma agent.
6. The use according to claim 4, wherein the anti-tumor drug is in a form of at least one preparation selected from the group consisting of tablets, capsules, granules, drop pills, suspensions, syrups, enteric preparations, emulsion suspensions and injections.
7. A method for inhibiting proliferation of tumor cells in vitro, comprising adding the isosteviol derivative of claim 1 or 2 to a culture solution of tumor cells.
8. The method of claim 7, wherein the tumor cell is lymphoma cell mino or multiple myeloma cell mm.1s.
9. The method of inhibiting proliferation of tumor cells in vitro according to claim 7, wherein the isosteviol derivative is added at a concentration of 50 μm.
CN202310155674.8A 2023-02-23 2023-02-23 Isosteviol derivative and application thereof in preparation of antitumor drugs Pending CN116283562A (en)

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