CN108383892B - Diosgenin quaternary ammonium salt derivative and preparation method and application thereof - Google Patents

Diosgenin quaternary ammonium salt derivative and preparation method and application thereof Download PDF

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CN108383892B
CN108383892B CN201810199580.XA CN201810199580A CN108383892B CN 108383892 B CN108383892 B CN 108383892B CN 201810199580 A CN201810199580 A CN 201810199580A CN 108383892 B CN108383892 B CN 108383892B
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diosgenin
quaternary ammonium
ammonium salt
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杨鸿均
马晓东
王璐红
曾倩倩
迟福云
阳耀月
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Southwest Minzu University
Dalian Medical University
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Abstract

The invention belongs to the technical field of medicine and pharmacology, and discloses a diosgenin quaternary ammonium salt derivative, a preparation method and application thereof. Pharmacological experiments show that: all the synthesized diosgenin quaternary ammonium salt derivatives have obvious inhibition effects on A549 cells, H1975 cells, HCT-116 cells and Aspc-1 cells, the antitumor activity of the derivatives is superior to that of diosgenin, the antitumor activity of most of the derivatives on Ramos cells and A431 cells is superior to that of diosgenin, and part of the derivatives have low toxicity on HBE cells and LO-2 cells; the invention belongs to an application basic project No.2016JY0212 of science and technology hall of Sichuan province, and a capital No.2018NQN31 special for basic scientific research service fees of central colleges and universities of southwest national university.

Description

Diosgenin quaternary ammonium salt derivative and preparation method and application thereof
Technical Field
The invention belongs to the technical field of medicine and pharmacology, and particularly relates to a diosgenin quaternary ammonium salt derivative as well as a preparation method and application thereof.
Background
Currently, the current state of the art commonly used in the industry is such that:
cancer is a serious disease threatening human life and health, and has become one of the important factors of human death. With the change of environment and life style, the cancer morbidity and mortality of China continuously rise. Therefore, the search for novel antitumor drugs has become one of the important directions for the development of new drugs.
The natural active antitumor drug has the advantages of obvious curative effect, small toxic and side effect and the like. Diosgenin has abundant natural resources, and has various pharmacological activities of resisting tumor, reducing blood lipid, resisting thrombosis, resisting inflammation, etc. A great deal of research work at home and abroad shows that diosgenin and certain derivatives thereof have obvious anti-tumor effect. The diosgenin is used as a primer for structural modification, provides a way for searching better antitumor drugs, is valued by domestic and foreign scientists, and is a research work with great value and prospect.
In recent years, researchers mainly focus on the A-loop and the F-loop for structural modification and modification of diosgenin, and some diosgenin derivatives have been reported to have significant anti-tumor activity, but the defects of diosgenin are not completely solved, and a better drug structure needs to be searched from the diosgenin. Therefore, reasonable structural modification is carried out on diosgenin, a novel derivative is designed and synthesized, a more effective chemical structure is screened out, and certain challenges are still provided.
In summary, the problems of the prior art are as follows:
diosgenin and its derivatives as potential anti-tumor active substances also have the defects of high toxicity, strong hydrophobicity, low bioavailability and the like, which limits the application range of the diosgenin to a great extent.
The difficulty and significance for solving the technical problems are as follows:
the invention aims at improving the water solubility of the diosgenin and increasing the anti-tumor activity of the diosgenin, designs and synthesizes a novel diosgenin quaternary ammonium salt derivative, and all the target derivatives are not reported at home and abroad. In order to synthesize diosgenin quaternary ammonium salt derivatives, an amino group needs to be introduced on a steroid ring.
The invention relates to a method for preparing a series of corresponding quaternary ammonium salt derivatives by converting hydroxyl at C3-position of diosgenin into amino through three steps of reaction, and performing substitution reaction with different halogenated hydrocarbons by taking the amino as an intermediate.
Disclosure of Invention
Aiming at the problems in the prior art, the invention provides a diosgenin quaternary ammonium salt derivative, a preparation method and application thereof. Diosgenin has anti-tumor effect. A large number of researches show that the diosgenin has broad-spectrum anti-tumor activity, and can effectively play a role in inhibiting cell proliferation and inducing cell apoptosis on various tumor cells such as HeLa, K562, HEL, HEP-2 and the like. However, diosgenin and its derivatives, as potential anti-tumor active substances, also have the disadvantages of poor water solubility, low bioavailability, large cytotoxicity, relatively narrow application range, etc., so structural modification and pharmacological research are required to improve the bioavailability and application range.
The invention is realized by the following method for synthesizing the diosgenin quaternary ammonium salt derivative: firstly, diosgenin is used as a precursor to react with methanesulfonyl chloride to sulfonylate C3-hydroxy to obtain a compound 1, then the compound 1 and sodium azide undergo nucleophilic substitution reaction to obtain a compound 2, and triphenylphosphine is used to reduce C3-azido to amino to obtain a compound 3. The compound 3 obtained by the three-step reaction is used as a common intermediate of diosgenin C3-position derivatives, and respectively carries out substitution reaction with different halogenated hydrocarbons to obtain a series of corresponding quaternary ammonium salt derivatives. The general molecular structure formula is:
Figure BDA0001594087970000031
wherein R is1、R2、R3Is a hydrocarbyl or substituted hydrocarbyl group;
X＝F、Cl、Br、I。
another object of the present invention is to provide a method for preparing a diosgenin quaternary ammonium salt derivative, comprising:
dissolving diosgenin C-3 amino derivative (1g,1eq) in acetonitrile (5-100 mL) or a mixed solvent (5-100 mL) of acetonitrile and dichloromethane (v/v ═ 1:1), adding potassium carbonate (5-10eq) and halogenated hydrocarbon (10-30eq), and heating and refluxing for 5-50 h;
filtering the reaction solution, and concentrating the filtrate under reduced pressure;
dissolving an intermediate (1g,1eq) obtained by column chromatography in a mixed solvent (5-100 mL) of dichloromethane and acetonitrile (v/v ═ 1:1), adding 30eq of iodomethane, heating and refluxing for 5-50h, and concentrating the reaction solution under reduced pressure;
recrystallizing or performing column chromatography to obtain diosgenin quaternary ammonium salt derivative compound.
Further, the reaction formula of the preparation method of the diosgenin quaternary ammonium salt derivative is as follows:
Figure BDA0001594087970000032
the invention also aims to provide an anti-tumor medicament prepared by using the diosgenin quaternary ammonium salt derivative
The invention also aims to provide a medicament for inhibiting A549 lung cancer cells, which is prepared by using the diosgenin quaternary ammonium salt derivative.
The invention also aims to provide a medicament prepared from the diosgenin quaternary ammonium salt derivative for inhibiting A431 skin squamous carcinoma cells.
The invention also aims to provide a medicament for inhibiting H1975 lung adenocarcinoma cells, which is prepared by using the diosgenin quaternary ammonium salt derivative.
The invention also aims to provide a drug for HCT-116 colorectal adenocarcinoma cell inhibition prepared by using the diosgenin quaternary ammonium salt derivatives.
The invention also aims to provide a medicine for inhibiting spc-1 metastatic pancreatic cancer cells, which is prepared by using the diosgenin quaternary ammonium salt derivative.
The invention also aims to provide a medicine for inhibiting Ramos B lymphoma cells, which is prepared by using the diosgenin quaternary ammonium salt derivative.
In summary, the advantages and positive effects of the invention are:
the invention improves the water solubility of the diosgenin, designs the diosgenin quaternary ammonium salt derivatives with the purposes of anti-tumor activity and reducing toxic and side effects, and screens out the steroid compounds with higher anti-tumor activity.
All synthetic novel derivativesAll things of structure are through1H NMR，13C NMR, HRMS (ESI) confirmed. The water solubility of the target derivatives, and the antitumor activity of A549 (human lung cancer cells), H1975 (human lung adenocarcinoma cells), A431 (human skin squamous carcinoma cells), HCT-116 (human colorectal adenocarcinoma cells), Aspc-1 (human metastatic pancreatic cancer cells), Ramos (human B lymphoma cells) and the cytotoxicity of HBE (human bronchial epithelial-like cells) and LO-2 (normal liver cells) were also examined.
The water-solubility test shows that: the water solubility of all synthesized diosgenin quaternary ammonium salt derivatives is better than that of the lead diosgenin in different degrees.
Figure BDA0001594087970000051
Pharmacological experiments show that: all the synthesized diosgenin quaternary ammonium salt derivatives have obvious inhibition effects on A549 cells, H1975 cells, HCT-116 cells and Aspc-1 cells, the antitumor activity of the derivatives is superior to that of diosgenin, the antitumor activity of most of the derivatives on Ramos cells and A431 cells is superior to that of diosgenin, and part of the derivatives have low toxicity on HBE cells and LO-2 cells.
Figure BDA0001594087970000052
Figure BDA0001594087970000061
The invention belongs to an application basic project No.2016JY0212 of science and technology hall of Sichuan province.
Drawings
Fig. 1 is a flow chart of a preparation method of diosgenin quaternary ammonium salt derivatives according to an embodiment of the present invention.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
In the prior art, the water solubility of diosgenin is not improved, and the effects of resisting tumor activity and reducing toxic and side effects are poor.
The diosgenin quaternary ammonium salt derivative provided by the embodiment of the invention is represented by the following general formula (I):
Figure BDA0001594087970000062
Figure BDA0001594087970000071
wherein R is1、R2、R3Is a hydrocarbyl or substituted hydrocarbyl group;
X＝F、Cl、Br、I；
the preparation method of the diosgenin quaternary ammonium salt derivative provided by the embodiment of the invention has the chemical reaction formula as follows:
Figure BDA0001594087970000072
as shown in fig. 1, the preparation method of diosgenin quaternary ammonium salt derivatives provided by the embodiment of the present invention specifically includes:
s101: dissolving diosgenin C-3 amino derivative (1eq) in acetonitrile (or mixed solvent of acetonitrile and dichloromethane), adding potassium carbonate (5-10eq) and halogenated hydrocarbon (10-30eq), and heating under reflux for 5-50 h.
S102: the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure.
S103: dissolving the intermediate (1eq) obtained by column chromatography in a mixed solvent of dichloromethane and acetonitrile, adding iodomethane (30eq), heating and refluxing for 5-50h, and concentrating the reaction solution under reduced pressure.
S104: recrystallizing or carrying out column chromatography to obtain the compound with the general formula (I).
The invention is further described below with reference to specific assays.
1) All the novel compound structures synthesized by the invention1H NMR，13C NMR, IR, HRMS (ESI) confirmed, and characterized by infrared, melting point, and optical rotation. The synthesized quaternary ammonium salt derivatives are A549 (human lung cancer cells), A431 (human skin squamous carcinoma cells), H1975 (human lung adenocarcinoma cells), HCT-116 (human colorectal adenocarcinoma cells), Aspc-1 (human metastatic pancreatic cancer cells), Ramos (human B lymphoma cells), HBE (human bronchial epithelial-like cells) and LO-2 (normal liver cells). The cells were subjected to the corresponding bioactivity assay.
2) The reagents used in the experiment were analytically pure reagents unless otherwise specified, and were used without purification.1H NMR and13c NMR was measured using an Agilent DD2400-MR (400MHz) nuclear magnetic resonance spectrometer with TMS as internal standard and CDCl3As a solvent; IR was measured by FTS 3000 Fourier transform Infrared Spectroscopy (Digilab, USA) with KBr pellet; HRMS was measured with LCQAdvantage Max mass spectrometer; the optical rotation was measured with an SGW-1 (Shanghai apparatus electro-physical optics Instrument Co., Ltd.) polarimeter; melting points were measured using an SGW X-4 micro melting point tester (Shanghai precision scientific instruments, Inc.) without temperature calibration.
3) Cell culture:
cells in logarithmic growth phase of A549, A431, H1975, HCT-116, Aspc-1, Ramos, HBE, LO-2 were collected, and the cell suspension concentration was adjusted to 7X 10 cells per well3Cells were seeded in 96-well plates in 100. mu.L per well volume, 4 wells per well (marginal wells filled with sterile PBS). After cell attachment, 0% FBS RPMI-1640 was starved for 8h, and the control group was cultured with 10% FBS RPMI-1640. 37 ℃ and 5% CO2The cultivation was continued in the incubator for 48 h.
4) MTT detection:
after culturing the eight groups of cells for 48 hours, 100. mu.L of MTT solution (5 mg. multidot.mL) was added-1) And after 4h, terminating the culture, adding 100 mu L of triple liquid into each hole, and oscillating on a shaking table at a low speed for 10min to fully dissolve crystals. The absorbance value (OD value) of each well is measured on an enzyme linked immunosorbent assay detector, the wavelength of 570nm is selected, the blank well of cell-free RPMl-1640 culture solution is adjusted to zero, and the absorbance value of each well is measured. The experiment was repeated three times and the results were recorded: cell growth inhibition ═ (control absorbance value-experimental absorbance value)/control absorbance value × 100%. Mapping Soft in GraphPad PrismThe article is plotted against inhibitor concentration to determine the log [ inhibitor ] of]Variable slope model estimation of IC versus response50The value is obtained.
5) And (3) water solubility detection:
the compounds 5a-5k are respectively prepared into solutions with different concentrations by using methanol as a solvent, and the ultraviolet absorption value is measured at 199nm wavelength to make corresponding standard curves. And dissolving 5mg of compounds 5a-5k in 5mL of water respectively, performing ultrasonic treatment for 10min to obtain insoluble substances in the water solution, passing the suspension through a filter membrane, diluting 1mL of filtrate with water to 6mL, and substituting ultraviolet absorption values measured at 199nm wavelength into corresponding standard curves to obtain relative concentration values respectively.
The invention is further described with reference to specific examples.
The preparation method of the diosgenin quaternary ammonium salt derivative provided by the embodiment of the invention has the following preparation route of the compound with the general formula (I):
Figure BDA0001594087970000091
1. synthesis of Compound 1
Under the protection of nitrogen, diosgenin (3.00g,7.24mmol) is dissolved in dichloromethane (30mL), triethylamine (5.0mL,36.2mmol) is added, methanesulfonyl chloride (2.2mL,28.9mmol) is added dropwise under ice bath, and the mixture is stirred at room temperature until the TLC detection reaction is complete. The reaction mixture was washed with saturated sodium bicarbonate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 1(3.32g, 93%) as a pale yellow solid.1H NMR(400MHz,CDCl3)δ5.41(d,J＝4.1Hz,1H,H-6),4.50(tt,J＝10.8,5.2Hz,1H,H-3),4.39(q,J＝7.3Hz,1H,H-16),3.46(d,J＝7.0Hz,1H,H-26α),3.36(t,J＝10.9Hz,1H,H-26β),2.99(s,3H,CH3S),2.61-2.39(m,2H).13C NMR(100MHz,CDCl3)δ138.81,123.65,109.40,82.02,80.87,66.96,62.18,56.48,49.95,41.72,40.37,39.77,39.25,38.89,36.98,36.64,32.13,31.93,31.50,31.45,30.40,29.07,28.91,20.93,19.34,17.26,16.39,14.64.HR-ESI-MS m/z calcd for C28H44O5S[M+H]+493.2987,found 493.2999.
2. Synthesis of Compound 2
Compound 1(3.00g,6.09mmol) was dissolved in DMF (20mL) and NaN was added at 80 deg.C3(0.79g,12.2mmol), reacted at 90 ℃ for 12h and checked by TLC for completion. The reaction mixture was diluted with ethyl acetate, washed successively with a saturated sodium chloride solution, water and a saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Separation by column chromatography (petroleum ether: ethyl acetate 150:1) gave 2(1.37g, 51%) as a white solid.1H NMR(400MHz,CDCl3)δ5.39(d,J＝4.7Hz,1H,H-6),4.40(q,J＝7.5Hz,1H,H-16),3.87(s,1H,H-3),3.46(dd,J＝10.2,3.4Hz,1H,H-26α),3.36(t,J＝10.9Hz,1H,H-26β),2.51(d,J＝14.9Hz,1H),2.19(d,J＝15.0Hz,1H).13C NMR(100MHz,CDCl3)δ138.25,123.02,109.40,80.94,66.97,62.20,58.30,56.60,49.96,41.75,40.37,39.87,37.35,36.18,33.73,32.10,31.95,31.53,31.45,30.45,28.96,26.23,20.65,19.16,17.29,16.43,14.67.HR-ESI-MS m/z calcd for C27H41N3O2[M+H]+440.3277,found 440.3278.
3. Synthesis of Compound 3
Compound 2(2.50g,5.69mmol) was dissolved in tetrahydrofuran (20mL), and water (2mL), PPh was added3(2.98g,11.4mmol), stirring at 60 ℃, detecting the completion of the reaction by TLC, and recovering the solvent under reduced pressure. Column chromatography (dichloromethane: methanol ═ 50:1) afforded 3(1.41g, 60%) as a white solid.1H NMR(400MHz,CDCl3)δ5.37(d,J＝5.0Hz,1H,H-6),4.41(q,J＝7.5Hz,1H,H-16),3.47(dd,J＝10.2,3.4Hz,1H,H-26α),3.37(t,J＝10.9Hz,1H,H-26β),3.20(s,1H,H-3),2.58(d,J＝13.9Hz,1H).13C NMR(100MHz,CDCl3)δ138.92,123.36,109.42,80.97,66.97,62.23,56.65,50.46,47.07,41.75,40.38,39.92,39.87,37.69,33.16,32.27,31.97,31.53,30.44,29.84,29.35,28.95,20.71,19.01,17.28,16.42,14.68.HR-ESI-MS m/z calcd for C27H43NO2[M+H]+414.3372,found 414.3366.
4. Synthesis of Compound 5a
Compound 3(0.20g,0.48mmol,1eq) was dissolved in a mixed solvent of dichloromethane (10mL) and acetonitrile (10mL), and potassium carbonate (0.33g,2.42mmol,5eq) and iodomethane were addedAlkane (0.3mL,4.83mmol,10eq), reacted at 60 ℃ until completion of TLC detection. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. Separation by column chromatography (dichloromethane: methanol ═ 50:1) gave 5a (0.24g, 84%) as a pale yellow solid. mp265-266 ℃.
Figure BDA0001594087970000111
–59.5(c 0.002,CHCl3).IR(KBr)νmax3547,3487,2963,1467,1059,807cm-1.1H NMR(400MHz,acetone-d6)δ5.73(s,1H,H-6),4.36(q,J＝7.8Hz,1H,H-16),4.04(s,1H,H-3),3.41(d,J＝9.5Hz,1H,H-26α),3.34(s,9H,N+-CH3),3.29(t,J＝11Hz,1H,H-26β).13C NMR(100MHz,CD3OD)δ139.43,126.34,110.58,82.20,73.01,67.86,63.71,57.88,52.22,52.19,52.16,47.90,42.88,41.60,40.86,37.93,32.75,32.70,32.62,32.58,32.42,31.43,30.65,29.88,22.09,17.50,16.89,14.89.HR-ESI-MS m/z calcd for C30H50O2N+[M–I]+493.2987,found 493.2999.
5. Synthesis of Compound 4b
Compound 3(0.45g,1.09mmol,1eq) was dissolved in a mixed solvent of dichloromethane (20mL) and acetonitrile (20mL), potassium carbonate (1.51g,10.9mmol,10eq) and allyl bromide (0.9mL,10.9mmol,10eq) were added, and the mixture was stirred at 40 ℃ until the reaction was complete by TLC. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. Separation by column chromatography (petroleum ether: ethyl acetate 50:1) yielded 4b (0.050g, 93%) as a yellow solid. mp 267-269 ℃.
Figure BDA0001594087970000121
–84.0(c 0.001,CHCl3).IR(KBr)νmax3457,2939,2865,1463,1267,1058,914,805cm-1.1H NMR(400MHz,CDCl3)δ5.86(d,J＝6.8Hz,2H,-CH＝CH2in allyl moiety),5.25(s,1H,H-6),5.12(d,J＝16.1Hz,4H,-CH＝CH 2in allyl moiety),4.40(q,J＝7.4Hz,1H,H-16),3.47(d,J＝8.4Hz,1H,H-26α),3.37(t,J＝10.9Hz,1H,H-26β),3.20(s,4H,N-CH2-),2.77(s,1H,H-3),2.29(q,J＝14.5Hz,1H).13C NMR(100MHz,CDCl3)δ136.16,120.63,116.71,109.40,81.04,66.98,62.23,56.73,55.18,52.33,49.53,41.75,40.45,40.00,37.33,35.53,33.59,32.08,31.96,31.54,30.46,29.85,29.52,28.96,25.06,22.84,20.75,20.27,17.29,16.47,14.68,14.27,1.16.HR-ESI-MS m/z calcd for C33H51NO2[M+H]+494.3998,found 494.3999.
6. Synthesis of Compound 4c
Compound 3(0.40g,0.97mmol,1eq) was dissolved in a mixed solvent of dichloromethane (15mL) and acetonitrile (15mL), and potassium carbonate (1.34g,9.70mmol,10eq), potassium iodide (1.48g,2.89mmol,3eq), propargyl chloride (2.1mL,29.3mmol,30eq) were added and reacted at 60 ℃ until completion of the reaction by TLC. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. Separation by column chromatography (dichloromethane: acetone ═ 60:1) gave 4c (0.38g, 80%) as a yellow solid. mp 160-.
Figure BDA0001594087970000131
–99.0(c0.002,CHCl3).IR(KBr)νmax3453,3316,2953,1459,1382,1061,986,903,807,638cm-1.1HNMR(400MHz,CDCl3)δ5.25(s,1H,H-6),4.39(q,J＝7.3Hz,1H,H-16),3.60-3.27(m,6H,N-CH2-and H-26),2.71(s,1H,H-3),2.37(d,J＝15.3Hz,1H).13C NMR(100MHz,CDCl3)δ140.61,120.78,109.38,80.98,79.79,72.74,66.95,62.19,56.66,55.17,49.57,41.73,40.39,39.95,39.70,37.31,35.50,33.64,32.07,32.00,31.50,31.45,30.44,29.84,28.94,25.21,22.83,20.65,19.90,17.28,16.43,14.66,1.15.HR-ESI-MS m/z calcd forC33H47NO2[M+H]+490.3685,found490.3685.
7. Synthesis of Compound 4d
Compound 3(0.30g,0.73mmol,1eq) was dissolved in a mixed solvent of dichloromethane (20mL) and acetonitrile (20mL), potassium carbonate (1.00g,7.24mmol,10eq) and bromomethylcyclopropane (1.4mL,15.2mmol,20eq) were added, and the reaction was stirred at 60 ℃ until TLC detection was complete. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. Column chromatography (dichloromethane: methanol 80:1) gave 4d (0.35g, 92%) as a white solid. mp169-172 ℃.
Figure BDA0001594087970000132
–81.0(c 0.002,CHCl3).IR(KBr)νmax3447,2956,2858,1462,1379,1177,1058,983,903cm-1.1H NMR(400MHz,CDCl3)δ5.20(s,1H,H-6),4.40(q,J＝15.0,7.5Hz,1H,H-16),3.47(d,J＝8.2Hz,1H,H-26α),3.38(t,J＝10.9Hz,1H,H-26β),2.95(s,1H,H-3),2.54(ddd,J＝40.1,13.7,6.2Hz,3H),2.34(s,1H),2.23(d,J＝14.5Hz,1H).13C NMR(100MHz,CDCl3)δ109.23,80.86,77.2,66.80,62.05,56.56,55.18,54.04,48.95,41.57,40.29,39.81,37.13,33.51,31.88,31.77,31.39,31.36,30.28,29.68,28.78,20.63,20.44,17.12,16.32,14.51,7.82,4.21,0.97.HR-ESI-MS m/z calcd for C35H55NO2[M+H]+522.4311,found 522.4316.
8. Synthesis of Compound 4e
Compound 3(0.30g,0.73mmol,1eq) was dissolved in a mixed solvent of dichloromethane (25mL) and acetonitrile (25mL), potassium carbonate (2.01g,14.5mmol,20eq), 1, 4-dibromobutane (0.9mL,7.33mmol,10eq) were added, and the reaction was stirred at 60 ℃ until completion of TLC detection. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. Column chromatography (dichloromethane: methanol 70:1) gave 4e (0.23g, 80%) as a white solid. mp 189-191 ℃.
Figure BDA0001594087970000141
–93.6(c 0.002,CHCl3).IR(KBr)νmax3444,2968,2789,1462,1382,1052,980,903cm-1.1H NMR(400MHz,CDCl3)δ5.30(s,1H,H-6),4.38(q,J＝7.5Hz,1H,H-16),3.45(d,J＝8.2Hz,1H,H-26α),3.35(t,J＝10.9Hz,1H,H-26β),2.65(s,br.,4H),2.43(d,J＝12.7Hz,1H),2.19(d,J＝14.8Hz,1H).13C NMR(100MHz,CDCl3)δ109.20,80.84,77.21,66.77,62.87,61.99,56.22,52.21,48.83,41.56,40.21,39.65,37.18,33.27,31.84,31.78,31.37,31.34,30.26,28.78,23.67,20.50,19.64,17.11,16.25,14.50,0.98.HR-ESI-MS m/z calcd for C31H49NO2[M+H]+468.3841,found 468.3844.
9. Synthesis of Compound 4f
The compound3(0.20g,0.48mmol,1eq) was dissolved in acetonitrile (25mL), potassium carbonate (0.67g,4.85mmol,10eq) and n-bromobutane (1.0mL,9.71mmol,20eq) were added and stirred at 80 ℃ until the reaction was complete by TLC. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. Column chromatography (dichloromethane: ethanol ═ 50:1) afforded 4f (0.23g, 92%) as a yellow oil.
Figure BDA0001594087970000142
–54.7(c 0.003,CHCl3).IR(KBr)νmax3456,2944,2881,1462,1388,1052,986,903cm-1.1H NMR(400MHz,CDCl3)δ5.41(s,1H,H-6),4.40(q,J＝7.3Hz,1H,H-16),3.47(d,J＝8.5Hz,1H,H-26α),3.36(t,J＝10.9Hz,1H,H-26β),3.17(s,1H,H-3),2.83(d,J＝38.3Hz,3H),2.55(s,1H),2.39(d,J＝15.4Hz,1H).13C NMR(100MHz,CDCl3)δ109.40,80.98,77.36,66.97,62.17,56.48,50.53,48.37,41.75,40.45,39.78,37.23,33.11,31.98,31.92,31.54,31.51,30.44,29.84,28.96,26.84,20.83,20.70,20.64,17.28,16.48,14.67,13.95,1.16.HR-ESI-MS m/z calcd for C35H59NO2[M+H]+526.4624,found526.4623.
10. Synthesis of Compound 4g
Compound 3(0.30g,0.73mmol,1eq) was dissolved in acetonitrile (30mL), potassium carbonate (1.00g,7.24mmol,10eq) and 2-bromoethyl methyl ether (2.1mL,21.9mmol,30eq) were added and stirred at 80 ℃ until the TLC check reaction was complete. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. Column chromatography (dichloromethane: acetone ═ 25:1) afforded 4g (0.28g, 73%) of a yellow oil.
Figure BDA0001594087970000151
–44.3(c 0.002,CHCl3).IR(KBr)νmax3461,2938,1459,1385,1260,1177,1117,1058,903cm-1.1H NMR(400MHz,CDCl3)δ5.30(s,1H,H-6),4.40(q,J＝7.4Hz,1H,H-16),3.62-3.20(m,8H,-OCH3and H-26),2.82(s,4H),2.33(d,J＝59.4Hz,3H).13C NMR(100MHz,CDCl3)δ109.43,81.01,77.37,66.98,62.18,59.02,56.70,50.69,49.09,41.73,40.45,39.94,37.25,33.25,32.03,31.92,31.50,30.44,29.85,29.80,28.93,22.85,20.78,20.51,17.29,16.49,14.67,1.17.HR-ESI-MS m/z calcd for C33H55NO4[M+H]+530.4209,found 530.4208.
11. Synthesis of Compound 4h
Compound 3(0.30g,0.73mmol,1eq) was dissolved in acetonitrile (40mL), potassium carbonate (1.00g,7.24mmol,10eq), potassium iodide (0.36g,2.17mmol,3eq), 2-chloroethanol (1.5mL,21.9mmol,30eq) were added and stirred at 80 ℃ until completion of the reaction as detected by TLC. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. Column chromatography (ethyl acetate: methanol 60:1) afforded a white solid, 4h (0.28g, 76%). mp229-231 ℃.
Figure BDA0001594087970000152
–42.4(c 0.009,CHCl3).IR(KBr)νmax3429,2971,1465,1385,1266,1061,805cm-1.1H NMR(400MHz,CDCl3)δ5.62(s,1H,H-6),4.40(q,J＝7.5Hz,1H,H-16),4.05(s,4H,-CH 2-OH),3.85(s,1H,H-3),3.29-3.70(m,6H,N-CH2-and H-26),2.79(d,J＝13.9Hz,1H),2.52(d,J＝16.2Hz,1H).13C NMR(100MHz,CDCl3)δ135.99,127.06,109.40,80.89,66.98,62.11,60.93,56.28,55.55,53.93,48.16,41.73,40.42,39.63,37.20,32.66,32.47,31.94,31.87,31.51,31.38,30.41,29.82,28.92,22.52,20.82,20.44,17.27,16.45,14.67,1.14.HR-ESI-MS m/z calcd forC31H51NO4[M+H]+502.3896,found 502.3894.
12. Synthesis of Compound 4i
Phthalimide (3.20g,0.05mmol) was dissolved in acetone (40mL), potassium carbonate (10.4g,0.15mmol) and 1, 4-dibromobutane (9.1mL,0.15mmol) were added, the reaction was carried out at 50 ℃ for 12h, and the completion of the reaction was checked by TLC. The reaction mixture was concentrated under reduced pressure, water (50mL) was added, and the mixture was extracted with methylene chloride (3X 25mL), and the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Column chromatography (petroleum ether: ethyl acetate: 3:1) afforded N- (4-bromobutyl) phthalimide (6.10g, 86%).1HNMR(400MHz,CDCl3)δ7.86-7.77(m,2H),7.75-7.64(m,2H),3.70(t,J＝6.7Hz,2H),3.42(t,J＝6.4Hz,2H),1.95-1.77(m,4H).
The preparation was as in 4f, the halohydrocarbon was N- (4-bromobutyl) phthalimide above, and separation by column chromatography (dichloromethane: acetone ═ 20:1) gave 4i as a yellow solid in 63% yield. mp 124-.
Figure BDA0001594087970000161
–32.8(c 0.006,CHCl3).IR(KBr)νmax3453,2953,1715,1403,1052,724cm-1.1H NMR(400MHz,CDCl3)δ7.83(dd,J＝5.3,3.1Hz,4H,H-Ar),7.70(dd,J＝5.3,3.0Hz,4H,H-Ar),5.16(s,1H,H-6),4.33(q,J＝7.5Hz,1H,H-16),3.66(t,J＝7.3Hz,4H),3.48(d,J＝10.2Hz,1H,H-26α),3.38(t,J＝10.9Hz,1H,H-26β),2.65(s,1H,H-3),2.51(t,J＝7.0Hz,3H),2.29(d,J＝14.3Hz,1H),2.13(d,J＝14.9Hz,1H).13C NMR(100MHz,CDCl3)δ168.41,134.25,132.06,123.51,109.25,80.85,66.84,62.00,56.13,47.86,41.63,40.31,39.66,37.01,33.20,32.59,32.02,31.77,31.44,31.19,30.31,29.71,29.29,28.84,26.73,20.98,20.79,17.17,16.41,14.58,14.15,10.06,1.04.HR-ESI-MS m/z calcd for C51H65N3O6[M+H]+816.4951,found816.4952.
13. Synthesis of Compound 4j
The preparation method is the same as 4g, and the halogenated hydrocarbon is cinnamyl chloride. Separation by column chromatography (dichloromethane: methanol ═ 90:1) afforded 4j as a yellow solid in 73% yield. mp 175 and 177 ℃.
Figure BDA0001594087970000171
–32.0(c 0.003,CHCl3).IR(KBr)νmax3441,2959,1664,1456,1382,1058,977,906,751,698cm-1.1H NMR(400MHz,CDCl3)δ7.48-7.16(m,10H,H-Ar),6.52(d,J＝15.3Hz,2H,-CH＝CH-),6.36(s,2H,-CH＝CH-),5.35(s,1H,H-6),4.42(q,J＝7.2Hz,1H,H-16),3.76-3.21(m,6H,N-CH2-and H-26).13C NMR(100MHz,CDCl3)δ128.69,127.62,126.47,114.08,109.41,81.02,77.36,66.97,62.20,56.68,52.21,49.30,41.75,40.45,39.95,37.34,33.52,32.06,31.94,31.53,30.44,29.84,28.95,20.78,20.33,17.28,16.48,14.67,14.27,1.16.HR-ESI-MS m/z calcd for C45H59NO2[M+H]+646.4624,found 646.4622.
14. Synthesis of Compound 4k
The preparation method is the same as 4c, and the halogenated hydrocarbon is 2-chloroacetonitrile. Separation by column chromatography (petroleum ether: ethyl acetate ═ 20:1) afforded 4k as a yellow solid in 68% yield. mp 212 and 214 ℃.
Figure BDA0001594087970000172
–114(c 0.001,CHCl3).IR(KBr)νmax3423,2953,1465,1379,1054,983,897cm-1.1H NMR(400MHz,CDCl3)δ5.31(s,1H,H-6),4.40(q,J＝7.5Hz,1H,H-16),3.57(s,2H,N-CH2-CN),3.46(d,J＝10.7Hz,1H,H-26α),3.37(t,J＝10.9Hz,1H,H-26β),3.09(s,1H,H-3),2.55(d,J＝14.3Hz,1H).13C NMR(100MHz,CDCl3)δ139.31,122.60,110.36,109.51,81.02,67.07,62.28,56.75,52.50,50.34,41.83,40.47,39.99,37.65,37.09,34.96,33.45,32.17,32.02,31.60,31.57,30.53,29.03,25.78,20.77,19.33,17.37,16.51,14.76.HR-ESI-MS m/z calcd for C29H44N2O2[M+H]+453.3481,found 453.3480.
15. Synthesis of Compound 5b
Compound 4b (0.25g, 0.51mmol,1eq) was dissolved in a mixed solvent of dichloromethane (10mL) and acetonitrile (10mL), iodomethane (1.0mL,15.2mmol,30eq) was added, the mixture was stirred at 60 ℃ until completion of the TLC detection reaction, and the reaction mixture was concentrated under reduced pressure. Separation by column chromatography (dichloromethane: methanol ═ 50:1) gave 5b (0.20g, 61%) as a yellow solid. mp 209-.
Figure BDA0001594087970000181
–50.7(c 0.003,CHCl3).IR(KBr)νmax3447,2968,1461,1056,984,903cm-1.1H NMR(400MHz,CDCl3)δ6.17-6.00(m,2H,-CH＝CH2in allyl moiety),5.85(s,1H,H-6),5.83-5.73(m,2H,-CH＝CHHin allyl moiety),5.69(d,J＝10.0Hz,2H,-CH＝CHH in allylmoiety),4.37(q,J＝7.3Hz,1H,H-16),4.19(dd,J＝13.3,7.1Hz,1H,N+-CHH-),4.12(d,J＝7.0Hz,2H,N+-CHH-),4.00(dd,J＝13.3,7.3Hz,1H,N+-CHH-),3.89(s,1H,H-3),3.43(d,J＝8.0Hz,1H,H-26α),3.33(t,J＝10.9Hz,1H,H-26β),3.09(s,3H,N+-CH3),2.78(d,J＝16.3Hz,2H).13C NMR(100MHz,CDCl3)δ137.80,129.47,129.27,125.82,124.78,124.70,109.31,80.78,77.37,68.46,66.87,62.51,62.02,56.59,46.38,46.18,41.60,40.47,39.68,36.87,32.01,31.71,31.55,31.39,31.35,30.30,29.45,28.81,22.01,21.26,21.06,17.19,16.48,14.58.HR-ESI-MS m/z calcd for C34H54O2N+[M–I]+508.4149,found508.4154.
16. Synthesis of Compound 5c
The same procedure as for preparation 5b was followed and column chromatography (dichloromethane: methanol ═ 70:1) gave 5c as a yellow solid in 65% yield. mp 190 and 192 ℃.
Figure BDA0001594087970000182
–55.3(c 0.003,CHCl3).IR(KBr)νmax3473,3241,2961,2915,2135,1463,1056,985,902cm-1.1H NMR(400MHz,CDCl3)δ5.82(s,1H,H-6),4.81-4.47(m,4H,N+-CH2-),4.35(s,1H,H-16),4.19(s,1H,H-3),3.55-3.19(m,5H,N+-CH3and H-26),3.00(d,J＝1.7Hz,2H,CH in propargyl moiety),2.89(d,J＝16.6Hz,1H),2.78(s,1H).13C NMR(100MHz,CDCl3)δ137.08,126.08,109.21,82.46,82.42,80.69,77.37,70.97,70.02,66.77,61.92,56.43,52.18,52.09,46.57,46.33,41.51,40.36,39.54,36.77,31.88,31.64,31.49,31.30,31.25,30.21,30.07,29.44,28.72,21.79,20.94,17.12,16.39,14.51.HR-ESI-MS m/z calcd for C34H50O2N+[M–I]+504.3836,found 504.3833.
17. Synthesis of Compound 5d
The preparation was as in 5b and was isolated by column chromatography (dichloromethane: methanol 70:1) to yield 5d as a white solid in 96% yield. mp 229-.
Figure BDA0001594087970000191
–47.7(c 0.003,CHCl3).IR(KBr)νmax3450,2965,1464,1058,985,903cm-1.1H NMR(400MHz,CDCl3)δ5.63(s,1H,H-6),4.38(q,J＝7.2Hz,1H,H-16),4.22(d,J＝5.6Hz,1H,H-3),3.58-3.38(m,5H,N+-CH2-and H-26α),3.33(t,J＝11.0Hz,1H,H-26β),3.20(s,3H,N+-CH3),2.75(s,1H),2.59(d,J＝16.5Hz,1H).13C NMR(100MHz,CDCl3)δ138.14,125.52,109.35,80.80,77.36,67.89,66.91,64.83,64.33,62.05,56.62,46.77,46.58,41.63,40.49,39.71,36.91,32.18,31.73,31.61,31.41,31.36,30.32,29.89,28.83,22.05,21.28,21.06,17.21,16.50,14.59,5.57,5.51,5.26,5.20,5.03.HR-ESI-MSm/z calcd for C36H58O2N+[M–I]+536.4462,found 536.4464.
18. Synthesis of Compound 5e
The same procedure as for preparation 5b was followed and column chromatography (dichloromethane: methanol 70:1) gave 5e as a white solid in 65% yield. mp 272 and 273 ℃.
Figure BDA0001594087970000192
–51.3(c 0.003,CHCl3).IR(KBr)νmax3461,2965,1462,1060,986,903cm-1.1H NMR(400MHz,CDCl3)δ5.57(s,1H,H-6),4.34(d,J＝6.3Hz,1H,H-16),4.09(s,1H,H-3),3.72(d,J＝33.6Hz,4H,N+-CH2-),3.39(s,1H,H-26α),3.29(t,J＝10.8Hz,1H,H-26β),3.00(s,3H,N+-CH3),2.81(s,1H),2.43(d,J＝16.7Hz,1H),2.25(s,4H).13C NMR(100MHz,CDCl3)δ137.93,125.09,109.21,80.66,77.37,70.17,66.77,64.58,64.23,61.90,56.44,47.01,46.22,41.49,40.30,39.55,36.81,32.10,31.60,31.53,31.27,31.20,30.19,28.70,22.32,21.71,21.50,21.34,20.82,17.10,16.35,14.48.HR-ESI-MSm/z calcd for C32H52O2N+[M–I]+482.3993,found 482.3997.
19. Synthesis of Compound 5f
Preparation was as in 5b, and recrystallized (petroleum ether: ethanol ═ 5:1) to give 5f (0.13g, 41%) as a white solid. mp 211 and 212 ℃.
Figure BDA0001594087970000201
–47.0(c 0.002,CHCl3).IR(KBr)νmax3464,2970,2884,1464,1387,1058,987,904cm-1.1H NMR(400MHz,CDCl3)δ5.68(s,1H,H-6),4.38(q,J＝7.3Hz,1H,H-16),3.97(d,J＝6.6Hz,1H,H-3),3.33(m,6H,N+-CH2-and H-26),3.12(s,3H,N+-CH3),2.86-2.73(m,1H),2.59(d,J＝16.7Hz,1H).13C NMR(100MHz,CDCl3)δ138.12,125.63,109.35,80.81,77.36,68.59,66.91,62.06,60.11,59.89,56.66,46.96,46.49,41.64,40.50,39.72,36.98,31.99,31.73,31.63,31.42,31.36,30.33,29.59,28.84,24.74,24.66,21.99,21.09,20.01,19.98,17.21,16.50,14.59,13.83,13.79.HR-ESI-MS m/z calcd for C36H62O2N+[M–I]+540.4775,found 540.4774.
20. Synthesis of Compound 5g
The same procedure as in 5b was followed and column chromatography (dichloromethane: ethanol 80:1) gave 5g of a yellow solid in 75% yield. mp 215 and 216 ℃.
Figure BDA0001594087970000202
–44.0(c 0.002,CHCl3).IR(KBr)νmax3453,2966,1466,1388,1124,1059,984,903cm-1.1H NMR(400MHz,CDCl3)δ5.68(s,1H,H-6),4.38(q,J＝7.2Hz,1H,H-16),4.11(d,J＝6.1Hz,1H,H-3),3.99-3.62(m,8H,N+-CH2-CH2-),3.44(d,J＝10.1Hz,1H,H-26α),3.41-3.29(m,7H,-O-CH3and H-26β),3.22(s,3H,N+-CH3),2.85-2.70(m,1H),2.60(d,J＝16.6Hz,1H).13C NMR(100MHz,CDCl3)δ138.25,125.67,109.35,80.84,77.37,70.54,66.92,66.47,66.43,62.10,60.85,60.37,59.39,56.67,47.82,46.44,41.67,40.53,39.75,36.89,32.00,31.75,31.56,31.44,31.41,30.35,30.02,29.76,28.86,22.13,21.29,17.21,16.50,14.58.HR-ESI-MS m/z calcd for C34H58O2N+[M–I]+544.4360,found544.4360.
21. Synthesis of Compound 5h
The preparation was carried out as in 5b, and recrystallization (petroleum ether: ethanol ═ 3:1) gave 5h as a white solid in 55% yield. mp 248-249 ℃.
Figure BDA0001594087970000211
–46.5(c 0.002,CHCl3).IR(KBr)νmax3378,2967,1464,1384,1059,985,903cm-1.1H NMR(400MHz,CDCl3)δ5.65(s,1H,H-6),4.40(q,J＝7.2Hz,1H,H-16),4.14(s,5H,-CH 2-OH and H-3),3.74(s,4H,N+-CH2-),3.46(d,J＝7.5Hz,1H,H-26α),3.36(t,J＝10.8Hz,1H,H-26β),3.22(s,3H,N+-CH3),2.74(d,J＝31.6Hz,1H),2.53(d,J＝16.0Hz,1H).13C NMR(100MHz,CDCl3)δ138.26,125.76,109.40,80.90,77.36,69.83,66.99,62.39,62.14,61.71,56.67,56.12,48.26,46.43,41.72,40.58,39.80,37.00,32.03,31.83,31.66,31.48,30.41,30.07,29.83,28.93,22.19,21.19,17.28,16.58,14.67,1.14.HR-ESI-MS m/z calcd for C32H54O4N+[M–I]+516.4047,found 516.4053.
22. Synthesis of Compound 5i
The preparation was as in 5b and was isolated by column chromatography (dichloromethane: ethanol ═ 50:1) to give 5i as a yellow solid in 64% yield. mp 189-.
Figure BDA0001594087970000212
–27.0(c 0.002,CHCl3).IR(KBr)νmax3436,2966,1718,1405,1055,722cm-1.1H NMR(400MHz,CDCl3)δ7.77(dd,J＝5.3,3.1Hz,4H,H-Ar),7.68(dd,J＝5.3,2.9Hz,4H,H-Ar),5.75(s,1H,H-6),4.36(dd,J＝14.9,7.3Hz,1H,H-16),3.96(d,J＝5.3Hz,1H,H-3),3.77-3.48(m,8H,N+-CH 2-CH2-CH2-CH 2-),3.43(d,J＝7.3Hz,1H,H-26α),3.33(t,J＝10.9Hz,1H,H-26β),3.15(s,3H,N+-CH3),2.80(d,J＝19.3Hz,1H),2.67(d,J＝16.5Hz,1H).13C NMR(100MHz,CDCl3)δ168.53,138.25,134.24,131.91,125.58,123.41,109.32,80.82,77.36,68.98,66.88,62.06,59.39,59.17,56.59,46.89,46.34,41.63,40.48,39.70,36.94,36.47,31.96,31.72,31.63,31.42,31.36,30.32,29.73,29.40,28.83,25.84,21.99,21.08,21.00,19.83,19.65,17.19,16.48,14.58.HR-ESI-MS m/zcalcd for C52H68O6N3 +[M–I]+830.5103,found 830.5104.
23. Synthesis of Compound 5j
The preparation is as in 5b and recrystallisation (petroleum ether: ethanol ═ 4:1) gives 5j as a light purple solid in 69% yield. mp208-209 ℃.
Figure BDA0001594087970000221
–17.0(c 0.002,CHCl3).IR(KBr)νmax3434,2964,1659,1461,1058,986,902,751,695cm-1.1H NMR(400MHz,CDCl3)δ7.51(s,4H,H-Ar),7.28(s,6H,H-Ar),7.11(dd,J＝22.0,15.7Hz,2H,＝CH-Ph),6.42(s,2H,-CH＝CH-Ph),5.84(s,1H,H-6),4.41(dd,J＝17.7,8.2Hz,4H,N+-CH2-),4.26(s,1H,H-16),3.94(s,1H,H-3),3.47(d,J＝8.3Hz,1H,H-26α),3.36(t,J＝10.9Hz,1H,H-26β),3.13(s,3H,N+-CH3),2.89(d,J＝16.3Hz,1H),2.76(s,1H).13C NMR(100MHz,CDCl3)δ143.04,142.90,137.92,134.87,134.82,129.46,129.43,128.90,128.87,127.64,127.61,125.90,114.90,114.85,109.37,80.87,77.36,68.43,66.95,62.79,62.12,56.69,46.44,46.04,41.68,40.52,39.76,36.93,32.15,31.77,31.63,31.47,31.37,30.38,29.64,28.89,21.99,21.57,21.10,17.25,16.52,14.63.HR-ESI-MS m/z calcd for C46H62O2N+[M–I]+660.4775,found 660.4772.
24. Synthesis of Compound 5k
Compound 4k (0.20g,0.44mmol,1eq) was dissolved in acetonitrile (20mL), potassium carbonate (0.61g,4.42mmol,10eq) and iodomethane (0.8mL,13.2mmol,30eq) were added and stirred at 80 ℃ until the reaction was complete by TLC. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. Column chromatography (dichloromethane: ethanol 80:1) gave 5k (0.23g, 85%) as a white solid. mp 203-.
Figure BDA0001594087970000231
–49.2(c 0.002,CHCl3).IR(KBr)νmax3459,2966,1465,1385,1062,984,903cm-1.1H NMR(400MHz,DMSO-d6)δ5.62(s,1H,H-6),4.85(s,2H,-CH2-CN),4.29(d,J＝6.5Hz,1H,H-16),3.84(s,1H,H-3),3.41(d,J＝10.7Hz,1H,H-26α),3.35(s,1H,H-26β),3.21(d,J＝10.8Hz,1H),3.15(d,J＝10.5Hz,6H,N+-CH3),2.66(s,2H).13C NMR(100MHz,DMSO-d6)δ137.80,124.54,112.27,108.42,80.22,71.46,65.90,61.74,56.06,50.20,49.67,49.50,45.56,41.07,39.23,36.22,31.28,30.97,30.88,30.80,29.79,28.46,28.17,21.33,20.54,20.36,17.08,16.14,14.64.HR-ESI-MS m/z calcd for C31H49O2N2 +[M–I]+481.3789,found 481.3790.
The water solubility test results of diosgenin quaternary ammonium salt derivatives are shown in the following table:
Figure BDA0001594087970000232
Figure BDA0001594087970000241
the results of the in vitro antitumor activity test of diosgenin quaternary ammonium salt derivatives are shown in the following table:
Figure BDA0001594087970000242
the above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents and improvements made within the spirit and principle of the present invention are intended to be included within the scope of the present invention.

Claims (9)

1. A diosgenin quaternary ammonium salt derivative is characterized in that the molecular structure of the diosgenin quaternary ammonium salt derivative is as follows:
Figure FDA0002370938080000011
wherein R1, R2 are hydrocarbyl or substituted hydrocarbyl; r3 is methyl; wherein
Figure FDA0002370938080000012
Figure FDA0002370938080000013
X＝I。
2. A method for preparing the diosgenin quaternary ammonium salt derivative according to claim 1, wherein the method for preparing the diosgenin quaternary ammonium salt derivative comprises the following steps:
dissolving the diosgenin C-3 amino derivative in acetonitrile or a mixed solvent of acetonitrile and dichloromethane, adding potassium carbonate and halogenated hydrocarbon, and heating and refluxing for 5-50 h; wherein acetonitrile and dichloromethane v/v ═ 1: 1;
filtering the reaction solution, and concentrating the filtrate under reduced pressure;
dissolving the intermediate obtained by column chromatographic separation in a mixed solvent of dichloromethane and acetonitrile, adding 30eq of iodomethane, heating and refluxing for 5-50h, and concentrating the reaction solution under reduced pressure; wherein dichloromethane and acetonitrile v/v ═ 1: 1;
recrystallizing or performing column chromatography to obtain diosgenin quaternary ammonium salt derivative compound;
the reaction formula of the preparation method of the diosgenin quaternary ammonium salt derivative is as follows:
Figure FDA0002370938080000021
3. use of the diosgenin quaternary ammonium salt derivative of claim 1 in preparation of antitumor drugs.
4. An application of the diosgenin quaternary ammonium salt derivative in the claim 1 in preparing a medicament for inhibiting A549 lung cancer cells.
5. Use of the diosgenin quaternary ammonium salt derivative of claim 1 in preparation of a medicament for inhibiting A431 skin squamous cell carcinoma cells.
6. Use of the diosgenin quaternary ammonium salt derivative of claim 1 in preparation of medicaments for inhibiting H1975 lung adenocarcinoma cells.
7. Use of the diosgenin quaternary ammonium salt derivative of claim 1 in preparation of a medicament for inhibiting HCT-116 colorectal adenocarcinoma cells.
8. Use of the diosgenin quaternary ammonium salt derivative of claim 1 in preparation of drugs for inhibiting spc-1 metastatic pancreatic cancer cells.
9. Use of the diosgenin quaternary ammonium salt derivative of claim 1 in the preparation of a medicament for inhibiting RamosB lymphoma cells.
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