CN110452283A - A kind of antitumor quaternary ammonium salt derivative and preparation method and application - Google Patents
A kind of antitumor quaternary ammonium salt derivative and preparation method and application Download PDFInfo
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Abstract
The invention belongs to medicine and pharmacology technical field, a kind of antitumor quaternary ammonium salt derivative and preparation method and application is disclosed, is chemically reacted be prepared for a series of antitumor derivatives and derivative in the application of anti-tumor aspect accordingly.The present invention shows through pharmacological evaluation: the diosgenin quaternary ammonium salt derivative of all synthesis significantly inhibits A549 lung carcinoma cell, H1975 lung adenocarcinoma cell, Aspc-1 transfer pancreatic cancer cell, A431 Skin Squamous Cell Carcinoma cell, anti-tumor activity is superior to diosgenin, and most of derivative is better than diosgenin to Ramos B lymphoma cell anti-tumor activity.
Description
Technical field
The invention belongs to medicine and pharmacology technical fields more particularly to a kind of antitumor quaternary ammonium salt derivative and preparation method thereof
And application.
Background technique
Currently, the prior art commonly used in the trade is such that
Cancer is to threaten the major disease of human life and health, it has also become one of an important factor for human death.With
The variation of environment and life style, China's cancer morbidity, the death rate persistently rise.Therefore, novel antineoplastic is explored
One of important directions as new drug development.
Natural active antineoplastic agents have many advantages, such as that significant in efficacy, toxic side effect is small.Diosgenin is in nature
In it is resourceful, have a variety of pharmacological activity such as antitumor, reducing blood lipid, antithrombotic, anti-inflammatory.Domestic and international a lot of research work table
Bright, diosgenin and its certain derivatives have obvious antitumor action.Structure is carried out as primer using diosgenin to repair
Decorations provide an approach to find better anti-tumor drug, the attention by domestic and international scientific worker, be one quite
The research work of tool value and prospect.
In recent years, researcher is concentrated mainly on A ring and F ring the structural modification of diosgenin and transformation, portion
Divide and reported that diosgenin derivative has significant ground anti-tumor activity, but is not fully solved existing for diosgenin and lacks
It falls into, also needs therefrom to explore more preferably medicines structure.Therefore, reasonable structural modification, design synthesis are carried out to diosgenin
New derivatives filter out significantly more efficient chemical structure, still have certain challenge.
In conclusion problem of the existing technology is:
Diosgenin and its derivative are as potential anti-tumor active substance, but its anti-tumor activity is still lower scarce
It falls into, which greatly limits its scope of applications.
Solve the difficulty and meaning of above-mentioned technical problem:
The present invention has designed and synthesized novel diosgenin derivative for the purpose of increasing its anti-tumor activity, and
All target derivatives are not reported both at home and abroad.In order to synthesize diosgenin derivative, need to introduce ester group on steroidal ring.
C3- hydroxyls of diosgenin are obtained carboxylate by esterification by present invention design, as intermediate and
Various reactive tertiary amines obtain a series of quaternary ammonium salt derivatives.
Summary of the invention
To solve the above-mentioned problems of the prior art, the purpose of the present invention is to provide a kind of diosgenin quaternary ammonium salts
Analog derivative and preparation method and application.
In order to achieve the above objectives, the technical solution of the present invention is as follows: a kind of antitumor quaternary ammonium salt derivative, feature exist
In the molecular structure of the derivative are as follows:
Wherein Y is tertiary amine groups or substituted tertiary amine groups；
X=F, Cl, Br, I.
Preferably, a kind of preparation method of antitumor quaternary ammonium salt derivative, which is characterized in that the preparation side
Method includes:
Step 1: being dissolved in methylene chloride for diosgenin, sequentially adds condensing agent, organic base, 5- halovaleric acid, TLC
Detect fully reacting；Compound 3 is recrystallized to obtain with alcohol after reduced pressure；
Step 2: being dissolved in acetonitrile for compound 3, and tertiary amine is added, is stirred to react at 80 DEG C to complete；Reaction solution is depressurized dense
Contracting, through isolated quaternary ammonium salt derivative 1a, 1d, 1e, 1f, 1h, 1i, 1j, the 1k of silica gel column chromatography.
Preferably, the preparation method of a kind of antitumor quaternary ammonium salt derivative, the condensing agent of the step 1 can be with
It is: 1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride or dicyclohexylcarbodiimide；The organic base can be with
It is: triethylamine, pyridine etc.；The alcohol may is that methanol, ethyl alcohol, propyl alcohol；Compound 3 is dissolved in acetonitrile by the step 2, is added
Tertiary amine after reaction detects fully reacting to TLC at 80 DEG C, then reaction solution is concentrated under reduced pressure, n-hexane is added, stirs at 25 DEG C
3h is filtered, and filter cake is quaternary ammonium salt derivative 1b, 1c.
Preferably, compound 3 is dissolved in by a kind of preparation method of antitumor quaternary ammonium salt derivative, the step 2
Acetonitrile is added tertiary amine and is cooled to room temperature after reaction detects fully reacting to TLC at 80 DEG C, a large amount of solids are precipitated, filters, filter cake
For quaternary ammonium salt derivative 1g.
Preferably, a kind of preparation method of antitumor quaternary ammonium salt derivative, which is characterized in that the Chinese yam soap
The reaction equation of the preparation method of aglycon quaternary ammonium salt derivative are as follows:
Preferably, the antitumor quaternary ammonium salt derivative application in preparation of anti-tumor drugs.
Preferably, the antitumor quaternary ammonium salt derivative inhibits the application in cancer cell drug in preparation.
Preferably, the antitumor quaternary ammonium salt derivative inhibits the application in cancer cell drug, feature in preparation
It is, the inhibition cancer cell is A549 lung carcinoma cell, A431 Skin Squamous Cell Carcinoma cell, H1975 lung adenocarcinoma cell, spc-1 transfer
Pancreatic cancer cell, Ramos B lymphoma cell.
Preferably, a kind of antitumor quaternary ammonium salt derivative, the antitumor quaternary ammonium salt derivative are antitumor
Activity is higher than primer diosgenin.
Compared with the existing technology, it the invention has the benefit that the present invention is for the purpose of improving anti-tumor activity, devises
Diosgenin quaternary ammonium salt derivative, has filtered out with the steroidal compounds compared with high anti-tumor activity.
Specific embodiment
In order to make the objectives, technical solutions, and advantages of the present invention clearer, with reference to embodiments, to the present invention
It is further elaborated.It should be appreciated that the specific embodiments described herein are merely illustrative of the present invention, it is not used to
Limit the present invention.
In the prior art, poor in anti-tumor activity effect.
Diosgenin quaternary ammonium salt derivative provided in an embodiment of the present invention is indicated with general formula (1):
Wherein R1、R2、R3For alkyl or substituted hydrocarbon radical；
X=F, Cl, Br, I；
The preparation method of diosgenin quaternary ammonium salt derivative provided in an embodiment of the present invention, chemical equation are as follows:
Below with reference to concrete analysis, the invention will be further described.
1) new compound structure of all synthesis of the present invention all passes through1H NMR,13C NMR, IR, HRMS (ESI) confirmation, are used
Infrared, fusing point, optical activity characterization.Synthesized quaternary ammonium salt derivative is to A549 (human lung carcinoma cell), A431 (application on human skin squamous carcinoma
Cell), H1975 (human lung adenocarcinoma cell), Aspc-1 (people shift pancreatic cancer cell), Ramos (Human B lymphoma cell), carry out
Corresponding biological activity test.
2) experiment agents useful for same is all analytical reagents, and not purified direct use unless otherwise indicated.1H NMR
With13C NMR is measured with Agilent DD2 400-MR (400MHz) nuclear magnetic resonance chemical analyser, and TMS is as internal standard, CDCl3As
Solvent；IR is measured with 3000 Fourier Transform Infrared Spectrometer of FTS (Digilab company, the U.S.), KBr tabletting；HRMS LCQ
The measurement of Advantage Max mass spectrograph；Optically-active is measured with SGW-1 (Shanghai Instrument Physical Optics Instrument Co., Ltd.) polarimeter；
Fusing point SGW X-4 micro melting point tester (Shanghai Precision Scientific Apparatus Co., Ltd), temperature is not calibrated.
3) cell culture:
The logarithmic growth phase cell of A549, A431, H1975, HCT-116, Aspc-1, Ramos are collected, cell suspension is adjusted
Concentration, with every hole 7 × 103A cell, every 100 μ L of pore volume are inoculated into 96 orifice plates, and every hole sets 4 multiple holes, and (edge hole is with sterile
PBS filling).After cell is adherent, 0%FBS RPMI-1640 starvation 8h, control group is cultivated with 10%FBS RPMI-1640.37
DEG C, 5%CO2Continue to cultivate 48h in incubator.
4) MTT is detected:
In eight groups of cells after cultivating 48h, 100 μ L MTT solution (5mgmL are added-1), culture is terminated after 4h,
100 μ L, tri- liquid is added in every hole makes to crystallize abundant dissolution in low-speed oscillation 10min on shaking table.It is surveyed on enzyme-linked immunosorbent assay instrument
Fixed each hole shading value (OD value), selects 570nm wavelength, with cell-free i.e. RPMl-1640 culture solution blank well zeroing, surveys each
The absorbance value in hole.Experiment in triplicate, records result: inhibitory rate of cell growth=(control group absorbance value-experimental group extinction
Angle value)/control group absorbance value × 100%.Figure is done for inhibitor concentration in GraphPad Prism mapping software, so as to
By log [inhibitor] relative to reaction, variable slope model estimates IC50Value.
The invention will be further described combined with specific embodiments below.
The preparation method of diosgenin quaternary ammonium salt derivative provided in an embodiment of the present invention, general formula (1) compound
Preparation route:
The synthesis of compound 3
Diosgenin (10.0g, 24.1mmol) is dissolved in methylene chloride (300mL), sequentially adds EDCHCl
(18.4g, 96.3mmol), 4-dimethylaminopyridine (1.20g, 9.82mmol), 5- bromine valeric acid (17.5 g, 96.7mmol), 25
DEG C reaction 3h, TLC detect fully reacting.Reaction solution successively use 2N hydrochloric acid (3 × 100 mL), saturated sodium bicarbonate (3 ×
100mL), water (3 × 100mL) washs, and organic layer is dry with anhydrous sodium sulfate, is obtained after reduced pressure with ethyl alcohol recrystallization white solid
Body 3 (11.0g, 79%).m.p.108-109℃.[α]18 D–94.3(c 0.003,CHCl3).IR(KBr)νmax 3464,
2959,1745,1459,1388,1281,1200, 1052,1010,989,903cm-1.1H NMR(400MHz,CDCl3)δ5.37
(d, J=3.4Hz, 1H, H-6), 4.68-4.53 (m, 1H, H-3), 4.40 (q, J=6.8Hz, 1H, H-16), 3.52-3.29
(m,4H,H-26and -CH2-Br),2.41-2.23(m,4H,H-4and-COCH2-)ppm.13C NMR(100MHz,CDCl3)δ
172.66,139.75,122.53,109.40,80.92,74.04,66.96,62.18,56.54,50.04,41.73,40.38,
39.84,38.24,37.06,36.85,33.76,33.22,32.16,32.12,31.96,31.51,30.42,28.93,
27.90,23.71,20.94,19.47,17.28,16.42,14.67ppm.HR-ESI-MS m/z calcd for
C32H49BrO4Na[M+Na]+601.2692,found 601.2690.
The synthesis of compound 1a
Compound 3 (0.60g, 1.04mmol, 1eq.) is dissolved in acetonitrile (15mL), addition triallylamine (3.6mL,
20.8mmol, 20eq.), stirring detects fully reacting to TLC at 80 DEG C.Reaction solution is concentrated under reduced pressure, methylene chloride is added
(30mL) dissolution, is washed with 5%HBr (3 × 15mL), and organic layer is dry with anhydrous sodium sulfate, and solvent is recovered under reduced pressure.Through silicagel column
Chromatography (methylene chloride: methanol (v/v)=100:1) isolated yellow solid 1a (0.26g, 35%).m.p.178-179℃.
[α]18D–67.0(c 0.002,CHCl3).IR (KBr)νmax 3421,2963,1738,1464,1382,1264,1184,
1057,1015,990,962,899cm-1. 1H NMR(400MHz,CDCl3)δ6.10-5.92(m,3H,-CH=CH2 in
Allyl moiety), 5.84-5.55 (m, 6H ,-CH=CH 2 in allyl moiety),5.28(s,1H,H-6),4.49
(d, J=5.3Hz, 1H, H-3), 4.33 (d, J=7.5Hz, 1H, H-16), 4.08 (d, J=6.1Hz, 6H, N+-CH2-in
Allyl moiety), 3.39 (d, J=10.0Hz, 1H, H-26 α), 3.27 (d, J=10.2Hz, 3H, N+-CH2-and H-26
β),2.32(m,2H,-COCH2), 2.22 (d, J=7.6Hz, 2H, H-4) ppm.13C NMR(100MHz,CDCl3)δ
172.36,139.56,129.36, 124.26,122.43,109.26,80.76,74.17,66.81,62.04,61.66,
58.57,56.40,49.91,41.57, 40.23,39.68,38.08,36.90,36.70,33.36,32.01,31.80,
31.35,30.25,29.66,28.77, 27.73,21.74,21.64,20.79,19.32,17.13,16.26,
14.51ppm.HR-ESI-MS m/z calcd for C41H64O4N[M–Br]+634.4830,found 634.4836.
The synthesis of compound 1b
Compound 3 (0.80g, 1.39mmol, 1eq.) is dissolved in acetonitrile (20mL), N, N- dimethyl butylamine is added
(3.9mL, 27.8mmol, 20eq.), reaction detects fully reacting to TLC at 80 DEG C.Reaction solution is concentrated under reduced pressure, be added just oneself
Alkane (3 × 30mL) stirs 3h at 25 DEG C, filters, and filter cake is white solid 1b (0.81g, 86%).m.p.226-227℃.[α]
18D–83.3(c 0.003,CHCl3).IR(KBr)νmax 3461, 2960,1737,1465,1384,1254,1185,1061,
1015,987,903cm-1.1H NMR(400MHz, CDCl3)δ5.33(s,1H,H-6),4.54(s,1H,H-3),4.38(d,J
=7.2Hz, 1H, H-16), 3.70-3.40 (m, 6H, N+-CH2-and H-26),3.37(s,6H,N+-CH3), 2.36 (d, J=
6.1Hz,2H,-COCH2-), 2.32-2.04(m,4H)ppm.13C NMR(100MHz,CDCl3)δ172.29,139.60,
122.53,109.33, 80.84,74.26,66.89,63.96,63.53,62.12,56.48,51.38,49.98,41.65,
40.30,39.76, 38.16,36.97,36.78,33.58,32.09,31.88,31.43,30.33,28.85,27.82,
24.70,22.15, 21.65,20.86,19.70,19.39,17.20,16.34,14.58,13.79ppm.HR-ESI-MS m/z
calcd for C38H64O4N[M–Br]+598.4830,found 598.4835.
The synthesis of compound 1c
The same 1b of preparation method obtains white solid 1c, yield 90%.m.p.248-249℃.[α]18D–78.0 (c
0.003,CHCl3).IR(KBr)νmax 3447,2962,1735,1464,1383,1251,1184,1059,1013, 989,
905cm-1.1H NMR(400MHz,CDCl3) δ 5.33 (s, 1H, H-6), 4.54 (d, J=4.5Hz, 1H, H-3), 4.44-4.30
(m,1H,H-16),3.78(s,4H,N+-CH2-in pyrrolidine moiety),3.72-3.59 (m,2H,N+-CH2-),
3.43 (d, J=9.5Hz, 1H, H-26 α), 3.34 (t, J=10.8Hz, 1H, H-26 β), 3.26 (s, 3H, N+-CH3)ppm.13C
NMR(100MHz,CDCl3)δ172.44,139.63,122.53,109.34, 80.85,74.25,66.89,64.62,63.74,
62.13,56.49,49.99,48.85,41.65,40.31,39.77, 38.16,36.98,36.79,33.62,32.10,
31.89,31.44,30.34,28.85,27.82,23.41,21.78, 20.87,19.40,17.20,16.34,
14.59ppm.HR-ESI-MS m/z calcd for C37H60O4N[M–Br]+ 582.4517,found 582.4521.
The synthesis of compound 1d
The same 1a of preparation method, through silica gel column chromatography (methylene chloride: methanol (v/v)=70:1) isolated white solid
1d, yield 47%.m.p.247-249℃.[α]18D–76.3(c 0.003,CHCl3).IR(KBr)νmax 3459,2963,
1736,1463,1384,1250,1184,1059,1013,989,904cm-1.1H NMR(400 MHz,CDCl3)δ5.33(s,
1H, H-6), 4.55 (d, J=7.5Hz, 1H, H-3), 4.37 (q, J=7.2Hz, 1H, H-16), 3.85-3.51 (m, 6H, N+-
CH2), 3.44 (d, J=8.4Hz, 1H, H-26 α), 3.39-3.19 (m, 4H, H-26 β and N+-CH3),2.38(s,2H,-
COCH2), 2.27 (d, J=7.4Hz, 2H, H-4) ppm.13C NMR (100MHz,CDCl3)δ172.40,139.62,
122.52,109.33,80.83,74.24,66.88,62.11,61.25, 56.48,49.98,41.64,40.30,39.76,
38.18,36.98,36.78,33.73,32.09,31.87,31.42, 30.33,28.84,27.85,21.88,21.54,
20.89,20.85,20.36,19.41,17.19,16.34,14.58 ppm.HR-ESI-MS m/z calcd for C38H62O4N
[M–Br]+596.4673,found 596.4706.
The synthesis of compound 1e
The same 1a of preparation method, through silica gel column chromatography (methylene chloride: methanol (v/v)=50:1) isolated yellow solid
1e, yield 67%.m.p.232-234℃.[α]18D–63.0(c 0.002,CHCl3).IR(KBr)νmax 3449,2970,
2375,1708,1461,1399,1265,1060,801cm-1.1H NMR(400MHz,CDCl3) δ5.36(s,1H,H-6),
4.55 (s, 1H, H-3), 4.40 (d, J=7.3Hz, 1H, H-16), 4.33-3.51 (m, 14H, CH2 in morpholine,N+-
CH2-and-CH 2-CH 2- OH), 3.46 (d, J=8.6Hz, 1H, H-26 α), 3.36 (t, J=10.8Hz, 1H, H-26 β)
ppm.13C NMR(100MHz,CDCl3)δ172.66,139.76,122.59, 109.36,80.90,74.28,66.95,
62.25,61.08,60.64,59.64,56.57,55.87,50.06,41.73, 40.39,39.86,38.30,37.10,
36.88,33.99,32.21,31.99,31.53,30.42,28.94,28.00, 22.01,21.69,20.97,19.55,
17.28,16.44,14.69ppm.HR-ESI-MS m/z calcd for C38H62O6N[M–Br]+628.4572,found
628.4565.
The synthesis of compound 1f
The same 1a of preparation method, through silica gel column chromatography (methylene chloride: methanol (v/v)=90:1) isolated yellow solid
1f, yield 59%.m.p.141-142℃.[α]18D–68.5(c 0.002,CHCl3).IR(KBr)νmax 3438, 2962,
1736,1463,1379,1260,1182,1057,986,903,698cm-1.1H NMR(400MHz, CDCl3) δ 7.90 (d, J=
8.1Hz, 2H, H-Ph), 7.56 (t, J=7.6Hz, 2H, H-Ph), 7.46 (t, J=7.2Hz, 1H, H-Ph), 5.26 (s, 1H,
H-6,),4.50-4.28(m,4H,N+-CH2-,H-3and H-16),3.91(s,6H, N+-CH3), 3.41 (d, J=8.2Hz,
1H, H-26 α), 3.31 (t, J=10.9Hz, 1H, H-26 β), 2.20 (t, J=6.7 Hz, 2H ,-COCH2), 2.13 (d, J=
7.7Hz,2H,H-4)ppm.13C NMR(100MHz,CDCl3)δ 172.12,144.34,139.57,130.82,130.41,
122.37,120.85,109.27,80.78,73.97,68.31, 66.82,62.07,56.42,55.21,55.15,49.91,
41.59,40.24,39.70,38.01,36.88,36.69, 33.64,32.02,31.82,31.37,30.28,28.79,
27.66,22.97,21.37,20.80,19.33,17.15, 16.28,14.54ppm.HR-ESI-MS m/z calcd for
C40H60O4N[M–Br]+618.4517,found 618.4501.
The synthesis of compound 1g
Compound 3 (0.50g, 0.87mmol, 1eq.) is dissolved in acetonitrile (20mL), N, N- dimethyl benzylamine is added
(2.6mL, 17.4mmol, 20eq.), stirring detects fully reacting to TLC at 80 DEG C, is cooled to room temperature, a large amount of solids are precipitated, and takes out
Filter, filter cake are white solid 1g (0.55g, 77%).m.p.250-251℃.[α]18D –79.9(c 0.003,CHCl3).IR
(KBr)νmax 3459,2964,1730,1463,1388,1257,1178,1057, 1014,986cm-1.1H NMR(400MHz,
CDCl3) δ 7.64 (d, J=6.7Hz, 2H, H-Ph), 7.49-7.35 (m, 3H, H-Ph), 5.34 (d, J=3.6Hz, 1H, H-
6),5.02(s,2H,N+-CH2- Ph), 4.61-4.49 (m, 1H, H-3), 4.38 (q, J=7.4Hz, 1H, H-16), 3.64-
3.52(m,2H,N+-CH2), 3.48-3.41 (m, 1H, H-26 α), 3.34 (t, J=10.9Hz, 1H, H-26 β), 3.29 (s,
6H,N+-CH3), 2.35 (dd, J=14.2,7.2Hz, 3H), 2.27 (d, J=7.8Hz, 2H) ppm.13C NMR(100MHz,
CDCl3)δ172.30,139.61,133.28, 130.81,129.30,127.29,122.52,109.33,80.83,74.23,
67.44,66.88,63.18,62.12, 56.48,49.97,49.87,41.65,40.30,39.76,38.15,36.97,
36.77,33.57,32.09,31.88, 31.43,30.33,28.84,27.81,22.30,21.66,20.86,19.39,
17.20,16.34,14.59ppm. HR-ESI-MS m/z calcd for C41H62O4N[M–Br]+632.4673,found
632.4657.
The synthesis of compound 1h
The same 1a of preparation method, through silica gel column chromatography (methylene chloride: methanol (v/v)=40:1) isolated white solid
1h, yield 75%.m.p.256-257℃.[α]18D–77.7(c 0.003,CHCl3).IR(KBr)νmax 3459,2963,
1735,1464,1403,1268,1189,1062,987cm-1.1H NMR(400MHz,CDCl3) δ5.34(s,1H,H-6),
4.63-4.49 (m, 1H, H-3), 4.38 (q, J=7.3Hz, 1H, H-16), 3.69-3.11 (m, 10H, N+-CH2-and H-
26), 2.40 (t, J=6.5Hz, 2H ,-COCH2), 2.28 (d, J=8.0Hz, 2H, H-4) ppm.13C NMR(100MHz,
CDCl3)δ172.26,139.51,122.41,109.22,80.73,74.13, 66.77,62.03,57.09,56.38,
53.53,49.88,41.54,40.20,39.65,38.05,36.87,36.67, 33.40,31.98,31.77,31.33,
30.22,28.74,27.70,21.67,21.33,20.75,19.28,17.10, 16.23,14.48,8.04ppm.HR-ESI-
MS m/z calcd for C38H64O4N[M–Br]+598.4830,found 598.4813.
The synthesis of compound 1i
The same 1a of preparation method, through silica gel column chromatography (methylene chloride: methanol (v/v)=50:1) isolated white solid
1i, yield 65%.m.p.219-220℃.[α]18D–85.0(c 0.003,CHCl3).IR(KBr)νmax 3426, 2962,
1736,1462,1388,1257,1182,1058,900cm-1.1H NMR(400MHz,CDCl3)δ5.29 (s,1H,H-6),
4.52(s,1H,H-3),4.37(s,2H,H-16and-CH-OH),3.98(s,2H,N+-CH2-), 3.72-3.14(m,8H,N+-
CH2-and H-26)ppm.13C NMR(100MHz,CDCl3)δ172.59, 139.70,122.52,109.35,80.87,
74.22,66.92,64.14,63.89,62.17,56.52,55.08,54.21, 50.00,41.68,40.34,39.79,
38.18,37.02,36.82,33.78,32.14,31.92,31.47,30.37, 28.89,27.85,26.41,21.87,
21.83,21.68,20.91,19.45,18.19,17.24,16.39,14.64ppm. HR-ESI-MS m/z calcd for
C39H62O5N[M–Br]+624.4623,found 624.4609.
The synthesis of compound 1j
The same 1a of preparation method, through silica gel column chromatography (methylene chloride: methanol (v/v)=70:1) isolated yellow solid
1j, yield 63%.m.p.244-245℃.[α]18D–78.7(c 0.003,CHCl3).IR(KBr)νmax 3452, 2952,
2378,1732,1521,1459,1405,1179,1054cm-1.1H NMR(400MHz,CDCl3)δ 5.36(s,1H,H-6),
4.58 (s, 1H, H-3), 4.40 (d, J=7.2Hz, 1H, H-16), 4.11 (s, 2H ,-CH 2-OH), 3.90-3.00(m,10H,N+-CH2-and H-26)ppm.13C NMR(100MHz,CDCl3)δ172.46, 139.70,122.57,109.39,80.90,
74.30,66.95,62.19,61.10,60.37,58.94,56.55,55.49, 50.05,41.72,40.37,39.83,
38.22,37.04,36.85,33.62,32.16,31.95,31.50,30.40, 28.91,27.87,21.82,21.35,
21.05,20.93,20.06,19.46,17.25,16.40,14.64ppm. HR-ESI-MS m/z calcd for C39H64O5N
[M–Br]+626.4779,found 626.4779.
The synthesis of compound 1k
The same 1a of preparation method, through silica gel column chromatography (methylene chloride: methanol (v/v)=50:1) isolated yellow solid
1k, yield 73%.m.p.222-223℃.[α]18D–62.0(c 0.003,CHCl3).IR(KBr)νmax 3443,2958,
2378,1732,1461,1185,1057,902cm-1.1H NMR(400MHz,CDCl3)δ5.36 (s,1H,H-6),4.55(s,
1H, H-3), 4.39 (q, J=7.4Hz, 1H, H-16), 4.28-3.50 (m, 13H, CH2 in morpholine,N+-CH2-and
N+-CH3), 3.46 (d, J=7.6Hz, 1H, H-26 α), 3.35 (t, J=10.9Hz, 1H, H-26 β) ppm.13C NMR
(100MHz,CDCl3)δ172.43,139.56,122.47,109.24,80.75, 74.20,66.80,65.22,62.06,
61.15,60.26,56.41,49.90,48.50,41.57,40.22,39.69, 38.15,36.93,36.72,33.81,
32.03,31.81,31.36,30.25,28.77,27.85,21.86,21.58, 20.79,19.36,17.11,16.26,
14.51ppm.HR-ESI-MS m/z calcd for C37H60O5N[M–Br]+ 598.4466,found 598.4471.
Test result is as follows shown in table for diosgenin quaternary ammonium salt derivative anti tumor activity in vitro:
Can reflect from anti-tumor activity test data: the anti-tumor activity of synthesized compound 1a-1k compares guide
The activity of object 2 is stronger.
The foregoing is merely illustrative of the preferred embodiments of the present invention, is not intended to limit the invention, all in essence of the invention
Made any modifications, equivalent replacements, and improvements etc., should all be included in the protection scope of the present invention within mind and principle.
The above description is merely a specific embodiment, but scope of protection of the present invention is not limited thereto, any
The change or replacement expected without creative work, should be covered by the protection scope of the present invention.Therefore, of the invention
Protection scope should be determined by the scope of protection defined in the claims.
Claims (9)
1. a kind of antitumor quaternary ammonium salt derivative, which is characterized in that the molecular structure of the derivative are as follows:
Wherein Y is tertiary amine groups or substituted tertiary amine groups；
X=F, Cl, Br, I.
2. a kind of preparation method of antitumor quaternary ammonium salt derivative as described in claim 1, which is characterized in that the preparation
Method includes:
Step 1: being dissolved in methylene chloride for diosgenin, sequentially adds condensing agent, organic base, 5- halovaleric acid, TLC detection
Fully reacting；Compound 3 is recrystallized to obtain with alcohol after reduced pressure；
Step 2: being dissolved in acetonitrile for compound 3, and tertiary amine is added, is stirred to react at 80 DEG C to complete；Reaction solution is concentrated under reduced pressure,
Through isolated quaternary ammonium salt derivative 1a, 1d, 1e, 1f, 1h, 1i, 1j, the 1k of silica gel column chromatography.
3. a kind of preparation method of antitumor quaternary ammonium salt derivative as claimed in claim 2, the condensing agent of the step 1
It may is that 1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride or dicyclohexylcarbodiimide；The organic base
It may is that triethylamine, pyridine etc.；The alcohol may is that methanol, ethyl alcohol, propyl alcohol；Compound 3 is dissolved in acetonitrile by the step 2,
Tertiary amine is added, is reacted at 80 DEG C after detecting fully reacting to TLC, then reaction solution is concentrated under reduced pressure, n-hexane is added, is stirred at 25 DEG C
3h is mixed, is filtered, filter cake is quaternary ammonium salt derivative 1b, 1c.
4. a kind of preparation method of antitumor quaternary ammonium salt derivative as claimed in claim 2, the step 2 is by compound 3
It is dissolved in acetonitrile, tertiary amine is added and is cooled to room temperature after reaction detects fully reacting to TLC at 80 DEG C, a large amount of solids is precipitated, filters,
Filter cake is quaternary ammonium salt derivative 1g.
5. a kind of preparation method of antitumor quaternary ammonium salt derivative as claimed in claim 2, which is characterized in that the Chinese yam
The reaction equation of the preparation method of sapogenin quaternary ammonium salt derivative are as follows:
6. a kind of antitumor quaternary ammonium salt derivative application in preparation of anti-tumor drugs as described in claim 1.
7. a kind of antitumor quaternary ammonium salt derivative as described in claim 1 inhibits the application in cancer cell drug in preparation.
8. antitumor quaternary ammonium salt derivative according to claim 7 inhibits the application in cancer cell drug in preparation,
It is characterized in that, the inhibition cancer cell is A549 lung carcinoma cell, A431 Skin Squamous Cell Carcinoma cell, H1975 lung adenocarcinoma cell, spc-1
Shift pancreatic cancer cell, Ramos B lymphoma cell.
9. application according to claim 6, which is characterized in that the antitumor quaternary ammonium salt derivative anti-tumor activity is high
In primer diosgenin.
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