CN107722035B - Artemisinin-piperazine derivatives, preparation method thereof and application thereof in preparation of anti-liver cancer drugs - Google Patents
Artemisinin-piperazine derivatives, preparation method thereof and application thereof in preparation of anti-liver cancer drugs Download PDFInfo
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Abstract
The invention discloses an artemisinin-piperazine derivative, a preparation method thereof and application of the derivative in preparation of anti-liver cancer drugs. The method takes triethylamine as an acid-binding agent, prepares the artemisinin-piperazine derivative by a one-pot method, and has the advantages of mild reaction conditions, simple and convenient operation and better yield. In addition, the prepared derivative has obvious in-vitro inhibition effect on human liver cancer SMMC-7721 cells, and the inhibition effect is equivalent to that of a first-line anti-liver cancer clinical chemotherapeutic medicament vincristine. The invention provides a feasible strategy for the application of the artemisinin-piperazine derivative in the preparation of anti-liver cancer drugs.
Description
Technical Field
The invention relates to an artemisinin-piperazine derivative, a preparation method thereof and application thereof in preparing anti-liver cancer drugs.
Background
Artemisinin has good antimalarial activity, but its antitumor activity is less studied. Although artemisinin and its derivatives are clinically used for many years, the application of artemisinin is still limited due to the defects of poor oil solubility and water solubility, poor thermal stability, easy decomposition caused by the influence of moisture, heat and reducing substances, high clinical recurrence rate and the like. Therefore, it is a significant work to design and prepare a series of novel artemisinin derivatives by a chemical modification method and examine the antitumor activity of the artemisinin derivatives.
Piperazine can improve the biological activity of the drug by forming a plurality of hydrogen bonds or ionic bonds, can also adjust the solubility and acid-base balance of the drug, promotes the pharmacokinetics of the drug, and has obvious effect on the aspect of tumor resistance. Therefore, it is often introduced into drug molecules as a kind of potentiating group.
The dithiocarbamate compounds are important sulfur-containing compounds with unique structures and properties, and occupy important positions in the synthesis of medicaments. It has wide bioactivity, such as antibacterial, antiviral, antioxidant, and chronic alcoholism and heavy metal poisoning. In recent years, more and more researches show that the dithiocarbamates have better tumor prevention and anti-tumor activity, and attract the research interest of scholars at home and abroad.
The artemisinin-piperazine derivative prepared by using piperazine as a connector and introducing an amino dithioformate structure into an artemisinin molecule under mild conditions has an obvious inhibition effect on the growth of human liver cancer cells (SMMC-7721), so that the artemisinin-piperazine derivative has a very promising prospect as a potential anti-liver cancer drug.
Disclosure of Invention
In view of the above, the present invention aims to provide a class of artemisinin-piperazine derivatives. The derivatives have simple preparation method and high anti-liver cancer activity.
The invention also aims to provide a preparation method of the artemisinin-piperazine derivative.
The invention also aims to provide the application of the artemisinin-piperazine derivatives in the aspect of resisting liver cancer.
The purpose of the invention is realized by the following technical scheme:
an artemisinin-piperazine derivative is characterized by the following general formula:
wherein R is:
the preparation method of the artemisinin-piperazine derivative comprises the following steps:
dissolving artemisinin-piperazine and carbon disulfide in an amount which is four times that of artemisinin-piperazine in acetonitrile, adding triethylamine in an amount which is ten times that of artemisinin-piperazine, stirring at room temperature for 10min, adding a halide acetonitrile solution in an amount which is twice that of artemisinin-piperazine, gradually raising the temperature to 60 ℃, reacting for 4-12 h, tracking by TLC, developing phosphomolybdic acid, evaporating the solvent after the reaction is finished, and separating and purifying by silica gel column chromatography (PE: EA is 16: 1-6: 1) to obtain the artemisinin-piperazine derivative.
The artemisinin-piperazine derivative reaction is represented by the following chemical formula:
the advantages and the beneficial effects of the invention are as follows:
1. the invention takes triethylamine as an acid-binding agent, and prepares the artemisinin-piperazine with high efficiency through multi-component series reaction under the condition of 'one-pot boiling', the reaction condition is mild, the experimental operation is simple, convenient and feasible, the reaction is not required to be carried out under the harsh anhydrous and anaerobic conditions, no metal reagent is used, the environment is friendly, and the atom utilization rate is high.
2. The artemisinin-piperazine derivative has obvious inhibition effect on the growth of human liver cancer SMMC-7721 cells, so the artemisinin-piperazine derivative can be applied to the preparation of anti-liver cancer drugs.
Detailed Description
The present invention is further illustrated in detail by the following examples, but the scope of the present invention is not limited by these examples at all.
The first embodiment is as follows: preparation of artemisinin-piperazine-aminodithiobenzoic acid benzyl ester (Compound 1)
After adding artemisinin piperazine (1.2mmol,0.42g), (4.8mmol,0.36g), carbon disulfide, 20mL acetonitrile and (12mmol,1mL) triethylamine to a round bottom flask in this order at room temperature, stirring for 10 minutes, adding 5mL acetonitrile solution dissolved with (2.5mmol,0.43g) bromobenzyl, gradually heating to 60 ℃, reacting for 12 hours, after the TLC tracing reaction, evaporating off the solvent, and performing silica gel column chromatography [ eluent: v (petroleum ether): v (ethyl acetate) ═ 16:1]Purifying to obtain the target compound. White solid, yield 72.6%, m.p.130.4-130.8 deg.c,
1H NMR(400MHz,CDCl3)δ:7.37(t,J＝12.6Hz,2H),7.32–7.26(m,3H),5.29(d,J＝10.7Hz,1H),4.56(s,2H),4.35(s,2H),4.07(d,J＝9.8Hz,1H),3.89(s,2H),3.07(s,2H),2.79(s,2H),2.58(s,1H),2.34(td,J＝13.8,3.5Hz,1H),2.00(d,J＝14.4Hz,1H),1.94–1.81(m,1H),1.78–1.65(m,2H),1.55(d,J＝12.8Hz,2H),1.49–1.15(m,5H),1.03(dd,J＝18.0,7.7Hz,2H),0.95(d,J＝6.1Hz,3H),0.83(d,J＝6.5Hz,3H)；13C NMR(101MHz,CDCl3)δ:196.01,135.90,129.36,128.54,127.44,103.98,91.54,90.35,80.19,77.20,51.63,46.92,45.70,42.07,37.35,36.25,34.20,28.50,25.97,24.70,21.57,20.25,13.46；IR(KBr)ν/cm-1:2981,2941,2866,1600,1491,1447,1378,1310,1217,1161,1101,1039,999,955,926,880,842,743,712,611,550,486；HRMS m/z:calcd for C27H38N2NaO4S2541.2168,found 541.2170[M+Na]+.
example two: preparation of artemisinin-piperazine-aminodithiocarboxylic acid- (2-methyl) benzyl ester (Compound 2)
The preparation method is the same as the first embodiment, o-methylbenzyl bromide is used for replacing benzyl bromide to obtain the target compound, the target compound is a light yellow solid, the yield is 55.6%, the m.p.87.4-88.4 ℃,
1H NMR(400MHz,CDCl3)δ:7.34(d,J＝7.1Hz,1H),7.16(tt,J＝6.2,3.7Hz,3H),5.27(s,1H),4.51(s,2H),4.35(s,2H),4.06(d,J＝10.2Hz,1H),3.89(s,2H),3.06(s,2H),2.78(s,2H),2.57(dqd,J＝11.2,7.3,4.7Hz,1H),2.44–2.27(m,4H),1.99(ddd,J＝14.6,5.0,2.9Hz,1H),1.86(ddt,J＝13.6,6.7,3.4Hz,1H),1.70(dp,J＝10.6,3.4Hz,2H),1.60–1.38(m,5H),1.38–1.16(m,4H),1.08–0.91(m,3H),0.82(d,J＝7.1Hz,3H)；13C NMR(101MHz,CDCl3)δ:196.11,137.36,133.17,130.40,130.38,127.85,126.13,103.92,91.49,90.29,80.14,51.58,50.16,46.87,45.65,40.67,37.29,36.20,34.15,28.45,25.93,24.65,21.52,20.22,19.28,13.42；IR(KBr)ν/cm-1:2924,2870,1462,1422,1376,1310,1275,1230,1209,1130,1101,1040,1020,982,879,734,550,510；HRMS m/z:calcd for C28H41N2O4S2533.2429,found 533.2514[M+H]+.
example three: preparation of artemisinin-piperazine-aminodithiocarboxylic acid- (4-methyl) benzyl ester (Compound 3)
The preparation method is the same as the first embodiment, and 4-methylbenzyl bromide is used for replacing benzyl bromide to obtain the target compound. White solid, yield 50.3%, m.p.135.9-136.9 deg.C,
1H NMR(400MHz,CDCl3)δ:7.27(d,J＝7.5Hz,2H),7.12(d,J＝7.8Hz,2H),5.27(s,1H),4.52(s,2H),4.35(s,2H),4.06(d,J＝10.3Hz,1H),3.91(s,2H),3.05(s,2H),2.78(s,2H),2.57(ddd,J＝10.9,7.2,4.3Hz,1H),2.35–2.29(m,4H),2.00(ddd,J＝14.4,4.9,3.0Hz,1H),1.86(ddt,J＝13.6,6.8,3.6Hz,1H),1.70(ddd,J＝13.0,7.3,3.5Hz,2H),1.59(s,2H),1.55(dt,J＝13.8,4.4Hz,1H),1.49–1.40(m,1H),1.38(s,2H),1.32(td,J＝13.4,3.6Hz,1H),1.22(td,J＝11.3,6.5Hz,1H),1.00(dd,J＝12.1,3.7Hz,1H),0.94(d,J＝6.2Hz,3H),0.82(d,J＝7.1Hz,3H)；13C NMR(101MHz,CDCl3)δ:196.19,137.20,132.67,129.28,129.26,104.00,91.55,90.36,80.20,77.20,51.65,46.93,45.72,41.91,37.36,36.26,34.21,28.52,25.97,24.71,21.59,21.13,20.26,13.46；IR(KBr)ν/cm-1:2924,2869,2846,1512,1456,1416,1376,1278,1230,1135,1055,980,879,825,741,487；HRMS m/z:calcd forC28H40NaN2O4S2555.2429,found 555.2338[M+Na]+.
example four: preparation of artemisinin-piperazine-aminodithiocarboxylic acid- (2-chloro) benzyl ester (Compound 4)
The preparation method is the same as the first embodiment, o-chlorobenzyl chloride is used for replacing benzyl bromide, and the heating reaction is carried out for 4 hours to obtain the targetCompound, pink solid, yield 50.6%, m.p.90.3-91 deg.c,
1H NMR(400MHz,CDCl3)δ:7.56(dd,J＝5.8,3.6Hz,1H),7.37(dd,J＝5.7,3.6Hz,1H),7.21(dd,J＝5.9,3.5Hz,2H),5.27(s,1H),4.72(s,2H),4.35(s,2H),4.06(d,J＝10.2Hz,1H),3.91(s,2H),3.50(s,1H),3.06(s,2H),2.78(s,2H),2.57(ddd,J＝10.9,7.2,4.4Hz,1H),2.34(td,J＝13.9,3.9Hz,1H),2.03–1.96(m,1H),1.91–1.82(m,1H),1.71(ddd,J＝12.4,7.3,3.5Hz,2H),1.56(s,2H),1.48–1.41(m,1H),1.38(s,3H),0.94(d,J＝6.2Hz,3H),0.82(d,J＝7.1Hz,3H)；13C NMR(101MHz,CDCl3)δ:195.76,134.45,134.18,131.48,129.46,128.89,126.87,104.01,91.52,90.32,80.21,77.20,51.58,50.55,45.66,39.42,37.30,36.19,34.13,28.48,25.86,24.63,21.53,20.18,13.40；IR(KBr)ν/cm-1:3096,3023,1885,1472,1404,1275,1231,1208,1185,1130,1053,983,926,879,826,743,550；HRMS m/z:calcd for C27H37ClNaN2O4S2575.1776,found 575.1778[M+Na]+.
example five: preparation of artemisinin-piperazine-aminodithiocarboxylic acid- (4-chloro) benzyl ester (Compound 5)
The preparation method is the same as the first embodiment, p-chlorobenzyl bromide is used for replacing benzyl bromide to obtain the target compound, white solid with the yield of 71.5 percent and the m.p.111.3-112.2 ℃,
1H NMR(400MHz,CDCl3)δ:7.35–7.30(m,2H),7.28(d,J＝2.3Hz,2H),5.27(s,1H),4.54(s,2H),4.34(s,2H),4.07(d,J＝10.2Hz,1H),3.97–3.83(m,2H),3.49(d,J＝5.0Hz,1H),3.06(s,2H),2.78(s,2H),2.57(ddd,J＝11.0,7.1,4.3Hz,1H),2.34(td,J＝13.9,3.9Hz,1H),2.00(dt,J＝14.6,3.8Hz,1H),1.90–1.82(m,1H),1.71(ddd,J＝12.5,7.4,3.5Hz,2H),1.58–1.42(m,3H),1.38(s,4H),1.04–0.97(m,1H),0.95(d,J＝6.2Hz,3H),0.82(d,J＝7.1Hz,3H)；13C NMR(101MHz,CDCl3)δ:195.48,134.85,133.20,130.67,128.64,104.00,91.56,90.35,80.20,77.20,51.63,50.90,45.70,41.02,37.36,36.25,34.19,28.51,25.98,24.69,21.58,20.26,13.46；IR(KBr)ν/cm-1:2926,2865,1738,1488,1424,1378,1305,1276,1159,1104,1052,978,926,879；HRMS m/z:calcd for C27H37ClNaN2O4S2575.1780,found 575.1782[M+Na]+.
example six: preparation of artemisinin-piperazine-aminodithiocarboxylic acid- (4-bromo) benzyl ester (Compound 6)
The preparation method is the same as the first embodiment, p-bromobenzyl chloride is used for replacing bromobenzyl to obtain a target compound which is a white solid, the yield is 55.7 percent, the m.p.136.9-138 ℃,
1H NMR(400MHz,CDCl3)δ:7.45–7.40(m,2H),7.30–7.24(m,4H),5.27(s,1H),4.53(s,2H),4.34(s,2H),4.06(d,J＝10.3Hz,1H),3.90(d,J＝27.5Hz,2H),3.06(s,2H),2.78(s,2H),2.57(ddd,J＝10.7,7.2,4.3Hz,1H),2.38–2.29(m,1H),2.00(ddd,J＝14.5,4.9,2.9Hz,1H),1.86(ddt,J＝10.1,7.0,3.4Hz,1H),1.75–1.66(m,1H),1.59–1.46(m,2H),1.38(s,3H),1.30(dd,J＝13.7,3.7Hz,1H),1.22(td,J＝11.2,6.5Hz,1H),1.07–0.98(m,1H),0.95(d,J＝6.2Hz,3H),0.82(d,J＝7.2Hz,3H)；13C NMR(101MHz,CDCl3)δ:195.44,135.42,131.59,131.01,121.32,104.00,91.56,90.35,80.20,77.20,51.64,46.94,45.71,41.04,37.36,36.25,34.20,28.51,25.98,24.70,21.58,20.25,13.46；IR(KBr)ν/cm-1:2925,2865,1476,1425,1378,1305,1276,1229,1158,1042,1020,979,931,879,826,609；HRMS m/z:calcd forC27H38BrN2O4S2597.1378,found 597.1465[M+H]+.
example seven: preparation of artemisinin-piperazine-aminodithiocarboxylic acid- (4-cyano) benzyl ester (Compound 7)
The preparation method is the same as that of the first example, p-cyanobenzyl bromide is used for replacing benzyl bromide, the heating reaction is carried out for 4 hours, and the mixture is subjected to silica gel column chromatography [ eluent: v (petroleum ether): v (ethyl acetate) ═ 12:1]Purifying to obtain light yellow solid with yield of 65.8%, m.p.146.7-147.3 deg.C,
1H NMR(400MHz,CDCl3)δ:7.62–7.57(m,2H),7.52–7.48(m,2H),5.27(s,1H),4.65(s,2H),4.34(s,2H),4.07(d,J＝10.3Hz,1H),3.91(d,J＝29.7Hz,2H),3.07(s,2H),2.79(s,2H),2.57(ddd,J＝10.9,7.3,4.4Hz,1H),2.34(ddd,J＝14.5,13.3,4.0Hz,1H),2.05–1.96(m,1H),1.86(ddt,J＝13.6,6.7,3.6Hz,1H),1.75–1.67(m,2H),1.57(d,J＝1.9Hz,1H),1.55–1.46(m,1H),1.38(s,4H),1.34–1.27(m,1H),1.27–1.19(m,1H),1.02(td,J＝13.1,12.2,4.0Hz,1H),0.95(d,J＝6.2Hz,3H),0.82(d,J＝7.2Hz,3H)；13C NMR(101MHz,CDCl3)δ:194.67,142.62,132.19,129.98,118.78,111.03,104.01,91.56,90.34,80.20,77.20,51.62,50.87,45.69,40.78,37.35,36.23,34.18,28.50,25.97,24.68,21.57,20.24,13.45；IR(KBr)ν/cm-1:3140,2937,2864,2229,1736,1606,1477,1378,1305,1276,1158,1051,980,926,880,543cm-1；HRMS m/z:calcd forC28H37NaN3O4S2566.2116,found 566.2118[M+Na]+.
example eight: preparation of artemisinin-piperazine-aminodithiocarboxylic acid- (4-nitro) benzyl ester (Compound 8)
The preparation method is the same as that of the first embodiment, 4-nitrobenzyl bromide is used for replacing benzyl bromide to obtain a target compound, yellow solid, the yield is 67.6 percent, the m.p.82.2-82.9 ℃,
1H NMR(400MHz,CDCl3)δ:8.19–8.13(m,2H),7.59–7.54(m,2H),5.27(s,1H),4.69(s,2H),4.34(s,2H),4.07(d,J＝10.3Hz,1H),3.92(d,J＝31.3Hz,2H),3.07(s,2H),2.80(s,2H),2.57(ddd,J＝10.9,7.2,4.3Hz,1H),2.39–2.29(m,1H),2.00(dt,J＝14.4,4.1Hz,1H),1.90–1.82(m,1H),1.71(ddd,J＝12.7,7.6,3.6Hz,2H),1.59–1.46(m,2H),1.42(s,1H),1.38(s,3H),1.34–1.18(m,2H),1.07–0.92(m,4H),0.90–0.78(m,3H)；13C NMR(101MHz,CDCl3)δ:196.96,194.68,142.62,132.20,129.98,111.04,104.02,103.98,91.56,90.34,80.21,77.20,51.63,50.88,45.69,40.79,37.35,37.16,36.26,34.20,31.16,28.51,28.32,25.97,24.69,22.28,21.58,20.25,13.96,13.46；IR(KBr)ν/cm-1:3316,3047,2924,2870,2011,1754,1599,1453,1345,1275,1159,1041,983,879,724cm-1；HRMS m/z:calcd for C27H37N3NaO6S2586.2016,found586.2018[M+Na]+.
example nine: preparation of artemisinin-piperazine-aminodithio-2-naphthalenemethyl ester (Compound 9)
The preparation method is the same as example one, 2-bromomethylnaphthalene is used to replace benzyl bromide, and silica gel column chromatography is carried out [ eluent: v (petroleum ether): v (ethyl acetate) ═ 12:1]Purifying to obtain white solid with yield of 60.3%, m.p.143.8-144.0 deg.C,
1H NMR(400MHz,CDCl3)δ:7.86–7.77(m,5H),7.51–7.42(m,3H),5.27(s,1H),4.74(s,2H),4.37(s,2H),4.07(d,J＝10.2Hz,1H),3.93(s,2H),3.07(s,2H),2.79(s,2H),2.57(tt,J＝11.2,6.9Hz,1H),2.38–2.29(m,1H),1.99(dd,J＝14.4,4.2Hz,1H),1.86(ddd,J＝13.6,6.6,3.4Hz,1H),1.71(ddd,J＝12.7,7.6,3.6Hz,2H),1.58(s,3H),1.40(d,J＝16.5Hz,4H),1.34–1.18(m,1H),1.07–0.90(m,3H),0.90–0.78(m,3H)；13C NMR(101MHz,CDCl3)δ:195.88,133.41,133.26,132.64,128.27,128.11,127.70,127.59,127.27,126.11,125.87,103.96,91.52,90.33,80.17,77.20,51.61,46.91,45.68,42.28,40.07,37.32,36.23,34.17,28.49,26.85,25.95,24.67,21.55,20.23,13.44；IR(KBr)ν/cm-1:2924,2870,1599,1508,1422,1376,1309,1275,1231,1159,1130,1020,982,879,755,474；HRMS m/z:calcd for C31H40NaN2O4S2591.2429,found 591.2342[M+Na]+.
example ten: preparation of artemisinin-piperazine-aminodithioformic acid pentyl ester (Compound 10)
The preparation method is the same as the first embodiment, chloropentane is used for replacing benzyl bromide, and the heating reaction is carried out for 10 hours to obtain the target compound, namely a light yellow solid, wherein the yield is 58.0 percent, and the m.p.135.8-136.2 ℃.
1H NMR(400MHz,CDCl3)δ:5.25(s,1H),4.32(s,2H),4.05(d,J＝10.2Hz,1H),4.00–3.82(m,2H),3.27(t,J＝7.4Hz,2H),3.04(dt,J＝11.8,5.2Hz,2H),2.76(p,J＝4.9Hz,2H),2.56(ddt,J＝10.1,7.1,3.6Hz,1H),2.32(td,J＝13.9,3.9Hz,1H),1.98(ddd,J＝14.5,5.0,3.0Hz,1H),1.84(ddt,J＝13.6,6.8,3.5Hz,2H),1.69(ddt,J＝14.8,10.2,5.4Hz,5H),1.53(dt,J＝13.6,4.3Hz,1H),1.47–1.26(m,8H),1.21(td,J＝11.2,6.4Hz,1H),1.07–0.96(m,1H),0.96–0.85(m,6H),0.81(d,J＝7.1Hz,3H)；13C NMR(101MHz,CDCl3)δ:196.89,103.92,91.51,90.29,80.16,51.60,50.11,46.87,45.68,37.31,37.11,36.22,34.17,31.12,28.48,28.28,25.93,24.66,22.24,21.55,20.23,13.93,13.44；IR(KBr)ν/cm-1:3232,3079,2937,1755,1423,1388,1277,1233,1160,1131,1022,999,932,881cm-1；HRMS m/z:calcd for C25H42N2NaO4S2521.2477,found 521.2479[M+Na]+.
Example eleven: preparation of artemisinin-piperazine-aminodithiocarbamic acid octadecyl ester (Compound 11)
The preparation method is the same as the first embodiment, 1-chlorooctadecane is used for replacing benzyl bromide to obtain the target compound, yellow waxy solid with the yield of 49.3 percent,
1H NMR(400MHz,CDCl3)δ:5.25(s,1H),4.32(s,2H),4.05(d,J＝10.2Hz,1H),3.27(t,J＝7.5Hz,2H),3.04(dt,J＝11.0,4.9Hz,2H),2.76(dt,J＝11.3,4.8Hz,2H),2.56(ddd,J＝11.2,7.2,4.2Hz,1H),2.32(td,J＝13.9,3.9Hz,1H),1.98(ddd,J＝14.5,4.9,2.9Hz,1H),1.84(ddt,J＝13.5,6.7,3.5Hz,1H),1.74–1.63(m,4H),1.53(dt,J＝13.9,4.4Hz,1H),1.30(d,J＝49.8Hz,39H),1.01(td,J＝13.1,12.3,4.0Hz,1H),0.93(d,J＝6.2Hz,3H),0.89–0.77(m,6H)；13C NMR(101MHz,CDCl3)δ:196.84,103.87,91.47,90.27,80.12,51.58,46.87,45.66,37.28,37.12,36.20,34.16,31.84,29.62,29.60,29.58,29.53,29.44,29.29,29.15,28.97,28.56,28.45,25.90,24.64,22.61,21.52,20.20,14.07,13.41；IR(KBr)ν/cm-1:2923,2852,1466,1421,1376,1310,1275,1231,1130,1055,983,880,834,721,551；HRMS m/z:calcd for C38H69N2O4S2681.4621,found681.4713[M+H]+.
example twelve: preparation of artemisinin-piperazine-aminodithiocarboxylic acid- (benzyloxyacyl) methyl ester (Compound 12)
The preparation method is the same as that of the first example, benzyl bromoacetate is used for replacing benzyl bromide, and silica gel column chromatography is carried out (eluent: v (petroleum ether): v (ethyl acetate) ═ 6:1]Purifying to obtain orange yellow solid with yield of 35%, m.p.82.3-83.3 deg.C,
1H NMR(400MHz,CDCl3)δ:7.40–7.36(m,4H),7.33(dddd,J＝11.4,4.9,2.9,1.8Hz,1H),5.28(s,1H),5.19(s,2H),4.31(s,2H),4.21(s,2H),4.07(d,J＝10.2Hz,1H),3.95(d,J＝32.2Hz,2H),3.08(dt,J＝11.3,5.0Hz,2H),2.80(dt,J＝11.5,5.2Hz,2H),2.63–2.53(m,1H),2.34(ddd,J＝14.5,13.3,3.9Hz,1H),2.05–1.96(m,1H),1.87(ddd,J＝13.6,6.6,3.4Hz,1H),1.71(ddt,J＝11.2,6.5,3.5Hz,2H),1.60(s,1H),1.55(dt,J＝13.6,4.3Hz,1H),1.49–1.41(m,1H),1.38(s,3H),1.35–1.18(m,2H),1.07–0.98(m,1H),0.95(d,J＝6.2Hz,3H),0.83(d,J＝7.1Hz,3H)；13C NMR(101MHz,CDCl3)δ:194.32,168.57,135.47,128.52,128.30,128.29,104.01,91.54,90.36,80.20,67.46,51.64,46.91,45.71,38.91,37.36,36.26,34.21,28.53,26.88,25.97,24.71,21.59,20.26,13.46；IR(KBr)ν/cm-1:2925,2871,1738,1425,1376,1275,1235,1040,980,925,878,741,697,550；HRMS m/z:calcd for C29H40NaN2O6S2599.2328,found 599.2246[M+Na]+.
example thirteen: in vitro activity study of artemisinin-piperazine derivative on anti-human liver cancer SMMC-7721 cells
Selecting artemisinin-piperazine derivatives (compounds 1-12) by adopting MTT (tetramethyl azoazolate colorimetric method), determining the inhibition rate of the artemisinin-piperazine derivatives on human liver cancer SMMC-7721 cells, and calculating IC50Value (. mu.M). The specific operation steps are as follows:
1. cell resuscitation
Cell culture medium: 1640+ 10% FBS + 1% (Penicilin-Streptomycin Solution)
(1) Respectively taking out SMMC7721 cells from liquid nitrogen, quickly placing into a water bath kettle at 37 ℃, and slightly shaking the freezing tube to dissolve the freezing solution;
(2) after the cells are dissolved, transferring the cells into a centrifuge tube containing 5mL of culture medium respectively, centrifuging to collect the cells, centrifuging at room temperature of 1000rpm for 5min, and removing supernatant;
(3) suspending cells in complete culture medium containing 10% fetal calf serum, inoculating to culture dish, gently blowing, mixing, and stirring at 37 deg.C with 5% CO2And culturing under saturated humidity condition.
2. Cell passage
When the density of the cells reaches 80%, the cells are passaged:
(1) removing the culture medium, and washing with PBS once;
(2) adding 1-2mL of 0.25% trypsin to digest the cells, observing under a microscope, digesting for 30-60s, and observing that the cells are separated from each other and become round, namely, the digestion is finished;
(3) rapidly removing pancreatin, adding complete culture medium, blowing to obtain single cell suspension, subculturing at a ratio of 1:3, and culturing at 37 deg.C with 5% CO2And carrying out amplification culture under the saturated humidity condition.
3. Cell processing and MTT assay
(1) Collecting SMMC7721 cells in logarithmic growth phase and good growth state, adjusting cell density to 1 × 10 with 1640 culture medium4One cell per mL of the cells was inoculated into a 96-well plate, 100. mu.L of cell suspension per well was added to the plate, and a blank was set and cultured overnight at 37 ℃ (100. mu.L of sterile PBS was added to the wells around the cell wells);
(2) and after the cells grow well adherent to the wall for 24 hours, absorbing the old culture solution, and adding test solutions of compounds with different concentrations of 1-12 into each culture hole. 5 replicate wells per concentration were made in parallel with equal volumes of dimethyl sulfoxide (DMSO) solvent and drug-free medium in blank control wells at 37 ℃ in 5% CO2The cultivation is continued in the incubator.
Respectively culturing for 24h, 48h and 72h, discarding the supernatant, adding 10 mu L (2mg/mL in PBS) MTT into each well, continuously culturing for 4h, sucking out the culture supernatant in each well, adding 150 mu L dimethyl sulfoxide into each well, oscillating for 10min to fully dissolve the bluish violet crystal, measuring the absorbance value (OD value) of each well sample at 568nm of wavelength by using a microplate reader, removing the highest value and the lowest value, and taking the average value of the rest values.
Calculation of inhibition ratio: the inhibition rate of cell growth was calculated according to the following formula:
inhibition (%) [1- (test sample OD value-blank OD value)/(negative control OD value-blank OD value) ] × 100%
TABLE 1 inhibition rate of 1-12 artemisinin-piperazine derivatives on human liver cancer SMMC-7721 cells
TABLE 2 inhibition IC of 1-12 artemisinin-piperazine derivatives on human liver cancer SMMC-7721 cells50Value (μ M)
[a]Zhaohongyang, Qirong, Zhengrong Beam, university of Lanzhou, school newspaper (from Kyoho), 2000,36(4),66-68 (vincristine: IC)50＝63.2±1.8μg/mL＝0.074±0.002μM)；[b]J.J.Lu,L.H.Meng,Y.J.Cai,etal.Cancer.Biol.Ther.2008,7,1017-1023.
Claims (3)
1. An artemisinin-piperazine derivative is characterized by having the following general formula (I):
wherein R is:
2. the method for preparing artemisinin-piperazine derivatives of claim 1, wherein the method comprises the following steps: the method is characterized by dissolving artemisinin-piperazine and carbon disulfide in four times of amount of artemisinin-piperazine in acetonitrile, then adding triethylamine in ten times of amount of artemisinin-piperazine, stirring for 10min at room temperature, adding a halide acetonitrile solution in two times of amount of artemisinin-piperazine, gradually raising the temperature to 60 ℃, reacting for 4-12 h, tracking by TLC, developing color by phosphomolybdic acid, after the reaction is finished, evaporating the solvent, and separating and purifying PE by silica gel column chromatography, wherein EA is 16: 1-6: 1, so as to obtain the artemisinin-piperazine derivative.
3. The use of the artemisinin-piperazine derivatives of claim 1 in the preparation of drugs against human hepatoma cells SMMC-7721.
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