CN111825615A - Oxidized isoaporphine alkaloid derivative and application thereof - Google Patents

Oxidized isoaporphine alkaloid derivative and application thereof Download PDF

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CN111825615A
CN111825615A CN202010706122.8A CN202010706122A CN111825615A CN 111825615 A CN111825615 A CN 111825615A CN 202010706122 A CN202010706122 A CN 202010706122A CN 111825615 A CN111825615 A CN 111825615A
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azabenzanthrone
isoaporphine
oxidized
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butoxy
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CN111825615B (en
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孙建博
张佳瑶
王豫锦
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China Pharmaceutical University
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Abstract

The invention discloses an oxidized isoaporphine derivative shown as a formula I, wherein R is shown as
Figure DDA0002594813200000011
A is selected from-O-or a covalent bond, n is an integer of 0-4, R1Is selected from
Figure DDA0002594813200000012
Figure DDA0002594813200000013
‑NR2R3；R2Selected from H, R3A linear or branched alkyl selected from C1-C3; with the proviso that A is selected from-O-, n ═ 2, 3, R1Is selected from
Figure DDA0002594813200000014
Compared with the oxidized isoaporphine, the oxidized isoaporphine alkaloid derivative has obviously improved inhibitory activity and solubility on lung cancer, liver cancer and breast cancer. The invention also discloses the application of the oxidized isoaporphine derivative in preparing antitumor drugs.

Description

Oxidized isoaporphine alkaloid derivative and application thereof
Technical Field
The invention belongs to the field of pharmaceutical chemistry and pharmacotherapeutics, and particularly relates to an oxidized isoaporphine alkaloid derivative, a preparation method thereof and application of the novel compound in preparing anticancer drugs.
Background
Cancer is a major disease affecting human health and life, and has become one of the world's important public health problems. According to the global cancer report, 1810 ten thousands of cancer cases are predicted to be newly added in 2018 all over the world, the number of deaths reaches 960 ten thousands, the global cancer burden is further increased, and more people pay attention to the treatment of cancer. The natural product is a treasure house for finding novel antitumor drugs, various natural products are proved to have antitumor activity at present, but the natural products often have the problems of toxic and side effects, solubility, stability and the like, and the natural products need to be structurally modified to become the antitumor drugs which can be clinically used.
Oxoisoaporphine alkaloids (Oxoisoaporphine) refer to isoquinoline alkaloids containing 1-azabenzanthrone (1-azabenzanthrone) skeleton. It was originally isolated from Menispermum dauricum DC (Menispermum dauricum DC) belonging to Menispermum of Menispermaceae. In recent years, the antitumor activity of the oxidized isoaporphine alkaloid draws attention, and researches show that the skeleton 1 of the oxidized isoaporphine alkaloid can be embedded into a double-helix structure of DNA through pi-pi accumulation so as to induce the generation of an apoptosis mechanism; inhibiting topoisomerase to affect cell proliferation, and further showing antitumor activity.
The oxidized isoaporphine alkaloid and the derivative thereof are expected to become novel high-efficiency antitumor drugs. The activity of such alkaloids can be significantly improved by appropriate side chain introduction.
Disclosure of Invention
The invention aims to select common mother ring-1-azabenzanthrone of the oxidized isoaporphine alkaloid as a precursor to carry out structural modification on C-4 position, thereby obtaining a series of oxidized isoaporphine alkaloid derivatives with obviously improved activity and increased solubility compared with the oxidized isoaporphine.
The purpose of the invention is realized by the following technical scheme:
an oxidized isoaporphine derivative represented by formula I:
Figure BDA0002594813190000011
wherein R is as
Figure BDA0002594813190000012
A is selected from-O-or a covalent bond, n is an integer of 0-4, R1Is selected from
Figure BDA0002594813190000013
Figure BDA0002594813190000021
-NR2R3；R2Selected from H, R3A linear or branched alkyl selected from C1-C3; with the proviso that A is selected from-O-, n ═ 2, 3, R1Is selected from
Figure BDA0002594813190000022
Preferably, A is selected from-O-, n is an integer of 2-4, and R is1Is selected from
Figure BDA0002594813190000023
Figure BDA0002594813190000024
But not including n 2, 3, R1Is selected from
Figure BDA0002594813190000025
Or A is selected from covalent bond, n is 0, R1Is selected from
Figure BDA0002594813190000026
More preferably, a is selected from-O-, n ═ and2，R1is selected from
Figure BDA0002594813190000027
Figure BDA0002594813190000028
In particular, the compound of formula I is selected from the following compounds:
4- [ (2-morpholine) ethoxy ] -1-azabenzanthrone; 4- [ (2-isopropylamino) ethoxy ] -1-azabenzanthrone; 4- [2- (2-methylpiperidine) ethoxy ] -1-azabenzanthrone; 4- [2- (4-hydroxyethylpiperazine) ethoxy ] -1-azabenzanthrone; 4- [ (3-morpholine) propoxy ] -1-azabenzanthrone; 4- [3- (2-methylpiperidine) propoxy ] -1-azabenzanthrone; 4- [4- (2-methylpiperidine) butoxy ] -1-azabenzanthrone; 4- [ (4-morpholine) butoxy ] -1-azabenzanthrone; 4- [ (4-isopropylamino) butoxy ] -1-azabenzanthrone; 4- [4- (4-methylpiperazine) butoxy ] -1-azabenzanthrone; 4- [4- (4-hydroxyethylpiperazine) butoxy ] -1-azabenzanthrone; 4-piperazine-1-azabenzanthrone.
The invention also aims to provide a preparation method of the oxidized isoaporphine derivative shown as the formula I,
when A is selected from-O-, n is an integer of 2-4, R1Is selected from
Figure BDA0002594813190000029
Figure BDA00025948131900000210
But not including n 2, 3, R1Is selected from
Figure BDA00025948131900000211
The reaction scheme is as follows:
Figure BDA00025948131900000212
the method comprises the following steps:
dissolving 1-azabenzanthrone in diethylene glycol, providing a strong alkali environment with sodium hydroxide, and carrying out hydroxylation reaction with hydrazine hydrate to generate 4-hydroxy-1-azabenzanthrone;
step (2), taking 4-hydroxy-1-azabenzanthrone as a raw material, and reacting with a compound shown in the formula
Figure BDA0002594813190000031
The dibromoalkane reacts to obtain an intermediate; reacting the intermediate with a compound of formula R in the presence of potassium carbonate and a catalytic amount of CTAB catalyst1And (3) reacting secondary amine shown as H to obtain the oxidized isoaporphine derivative.
In the step (2), the solvent adopted is one or more selected from DMF, acetone, acetonitrile, toluene, benzene, xylene, 1, 4-dioxane, ethyl acetate, dichloromethane, chloroform, tetrahydrofuran or diethyl ether.
The molar ratio of the 4-hydroxy-1-azabenzanthrone to the potassium carbonate to the dibromoalkane is 1:1.5: 1; the reaction temperature is 0-80 ℃.
The molar ratio of the intermediate to potassium carbonate to secondary amine is 1:1.5: 1.2; the reaction temperature is 0-60 ℃.
When A is selected from covalent bond, n is 0, R1Is selected from
Figure BDA0002594813190000032
The reaction scheme is as follows:
Figure BDA0002594813190000033
the preparation method of the oxidized isoaporphine derivative has mild reaction conditions, low toxicity of the used reagent, easily obtained raw materials, convenient post-treatment and higher yield.
The oxidized iso-aporphine alkaloid derivative has excellent antitumor activity on lung cancer cell strains A549, liver cancer cells HepG-2, human breast cancer cell strains McF-7, MDA-MB-231 and adriamycin-resistant cell strains McF-7/ADR, and the activity is obviously improved compared with the oxidized iso-aporphine. Therefore, the invention also aims to provide the application of the oxidized isoaporphine alkaloid derivative shown as the formula I in preparing the antitumor drugs.
The tumor is lung cancer, liver cancer and breast cancer.
Detailed description of the preferred embodiments
To further illustrate the invention, a series of examples are set forth below. These examples are illustrative and should not be construed as limiting the invention.
Example 1: 4- [ (2-morpholine) ethoxy]-1-azabenzanthrone (I)1) Synthesis of (2)
The reaction formula is as follows:
Figure BDA0002594813190000034
4-hydroxy-1-azabenzanthrone (1eq) was dissolved in 5mL of anhydrous DMF and K was added2CO3(1.5eq) and 1, 2-dibromoethane (1eq), stirring at 80 ℃ overnight to stop the reaction, adding ethyl acetate and saturated brine into the reaction solution to extract DMF, purifying by silica gel column chromatography (eluent is petroleum ether: ethyl acetate P/E ═ 3:1) to obtain intermediate 4- (2-bromoethoxy) -1-azabenzanthrone, adding 4- (2-bromoethoxy) -1-azabenzanthrone (1eq) into the reaction flask, dissolving with 5mL of anhydrous DMF, adding K2CO3(1.5eq), CTAB and morpholine (1.2eq) at 60 ℃ overnight with stirring, stopping the reaction, extracting to remove DMF, and purifying by silica gel column chromatography (eluent petroleum ether: ethyl acetate P/E: 5:1) to give compound I1Yellow solid, yield 67%. Compound I1Identified as 4- [ (2-morpholine) ethoxy]-1-azabenzanthrone.
ESI-MS：360.4.[M+H]+。
1H-NMR(300MHz,CDCl3,ppm),H8.92(d,J＝6Hz,1H),8.78(d,J＝6Hz,1H),8.64(d,J＝9Hz,1H),8.44(d,J＝6Hz,1H),8.04(d,J＝6Hz,1H),7.81(t,J＝9Hz,1H),7.69(t,J＝9Hz,1H),7.16(d,J＝9Hz,1H),4.42(d,J＝6Hz,2H),3.78(4H,s),3.02(t,J＝6Hz,2H),2.70(4H,s).
Example 2: compound 4- [ (2-isopropylamino) ethoxy]-1-azabenzanthrone (I)2) Synthesis of (2)
The reaction formula is as follows:
Figure BDA0002594813190000041
reference Compound I1The preparation method comprises replacing compound morpholine with isopropylamine, and obtaining the target compound I under the same conditions2Yellow solid, 58% yield. Compound I2Identified as 4- [ (2-isopropylamino) ethoxy]-1-azabenzanthrone.
ESI-MS：333.2.[M+H]+。
1H-NMR(300MHz,CDCl3,ppm),H8.86(d,J＝9Hz,1H),8.77(d,J＝6Hz,1H),8.48(d,J＝9Hz,1H),8.28(d,J＝9Hz,1H),7.98(d,J＝6Hz,1H),7.87(t,J＝7.5Hz,1H)，7.73(t,J＝7.5Hz,1H),7.60(d,J＝9Hz,1H),4.6(s,1H)，3.96(t,J＝6Hz,2H),3.45(s,3H),1.24(d,J＝6Hz,6H).
Example 3: 4- [2- (2-methylpiperidine) ethoxy]-1-azabenzanthrone (I)3) Synthesis of (2)
The reaction formula is as follows:
Figure BDA0002594813190000042
reference Compound I1The target compound I is prepared by replacing compound morpholine with 2-methylpiperidine and keeping other conditions unchanged3Yellow solid, yield 80%. Compound I3Identified as 4- [2- (2-methylpiperidine) ethoxy]-1-azabenzanthrone.
ESI-MS：373.2[M+H]+。
1H-NMR(300MHz,CDCl3,ppm),H8.96(d,J＝6Hz,1H),8.82(d,J＝3Hz,1H),8.69(d,J＝6Hz,1H),8.48(d,J＝3H,1H),8.10(d,J＝3Hz,1H),7.84(t,J＝4.5Hz,1H),7.69(t,J＝4.5Hz,1H),7.23(d,J＝3Hz,1H),4.43(t,J＝3Hz,2H),3.32(d,J＝3Hz,1H),3.06(t,J＝3Hz,2H),2.53(t,J＝6Hz,J＝9Hz,2H),1.72(t,J＝6Hz,J＝9Hz,6H),1.25(d,3H).
Example 4: 4- [2- (4-Hydroxyethylpiperazine) ethoxy]-1-azabenzanthrone (I)4) Synthesis of (2)
The reaction formula is as follows:
Figure BDA0002594813190000051
reference Compound I1The target compound I is prepared by replacing compound morpholine with 4-hydroxyethyl piperazine under the same conditions4Yellow solid, yield 85%. Compound I4Identified as 4- [2- (4-hydroxyethylpiperazine) ethoxy]-1-azabenzanthrone.
ESI-MS：404.3[M+H]+。
1H-NMR(300MHz,CDCl3,ppm),H8.94(d,J＝6Hz,1H),8.81(d,J＝6Hz,1H),8.67(d,J＝6Hz,1H),8.46(d,J＝9Hz,1H),8.08(d,J＝6Hz,1H),7.81(t,J＝6Hz,1H),7.67(t,J＝6Hz,1H),7.20(d,J＝9Hz,1H),4.44(t,J＝6Hz,2H),3.65(t,J＝6Hz,2H),3.04(t,J＝6Hz,2H),2.74(s,8H),2.59(t,J＝6Hz,2H).
Example 5: 4- [ (3-morpholine) propoxy group]-1-azabenzanthrone (I)5) Synthesis of (2)
The reaction formula is as follows:
Figure BDA0002594813190000052
reference Compound I1The 1, 3-dibromopropane is used for replacing the compound 1, 2-dibromoethane, and other conditions are not changed to prepare the target compound I5Yellow solid, yield 55%. Compound I5Identified as 4- [ (3-morpholine) propoxy group]-1-azabenzanthrone.
ESI-MS：375.2.[M+H]+。
1H-NMR(300MHz,CDCl3,ppm),H8.95(d,J＝9Hz,1H),8.80(d,J＝6Hz,1H),8.66(d,J＝6Hz,1H),8.47(d,J＝9Hz,1H),8.08(d,J＝6Hz,1H),7.83(t,J＝7.5Hz,1H),7.69(t,J＝7.5Hz,1H),7.20(d,J＝6Hz,1H),4.8(t,J＝6Hz,2H),3.79(t,J＝4.5Hz,4H),2.68(t,J＝7.5Hz,2H),2.55(t,J＝4.5Hz,4H),2.21(q,J＝7.5Hz,2H).
Example 6: 4- [3- (2-methylpiperidine) propoxy group]-1-azabenzanthrone (I)6) Synthesis of (2)
The reaction formula is as follows:
Figure BDA0002594813190000061
reference Compound I1The target compound I is prepared by replacing morpholine with 2-methylpiperidine and replacing 1, 2-dibromoethane with 1, 3-dibromopropane, and keeping other conditions unchanged6Yellow solid, 73% yield. Compound I6Identified as 4- [3- (2-methylpiperidine) propoxy group]-1-azabenzanthrone.
ESI-MS：387.1[M+H]+。
1H-NMR(300MHz,CDCl3,ppm),H8.80(t,J＝7.5Hz,2H),8.50(d,J＝9Hz,1H),8.27(d,J＝9Hz,1H),8.03(d,J＝6Hz,1H),7.88(t,J＝7.5Hz,1H),7.73(t,J＝7.5Hz,1H),7.42(d,J＝6Hz,1H),4.36(s,2H),2.69(br,3H),2.10(br,2H),1.62(br,4H),1.32(br,4H),1.10(d,3H).
Example 7: 4- [4- (2-methylpiperidine) butoxy]-1-azabenzanthrone (I)7) Synthesis of (2)
The reaction formula is as follows:
Figure BDA0002594813190000062
reference Compound I1The target compound I is prepared by replacing morpholine with 2-methylpiperidine and replacing 1, 2-dibromoethane with 1, 4-dibromobutane under the same conditions7Yellow solid, yield 11%. Compound I7Identified as 4- [4- (2-methylpiperidine) butoxy]-1-azabenzanthrone.
ESI-MS：401.1[M+H]+。
1H-NMR(300MHz,CDCl3,ppm),H8.95(d,J＝6Hz,1H),8.79(d,J＝6Hz,1H),8.66(d,J＝6Hz,1H),8.47(d,J＝7.5Hz,1H),8.10(d,J＝7.5Hz,1H),7.83(t,J＝7.5Hz,1H),7.69(t,J＝7.5Hz,1H),7.18(d,J＝6Hz,1H),4.35(t,J＝6Hz,2H),3.86(t,J＝6Hz,2H),2.14(t,J＝7.5Hz,3H),1.92(t,J＝6Hz,2H),1.32(t,11H).
Example 8: 4- [ (4-morpholine) butoxy group]-1-azabenzanthrone (I)8) Synthesis of (2)
The reaction formula is as follows:
Figure BDA0002594813190000063
reference Compound I1The 1, 4-dibromobutane is used for replacing the 1, 2-dibromoethane of the compound, and other conditions are not changed to prepare the target compound I8Yellow solid, yield 49%. Compound I8Identified as 4- [ (4-morpholine) butoxy]-1-azabenzanthrone.
ESI-MS：389.2[M+H]+。
1H-NMR(300MHz,CDCl3,ppm),H8.93(d,J＝6Hz,1H),8.78(d,J＝6Hz,1H),8.64(d,J＝6Hz,1H),8.44(d,J＝6Hz,1H),7.93(t,J＝6Hz,1H),7.82(t,J＝7.5Hz,1H),7.67(d,J＝7.5Hz,1H),7.37(d,J＝9Hz,1H),4.05(t,J＝6Hz,2H),3.33(t,J＝3Hz,4H),2.80(t,J＝7.5Hz,2H),2.04(t,J＝6Hz,4H),1.65(m,2H),1.27(m,2H).
Example 9: 4- [ (4-isopropylamino) butoxy]-1-azabenzanthrone (I)9) Synthesis of (2)
The reaction formula is as follows:
Figure BDA0002594813190000071
reference Compound I1The target compound I is prepared by replacing morpholine with 4-isopropylamino and replacing compound 1, 2-dibromoethane with 1, 4-dibromobutane without changing other conditions9Yellow solid, yield 19%. Compound I9Identified as 4- [ (4-isopropylamino) butoxy]-1-azabenzanthrone.
ESI-MS：361.3[M+H]+。
1H-NMR(300MHz,CDCl3,ppm),H8.94(d,J＝6Hz,1H),8.77(d,J＝6Hz,1H),8.65(d,J＝9Hz,1H),8.45(d,J＝6Hz,1H),8.08(d,J＝6Hz,1H),7.81(t,J＝7.5Hz,1H),7.67(t,J＝7.5Hz,1H),7.17(d,J＝9Hz,1H),4.34(s,2H),2.98(m,1H),2.48(t,J＝6Hz,2H),1.91(m,4H),1.28(s,6H).
Example 10: 4- [4- (4-methylpiperazine) butoxy group]-1-azabenzanthrone (I)10) Synthesis of (2)
The reaction formula is as follows:
Figure BDA0002594813190000072
reference Compound I1The target compound I is prepared by replacing morpholine with 4-methylpiperazine and replacing 1, 2-dibromoethane with 1, 4-dibromobutane under the same conditions10Yellow solid, yield 12%. Compound I10Identified as 4- [4- (4-methylpiperazine) butoxy]-1-azabenzanthrone.
ESI-MS：402.3[M+H]+。
1H-NMR(300MHz,CDCl3,ppm),H8.94(d,J＝6Hz,1H),8.78(d,J＝9Hz,1H),8.64(d,J＝6Hz,1H),8.46(d,J＝9Hz,1H),8.08(d,J＝6Hz,1H),7.83(t,J＝7.5Hz,1H),7.68(t,J＝7.5Hz,1H),7.16(d,J＝6Hz,1H),4.34(t,J＝6Hz,2H),3.85(t,J＝6Hz,2H),2.12(m,J＝6Hz,2H),1.93(m,J＝6Hz,2H),1.71(br,3H),1.31(m,8H).
Example 11: 4- [4- (4-Hydroxyethylpiperazine) butoxy group]-1-azabenzanthrone (I)11) Synthesis of (2)
The reaction formula is as follows:
Figure BDA0002594813190000081
reference Compound I1The target compound I is prepared by replacing morpholine with 4-hydroxyethyl piperazinyl and replacing 1, 4-dibromobutane with 1, 2-dibromoethane under the same conditions11Yellow solid, yield 11%. Compound I11Identified as 4- [4- (4-hydroxyethylpiperazine) butoxy]-1-azabenzanthrone.
ESI-MS：432.2[M+H]+。
1H-NMR(300MHz,CDCl3,ppm),H8.99(d,J＝6Hz,1H),8.81(d,J＝6Hz,1H),8.68(d,J＝6Hz,1H),8.48(d,J＝6Hz,1H),8.13(d,J＝6Hz,1H),7.85(t,J＝7.5Hz,1H),7.70(t,J＝7.5Hz,1H),7.21(d,J＝6Hz,1H),4.38(t,J＝4.5Hz,2H),3.87(t,J＝4.5Hz,2H),2.15(t,J＝4.5Hz,2H),1.94(t,J＝4.5Hz,2H),1.38(m,12H).
Example 12: 4-piperazine-1-azabenzanthrone (Compound I)12) Synthesis of (2)
The reaction formula is as follows:
Figure BDA0002594813190000082
reference Compound I1The preparation method comprises the steps of taking 4- (2-bromoethoxy) -1-azabenzanthrone as a raw material, replacing a compound morpholine with piperazine, and preparing a target compound I under the same conditions12Yellow solid, yield 12%. Compound I12Identified as 4-piperazine-1-azabenzanthrone.
ESI-MS：316.1[M+H]+。
1H-NMR(300MHz,CDCl3,ppm),H8.93(d,J＝9Hz,1H),8.77(d,J＝9Hz,1H),8.63(d,J＝6Hz,1H),8.44(d,J＝9Hz,1H),7.93(d,J＝6Hz,1H),7.81(t,J＝7.5Hz,1H),7.66(t,J＝7.5Hz,1H),7.34(d,J＝9Hz,1H),3.32(t,J＝4.5Hz,4H),3.23(t,J＝3Hz,4H),1.27(s,1H).
TABLE 1 Compound I1-I12Substituent(s) of
Figure BDA0002594813190000083
Figure BDA0002594813190000091
Example 13: pharmacological experiments
The invention adopts a tetramethyl triazole blue colorimetric method (MTT method) to carry out an antitumor activity test on the oxidized iso-aporphine alkaloid derivative, uses oxidized iso-aporphine (Oxo) and adriamycin (Dox) as positive contrast drugs, and tests the inhibitory activity of a target compound and the positive contrast drugs on five cancer cell strains (lung cancer cell strain A549, liver cancer cell HepG-2, human breast cancer cell strain McF-7, MDA-MB-231 and adriamycin-resistant cell strain McF-7/ADR).
The instrument comprises the following steps: superclean bench (SW-CJ-1FD, AIRTECH, Sujing Antai), constant temperature CO2Incubator (3111, Thermo, usa), inverted biomicroscope (IX71, OLYMPUS, japan), enzyme linked immunosorbent assay (Model680, BIO-RAD, usa), shaker (Kylin-bell lab Instruments), autoclave (yxo. sg41.280, shanghai hua line), centrifuge (SIGMA).
Reagent: DMEM (Kayji), RPMI-1640 (Kayji), fetal bovine serum (GIBCO), trypsin (SIGMA), DMSO (SIGMA).
Cell lines: human non-small cell lung cancer cell strain A549, liver cancer cell HepG-2, human breast cancer cell strains McF-7 and MDA-MB-231, and adriamycin-resistant cell strain McF-7/ADR (all purchased from Jiangsu Kai Biotechnology GmbH). The human non-small cell lung cancer cell strain A549, the liver cancer cell HepG-2, the human breast cancer cell strain McF-7 and MDA-MB-231 adopt DMEM culture medium, and the adriamycin-resistant cell strain McF-7/ADR adopts RPMI-1640 culture medium.
Test compounds: compound I1-I12Oxidized isoaporphine and adriamycin DMSO are respectively prepared into mother liquor with the concentration of 10mM, and then are diluted into serial concentrations by DMEM or RPMI-1640 culture solution.
The method comprises the following steps: recovering the frozen cell strain, and placing the cell strain at the constant temperature of 37 ℃ in CO2Culturing in an incubator, changing the culture medium once every day, and paving when the culture medium is in an exponential growth phase and is in a good state. Adding 1mL of 0.25% trypsin digestive juice, digesting for 1-2min, observing cell state under microscope, removing digestive juice when adherent cells become round and shrink, adding 1-2mL of DMEM or RPMI-1640 medium containing 10% fetal calf serum to make cell suspension, counting cells, and making into 5 × 10 per well4Counting the number of individual cells and the total number of wells to calculate the amount of cell suspension required, plating the cell suspension on a 96-well plate at 100. mu.L/well, sealing the periphery with PBS, and placing at a constant temperature of 37 ℃ in CO2Culturing in an incubator for 24 h.
Collecting cells in exponential growth phase, pouring DMEM/RPMI-1640 culture solution, washing with PBS once, adding 1mL of 0.25% trypsinDigesting the solution for 1-2min, adding 1mL DMEM medium or RPMI-1640 culture solution containing 10% fetal calf serum, and making into the final product with density of 5 × 104one/mL cell suspension, inoculated in a 24-well plate (500. mu.L/well), incubated with CO2Culturing in an incubator for 24 h. Test compounds were added and incubated for 48h with DMSO as a blank. MTT reagent was added to 24-well plates (50. mu.L/well) and incubated in an incubator for 4 h. The supernatant was discarded and dissolved by adding DMSO (500. mu.L/well). Measuring absorbance (OD value) at 570nm wavelength with microplate reader, and calculating cell inhibition rate and IC of the tested compound according to formula50Values (GraphPad Prism5 software calculation).
Percent cell inhibition (blank average OD value-drug average OD value)/blank average OD value × 100%
TABLE 2 antiproliferative effect of test compounds on human tumor cell lines
Figure BDA0002594813190000101
As can be seen from Table 2, Compound I1Compound I12The inhibition activity to tumor cells is obviously better than that of oxidized isoaporphine, the inhibition activity to different tumor cells has certain selectivity, and the inhibition activity to human breast cancer cells McF-7 is better than that to human lung cancer cells A549, human liver cancer cells Hep-G2, human breast cancer cells MDA-MB-231 and adriamycin-resistant cell strains McF-7/ADR.
The biological activity of the compounds decreases with increasing carbon chain length, when n is 2 (compound I)1-I4) Shows better biological activity, compound I3(IC501.32-7.64 μ M) showed the most prominent inhibitory activity against tumor cells. The 4-position substituent on the anthrone ring of the compound has obvious influence on the cytotoxic activity of the compound, wherein the activity of the substitution with the methylpiperazine ring is optimal (I)3、I6、I7)。

Claims (6)

1. An oxidized isoaporphine derivative represented by formula I:
Figure FDA0002594813180000011
wherein R is as
Figure FDA0002594813180000012
A is selected from-O-or a covalent bond, n is an integer of 0-4, R1Is selected from
Figure FDA0002594813180000013
Figure FDA0002594813180000014
-NR2R3；R2Selected from H, R3A linear or branched alkyl selected from C1-C3; with the proviso that A is selected from-O-, n ═ 2, 3, R1Is selected from
Figure FDA0002594813180000015
2. The oxoisoaporphine derivative according to claim 1, wherein A is selected from the group consisting of-O-, n is an integer of 2 to 4, and R is1Is selected from
Figure FDA0002594813180000016
But not including n 2, 3, R1Is selected from
Figure FDA0002594813180000017
Or A is selected from covalent bond, n ═ 0, R1Is selected from
Figure FDA0002594813180000018
3. Oxidised isoaporphine derivatives according to claim 2, characterized in that a is selected from-O-, n-2, R1Is selected from
Figure FDA0002594813180000019
4. Oxidized isoaporphine derivatives according to claim 1, characterized in that they are selected from:
4- [ (2-morpholine) ethoxy ] -1-azabenzanthrone; 4- [ (2-isopropylamino) ethoxy ] -1-azabenzanthrone; 4- [2- (2-methylpiperidine) ethoxy ] -1-azabenzanthrone; 4- [2- (4-hydroxyethylpiperazine) ethoxy ] -1-azabenzanthrone; 4- [ (3-morpholine) propoxy ] -1-azabenzanthrone; 4- [3- (2-methylpiperidine) propoxy ] -1-azabenzanthrone; 4- [4- (2-methylpiperidine) butoxy ] -1-azabenzanthrone; 4- [ (4-morpholine) butoxy ] -1-azabenzanthrone; 4- [ (4-isopropylamino) butoxy ] -1-azabenzanthrone; 4- [4- (4-methylpiperazine) butoxy ] -1-azabenzanthrone; 4- [4- (4-hydroxyethylpiperazine) butoxy ] -1-azabenzanthrone; 4-piperazine-1-azabenzanthrone.
5. Use of the oxidized isoaporphine derivative according to any one of claims 1 to 4 for the preparation of an antitumor medicament.
6. The use according to claim 5, wherein said tumor is lung cancer, liver cancer, breast cancer.
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CN113264884A (en) * 2021-05-17 2021-08-17 中国药科大学 Oxidized isoaporphine alkaloid derivative and preparation method and application thereof
CN114349700A (en) * 2022-01-21 2022-04-15 中国药科大学 Oxidized isoaporphine alkaloid derivative, preparation method and anti-depression application thereof
CN114349700B (en) * 2022-01-21 2023-02-14 中国药科大学 Oxidized isoaporphine alkaloid derivative, preparation method and anti-depression application thereof
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