CN109369772B - Synthetic method and anti-tumor application of phenanthridine nitidine derivatives - Google Patents
Synthetic method and anti-tumor application of phenanthridine nitidine derivatives Download PDFInfo
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- CN109369772B CN109369772B CN201811557248.2A CN201811557248A CN109369772B CN 109369772 B CN109369772 B CN 109369772B CN 201811557248 A CN201811557248 A CN 201811557248A CN 109369772 B CN109369772 B CN 109369772B
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- tetrahydrobenzo
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- 230000000259 anti-tumor effect Effects 0.000 title claims abstract description 13
- -1 phenanthridine nitidine derivatives Chemical class 0.000 title claims description 26
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- 238000010189 synthetic method Methods 0.000 title claims description 9
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- 229940079593 drug Drugs 0.000 claims abstract description 4
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- 150000001875 compounds Chemical class 0.000 claims description 13
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- PHPDEFOCOJSCGM-UHFFFAOYSA-N 8,9-dimethoxy-2,3,4,5-tetrahydro-1h-benzo[c]phenanthridin-6-one Chemical compound C1CCCC2=C(NC(=O)C3=C4C=C(C(=C3)OC)OC)C4=CC=C21 PHPDEFOCOJSCGM-UHFFFAOYSA-N 0.000 claims description 11
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J73/00—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/04—Ortho- or peri-condensed ring systems
- C07D221/18—Ring systems of four or more rings
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
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Abstract
本发明属于有机合成化学技术领域，涉及两面针碱类药物领域，具体而言，提供了一种菲啶类两面针碱衍生物的合成方法及其抗肿瘤应用。实验证明，本发明的菲啶类两面针碱衍生物具有较好的抗肿瘤活性，对HepG2、A549、H460、CNE1癌细胞株都有明显的抑制作用，可用于抗肿瘤药物制备的研究。此外，本发明制备方法反应条件温和，转化率高，底物普适性广。The invention belongs to the technical field of organic synthetic chemistry, and relates to the field of amphotericin drugs. Experiments show that the phenanthridine derivatives of the present invention have good anti-tumor activity, have obvious inhibitory effects on HepG2, A549, H460, CNE1 cancer cell lines, and can be used for the research on the preparation of anti-tumor drugs. In addition, the preparation method of the present invention has mild reaction conditions, high conversion rate and wide substrate universality.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method and anti-tumor application of phenanthridine nitidine derivatives.
Background
Zanthoxylum nitidum (Zanthoxylum nitidum) also known as Digitalis purpurea, Zanthoxylum piperitum, Zanthoxylum nitidum, etc. is a vine of Zanthoxylum of Rutaceae. The method is mainly distributed in places such as Guangdong, Guangxi, Fujian and the like in China. The Guangxi is the genuine medicinal material producing area of radix zanthoxyli, which has the most abundant resources. The radix zanthoxyli plant has the effects of promoting blood circulation, removing blood stasis, promoting qi circulation, relieving pain, dispelling wind, dredging collaterals, detoxifying, reducing swelling and the like. The medicine is mainly used for treating traumatic injury, stomachache, toothache, rheumatism, pain, venomous snake bite, burn and scald, etc.
Nitidine (nitidine) is extracted and separated from the root of the nitidine plant. The structure of the compound is that the compound is composed of four rings, and a benzene ring and a phenanthridine ring are connected in parallel to form a conjugated aromatic ring with a planar structure. In recent years, scholars at home and abroad find that nitidine has good biological activity and has obvious effects on the aspects of tumor resistance, pain relief, inflammation diminishing, malaria resistance, bacteria resistance, HIV virus resistance, cardiovascular disease and the like. The cell activity test shows that the compound has obvious inhibition effect on liver cancer, lung cancer, breast cancer, nasopharyngeal cancer and the like, and can block cell cycle and induce apoptosis through various signal paths. Due to the high biological activity, nitidine gradually becomes an important lead compound for developing new drugs. The nitidine compound has poor water solubility, low bioavailability, low large-scale generation efficiency and high cost, is not beneficial to research needs and clinical use, and limits further development of the nitidine compound. Therefore, the modification of the chemical structure thereof has been focused on and studied. In the invention, the nitidine is expected to overcome the defects by carrying out structural modification on the nitidine, improve the drug-forming property of the derivative, improve the antitumor activity and reduce the toxicity at the same time. N-5 and C-6 positions on the B ring of nitidine are important modifiable bond positions, and the N-5 and C-6 positions can simplify the mother nucleus and design and synthesize some analogs with simplified structures on the basis of keeping the specific group of nitidine, thereby obtaining a series of derivatives with the activities of resisting tumors, inflammation, bacteria, HIV and the like.
Disclosure of Invention
The invention aims to provide a synthesis method and anti-tumor application of a novel phenanthridine nitidine derivative.
The technical scheme of the invention is realized as follows:
a phenanthridine nitidine derivative 6- (2-dimethylaminoethyl) amino-8, 9-dimethoxy-1, 2,3, 4-tetrahydrobenzo [ c ] phenanthridine (6) has a structural formula as follows:
the invention provides a synthesis method of the phenanthridine nitidine derivative 6- (2-dimethylaminoethyl) amino-8, 9-dimethoxy-1, 2,3, 4-tetrahydrobenzo [ c ] phenanthridine (6), which comprises the following steps:
1) 2-bromo-4, 5-dimethoxybenzoic acid is used as a starting material and reacts with 5,6,7, 8-tetrahydro-1-naphthylamine in an organic solvent to obtain 2-bromo-4, 5-dimethoxy-N- (5,6,7, 8-tetrahydronaphthalene-1-yl) benzamide (1);
2) introducing a protecting group into 2-bromo-4, 5-dimethoxy-N- (5,6,7, 8-tetrahydronaphthalen-1-yl) benzamide (1) in an organic solvent to obtain a compound (2);
3) the compound (2) is subjected to coupling reaction in an organic solvent to obtain a key intermediate 8, 9-dimethoxy-5- (4-methoxybenzyl) -1,2,3, 4-tetrahydrobenzo [ c ] phenanthridine-6-ketone (3);
4) deprotection of the key intermediate 8, 9-dimethoxy-5- (4-methoxybenzyl) -1,2,3, 4-tetrahydrobenzo [ c ] phenanthridine-6-one (3) under acidic conditions gives the product 8, 9-dimethoxy-1, 2,3, 4-tetrahydrobenzo [ c ] phenanthridine-6 (5H) -one (4);
5) carrying out chlorination reaction on 8, 9-dimethoxy-1, 2,3, 4-tetrahydrobenzo [ c ] phenanthridine-6 (5H) -ketone (4) under the action of a chlorinating agent to obtain a product 6-chloro-8, 9-dimethoxy-1, 2,3, 4-tetrahydrobenzo [ c ] phenanthridine (5);
6) the 6-chloro-8, 9-dimethoxy-1, 2,3, 4-tetrahydrobenzo [ c ] phenanthridine (5) is subjected to substitution reaction to obtain a target product 6- (2-dimethylaminoethyl) amino-8, 9-dimethoxy-1, 2,3, 4-tetrahydrobenzo [ c ] phenanthridine (6), and the synthetic route is shown as follows:
in the above synthetic route, the organic solvent may be selected from N, N-dimethylformamide (abbreviated as DMF) and methylene chloride according to the reaction requirements. The reaction temperature may be appropriately selected depending on the type of the reaction. The reaction time can be determined by monitoring the reaction starting materials.
The invention relates to a synthetic method of nitidine derivative 6- (2-dimethylaminoethyl) amino-8, 9-dimethoxy-1, 2,3, 4-tetrahydrobenzo [ c ] phenanthridine, which specifically comprises the following steps:
1) taking 2-bromo-4, 5-dimethoxybenzoic acid to react in thionyl chloride, distilling the reactant under reduced pressure to remove the solvent to obtain intermediate acyl chloride, dissolving the acyl chloride with dichloromethane, adding 5,6,7, 8-tetrahydro-1-naphthylamine, and carrying out nucleophilic substitution reaction to obtain intermediate 1 amide.
2) Dissolving amide 1 in N, N-dimethylformamide, adding sodium hydride for reaction, adding 4-methoxybenzyl chloride, and subjecting the obtained product to silica gel column chromatography to obtain intermediate 2.
3) And dissolving the intermediate 2 in N, N-dimethylformamide, adding palladium acetate, tri (o-tolyl) phosphine and potassium carbonate to react under the protection of inert gas atmosphere, and performing silica gel column chromatography on the obtained product to obtain an intermediate 3.
4) And taking the intermediate 3, adding trifluoroacetic acid for reaction, and performing silica gel column chromatography on the obtained product to obtain a compound 4.
5) Taking the compound 4, adding phosphorus oxychloride for reaction, treating the obtained product with ice water and concentrated ammonia water, and filtering to obtain a compound 5.
6) And taking the compound 5, adding N, N-dimethylamino ethylenediamine, distilling the reactant under reduced pressure to remove the solvent, and washing the obtained solid substance to obtain a target product 6.
In the step 1) of the above synthesis reaction, the reaction temperature of 2-bromo-4, 5-dimethoxybenzoic acid and thionyl chloride is preferably 65 ℃, the reaction is preferably carried out in a heating reflux manner, the temperature of nucleophilic substitution reaction is preferably 0 ℃ to room temperature, whether the reaction is complete or not can be monitored by thin layer chromatography tracking, and the reaction takes about 3 hours to complete under the above conditions. After the reaction is finished, amide 1 is obtained by extraction, concentration and column separation. The molar ratio of 2-bromo-4, 5-dimethoxybenzoic acid to 5,6,7, 8-tetrahydro-1-naphthylamine in this step is preferably 1:1.1, and to avoid a vigorous reaction, the acid chloride is added in portions. When the substance obtained in the step is subjected to silica gel column chromatography, the substance is preferably eluted by a mixed solvent eluent consisting of petroleum ether and ethyl acetate in a volume ratio of 2:1 to obtain an intermediate amide 1.
In the above synthesis reaction step 2), the molar ratio of the amide 1, sodium hydride and 4-methoxybenzyl chloride is preferably 1:2: 3; the reaction is preferably carried out at room temperature, and the completion of the reaction can be monitored by thin layer chromatography, under which the reaction takes about 8 hours to complete. When the substance obtained in the step is subjected to silica gel column chromatography, the substance is preferably eluted by a mixed solvent eluent consisting of petroleum ether and ethyl acetate in a volume ratio of 2:1 to obtain an intermediate 2.
In the above synthesis reaction step 3), the molar ratio of the intermediate 2, palladium acetate, tri (o-tolyl) phosphine, and potassium carbonate is preferably 1:0.1:0.2: 4; the reaction is preferably carried out at 100 ℃, the atmosphere is preferably nitrogen, and the reaction is preferably carried out by heating under reflux. Under the above conditions, it took about 10 hours for the reaction to be complete. When the substance obtained in the step is subjected to silica gel column chromatography, the substance is preferably eluted by a mixed solvent eluent consisting of petroleum ether and ethyl acetate in a volume ratio of 2:1 to obtain an intermediate 3.
In the above synthesis reaction step 4), the reaction is preferably carried out at 75 ℃.
In the above step 5), the reaction temperature is preferably 105 deg.C (whether the reaction is complete or not can be monitored by thin layer chromatography), and the reaction time is preferably 2 h.
In the above synthesis reaction step 6), the molar ratio of the compound 5 to N, N-dimethylaminoethylenediamine is preferably 1: 0.04; the preferable reaction temperature is 104-105 ℃, the preferable reaction time is 5h, the preferable atmosphere condition is nitrogen, and the preferable reaction is carried out in a heating reflux mode.
Activity tests prove that the phenanthridine nitidine derivative shown in the formula 6 designed and synthesized by the invention has a good anti-tumor effect.
Therefore, the invention provides the application of the phenanthridine nitidine derivative shown as the formula 6 in preparing an anti-tumor medicament. Cell activity tests prove that the derivative has good anti-tumor effect and is expected to be used as an anti-tumor medicament in clinic. In addition, the preparation method has the advantages of mild reaction conditions, easily obtained raw materials, low cost, high yield and easy operation and implementation.
Drawings
FIG. 1 shows 8, 9-dimethoxy-5- (4-methoxybenzyl) -1,2,3, 4-tetrahydrobenzo [ c ] prepared in example 1 of the present invention]Process for preparing phenanthridin-6-ones1H-NMR chart;
FIG. 2 shows 8, 9-dimethoxy-5- (4-methoxybenzyl) -1,2,3, 4-tetrahydrobenzo [ c ] prepared in example 1 of the present invention]Process for preparing phenanthridin-6-ones13C-NMR chart;
FIG. 3 is an ESI-MS diagram of 8, 9-dimethoxy-5- (4-methoxybenzyl) -1,2,3, 4-tetrahydrobenzo [ c ] phenanthridin-6-one prepared in example 1 of the present invention;
FIG. 4 shows 8, 9-dimethoxy-1, 2,3, 4-tetrahydrobenzo [ c ] prepared in example 2 of the present invention]Process for preparing phenanthridin-6 (5H) -ones1H-NMR chart;
FIG. 5 shows 8, 9-dimethoxy-1, 2,3, 4-tetrahydrobenzo [ c ] prepared in example 2 of the present invention]Process for preparing phenanthridin-6 (5H) -ones13C-NMR chart;
FIG. 6 is an ESI-MS diagram of 8, 9-dimethoxy-1, 2,3, 4-tetrahydrobenzo [ c ] phenanthridin-6 (5H) -one prepared in example 2 of this invention;
FIG. 7 shows 6-chloro-8, 9-dimethoxy-1, 2,3, 4-tetrahydrobenzo [ c ] prepared in example 3 of the present invention]Of phenanthridines1H-NMR chart;
FIG. 8 is 6-chloro-8, 9-dimethoxy-1, 2,3, 4-tetrahydrobenzo [ c ] prepared according to example 3 of the present invention]Of phenanthridines13C-NMR chart;
FIG. 9 is an ESI-MS diagram of 6-chloro-8, 9-dimethoxy-1, 2,3, 4-tetrahydrobenzo [ c ] phenanthridine prepared in example 3 of the present invention;
FIG. 10 is 6- (2-dimethylaminoethyl) amino-8, 9-dimethoxy-1, 2,3, 4-tetrahydrobenzo [ c ] prepared according to example 4 of this invention]Of phenanthridines1H-NMR chart;
FIG. 11 is 6- (2-dimethylaminoethyl) amino-8, 9-dimethoxy-1, 2,3, 4-tetrahydrobenzo [ c ] prepared according to example 4 of this invention]Of phenanthridines13C-NMR chart;
FIG. 12 is an ESI-MS diagram of 6- (2-dimethylaminoethyl) amino-8, 9-dimethoxy-1, 2,3, 4-tetrahydrobenzo [ c ] phenanthridine prepared in example 4 of this invention.
Detailed Description
The invention is further illustrated below with reference to specific examples and results of biological activity tests, but is not meant to be limiting.
EXAMPLE 1.8 preparation of 9-dimethoxy-5- (4-methoxybenzyl) -1,2,3, 4-tetrahydrobenzo [ c ] phenanthridin-6-one (3)
1) Preparation of intermediate (1)
To 2-bromo-4, 5-dimethoxybenzoic acid (1.50g, 5.74mmol) was added 15mL of thionyl chlorideHeating and refluxing for 1h at 65 ℃, and removing the solvent by rotary evaporation to obtain white solid acyl chloride. M-anisidine (0.930g, 6.32mmol) was dissolved in 3mL of dichloromethane, to which 7mL of N, N-diisopropylethylamine and the acid chloride dissolved in dichloromethane (added in 3 portions over 10 min) were added at 0 ℃ and after 1h of reaction, transferred to room temperature and stirred for 1 h. After the reaction is finished, 1M hydrochloric acid is added for quenching, dichloromethane is used for extraction, an organic phase is respectively washed by saturated sodium bicarbonate and saturated common salt water, after anhydrous sodium sulfate is dried, the mixture is decompressed and concentrated, and column separation is carried out to obtain a white solid, namely the 2-bromine-4, 5-dimethoxy-N- (5,6,7, 8-tetrahydronaphthalene-1-yl) benzamide (1), the yield is 88.7 percent, and the specific transfer value R isf0.45 (the developing solvent is petroleum ether: ethyl acetate: 2: 1).
2) Preparation of intermediate (2)
1mmol of the intermediate (1) was dissolved in 10mL of dry N, N-dimethylformamide, 2 times the amount of sodium hydride was added thereto, and the mixture was stirred at room temperature for 30min, and 3 times the amount of 4-methoxybenzyl chloride was slowly added thereto, and the mixture was further slowly stirred for 8 hours. After the reaction is finished, adding water for quenching, extracting by ethyl acetate, combining organic phases, washing by water and saturated saline solution, drying by anhydrous sodium sulfate, concentrating under reduced pressure, and performing column chromatography separation by using a mixed solution of petroleum ether and ethyl acetate as an eluent to obtain an intermediate (2), wherein the yield is 93.2%.
3) Preparation of 8, 9-dimethoxy-5- (4-methoxybenzyl) -1,2,3, 4-tetrahydrobenzo [ c ] phenanthridin-6-one (3)
Intermediate (2) (1.400g, 2.74mmol) was dissolved in 15mL of dry N, N-dimethylformamide, and palladium acetate (0.062g, 0.27mmol), tri (o-tolyl) phosphine (0.167g, 0.5mmol), and potassium carbonate (1.513g, 10.97mmol) were added and heated at 100 ℃ under nitrogen reflux for 10 h. Cooling to room temperature after the reaction is finished, adding water for quenching, extracting by dichloromethane, washing an organic phase by water and saturated salt water, drying by anhydrous sodium sulfate, and then carrying out column separation by eluent with the volume ratio of petroleum ether to ethyl acetate being 2:1 to obtain a white solid, namely 8, 9-dimethoxy-5- (4-methoxybenzyl) -1,2,3, 4-tetrahydrobenzo [ c ] c]Phenanthridin-6-one (3), yield: 85.3 percent. m.p.142.8-144.8 ℃; IR (KBr, cm)-1):3437,3136,1639,1601,1513,1457,1400,1302,1243,1175,1129,1022,779；1H-NMR(500MHz,CDCl3)7.89(d,J＝8.2Hz,1H),7.85(s,1H),7.54(s,1H),7.06(d,J＝8.2Hz,1H),6.98(d,J＝8.6Hz,2H),6.75(d,J＝8.6Hz,2H),5.47(s,2H),4.08(s,3H),4.00(s,3H),3.79(d,J＝8.2Hz,2H),3.73(s,3H),3.60(s,1H),2.90(t,J＝6.9Hz,2H),2.84(t,J＝5.9Hz,2H),2.49(s,1H)；13C-NMR(126MHz,CDCl3)164.84,158.27,153.59,149.49,139.36,139.21,131.05,130.86,129.31,128.64,127.44,125.87,124.84,122.74,119.90,113.88,113.68,109.19,102.77,56.26,56.22,55.30,52.91,30.38,29.71,23.28,22.11.ESI-MS m/z:430.91([M+H]+)。
EXAMPLE 2 preparation of 8, 9-dimethoxy-1, 2,3, 4-tetrahydrobenzo [ c ] phenanthridin-6 (5H) -one (4)
Compound (3) (0.640g, 1.49mmol) was added to 2mL of trifluoroacetic acid and heated at 75 ℃ under reflux for 10 hours. Cooling to room temperature after the reaction is finished, adding ethyl acetate, quenching with water, extracting with ethyl acetate, washing an organic phase with water, washing with saturated sodium bicarbonate, drying with anhydrous sodium sulfate, and performing column separation with an eluent with the volume ratio of dichloromethane to ethyl acetate of 10:1 to obtain a white solid, namely 8, 9-dimethoxy-1, 2,3, 4-tetrahydrobenzo [ c ] c]Phenanthridin-6 (5H) -one (4), yield: 75.6 percent. m.p.253.0-255.0 ℃; IR (KBr, cm)-1):3439,3132,1651,1610,1496,1398,1234,1129,1079,836；1H-NMR(500MHz,CDCl3)8.56(s,1H),7.87(d,J＝7.4Hz,2H),7.59(s,1H),7.03(d,J＝8.3Hz,1H),4.10(s,3H),4.04(s,3H),2.88(t,J＝6.1Hz,2H),2.77(t,J＝6.4Hz,2H),2.51-2.47(m,1H),2.01-1.94(m,2H),1.88-1.81(m,2H)；13C-NMR(126MHz,CDCl3)153.79,149.51,138.32,123.84,121.76,119.57,115.92,108.37,102.98,56.25,56.16,29.96,23.44,22.67,22.40；ESI-MS m/z:310.15([M+H]+)。
EXAMPLE 3 preparation of 6-chloro-8, 9-dimethoxy-1, 2,3, 4-tetrahydrobenzo [ c ] phenanthridine (5)
The compound (4) (0.02mmol) was placed in a reaction flask, 40mL of phosphorus oxychloride was added, and the mixture was heated under reflux at 105 ℃ for 2 h. Cooling to room temperature after the reaction is finished, carefully pouring into a beaker filled with ice water, dropwise adding concentrated ammonia water until the pH value is alkaline, filtering and precipitating, washing a filter cake for multiple times by using water, and performing column chromatography by using an eluent with the volume ratio of petroleum ether to dichloromethane being 1:1Separating to obtain white solid, namely 6-chloro-8, 9-dimethoxy-1, 2,3, 4-tetrahydrobenzo [ c ]]Phenanthridine (5), yield: 84.8 percent. m.p.201.3-202.3 ℃; IR (KBr, cm)-1):3434,3133,2928,1613,1578,1523,1501,1465,1402,1299,1249,1206,1160,1081,1043,953,840；1H-NMR(500MHz,CDCl3)8.13(d,J＝8.4Hz,1H),7.83(s,1H),7.72(s,1H),7.35(d,J＝8.5Hz,1H),4.14(s,3H),4.09(s,3H),3.35(t,J＝6.1Hz,2H),2.96(t,J＝6.0Hz,2H),1.93(ddd,J＝17.9,10.9,5.6Hz,4H),1.25(s,2H)；13C-NMR(126MHz,CDCl3)153.11,149.79,148.43,141.77,137.49,135.21,130.77,128.59,121.41,119.46,118.50,106.78,102.04,56.20,56.14,30.07,25.23,22.98,22.95；ESI-MS m/z:328.11([M+H]+)。
EXAMPLE 4 preparation of 6- (2-dimethylaminoethyl) amino-8, 9-dimethoxy-1, 2,3, 4-tetrahydrobenzo [ c ] phenanthridine (6)
Mixing a compound (5) (5mmol) and N, N-dimethylamino ethylenediamine (0.2mmol), heating and refluxing for 5h at 104-106 ℃ under the protection of nitrogen, cooling to room temperature after the reaction is finished, removing the solvent by rotary evaporation, adding dichloromethane for dissolution, washing an organic phase for 2 times by using a 5% sodium hydroxide aqueous solution, then washing by using water, drying by using anhydrous sodium sulfate to obtain a solid crude product, and carrying out column separation on the solid crude product by using an eluent with the volume ratio of dichloromethane to methanol of 10:1 to obtain a yellow solid, namely 6- (2-dimethylaminoethyl) amino-8, 9-dimethoxy-1, 2,3, 4-tetrahydrobenzo [ c ] c]Phenanthridine (6), yield: 78.0 percent. m.p.121.6-123.0 ℃; IR (KBr, cm)-1):3430,3134,2926,1593,1530,1488,1401,1262,1253,1207,1037,837,784；1H-NMR(500MHz,CDCl3)7.98(d,J＝8.3Hz,1H),7.77(s,1H),7.42(s,1H),7.06(d,J＝8.3Hz,1H),4.08(d,J＝4.4Hz,6H),3.88(t,J＝5.6Hz,2H),3.21(t,J＝6.2Hz,2H),2.91(t,J＝6.1Hz,2H),2.88-2.81(m,3H),2.42(s,6H),1.25(s,2H)；13C-NMR(126MHz,CDCl3)152.25,152.19,149.40,142.09,137.09,132.72,130.04,124.12,118.72,118.16,113.34,104.03,103.24,58.99,56.80,56.28,45.62,39.47,30.54,25.64,23.82,23.61；ESI-MS m/z:380.22([M+H]+)。
Example 5 antitumor Activity test of phenanthridine nitidine derivatives
The phenanthridine nitidine derivatives prepared in examples 1 to 4 were subjected to in vitro antitumor activity assay.
Selecting cell strains: liver cancer cell HepG2, lung cancer cells A549 and H460, nasopharyngeal carcinoma cell CNE 1.
The experimental method comprises the following steps: the derivative is dissolved and diluted by dimethyl sulfoxide to the concentration of the required solution. Taking cells in logarithmic growth phase, digesting with pancreatin to obtain 4 × 104～5×104each.mL-1The cell suspension is evenly inoculated into a 96-well culture plate, each well is 100 mu L, in order to prevent edge effect, 100 mu L PBS is added into each well around the 96-well plate, and the mixture is placed in CO2After 24 hours of incubation in the incubator, 10. mu.L of test solution per well was added and incubated for 48 hours. Adding 3- (4, 5-dimethylthiazole-2) -2, 5-diphenyl tetrazolium bromide (MTT) into a 96-well plate, wherein each well is 10 mu L, and reacting in an incubator for 4 h. Discarding the supernatant, adding dimethyl sulfoxide (DMSO), adding 100 μ L of DMSO into each well, shaking on a micro-oscillator for 5min, measuring absorbance of each well at 570nm with a microplate reader, and calculating the inhibition rate of the cells.
Cytostatic rate (inhibition rate, 100%), (drug OD-blank OD)/(control OD-blank OD) × 100%
The results of the experiments are shown in the following table.
Experimental data show that the phenanthridine nitidine derivative has a strong effect on tumor cell proliferation, and particularly 8, 9-dimethoxy-5- (4-methoxybenzyl) -1,2,3, 4-tetrahydrobenzo [ c ] phenanthridine-6-one (3) and 6- (2-dimethylaminoethyl) amino-8, 9-dimethoxy-1, 2,3, 4-tetrahydrobenzo [ c ] phenanthridine (6) have high anti-tumor activity. Therefore, the compound can be used for preparing anticancer candidate drugs.
Claims (8)
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| CN104356139A (en) * | 2014-11-21 | 2015-02-18 | 刘华钢 | Synthetic method of nitidine chloride |
Non-Patent Citations (3)
| Title |
|---|
| A Formal New Access to the Benzo[c]phenanthridine Alkaloids, Synthesis of Nitidine and O-Methyl Fagaronine Analogues;Yves L.Janin等;《Tetrahedron》;19931231;第49卷(第45期);第10305-10316页 * |
| Novel applications of hypervalent iodine: PIFA mediated synthesis of benzo[c]phenanthridines and benzo[c]phenanthridinones;Isabel Moreno等;《Tetrahedron》;20011231;第57卷(第25期);第5403-5411页 * |
| Synthesis and Evaluation of New 6-Amino-Substituted Benzo[c]phenanthridine Derivatives;Yves L.Janin等;《J. Med. Chem.》;19931231;第36卷(第23期);第3686-3692页 * |
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