CN108947916B - Perimidine quinone derivative and preparation method and application thereof - Google Patents

Perimidine quinone derivative and preparation method and application thereof Download PDF

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CN108947916B
CN108947916B CN201710391780.0A CN201710391780A CN108947916B CN 108947916 B CN108947916 B CN 108947916B CN 201710391780 A CN201710391780 A CN 201710391780A CN 108947916 B CN108947916 B CN 108947916B
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CN108947916A (en
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黄世亮
黄志纾
古练权
周笃超
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Sun Yat Sen University
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    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07—ORGANIC CHEMISTRY
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    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
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Abstract

The invention belongs to the technical field of medicines and chemical engineering, and discloses a Perimidine quinone derivative, a preparation method thereof and application thereof in preparing antitumor medicines. The structural formula of the Perimidine quinone derivative related in the invention is shown as formula (I) or formula (I)
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) As shown. The derivative provided by the invention has a simpler synthetic route and is easy to react. The derivative disclosed by the invention has a strong inhibition effect on topoisomerase II, has a remarkable inhibition effect on various cancer cell strains, and has a wide application space in preparation of anti-cancer drugs.
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（
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）（
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）。

Description

Perimidine quinone derivative and preparation method and application thereof
Technical Field
The invention belongs to the technical field of medicines and chemical engineering, and particularly relates to a Perimidine quinone derivative and a preparation method and application thereof.
Background
Topoisomerase is an enzyme which is widely existed in eukaryotic organisms and bacteria and solves the topological problem generated by DNA in replication, transcription and chromosome separation, and becomes an important target point of anti-tumor drugs as a current research hotspot.
The research of quinone compounds has attracted a great deal of interest since the National Cancer Institute (NCI) first identified quinone structures as an important pharmacophore of antitumor activity. These include 1,2 naphthoquinone (o-quinone) and 1,4 naphthoquinone (p-quinone), which are widely found in many natural products and exhibit various biological activities, such as anti-tumor, anti-bacterial, anti-viral, etc. Many o-quinone compounds including sabcomene, beta-lapachone, dunanone, mansonone and the like have good antitumor activity; further research proves that the compounds have certain inhibition effect on topoisomerase, so that the o-quinone structure plays an important role in the antitumor activity of the compounds. On the other hand, Perimine is a compound taking Perimidine as a parent nucleus, and research shows that the compound has certain antiproliferative activity, but the action mechanism is not clear. Based on the point, the Perimidine quinone derivative is designed and synthesized by combining an o-quinone structure with a Perimidine mother nucleus, so that a small molecular compound with good antitumor activity is expected to be obtained.
Disclosure of Invention
The invention aims to provide a Perimine quinone derivative.
Another object of the present invention is to provide a process for producing the above derivatives.
The invention also aims to provide application of the Perimine quinone derivative.
The purpose of the invention is realized by the following technical scheme:
the invention provides a Perimidine quinone derivative or pharmaceutically acceptable salt thereof, wherein the structural formula of the Perimidine quinone derivative is shown as a formula (I) or a formula (II):
Figure BDA0001307690180000021
wherein R is1Is alkyl, cycloalkyl, aryl, substituted aryl or aromatic heterocyclic radical, R2Is alkyl, R3Is hydrogen or halogen.
Preferably, R1Is C1-C10 alkyl, C3-C10 naphthenic base, phenyl, substituted phenyl or aromatic heterocyclic radical.
Preferably, the substituted phenyl is phenyl substituted with halogen, amine, alkyl or alkoxy.
Preferably, R2Is C1-C5 straight-chain alkyl.
Preferably, R3Is hydrogen, chlorine or bromine.
Preferably, R1Is methyl, ethyl, cyclopropyl, cyclohexyl, anilino, phenyl, 4-methylphenyl, 4-trifluoromethylphenyl, thienyl, furyl, N-ethylcarbazolyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-alkoxyphenyl, 2, 4-difluorophenyl, 2,3, 4-trifluorophenyl.
The invention also provides a preparation method of the Perimine quinone derivative, which comprises the following steps:
s1.1,8 reacting diaminonaphthalene with aldehyde to obtain a compound with a structural formula shown as a formula (III);
Figure BDA0001307690180000022
s2, alkylating-NH on the compound shown in the structural formula (III) obtained in the step S1 to obtain a knot
A compound with a structural formula shown as a formula (IV);
Figure BDA0001307690180000023
s3, nitrating the compound shown in the structural formula (IV) obtained in the step S2, reducing, oxidizing and finally reacting with NCS and NBS respectively to obtain a compound shown in the structural formula (I) or (II);
Figure BDA0001307690180000031
experiments prove that the novel Perimidine quinone derivative disclosed by the invention has a good inhibition effect on topoisomerase II, and in vitro experiments, the compounds b-16 and b-21 can completely inhibit the unwinding action of topoisomerase II on supercoiled DNA under 5 mu M and 2.5 mu M respectively, and the inhibition concentration is far higher than that (100 mu M) of positive control VP-16 (etoposide).
Compared with the traditional topoisomerase II poison, the derivative is a catalytic inhibitor, does not form an enzyme-DNA-drug ternary complex, and does not cause DNA damage; therefore, the derivatives can have lower toxic and side effects from a mechanism viewpoint. In addition, Toposisomerase II is generally highly expressed in tumor cells and becomes an important target for tumor treatment, and our compound proves to be effective on Toposisomerase II, which indicates that the compound has universality for resisting tumors.
Compared with the prior art, the invention has the following advantages and beneficial effects:
the derivative provided by the invention has a simpler synthetic route and is easy to react. Most compounds have obvious inhibiting effect on various tumor cell strains, and the Perimidine quinone derivative can be used for preparing an anti-cancer drug taking topoisomerase as a target spot, and has good application prospect in preparing novel anti-tumor drugs.
Drawings
FIG. 1 is a graph showing the inhibitory activity of Perimine quinone derivatives b-16 and b-21 on Topo II.
FIG. 2 is a graph showing the effect of Topo II-mediated DNA fragmentation assay.
Detailed Description
The present invention will be further described with reference to the following specific examples and drawings, which are not intended to limit the invention in any manner. Reagents, methods and apparatus used in the present invention are conventional in the art unless otherwise indicated.
Unless otherwise indicated, reagents and materials used in the present invention are commercially available.
Example 1: general procedure for the Synthesis of the end products (a-1 to a-21, b-1 to b-21)
1,8 diaminonaphthalene (P1) with different aldehydes under sodium dithionite in EtOH/H2Refluxing with O as solvent to obtain intermediate P2, reacting P2 with methyl iodide or ethyl iodide under alkaline condition to obtain intermediate P3, reacting P3 in NaNO2/CH3Reacting in a COOH system to obtain a nitro-substituted mixed intermediate P4, wherein Pd/C-H is used as a P42Reduction to the amino product P5, and oxidation of P5 to the o-quinone end product with a Fermi salt, followed by further derivatization to the compound d-1, d-2, d-3.
The aldehyde related to the present invention includes acetaldehyde, propionaldehyde, phenylacetaldehyde, N-ethyl-carbazole-3-formaldehyde, 2,3, 4-trifluorobenzaldehyde, 2, 4-difluorobenzaldehyde, 3-fluorobenzaldehyde, 2-fluorobenzaldehyde, cyclopropylformaldehyde, cyclohexylformaldehyde, p-trifluoromethylbenzaldehyde, furfural, 2-thiophenecarbaldehyde, p-tolualdehyde, p-hydroxybenzaldehyde, 2-chlorobenzaldehyde, 3-chlorobenzaldehyde, 4-fluorobenzaldehyde.
The catalyst of the present invention includes Pd/C.
Bases to which the invention relates include K2CO3，NaOH，KOH。
The reducing agent comprises sodium hydrosulfite and H2。
The synthetic route is as follows:
Figure BDA0001307690180000041
specific synthetic routes are given below:
6.2g (40mmol) of 1,8 diaminonaphthalene P1 were weighed out and dissolved in 40mL of ethanol; another 7.6g (40mmol) of sodium metabisulfite are dissolved in 20mL of water, mixed with each other, and finally 40mmol of aldehyde are added and the reaction is refluxed at 100 ℃. As the reaction proceeded, the reaction solution gradually changed from purple red to orange yellow or orange red, and a solid precipitated. After the reaction is finished, after the reaction liquid is cooled to room temperature, the reaction liquid is poured into 200mL of ice water to be continuously stirred, a product is separated out, an orange solid P2 is obtained through suction filtration, and the reaction liquid is washed with water for a plurality of times and dried and can be put into the next reaction without purification.
Weighing 10mmol of intermediate P2 and 20mmol of NaOH in a pressure-resistant tube, weighing 10mL of DMF for dissolving, and finally adding 10mmol of CH3I or CH3CH2I, and reacting for 3 hours at 80 ℃. After the reaction is finished, pouring the reaction liquid into water, extracting the reaction liquid for 3 times by using ethyl acetate, washing the reaction liquid for 3 times by using saturated saline solution to obtain an organic layer, drying the organic layer by using anhydrous sodium sulfate, and purifying the organic layer by using 200-mesh and 300-mesh silica gel as a stationary phase to obtain a crude product, namely a yellow solid P3.
10mmol of intermediate P3 and 10mmol of sodium nitrite are weighed out and dissolved in 15mL of glacial acetic acid, and the reaction is stirred at room temperature. The color of the reaction solution immediately changes from light yellow to red, and bubbles are generated, and the reaction can be completed within 20 min. The solvent is directly dried by spinning through reduced pressure distillation, the sample is mixed with 100-plus 200-mesh silica gel, and the purification is carried out by taking 200-plus 300-mesh silica gel as a stationary phase, so as to obtain a crude product, namely a red solid P4.
Dissolving 2mmol of intermediate P4 in 20mL of ethyl acetate, adding 10% of Pd/C powder, vacuumizing the reaction system, continuously introducing hydrogen, stirring at 50 ℃ for reaction, gradually changing the reaction color from red to light yellow, and detecting by TLC (thin layer chromatography) after the reaction is complete; and stirring the sample by 100-mesh silica gel and purifying by using 200-mesh silica gel as a stationary phase to obtain a crude product, namely a light yellow solid, namely an intermediate P5.
The pale yellow amino product obtained in the previous step was dissolved in 20mL of acetone, 50mL of 0.06M potassium dihydrogen phosphate buffer containing Fresmy's salt (2.5 equiv.) was added, and the reaction was stirred at room temperature for 30 min. The reaction system is immediately changed from light yellow to purple red, when the reaction is complete, chloroform is directly used for extracting for 3 times, organic phases are combined, washed once by water, and dried by anhydrous sodium sulfate. The crude product was purified by gradient elution (dichloromethane/methanol (100:1), dichloromethane/methanol (50:1)) to give two products, one red product and one violet product.
With reference to the above synthesis, the following compounds were obtained, replacing the different reactants:
Figure BDA0001307690180000061
a-1 red solid, 24% yield. m.p.>200℃.1H NMR(400MHz,DMSO)δ7.97(dd,J＝5.4,3.2Hz,1H),7.80–7.74(m,2H),5.84(s,1H),3.52(s,3H),2.60(s,3H).13C NMR(101MHz,DMSO)δ180.69,177.17,155.80,151.72,142.29,134.25,133.64,129.66,129.63,117.89,99.77,36.57,24.09.HRMS(ESI):calcd for C13H10N2O2[M+H]+227.0815,found 227.0809.HPLC purity:99.6％.
b-1 purple solid, 21% yield. m.p.>200℃.1H NMR(400MHz,DMSO)δ7.99(d,J＝8.5Hz,1H),7.94(d,J＝7.3Hz,1H),7.82(t,J＝8.0Hz,1H),5.74(s,1H)，3.74(s,3H),2.58(s,3H).13C NMR(101MHz,DMSO)δ181.96,177.80,160.43,158.08,137.69,133.73,130.03,128.33,123.55,116.52,108.92,35.80,24.37.HRMS(ESI):calcd for C13H10N2O2[M+H]+227.0815,found 227.0811.HPLC purity:99.1％.
a-2 red solid, yield 27%. m.p.>200℃.1H NMR(400MHz,DMSO)δ7.97(dd,J＝6.3,2.3Hz,1H),7.84–7.73(m,2H),5.84(s,1H),3.51(s,3H),2.92(q,J＝7.2Hz,2H),1.27(t,J＝7.3Hz,3H).13C NMR(101MHz,DMSO)δ180.73,177.15,158.62,151.87,142.12,134.52,133.60,129.64,129.62,117.82,99.79,35.71,28.55,11.17.HRMS(ESI):calcd for C14H12N2O2[M+Na]+241.0947,found 241.0944.HPLC purity:99.5％.
b-2 purple solid, yield 23.5%. m.p.>200℃.1H NMR(400MHz,DMSO)δ7.98(dd,J＝19.9,8.0Hz,2H),7.85–7.80(m,1H),5.77(s,1H),3.75(s,3H),2.89(q,J＝7.4Hz,2H),1.25(t,J＝7.3Hz,3H).13C NMR(101MHz,DMSO)δ181.98,177.81,163.32,158.05,137.87,133.72,129.98,128.37,123.70,116.43,109.22,35.09,28.95,11.28.HRMS(ESI):calcd for C14H12N2O2[M+H]+241.0966,found 241.0972.HPLC purity:98.2％.
a-3 red solid, yield 10.4%. m.p.>200℃.1H NMR(400MHz,DMSO)δ7.95(dd,J＝6.9,1.5Hz,1H),7.80–7.69(m,2H),5.87(s,1H),3.72(s,3H),2.32(ddd,J＝13.2,8.1,5.1Hz,1H),1.18–1.02(m,4H).13C NMR(101MHz,CDCl3)δ180.46,177.74,156.93,152.19,142.10,134.44,132.98,130.15,129.39,117.72,99.76,35.35,15.11,8.63(2C).HRMS(ESI):calcd for C15H12N2O2[M+H]+253.0972,found253.0970.HPLC purity:100％.
b-3 purple solid, 16.4% yield. m.p.>200℃.1H NMR(400MHz,DMSO)δ8.00(d,J＝8.5Hz,1H),7.93(d,J＝7.3Hz,1H),7.82(t,J＝8.0Hz,1H),5.68(s,1H),3.92(s,3H),2.34(d,J＝4.7Hz,1H),1.47–1.01(m,4H).13C NMR(101MHz,DMSO)δ182.07,177.51,163.12,158.06,137.98,133.64,129.94,128.12,123.63,116.44,108.84,35.26,14.70,10.22(2C).HRMS(ESI):calcd for C15H12N2O2[M+H]+253.0972,found 253.0975.HPLC purity:99.6％.
a-4 red solid, yield 19.4%. m.p.>200℃.1H NMR(400MHz,CDCl3)δ8.08(d,J＝7.3Hz,1H),7.74(d,J＝8.1Hz,1H),7.63(t,J＝7.8Hz,1H),5.86(s,1H),3.56(s,3H),2.84(dd,J＝15.3,7.1Hz,1H),2.22–1.46(m,10H).13C NMR(101MHz,CDCl3)δ180.45,177.73,159.53,152.31,142.01,134.75,132.87,130.23,129.31,117.66,99.92,42.35,35.04,31.15,26.06(2C),25.72(2C).HRMS(ESI):calcd for C18H18N2O2[M+H]+295.1441,found 295.1439.HPLC purity:99.9％.
b-4 purple solid, 25.4% yield. m.p.>200℃.1H NMR(400MHz,DMSO)δ8.01(d,J＝8.2Hz,1H),7.94(d,J＝7.0Hz,1H),7.82(t,J＝7.5Hz,1H),5.75(s,1H),3.79(s,3H),3.05(t,J＝10.7Hz,1H),1.89(d,J＝11.6Hz,2H),1.76(dd,J＝34.7,11.5Hz,3H),1.58(dd,J＝24.1,11.7Hz,2H),1.51–1.34(m,2H),1.25(d,J＝14.7Hz,1H).13C NMR(101MHz,DMSO)δ181.99,177.72,165.31,159.45,158.05,138.02,133.68,129.90,128.43,124.13,116.38,109.28,41.68,35.04,30.86(2C),25.89,25.71(2C).HRMS(ESI):calcd for C18H18N2O2[M+H]+295.1441,found295.1437.HPLC purity:97.6％.
a-5 red solid, yield 28%. m.p.173.3-175.1 ℃.1H NMR(400MHz,DMSO)δ8.03(dd,J＝7.0,1.5Hz,1H),7.86(dd,J＝8.1,1.5Hz,1H),7.84–7.79(m,1H),7.41–7.22(m,5H),5.83(d,J＝10.1Hz,1H),4.35(s,2H),3.44(s,3H).13C NMR(101MHz,CDCl3)δ180.16,177.74,154.89,152.07,141.81,134.68,134.25,133.18,130.76,129.45,129.40(2C),128.06(2C),127.78,118.20,100.00,43.03,36.05.HRMS(ESI):calcd for C19H14N2O2[M+H]+303.1128,found 303.1128.HPLC purity:97.9％.
b-5 purple solid, 26% yield. m.p.>200℃.1H NMR(400MHz,DMSO)δ7.94(d,J＝7.4Hz,2H),7.88–7.78(m,1H),7.32(d,J＝26.5Hz,5H),5.81(s,1H),4.30(s,2H),3.68(s,3H).13C NMR(101MHz,DMSO)δ181.72,178.01,160.89,157.74,137.89,135.84,133.73,130.05,129.34(2C),128.97(2C),128.64,127.51,123.82,116.70,109.54,42.09,35.88.HRMS(ESI):calcd for C19H14N2O2[M+H]+303.1128,found 303.1120.HPLC purity:95.9％.
a-6 red solid, 41.4% yield. m.p.>200℃.1H NMR(400MHz,CDCl3)δ8.24(dd,J＝7.4,1.0Hz,1H),7.89(dd,J＝8.1,0.9Hz,1H),7.74(t,J＝7.8Hz,1H),7.66–7.56(m,5H),5.96(s,1H),3.50(s,3H).13C NMR(101MHz,CDCl3)δ179.13,176.83,154.92,151.08,140.90,133.94,133.37,132.27,129.89,129.80,128.43,128.22(2C),127.18(2C),117.03,99.47,37.95.HRMS(ESI):calcd for C18H12N2O2[M+H]+289.0972,found 289.0974.HPLC purity:99.0％.
b-6 purple solid, 44.4% yield. m.p.>200℃.1H NMR(400MHz,DMSO)δ8.02(d,J＝7.9Hz,2H),7.96–7.84(m,1H),7.71(d,J＝5.9Hz,2H),7.59(d,J＝6.9Hz,3H),5.84(s,1H),3.63(s,3H).13C NMR(101MHz,DMSO)δ181.62,177.99,160.14,157.59,138.11,135.17,133.89,131.06,129.90,129.30(2C),129.01(2C),128.91,124.46,116.82,109.89,38.70.HRMS(ESI):calcd for C18H12N2O2[M+H]+289.0972,found 289.0966.HPLC purity:97.9％.
a-7 red solid, 30% yield. m.p.>200℃.1H NMR(400MHz,DMSO)δ8.04(dd,J＝7.1,1.3Hz,1H),7.85(dd,J＝8.1,1.3Hz,1H),7.83–7.78(m,1H),7.57(d,J＝8.0Hz,2H),7.36(d,J＝7.9Hz,2H),5.86(s,1H),3.39(s,3H),2.39(s,3H).13C NMR(101MHz,CDCl3)δ180.23,177.83,156.15,152.24,142.04,141.27,134.95,133.25,131.51,130.77,129.83(2C),129.43,128.24(2C),117.96,100.47,39.08,21.54.HRMS(ESI):calcd for C19H14N2O2[M+H]+303.1128found 303.1122.HPLC purity:99.3％.
b-7 purple solid, 29% yield. m.p.>200℃.1H NMR(400MHz,DMSO)δ8.01(d,J＝7.9Hz,2H),7.94–7.82(m,1H),7.61(d,J＝8.1Hz,2H),7.39(d,J＝8.0Hz,2H),5.82(s,1H),3.65(s,3H),2.42(s,3H).13C NMR(101MHz,CDCl3)δ181.04,178.33,160.16,157.25,141.64,137.49,133.35,131.44,129.65(2C),128.89,128.79(2C),122.38,117.12,111.38,99.99,38.21,21.58.HRMS(ESI):calcd for C19H14N2O2[M+H]+303.1128,found 303.1121.HPLC purity:99.9％.
a-8 red solid, 16.3% yield. m.p.>200℃.1H NMR(400MHz,CDCl3)δ8.24(d,J＝7.3Hz,1H),7.86(d,J＝8.0Hz,3H),7.82–7.70(m,3H),5.95(s,1H),3.47(s,3H).13C NMR(101MHz,CDCl3)δ179.88,177.89,154.46,151.74,141.64,137.87,135.00,134.96,133.45,131.28,129.55,128.87(2C),126.31(dd,J＝7.2,3.5Hz),118.29,109.39,100.71,38.82.HRMS(ESI):calcd for C19H11N2O2F3[M+H]+357.0845,found 357.0841.HPLC purity:100％.
b-8 purple solid, 39.9% yield. m.p.>200℃.1H NMR(400MHz,CDCl3)δ8.00(d,J＝7.4Hz,1H),7.96–7.76(m,4H),7.70(t,J＝8.0Hz,1H),7.62–7.49(m,1H),6.00(s,1H),3.64(s,3H).13C NMR(101MHz,CDCl3)δ180.63,178.47,158.45,156.45,137.79,137.19,133.47,133.08,132.75,129.70,129.36,129.19(2C),126.21–126.04(m),122.36,117.31,112.00,37.89.HRMS(ESI):calcd for C19H11N2O2F3[M+H]+357.0845,found 357.0840.HPLC purity:99.7％.
a-9 red solid, yield 32.9%. m.p.>200℃.1H NMR(400MHz,DMSO)δ8.05(d,J＝7.0Hz,1H),7.87(d,J＝7.1Hz,1H),7.85–7.80(m,1H),7.67(d,J＝8.6Hz,2H),7.12(d,J＝8.6Hz,2H),5.88(s,1H),3.86(s,3H),3.45(s,3H).13C NMR(101MHz,CDCl3)δ180.21,177.77,161.54,155.93,152.35,142.10,134.84,133.17,130.55,130.13(2C),129.40,126.55,117.84,114.53(2C),100.53,55.58,39.26.HRMS(ESI):calcd for C19H14N2O3[M+H]+319.1077,found 319.1073.HPLC purity:99.6％.
b-9 purple solid, 25.7% yield. m.p.>200℃.1H NMR(400MHz,DMSO)δ8.02(d,J＝7.9Hz,2H),7.89(dd,J＝8.6,7.3Hz,1H),7.76–7.66(m,2H),7.15–7.10(m,2H),5.84(s,1H),3.86(s,3H),3.69(s,3H).13C NMR(101MHz,DMSO)δ181.86,177.91,161.62,160.06,157.76,138.45,133.83,131.59,129.93,129.80,128.71,127.12,124.54,116.80,114.35,109.65,99.99,55.96,39.11.HRMS(ESI):calcd for C19H14N2O3[M+H]+319.1077,found 319.1075.HPLC purity:99.6％.
a-10 red solid, 16% yield. m.p.>200℃.1H NMR(400MHz,DMSO)δ8.04(d,J＝7.2Hz,2H),7.88(d,J＝7.9Hz,1H),7.85–7.79(m,1H),7.32(d,J＝3.4Hz,1H),6.79(dd,J＝3.3,1.6Hz,1H),5.93(s,1H),3.64(s,3H).13C NMR(101MHz,CDCl3)δ180.11,177.84,152.41,146.72,146.32,145.33,142.01,134.83,133.30,130.99,129.52,118.13,116.69,112.24,100.67,38.63.HRMS(ESI):calcd for C16H10N2O3[M+H]+279.0764,found 279.0760.HPLC purity:98.6％.
b-10 purple solid, yield 27%. m.p.>200℃.1H NMR(400MHz,DMSO)δ8.07–7.91(m,3H),7.84(dt,J＝12.9,8.4Hz,2H),5.79(s,1H),5.17(dt,J＝26.8,13.4Hz,1H),3.80(s,3H).HRMS(ESI):calcd for C16H10N2O3[M+H]+279.0764,found 279.0756.HPLC purity:98.6％.
a-11 as red solid in 14.4% yield. m.p.>200℃.1H NMR(400MHz,CDCl3)δ8.19(d,J＝7.3Hz,1H),7.84(d,J＝8.1Hz,1H),7.71(t,J＝7.7Hz,1H),7.63(d,J＝4.8Hz,1H),7.53(d,J＝2.7Hz,1H),7.24–7.18(m,1H),5.97(s,1H),3.73(s,3H).13C NMR(101MHz,CDCl3)δ180.08,177.89,152.51,150.12,141.91,135.72,134.86,133.34,130.99,130.52,130.32,129.41,127.74,117.84,100.89,39.36.HRMS(ESI):calcd for C16H10N2O2S[M+H]+295.0536,found 295.0534.HPLC purity:99.1％.
b-11 purple solid, yield 12.4%. m.p.>200℃.1H NMR(400MHz,DMSO)δ8.02(dd,J＝14.9,6.5Hz,3H),7.86(s,2H),7.31(s,1H),5.82(s,1H),3.94(s,3H).13CNMR(101MHz,DMSO)δ181.71,177.83,157.28,154.06,138.57,137.02,133.89,133.66,133.38,129.94,128.74,128.67,124.62,116.78,109.47,38.76.HRMS(ESI):calcd for C16H10N2O2S[M+H]+295.0536,found 295.0531.HPLC purity:99.7％.
a-12 red solid, 21% yield. m.p.>200℃.1H NMR(400MHz,CDCl3)δ8.37(s,1H),8.15(dd,J＝12.2,7.6Hz,2H),7.86(d,J＝8.1Hz,1H),7.69(t,J＝7.8Hz,2H),7.63–7.51(m,2H),7.48(d,J＝8.2Hz,1H),7.29(t,J＝7.4Hz,1H),5.95(s,1H),4.43(q,J＝7.1Hz,2H),3.58(s,3H),1.47(t,J＝7.2Hz,3H).13C NMR(101MHz,CDCl3)δ180.37,177.88,157.04,152.59,142.25,140.90,140.60,134.87,133.17,130.52,129.49,126.79,125.70,124.61,123.23,122.53,121.15,120.80,119.87,117.84,109.05,108.94,100.49,39.63,37.87,13.83.HRMS(ESI):calcd for C26H19N3O2[M+H]+406.1550,found 406.1538.HPLC purity:99.8％.
b-12 purple solid, 24% yield. m.p.>200℃.1H NMR(400MHz,DMSO)δ8.58(s,1H),8.27(d,J＝7.6Hz,1H),8.04(t,J＝8.6Hz,2H),7.94–7.88(m,1H),7.81(dd,J＝16.8,8.4Hz,2H),7.69(d,J＝8.3Hz,1H),7.55–7.50(m,1H),7.30–7.25(m,1H),5.89(s,1H),4.53(d,J＝7.3Hz,3H),3.78(s,3H),1.38–1.33(m,2H).HRMS(ESI):calcd for C26H19N3O2[M+H]+406.1550,found 406.1554.HPLC purity:95.9％.
a-13 as red solid in 32% yield. m.p.>200℃.1H NMR(400MHz,CDCl3)δ8.27(dd,J＝7.4,1.2Hz,1H),7.88(dd,J＝8.1,1.2Hz,1H),7.80–7.73(m,1H),7.62–7.43(m,4H),5.95(s,1H),3.39(s,3H).13C NMR(101MHz,CDCl3)δ180.03,177.82,153.49,151.26,141.81,134.99,133.79,133.31,132.36,131.90,131.19,130.12,129.98,129.60,128.07,118.37,100.41,36.86.HRMS(ESI):calcd for C18H11N2O2Cl[M+H]+323.0582,found 323.0575.HPLC purity:97.8％.
b-13 purple solid, yield 34%. m.p.>200℃.1H NMR(400MHz,CDCl3)δ8.12(d,J＝7.4Hz,1H),7.79–7.70(m,1H),7.63(dd,J＝5.9,3.0Hz,1H),7.58–7.45(m,4H),6.16(s,1H),3.55(s,3H).13C NMR(101MHz,DMSO)δ181.24,178.33,157.42,157.12,137.32,134.27,134.05,132.41,131.21,130.63,130.19,130.08,129.33,128.45,124.14,117.03,110.35,36.74.HRMS(ESI):calcd for C18H11N2O2Cl[M+H]+323.0582,found 323.0575.HPLC purity:97.6％.
a-14 as red solid in 29% yield. m.p.>200℃.1H NMR(400MHz,CDCl3)δ8.24(d,J＝7.4Hz,1H),7.85(d,J＝8.1Hz,1H),7.74(t,J＝7.8Hz,1H),7.62–7.42(m,4H),5.98(s,1H),3.92(dq,J＝14.2,7.0Hz,1H),3.78(dq,J＝14.6,7.2Hz,1H),1.26(t,J＝7.1Hz,3H).13C NMR(101MHz,CDCl3)δ180.05,177.92,153.16,150.15,141.77,135.03,133.79,133.35,132.32,131.75,131.34,130.23,129.86,129.50,127.71,118.63,100.53,44.34,12.07.HRMS(ESI):calcd for C19H13N2O2Cl[M+H]+337.0738,found 337.0735.HPLC purity:99.9％.
b-14 purple solid, 22% yield. m.p.>200℃.1H NMR(400MHz,DMSO)δ8.09(d,J＝8.6Hz,1H),8.05(d,J＝7.4Hz,1H),7.89(dd,J＝16.4,8.2Hz,1H),7.77(dd,J＝7.4,1.6Hz,1H),7.71(d,J＝8.0Hz,1H),7.67–7.52(m,2H),5.85(s,1H),4.21(dq,J＝14.2,6.9Hz,1H),3.82(dq,J＝14.5,7.2Hz,1H),1.19(t,J＝7.1Hz,3H).13C NMR(101MHz,DMSO)δ181.17,178.31,157.02,136.00,134.22,134.15,132.31,130.98,130.57,130.23,130.20,129.37,128.36,124.14,117.32,110.40,100.00,44.02,14.18.HRMS(ESI):calcd for C19H13N2O2Cl[M+H]+337.0738,found 337.0731.HPLC purity:97.5％.
a-15 red solid, yield 36%. m.p.>200℃.1H NMR(400MHz,CDCl3)δ8.26(dd,J＝7.4,1.2Hz,1H),7.87(dd,J＝8.1,1.2Hz,1H),7.81–7.73(m,1H),7.61–7.43(m,4H),5.95(s,1H),3.49(s,3H).13C NMR(101MHz,CDCl3)δ179.93,177.82,154.52,151.79,141.70,136.02,135.45,134.92,133.37,131.06,131.00,130.53,129.45,128.54,126.38,118.15,100.69,38.91.HRMS(ESI):calcd for C18H11N2O2Cl[M+H]+323.0582,found 323.0577.HPLC purity:99.8％.
b-15 purple solid, 31% yield. m.p.>200℃.1H NMR(400MHz,DMSO)δ8.08–7.96(m,2H),7.87(dd,J＝10.6,5.2Hz,1H),7.77(s,1H),7.65(d,J＝7.3Hz,2H),7.58(dd,J＝8.8,6.6Hz,1H),5.83(d,J＝0.9Hz,1H),3.59(s,3H).13C NMR(101MHz,CDCl3)δ180.97,179.04,157.32,156.67,137.00,134.00,133.32,132.18,132.04,130.39,130.18,130.14,129.57,128.18,121.88,117.91,112.40,36.09.HRMS(ESI):calcd for C18H11N2O2Cl[M+H]+323.0582,found 323.0575.HPLC purity:100％.
a-16 red solid, 14% yield. m.p.>200℃.1H NMR(400MHz,DMSO)δ8.06(dd,J＝7.2,1.3Hz,1H),7.88(dd,J＝8.1,1.3Hz,1H),7.86–7.81(m,1H),7.77–7.73(m,2H),7.68–7.63(m,2H),5.89(d,J＝2.3Hz,1H),3.39(s,3H).13C NMR(101MHz,CDCl3)δ180.02,177.85,154.92,152.01,141.78,137.23,134.95,133.40,132.76,131.08,129.79(2C),129.56(2C),129.44,118.09,100.66,39.01.HRMS(ESI):calcd for C18H11N2O2Cl[M+H]+323.0582,found 323.0576.HPLC purity:100％.
b-16 purple solid, yield 28%. m.p.>200℃ 1H NMR(400MHz,DMSO)δ8.02(d,J＝7.9Hz,2H),7.94–7.82(m,1H),7.75(d,J＝8.6Hz,2H),7.66(d,J＝8.6Hz,2H),5.84(s,1H),3.62(s,3H).13C NMR(101MHz,DMSO)δ181.58,178.07,159.20,157.49,138.13,135.91,133.98,133.93,131.35(2C),129.93,129.14(2C),124.49,116.88,109.96,99.99,38.73.HRMS(ESI):calcd for C18H11N2O2Cl[M+H]+323.0588,found 323.0582.HPLC purity:95.2％.
a-17 red solid, 18% yield. m.p.>200℃.1H NMR(400MHz,DMSO)δ8.10(dd,J＝7.1,1.5Hz,1H),7.94–7.83(m,2H),7.70(tdd,J＝7.4,6.6,1.7Hz,2H),7.52–7.39(m,2H),5.92(s,1H),3.38(d,J＝1.3Hz,3H).13C NMR(101MHz,CDCl3)δ180.03,177.82,159.27(d,J＝249.8Hz),151.71,151.52,141.87,134.96,133.08(d,J＝8.2Hz),,133.04,131.18,130.65(d,J＝1.8Hz),129.55,125.52(d,J＝3.3Hz),122.63(d,J＝15.1Hz),118.32,116.23(d,J＝20.6Hz),100.51,37.49(d,J＝2.7Hz).HRMS(ESI):calcd for C18H11N2O2F[M+H]+307.0877,found 307.0869.HPLC purity:95.6％.
b-17 purple solid, 22% yield. m.p.>200℃.1H NMR(400MHz,DMSO)δ8.04–7.97(m,2H),7.86(dd,J＝8.6,7.4Hz,1H),7.73–7.59(m,2H),7.50–7.30(m,2H),5.82(s,1H),3.56(d,J＝1.4Hz,3H).13C NMR(101MHz,DMSO)δ181.33,178.32,158.93(d,J＝247.8Hz),157.15,155.56,137.58,134.01,133.54(d,J＝8.3Hz),131.28(d,J＝1.8Hz),130.12,129.32,125.69(d,J＝3.2Hz),124.28,123.08(d,J＝15.0Hz),116.96,116.52(d,J＝20.6Hz),110.28,37.46(d,J＝1.7Hz).HRMS(ESI):calcd for C18H11N2O2F[M+H]+307.0877,found 307.0874.HPLC purity:99.7％.
a-18 red solid, yield 19%. m.p.>200℃.1H NMR(400MHz,DMSO)δ8.12–8.04(m,1H),7.94–7.83(m,3H),7.76–7.65(m,2H),7.52–7.37(m,2H),5.92(s,1H),3.38(s,3H).13C NMR(101MHz,CDCl3)δ180.04,177.85,159.29(d,J＝250.0Hz),151.70,151.54,141.88,133.08(d,J＝8.3Hz),133.12,133.04,131.22,130.64(d,J＝1.8Hz),129.58,125.52(d,J＝3.2Hz),124.03(d,J＝3.4Hz),118.35,116.24(d,J＝20.5Hz),100.52,37.47(d,J＝2.8Hz).HRMS(ESI):calcd for C18H11N2O2F1[M+H]+307.0877,found 307.0871.HPLC purity:99.7％.
b-18 purple solid, yield 20%. m.p.>200℃.1H NMR(400MHz,DMSO)δ8.03(dd,J＝7.7,3.9Hz,2H),7.89(dd,J＝8.5,7.4Hz,1H),7.76–7.59(m,2H),7.51–7.40(m,2H),5.85(s,1H),3.61(s,3H).HRMS(ESI):calcd for C18H11N2O2F1[M+H]+307.0877,found 307.0873.HPLC purity:100％.
a-19 red solid, 26.1% yield. m.p.>200℃.1H NMR(400MHz,DMSO)δ8.07(d,J＝6.8Hz,1H),7.87(dd,J＝16.1,7.5Hz,2H),7.81–7.76(m,2H),7.43(t,J＝8.4Hz,2H),5.90(s,1H),3.41(s,3H).13C NMR(101MHz,CDCl3)δ180.00,177.75,163.99(d,J＝252.6Hz),155.09,151.96,141.82,134.88(2C),133.28(2C),130.76(d,J＝8.1Hz),130.63,130.53(d,J＝3.6Hz),129.36,117.98,116.47(d,J＝22.1Hz),100.68,39.04.HRMS(ESI):calcd for C18H11N2O2F[M+H]+307.0877,found 307.0872.HPLC purity:98.8％.
b-19 purple solid, 21% yield. m.p.>200℃.1H NMR(400MHz,DMSO)δ8.03(d,J＝7.9Hz,2H),7.89(dd,J＝16.0,7.5Hz,1H),7.82–7.77(m,2H),7.43(t,J＝8.9Hz,2H),5.85(s,1H),3.63(s,3H).13C NMR(101MHz,DMSO)δ181.66,178.06,163.67(d,J＝248.2Hz),159.34,157.54,138.21(2C),133.91,132.06(d,J＝8.8Hz),131.65(d,J＝3.0Hz),129.96(2C),128.95,124.50,116.90,116.11(d,J＝22.1Hz),109.90,38.78.HRMS(ESI):calcd for C18H11N2O2F[M+H]+307.0877,found 307.0871.HPLC purity:96.7％.
a-20 red solid, yield 19.3%. m.p.>200℃.1H NMR(400MHz,CDCl3)δ8.30–8.20(m,1H),7.86(d,J＝8.1Hz,1H),7.75(t,J＝7.8Hz,1H),7.65(td,J＝8.3,6.3Hz,1H),7.14(td,J＝8.0,1.7Hz,1H),7.08–6.95(m,1H),5.95(s,1H),3.47(d,J＝2.1Hz,3H).13C NMR(101MHz,CDCl3)δ179.92,177.79,164.66(dd,J＝255.4,11.9Hz),159.80(dd,J＝252.5,12.4Hz),151.49,150.92,141.76,134.95,133.37,132.12(dd,J＝10.1,4.0Hz),131.28,129.48,118.97(dd,J＝15.6,4.0Hz),118.30,113.12(dd,J＝21.8,3.4Hz),104.84(t,J＝25.3Hz),100.65,37.55(d,J＝3.1Hz).HRMS(ESI):calcd for C18H10N2O2F2[M+H]+325.0783,found 325.0781.HPLC purity:100％.
b-20 purple solid, yield 17.4%. m.p.>200℃.1H NMR(400MHz,CDCl3)δ8.06(d,J＝7.4Hz,1H),7.84–7.76(m,1H),7.73(dd,J＝13.9,5.5Hz,1H),7.63–7.52(m,1H),7.14(td,J＝8.1,2.0Hz,1H),7.07–6.92(m,1H),6.07(s,1H),3.65(d,J＝2.3Hz,3H).13C NMR(101MHz,DMSO)δ180.19,177.23,163.06(dd,J＝250.6,12.3Hz),158.44(dd,J＝250.4,12.9Hz),156.00,153.77,136.53,132.92,131.86(d,J＝10.3Hz),128.99,128.26,123.25,118.72(d,J＝11.2Hz),115.87,112.04(d,J＝21.9Hz),109.22,104.19(t,J＝25.9Hz),36.46(d,J＝1.9Hz).HRMS(ESI):calcd for C18H10N2O2F2[M+H]+325.0783,found 325.0775.HPLC purity:99.9％.
a-21 red solid, 24% yield. m.p.>200℃.1H NMR(400MHz,DMSO)δ8.10(d,J＝6.4Hz,1H),8.01–7.79(m,2H),7.61(d,J＝5.8Hz,2H),5.94(s,1H),3.40(s,3H).13C NMR(101MHz,CDCl3)δ179.73,177.77,154.24(dd,J＝7.8,3.7Hz),151.67(dd,J＝7.4,3.7Hz),151.27,149.76(d,J＝2.7Hz),148.22–147.28(m),141.55(d,J＝3.7Hz),134.95,133.41,131.42,129.50,124.65,121.16–119.55(m),118.39,113.95(dd,J＝17.7,2.1Hz),100.82,37.53.HRMS(ESI):calcd for C18H19N2O2F3[M+H]+343.0689,found 343.0682.HPLC purity:100％.
b-21 purple solid, yield 17.4%. m.p.>200℃.1H NMR(400MHz,DMSO)δ8.09–8.00(m,2H),7.90(dd,J＝8.6,7.4Hz,1H),7.71–7.46(m,2H),5.85(s,1H),3.62(s,3H).HRMS(ESI):calcd for C18H19N2O2F3[M+H]+343.0689,found 343.0684.HPLC purity:100％.
Example 2: general Synthesis method of Compound (d-1, d-3)
Adding an o-quinone product (1mmol), bromosuccinimide (1.1mmol), benzoyl peroxide (15mg) into a reaction bottle, dissolving in chloroform, reacting for 2 hours at 80 ℃ with stirring, stopping the reaction, and purifying by column chromatography to obtain the product.
Figure BDA0001307690180000171
d-1 red solid, 71% yield. m.p.>200℃.1H NMR(400MHz,CDCl3)δ8.21(d,J＝7.4Hz,1H),7.89(d,J＝8.1Hz,1H),7.73(t,J＝7.7Hz,1H),7.66(d,J＝6.9Hz,1H),7.62–7.46(m,3H),3.74(d,J＝5.9Hz,3H).13C NMR(101MHz,CDCl3)δ177.51,173.91,155.44,152.49,141.28,135.19,133.53,132.94,132.59,132.32,131.33,130.85,130.59,127.99,127.72,120.54,98.23,44.52.HRMS(ESI):calcd for C18H10N2O2ClBr[M+H]+400.9687,found 400.9683.HPLC purity:97.8％.
d-3 red solid, 77.5% yield. m.p.175.1-176.7 ℃.1H NMR(400MHz,CDCl3)δ8.12(d,J＝7.4Hz,1H),7.79(d,J＝8.0Hz,1H),7.67(t,J＝7.7Hz,1H),3.91(s,3H),2.89(q,J＝7.3Hz,2H),1.44(t,J＝7.3Hz,3H).13C NMR(101MHz,CDCl3)δ177.84,173.92,159.66,153.16,141.23,134.64,132.73,130.45,127.47,120.00,97.02,42.68,28.54,11.13.HRMS(ESI):calcd for C14H11N2O2Br[M+H]+319.0077,found 319.0073.HPLC purity:98.7％.
Example 3: general Synthesis method of Compound P8 (d-2)
Adding an o-quinone product (1mmol), chlorosuccinimide (1.1mmol), benzoyl peroxide (15mg) and chloroform into a reaction bottle, dissolving, stirring at 80 ℃ for 2 hours, stopping reaction, and purifying by column chromatography to obtain the product.
Figure BDA0001307690180000181
d-2 red solid, 63% yield. m.p.>200℃.1H NMR(400MHz,CDCl3)δ8.23(d,J＝7.2Hz,1H),7.89(d,J＝7.9Hz,1H),7.73(t,J＝7.6Hz,1H),7.63(t,J＝8.6Hz,1H),7.61–7.45(m,3H),3.73(s,3H).13C NMR(101MHz,CDCl3)δ177.96,173.72,155.37,149.98,141.48,135.28,133.53,132.93,132.56,132.29,131.47,130.72,130.59,127.99,127.73,119.60,108.34,43.66.HRMS(ESI):calcd for C18H10N2O2Cl2[M+H]+357.0192,found 357.0191.HPLC purity:97.9％.
Example 4 inhibition of Perimine quinone derivatives on several tumor cell lines
TABLE 1 toxicity test results of Perimine quinone derivatives against several tumor cell lines
Figure BDA0001307690180000182
Figure BDA0001307690180000191
Compounds were tested for anti-tumor activity by MTT method: taking corresponding cell strain in logarithmic growth phase5000 cells per well are respectively packed in a 96-well culture plate, 100 mu L of each well is cultured for 24 hours, 100 mu L of corresponding drug solutions with different concentrations are respectively added after the cells adhere to the wall, and a positive control group (VP-16) and a drug administration group with different concentrations are set in the experiment. Each set was provided with 3 parallel holes. Constant temperature of 5% CO2Incubators were incubated at 37 ℃ for 48 hours, 20. mu.L of MTT medium (2.5mg/ml) was added to each well 4 hours before the end of the experiment, the medium was aspirated 4 hours later, 100. mu.L of DMSO was added to each well, and the plate shaker shaken. 5 minutes after the crystal is dissolved, an enzyme-linked detector is arranged, the OD value of each hole is measured at the wavelength of 570nm, the growth inhibition rate is calculated according to the following formula, and then IC is calculated50。
The tumor cell inhibition rate of the drug was (1-mean OD value in drug group/mean OD value in control group) × 100%.
The compounds were tested for anti-tumor activity by in vitro cytotoxicity assay and the results are shown in table 1. The compound disclosed by the patent has a strong inhibition effect on the tumor cell strains in vitro.
Example 5 inhibition of topoisomerase II by Perimine quinone derivatives as described in this patent
The compound is used for inhibiting test of topoisomerase II, and the topoisomerase activity outside a cell system is measured by adopting a pBR322 plasmid loose method. Wherein recombinant human topoisomerase II α is obtained from TopoGEN. Mixing 1U of topoisomerase, a drug to be detected with a specified concentration and 0.2 mu g of supercoiled pBR322 plasmid, adding into a topoisomerase buffer solution, incubating in a water bath at 37 ℃ for 30 minutes, performing agarose gel electrophoresis, and detecting by using a gel imager after GelRed staining. The results show that the compounds b-16 and b-21 in Table 1, which have better tumor activity, can completely inhibit the activity of topoisomerase II in vitro experiments at 5. mu.M and 2.5. mu.M, respectively, which is much higher than the inhibitory concentration (100. mu.M) of the positive control VP-16 (etoposide).
In addition, the other compounds described in the patent can completely inhibit topoisomerase II at 50 mu M, and all show good inhibition effect.
Example 6: topo II-mediated DNA fragmentation assay
The compound b-16 was selected to study the mechanism of action of the compound in inhibiting human DNA topoisomerase II, and the Topo II-mediated DNA fragmentation assay was performed using VP16 as a positive control, according to the instructions for the reagents, and the results are shown in FIG. 2. Illustrated in fig. 2 is as follows: (D: DNA control; T: DNA + Topo II; E: VP 16; N: gapped DNA; L: linear DNA; R: bulk DNA; S: supercoiled DNA). As can be seen from FIG. 2, a clear linear DNA band appeared in the middle of the electrophoretogram of the positive control group to which VP16 was added, compared with the control DNA blank group and the control group to which only enzyme and DNA were added, indicating that VP16 significantly promotes the formation of a fragmentation complex. In contrast, compound b-16 did not produce linear DNA at 20. mu.M concentration, but also reduced the production of Topo II poison linear DNA, indicating that b-16 is a catalytic inhibitor of Topo II.
The results of in vitro and in vivo experiments show that the Perimidine quinone derivative can be used for preparing antitumor drugs taking topoisomerase II as a target.

Claims (6)

1. A Perimine quinone derivative or a pharmaceutically acceptable salt thereof, wherein the structural formula of the Perimine quinone derivative is shown as a formula (I) or a formula (II):
Figure FDA0002961749110000011
wherein R is1Is methyl, ethyl, cyclopropyl, cyclohexyl, anilino, phenyl, 4-methylphenyl, 4-trifluoromethylphenyl, thienyl, furyl, N-ethylcarbazolyl, 2-chlorophenyl, 3-chlorophenyl, 4-alkoxyphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2, 4-difluorophenyl, 2,3, 4-trifluorophenyl, R2Is methyl or ethyl, R3Is hydrogen or halogen.
2. The Perimidine quinone derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein R is3Is hydrogen, chlorine or bromine.
3. A process for preparing a Perimidine quinone derivative or a pharmaceutically acceptable salt thereof according to claim 1, comprising the steps of:
s1.1,8 reacting diaminonaphthalene with aldehyde to obtain a compound with a structural formula shown as a formula (III);
Figure FDA0002961749110000012
s2, alkylating-NH on the compound shown in the structural formula (III) obtained in the step S1 to obtain a compound shown in the structural formula (IV);
Figure FDA0002961749110000013
s3, nitrating the compound shown in the structural formula (IV) obtained in the step S2, reducing, oxidizing and finally reacting with NCS and NBS respectively to obtain a compound shown in the structural formula (I) or (II);
Figure FDA0002961749110000021
4. use of a Perimidine quinone derivative or a pharmaceutically acceptable salt thereof as claimed in claim 1 or 2 for the preparation of an anticancer agent.
5. The use as claimed in claim 4, wherein the Perimidine quinone derivative is used in the preparation of a medicament for treating human colon or cervical cancer.
6. A topoisomerase inhibitor characterized by containing the Perimine quinone derivative or a pharmaceutically acceptable salt thereof according to claim 1 or 2.
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