CN104230786B - Indole-structure-containing compound with anti-tumor activity and synthesis method thereof - Google Patents

Indole-structure-containing compound with anti-tumor activity and synthesis method thereof Download PDF

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CN104230786B
CN104230786B CN201410497216.3A CN201410497216A CN104230786B CN 104230786 B CN104230786 B CN 104230786B CN 201410497216 A CN201410497216 A CN 201410497216A CN 104230786 B CN104230786 B CN 104230786B
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reaction
preparation
compound
product
indoles
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CN104230786A (en
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梁承远
宋慧慧
张诗韵
毛跟年
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SHAANXI PIONEER BIOTECH Co.,Ltd.
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Shaanxi University of Science and Technology
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/40—Nitrogen atoms, not forming part of a nitro radical, e.g. isatin semicarbazone

Abstract

The invention discloses an indole-structure-containing compound with anti-tumor activity shown in a structural formula (I). The indole-structure-containing compound is synthesized through a catalytic reduction method by taking indole derivatives, cinnamoyl chloride and phenylhydrazine as raw materials. The raw materials are economical and easily obtained. A one-pot method is adopted in the synthesis process, the complicated multi-step operation is avoided, the operation is simple and convenient, reaction conditions are mild, and the yield is higher. An activity test research result obtained by using an MTT (Methyl Thiazolyl Tetrazolium) method preliminarily shows that the compound has good inhibitory activity on various tumor cell strains and has a better medicine application prospect.

Description

A kind of compound containing indole structure with antitumor activity and its synthetic method
Technical field
The present invention relates to a kind of compound containing indole structure with antitumor activity and its synthetic method, such chemical combination Thing has anti-tumor biological, belongs to pharmaceutical technology field.
Background technology
With the further investigation to oncobiology and its related discipline, people recognize intracellular signal transduction pathway gradually Imbalance cause the essence that the infinite multiplication of cell is cell carcinogenesis.This causes the focus of medicament research and development slowly from traditional cell Cytotoxic drug is to the antineoplastic transfer of new generation for tumour cell abnormal signal system.Conventional cell cytotoxic drug selectivity Differ from, be also easy to produce drug resistance, be different from, targeting anti-tumor medicine is reached for the difference between tumour cell and normal cell The therapeutic effect of hypotoxicity, high selectivity is arrived.The Main way of research antineoplastic is at present：Find new action target spot （Acceptor, enzyme）, new antitumor activity molecule and new experimental technique.And in terms of antitumor activity molecule, natural products and Derivative obtained by its structure of modification is very important source.
Benzazole compounds are the important heterocyclic compounds of a class, with significant biologically active and application function.Indoles And its homologue and derivative are primarily present in natural flower oil, such as in Jasmine, bigarabe flower, daffodil, fragrant rowland etc..For example, Indoles is obtained by indigo degraded earliest；Indoles and its homologue are existed in coal tar；Essential oil（Such as refined jasmine oil etc.）In Also contain indoles；Contain 3- methyl indols in excrement；Many vat dyestuffss are the derivatives of indoles；One essential amino acid of animal Tryptophan is the derivative of indoles；The very strong natural materials of some physiologically actives, such as alkaloid, auximone etc., are all Yin Diindyl derivative.
Some in nature contain polycyclic Benzazole compounds and are used to treat various diseases, such as cancer, tumour, Chinese mugwort Grow disease, anti-inflammatory analgesic and viral disease and communicable disease.For example widely known rescisan of representational medicine, It is new in minorine, Ah, educate and groan guest, gardnerine, reserpine, banisterine and donaxine etc..
The content of the invention
One of the technical problem to be solved in the present invention is to provide the novel compound containing indole structure of a class, such chemical combination Thing has such as following formulas（1）Shown structure.
It is a further object to provide the synthetic method of such new construction indole derivatives.Specific building-up process Using novel phenylhydrazine method of reducing, the structure of C-N keys is also not used (transition) metallic catalyst, and raw material economics is easy to get.
It is also another object of the present invention to provide formula（1）Shown compound is being prepared for treatment or prevention of tumor life The long application with the medicine of transfer.
The present invention realizes that process is as follows：
General structure（I）Shown compound,
Wherein, R1=H, halogen, NO2、C1-C5Alkyl or C1-C5Alkoxyl；
R2=H、C1-C5Alkyl or C1-C5Alkoxyl.
R1Preferably methyl, methoxyl group, fluorine, chlorine, bromine or iodine, R2Preferably methyl or methoxy.
Formula（I）Compound preferably is selected from following compounds, and its structural formula is as follows：
Structural formula（I）The preparation method of compound, its synthetic route is：
。
Specifically, it is by mol ratio 1:1:1～1:2:It is molten that 2 indole derivatives, cinnamoyl chloride and phenylhydrazine add to toluene In agent, in 60 ~ 120 DEG C of heating reflux reactions, after reaction terminates, by reactant liquor concentrated by rotary evaporation, it is thick that column chromatography for separation obtains product Product, further recrystallize to obtain product.
The preferred mol ratio of indole derivatives, cinnamoyl chloride and phenylhydrazine is 1:1:1～1:1.5:1.5, reaction temperature be 80 ~ 110 DEG C, the reaction time is 4 ~ 10 hours, and in column chromatography mobile phase, ethyl acetate and petroleum ether volume ratio are 1:5, recrystallization solvent From ethanol-water solution.
The present invention is synthesized by catalytic reduction method, and the structure of C-N keys adopts green synthesis process, (transition) is not used Metallic catalyst, raw material economics are easy to get, and building-up process adopts one kettle way, it is to avoid numerous and diverse many more manipulations, easy to operate, reaction Mild condition, yield are preferable.The present invention carries out active testing with mtt assay, and result of study tentatively shows, such compound is to various Tumor cell line has good inhibitory activity, with preferable medical applications prospect.
Specific embodiment
With reference to specific embodiment, the present invention is further elaborated.These embodiments are only in order at the mesh of explanation , and do not limit the scope of the invention and essence.
Optimization of process conditions embodiment
Embodiment 1
Different solvents system is investigated to reacting the impact of target product yield, as a result as shown in table 1：
Reaction condition is：Molar ratio indole derivatives, cinnamoyl chloride and phenylhydrazine are 1:1:1, reaction temperature is 80 DEG C, Reaction time is 6 hours, and solvent is respectively toluene, ethyl acetate, second alcohol and water, as a result shows, when reaction dissolvent is toluene Yield is most preferable.
Embodiment 2
Impact of the differential responses temperature to target product yield is investigated, as a result as shown in table 2：
Reaction condition is：Molar ratio indole derivatives, cinnamoyl chloride and phenylhydrazine are 1:1:1, solvent is made with toluene, instead It is 6 hours between seasonable, reaction temperature is respectively 25 DEG C, 60 DEG C, 80 DEG C, 105 DEG C, as a result shows, reaction temperature is 105 DEG C（Return Stream temperature）When, yield highest.
Embodiment 3
Impact of the differential responses time to target product yield is investigated, as a result as shown in table 3：
Reaction condition is：Molar ratio indole derivatives, cinnamoyl chloride and phenylhydrazine are 1:1:1, solvent is made with toluene, instead Temperature is answered to be respectively 105 DEG C, the reaction time is respectively 4 hours, 6 hours, 8 hours, 10 hours, as a result shows, the reaction time is 6 Hour, yield highest.
Embodiment 4
Investigate raw material difference inventory ratio（Mol ratio）To target product yield（Calculated with raw material indole derivatives）Shadow Ring, as a result as shown in table 4：
Reaction condition is：Solvent is made with toluene, reaction temperature is respectively 105 DEG C, and the reaction time is respectively 6 hours, feeds intake Amount ratio（Mol ratio）Indole derivatives, cinnamoyl chloride and phenylhydrazine are respectively 1:1:1、1:1.2:1.2、1:1.5:1.5、1:1.5:2, As a result show, indole derivatives, cinnamoyl chloride and phenylhydrazine molar ratio are 1:1.2:When 1.2, in terms of raw material indole derivatives Calculate, yield highest.
Prepare embodiment
Embodiment 1
5-nitro-1-（5-nitroindoline quinoline-3- bases）- 1H- indoles（A-1）Preparation：
5- nitro -1H- indoles is added in 250ml round-bottomed flasks（50mmol）, add 100ml toluene to be mixed, then Add cinnamoyl chloride（60mmol）, room temperature reaction 1 hour, after separating out completely to compound, addition phenylhydrazine（60mmol）, with heating Set is heated to 105 DEG C, is placed on magnetic stirring apparatus, is heated at reflux reaction 6 hours, and in course of reaction, continuous point sample observation, treats original Stop heating after material reaction completely, remove condensing unit.By reactant liquor concentrated by rotary evaporation, column chromatography for separation obtains product crude product.Will Crude product is recrystallized with ethanol-water solution, is dried, is obtained final product product（Yellow-brown solid 10.12g, yield 69.7%）.
Brownish-yellow powder, M.P.187.6-188.9 DEG C；
1H-NMR(300MHz,DMSO-d6)δ:9.71(1H,s),8.08-8.20(2H,s),7.95(2H,s),7.44 (1H,d),6.82(1H,s), 6.35(1H,d),5.21(1H,t),3.72(2H,d),4.0(1H,t);
13C-NMR(75MHz,DMSO-d6)δ:156.6,142.5,142.1,136.3,132.3,129.5,128.8, 124.9,121.8,114.4, 114.0,112.1,100.9,76.8,48.5;
HRMS(ESI)for(M+H)+:calcd324.0858, found 324.0862。
Embodiment 2
5-methyl isophthalic acid-（5- methyl indoline -3- bases）- 1H- indoles（A-2）Preparation
5- Methyl-1H-indoles are added in 250ml round-bottomed flasks（50mmol）, add 100ml toluene to be mixed, then Add cinnamoyl chloride（60mmol）, room temperature reaction 1 hour, after separating out completely to compound, addition phenylhydrazine（60mmol）, with heating Set is heated to 105 DEG C, is placed on magnetic stirring apparatus, is heated at reflux reaction 6 hours, and in course of reaction, continuous point sample observation, treats original Stop heating after material reaction completely, remove condensing unit.By reactant liquor concentrated by rotary evaporation, column chromatography for separation obtains product crude product.Will Crude product is recrystallized with ethanol-water solution, is dried, is obtained final product product（White solid 11.20g, yield 83.9%）.
White powder, M.P.176.9-178.5 DEG C；
1H-NMR(300MHz,DMSO-d6)δ:8.71(1H,s),7.83(1H,s),7.44(1H,d),7.31(1H,s), 6.92(2H,s),6.43(1H,s),6.35(1H,d),5.21(1H,t),4.0(1H,t)3.71(2H,d),2.34(2H,s);
13C-NMR(75MHz,DMSO-d6)δ:147.5,133.6,130.4,128.8,128.7,127.1,126.5, 123.7,123.1,113.4, 108.2,100.9,78.3,48.5,21.7,21.5;
HRMS (ESI) for (M+H)+: calcd 262.3487, found 262.3490。
Embodiment 3
5- methoxyl group -1-（5- melonia -3- bases）- 1H- indoles（A-3）Preparation
5- methoxyl group -1H- indoles is added in 250ml round-bottomed flasks（50mmol）, add 100ml toluene to be mixed, Add cinnamoyl chloride（60mmol）, room temperature reaction 1 hour, after separating out completely to compound, addition phenylhydrazine（60mmol）, use and add Hot jacket is heated to 105 DEG C, is placed on magnetic stirring apparatus, is heated at reflux reaction 6 hours, and in course of reaction, continuous point sample observation, treats Raw material reaction stops heating completely afterwards, removes condensing unit.By reactant liquor concentrated by rotary evaporation, column chromatography for separation obtains product crude product. Crude product is recrystallized with ethanol-water solution, is dried, is obtained final product product（Pale red solid 10.81g, yield 72.4%）.
Pale red powder, M.P.175.8-177.2 DEG C；
1H-NMR(300MHz,DMSO-d6)δ:7.92(2H,s),7.44(1H,d),6.86(1H,s),6.61(2H,s), 6.44(1H,s), 6.35(1H,d),5.21(1H,t),4.0(1H,t),3.85(6H,s)3.72(2H,d);
13C-NMR(75MHz,DMSO-d6)δ:154.0,148.7,142.8,129.6,128.8,128.9,114.4, 112.7,112.4,109.5, 100.9,78.3,55.7,48.5;
HRMS(ESI)for(M+H)+: calcd 294.1368, found 294.1373。
Embodiment 4
5-chloro- 1-（5- chlorine dihydropyridine -3- bases）- 1H- indoles（A-4）Preparation
The chloro- 1H- indoles of 5- is added in 250ml round-bottomed flasks（50mmol）, add 100ml toluene to be mixed, then plus Enter cinnamoyl chloride（60mmol）, room temperature reaction 1 hour, after separating out completely to compound, addition phenylhydrazine（60mmol）, use heating mantle 105 DEG C are heated to, are placed on magnetic stirring apparatus, be heated at reflux reaction 6 hours, continuous point sample observation, treats raw material in course of reaction Stop heating after reaction completely, remove condensing unit.By reactant liquor concentrated by rotary evaporation, column chromatography for separation obtains product crude product.Will be thick Product are recrystallized with ethanol-water solution, are dried, are obtained final product product（Pale solid 11.64g, yield 75.3%）.
Pale powder, M.P.183.4-185.4 DEG C；
1H-NMR(300MHz,DMSO-d6)δ:8.07(1H,s),7.68(1H,s),7.44(1H,d),7.27(1H,s), 7.08(2H,s), 6.47(1H,s),6.35(1H,d),5.21(1H,t),4.0(1H,t),3.72(2H,d);
13C-NMR(75MHz,DMSO-d6)δ:148.8,134.5,129.8,128.9,128.4,126.7,125.8, 125.5,122.7,122.5, 121.8,112.9,100.9,77.5,48.5;
HRMS (ESI) for (M+H)+: calcd 302.0378, found 302.0384。
Embodiment 5
The bromo- 1- of 5-（5- bromine indoline -3- bases）- 1H- indoles（A-5）Preparation
The bromo- 1H- indoles of 5- is added in 250ml round-bottomed flasks（50mmol）, add 100ml toluene to be mixed, then plus Enter cinnamoyl chloride（60mmol）, room temperature reaction 1 hour, after separating out completely to compound, addition phenylhydrazine（60mmol）, use heating mantle 105 DEG C are heated to, are placed on magnetic stirring apparatus, be heated at reflux reaction 6 hours, continuous point sample observation, treats raw material in course of reaction Stop heating after reaction completely, remove condensing unit.By reactant liquor concentrated by rotary evaporation, column chromatography for separation obtains product crude product.Will be thick Product are recrystallized with ethanol-water solution, are dried, are obtained final product product（Brown solid 14.27g, yield 76.1%）.
Brown powder, M.P.186.2-188.1 DEG C；
1H-NMR(300MHz,DMSO-d6)δ:8.15(1H,s),7.73(2H,s),7.44(1H,d),7.20(2H,s), 6.45(1H,s), 6.35(1H,d),5.21(1H,t),4.0(1H,t),3.72(2H,d);
13C-NMR(75MHz,DMSO-d6)δ:149.5,135.5,133.3,130.8,129.6,128.8,126.2, 124.6,121.0,113.8, 113.2,111.3,110.2,100.9,77.1,48.5;
HRMS(ESI)for(M+H)+: calcd 391.9346, found 391.9351。
Embodiment 6
7- methyl isophthalic acids-（7- methyl indoline -3- bases）- 1H- indoles（A-6）Preparation
7- Methyl-1H-indoles are added in 250ml round-bottomed flasks（50mmol）, add 100ml toluene to be mixed, then Add cinnamoyl chloride（60mmol）, room temperature reaction 1 hour, after separating out completely to compound, addition phenylhydrazine（60mmol）, with heating Set is heated to 105 DEG C, is placed on magnetic stirring apparatus, is heated at reflux reaction 6 hours, and in course of reaction, continuous point sample observation, treats original Stop heating after material reaction completely, remove condensing unit.By reactant liquor concentrated by rotary evaporation, column chromatography for separation obtains product crude product.Will Crude product is recrystallized with ethanol-water solution, is dried, is obtained final product product（White solid 7.22g, yield 62.5%）.
White powder, M.P.173.8-174.9 DEG C；
1H-NMR(300MHz,DMSO-d6)δ:,7.44(1H,d),7.21(2H,s),6.90(2H,s),6.35(1H,d), 5.21(1H,t), 4.0(1H,t),3.70(2H,d),2.12(1H,s),1.91(3H,s);
13C-NMR(75MHz,DMSO-d6)δ:150.0,128.8,128.9,128.6,128.4,126.7,125.5, 123.8,122.2,121.7, 117.8,116.9,100.9,97.8,78.5,48.8,19.6,17.8;
HRMS (ESI) for (M+H)+: calcd 262.3488, found 262.3493。
Embodiment 7
7- methoxyl group -1-（7- melonia -3- bases）- 1H- indoles（A-7）Preparation
7- methoxyl group -1H- indoles is added in 250ml round-bottomed flasks（50mmol）, add 100ml toluene to be mixed, Add cinnamoyl chloride（60mmol）, room temperature reaction 1 hour, after separating out completely to compound, addition phenylhydrazine（60mmol）, use and add Hot jacket is heated to 105 DEG C, is placed on magnetic stirring apparatus, is heated at reflux reaction 6 hours, and in course of reaction, continuous point sample observation, treats Raw material reaction stops heating completely afterwards, removes condensing unit.By reactant liquor concentrated by rotary evaporation, column chromatography for separation obtains product crude product. Crude product is recrystallized with ethanol-water solution, is dried, is obtained final product product（White solid 12.37g, yield 81.6%）.
White powder, M.P.183.6-184.9 DEG C；
1H-NMR(300MHz,DMSO-d6)δ:7.45(2H,t),7.15(1H,s),6.65(4H,s),6.35(1H,d) , 5.21(1H,t), 4.0(1H,t),3.72(2H,d),2.14(1H,s),1.93(3H,s);
13C-NMR(75MHz,DMSO-d6)δ:146.5,146.2,141.0,134.2,129.6,128.9,125.0, 120.7,118.0,113.6, 113.0,110.5,104.5,100.9,78.6,55.8,48.7;
HRMS (ESI) for (M+H)+: calcd 294.1369, found 294.1374。
Embodiment 8
7- methyl isophthalic acids-（7- methyl-5-nitro indoline -3- bases）- 5- nitro -1H- indoles（A-8）Preparation
7- methyl-5-nitro -1H- indoles is added in 250ml round-bottomed flasks（50mmol）, add 100ml toluene by its Mix, add cinnamoyl chloride（60mmol）, room temperature reaction 1 hour, after separating out completely to compound, addition phenylhydrazine （60mmol）, with heating mantle heats to 105 DEG C, it is placed on magnetic stirring apparatus, is heated at reflux reaction 6 hours, in course of reaction not Breakpoint sample is observed, and stops heating, remove condensing unit after raw material reaction is complete.By reactant liquor concentrated by rotary evaporation, column chromatography for separation Obtain product crude product.Crude product is recrystallized with ethanol-water solution, is dried, is obtained final product product（White solid 13.10g, yield 79.2%）.
Pale powder, M.P.187.9-189.2 DEG C；
1H-NMR(300MHz,DMSO-d6)δ:9.54(1H,s),8.24(1H,s),7.76(2H,s),7.44(1H,d) , 6.35(1H,d),5.21(1H,t),4.0(1H,t),3.72(2H,d),2.12(3H,s),1.93(3H,s);
13C-NMR(75MHz,DMSO-d6)δ:146.5,146.1,141.1,134.0,129.4,128.9,125.0, 120.6,118.0,113.6, 113.0,110.5,104.5,100.9,78.6,55.8,48.9;
HRMS (ESI) for (M+H)+: calcd 352.3442, found 352.3445。
Embodiment 9
7- methoxyl group -1-（7- methoxyl group -5- nitroindoline quinoline -3- bases）- 5- nitro -1H- indoles（A-9）Preparation
7- methoxyl group -5- nitro -1H- indoles is added in 250ml round-bottomed flasks（50mmol）, addition 100ml toluene will Its mixing, adds cinnamoyl chloride（60mmol）, room temperature reaction 1 hour, after separating out completely to compound, addition phenylhydrazine （60mmol）, with heating mantle heats to 105 DEG C, it is placed on magnetic stirring apparatus, is heated at reflux reaction 6 hours, in course of reaction not Breakpoint sample is observed, and stops heating, remove condensing unit after raw material reaction is complete.By reactant liquor concentrated by rotary evaporation, column chromatography for separation Obtain product crude product.Crude product is recrystallized with ethanol-water solution, is dried, is obtained final product product（Brown solid 14.72g, yield 78.2%）.
Brown ceramic powder, M.P.188.5-189.8 DEG C；
1H-NMR(300MHz,DMSO-d6)δ:9.27(1H,s),7.96(1H,s),7.50(2H,s),7.43(1H,d) , 6.35(1H,d), 5.21(1H,t),4.0(1H,t),3.84(6H,s),3.75(2H,d);
13C-NMR(75MHz,DMSO-d6)δ:147.2,147.1,137.2,135.7,134.5,134.0,128.8, 125.9,120.7,117.2, 116.9,103.5,100.9,77.4,55.8,,48.9;
HRMS(ESI)for(M+H)+: calcd 384.1072, found 384.1076。
Embodiment 10
7- methyl isophthalic acids-（- 5 methyl indol quinoline -3- bases of 7- methyl）- 5 Methyl-1H-indoles（A-10）Preparation
7- methyl -5- Methyl-1H-indoles are added in 250ml round-bottomed flasks（50mmol）, add 100ml toluene by its Mix, add cinnamoyl chloride（60mmol）, room temperature reaction 1 hour, after separating out completely to compound, addition phenylhydrazine （60mmol）, with heating mantle heats to 105 DEG C, it is placed on magnetic stirring apparatus, is heated at reflux reaction 6 hours, in course of reaction not Breakpoint sample is observed, and stops heating, remove condensing unit after raw material reaction is complete.By reactant liquor concentrated by rotary evaporation, column chromatography for separation Obtain product crude product.Crude product is recrystallized with ethanol-water solution, is dried, is obtained final product product（Pale solid 14.25g, receives Rate 74.2%）.
Pale powder, M.P.175.4-177.4 DEG C；
1H-NMR(300MHz,DMSO-d6)δ:8.54(1H,s),7.45(1H,d),7.12(1H,s),6.72(2H,s), 6.37(1H,d),5.22(1H,t),4.0(1H,t),3.73(2H,d),2.34(6H,s)2.13(3H,s)1.94(3H,s);
13C-NMR(75MHz,DMSO-d6)δ:147.0,128.8,128.9,128.8,127.5,126.6,126.1, 123.8,123.3,120.4, 120.3,100.9,94.9,78.8,48.9,22.0,22.0,18.2,17.3;
HRMS (ESI) for (M+H)+: calcd 290.1785, found 290.1789。
Embodiment 11
7- methoxyl group -1-（7- methoxyl group -5- methyl dihydropyridine -3- bases）- 5- Methyl-1H-indoles（A-11）Preparation
7- methoxyl group -5- Methyl-1H-indoles are added in 250ml round-bottomed flasks（50mmol）, addition 100ml toluene will Its mixing, adds cinnamoyl chloride（60mmol）, room temperature reaction 1 hour, after separating out completely to compound, addition phenylhydrazine （60mmol）, with heating mantle heats to 105 DEG C, it is placed on magnetic stirring apparatus, is heated at reflux reaction 6 hours, in course of reaction not Breakpoint sample is observed, and stops heating, remove condensing unit after raw material reaction is complete.By reactant liquor concentrated by rotary evaporation, column chromatography for separation Obtain product crude product.Crude product is recrystallized with ethanol-water solution, is dried, is obtained final product product（White solid 8.20g, yield 70.5%）.
Pale powder, M.P.180.1-182.1 DEG C；
1H-NMR(300MHz,DMSO-d6)δ:8.28(1H,s),7.45(1H,d),6.81(1H,s),6.56(2H,s), 6.35(1H,d),5.22(1H,t),4.0(1H,t),3.85(6H,s)3.71(2H,d),2.35(6H,s);
13C-NMR(75MHz,DMSO-d6)δ:146.4,144.5,138.0,129.8,129.6,129.5,,128.9, 126.7,124.9,122.8, 115.9,111.1,105.7,100.9,78.8,55.8,48.9,22.2,21.9;
HRMS (ESI) for (M+H)+: calcd 322.4011, found 322.4015。
Embodiment 12
5- methoxyl group -1-（5- methoxyl group -7- methyl indoline -3- bases）- 7- Methyl-1H-indoles（A-12）Preparation
7- methyl -5- methoxyl group -1H- indoles is added in 250ml round-bottomed flasks（50mmol）, addition 100ml toluene will Its mixing, adds cinnamoyl chloride（60mmol）, room temperature reaction 1 hour, after separating out completely to compound, addition phenylhydrazine （60mmol）, with heating mantle heats to 105 DEG C, it is placed on magnetic stirring apparatus, is heated at reflux reaction 6 hours, in course of reaction not Breakpoint sample is observed, and stops heating, remove condensing unit after raw material reaction is complete.By reactant liquor concentrated by rotary evaporation, column chromatography for separation Obtain product crude product.Crude product is recrystallized with ethanol-water solution, is dried, is obtained final product product（Pale pink solid 12.71g, receives Rate 80.2%）.
Pale pink powder, M.P.179.5-180.2 DEG C；
1H-NMR(300MHz,DMSO-d6)δ:7.70(1H,s),7.46(1H,d),6.84(1H,s),6.63(2H,s), 6.37(1H,d), 5.21(1H,t),4.0(1H,t),3.84(6H,s),3.73(2H,d),2.14(3H,s),1.93(3H,s);
13C-NMR(75MHz,DMSO-d6)δ:155.5,148.7,142.3,129.5,128.7,127.2,124.7, 121.6,118.8,109.6, 108.7,105.9,100.8,90.1,78.8,55.9,48.9,18.2,17.4;
HRMS(ESI) for (M+H)+: calcd 322.1683, found 322.1687。
Embodiment 13
1-（5,7- dimethoxy dihydropyridine -3- bases）- 5,7- dimethoxy -1H- indoles（A-13）Preparation
5,7- dimethoxy -1H- indoles is added in 250ml round-bottomed flasks（50mmol）100ml toluene is added to be mixed It is even, add cinnamoyl chloride（60mmol）, room temperature reaction 1 hour, after separating out completely to compound, addition phenylhydrazine（60mmol）, With heating mantle heats to 105 DEG C, it is placed on magnetic stirring apparatus, is heated at reflux reaction 6 hours, continuous point sample is seen in course of reaction Examine, stop heating after raw material reaction is complete, remove condensing unit.Reactant liquor concentrated by rotary evaporation, column chromatography for separation are obtained into product Crude product.Crude product is recrystallized with ethanol-water solution, is dried, is obtained final product product（Pink solid 13.25g, yield 82.5%）.
Pink powder, M.P.185.6-186.9 DEG C；
1H-NMR(300MHz,DMSO-d6)δ:7.46(2H,t),6.51(2H,s),6.35(1H,d),6.19(1H,s), 5.22(1H,t),4.0(1H,t), 3.84(6H,s),3.72(2H,d);
13C-NMR(75MHz,DMSO-d6)δ:156.6,149.9,147.5,145.6,133.3,130.7,128.9, 126.2,121.8,105.1, 103.9,100.8,98.4,85.6,78.8,55.9,49.0;
HRMS(ESI) for (M+H)+: calcd 354.1582 found 354.1586。
Embodiment 14
5-chloro- 1-（The chloro- 7- methyl indoline -3- bases of 5-）- 7- Methyl-1H-indoles（A-14）Preparation
- 5 chloro- 1H- indoles of 7- methyl is added in 250ml round-bottomed flasks（50mmol）, add 100ml toluene to be mixed It is even, add cinnamoyl chloride（60mmol）, room temperature reaction 1 hour, after separating out completely to compound, addition phenylhydrazine（60mmol）, With heating mantle heats to 105 DEG C, it is placed on magnetic stirring apparatus, is heated at reflux reaction 6 hours, continuous point sample is seen in course of reaction Examine, stop heating after raw material reaction is complete, remove condensing unit.Reactant liquor concentrated by rotary evaporation, column chromatography for separation are obtained into product Crude product.Crude product is recrystallized with ethanol-water solution, is dried, is obtained final product product（Pale solid 10.79g, yield 78.5%）.
Pale powder, M.P.181.8-183.4 DEG C；
1H-NMR(300MHz,DMSO-d6)δ:7.89(1H,s),7.45(1H,d),7.33(1H,s),7.05(2H,s), 6.35(1H,d), 5.22(1H,t),4.0(1H,t),2.14(3H,s),1.93(3H,s);
13C-NMR(75MHz,DMSO-d6)δ:148.2,130.4,129.8,129.2,127.4,126.6,125.2, 122.5,121.7,120.7, 118.6,100.9,95.8,78.0,48.8,17.5,16.6;
HRMS (ESI) for M+H)+: calcd 330.0693 found 330.0697。
Embodiment 15
The chloro- 1- of 5-（The chloro- 7- melonias -3- bases of 5-）- 7- methoxyl group -1H- indoles（A-15）Preparation
- 5 chloro- 1H- indoles of 7- methoxyl groups is added in 250ml round-bottomed flasks（50mmol）, add 100ml toluene by its Mix, add cinnamoyl chloride（60mmol）, room temperature reaction 1 hour, after separating out completely to compound, addition phenylhydrazine （60mmol）, with heating mantle heats to 105 DEG C, it is placed on magnetic stirring apparatus, is heated at reflux reaction 6 hours, in course of reaction not Breakpoint sample is observed, and stops heating, remove condensing unit after raw material reaction is complete.By reactant liquor concentrated by rotary evaporation, column chromatography for separation Obtain product crude product.Crude product is recrystallized with ethanol-water solution, is dried, is obtained final product product（White solid 9.26g, yield 70.4%）.
White powder, M.P.187.6-189.2 DEG C；
1H-NMR(300MHz,DMSO-d6)δ:7.65(1H,s),7.44(1H,d),7.04(1H,s),6.82(2H,s), 6.35(1H,d), 5.22(1H,t),4.0(1H,t),3.84(6H,s),3.72(2H,d);
13C-NMR(75MHz,DMSO-d6)δ:147.7,145.8,139.3,135.4,128.9,127.6,126.4, 123.5,120.6,117.6, 114.0,105.7,100.7,78.0,55.8, 48.9;
HRMS (ESI)for(M+H)+: calcd 362.0590 found 362.0595。
Embodiment 16
5-bromo- 1-（5- bromine-7-methyl indoline -3- bases）- 7- Methyl-1H-indoles（A-16）Preparation
- 5 bromo- 1H- indoles of 7- methyl is added in 250ml round-bottomed flasks（50mmol）, add 100ml toluene to be mixed It is even, add cinnamoyl chloride（60mmol）, room temperature reaction 1 hour, after separating out completely to compound, addition phenylhydrazine（60mmol）, With heating mantle heats to 105 DEG C, it is placed on magnetic stirring apparatus, is heated at reflux reaction 6 hours, continuous point sample is seen in course of reaction Examine, stop heating after raw material reaction is complete, remove condensing unit.Reactant liquor concentrated by rotary evaporation, column chromatography for separation are obtained into product Crude product.Crude product is recrystallized with ethanol-water solution, is dried, is obtained final product product（White solid 15.2g, yield 77.5%）.
White powder, M.P.193.6-195.1 DEG C
1H-NMR(300MHz,DMSO-d6)δ:7.95(1H,s),7.49(1H,s),7.45(1H,d),7.00(2H,s), 6.35(1H,d), 5.22(1H,t),4.0(1H,t),3.72(2H,d),2.13(3H,s),1.94(3H,s);
13C-NMR(75MHz,DMSO-d6)δ:149.0,131.9,130.5,128.9,128.4,126.2,123.5, 122.7,118.1,116.8, 109.5,100.9,96.7,77.8,48.9,17.2,16.4;
HRMS (ESI) for M+H)+: calcd 419.9662 found 419.9665。
Embodiment 17
The bromo- 1- of 5-（The bromo- 7- melonias -3- bases of 5-）- 7- methoxyl group -1H- indoles（A-17）Preparation
Add -5 bromo- 1H- indoles of 7- methoxyl groups successively in 250ml round-bottomed flasks（50mmol）, add 100ml toluene Mixed, added cinnamoyl chloride（60mmol）, room temperature reaction 1 hour, after separating out completely to compound, addition phenylhydrazine （60mmol）, with heating mantle heats to 105 DEG C, it is placed on magnetic stirring apparatus, is heated at reflux reaction 6 hours, in course of reaction not Breakpoint sample is observed, and stops heating, remove condensing unit after raw material reaction is complete.By reactant liquor concentrated by rotary evaporation, column chromatography for separation Obtain product crude product.Crude product is recrystallized with ethanol-water solution, is dried, is obtained final product product（Faint yellow solid 17.9g, yield 81.3%）.
Pale yellow powder, M.P.193.4-194.9 DEG C；
1H-NMR(300MHz,DMSO-d6)δ:7.72(1H,s),7.44(1H,d),7.18(1H,s),6.81(2H,s), 6.35(1H,d), 5.22(1H,t),4.0(1H,t),3.84(6H,s)3.72(2H,d);
13C-NMR(75MHz,DMSO-d6)δ:148.7,146.2,140.0,131.8,128.9,127.4,125.6, 118.0,115.7,113.3, 112.4,105.1,100.9,77.9,55.8,48.9;
HRMS(ESI)for(M+H)+: calcd 451.9559 found 451.9564。
The antitumor activity testing example of the compounds of this invention
Cytostatic to tumor cell test is carried out to the compound of the present invention, test method is using conventional mtt assay.
Cell line is selected：Non-small cell lung cancer cell (A549), human esophagus cancer cell (EC-9706), human liver cancer cell (SMMC-7721), ovarian cancer cell (XB1309), human colon cancer cell (HT-29).Nutrient solution is that DMEM+15%NBS+ is dual anti-.
The preparation of sample liquid：Synthesized compound sample with DMSO (Merck) dissolving after, add PBS (-) be made into 100 The solution or uniform suspension of μm ol/L, then with PBS (-) dilution of DMSO, ultimate density is respectively 0.1,1,10, 20,40,60,80,100 μm of ol/L.
The antineoplastic cytarabine (Ara-C) of listing is made into into reference substance solution with same condition.
Cell culture：Adherent growth tumor cell culture is in containing 10% inactivation NBCS and penicillin, streptomysin（Respectively 1000000 U/L）RPMI-1640 in, be placed in 37 DEG C, 5% CO2, in the CO2gas incubator of saturated humidity cultivate.Cell is pasted Wall grows, and passed on per 2～3 days 1 time, pours out nutrient solution when passing on first, and PBS is washed 2 times, after pancreatin digestion, adds fresh Nutrient solution piping and druming is uniform, adjusts cell to debita spissitudo and moves in new blake bottle, and addition nutrient solution is to appropriate.Take the logarithm growth Phase cell is used to test.
Mtt assay detects cytoactive and IC50Measure：
Experimental principle：In living cells mitochondria, the MTT of yellow can be reduced into water-fast bluish violet product by dehydrogenase First (MTT formazan), and be deposited in cell, the amount of generation is directly proportional to number of viable cells, and dead cell does not have this Plant function.DMSO can dissolve bluish violet crystal, and shade is directly proportional to contained amount, therefore the light determined with ELIASA is inhaled Receipts value can reflect cell survival rate.
Experimental technique：Take the logarithm growth period cell, digestion, count, the training of 96 holes is inoculated in the density of 2 × 104/mL In foster plate, per 100 μ l of hole.After culture 24 hours, by testing compound with 0.1,1,10,20,40,60,80,100 μm of ol/L Concentration processes cell.Experimental group each concentration sets 5 multiple holes, is compared with the nutrient solution containing 0.4% DMSO.Medicine effect 48 After hour, supernatant is removed, 100 μ l MTT are added per hole（2- (4,5- dimethyl -2- thiazolyls) -3,5- diphenyl -2H- tetrazolium hydrogen Bromate）(1mg/mL), continue culture 4 hours, abandon supernatant, add per hole 100 μ l DMSO, vibration to mix, existed with ELIASA Mensuration absorbance value at 570 nm, using IC50Software for calculation obtains half-inhibition concentration (IC50)。
17 kinds of compounds to synthesizing have carried out primary dcreening operation to antitumor activity using mtt assay, wherein 8 kinds of compounds are in difference Tumor cell line show good antitumor activity.Their 50 % inhibition concentrations（IC50）The results detailed in Table 5, wherein, The compound containing indole structure that sample is prepared in referring to corresponding embodiment, resulting change in sample number into spectrum correspondence preparation embodiment The concrete numbering of compound.
As can be seen from Table 5, eight kinds of compounds above of synthesis are to non-small cell lung cancer cell (A549), human esophagus cancer Cell（EC-9706）, human liver cancer cell (SMMC-7721), ovarian cancer cell（XB1309）, human colon cancer cell（HT-29） There is certain inhibitory activity, wherein, compound A-4 is to ovarian cancer cell（XB1309）, human colon cancer cell（HT-29）Have preferably Ground inhibitory activity, compound A-17 is to non-small cell lung cancer cell (A549), human esophagus cancer cell（EC-9706）, human liver cancer is thin Born of the same parents (SMMC-7721) have preferable inhibitory activity.Jing generalized analysis, compound A-4, A-17 than other 2', the double hydrogen of 3'-- The inhibitory action of 1,3'- bis-indole compounds is higher, it is considered to be most have the compound of researching value, is worth further grinding Study carefully.
Above test result indicate that, the present invention compound there is good antitumor activity, particularly part contain indoles The activity of structural compounds antitumor activity in specific cells strain is better than cytarabine, and the present invention can be used for preparing antitumor Medicine.

Claims (10)

1. general structure（I）Shown compound,
Wherein, R1=halogen, NO2Or C1-C5Alkoxyl；
R2=H、C1-C5Alkyl or C1-C5Alkoxyl.
2. compound according to claim 1, it is characterised in that：R1For methoxyl group, fluorine, chlorine, bromine or iodine.
3. compound according to claim 1, it is characterised in that：R2For methyl or methoxy.
4. the preparation method of compound described in claim 1, it is characterised in that synthetic route is：
。
5. preparation method according to claim 4, it is characterised in that：By mol ratio 1:1:1～1:2:2 indoles derives Thing, cinnamoyl chloride and phenylhydrazine are added in toluene solvant, in 60 ~ 120 DEG C of heating reflux reactions, after reaction terminates, reactant liquor are revolved Inspissation contracts, and column chromatography for separation obtains product crude product, further recrystallizes to obtain product.
6. preparation method according to claim 4, it is characterised in that：Indole derivatives, cinnamoyl chloride and phenylhydrazine mole Than for 1:1:1～1:1.5:1.5.
7. preparation method according to claim 4, it is characterised in that：Reaction temperature be 80 ~ 110 DEG C, the reaction time be 4 ~ 10 hours.
8. preparation method according to claim 4, it is characterised in that：Ethyl acetate and petroleum ether body in column chromatography mobile phase Product is than being 1:5.
9. preparation method according to claim 4, it is characterised in that：Recrystallization solvent selects ethanol-water solution.
10. compound described in claim 1 prepare for treat or prevent cancer cell A549, EC-9706, SMMC-7721, Application in XB1309 or HT-29 growths and diversion medicaments.
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