CN104059062A - Benzothiazole and triazolediheterocycle-containing fused ring compound and application thereof - Google Patents
Benzothiazole and triazolediheterocycle-containing fused ring compound and application thereof Download PDFInfo
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Abstract
The invention relates to a benzothiazole and triazolediheterocycle-containing fused ring compound which has a structure of a general formula Y shown in the specification. According to the compound, cyclic amine with bioactivity is connected to the site 4 of naphthalimide, a structure that an imine nitrogen atom of naphthalimide is spaced from a triazole nitrogen atom connected with a side chain by two carbon atoms is kept, and molecules are introduced into sulfur-containing heterocyclic benzothiazole through linkage of triazole, so that the diversity of naphthalimide derivatives, the bioactivity of naphthalimide and the DNA identification and intercalation capability are improved; the compound has a relatively good inhibition effect on normal growth of tumor cells, with different tissue sources, of cervical cancers, liver cancers, breast cancers and the like.
Description
Technical field
The present invention relates to benzothiazole and triazole two heterocycle naphthoyl imide compounds, its preparation method and application thereof in biological organic synthesis field.
Background technology
The molecule that the overwhelming majority contains naphthalimide precursor structure has fluorescence and compound to show biological activity widely, as cancer therapy drug, and antitrypanosomal agent, antiviral, toponarcosis, pain killer, thrombotonin 5-HT3 and 5-HT4 antibody antagonist, chemical sensor etc.Cancer therapy drug taking naphthalimide as parent also enters the clinical trial of different steps as pacified how Fitow (Amonafide), Mitonafide (Mitonafide) and UNBS5162 etc., but amonafide and Mitonafide are because its toxic side effect has suppressed further research.To 1973,
etc. reported first 3-nitro-naphthalene imide derivative there is anti-tumor activity, subsequently by the modification in various degree of naphthalimide precursor structure, synthesized many naphthoyl imide compounds with anti-tumor activity.Connecting aromatic nucleus with the formal bond of " non-naphtho-" is a kind of new transformation strategy to naphthalimide, has improved to a certain extent the anti-tumor activity of naphthalimide.
In the recent period, Amonafide has entered the clinical III phase for the treatment of secondary myelogenous leukemia and has tested, and this has inspired the research of scientific research personnel using naphthalimide derivative as potential cancer therapy drug more.
Benzothiazole is twin nuclei, is also many parts that have bioactive ocean and land natural compounds structure simultaneously.Due to its pharmacologically active widely, taking benzothiazole as core is an important thinking of medicament research and development.In the document of having reported, benzothiazole derivant is effective antitumor and anticancer agent, LTD4 receptor antagonist, Alzheimer amyloid preparation, anticonvulsive agent, antiseptic-germicide, antidiabetic drug, muscarinic receptor antagonist, spasmolytic etc.2-(4-aminophenyl) benzothiazole and derivative thereof, 2-(4-aminophenyl)-5-fluoro benzothiazole is the research and development of institute of oncology of Univ Nottingham UK, this medicine series has the high cytotoxicity of selecting, IC to mammary cancer
50value can reach nM level.The west of benzothiazole not alkali also has certain antitumor curative effect, IC
50value can reach μ M level.Ott etc. introduce mercaptobenzothiazole in naphthalimide parent, have obtained the series derivates that sulfur-bearing replaces, and this series is main with topoisomerase effect and show phototoxicity.
Triazole class compounds has pharmacologically active widely, as antibacterial, analgesia, anti-inflammatory, toponarcosis, antiviral, anti-malignant cell hyperplasia, hypertension, anticancer etc.For example compd E 4896 is at present the clinical III phase and tests, and can be used for the treatment of mammary cancer, lung cancer, advanced ovarian cancer, kidney, in addition micromolecular lung cancer activity experiment result is shown: it can reduce by 51% vasculogenesis.
Summary of the invention
The present invention has multiple avtive spots according to naphthalimide, and structure is also easy to modify, be connected to 4 of naphthalimide by thering is bioactive cyclic amine, and the be separated by structure of two carbon of the triazole atom that has kept the imines position nitrogen-atoms of naphthalimide to be connected with side chain.In addition, also sulfur heterocyclic ring benzothiazole has been introduced to molecule by the link of triazole, continued to expand the diversity of naphthalimide derivative, expected to improve the biological activity of naphthalimide, improved identification and embedding ability to DNA.Of the present invention is at 4-bromo-1 containing compound, on 8 naphthalene acid anhydride parents, introduce five yuan of triazole rings and connect mercaptobenzothiazole group with flexible side-chains, its objective is: by reactions such as amino condensation, amino replacement, phosphorus tribromide substituted hydroxy, azide, " Click chemistry ", synthetic containing benzothiazole and the two heterocycle naphthoyl imide compounds of triazole, to tumor cell in vitro, growth has inhibition ability.
The present invention solves the problems of the technologies described above adopted technical scheme: containing the fused ring compound of benzothiazole and the two heterocycles of triazole, described compound has the structure of general formula Y:
In general formula Y: R is selected from X
1, X
2, X
3, X
4, X
5or X
6
Further, described compound is selected from:
N-[2 '-(4-((benzothiazole-2-sulfydryl) methyl)-[1,2,3]-triazole)-ethyl]-4-hexahydropyridine-1,8-naphthalimide;
N-[2 '-(4-((benzothiazole-2-sulfydryl) methyl)-[1,2,3]-triazole)-ethyl]-4-morpholine-1,8-naphthalimide;
N-[2 '-(4-((benzothiazole-2-sulfydryl) methyl)-[1,2,3]-triazole)-ethyl]-4-thiomorpholine-1,8-naphthalimide;
N-[2 '-(4-((benzothiazole-2-sulfydryl) methyl)-[1,2,3]-triazole)-ethyl]-4-methylpiperazine-1,8-naphthalimide;
Or N-[2 '-(4-((benzothiazole-2-sulfydryl) methyl)-[1,2,3]-triazole)-ethyl]-4-pyrroles-1,8-naphthalimide.
The preparation method of compound of the present invention, comprises the following steps:
1. prepare intermediate 1: under triethylamine exists, taking acetone as solvent, propargyl bromide reacts with 2-mercaptobenzothiazole and generates 2-(2-alkynes-1-propyl dithiocarbamate) benzo [d] thiazole, as intermediate 1;
2. prepare intermediate 3:4-bromo-1,8-naphthalene acid anhydride and thanomin are dissolved in ethanol, are warming up to back flow reaction, generate N-(2 '-hydroxyethyl)-4-bromo-1, and 8-naphthalimide, as intermediate 3;
3. prepare intermediate 4: intermediate 3 is dissolved in to ethylene glycol monomethyl ether, adds corresponding cyclic amine, reaction obtains having the intermediate 4 of formula I structure;
4. prepare intermediate 5: intermediate 4 is dissolved in to ethyl acetate, adds phosphorus tribromide reaction to generate the intermediate 5 with general formula II structure;
5. prepare intermediate 6: intermediate 5 is dissolved in to DMF, adds NaN
3, reaction generates the intermediate 6 with general formula III structure;
6. prepare described compound: intermediate 6 and intermediate 1 are dissolved in to the mixed solution of the trimethyl carbinol and water, add catalyzer sodium ascorbate and cupric sulfate pentahydrate, under nitrogen protection, reaction generates described compound.
Synthetic route is as follows:
Further, step 1. in, propargyl bromide: 2-mercaptobenzothiazole: the optimum mole ratio of triethylamine is 1:1:1; First by 2-mercaptobenzothiazole with acetone solution, add triethylamine, now reaction solution is orange transparent liquid, then adds propargyl bromide, sonic oscillation to react about 10min, filters, and obtains brown filtrate, and filtrate decompression distillation, except desolventizing, is obtained to brown oily solid.
Further, step 2. in bromo-1, the 8 naphthalene acid anhydride of 4-and thanomin be that 1:1.2 feeds intake according to optimum mole ratio, be warming up to backflow, there is amino condensation reaction in the two, TLC tracks to and reacts completely, cooling, pours frozen water into, separates out pale precipitation, suction filtration is dried.
Further, step 3. middle intermediate 3 is that amino substitution reaction occurs in 1:2.9～3.5 with the mol ratio of corresponding cyclic amine, temperature of reaction most preferably is 125 DEG C, be the reflux temperature of ethylene glycol monomethyl ether, after having reacted, cooling, pour into and in cold water, separate out yellow mercury oxide, filter, washing, is dried to obtain yellow solid.
Further, step 4. in intermediate 4 under condition of ice bath, be dissolved in ethyl acetate, continue ice bath 0.5h after adding phosphorus tribromide, optimum mole ratio 1:2.9～3.1 of intermediate 4 and phosphorus tribromide; Remove ice bath, be heated to reflux temperature, TLC tracks to and reacts completely, cooling, adds in methyl alcohol and extremely no longer smolders with excessive phosphorus tribromide, pours in saturated aqueous common salt and separates out yellow mercury oxide, filters washing, the dry yellow solid that to obtain.
Further, step 5. middle intermediate 5 is 1:3 with the optimum mole ratio of sodium azide, and this azido reaction temperature is generally less than 60 DEG C, and temperature of reaction the best is 55 DEG C, after reaction finishes, pours salt solution into, suction filtration, and washing, dry, obtain yellow solid.
Further, step 6. in, the optimum mole ratio of intermediate 6 and intermediate 1 is 1:2, the trimethyl carbinol and water mix with 1:1, through " the Click chemistry " of Cu (I) catalysis reaction, 70 DEG C of lucifuges are reacted to reacting completely, cooling, pour in saturated aqueous common salt, leave standstill, filter, dry, silica gel column chromatography separates and obtains solid, is described compound.
Compound of the present invention has the effect of inhibition tumor cell growth, and described tumour cell comprises MCF-7 breast cancer cell, Hela cervical cancer cell and SMMC-7721 liver cancer cell.
Compound of the present invention is carried out to the mensuration of extracorporeal suppression tumor cell growth activity to MCF-7 breast cancer cell, Hela cervical cancer cell and SMMC-7721 liver cancer cell by tetrazolium reduction method, result shows, this compounds has the activity that suppresses growth to the tumour cell of the multiple different tissue sources such as cervical cancer, liver cancer, mammary cancer.
Described tetrazolium reduction method experimental procedure is as follows:
1, inoculating cell
Respectively MCF-7 Breast Cancer Cell, human cervical carcinoma Hela cell and SMMC-7721 liver cancer cells are collected in substratum, 200 μ L cell suspensions are inoculated in every hole after cell dilution, ensure 2000～5000 cells of every Kong Zhongyue, outermost adds 200 μ LPBS, provide sufficient moisture to ensure the growing environment of cell, culture plate is put to 37 DEG C, 5%CO
2environment in incubation incubation 24h～48h.
2, add medicine
Compound of the present invention is diluted to respectively to 10 with substratum
-8, 10
-7, 10
-6, 10
-5tetra-gradient concentrations of M, suck the substratum that in 96 orifice plates, 2-11 is listed as, and are careful herein and do not siphon away cell; Then add medicine, 6 multiple holes are set, reduce error; After finishing dealing with, 96 orifice plates are put back to CO
2in incubator, cultivate 48h.
3, the detection of survivaling cell number
In institute is porose, all add 20 μ L MTT, be put into CO
2incubation 4h in incubator; Discard substratum and MTT in hole, add 200 μ L DMSO, dissolve residual MTT-formazan crystallization.In microplate reader, measure each hole absorbancy and record result, calculate the inhibiting rate of analyte to growth of cancer cells by following formula:
Tumor control rate=(control group OD value-treatment group OD value)/control group OD value × 100%.
Beneficial effect of the present invention:
First, the present invention is connected to 4 of naphthalimide having bioactive cyclic amine, and the be separated by structure of two carbon of the triazole atom that has kept the imines position nitrogen-atoms of naphthalimide to be connected with side chain, link by triazole has also been introduced molecule by sulfur heterocyclic ring benzothiazole, expand the diversity of naphthalimide derivative, improve the biological activity of naphthalimide, improved identification and embedding ability to DNA;
The second, to tumor cell in vitro, growth has inhibition ability, for example MCF-7 breast cancer cell, Hela cervical cancer cell and SMMC-7721 liver cancer cell to the fused ring compound containing benzothiazole and the two heterocycles of triazole of the present invention.
Embodiment
Below by embodiment, the present invention is further illustrated, but do not limit the present invention in any way.
Embodiment 1
N-[2 '-(4-((benzothiazole-2-sulfydryl) methyl)-[1,2,3]-triazole)-ethyl]-4-hexahydropyridine-1,8-naphthalimide (compound F 17-hydroxy-corticosterone 4) synthetic:
(1) 2-(2-alkynes-1-propyl dithiocarbamate) benzo [d] thiazole (intermediate 1) is synthetic
Take 2-mercaptobenzothiazole 3.02g (18mmol) mercaptobenzothiazole, use 35mL acetone solution, add 2.51mL (18mmol) triethylamine, now reaction solution is orange transparent liquid, adds 1.41mL (18mmol) propargyl bromide, ultrasonic concussion 10 minutes, stopped reaction, filter, obtain brown filtrate, filtrate decompression distillation is removed to desolventizing.Obtain brown oily solid 3.61g, productive rate: 98.0%.
(2) N-(2 '-hydroxyethyl)-4-is bromo-1,8-naphthalimide (intermediate 3) synthetic
In 50mL bottle with two necks, add 2.76g (10mmol) 4-bromo-1,8-naphthalene acid anhydride, adds 0.7mL thanomin, and 28mL dehydrated alcohol is warming up to backflow under magnetic agitation, under reflux temperature, reacts 3h, and TLC tracks to and reacts completely.Stop heating, be cooled to after room temperature, reaction system is poured in frozen water, separate out pale precipitation, suction filtration, is dried to obtain product 2.79g.Productive rate: 87.4%.
(3) N-(2 '-hydroxyethyl)-4-hexahydropyridine base-1,8-naphthalimide (intermediate 4) synthetic
Get 2.0g (6.3mmol) intermediate 3, add 25mL ethylene glycol monomethyl ether stirring and dissolving, then add 1.86mL (1.9mmol) hexahydropyridine in system, be heated to 125 DEG C, keep this temperature to continue reaction 3h, TLC tracks to and reacts completely, and stops heating, and the system for the treatment of is cooled to room temperature, be poured into water and separate out yellow mercury oxide, filter, washing, is dried to obtain yellow solid 1.99g.Productive rate: 98.2%.
(4) N-(2 '-bromotrifluoromethane)-4-hexahydropyridine base-1,8-naphthalimide (intermediate 5) synthetic
Get 1.99g (6.1mmol) intermediate 4, add 25mL ethyl acetate stirring and dissolving under ice-water bath, after near 0 DEG C of system, slowly drip 1.75mL (18.5mmol) phosphorus tribromide to system, continue ice bath 0.5h, remove ice-water bath, reaction is heated to react 2h under reflux temperature, TLC tracks to and reacts completely, stop heating, leave standstill and be cooled to room temperature, in system, add in appropriate methyl alcohol and excessive phosphorus tribromide, till treating no longer to smolder.Pour in saturated aqueous common salt and separate out yellow mercury oxide, filter, washing, is dried to obtain yellow solid 2.24g.Productive rate: 94.3%.
(5) N-(2 '-azidoethyl)-4-hexahydropyridine base-1,8-naphthalimide (intermediate 6) synthetic
In 50mL reaction bottle with two necks, add 2.24g (5.8mmol) compound 5, add 28mL DMF solvent, more slowly add 1.13g NaN to system
3(17.4mmol), be heated to 55 DEG C, after reaction 1.5h, system be cooled to room temperature, pour saturated aqueous common salt into, suction filtration, washing, dry, obtain yellow solid 1.89g.Productive rate: 93.3%.
(6) N-[2 '-(4-((benzothiazole-2-sulfydryl) methyl)-[1,2,3]-triazole)-ethyl]-4-hexahydropyridine-1,8-naphthalimide (compound F 17-hydroxy-corticosterone 4) synthetic
In 50mL bottle with two necks, add 1.89g (5.42mmol) compound 6,2.22g (10.84mmol) intermediate 1, by the mixing solutions stirring and dissolving of the 1:1 of the 32mL trimethyl carbinol and water, add again catalyzer 3.22g sodium ascorbate (VC sodium) and 1.36g cupric sulfate pentahydrate, N
2under protection, at 70 DEG C of lucifuge reaction 24h, TLC tracks to and reacts completely.After reaction finishes, pour in saturated aqueous common salt after system is cooled to room temperature, leave standstill, filter, dry.(column chromatography elutriant is CH in silica gel column chromatography separation
2cl
2: CH
3oH=20:1), obtain target product 1.26g (compound F 17-hydroxy-corticosterone 4), yellow solid, productive rate 42.0%.Fusing point: 176.1-178.4 DEG C.
1H NMR(400MHz,CDCl
3)δ8.45(dd,J＝7.3,1.1Hz,1H),8.41–8.32(m,2H),7.82(d,J＝7.8Hz,1H),7.74(s,2H),7.61(d,J＝1.0Hz,1H),7.42–7.36(m,1H),7.29(dd,J＝11.5,4.5Hz,1H),7.12(d,J＝8.2Hz,1H),4.71(t,J＝6.1Hz,2H),4.67–4.59(m,4H),3.28–3.12(m,4H),1.93–1.84(m,4H),1.77–1.69(m,2H).
+ ESI MS (M+H): C
29h
26n
6o
2s
2, calculated value: 555.1559, measured value: 555.1628.
Embodiment 2
N-[2 '-(4-((benzothiazole-2-sulfydryl) methyl)-[1,2,3]-triazole)-ethyl]-4-morpholine-1,8-naphthalimide (compound F 17-hydroxy-corticosterone 1) synthetic:
Except replacing hexahydropyridine with morpholino in (3), other is synthetic and test treatment process with embodiment 1.Through silica gel column chromatography separation, (column chromatography elutriant is CH
2cl
2: CH
3oH=14:1), obtain target product F1, yellow-green colour solid, productive rate 79.8%.Fusing point: 212.2-215.6 DEG C.
1H NMR(400MHz,CDCl
3)δ8.48(d,J＝7.3Hz,1H),8.41(dd,J＝13.7,8.2Hz,2H),7.86(d,J＝8.0Hz,1H),7.74(d,J＝8.4Hz,2H),7.69–7.62(m,1H),7.41(t,J＝7.2Hz,1H),7.31(d,J＝8.0Hz,1H),7.18(d,J＝8.1Hz,1H),4.72(t,J＝6.0Hz,2H),4.70–4.48(m,4H),4.16–3.91(m,4H),3.37–3.11(m,4H).
13C NMR(101MHz,CDCl3)δ165.99,164.10,163.56,155.97,153.00,135.40,132.85,131.43,130.47,129.92,126.05,126.02,125.79,124.28,123.52,122.58,121.48,121.02,116.28,114.93,66.93,53.40,47.95,39.43,27.87.
+ ESI MS (M+H): C
28h
24n
6o
3s
2, calculated value: 557.1351, measured value: 557.1427.
Embodiment 3
N-[2 '-(4-((benzothiazole-2-sulfydryl) methyl)-[1,2,3]-triazole)-ethyl]-4-thiomorpholine-1,8-naphthalimide (compound F 17-hydroxy-corticosterone 2) synthetic:
Except replacing hexahydropyridine with thiomorpholine in (3), other is synthetic and test treatment process with embodiment 1.Through silica gel column chromatography separation, (column chromatography elutriant is CH
2cl
2: CH
3oH=6:1), obtain target product F2, yellow solid, productive rate 75.7%.Fusing point: 206.5-208.1 DEG C.
1H NMR(400MHz,CDCl
3)δ8.48(dd,J＝7.3,1.0Hz,1H),8.42(d,J＝8.1Hz,1H),8.34(dd,J＝8.4,1.0Hz,1H),7.85(d,J＝7.7Hz,1H),7.75(d,J＝7.9Hz,2H),7.66(dd,J＝8.4,7.4Hz,1H),7.41(t,J＝7.2Hz,1H),7.30(t,J＝7.6Hz,1H),7.19(d,J＝8.1Hz,1H),4.73(t,J＝6.0Hz,2H),4.70–4.56(m,4H),3.51(s,4H),2.99(s,4H).
+ ESI MS (M+H): C
28h
24n
6o
2s
3, calculated value: 573.1123, measured value: 573.1181.
Embodiment 4
N-[2 '-(4-((benzothiazole-2-sulfydryl) methyl)-[1,2,3]-triazole)-ethyl]-4-methylpiperazine-1,8-naphthalimide (compound F 17-hydroxy-corticosterone 3) synthetic:
Except replacing hexahydropyridine with methylpiperazine in (3), other is synthetic and test treatment process with embodiment 1.Through silica gel column chromatography separation, (column chromatography elutriant is CH
2cl
2: CH
3oH: triethylamine=14:1:1), obtain target product F3, yellow-green colour solid, productive rate 50.3%.Fusing point: 186.4-188.0 DEG C.
1H NMR(400MHz,CDCl
3)δ8.48(d,J＝7.2Hz,1H),8.41(d,J＝8.1Hz,1H),8.38(d,J＝8.4Hz,1H),7.83(d,J＝8.1Hz,1H),7.73(d,J＝7.2Hz,2H),7.68–7.59(m,1H),7.43–7.37(m,1H),7.33–7.28(m,1H),7.17(d,J＝8.1Hz,1H),4.72(t,J＝6.1Hz,2H),4.69–4.57(m,4H),3.31(s,4H),2.76(s,4H),2.45(s,3H).
+ ESI MS (M+H): C
29h
27n
7o
2s
2, calculated value: 570.1668, measured value: 570.1729.
Embodiment 5
N-[2 '-(4-((benzothiazole-2-sulfydryl) methyl)-[1,2,3]-triazole)-ethyl]-4-pyrroles-1,8-naphthalimide (compound F 17-hydroxy-corticosterone 5) synthetic:
Except replacing hexahydropyridine with pyrroles in (3), other is synthetic and test treatment process with embodiment 1.Through silica gel column chromatography separation, (column chromatography elutriant is CH
2cl
2: CH
3oH=17:1), obtain target product F5, orange solid, productive rate 58.1%.Fusing point: 117.7-119.2 DEG C.
1H NMR(400MHz,CDCl
3)δ8.55(d,J＝8.6Hz,1H),8.47(d,J＝6.7Hz,1H),8.32(d,J＝8.7Hz,1H),7.83(d,J＝8.1Hz,1H),7.79–7.67(m,2H),7.53–7.44(m,1H),7.39(t,J＝7.7Hz,1H),7.29(d,J＝7.1Hz,1H),6.76(d,J＝8.7Hz,1H),4.72(t,J＝6.0Hz,2H),4.69–4.45(m,4H),3.78(t,J＝6.4Hz,4H),2.29–2.00(m,4H).
+ ESI MS (M+H): C
28h
24n
6o
2s
2, calculated value: 541.1402, measured value: 541.1449.
Application examples
Extracorporeal suppression tumor cell growth activity is measured:
MCF-7 breast cancer cell, Hela cervical cancer cell and SMMC-7721 liver cancer cell are carried out to extracorporeal suppression tumor cell growth activity mensuration by tetrazolium (microculture tetrozolium, MTT) reduction method.
Taking compound F 17-hydroxy-corticosterone 1 as example, the concrete operations of tetrazolium (MTT) reduction method are:
1, inoculating cell
Some amount is collected in substratum in the tumour cell of logarithmic phase, 200 μ L cell suspensions are inoculated in every hole after cell dilution, ensure 2000～5000 cells of every Kong Zhongyue, outermost adds 200 μ LPBS, provide sufficient moisture to ensure the growing environment of cell, culture plate is put to 37 DEG C, 5%CO
2incubation 24h in the incubator of environment.
2, add medicine
The compound F 17-hydroxy-corticosterone 1 of with substratum being prepared by embodiment 1 is diluted to respectively 10
-8, 10
-7, 10
-6, 10
-5tetra-gradient concentrations of M; Suck the substratum of 2-11 row in 96 orifice plates, be careful herein and do not siphon away cell, then add medicine, each concentration arranges 6 multiple holes, reduces error; After finishing dealing with, 96 orifice plates are put back to CO
2in incubator, cultivate 48h.
3, the detection of survivaling cell number
In institute is porose, all add 20 μ L MTT, be put into CO
2incubation 4h in incubator; Discard substratum and MTT in hole, add 200 μ L DMSO, lysigenous crystallization.In microplate reader, measure each hole absorbancy and record result, calculate the inhibiting rate of analyte to growth of cancer cells by following formula:
Tumor control rate=(control group OD value-treatment group OD value)/control group OD value × 100%.
The detection method of compound F 17-hydroxy-corticosterone 2～F6 is the same.
According to the tumor control rate of compound F 17-hydroxy-corticosterone 1～F6, calculate its IC
50value, result is as following table:
The IC of table 1. compound F 17-hydroxy-corticosterone 1～F6 to Hela, MCF-7 and 7721 cancer cells
50value
Table 1 has been listed the IC of compound F 17-hydroxy-corticosterone 1～F6 to MCF-7, Hela and 7,721 three kinds of cancer cells
50value, this series compound general performance goes out good antitumous effect, wherein good than 7721 cells to the selectivity of MCF-7 and Hela cell.F1 has shown stronger inhibition, IC to three kinds of cells
50value is respectively 0.65 μ M, 2.26 μ M and 3.15 μ M, the especially IC to MCF-7
50value is 2.58 times of amonafide.The F2 that connects parathiazan does not demonstrate better inhibition activity than F1, illustrates that sulphur atom just can strengthen the cytotoxicity of compound in some cases.The IC of F3 to MCF-7
50reaching 1.07 μ M, is 1.57 times of amonafide, to the IC of Hela cell
50reaching 0.84 μ M, is 2.06 times of amonafide.
Claims (5)
1. containing the fused ring compound of benzothiazole and the two heterocycles of triazole, it is characterized in that described compound has the structure of general formula Y:
In general formula Y: R is selected from X
1, X
2, X
3, X
4, X
5or X
6
2. compound according to claim 1, is characterized in that described compound is selected from:
N-[2 '-(4-((benzothiazole-2-sulfydryl) methyl)-[1,2,3]-triazole)-ethyl]-4-hexahydropyridine-1,8-naphthalimide;
N-[2 '-(4-((benzothiazole-2-sulfydryl) methyl)-[1,2,3]-triazole)-ethyl]-4-morpholine-1,8-naphthalimide;
N-[2 '-(4-((benzothiazole-2-sulfydryl) methyl)-[1,2,3]-triazole)-ethyl]-4-thiomorpholine-1,8-naphthalimide;
N-[2 '-(4-((benzothiazole-2-sulfydryl) methyl)-[1,2,3]-triazole)-ethyl]-4-methylpiperazine-1,8-naphthalimide;
Or N-[2 '-(4-((benzothiazole-2-sulfydryl) methyl)-[1,2,3]-triazole)-ethyl]-4-pyrroles-1,8-naphthalimide.
3. the preparation method of compound described in claim 1 or 2, is characterized in that comprising the following steps:
1. prepare intermediate 1: under triethylamine exists, taking acetone as solvent, propargyl bromide reacts with 2-mercaptobenzothiazole and generates 2-(2-alkynes-1-propyl dithiocarbamate) benzo [d] thiazole, as intermediate 1;
2. prepare intermediate 3:4-bromo-1,8-naphthalene acid anhydride and thanomin are dissolved in ethanol, are warming up to back flow reaction, generate N-(2 '-hydroxyethyl)-4-bromo-1, and 8-naphthalimide, as intermediate 3;
3. prepare intermediate 4: intermediate 3 is dissolved in to ethylene glycol monomethyl ether, adds corresponding cyclic amine, reaction obtains having the intermediate 4 of formula I structure;
4. prepare intermediate 5: intermediate 4 is dissolved in to ethyl acetate, adds phosphorus tribromide reaction to generate the intermediate 5 with general formula II structure;
5. prepare intermediate 6: intermediate 5 is dissolved in to DMF, adds NaN
3, reaction generates the intermediate 6 with general formula III structure;
6. prepare described compound: intermediate 6 and intermediate 1 are dissolved in to the mixed solution of the trimethyl carbinol and water, add catalyzer sodium ascorbate and cupric sulfate pentahydrate, under nitrogen protection, reaction generates described compound.
4. the application of the compound described in claim 1 or 2 in inhibition tumor cell growth.
5. application according to claim 4, is characterized in that described tumour cell comprises MCF-7 breast cancer cell, Hela cervical cancer cell and SMMC-7721 liver cancer cell.
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| CN107540608A (en) * | 2017-07-17 | 2018-01-05 | 大连理工大学 | 4 substitution naphthoyl imide compounds and its application |
| CN112979671A (en) * | 2021-03-05 | 2021-06-18 | 郑州大学 | Oridonin-naphthalimide fluorescent probe as well as preparation method and application thereof |
| CN115109033A (en) * | 2021-05-07 | 2022-09-27 | 河南师范大学 | Synthesis and biological activity research of 1, 8-naphthalimide derivative |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107540608A (en) * | 2017-07-17 | 2018-01-05 | 大连理工大学 | 4 substitution naphthoyl imide compounds and its application |
| CN112979671A (en) * | 2021-03-05 | 2021-06-18 | 郑州大学 | Oridonin-naphthalimide fluorescent probe as well as preparation method and application thereof |
| CN112979671B (en) * | 2021-03-05 | 2022-02-22 | 郑州大学 | Oridonin-naphthalimide fluorescent probe as well as preparation method and application thereof |
| CN115109033A (en) * | 2021-05-07 | 2022-09-27 | 河南师范大学 | Synthesis and biological activity research of 1, 8-naphthalimide derivative |
| CN115109033B (en) * | 2021-05-07 | 2023-11-14 | 河南师范大学 | Synthesis and bioactivity research of 1, 8-naphthalimide derivative |
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