CN103450176A - Naphthalimide compound containing 2-(4-aminophenyl) benzothiazole and application thereof - Google Patents
Naphthalimide compound containing 2-(4-aminophenyl) benzothiazole and application thereof Download PDFInfo
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- CN103450176A CN103450176A CN2013103619714A CN201310361971A CN103450176A CN 103450176 A CN103450176 A CN 103450176A CN 2013103619714 A CN2013103619714 A CN 2013103619714A CN 201310361971 A CN201310361971 A CN 201310361971A CN 103450176 A CN103450176 A CN 103450176A
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- benzothiazole
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Abstract
The invention relates to an anti-tumor naphthalimide compound containing 2-(4-aminophenyl) benzothiazole and an application thereof in the field of organisms. The compound is characterized in that 2-(4-aminophenyl)-benzothiazole is introduced to a naphthalimide matrix structure in a side chain form through reactions such as amino condensation and amino substitution. The compound has wide anti-tumor activity, and has a better inhibition effect on normal growth of tumor cells with various different tissue origins such as cervical cancer, liver cancer and breast cancer.
Description
Technical field
The present invention relates to a class in biological organic synthesis field antitumor containing the 2-(4-aminophenyl) the synthetic and application of benzothiazole naphthalimide compound.
Background technology
Research finds that naphthalimide derivative has good antitumour activity, Amonafide (N-(beta-dimethyl-amino-ethyl)-3-amido-1 wherein, the 8-naphthalimide) (Malviya V K, Liu P Y, Alberts D S, et al.Am.J.Clin.Oncol., 1992, 15:41-44.) and Mitonafide (N-(beta-dimethyl-amino-ethyl)-3-nitro-1, the 8-naphthalimide) (Brana M.F, Santos A., Roldan C.M., et al.Eur.J.Med.Chem.Chim.Ther., 1981, 16, 207-212) be two very famous compounds, entered phase ii clinical trial.This compounds is the growth of inhibition tumor cell effectively, its mechanism of action is that intercalation enters between the base pair of DNA, inducing DNA chain break under the intervention of type Ⅱ topoisomerase, affect the normal physiological function of DNA, thereby reach the effect of anticancer propagation.But, in the clinical trial to Mitonafide, find that it has very serious central nervous system (CNS) toxicity, and its clinical activity is limited; The performance of Amonafide in clinical trial is also not fully up to expectations, causes bone marrow depression, vomiting, fash and the moderate side effects such as phlebitis.
The 2-(4-aminophenyl)-benzothiazole finds at first in monitoring TYR kinase inhibitor process, and the present invention is containing the 2-(4-aminophenyl) the benzothiazole naphthalimide derivative shows very strong tumors inhibition activity.
Summary of the invention
The objective of the invention is to introduce the 2-(4-aminophenyl in the mode of side chain on the naphthalimide parent)-benzothiazole, expand the naphthalimide derivative activity, design has been synthesized a class containing the 2-(4-aminophenyl) compound of benzothiazole naphthalimide.Synthesized a class by reactions such as amino condensation, amido replacements and contained the 2-(4-aminophenyl) naphthalimide derivative of benzothiazole, wish to enlarge on the one hand the conjugate area of parent, wish to change by introducing benzothiazole on the other hand the electron distributions situation of parent, the mode of action of impact and DNA, the antitumor drug obtain more effectively, toxic side effect is little.
The present invention solves the problems of the technologies described above adopted technical scheme: a class is containing the 2-(4-aminophenyl) the benzothiazole naphthalimide compound, 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
5, X
6, X
7, X
8or X
9
Compound of the present invention is:
The N-[2-(4-aminophenyl) benzothiazole]-4-morpholinyl-1,8-naphthalimide (Y1);
The N-[2-(4-aminophenyl) benzothiazole]-4-thio-morpholinyl-1,8-naphthalimide (Y2);
The N-[2-(4-aminophenyl) benzothiazole]-4-hexahydropyridine base-1,8-naphthalimide (Y3);
The N-[2-(4-aminophenyl) benzothiazole]-4-piperazinyl-1,8-naphthalimide (Y4).
The preparation method of compound of the present invention, with bromo-1, the 8 naphthalene acid anhydride of compound 1(4-) for starting raw material, react to obtain corresponding intermediate a(4-amido-1,8 anhydride naphthalene derivative with corresponding amine in ethylene glycol monomethyl ether); With compound 2(2-mercaptoaniline) and compound 3(p-Aminobenzaldehyde) reaction condensation obtain intermediate b(2-(4-aminophenyl) benzothiazole); Reflux in glacial acetic acid and condensation reaction occurs obtain described compound by intermediate a and intermediate b again.
Synthetic route is as follows:
The application of derivative of the present invention in the inhibition tumor cell growth, the preferred MCF-7 Breast Cancer Cell of described tumour cell, human cervical carcinoma Hela cell and SMMC-7721 liver cancer cells.
By above-mentioned synthetic containing the 2-(4-aminophenyl) naphthalimide compound of benzothiazole carries out respectively the mensuration of extracorporeal suppression tumor cell growth activity to MCF-7 Breast Cancer Cell, human cervical carcinoma Hela cell and SMMC-7721 liver cancer cells by the tetrazolium reduction method, result shows, this compounds has to the tumour cell of the multiple different tissue sources such as cervical cancer, liver cancer, mammary cancer the activity that suppresses growth.
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, approximately 2000～4000 cells are inoculated in the every hole of cell dilution, outermost adds 200 μ LPBS, provides sufficient moisture to guarantee the growing environment of cell, and culture plate is put to CO
2in incubator, incubation is one to two day.
2, add medicine
With substratum, compound of the present invention is diluted to respectively to 10
-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 is careful herein and do not siphon away cell; Then add medicine, 5 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
All add 20 μ L MTT in institute is porose, is put into CO
2incubation 4h in incubator; The solution discarded in hole adds 200 μ L DMSO, lysigenous crystallization.Measure each hole absorbancy and record result on microplate reader, calculate the IC of analyte by following formula
50value.
lgIC
50=X
m-I[P-(3-P
m-P
n)/4]
X wherein
m: the lg maximal dose; I:lg (maximal dose/dosage is connected); P: positive reaction rate sum; P
m: maximum positive reaction rate; P
n: minimum positive reaction rate.
Embodiment
Below by embodiment, the present invention is further illustrated, but do not limit the present invention in any way.
Embodiment 1
The N-[2-(4-aminophenyl) benzothiazole]-4-morpholinyl-1,8-naphthalimide (compound Y1) synthetic:
(1) intermediate a1's is synthetic
By 1g(3.6mmol) compound 1(4-is bromo-1,8-naphthalene acid anhydride) pour in the 50mL two-mouth bottle, add the 15mL ethylene glycol monomethyl ether, add morpholine 1.2mmol under magnetic agitation, after back flow reaction 5h, TLC(thin-layer chromatography) follow the tracks of reaction to fully.Cooling system, to room temperature, is poured in frozen water, separates out precipitation, direct suction filtration, and water rinses, and drying, weigh.Productive rate is 85%.
(2) intermediate b1's is synthetic
In the 50mL bottle with two necks, add 1.5g(0.12mol) compound 3(p-Aminobenzaldehyde), 1mL compound 2(2-mercaptoaniline) and, 30mL water, be warming up to 80 ℃ under magnetic agitation, now p-Aminobenzaldehyde all dissolves, and keeps 80 ℃ to continue reaction 5h, and TLC follows the tracks of reaction extremely fully, cooling system is to room temperature, directly suction filtration, obtain orange solids, and drying is weighed.Productive rate is 80%.
(3) compound Y1's is synthetic
In the 25mL bottle with two necks, add 226mg(1mmol) intermediate b1(2-(4-aminophenyl) benzothiazole), 340mg(1.2mmol) intermediate a1(4-morpholinyl-1,8-naphthalene acid anhydride), the 15mL Glacial acetic acid, be warming up to 118 ℃ under magnetic agitation, backflow 4h, TLC follows the tracks of reaction to fully, and reaction system is cooled to room temperature, pour in frozen water, suction filtration obtains solid.(elutriant is: CH in the silica gel column chromatography separation
2cl
2) productive rate 75%.Fusing point: > 300 ℃.
1H?NMR(400MHz,CDCl
3)δ8.66(d,J=6.7Hz,1H),8.60(d,J=8.0Hz,1H),8.50(d,J=5.0Hz,1H),8.28(d,J=8.4Hz,2H),8.12(s,1H),7.94(d,J=7.9Hz,1H),7.80–7.72(m,1H),7.52(t,J=7.6Hz,1H),7.47(d,J=8.4Hz,2H),7.42(t,J=7.6Hz,1H),7.29(d,J=8.1Hz,1H),4.09–4.01(m,4H),3.34–3.28(m,4H).
13C?NMR(400MHz,CDCl
3)δ193.55,190.76,180.81,152.34,133.44,132.78,130.48,128.47,123.18,225.52,67.17,53.60.
+ ESI MS (M+H): C
29h
21n
3o
3s, calculated value: 492.1304, measured value: 492.1370.
Embodiment 2
The N-[2-(4-aminophenyl) benzothiazole]-4-thio-morpholinyl-1,8-naphthalimide (compound Y2) synthetic:
Except substituting morpholine with thiomorpholine, other synthesizing progress methods, with embodiment 1, obtain target compound Y2.
1H?NMR(400MHz,CDCl
3)δ8.66(dd,J=7.3,1.1Hz,1H),8.59(d,J=8.0Hz,1H),8.45(dd,J=8.5,1.1Hz,1H),8.33(d,J=8.5Hz,2H),8.19(d,J=8.1Hz,1H),7.95(d,J=7.4Hz,1H),7.77(dd,J=8.4,7.3Hz,1H),7.54(dd,J=11.3,4.2Hz,1H),7.48(dd,J=7.8,4.8Hz,2H),7.44(d,J=7.2Hz,1H),7.30(d,J=8.1Hz,1H),3.60–3.52(m,4H),3.03–2.97(m,4H).
+ ESI MS (M+H): C
31h
21n
3o
2s
2, calculated value: 508.1705, measured value: 508.1198.
Embodiment 3
The N-[2-(4-aminophenyl) benzothiazole]-4-hexahydropyridine base-1,8-naphthalimide (compound Y3) synthetic:
Except substituting morpholine with hexahydropyridine, other synthesizing progress methods, with embodiment 1, obtain target compound Y3.
1H?NMR(400MHz,CDCl
3)δ8.68(d,J=6.7Hz,1H),8.59(d,J=8.0Hz,1H),8.50(d,J=5.0Hz,1H),8.32(d,J=8.5Hz,2H),8.12(s,1H),8.04(d,J=7.9Hz,1H),7.80–7.72(m,1H),7.58(t,J=8.4Hz,1H),7.47(d,J=8.4Hz,2H),7.41(t,J=7.6Hz,1H),7.27(d,J=7.9Hz,1H),4.09–4.01(m,4H),3.41–3.31(m,6H).
+ ESI MS (M+H): C
30h
23n
3o
2s, calculated value: 490.1511, measured value: 490.1600.
Embodiment 4
The N-[2-(4-aminophenyl) benzothiazole]-4-piperazinyl-1,8-naphthalimide (compound Y4) synthetic:
Except substituting morpholine with piperazine, other synthesizing progress methods, with embodiment 1, obtain target compound Y4.
1H?NMR(400MHz,CDCl
3)δ8.76(d,J=7.5,1.1Hz,1H),8.62(d,J=8.0Hz,1H),8.53(dd,J=8.7,1.1Hz,1H),8.33(d,J=8.2Hz,2H),8.21(d,J=7.9Hz,1H),7.95(d,J=7.4Hz,1H),7.77(dd,J=8.4,7.3Hz,1H),7.54(dd,J=11.3,4.2Hz,1H),7.48(dd,J=7.8,4.8Hz,2H),7.44(d,J=7.2Hz,1H),7.30(d,J=8.1Hz,1H),3.71–3.62(m,4H),2.79(t,5H).
+ ESI MS (M+H): C
29h
22n
4o
2s, calculated value: 491.1463, measured value: 491.1515.
Embodiment 5
The extracorporeal suppression tumor cell growth activity is measured:
By tetrazolium (microculture tetrozolium, MTT) reduction method, Hela cervical cancer cell, SMMC-7721 liver cancer cell and MCF-7 breast cancer cell are carried out to extracorporeal suppression tumor cell growth activity mensuration.
Take compound Y1 as example, and the concrete operations of tetrazolium (MTT) reduction method are:
1, inoculating cell
Each cancer cells is collected in substratum, approximately 2000～4000 cells are inoculated in the every hole of cell dilution, outermost adds 200 μ L PBS, provides sufficient moisture to guarantee the growing environment of cell, and culture plate is put to CO
2in incubator, incubation is one to two day.
2, add medicine
With substratum, the compound Y1 of embodiment 1 preparation is diluted to respectively to 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, 5 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
All add 20 μ L MTT in institute is porose, is put into CO
2incubation 4h in incubator; The solution discarded in hole adds 200 μ L DMSO, lysigenous crystallization.Measure each hole absorbancy and record result on microplate reader, calculate the IC of analyte by following formula
50value.
lgIC
50=X
m-I[P-(3-P
m-P
n)/4]
X wherein
m: the lg maximal dose; I:lg (maximal dose/dosage is connected); P: positive reaction rate sum; P
m: maximum positive reaction rate; P
n: minimum positive reaction rate
The detection method of compound Y2～Y3 is the same.
Extracorporeal suppression tumor cell growth activity result to compound Y1～Y4 is as follows:
The IC of table 1. compound Y1～Y4 to Hela, MCF-7 and 7721 cancer cells
50value
Compound Y1～Y4 shows stronger inhibition to tumor cell line Hela, MCF-7 and SMMC-7721 as can be seen from Table 1, of the present invention containing the 2-(4-aminophenyl) the benzothiazole naphthalimide derivative has anti-tumor activity widely.
Claims (5)
1. a class is containing the 2-(4-aminophenyl) the benzothiazole naphthalimide compound, 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
5, X
6, X
7, X
8or X
9
2. compound according to claim 1 is characterized in that described compound is:
The N-[2-(4-aminophenyl) benzothiazole]-4-morpholinyl-1, the 8-naphthalimide;
The N-[2-(4-aminophenyl) benzothiazole]-4-thio-morpholinyl-1, the 8-naphthalimide;
The N-[2-(4-aminophenyl) benzothiazole]-4-hexahydropyridine base-1, the 8-naphthalimide;
The N-[2-(4-aminophenyl) benzothiazole]-4-piperazinyl-1, the 8-naphthalimide.
3. the preparation method of the described compound of claim 1, is characterized in that with bromo-1, the 8 naphthalene acid anhydride of 4-reacting to obtain corresponding intermediate 4-amido-1,8 anhydride naphthalene derivative with corresponding amine for starting raw material in ethylene glycol monomethyl ether; Obtain intermediate 2-(4-aminophenyl with 2-mercaptoaniline and p-Aminobenzaldehyde reaction condensation) benzothiazole; Again by intermediate 4-amido-1,8 anhydride naphthalene derivative and intermediate 2-(4-aminophenyl) the benzothiazole generation condensation reaction that refluxes in glacial acetic acid obtains described compound.
4. the application of compound claimed in claim 1 in the inhibition tumor cell growth.
5. application according to claim 4, is characterized in that described tumour cell comprises MCF-7 Breast Cancer Cell, human cervical carcinoma Hela cell and SMMC-7721 liver cancer cells.
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Cited By (6)
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| CN105130896A (en) * | 2015-08-04 | 2015-12-09 | 大连理工大学 | Naphthalimide derivatives containing thiourea substituent, preparation method and applications thereof |
| CN105130895A (en) * | 2015-08-04 | 2015-12-09 | 大连理工大学 | Naphthalimide derivatives, preparation method and applications thereof |
| CN105130897A (en) * | 2015-08-04 | 2015-12-09 | 大连理工大学 | Nitrogen-containing sulfur substituent naphthalimide compound, preparation method and applications thereof |
| CN107540608A (en) * | 2017-07-17 | 2018-01-05 | 大连理工大学 | 4 substitution naphthoyl imide compounds and its application |
| CN107698571A (en) * | 2017-08-30 | 2018-02-16 | 大连理工大学 | Naphthalimide Coumarins DNA target is to dual damascene agent and its synthesis and application |
| CN112375066A (en) * | 2020-09-30 | 2021-02-19 | 大连理工大学 | 1, 8-naphthalic anhydride derivatives containing 8- (benzoylamino) quinoline and synthesis and application thereof |
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105130896A (en) * | 2015-08-04 | 2015-12-09 | 大连理工大学 | Naphthalimide derivatives containing thiourea substituent, preparation method and applications thereof |
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| CN105130897A (en) * | 2015-08-04 | 2015-12-09 | 大连理工大学 | Nitrogen-containing sulfur substituent naphthalimide compound, preparation method and applications thereof |
| CN105130896B (en) * | 2015-08-04 | 2017-11-10 | 大连理工大学 | The naphthalimide derivative of a kind of substituent containing thiocarbamide, its preparation method and application |
| CN107540608A (en) * | 2017-07-17 | 2018-01-05 | 大连理工大学 | 4 substitution naphthoyl imide compounds and its application |
| CN107698571A (en) * | 2017-08-30 | 2018-02-16 | 大连理工大学 | Naphthalimide Coumarins DNA target is to dual damascene agent and its synthesis and application |
| CN112375066A (en) * | 2020-09-30 | 2021-02-19 | 大连理工大学 | 1, 8-naphthalic anhydride derivatives containing 8- (benzoylamino) quinoline and synthesis and application thereof |
| CN112375066B (en) * | 2020-09-30 | 2022-05-27 | 大连理工大学 | 1, 8-naphthalic anhydride derivatives containing 8- (benzoylamino) quinoline and synthesis and application thereof |
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