CN102731493B - Anti-tumor compound containing benzothiazole heterocyclic structure and application thereof - Google Patents
Anti-tumor compound containing benzothiazole heterocyclic structure and application thereof Download PDFInfo
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- CN102731493B CN102731493B CN201210235719.4A CN201210235719A CN102731493B CN 102731493 B CN102731493 B CN 102731493B CN 201210235719 A CN201210235719 A CN 201210235719A CN 102731493 B CN102731493 B CN 102731493B
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Abstract
The invention relates to an anti-tumor compound containing a benzothiazole heterocyclic structure and application of the anti-tumor compound, which belong to the technical field of biological organic synthesis. The compound provided by the invention is characterized in that a benzothiazole ring is connected on a naphthalimide matrix structure by means of a side chain through Vilsmeier reaction, ring formation, oxidation and nucleophilic reaction. This type of compound has wide anti-tumor activity, and has stronger effect in inhibiting normal growth of various tumor cells.
Description
Technical field
The present invention relates to a class antitumor compound and application thereof containing benzothiazole heterocycle structure, belong to biological technical field of organic synthesis.
Background technology
Through the drug research of decades, the exploitation of naphthalimide series antineoplastic medicament makes some progress.The mechanism of the growth of naphthoyl imide compounds inhibition tumor cell is that intercalation enters between the base pair of DNA, suppresses the synthetic of DNA and RNA, and can suppress type Ⅱ topoisomerase, thereby reach the object of inhibition tumor cell growth.
The present invention is connected to amine chain on naphthalimide parent, and first benzothiazole is connected on naphthalimide ring with the form of singly-bound, obtains antitumous effect stronger, and kinds of tumor cells is had to the naphthalimide analog derivative of inhibition.
Summary of the invention
The object of the invention is on naphthalimide aromatic ring or on side chain, to introduce the benzothiazoles group with good biological activity, improve the biologic activity of molecule, thereby improve its antitumor performance.
The present invention solves the problems of the technologies described above adopted technical scheme: the antitumor compound containing benzothiazole heterocycle structure of a class, and its chemical molecular general structure is as follows:
In general formula (A),
R be C1-C6 alkyl,
or
Wherein: R ' is methyl or ethyl.
The antitumor compound containing benzothiazole structure of a described class is in the application of preparing in antitumor drug.
The above-mentioned antitumor synthetic route containing benzothiazole naphthalimide compound is as follows:
Taking acenaphthene (a) as raw material, react to obtain compound (b) by Vilsmeier; Obtain formula (c) compound by formula (b) and near amino thiophenols cyclisation in organic solvent; In acetic acid, be oxidized to obtain formula (d) compound by formula (c) compound and potassium bichromate; In ethanol, reflux and within 3 hours, can obtain the above-described naphthalimide compound containing benzothiazole by formula (d) compound and corresponding primary amine reaction.
By above-mentioned synthetic mensuration of by tetrazolium reduction method, MCF-7 breast cancer cell and Hela cervical cancer cell being carried out respectively extracorporeal suppression tumor cell growth activity containing benzothiazole heterogeneous ring compound, result shows, this compounds has the growth of inhibition tumor promotion to the cell of the multiple different tissue sources such as mammary cancer, cervical cancer.
MCF-7 breast cancer cell and Hela cervical cancer cell are inoculated in 96 hole microtest plates with 90 μ L/ holes by tetrazolium reduction method, after cultivating 24h, add liquid 10 μ L/ holes, to each cell strain, each concentration is three multiple holes, has color will do the acellular zeroing of relative medicine concentration hole if separately establish acellular zeroing hole medicine; Tumour cell is at 37 ° of C, 5%CO
2under condition, cultivate after 48h, add MTT liquid 5mg/mL physiological saline preparation 20L/ hole, continue to cultivate after 4h, add the three liquid 50 μ L/ holes that formed by 10% sodium lauryl sulphate, 5% isopropylcarbinol, 0.01mol/L HCl, in CO
2in incubator, spend the night, then survey OD570 value by microplate reader, calculate the IC of analyte to growth of cancer cells
50value.
7721 liver cancer cells are inoculated in 96 hole microtest plates with 90 μ L/ holes by tetrazolium reduction method, add liquid 10 μ L/ holes after cultivating 24h, to each cell strain, each concentration is three multiple holes.There is color will do the acellular zeroing of relative medicine concentration hole if separately establish acellular zeroing hole medicine.Tumour cell is at 37 ° of C, 5%CO
2under condition, cultivate after 48h, add MTT liquid 5mg/mL physiological saline preparation 20L/ hole; Continue to cultivate after 4h, add the three liquid 50 μ L/ holes that formed by 10%SDS, 5% isopropylcarbinol, 0.01mol/L HCl, in CO
2in incubator, spend the night.Then survey OD570 value by microplate reader.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 invention has the beneficial effects as follows: the described antitumor compound containing benzothiazole heterocycle structure is to be connected benzothiazole ring with nucleophilic reaction mode with side chain form through Vilsmeier reaction, Cheng Huan, oxidation on naphthalimide precursor structure, this compounds has anti-tumor activity widely, and the normal growth of kinds of tumor cells is had to stronger restraining effect.
Embodiment
Below by embodiment, the present invention is further illustrated.
Embodiment 1
N, N-dimethyl-ethylenediamine-4-(2-[4-morpholinodithio)-1,8-naphthalimide (S1) (compound 1) synthetic
(1) 1mL DMF is added in the two-mouth bottle of 25mL, stir, ice bath, slowly drips 1mL phosphorus oxychloride, stirring at normal temperature 1h, by 1g(6.5mmol) acenaphthene adds in reaction flask after being dissolved in 10mL DMF, is warming up to 90 ° of C, stir 3h, stopped reaction, is poured into water after cooling, there is solid to separate out, suction filtration, dry, filter the 0.57g that weighs, productive rate 45%.
(2) get 2 grams by the synthetic product of step (1) and 1.5ml near amino thiophenols, add in 10 milliliters of organic solvent dimethyl sulfoxide (DMSO), heat up, reflux, thin plate chromatography is followed the tracks of reaction, until react completely, leaves standstill, and filters, and obtains 2.9 grams of solids.
(3) get 0.58 gram by the synthetic product of step (2) and 1.55 grammes per square metre Sodium chromates, add in 20ml ethyl acetate, temperature rising reflux 3 hours, leaves standstill, and by reaction solution impouring frozen water, filters, and washing, dries, and obtains 0.58 gram of solid, productive rate 88%.
(4) get 0.1g(0.3mmol) the synthetic compound of step (3), N, N-dimethyl-ethylenediamine 60 μ L (0.6mmol), 10mL ethanol, stirs, and reflux 3h, is poured into water, and has Precipitation, and suction filtration obtains 0.1 gram of solid, productive rate 86%.(column chromatography elutriant is: C in silica gel column chromatography separation
h2Cl
2: CH
3oH=10:1) obtain yellow-green colour solid S
1.
1HNMR(d
6-DMSO，400MHz):δ(ppm):9.43(d,J=8.4Hz,1H),8.666(t,J
1=7.2Hz,J
2=7.6Hz,2H),8.211(d,J=8.4Hz,1H),8.157(d,J=7.6Hz,1H),7.996(d,J=8.0Hz,1H),7.865(t,J
1=8.4Hz,J
2=7.2Hz,1H),7.600(t,J
1=7.6Hz,J
2=8.0Hz,1H),7.52(t,J
1=7.6Hz,J
2=8.0Hz,1H),4.358(t,J
1=7.6Hz,J
2=6.8Hz,2H),2.701(t,J
1=J
2=7.2Hz,2H),2.384（s,6H）.
HR-MS (m/z): C
23h
19n
3o
2s, calculated value: 401.1198, measured value: 401.1192.
Embodiment 2
N, N-dimethylated propyl diethylenetriamine-4-(2-[4-morpholinodithio)-1,8-naphthalimide (compound 2) synthetic:
Except using N, N-dimethyl-ethylenediamine changes N into, and outside N-dimethylated propyl diethylenetriamine, other synthesizing progress methods, with embodiment 1, obtain target compound 2
1HNMR(d
6-DMSO，400MHz):δ(ppm):9.44(d,J=8.0Hz,1H),8.68(t,J
1=4.0Hz,J
2=8.0Hz2H),8.22(d,J=8.0Hz,1H),8.17(d,J=8.0Hz,1H),8.01(d,J=8.0Hz,1H),7.88(t,J
1=J
2=8.0Hz,1H),7.61(t,J
1=J
2=8.0Hz,1H),7.52(t,J
1=J
2=8.0Hz,1H),4.27(t,J
1=8.0Hz,J
2=8.0Hz,2H),2.53(t,J
1=J
2=8.0Hz,2H),2.32（s,6H）。
HR-MS (m/z): C
24h
21n
3o
2s, calculated value: 415.1354, measured value: 415.1354.
Embodiment 3
N, N-diethyl ethylenediamine-4-(2-[4-morpholinodithio)-1,8-naphthalimide (compound 3) synthetic:
Except using N, N-dimethyl-ethylenediamine changes N into, and outside N-diethyl ethylenediamine, other synthesizing progress methods are same
Embodiment 1, obtains target compound 3
1HNMR(d
6-DMSO，400MHz):δ(ppm):9.45(d,J=8.0Hz,1H),8.67(t,J
1=8.0Hz,J
2=8.0Hz2H),8.22(d,J=8.0Hz,1H),8.17(d,J=8.0Hz,1H),8.01(d,J=8.0Hz,1H),7.89(t,J
1=J
2=8.0Hz,1H),7.61(t,J
1=J
2=8.0Hz,1H),7.52(t,J
1=J
2=8.0Hz,1H),4.44(t,J
1=4.0Hz,J
2=8.0Hz,2H),3.07(t,J
1=J
2=8.0Hz,2H),2.93(q,J
1=J
2=8.0Hz,4H),1.26(t,J
1=8.0Hz,J
2=4.0Hz,6H).
HR-MS (m/z): C
25h
23n
3o
2s, calculated value: 429.1511, measured value: 429.1504.
Embodiment 4
Extracorporeal suppression tumor cell growth activity is measured:
MCF-7 breast cancer cell, Hela cervical cancer cell, 7721 liver cancer cells, HL-60 leukemia cell and SGC-7901 stomach cancer cell are carried out to extracorporeal suppression tumor cell growth activity mensuration by tetrazolium (microculture tetrozolium, MTT) reduction method.
The concrete operations of tetrazolium (MTT) reduction method are: by different tumor growth rates, tumour cell 90 μ L/ holes by some amount in logarithmic phase are inoculated in 96 hole microtest plates, after cultivating 24h, add liquid 10 μ L/ holes, to each cell strain, each concentration is three multiple holes, has color will do the acellular zeroing of relative medicine concentration hole if separately establish acellular zeroing hole medicine; Tumour cell is at 37 ° of C, 5%CO
2under condition, cultivate after 48h, add MTT liquid 5mg/mL physiological saline preparation 20L/ hole, continue to cultivate after 4h, add the three liquid 50 μ L/ holes that formed by 10% sodium lauryl sulphate, 5% isopropylcarbinol, 0.01mol/L HCl, in CO
2in incubator, spend the night, then survey OD570 value by microplate reader; Calculate analyte pair by following formula
The IC of growth of cancer cells
50value (IC
50refer to the concentration of a suppressed half inhibitor):
External raw survey result to compound 1～3 is as follows:
The IC of table 1 compound to tumour cell
50value
Claims (2)
1. the antitumor compound containing benzothiazole structure of a class, is characterized in that: this compound has following chemical molecular general structure:
In general formula (A):
N=2, R ' is methyl or is ethyl; N=3, R ' is methyl.
2. the antitumor compound containing benzothiazole structure of a class according to claim 1 is in the application of preparing in antitumor drug.
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| CN103435574B (en) * | 2013-08-15 | 2014-10-29 | 大连理工大学 | Mercapto benzothiazole substituent acenaphtho-heterocycle compound and application thereof |
| CN103450176B (en) * | 2013-08-15 | 2016-07-06 | 大连理工大学 | One class is containing 2-(4-aminophenyl) benzothiazole naphthalimide compound and application thereof |
| CN107087409B (en) * | 2014-09-19 | 2020-07-31 | 吕衍达 | Benzoheterocyclic compounds and their use |
| CN107698571B (en) * | 2017-08-30 | 2020-07-14 | 大连理工大学 | Naphthalimide-coumarin DNA targeting double-intercalator, synthesis and application thereof |
| CN115385890B (en) * | 2022-07-19 | 2023-08-08 | 杭州庆正鸿科技有限公司 | 1,8 naphthalimide derivative and preparation method and application thereof |
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| CN102206203A (en) * | 2011-04-04 | 2011-10-05 | 大连理工大学 | Synthesis of benzimidazole-containing naphthalimide derivatives and applications of benzimidazole-containing naphthalimide derivatives on cancer resistance |
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