CN105130897A - Nitrogen-containing sulfur substituent naphthalimide compound, preparation method and applications thereof - Google Patents

Nitrogen-containing sulfur substituent naphthalimide compound, preparation method and applications thereof Download PDF

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Publication number
CN105130897A
CN105130897A CN201510474899.5A CN201510474899A CN105130897A CN 105130897 A CN105130897 A CN 105130897A CN 201510474899 A CN201510474899 A CN 201510474899A CN 105130897 A CN105130897 A CN 105130897A
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compound
preparation
naphthalimide
general formula
atom
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CN105130897B (en
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李晓莲
徐强
范丽丽
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Dalian University of Technology
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Dalian University of Technology
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/04—Ortho- or peri-condensed ring systems
    • C07D221/06—Ring systems of three rings
    • C07D221/14—Aza-phenalenes, e.g. 1,8-naphthalimide

Abstract

The present invention discloses a class of nitrogen-containing sulfur substituent naphthalimide compound, a preparation method and applications thereof, wherein the compound has a structure represented by a general formula Y, R is one selected from a six-membered ring containing hetero atom, the following structures defined in the specification, -NHCH2CH2OH, -NHCH2CH2N(CH3) and -NHCH2CH2CH2CH3, the hetero atom is at least one selected from N, O and S, the six-membered ring containing the hetero atom at least has a N atom, and R is bound with the mother nucleus in the general formula T through the N atom. According to the present invention, the methyldithiocarbazate is bounded into the active site of the naphthalimide to prepare the compound of the present invention, and the class of the compounds provide growth inhibition activities on breast cancer cells, cervical cancer cells and a variety of tumor cells with different tissue origins while provide low inhibition activities on human body normal cells, and have wide prospects in the tumor cell growth inhibition drug preparation. The general formula Y is defined in the specification.

Description

The nitrogenous sulphur of one class substituent naphthalimide compound, its preparation method and application
Technical field
The present invention relates to the antitumor nitrogenous sulphur substituting group naphthalimide compound of a class, belong to technical field of organic synthesis.
Background technology
Research finds that naphthalimide derivative has good antitumour activity, wherein Amonafide (N-(beta-dimethyl-amino-ethyl)-3-amido-1, 8-naphthalimide) (MalviyaVK, LiuPY, AlbertsDS, etal.Am.J.Clin.Oncol., 1992, 15:41-44.) with Mitonafide (N-(beta-dimethyl-amino-ethyl)-3-nitro-1, 8-naphthalimide) (BranaM.F, SantosA., RoldanC.M., etal.Eur.J.Med.Chem.Chim.Ther., 1981, 16, 207-212) be two very famous compounds, enter phase ii clinical trial.This compounds can 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, affects the normal physiological function of DNA, thus reaches the effect of anticancer propagation.But, in the clinical trial of 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 the side effects such as bone marrow depression, vomiting, fash and moderate phlebitis.
The group such as aminoguanidine, amido urea, amidoxime, different hydroxyl oxime, hydroxyl amino urea is widely studied for antitumor drug, these compounds have identical constitutional features (NHC (=X) NHOH, X=O, NH, S), this structure and analog structure are confirmed to be the basic pharmacophore of anti-tumor activity medicine, and its derivative shows extraordinary tumors inhibition activity.
Summary of the invention
The object of the invention is, at naphthalimide avtive spot access Methyl hydrazinecarbodithioate, to expand the kind of naphthalimide medicine with this, and obtain the antitumor drug more effective, toxic side effect is little.On naphthalimide parent, amido, Methyl hydrazinecarbodithioate is introduced by reactions such as amido replacement, amino condensations, the substituent naphthalimide derivative of the nitrogenous sulphur of design and synthesis one class, wish the solvability improving parent on the one hand, wish the electron distributions situation changing parent by introducing nitrogenous sulphur substituting group on the other hand, impact and the mode of action of DNA, test and prove that it has rejection ability to tumor cell in vitro growth.
The present invention solves the problems of the technologies described above adopted technical scheme: the substituent naphthalimide compound of the nitrogenous sulphur of a class, and described compound has the structure of general formula Y:
In general formula Y: R be selected from containing heteroatomic six-ring, -NHCH 2cH 2oH ,-NHCH 2cH 2n (CH 3) 2with-NHCH 2cH 2cH 2cH 3in one, described heteroatoms is at least one in N, O, S atom, described containing having at least one atom N in heteroatomic six-ring, and R is connected with the parent nucleus in general formula T by atom N.
Further, to be describedly selected from containing heteroatomic six-ring in one.
Further, compound of the present invention most preferably is: and N-(N '-dithiocarbonic acid methyl esters amido)-6-piperidyl-1,8-naphthalimide.
Another technical purpose of the present invention is the preparation method providing described compound, comprise the following steps: with 4-bromo-1,8 naphthalene acid anhydrides (compound 1) are starting raw material, corresponding intermediate 4-amido-1 is reacted to obtain with corresponding amine, 8 naphthalene anhydridization compounds (compound 2), there is amino condensation reaction and generate described compound in 4-amido-1,8 naphthalene anhydridization compound and Methyl hydrazinecarbodithioate (compound 4).
Further, described Methyl hydrazinecarbodithioate, by the mixing of hydrazine hydrate (compound 3), dithiocarbonic anhydride and methyl iodide, is prepared with " one kettle way " reaction.
Further, the solvent adopted when 4-amido-1,8 naphthalene anhydridization compound and Methyl hydrazinecarbodithioate react in described preparation method is ethanol.
Synthetic route is as follows:
Another technical purpose of the present invention is to provide described compound preparing the application in inhibition tumor cell growth medicine, and described tumour cell comprises MCF-7 Breast Cancer Cell and human cervical carcinoma Hela cell.
The substituent naphthalimide compound of nitrogenous sulphur of above-mentioned synthesis is carried out respectively the mensuration of extracorporeal suppression tumor cell growth activity by tetrazolium reduction method to MCF-7 Breast Cancer Cell and human cervical carcinoma Hela cell, and carry out the mensuration of above compound to the vitro inhibition cells growth activity of HL7702 Human normal hepatocyte simultaneously.
Described tetrazolium reduction method experimental procedure is as follows:
1, inoculating cell
Respectively MCF-7 Breast Cancer Cell, human cervical carcinoma Hela cell and HL7702 Human normal hepatocyte are collected in substratum, by every for cell dilution hole inoculation about 5000 cells, outermost adds 200 μ LPBS, provides sufficient moisture to ensure the growing environment of cell, puts culture plate to CO 2incubation one to two days in incubator.
2, medicine is added
When cell culture can add medicine to during logarithmic phase, with substratum, compound of the present invention is diluted to 2 μMs, 20 μMs, 40 μMs, 80 μMs four gradient concentrations respectively, in cell, adds medicine, each drug level arranges 4 multiple holes, reduce error, and control group is set, put back to CO 2in incubator, cultivate 24h.
3, the detection of survivaling cell number
In institute is porose, all adds 20 μ LMTT, is put into CO 2incubation 4h in incubator; The solution discarded in hole adds 200 μ LDMSO, lysigenous crystallization.Microplate reader measures each hole absorbancy record result, goes out the IC of analyte by following formulae discovery 50value.
Beneficial effect of the present invention:
The present invention is by having prepared the substituent naphthalimide compound of the nitrogenous sulphur of a class at naphthalimide active sites access Methyl hydrazinecarbodithioate, the tumour cell of this compounds to the multiple different tissue sources such as mammary cancer and cervical cancer has the activity of Developing restraint, and less to the inhibit activities of human normal cell, prepare inhibition tumor cell growth medicine in have broad prospects.
Embodiment
Following non-limiting example can make the present invention of those of ordinary skill in the art's comprehend, but does not limit the present invention in any way.
Embodiment 1
N-(N '-dithiocarbonic acid methyl esters amido)-6-piperidyl-1,8-naphthalimide (compound Y1) synthesis:
(1) 4-piperidyl-1.8-naphthalene acid anhydride synthesis
The 4-bromo-1 of 5g (18.1mmol) is added in 100mL two-mouth bottle, 8 naphthalene acid anhydrides, add 40mL ethylene glycol monomethyl ether stirring and dissolving, 2mL (20.2mmol) piperidines is added reaction system, be heated to backflow, stopped reaction after magnetic agitation 4h, cool under room temperature, cold water is added in reaction solution, separate out yellow mercury oxide, dry after filtering, purifying with silica gel column chromatography, (elutriant is CH 2cl 2) obtain yellow solid 4.77g, productive rate: 93.6%.
(2) synthesis of methyl dithiocarbazinate (compound 4)
6.6g (0.12mol) potassium hydroxide is added in 50mL there-necked flask, 8.0mL water and 6.7mL Virahol, be stirred to dissolve, 5.7mL (0.12mol) hydrazine hydrate (80%) is slowly added under ice-water bath 0 DEG C of condition, then less than 10 DEG C are maintained the temperature at, slowly drip freezing after dithiocarbonic anhydride, dropwise after about 1h, continue stir 2h.Maintain the temperature at less than 10 DEG C, in 1.5h, drip 6.2mL (0.12mol) cooled methyl iodide, dropwise rear continuation and stir 1h, separate out a large amount of white precipitate.Reaction is stopped, suction filtration, dry after cold wash.Thick product methylene dichloride recrystallization, obtains white solid 9.4g, productive rate: 64.5%.
(3) N-(N '-dithiocarbonic acid methyl esters amido)-6-piperidyl-1,8-naphthalimide (compound Y1) synthesis:
In 50mL two-mouth bottle, add 0.5g (1.8mmol) 4-piperidyl-1.8-naphthalene acid anhydride, 0.22g (1.8mmol) methyl dithiocarbazinate, use 30mL dissolve with ethanol, magnetic agitation, be warming up to back flow reaction 12h, stopped reaction, reaction solution is poured in cold water, separates out yellow mercury oxide, filters, dry after washing, silica gel column chromatography is purified (elutriant is methylene dichloride: ethyl acetate=50:1), obtains yellow solid 0.34g (D2), productive rate: 49.6%.Fusing point: 165.1-166.5 DEG C.
+ ESIMS (M+H): C 19h 19n 3o 2s 2, calculated value: 385.0919, measured value: 585.1000.
1HNMR(500MHz,DMSO)δ9.90(d,J＝206.2Hz,1H),8.57–8.41(m,3H),7.85(dd,J＝16.4,8.7Hz,1H),7.34(t,J＝7.7Hz,1H),3.29–3.17(m,4H),2.65(s,2H),2.46(s,1H),1.82(s,4H),1.67(d,J＝3.0Hz,2H).
13CNMR(126MHz,DMSO)δ201.12(s,1H),161.09(s,1H),160.49(s,1H),157.46(s,1H),133.10(s,3H),132.10(s,1H),131.60(s,3H),131.44(s,2H),129.19(s,1H),125.95(s,5H),125.56(s,2H),122.12(s,1H),115.06(s,4H),53.91(s,10H),25.62(s,10H),23.78(s,5H),17.67(s,3H).
Embodiment 2
Extracorporeal suppression tumor cell and normal cell growth determination of activity:
By tetrazolium (microculturetetrozolium, MTT) reduction method, vitro inhibition cells growth activity mensuration is carried out to Hela cervical cancer cell, MCF-7 breast cancer cell and HL7702 Human normal hepatocyte.
The concrete operations of tetrazolium (MTT) reduction method are:
(1) inoculating cell, culturing cell: when cell is in logarithmic phase, gets off with the cell dissociation of trypsinase by adherent growth, to collect in the substratum containing serum and diluting cells suspension concentration is about 4 × 10 5~ 6 × 10 5individual/mL.Be inoculated into by above-mentioned nutrient solution in aseptic 96 orifice plates, every hole adds 100 μ L cell suspensions (about 5000 cells in every hole), and the every hole of outermost adds the PBS damping fluid of 200 μ L, for Growth of Cells ring provides sufficient moisture environment.Postvaccinal culture plate is put to 37 DEG C, 5%CO 2incubation 24h in the incubator of environment, can add medicine when cell is in logarithmic phase.
(2) medicine is added: with substratum, drug dilution is become 2 μMs, 20 μMs, 40 μMs, 80 μMs of four gradient concentrations.Each concentration arranges 4 multiple holes to reduce error.Every hole adds 100 μ L drug solutions (now drug level dilutes a times), and control group arranges 8 ~ 10 multiple holes, and control group does not add medicine substratum and replaces.Culture plate puts back to incubation in incubator, makes drug effect 24h.
(3) survivaling cell number is detected: take out culture plate, every hole adds 20 μ LMTT.Put back in incubator and cultivate 4h.Sucking-off porose in substratum and MTT, note the purple crystal that do not siphon away bottom hole.Add 200 μ LDMSO Rong Xie formazan crystallizations in every hole, shaking table shakes 10 minutes.96 orifice plates are put into microplate reader and measure each hole absorbancy.Wavelength is 490nm, 570nm, 625nm.Calculate inhibitory rate of cell growth and IC 50value.
As follows to the external raw survey result of compound Y1:
Table 1. compound Y1 is to the IC of Hela, MCF-7 and HL7702 cell strain 50value
Compound Y1 shows good Inhibit proliferaton effect to tumor cell line Hela, MCF-7 as can be seen from Table 1, and it is less to the inhibit activities of normal cell HL7702, has selectivity.

Claims (8)

1. the substituent naphthalimide compound of the nitrogenous sulphur of a class, it is characterized in that, described compound has the structure of general formula Y:
In general formula Y: R be selected from containing heteroatomic six-ring, -NHCH 2cH 2oH ,-NHCH 2cH 2n (CH 3) 2with-NHCH 2cH 2cH 2cH 3in one, described heteroatoms is at least one in N, O, S atom, described containing having at least one atom N in heteroatomic six-ring, and R is connected with the parent nucleus in general formula T by atom N.
2. derivative according to claim 1, is characterized in that, is describedly selected from containing heteroatomic six-ring in one.
3. compound according to claim 1, is characterized in that described compound is N-(N '-dithiocarbonic acid methyl esters amido)-6-piperidyl-1,8-naphthalimide.
4. the preparation method of compound described in a claim 1, comprise the following steps: with 4-bromo-1,8 naphthalene acid anhydrides are starting raw material, corresponding intermediate 4-amido-1 is reacted to obtain with corresponding amine, 8 naphthalene anhydridization compounds, there is amino condensation reaction and generate described compound in 4-amido-1,8 naphthalene anhydridization compound and Methyl hydrazinecarbodithioate.
5. the preparation method of compound according to claim 4, is characterized in that described Methyl hydrazinecarbodithioate is by the mixing of hydrazine hydrate, dithiocarbonic anhydride and methyl iodide, with " one kettle way " reaction preparation.
6. the preparation method of compound according to claim 4, is characterized in that the solvent that 4-amido-1,8 naphthalene anhydridization compound and Methyl hydrazinecarbodithioate adopt when reacting is ethanol.
7. compound described in claim 1 is preparing the application in inhibition tumor cell growth medicine.
8. application according to claim 7, is characterized in that described tumour cell comprises MCF-7 Breast Cancer Cell and human cervical carcinoma Hela cell.
CN201510474899.5A 2015-08-04 2015-08-04 The naphthalimide compound of a kind of nitrogenous sulphur substituent group, preparation method and application Expired - Fee Related CN105130897B (en)

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Cited By (4)

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Publication number Priority date Publication date Assignee Title
CN106118125A (en) * 2016-06-27 2016-11-16 苏州大学 A kind of naphthalimide derivative, preparation method and application are in preparing fluorescent polyacrylonitrile
CN107540608A (en) * 2017-07-17 2018-01-05 大连理工大学 4 substitution naphthoyl imide compounds and its application
CN109490291A (en) * 2018-11-20 2019-03-19 上海应用技术大学 Purposes of the 1,8- naphthoyl imide compounds based on electron-withdrawing group substitution as the colour reagent of fluorine ion
CN112500602A (en) * 2020-12-04 2021-03-16 李桂云 High-molecular preparation for detecting heavy metals in outdoor water source and preparation method thereof

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106118125A (en) * 2016-06-27 2016-11-16 苏州大学 A kind of naphthalimide derivative, preparation method and application are in preparing fluorescent polyacrylonitrile
CN106118125B (en) * 2016-06-27 2017-10-10 苏州大学 A kind of naphthalimide derivative, preparation method and application are in preparing fluorescent polyacrylonitrile
CN107540608A (en) * 2017-07-17 2018-01-05 大连理工大学 4 substitution naphthoyl imide compounds and its application
CN109490291A (en) * 2018-11-20 2019-03-19 上海应用技术大学 Purposes of the 1,8- naphthoyl imide compounds based on electron-withdrawing group substitution as the colour reagent of fluorine ion
CN112500602A (en) * 2020-12-04 2021-03-16 李桂云 High-molecular preparation for detecting heavy metals in outdoor water source and preparation method thereof

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