CN105130897B - The naphthalimide compound of a kind of nitrogenous sulphur substituent group, preparation method and application - Google Patents
The naphthalimide compound of a kind of nitrogenous sulphur substituent group, preparation method and application Download PDFInfo
- Publication number
- CN105130897B CN105130897B CN201510474899.5A CN201510474899A CN105130897B CN 105130897 B CN105130897 B CN 105130897B CN 201510474899 A CN201510474899 A CN 201510474899A CN 105130897 B CN105130897 B CN 105130897B
- Authority
- CN
- China
- Prior art keywords
- compound
- preparation
- naphthalimide
- cell
- amido
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Classifications
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The present invention discloses the naphthalimide compound of a kind of nitrogenous sulphur substituent group, preparation method and application, and the compound has the structure of general formula Y, wherein R be selected from containing heteroatomic hexatomic ring,‑NHCH2CH2OH、‑NHCH2CH2N(CH3)2With-NHCH2CH2CH2CH3One of, the hetero atom is at least one of N, O, S atom, it is described containing there is at least one N atom in heteroatomic hexatomic ring, and R is connect by N atom with the parent nucleus in general formula T.The compound of the present invention is by accessing methyl dithiocarbazinate preparation in naphthalimide active site, such compound has the activity for inhibiting growth to the tumour cell of a variety of different tissue sources such as breast cancer and cervical carcinoma, and it is smaller to the inhibitory activity of human normal cell, inhibit to have broad prospects in growth of tumour cell drug in preparation.
Description
Technical field
The present invention relates to a kind of antitumor nitrogenous sulphur substituent group naphthalimide compounds, belong to technical field of organic synthesis.
Background technique
Research finds that naphthalimide derivative has good anticancer activity, wherein Amonafide (N- (beta-dimethyl ammonia
Base ethyl) -3- amido -1,8- 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 -
1,8- naphthalimide) (Brana M.F, Santos A., Roldan C.M., et
Al.Eur.J.Med.Chem.Chim.Ther., it is 1981,16,207-212) two very famous compounds, comes into
Phase ii clinical trial.Such compound can effectively inhibit the growth of tumour cell, and the mechanism of action is the alkali that intercalation enters DNA
Between base pair, the fracture of DNA chain is induced under the intervention of type Ⅱ topoisomerase, the normal physiological function of DNA is influenced, to reach
Inhibit the effect of cancer cell multiplication.But in the clinical test to Mitonafide, it is found that it has maincenter mind very serious
Through system (CNS) toxicity, and its clinical activity is limited；Performance of the Amonafide in clinical test is also not fully up to expectations, draws
Play the side effects such as bone marrow suppression, vomiting, fash and moderate phlebitis.
The groups such as aminoguanidine, amido urea, amidoxime, different hydroxyl oxime, hydroxyl amino urea are widely studied for anti-tumor drug, this
A little compound structure features having the same (NHC (=X) NHOH, X=O, NH, S), this structure and similar structure are confirmed to be
The basic pharmacophore of anti-tumor activity medicine, derivative show extraordinary tumors inhibition activity.
Summary of the invention
The purpose of the present invention is accessing Methyl hydrazinecarbodithioate in naphthalimide active site, naphthoyl is extended with this
The type of imines drug, and obtain anti-tumor drug more efficient, that toxic side effect is small.Replaced by amido, amino condensation
Amido, Methyl hydrazinecarbodithioate are introduced on naphthalimide parent Deng reaction, a kind of nitrogenous sulphur substituent group of design synthesis
On the one hand naphthalimide derivative wishes the dissolubility for improving parent, on the other hand wish to change by introducing nitrogenous sulphur substituent group
Become the electronics distribution situation of parent, influence the mode of action with DNA, inhibits experiments have shown that it has tumor cell in vitro growth
Ability.
The technical proposal adopted by the invention to solve the above technical problems is that: the naphthalimide of a kind of nitrogenous sulphur substituent group
Object is closed, the compound has the structure of general formula Y:
In general formula Y: R be selected from containing heteroatomic hexatomic ring,-NHCH2CH2OH、-NHCH2CH2N
(CH3)2With-NHCH2CH2CH2CH3One of, the hetero atom be at least one of N, O, S atom, it is described contain hetero atom
Hexatomic ring in have at least one N atom, and R is connect by N atom with the parent nucleus in general formula T.
Further, described to be selected from containing heteroatomic hexatomic ringOne of.
Further, compound of the present invention is most preferably: N- (N '-dithiocarbonic acid methyl esters amido) -6- piperidyl -
1,8- naphthalimide.
Another technical object of the present invention is to provide the preparation method of the compound, comprising the following steps: bromo- with 4-
1,8 naphthalene anhydride (compound 1) is starting material, reacts to obtain corresponding intermediate 4- amido -1,8 naphthalene anhydride compound (change with corresponding amine
Close object 2), 4- amido -1,8 naphthalene anhydride compound and Methyl hydrazinecarbodithioate (compound 4) occur amino condensation reaction and generate
The compound.
Further, the Methyl hydrazinecarbodithioate is mixed by hydrazine hydrate (compound 3), carbon disulfide and iodomethane
It closes, is reacted and prepared with " one kettle way ".
Further, when 4- amido -1,8 naphthalene anhydride compound is reacted with Methyl hydrazinecarbodithioate in the preparation method
The solvent used is ethyl alcohol.
Synthetic route is as follows:
Another technical object of the present invention is to provide the compound to inhibit in growth of tumour cell drug in preparation
Using the tumour cell includes MCF-7 Breast Cancer Cell and human cervical carcinoma Hela cell.
Use tetrazolium reduction method to breast cancer respectively the naphthalimide compound of the nitrogenous sulphur substituent group of above-mentioned synthesis
MCF-7 cell and human cervical carcinoma Hela cell carry out the measurement of extracorporeal suppression tumor cell growth activity, and simultaneously more than progress
Measurement of the compound to the external inhibition cells growth activity of HL7702 Human normal hepatocyte.
The tetrazolium reduction method experimental procedure is as follows:
1, inoculating cell
MCF-7 Breast Cancer Cell, human cervical carcinoma Hela cell and HL7702 Human normal hepatocyte are collected into culture respectively
In base, cell is diluted into every hole and is inoculated with about 5000 cells, 200 μ LPBS are added in outermost, provide sufficient moisture and guarantee cell
Growing environment, culture plate is put to CO2It is incubated one to two days in incubator.
2, drug is added
When cell culture to logarithmic growth phase can dosing object, compound of the present invention is diluted respectively with culture medium
At 2 μM, 20 μM, 40 μM, 80 μM of four gradient concentrations, drug is added into cell, each drug concentration is arranged 4 multiple holes, subtracts
Small error, and control group is set, put back to CO2In incubator, cultivate for 24 hours.
3, the detection of survivaling cell number
20 μ L MTT are added in all Kong Zhongjun, are put into CO24h is incubated in incubator；200 μ are added in the solution discarded in hole
L DMSO, lysigenous crystallization.Each hole absorbance record is measured in microplate reader as a result, measured object is calculated according to the following formula out
IC50Value.
Beneficial effects of the present invention:
The present invention is prepared for a kind of nitrogenous sulphur substitution by accessing Methyl hydrazinecarbodithioate in naphthalimide active sites
The naphthalimide compound of base, such compound have the tumour cell of a variety of different tissue sources such as breast cancer and cervical carcinoma
Inhibit the activity of growth, and it is smaller to the inhibitory activity of human normal cell, inhibit to have in growth of tumour cell drug in preparation
It holds out broad prospects.
Specific embodiment
Following non-limiting embodiments can with a person of ordinary skill in the art will more fully understand the present invention, but not with
Any mode limits the present invention.
Embodiment 1
The synthesis of N- (N '-dithiocarbonic acid methyl esters amido) -6- piperidyl -1,8- naphthalimide (compound Y1):
(1) 4- piperidyl -1.8- naphthalene anhydride synthesizes
The 4- bromo- 1 of 5g (18.1mmol) is added in 100mL two-mouth bottle, 8 naphthalene anhydrides are added 40mL glycol monoethyl ether and stir
Dissolution is mixed, reaction system is added in 2mL (20.2mmol) piperidines, is heated to flowing back, stops reaction after magnetic agitation 4h, at room temperature
It is cooling, cold water is added in reaction solution, yellow mercury oxide is precipitated, dry after filtering, (eluent is with silica gel column chromatography purification
CH2Cl2) obtain yellow solid 4.77g, yield: 93.6%.
(2) synthesis of methyl dithiocarbazinate (compound 4)
6.6g (0.12mol) potassium hydroxide is added into 50mL three-necked flask, 8.0mL water and 6.7mL isopropanol, stirring make
Dissolution is slowly added to 5.7mL (0.12mol) hydrazine hydrate (80%) under the conditions of 0 DEG C of ice-water bath, then maintain the temperature at 10 DEG C with
Under, the carbon disulfide after freezing is slowly added dropwise, is added dropwise after about 1h, continues to stir 2h.Maintain the temperature at 10 DEG C hereinafter, in
6.2mL (0.12mol) iodomethane after cooling is added dropwise in 1.5h, continues to stir 1h after being added dropwise, a large amount of white precipitates is precipitated.
Reaction is stopped, being filtered, cold water is dry after washing.Crude product recrystallize with dichloromethane obtains white solid 9.4g, yield:
64.5%.
(3) N- (N '-dithiocarbonic acid methyl esters amido) -6- piperidyl -1,8- naphthalimide (compound Y1) synthesizes:
In 50mL two-mouth bottle, 0.5g (1.8mmol) 4- piperidyl -1.8- naphthalene anhydride, two sulphur of 0.22g (1.8mmol) is added
It for methyl hydrazinocarboxylate, is dissolved with 30mL ethyl alcohol, magnetic agitation, is warming up to back flow reaction 12h, stop reaction, reaction solution pours into
In cold water, yellow mercury oxide is precipitated, filtering is dry after washing, and (eluent is methylene chloride: ethyl acetate for silica gel column chromatography purification
=50:1), obtain yellow solid 0.34g (D2), yield: 49.6%.Fusing point: 165.1-166.5 DEG C.
+ESI MS(M+H):C19H19N3O2S2, calculated value: 385.0919, measured value: 585.1000.
1H NMR (500MHz, DMSO) δ 9.90 (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)
13C NMR(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:
With tetrazolium (microculture tetrozolium, MTT) reduction method to Hela cervical cancer cell, MCF-7
Breast cancer cell and HL7702 Human normal hepatocyte carry out external inhibition cells growth activity measurement.
The concrete operations of tetrazolium (MTT) reduction method are:
(1) inoculating cell, culture cell: when cell is in logarithmic growth phase, with trypsase by the thin of adherent growth
Born of the same parents digest, and are collected into the culture medium containing serum and diluting cells suspension concentration is about 4 × 105~6 × 105A/mL.
Above-mentioned culture solution is inoculated into sterile 96 orifice plate, 100 μ L cell suspensions (about 5000, every hole cell) is added in every hole, outermost
The PBS buffer solution that 200 μ L are added in every hole is enclosed, sufficient moisture environment is provided for cell growth ring.Culture plate after inoculation is put
To 37 DEG C, 5%CO2It is incubated in the incubator of environment for 24 hours, it can dosing object when cell is in logarithmic growth phase.
(2) drug is added: with culture medium by drug dilution at 2 μM, 20 μM, 40 μM, 80 μM of four gradient concentrations.It is each dense
4 multiple holes are arranged to reduce error in degree.100 μ L drug solutions (drug concentration dilutes one times at this time) is added in every hole, and control group is set
8~10 multiple holes are set, control group is not added drug and is replaced with culture medium.Culture plate is put back in incubator and is incubated, and drug effect is made
24h。
(3) it detects survivaling cell number: taking out culture plate, 20 μ L MTT are added in every hole.It puts back to and cultivates 4h in incubator.It is sucked out
Culture medium and MTT in all holes are careful not to siphon away the purple crystal of hole bottom.200 μ L DMSO dissolution first is added in every hole
Za crystallization, shakes 10 minutes on shaking table.96 orifice plates are put into microplate reader and measure each hole absorbance.Wavelength is 490nm,
570nm, 625nm.Calculate inhibitory rate of cell growth and IC50Value.
It is as follows to the external raw survey result of compound Y1:
1. compound Y1 of table is to Hela, the IC of MCF-7 and HL7702 cell strain50Value
Compound Y1 shows good Inhibit proliferaton effect to tumor cell line Hela, MCF-7 as can be seen from Table 1
Fruit, and it is smaller to the inhibitory activity of normal cell HL7702, has selectivity.
Claims (7)
1. the naphthalimide compound of a kind of nitrogenous sulphur substituent group, which is characterized in that the compound has the structure of general formula Y:
In general formula Y: R is selected fromOne of.
2. compound according to claim 1, it is characterised in that the compound is N- (N '-dithiocarbonic acid methyl esters amine
Base) -6- piperidyl -1,8- naphthalimide.
3. a kind of preparation method of compound described in claim 1, comprising the following steps: with 4- bromo- 1,8 naphthalene anhydrides are that starting is former
Material reacts to obtain corresponding intermediate 4- amido -1,8 naphthalene anhydride compound, 4- amido -1,8 naphthalene anhydride compound and diazanyl with corresponding amine
Dithiocarbonic acid methyl esters occurs amino condensation reaction and generates the compound.
4. the preparation method of compound according to claim 3, it is characterised in that the Methyl hydrazinecarbodithioate passes through
Hydrazine hydrate, carbon disulfide and iodomethane mixing, are reacted with " one kettle way " and are prepared.
5. the preparation method of compound according to claim 3, it is characterised in that 4- amido -1,8 naphthalene anhydride compound and diazanyl
The solvent that dithiocarbonic acid methyl esters uses when reacting is ethyl alcohol.
6. compound described in claim 1 inhibits the application in growth of tumour cell drug in preparation.
7. application according to claim 6, it is characterised in that the tumour cell includes MCF-7 Breast Cancer Cell and people
Cervical cancer Hela cells.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510474899.5A CN105130897B (en) | 2015-08-04 | 2015-08-04 | The naphthalimide compound of a kind of nitrogenous sulphur substituent group, preparation method and application |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510474899.5A CN105130897B (en) | 2015-08-04 | 2015-08-04 | The naphthalimide compound of a kind of nitrogenous sulphur substituent group, preparation method and application |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN105130897A CN105130897A (en) | 2015-12-09 |
| CN105130897B true CN105130897B (en) | 2019-04-05 |
Family
ID=54716532
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510474899.5A Expired - Fee Related CN105130897B (en) | 2015-08-04 | 2015-08-04 | The naphthalimide compound of a kind of nitrogenous sulphur substituent group, preparation method and application |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105130897B (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN107540608B (en) * | 2017-07-17 | 2021-10-19 | 大连理工大学 | 4-substituted naphthalimide compound and application thereof |
| CN109490291B (en) * | 2018-11-20 | 2021-05-11 | 上海应用技术大学 | Use of 1, 8-naphthalimide compound substituted by electron-withdrawing group as fluorine ion developing reagent |
| CN112500602B (en) * | 2020-12-04 | 2021-08-31 | 江西月池天然矿泉水有限公司 | High-molecular preparation for detecting heavy metals in outdoor water source and preparation method thereof |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ZA200607620B (en) * | 2004-05-05 | 2008-05-28 | Unibioscreen Sa | Naphthalimide derivatives, methods for their production and pharmaceutical composition therefrom |
| CN101633640B (en) * | 2009-08-18 | 2011-08-03 | 华东理工大学 | Naphthalimide derivative |
| CN103113300A (en) * | 2013-03-06 | 2013-05-22 | 广西中医药大学 | Preparation method and application of compound with antitumor activity |
| 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 |
| CN104311470B (en) * | 2014-09-10 | 2016-08-17 | 首都师范大学 | N-substituted indole-2-ketone-3-S-methyldi-thiocarbazate and its production and use |
-
2015
- 2015-08-04 CN CN201510474899.5A patent/CN105130897B/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| CN105130897A (en) | 2015-12-09 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN106432190B (en) | The naphthalimide compound of one kind aminopyrimidine containing 2-, preparation method and application | |
| CN105829312B (en) | A kind of N- benzyls tryptamines ketone derivatives and its preparation method and application | |
| CN105130897B (en) | The naphthalimide compound of a kind of nitrogenous sulphur substituent group, preparation method and application | |
| CN104072493B (en) | One class contains 2-mercaptobenzothiazole and the naphthalimide compound of triazole heterocycle, its preparation method and application thereof | |
| CN108358973A (en) | Naphthalimide tetravalence platinum-like compounds, preparation method and its application in preparation of anti-tumor drugs | |
| CN105130895B (en) | A kind of naphthalimide derivative, its preparation method and application | |
| CN104557887B (en) | 1,8-naphthalimide derivative as well as synthesis method and application thereof | |
| CN103450176B (en) | One class is containing 2-(4-aminophenyl) benzothiazole naphthalimide compound and application thereof | |
| CN111559991A (en) | Preparation method and application of naphthylamine compound and salt thereof | |
| CN101948467A (en) | Thiazoleamide compound and use thereof for the preparation of anti-malignant tumor medicines | |
| CN104558094A (en) | Sapogenin derivative, preparation method of derivative and application thereof in preparation of antitumor drugs | |
| CN105646546B (en) | The position 20 of camptothecins ester derivant and its antitumor application thereof of acid-sensitive type | |
| CN104059062B (en) | Fused ring compound and its application containing benzothiazole and the double heterocycles of triazole | |
| CN105130896B (en) | The naphthalimide derivative of a kind of substituent containing thiocarbamide, its preparation method and application | |
| CN109608371A (en) | O2Two alkoxide derivative of -4- (3- (4- sulfamic phenyl) urea) phenylazo, Preparation method and use | |
| CN110054622A (en) | Furodiazole derivative, preparation method and its application in medicine | |
| CN108715589A (en) | A kind of coumarin derivatives and its application as caspase-3 activator | |
| CN103012394B (en) | Rhodanine derivative and preparation method thereof | |
| CN106565657A (en) | Hesperetin cinnamate compound with anti-tumor activity and synthetic method thereof | |
| CN105418698A (en) | Amide ethyoxyl-beta-D-glucoside compound and preparation method and application thereof | |
| CN107353287B (en) | A kind of quinoxaline and heterocyclic fourth ketone compounds and its application in antitumor | |
| CN106543155B (en) | Chalcone and flavonoid derivative as aurora kinase inhibitor | |
| CN110590686B (en) | Azacyclosyl 1,2,3-triazole nucleoside compound and preparation method and application thereof | |
| CN108864080A (en) | Four cyclics alternatively adjusted under property estrogen receptor and its application | |
| CN102382064A (en) | Quinnazolidone derivative, preparation method for same and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20190405 Termination date: 20210804 |