CN105130895B - A kind of naphthalimide derivative, its preparation method and application - Google Patents
A kind of naphthalimide derivative, its preparation method and application Download PDFInfo
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- CN105130895B CN105130895B CN201510470585.8A CN201510470585A CN105130895B CN 105130895 B CN105130895 B CN 105130895B CN 201510470585 A CN201510470585 A CN 201510470585A CN 105130895 B CN105130895 B CN 105130895B
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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 disclose a kind of naphthalimide derivative, and its preparation method and application, the derivative has a formula Y structure, wherein R be selected from contain heteroatomic hexatomic ring,‑NHCH2CH2OH、‑NHCH2CH2N(CH3)2And NHCH2CH2CH2CH3In one kind, the hetero atom is N, O, at least one of S atom, it is described contain in heteroatomic hexatomic ring have at least one N atoms, and R is connected by N atoms with the parent nucleus in formula T.The compound of the present invention is prepared by accessing methyl hydrazinocarboxylate in naphthalimide avtive spot, such compound has the activity for suppressing 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, suppress to have broad prospects in growth of tumour cell medicine preparing.
Description
Technical field
The present invention relates to a kind of antitumor naphthalimide derivative, belong to technical field of organic synthesis.
Background technology
Research finds that naphthalimide derivative has good active anticancer, wherein Amonafide (N- (beta-dimethyl ammonia
Base ethyl) -3- amido -1,8- naphthalimides) (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- nitros -
1,8- naphthalimides) (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 suppress the growth of tumour cell, and its mechanism of action is the alkali that intercalation enters DNA
Between base pair, the fracture of DNA is induced under the intervention of type Ⅱ topoisomerase, the normal physiological functions of DNA are influenceed, so as to reach
Suppress the effect of cancer cell multiplication.But in the clinical test to Mitonafide, it is found that it has very serious maincenter god
Through system (CNS) toxicity, and its clinical activity is limited；Performances 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 antineoplastic, this
A little compounds have identical architectural feature (NHC (=X) NHOH, X=O, NH, S), and this structure and similar structure are confirmed to be
The basic pharmacophore of anti-tumor activity medicine, its derivative show extraordinary tumors inhibition activity.
The content of the invention
The purpose of the present invention is to access methyl hydrazinocarboxylate in naphthalimide avtive spot, extends naphthalimide with this
The species of medicine, and obtain antineoplastic more efficient, that toxic side effect is small.Substituted by amido, amino condensation etc. reaction
Amido, methyl hydrazinocarboxylate are introduced on naphthalimide parent, design synthesizes a kind of naphthalimide derivative, on the one hand wishes to change
The dissolubility of kind parent, on the other hand wish to change the electronics distribution situation of parent by introducing methyl hydrazinocarboxylate substituent,
The mode of action with DNA is influenceed, experiment proves that it has rejection ability to tumor cell in vitro growth.
Technical scheme is used by the present invention solves above-mentioned technical problem：A kind of naphthalimide derivative, the derivative
Thing has formula Y structure：
In formula Y：R be selected from containing heteroatomic hexatomic ring,-NHCH2CH2OH、-NHCH2CH2N
(CH3)2With-NHCH2CH2CH2CH3In one kind, the hetero atom is N, O, at least one of S atom, described to contain hetero atom
Hexatomic ring in have at least one N atoms, and R is connected by N atoms with the parent nucleus in formula T.
Further, it is described to be selected from containing heteroatomic hexatomic ringIn one kind.
Further, derivative of the present invention is most preferably：N- (N '-methyl formate amido) -6- piperidyl -1,8- naphthalenes
Acid imide.
Another technical purpose of the present invention is the preparation method for providing the derivative, comprises the following steps：It is bromo- with 4-
1,8 naphthalene anhydride (compound 1) is initiation material, reacts to obtain corresponding intermediate 4- amido -1,8 naphthalene anhydrides compound (change with corresponding amine
Compound 2), 4- amido -1,8 naphthalene anhydride compounds occur to spread out described in amino condensation reaction generation with methyl hydrazinocarboxylate (compound 3)
Biology.
Further, the methyl hydrazinocarboxylate is prepared by hydrazine hydrate and dimethyl carbonate, using Zn as catalyst.
Further, used when 4- amido -1,8 naphthalene anhydride compounds are reacted with methyl hydrazinocarboxylate in the preparation method
Solvent is ethanol.
Synthetic route is as follows：
Another technical purpose of the present invention is in providing the derivative and preparing and suppress growth of tumour cell medicine
Using described tumour cell includes MCF-7 Breast Cancer Cell and human cervical carcinoma Hela cell.
By the naphthalimide derivative of above-mentioned synthesis respectively with tetrazolium reducing process to MCF-7 Breast Cancer Cell and Ren Gong
Neck cancer Hela cells carry out the measure of extracorporeal suppression tumor cell growth activity, and carry out above compound simultaneously to HL7702 people
The measure of the external suppression cells growth activity of normal liver cell.
The tetrazolium reducing process experimental procedure is as follows：
1st, inoculating cell
MCF-7 Breast Cancer Cell, human cervical carcinoma Hela cell and HL7702 Human normal hepatocytes are collected into culture respectively
In base, cell is diluted about 5000 cells are inoculated with per hole, outermost adds 200 μ LPBS, there is provided sufficient moisture ensures cell
Growing environment, culture plate is put to CO2Incubated one to two days in incubator.
2nd, medicine is added
When cell culture to exponential phase can dosing thing, compound of the present invention is diluted respectively with culture medium
Into 2 μM, 20 μM, 40 μM, 80 μM of four gradient concentrations, medicine is added into cell, each drug concentration sets 4 multiple holes, subtracted
Small error, and control group is set, put back to CO2In incubator, 24h is cultivated.
3rd, the detection of survivaling cell number
20 μ L MTT are added in all Kong Zhongjun, are put into CO24h is incubated in incubator；The solution discarded in hole adds 200 μ
L DMSO, lysigenous crystallization.Each hole absorbance record result is determined on ELIASA, measured object is calculated by following equation
IC50Value.
Beneficial effects of the present invention：
The present invention is taken by being prepared for one kind in naphthalimide active sites access methyl hydrazinocarboxylate containing methyl hydrazinocarboxylate
Dai Ji naphthalimide compound, such compound have to the tumour cell of a variety of different tissue sources such as breast cancer and cervical carcinoma
There is the activity for suppressing to grow, and it is smaller to the inhibitory activity of human normal cell, in suppression growth of tumour cell medicine is prepared
Have broad prospects.
Embodiment
Following non-limiting examples can make one of ordinary skill in the art be more fully understood the present invention, but not with
Any mode limits the present invention.
Embodiment 1
N- (N '-methyl formate amido) -6- piperidyl -1,8- naphthalimides (compound Y1) synthesize：
(1) 4- piperidyls -1.8- naphthalene anhydrides (compound 2) synthesize
5g (18.1mmol) 4- bromo- 1 is added in 100mL two-mouth bottles, 8 naphthalene anhydrides, 40mL glycol monoethyl ethers is added and stirs
Dissolving is mixed, 2mL (20.2mmol) piperidines is added into reaction system, is heated to flowing back, stops reaction after magnetic agitation 4h, at room temperature
Cooling, cold water is added in reaction solution, separate out yellow mercury oxide, dried after filtering, purify that (eluent is with silica gel column chromatography
CH2Cl2) obtain yellow solid 4.77g, yield：93.6%.
(2) synthesis of methyl hydrazinocarboxylate (compound 3)
In 25mL bottle with two necks, 3mL (35.6mmol) dimethyl carbonates and 0.85mL (17.5mmol) hydrazine hydrate are added
(80%) 0.2g zinc powders, are added as catalyst, temperature rising reflux 5h, are filtered off while hot except zinc powder, air-distillation goes out excessive carbon
Dimethyl phthalate, remaining liq cold water cooling and standings, separate out acicular crystal, dry white solid 1.11g, yield 70.6%.
(3) compound Y1 synthesis：
In 50mL two-mouth bottles, 0.5g (1.8moml) 4- piperidyl -1.8- naphthalene anhydrides (compound 2), 0.16g are added
(1.8mmol) methyl hydrazinocarboxylate, 30mL ethanol, magnetic agitation, back flow reaction 8h is warming up to, stops reaction, cold water is added
In reaction solution, orange-yellow precipitation is separated out, is filtered, is dried after washing, (eluent is dichloromethane for silica gel column chromatography purification:Acetic acid
Ethyl ester=10:1) yellow solid 0.33g (D1), yield, are obtained：52.3%.Fusing point：158.5-159.6℃.
+ESI MS(M+H):C19H19N3O4, calculated value：353.1376, measured value：543.1439.
1H NMR (500MHz, DMSO) δ 9.90 (d, J=206.2Hz, 1H), 8.51 (d, J=7.1Hz, 1H), 8.42 (t,
J=8.5Hz, 2H), 7.83 (t, J=7.8Hz, 1H), 7.31 (d, J=8.2Hz, 1H), 3.64 (d, J=88.8Hz, 3H),
3.21 (s, 4H), 1.82 (s, 4H), 1.66 (d, J=4.9Hz, 2H)
13C NMR(126MHz,DMSO)δ162.19(s,1H),161.56(s,1H),157.37(s,1H),155.70(s,
1H), 133.06 (s, 3H), 131.45 (d, J=16.1Hz, 6H), 129.10 (s, 1H), 125.97 (s, 3H), 125.52 (s,
2H),122.09(s,2H),115.08(s,3H),114.16(s,1H),53.91(s,7H),52.47(s,3H),25.62(s,
7H),23.78(s,3H).
Embodiment 2
Extracorporeal suppression tumor cell and normal cell growth determination of activity：
With tetrazolium (microculture tetrozolium, MTT) reducing process to Hela cervical cancer cells, MCF-7
Breast cancer cell and HL7702 Human normal hepatocytes carry out the external cells growth activity that suppresses and determined.
The concrete operations of tetrazolium (MTT) reducing process are：
(1) inoculating cell, culture cell：When cell is in exponential 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 × 105Individual/mL.
Above-mentioned nutrient solution is inoculated into sterile 96 orifice plate, 100 μ L cell suspensions (per about 5000, hole cell), outermost are added per hole
The PBS that every hole adds 200 μ L is enclosed, the moisture environment of abundance is provided for cell growth ring.Culture plate after inoculation is put
To 37 DEG C, 5%CO224h is incubated in the incubator of environment, can dosing thing when cell is in exponential phase.
(2) medicine is added：With culture medium by drug dilution into 2 μM, 20 μM, 40 μM, 80 μM of four gradient concentrations.It is each dense
Degree sets 4 multiple holes to reduce error.100 μ L drug solutions (now drug concentration dilutes one times) are added per hole, control group is set
8~10 multiple holes are put, control group is not added with medicine and replaced with culture medium.Culture plate is put back in incubator and incubated, and acts on medicine
24h。
(3) survivaling cell number is detected：Culture plate is taken out, 20 μ L MTT are added per hole.Put back to and 4h is cultivated in incubator.Suction out
Culture medium and MTT in all holes, it is careful not to siphon away the purple crystal in bottom hole portion.200 μ L DMSO dissolving first is added in per hole
Za crystallizes, and is shaken 10 minutes on shaking table.96 orifice plates are put into ELIASA and determine each hole absorbance.Wavelength is 490nm,
570nm, 625nm.Calculate inhibitory rate of cell growth and IC50Value.
It is as follows to compound Y1 external raw survey result：
The compound Y1 of table 1. is to Hela, the IC of MCF-7 and HL7702 cell lines50Value
Compound Y1 shows good Inhibit proliferaton effect to tumor cell line Hela, MCF-7 as can be seen from Table 1
Fruit, and its inhibitory activity to normal cell HL7702 is smaller, has selectivity.
Claims (6)
1. a kind of naphthalimide derivative, it is characterised in that the derivative has formula Y structure：
In formula Y：R is selected from containing heteroatomic-
NHCH2CH2OH、-NHCH2CH2N(CH3)2With-NHCH2CH2CH2CH3In one kind.
2. derivative according to claim 1, it is characterised in that the derivative is the change shown in following chemical structural formula
Compound：
3. the preparation method of derivative, comprises the following steps described in a kind of claim 1：It is starting with bromo- 1,8 naphthalene anhydrides (1) of 4-
Raw material, react to obtain corresponding intermediate 4- amido -1,8 naphthalene anhydride compounds (2), 4- amido -1,8 naphthalene anhydride compounds with corresponding amine
(2) amino condensation reaction occurs with methyl hydrazinocarboxylate (3) and generates the derivative (Y)：
4. the preparation method of derivative according to claim 3, it is characterised in that the methyl hydrazinocarboxylate (3) passes through hydration
Hydrazine is prepared with dimethyl carbonate.
5. the preparation method of derivative according to claim 3, it is characterised in that 4- amido -1,8 naphthalene anhydride compounds (2) and hydrazine
The solvent that base methyl formate (3) uses when reacting is ethanol.
6. derivative described in claim 1 is preparing the application in suppressing growth of tumour cell medicine, the choosing of described tumour cell
From MCF-7 Breast Cancer Cell and human cervical carcinoma Hela cell.
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| CN107540608B (en) * | 2017-07-17 | 2021-10-19 | 大连理工大学 | 4-substituted naphthalimide compound and application thereof |
| CN109180535A (en) * | 2018-09-27 | 2019-01-11 | 江苏师范大学 | A kind of synthetic method of 2- chloroethyl hydrazono- methyl formate |
| CN110947426A (en) * | 2018-09-27 | 2020-04-03 | 江苏师范大学 | Catalyst for synthesizing 2-chloroethyl hydrazono methyl formate |
| 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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| CN101284827B (en) * | 2008-06-06 | 2010-12-08 | 大连理工大学 | Antineoplastic compounds containing triazole ring naphthoyl imines and method for preparing same |
| CN101323591A (en) * | 2008-07-23 | 2008-12-17 | 大连理工大学 | 5- or 6-substited naphthoyl imines compounds and antineoplastic application |
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