CN104072478B - One 4, class naphthalene ring contains synthesis and the application thereof of the naphthalimide derivative of 1,2,3-triazole - Google Patents
One 4, class naphthalene ring contains synthesis and the application thereof of the naphthalimide derivative of 1,2,3-triazole Download PDFInfo
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
Abstract
The present invention relates to 4, a class naphthalene ring containing 1,2, the synthesis of the naphthalimide derivative of 3-triazole and application thereof, belong to organic synthesis field, and described derivative has the compound of general formula A structure, the preparation method of described derivative is with 4-bromo-1,8-naphthalene acid anhydride is raw material, through azide, with corresponding chain shape amine amide, amido propine reaction that is last and that be connected with cyclic amine is obtained, and described derivative is applied in inhibition tumor cell medicine.
Description
Technical field
The present invention relates to 4, a class naphthalene ring containing the synthesis of naphthalimide derivative of 1,2,3-triazole and application thereof, belong to organic synthesis field.
Background technology
It it is the focus of attention of chemistry and medicine, molecular biology cross discipline to the research of DNA intercalator. Intercalator is intercalated in the base pair of DNA, changes its conformation, causes DNA to untwist elongated, and then limits its copy table and reveal anti-tumor activity. Naphthalimide derivative makes the existing very big research progress of antitumor drug, such as famous naphthalimide lead drug Amonafide and Mitonafide, has entered clinical trial. But they show side effects such as causing bone marrow depression, vomiting, fash in clinical trial, and therefore the novel effective DNA target of design and synthesis has important using value to medicine. In addition, triazole derivative is widely used in the antibacterial field such as anticancer, it is possible to play antitumous effect as arimedex, angiogenesis inhibitor, enzyme inhibitors etc. Triazole pharmacophore is incorporated in the side chain of naphthalimide parent, will contribute to researching and developing the cancer therapy drug of new and effective low poison.
Summary of the invention
It is an object of the invention on 4, the naphthalene ring of naphthalimide, introduce the triazole pharmacophore having antitumour activity, to increase conjugation area, improve the biologic activity of molecule, thus improve antitumor performance.
4, naphthalene ring of the present invention is containing 1,2, the naphthalimide derivative of 3-triazole, it is introduce triazole pharmacophore on 4 of naphthalimide parent, design drug molecule by parent of the bromo-1,8-naphthalene acid anhydride of 4-through azide, amidation, and the steps such as ring, synthesize the naphthalimide derivative of a class containing triazole that tumor cell in vitro growth is had suppression power.
The present invention provides the naphthalimide derivative of 4, a class naphthalene ring containing 1,2,3-triazole, it is characterised in that: described derivative has the compound of general formula A structure:
In general formula A:
R is morpholinyl, parathiazan base, hexahydropyridine base, N-propargyl piperazinyl, methylpiperazine base or pyrrolidyl;
R' is N, N-dimethyl-ethylenediamine base, N, N-dimethylated propyl diethylenetriamine base, N, N-diethyl ethylenediamine base, N, N-diethyl propyldiamine base or n-butylamine-based.
R of the present invention is preferably morpholinyl, parathiazan base, hexahydropyridine base or N-propargyl piperazinyl.
R' of the present invention is preferably N, N-dimethyl-ethylenediamine base, N, N-dimethylated propyl diethylenetriamine base or n-butylamine-based.
It is a further object of the present invention to provide the preparation method of 4, above-mentioned naphthalene ring containing the naphthalimide derivative of 1,2,3-triazole, described preparation method taking the bromo-1,8-naphthalene acid anhydride of 4-as raw material, through azide, with corresponding chain shape amine amide, amido propine reaction that is last and that be connected with cyclic amine is obtained;
Described chain shape amine is N, N-dimethyl-ethylenediamine, N, N-dimethylated propyl diethylenetriamine, N, N-diethyl ethylenediamine, N, N-diethyl propyldiamine or n-Butyl Amine 99;
Described cyclic amine is morpholine, parathiazan, hexahydropyridine, N-propargyl piperazinyl, methylpiperazine or tetramethyleneimine.
Chain shape amine of the present invention is preferably N, N-dimethyl-ethylenediamine, N, N-dimethylated propyl diethylenetriamine or n-Butyl Amine 99.
Cyclic amine of the present invention is preferably morpholine, parathiazan, hexahydropyridine or N-propargyl piperazinyl.
Its reaction formula is as follows:
Compareing above-mentioned reaction formula, concrete preparation method is: taking bromo-1,8-naphthalene acid anhydride (a) of 4-as starting raw material, with NaN3DMF reacts to obtain formula compound (b); By formula compound (b) and chain shape amine R' in ethanol amidate action obtain formula compound (c); Formula compound (c) is obtained by reacting target product F with corresponding cyclic aminocarbonyl propine.
It is yet another object of the invention to provide 4, above-mentioned naphthalene ring containing the application in inhibition tumor cell medicine of the naphthalimide derivative of 1,2,3-triazole.
Tumour cell of the present invention is preferably mammary cancer MCF-7 cell, human cervical carcinoma Hela cell or liver cancer SMMC-7721 cell.
4, naphthalene ring of the present invention is containing 1,2, the naphthalimide derivative of 3-triazole, by tetrazolium reduction method, mammary cancer MCF-7 cell, human cervical carcinoma Hela cell and liver cancer SMMC-7721 cell are carried out the mensuration of extracorporeal suppression tumor cell growth activity, result shows, the multiple cancer cells such as mammary cancer, cervical cancer, liver cancer are had the effect of Developing restraint by this compounds.
By tetrazolium reduction method, mammary cancer MCF-7 cell, human cervical carcinoma Hela cell and liver cancer SMMC-7721 cell are inoculated in 96 well culture plates with 2000��3000/hole, gradient concentration liquid 100 �� L/ hole is added after cultivating 12h, to each tumor cell line, 6 multiple holes are set, separately establish acellular zeroing hole, if medicine has color to be done the acellular zeroing hole of relative medicine concentration; Tumour cell is at 37 DEG C, 5%CO2After cultivating 48h under condition, after adding the MTT liquid continuation cultivation 4h of 5mg/mL, add dimethyl sulfoxide (DMSO) (Dimethylsulfoxide or DMSO) dissolving crystallized, then survey OD by microplate reader570Value, utilizes bandit's formula improved method to calculate analyte to the IC of growth of cancer cells50Value.
Embodiment
Following non-limiting example can make the those of ordinary skill of this area more fully understand the present invention, but does not limit the present invention in any way.
Embodiment 1
The synthesis of N-(N', N'-dimethyl amido ethyl)-4-(4-morpholine methyl-[1,2,3]-triazole)-1,8-naphthalimide (F1)
1. in 50mL bottle with two necks, adding the bromo-1,8-naphthalene acid anhydride of 2.50g4-and 35mLDMF, stirred at ambient temperature is even, by 0.88gNaN3It is dissolved in 2mL water, drips reaction system, be heated to 40 DEG C of reaction 2h, pour in cold water after leaving standstill, take out filter, wash with water, dry, obtain compound (b) yellow-green colour solid 2.01g, product rate 93%.
2. in 50mL bottle with two necks, adding 1g compound (b) and 30mL dehydrated alcohol, stirred at ambient temperature is even, by 0.6mLN, N-dimethyl-ethylenediamine adds reaction system, it is heated to 50 DEG C of reaction 2h, pours in cold water after leaving standstill, take out filter, wash with water, drying, obtains compound (c) light yellow solid 1.17g, product rate 96%.
3., in 25mL bottle with two necks, 0.62g compound (c), 188 �� L3-morpholinyl propine, 4mL water and 4mL trimethyl carbinol mixed solution, 0.50gCuSO is added4��5H2O and 0.79gVcNa, the lower 60 DEG C of lucifuges reaction of nitrogen protection, TLC monitors to reacting completely, reaction solution CH2Cl2With water extraction, rotary evaporation organic layer, silica gel column chromatography separation (CH2Cl2: H2O=10:1), obtain target product F1 yellow solid 0.59g, product rate 68%. M.p.:134.8��135.5 DEG C.
1HNMR(400MHz,CDCl3) �� 8.75 8.68 (m, 2H), 8.26 (d, J=9.0Hz, 1H), 7.99 (s, 1H), 7.88 7.81 (m, 2H), 4.39 (t, J=6.7Hz, 2H), 3.86 (s, 2H), 3.77 (t, 4H), 2.76 (t, J=6.3Hz, 2H), 2.65 (t, 4H), 2.41 (s, 6H).
TOFMS (m/z): C23H27N6O3+, calculated value: 435.2145, measured value: 435.2129.
Embodiment 2
The synthesis of N-(N', N'-dimethyl amido ethyl)-4-(4-parathiazan methyl-[1,2,3]-triazole)-1,8-naphthalimide (F2)
Except replacing 3-morpholinyl propine with 3-parathiazan base propine, other synthesizing progress methods, with embodiment 1, obtain target product F2 light yellow solid, product rate 70%. M.p.:143.4��144.0 DEG C.
1HNMR(400MHz,CDCl3) �� 8.72 (d, J=7.2Hz, 2H), 8.27 (d, J=8.8Hz, 1H), 7.97 (s, 1H), 7.93 7.77 (m, 2H), 4.39 (t, J=6.3Hz, 2H), 3.89 (s, 2H), 2.90 (t, 4H), 2.75 (t, 2H), 2.74 (t, 4H), 2.42 (s, 6H).
TOFMS (m/z): C23H27N6O2S+, calculated value: 451.1916, measured value: 451.1918.
Embodiment 3
The synthesis of N-(N', N'-dimethyl amido ethyl)-4-(4-piperidine methyl-[1,2,3]-triazole)-1,8-naphthalimide (F3)
Except replacing 3-morpholinyl propine with 3-piperidines propine, other synthesizing progress methods, with embodiment 1, obtain target product F3 yellow solid, product rate 76%. M.p.:142.5��144.2 DEG C.
1HNMR(400MHz,CDCl3) �� 8.71 (d, J=7.7Hz, 2H), 8.30 (d, J=8.5Hz, 1H), 8.10 (s, 1H), 7.89 7.81 (m, 2H), 4.37 (t, J=6.9Hz, 2H), 3.89 (s, 2H), 2.70 (t, J=6.9Hz, 2H), 2.64 (t, 4H), 2.37 (s, 6H), 1.74 1.63 (m, 4H), 1.57 1.44 (m, 2H).
13CNMR(101MHz,CDCl3)��163.65,163.13,145.18,138.18,132.26,130.70,129.51,129.09,128.59,126.36,125.04,123.80,123.44,122.92,56.90,54.87,54.05,45.75,38.36,27.98.
TOFMS (m/z): C24H29N6O2+, calculated value: 433.2352, measured value: 433.2334.
Embodiment 4
The synthesis of N-(N', N'-dimethyl amido ethyl)-4-(4-propargyl piperazine methyl-[1,2,3]-triazole)-1,8-naphthalimide (F4)
Outside replacing 3-morpholinyl propine with N, N'-dipropargyl piperazine, other synthesizing progress methods, with embodiment 1, obtain target product F4 light yellow solid, product rate 66%. M.p:175.2��176.4 DEG C.
1HNMR(400MHz,CDCl3) �� 8.71 (d, J=7.5Hz, 2H), 8.27 (d, J=8.5Hz, 1H), 8.02 (s, 1H), 7.90 7.79 (m, 2H), 4.41 (t, J=6.4Hz, 2H), 3.91 (s, 2H), 3.33 (t, J=2.9Hz, 2H), 2.81 (s, 2H), 2.78 2.60 (m, 8H), 2.57 (s, 1H), 2.46 (s, 6H).
TOFMS (m/z): C26H30N7O2+, calculated value: 472.2461, measured value: 472.2477.
Embodiment 5
The synthesis of N-(N', N'-dimethyl amido propyl group)-4-(4-morpholine methyl-[1,2,3]-triazole)-1,8-naphthalimide (F5)
Outside replacing N, N-dimethyl-ethylenediamine with N, N-dimethylated propyl diethylenetriamine, other synthesizing progress methods, with embodiment 1, obtain target product F5 yellow solid, product rate 70%. M.p.:135.7��136.3 DEG C.
1HNMR(400MHz,CDCl3) �� 8.71 (d, J=7.7Hz, 2H), 8.27 (d, J=8.6Hz, 1H), 7.99 (s, 1H), 7.90 7.80 (m, 2H), 4.28 (t, 2H), 3.86 (s, 2H), 3.77 (t, 4H), 2.65 (t, 4H), 2.56 (t, J=7.0Hz, 2H), 2.35 (s, 6H), 2.09 1.94 (m, 2H).
TOFMS(m/z):C24H29N6O3+, calculated value: 449.2301, measured value: 449.2299.
Embodiment 6
The synthesis of N-normal-butyl-4-(4-morpholine methyl-[1,2,3]-triazole)-1,8-naphthalimide (F6)
Except replacing N with n-Butyl Amine 99, outside N-dimethyl-ethylenediamine, other synthesizing progress methods, with embodiment 1, obtain target product F6, white solid, product rate 72%. M.p.:157.1��157.9 DEG C.
1HNMR(400MHz,CDCl3) �� 8.71 (d, J=7.8Hz, 2H), 8.27 (d, J=8.6Hz, 1H), 8.07 (s, 1H), 7.90 7.79 (m, 2H), 4.22 (t, 2H), 3.91 (s, 2H), 3.81 (t, 4H), 2.70 (t, 4H), 1.86 1.68 (m, 2H), 1.54 1.38 (m, 2H), 1.00 (t, J=7.4Hz, 3H)
TOFMS(m/z):C23H26N5O3+, calculated value: 420.2036, measured value: 420.2017.
Application examples 1
The extracorporeal suppression tumor cell growth activity of target product F1��F6 that embodiment 1��6 is synthesized is measured:
With tetrazolium (microculturetetrozolium, MTT) reduction method is to three kinds of tumour cells, human breast cancer cell line Bcap-37, human cervical carcinoma cell Hela and human liver cancer cells Hep G2 carry out extracorporeal suppression tumor cell growth activity mensuration, and described MTT method of reducing is as follows:
One, inoculating cell
1, the monolayer cell of wall is pasted with tryptic digestion, by cell harvesting to containing in the substratum of serum.
2, count with tally.
3, by cell dilution, there are 2000��5000 cells in every hole, adds 100 �� L cell suspensions with adding sample device in the middle of flat 96 orifice plates in the ten each holes arranged.
4, PBS adds to around in each hole.
5, culture plate is put to 37 DEG C, 5%CO2Environment in temperature educate 12h, medicine can be added after waiting cell attachment.
Two, medicine is added
1, with substratum, cytotoxic drug being diluted to 100,20,4,0.8 ��Ms of four gradient concentrations, due to 100 �� L substratum original in hole, therefore after dosing, drug level by dilution one times, can be the concentration 50,10,2,0.4 ��Ms of test.
2, adding the substratum of 100 �� L Fresh in the 2nd row and the 11st 8 holes arranged, these cells are as blank.
3, adding the substratum containing cytotoxic drug in the cell of 3rd��10 row, each drug level only needs 6 multiple holes, and such A��D is capable can be used for the first medicine, and E��H is capable can be used for the 2nd kind of medicine.
4, culture plate is put back to 37 DEG C, 5%CO2Environment in, temperature educates 48h.
Three, the estimation of survivaling cell number
1, in the growth end of term, in 1st��11 all holes of row, 20 �� LMTT are respectively added.
2, at 37 DEG C, 5%CO2Environment in temperature educate 4h.
3, abandon the substratum in hole and MTT, in 1st��11 all holes of row, respectively add 200 �� LDMSO, collect together crystallization to dissolve the MTT-first of residual.
4, test: select to measure wavelength: 570nm, reference wavelength: 630nm, microplate reader measures each hole absorbancy record result, and goes out analyte to the inhibiting rate of growth of cancer cells by following formulae discovery: tumour growth inhibition rate=(control group OD value-treatment group OD value)/control group OD value �� 100%.
Analyte is to the IC of growth of cancer cells50Value (IC50The concentration of inhibitor when referring to suppressed half), the extracorporeal suppression tumor cell growth activity measurement result of target product F1��F6 is in table 1.
Table 1 target product F1��F6 is to the IC of tumour cell50Value
Conclusion: three kinds of tumour cells are had obvious Inhibit proliferaton effect by the target product F1��F6 of synthesis, target product F3 effect is best, to three kinds of tumour cell IC50Value can reach 0.89 ��M, 1.25 ��Ms and 0.73 ��M respectively, and the antitumous effect of MCF-7 is better than Hela and SMMC-7721 by other target product.
Claims (8)
1. 4, a class naphthalene ring is containing the naphthalimide derivative of 1,2,3-triazole, it is characterised in that: described derivative has the compound of general formula A structure:
In general formula A:
R is morpholinyl, parathiazan base, hexahydropyridine base, N-propargyl piperazinyl, methylpiperazine base or pyrrolidyl;
R' is N, N-dimethyl second diamino, N, N-dimethyl propylene diamino, N, N-diethyl second diamino, N, N-diethyl third diamino or positive fourth amino.
2. derivative according to claim 1, it is characterised in that: described R is morpholinyl, parathiazan base, hexahydropyridine base or N-propargyl piperazinyl.
3. derivative according to claim 2, it is characterised in that: described R' is N, N-dimethyl second diamino, N, N-dimethyl propylene diamino or positive fourth amino.
4. 4, naphthalene ring as described in claim 1,2 or 3 is containing 1,2, the preparation method of the naphthalimide derivative of 3-triazole, it is characterized in that: described preparation method is with 4-bromo-1,8-naphthalene acid anhydride is raw material, through azide, with corresponding chain shape amine amide, amino propine reaction that is last and that be connected with cyclic amine is obtained;
Described chain shape amine is N, N-dimethyl-ethylenediamine, N, N-dimethylated propyl diethylenetriamine, N, N-diethyl ethylenediamine, N, N-diethyl propyldiamine or n-Butyl Amine 99;
Described cyclic amine is morpholine, parathiazan, hexahydropyridine, N-propargyl piperazine, methylpiperazine or tetramethyleneimine.
5. preparation method according to claim 4, it is characterised in that: described chain shape amine is N, N-dimethyl-ethylenediamine, N, N-dimethylated propyl diethylenetriamine or n-Butyl Amine 99.
6. preparation method according to claim 5, it is characterised in that: described cyclic amine is morpholine, parathiazan, hexahydropyridine or N-propargyl piperazine.
7. 4, naphthalene ring as described in claim 1,2 or 3 containing the naphthalimide derivative of 1,2,3-triazole in the application prepared in inhibition tumor cell medicine.
8. application according to claim 7, it is characterised in that: described tumour cell is mammary cancer MCF-7 cell, human cervical carcinoma Hela cell or liver cancer SMMC-7721 cell.
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| 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 |
| CN105130895B (en) * | 2015-08-04 | 2017-11-10 | 大连理工大学 | A kind of naphthalimide derivative, its preparation method and application |
| KR20190092374A (en) * | 2016-10-03 | 2019-08-07 | 시질론 테라퓨틱스, 인크. | Compounds, Devices, and Uses thereof |
| CN107698571B (en) * | 2017-08-30 | 2020-07-14 | 大连理工大学 | Naphthalimide-coumarin DNA targeting double-intercalator, synthesis and application thereof |
| CN110194740B (en) * | 2019-07-08 | 2022-06-17 | 桂林医学院 | 4-tert-butyloxycarbonylpiperazine-1, 8-naphthalimide derivative and synthetic method and application thereof |
| CN110272388B (en) * | 2019-07-08 | 2022-06-17 | 桂林医学院 | 4-dithioformic acid piperazine-3-nitro-1, 8-naphthalimide derivative and synthesis method and application thereof |
| CN110317171B (en) * | 2019-07-08 | 2022-06-17 | 桂林医学院 | 4-dithioformic acid piperazine-1, 8-naphthalimide derivative and preparation method and application thereof |
| CN110283163B (en) * | 2019-07-08 | 2023-03-14 | 桂林医学院 | 4-tert-butyloxycarbonylpiperazine-3-nitro-1, 8-naphthalimide derivative and synthetic method and application thereof |
| CN110804039B (en) * | 2019-11-13 | 2020-08-14 | 大连理工大学 | Phthalimide-containing 1, 8-naphthalic anhydride derivatives, pharmaceutically acceptable salts thereof and application of anti-tumor drugs 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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