CN106279106B - The 1,8- naphthalene anhydrides analog derivative of a kind of side chain isoquinoline-containing and its synthesis and application - Google Patents
The 1,8- naphthalene anhydrides analog derivative of a kind of side chain isoquinoline-containing and its synthesis and application Download PDFInfo
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Abstract
The invention discloses 1,8- naphthalene anhydrides analog derivative, preparation method and the applications of a kind of side chain isoquinoline-containing, belong to biological organic synthesis field, the synthesis and application of 1, the 8- naphthalene anhydride analog derivatives of present invention one kind side chain isoquinoline-containing.The 1 of side chain isoquinoline-containing of the present invention, 8- naphthalene anhydride analog derivatives, it is to introduce 1,2,3 by alkyl chain in naphthalimide one end, 4- tetrahydroisoquinolines are as pharmacophore, different cyclic amine side chains is introduced in the naphthalimide other end, it is therefore an objective to the isoquinolin pharmacophore for having active anticancer is introduced on naphthalimide, to increase conjugate area, high molecular biological activity is put forward, to increase antitumous effect.
Description
Technical field
The present invention relates to the conjunctions of the 1,8- naphthalene anhydride analog derivatives of a kind of side chain isoquinoline-containing in biological organic synthesis field
At and application.
Background technology
DNA target is to the research hotspot that antitumor drug is always medical chemistry and molecular biology.DNA intercalators can be embedding
Enter DNA base centering, change its conformation, DNA chain is caused to be untwisted growth, change DNA replication dna process, shows significant antitumor
Activity.Naphthalimide analog derivative is very classical DNA intercalator parents, and the three-membered ring rigid structure with plane is easy to
Modification.Classical naphthalimide DNA intercalators have Amonafide and mitonafide, and wherein mitonafide is a kind of 3- nitros list
Naphthalimide analog derivative, mechanism of action is similar to Amonafide, but Amonafide and mitonafide are more toxic, and clinic is answered
With limited.Still with the research that deepens continuously to naphthalimide analog derivative, either the design synthesis of targeted drug molecule
Such antifungal, antineoplastic action Mechanism Study suffer from prodigious progress.
Invention content
The present invention provides the synthesis and application of the 1,8- naphthalene anhydride analog derivatives of a kind of side chain isoquinoline-containing.Purpose is in naphthoyl
Being introduced on imines has the isoquinolin effect group of active anticancer, to increase conjugate area, high molecular biological activity is put forward, to increase
Antitumous effect.
1, the 8- naphthalene anhydride analog derivatives of side chain isoquinoline-containing of the present invention, (1) passes through alkyl in naphthalimide one end
Chain introduces 1,2,3,4- tetrahydroisoquinolines as pharmacophore, enhances drug effect；(2) different cyclammonium is introduced in the naphthalimide other end
Side chain has synthesized 1, the 8- naphthalene anhydride analog derivatives for a kind of side chain isoquinoline-containing for having inhibiting effect to tumor cell in vitro growth.
Technical solution is used by the present invention solves above-mentioned technical problem：The 1,8- naphthalene anhydride classes of a kind of side chain isoquinoline-containing
Derivative, chemical molecular general structure are as follows：
In general formula A:
R is selected from morpholinyl, butylamine base, thio-morpholinyl, dimethylamino, pyrrolidinyl, the hexahydropyrrolo base of N substitutions,
The dimethylamino is N, N- dimethyl-ethylenediamines base, N, N- dimethylated propyl diethylenetriamine bases.
The present invention provides the preparation method of 1, the 8- naphthalene anhydride analog derivatives of above-mentioned side chain isoquinoline-containing, with bromo- 1, the 8- naphthalenes of 4-
Acid anhydride is starting material, and in naphthalene anhydride, 4 introduce different cyclammonium and fatty amine from R ' substitution reactions, and synthetic intermediate 4- replaces -1,
8- naphthalene anhydrides, then synthetic intermediate N- (3 '-hydroxyl-propyl) -4-R-1 is reacted with n-propanolamine, tribromide is added in 8- naphthalene anhydrides later
Hydroxyl bromination is generated N- (3 '-bromo- propyl) -4- piperidyl -1,8- naphthalene anhydrides by phosphorus, and finally with 1,2,3,4- tetrahydroisoquinolines are anti-
Target compound should be generated；
The R ' is selected from morpholine, butylamine, thiomorpholine, dimethylamine, pyrrolidines, hexahydropyrrolo.
The synthetic route of the 1,8- naphthalene anhydride analog derivatives of above-mentioned side chain isoquinoline-containing is as follows：
The present invention provides 1,8- naphthalene anhydrides analog derivative the answering in inhibiting tumour cell drug of above-mentioned side chain isoquinoline-containing
With.The tumour is MCF-7 Breast Cancer Cell and Human Gastric Cancer cell BCG-823 cells.
1,8- naphthalene anhydrides analog derivative with the side chain isoquinoline-containing of above-mentioned synthesis is thin to breast cancer MCF-7 with MTT reduction methods
Born of the same parents, people palace BGC-823 Cells carry out the measurement of extracorporeal suppression tumor cell growth activity, the results showed that, such compound
Have the effect of inhibiting growth to cancer cells such as gastric cancer, breast cancer.
MCF-7 Breast Cancer Cell, human cervical carcinoma Hela cell are connect with 4000-5000/hole with tetrazolium reduction method
100 holes μ L/ of gradient concentration liquid are added in kind after in 96 well culture plates, cultivating 12-16h, to each tumor cell line, setting 6
A multiple holes separately set acellular zeroing hole；Tumour cell is in 37 DEG C, 5%CO2Under the conditions of cultivate for 24 hours after, add the MTT liquid of 5mg/mL
Continue after cultivating 4h, addition DMSO is dissolving crystallized, then surveys OD with microplate reader570Value calculates measured object pair using bandit's formula improved method
The IC of growth of cancer cells50Value.
Description of the drawings
Fig. 1 is the front and back ultraviolet spectrogram of compound D1 and CT-DNA effect, R values are followed successively by 1.0,0.8,0.6,0.4,
0.2,0.1；
Fig. 2 is the front and back ultraviolet spectrogram of compound D2 and CT-DNA effect, R values are followed successively by 1.0,0.8,0.6,0.4,
0.2、0.1。
Specific implementation mode
Below by embodiment, the present invention is further illustrated.
Embodiment 1
N- [3 '-(- 2 (1H)-yl of 3 ", 4 "-bis- hydrogen isoquinolines)-propyl] -4- piperidyl -1,8- naphthalene anhydrides synthesize：
(1) synthesis of 1 4-R base -1.8- naphthalene anhydrides of intermediate：
The synthesis of intermediate 4- piperidyl -1,8- naphthalene anhydrides：
It takes bromo- 1, the 8- naphthalene anhydrides of 2.77g (10mmol) 4- to be placed in the neck round bottom flask of 100mL, 40mL ethylene glycol is added
Monomethyl ether is added 0.92mL (10mmol) piperidines, is warming up to 125 DEG C, stirs and flow back 3 hours as solvent, room temperature cooling half
Hour, it pours into and precipitation is precipitated in 200ml water, filter and dry, obtain 2.6g products, yield 92.53%.
(2) synthesis of intermediate N (3 '-hydroxyl-propyl) -4-R base -1,8- naphthalene anhydrides：
The synthesis of intermediate N (3 '-hydroxyl-propyl) -4- piperidyl -1,8- naphthalene anhydrides：
It takes 2.5g (8.8mmol) 4- piperidyl -1,8- naphthalene anhydrides to be placed in 100mL neck round bottom flask, it is anhydrous that 30mL is added
Ethyl alcohol stirs and is added n-propanolamine 0.74ml (9.68mmol) as solvent, and temperature rising reflux 3 hours is cooled to room temperature, pours into
In 150ml water, precipitation is precipitated, filters and dries, obtain 2.3g products, yield 77.18%.
(3) synthesis of intermediate N (3 '-bromo- propyl) -4- piperidyl -1,8- naphthalene anhydrides：
The synthesis of intermediate N (3 '-bromo- propyl) -4- piperidyl -1,8- naphthalene anhydrides：
2.2g (6.5mmol) N- (3 '-hydroxyl-propyl) -4- piperidyl -1,8- naphthalene anhydrides are taken to be placed in 100mL double-necked round bottoms burning
In bottle, 30mL ethyl acetate is added under condition of ice bath as solvent, stirs and is slowly dropped into phosphorus tribromide 0.61mL
Half an hour is stirred at room temperature after all dripping in (6.5mmol), is warming up to 77 DEG C and reacts 3 hours, is cooled to room temperature, pours into
In 150mL water, yellow mercury oxide is precipitated, filters and dries, use CH2Cl2Column chromatography obtains 2.1g products, yield 80.77%.
(4) final product D1N- [3 '-(- 2 (1H)-yl of 3 ", 4 "-bis- hydrogen isoquinolines)-propyl] -4- piperidyl -1,8- naphthalene anhydrides
Synthesis：
0.4g (1mmol) N- (3 '-bromo- propyl) -4- piperidyl -1,8- naphthalene anhydrides are added in 50mL neck round bottom flask,
15mL is added and removes water processed DMF, stirs and 1,2,3,4- tetrahydroisoquinolines of 0.125mL (1mmol), catalytic amount is added
Potassium carbonate, be warming up to 148 DEG C, 3 hours postcoolings of reaction are poured into 50mL ice water to room temperature, orange precipitation are precipitated, and filter,
Washing, vacuum drying, crude product silica gel column chromatography (eluent：CH2Cl2:MeOH=30:1) product 0.32g, yield, are obtained
70.56%.Fusing point：124.5-125.2℃.
+ESI MS(M+H):C29H31N3O2, calculated value：453.5753, measured value：453.2458.
1H NMR (400MHz, CDCl3) δ 8.54 (dd, J=7.3,1.0Hz, 1H), 8.47 (d, J=8.1Hz, 1H),
8.36 (dd, J=8.4,1.0Hz, 1H), 7.64 (dd, J=8.3,7.4Hz, 1H), 7.14 (d, J=8.1Hz, 1H), 7.08-
6.93 (m, 4H), 3.28-3.14 (m, 4H), 2.83 (t, J=5.6Hz, 2H), 2.78-2.64 (m, 4H), 2.05 (dt, J=
14.5,7.3Hz, 2H), 1.98-1.76 (m, 6H), 1.72 (d, J=5.3Hz, 2H), 1.25 (s, 2H)
13C NMR(126MHz,CDCl3)δ164.66,164.18,157.22,134.78,134.30,132.58,
130.93,130.52,129.92,128.49,126.55,126.25,125.94,125.43,125.30,123.16,116.01,
114.68,55.96,55.88,54.54,50.57,38.74,28.96,26.24,25.39,24.36.
Embodiment 2
N- [3 '-(- 2 (1H)-yl of 3 ", 4 "-bis- hydrogen isoquinolines)-propyl] -4- thio-morpholinyl -1,8- naphthalene anhydrides synthesize：
(1) synthesis of intermediate 4- thio-morpholinyls -1,8- naphthalene anhydrides：
1.01mL (10mmol) thiomorpholine is added and substitutes piperidines, remaining building-up process is same as Example 1, obtains 2.7g
Product, yield 90.30%.
(2) synthesis of intermediate N (3 '-hydroxyl-propyl) -4- thio-morpholinyl -1,8- naphthalene anhydrides：
It takes 2.5g (8.4mmol) 4- thio-morpholinyl -1,8- naphthalene anhydrides to replace 4- piperidyl -1,8- naphthalene anhydrides, 0.7mL is added
(9.24mmol) n-propanolamine, remaining building-up process obtain 2.5g products, yield 83.61% with embodiment 1.
(3) synthesis of intermediate N (3 '-bromo- propyl) -4- thio-morpholinyl -1,8- naphthalene anhydrides：
2.2g (6.2mmol) N- (3 '-hydroxyl-propyl) -4- thio-morpholinyl -1,8- naphthalene anhydrides are taken to replace N- (3 '-hydroxyls -
Propyl) -4- piperidyl -1,8- naphthalene anhydrides, 0.58mL (6.2mmol) phosphorus tribromide is added, remaining building-up process is obtained with embodiment 1
To 2.1g products, yield 77.78%.
(4) final product D2N- [3 '-(- 2 (1H)-yl of 3 ", 4 "-bis- hydrogen isoquinolines)-propyl] -4- thio-morpholinyls -1,8-
The synthesis of naphthalene anhydride：
0.42g (1mmol) N- (3 '-bromo- propyl) -4- thio-morpholinyl -1,8- naphthalene anhydrides replacement addition N- is added, and (3 '-is bromo-
Propyl) -4- piperidyl -1,8- naphthalene anhydrides, for remaining building-up process with embodiment 1, silica gel column chromatography eluant, eluent is CH2Cl2:MeOH=
25:1, obtain product 0.3g, yield 63.69%.Fusing point：142.4-143.2℃.
+ESI MS(M+H):C28H29N3O2S, calculated value：471.6138, measured value：471.2056.
1H NMR (400MHz, CDCl3) δ 8.57 (dd, J=7.3,1.0Hz, 1H), 8.50 (d, J=8.0Hz, 1H),
8.34 (dd, J=8.5,1.1Hz, 1H), 7.69 (dd, J=8.4,7.4Hz, 1H), 7.21 (d, J=8.1Hz, 1H), 7.06
(dt, J=8.2,4.2Hz, 2H), 6.99 (dt, J=9.1,4.3Hz, 2H), 4.31-4.25 (m, 2H), 3.67 (s, 2H),
3.56-3.45 (m, 4H), 3.01-2.94 (m, 4H), 2.76 (ddd, J=23.0,15.8,6.3Hz, 6H), 2.13-2.02 (m,
2H).
13C NMR(126MHz,CDCl3)δ163.46,163.00,155.58,133.15,131.31,130.06,
128.84,128.79,127.44,125.51,125.49,124.97,124.87,124.45,122.30,116.28,114.89,
54.83,54.78,54.53,49.50,37.77,27.79,27.14,24.21.
Embodiment 3
N- [3 '-(- 2 (1H)-yl of 3 ", 4 "-bis- hydrogen isoquinolines)-propyl] -4- morpholinyl -1,8- naphthalene anhydrides synthesize：
(1) synthesis of intermediate 4- morpholinyls -1,8- naphthalene anhydrides：
0.87mL (10mmol) morpholine is added and substitutes piperidines, remaining building-up process is same as Example 1, obtains 2.5g productions
Object, yield 88.34%.
(2) synthesis of intermediate N (3 '-hydroxyl-propyl) -4- morpholinyl -1,8- naphthalene anhydrides：
It takes 2.4g (8.5mmol) 4- morpholinyl -1,8- naphthalene anhydrides to replace 4- piperidyl -1,8- naphthalene anhydrides, 0.71mL is added
(9.35mmol) n-propanolamine, remaining building-up process obtain 2.3g products, yield 79.58% with embodiment 1.
(3) synthesis of intermediate N (3 '-bromo- propyl) -4- morpholinyl -1,8- naphthalene anhydrides：
2.2g (6.5mmol) N- (3 '-hydroxyl-propyl) -4- morpholinyl -1,8- naphthalene anhydrides are taken to replace N- (3 '-hydroxyls-the third
Base) -4- piperidyl -1,8- naphthalene anhydrides, 0.61mL (6.5mmol) phosphorus tribromide is added, remaining building-up process is obtained with embodiment 1
2.0g products, yield 76.92%.
(4) final product D3N- [3 '-(- 2 (1H)-yl of 3 ", 4 "-bis- hydrogen isoquinolines)-propyl] -4- morpholinyl -1,8- naphthalene anhydrides
Synthesis：
0.4g (1mmol) N- (3 '-bromo- propyl) -4- morpholinyl -1,8- naphthalene anhydrides are added to replace that N- (3 '-bromo- third is added
Base) -4- piperidyl -1,8- naphthalene anhydrides, for remaining building-up process with embodiment 1, silica gel column chromatography eluant, eluent is CH2Cl2:MeOH=25:
1, obtain product 0.27g, yield 59.34%.Fusing point：127.5-128.6℃.
+ESI MS(M+H):C28H29N3O3, calculated value：455.5482, measured value：455.2293.
1H NMR (400MHz, CDCl3) δ 8.57 (dd, J=7.3,1.1Hz, 1H), 8.51 (d, J=8.0Hz, 1H),
8.39 (dd, J=8.5,1.1Hz, 1H), 7.68 (dd, J=8.4,7.3Hz, 1H), 7.20 (d, J=8.1Hz, 1H), 7.08-
7.02(m,2H),7.02–6.94(m,2H),4.32–4.24(m,2H),4.05–3.99(m,4H),3.64(s,2H),3.30–
3.21 (m, 4H), 2.81 (t, J=5.7Hz, 2H), 2.77-2.66 (m, 4H), 2.10-2.01 (m, 2H)
13C NMR(126MHz,CDCl3)δ164.49,164.04,155.54,134.11,133.97,132.45,
131.11,129.99,129.85,128.49,126.57,126.11,125.79,125.58,123.32,117.19,114.92,
66.98,55.51,55.47,53.44,50.31,38.72,28.46,25.08.
Embodiment 4
N- [3 '-(- 2 (1H)-yl of 3 ", 4 "-bis- hydrogen isoquinolines)-propyl] -4- pyrrolidinyl -1,8- naphthalene anhydrides synthesize：
(1) synthesis of intermediate 4- pyrrolidinyls -1,8- naphthalene anhydrides：
0.82mL (10mmol) pyrrolidines is added and substitutes piperidines, remaining building-up process is same as Example 1, obtains 2.4g productions
Object, yield 89.89%.
(2) synthesis of intermediate N (3 '-hydroxyl-propyl) -4- pyrrolidinyl -1,8- naphthalene anhydrides：
It takes 2.2g (8.2mmol) 4- pyrrolidinyl -1,8- naphthalene anhydrides to replace 4- piperidyl -1,8- naphthalene anhydrides, 0.69mL is added
(9.02mmol) n-propanolamine, remaining building-up process obtain 2.4g products, yield 90.23% with embodiment 1.
(3) synthesis of intermediate N (3 '-bromo- propyl) -4- pyrrolidinyl -1,8- naphthalene anhydrides：
2.2g (6.8mmol) N- (3 '-hydroxyl-propyl) -4- pyrrolidinyl -1,8- naphthalene anhydrides are taken to replace N- (3 '-hydroxyls-the third
Base) -4- piperidyl -1,8- naphthalene anhydrides, 0.64mL (6.8mmol) phosphorus tribromide is added, remaining building-up process is obtained with embodiment 1
2.0g products, yield 80.00%.
(4) final product D4N- [3 '-(- 2 (1H)-yl of 3 ", 4 "-bis- hydrogen isoquinolines)-propyl] -4- pyrrolidinyl -1,8- naphthalenes
The synthesis of acid anhydride：
0.39g (1mmol) N- (3 '-bromo- propyl) -4- pyrrolidinyl -1,8- naphthalene anhydrides are added to replace that N- (3 '-bromo- third is added
Base) -4- piperidyl -1,8- naphthalene anhydrides, for remaining building-up process with embodiment 1, silica gel column chromatography eluant, eluent is CH2Cl2:MeOH=30:
1, obtain product 0.28g, yield 63.71%.Fusing point：142.7-143.2℃.
+ESI MS(M+H):C28H29N3O2, calculated value：439.5488, measured value：439.2329.
1H NMR (400MHz, CDCl3) δ 8.56 (dd, J=7.9,3.1Hz, 2H), 8.41 (d, J=8.6Hz, 1H),
7.54-7.48 (m, 1H), 7.13-6.97 (m, 4H), 6.80 (d, J=8.7Hz, 1H), 4.32-4.23 (m, 2H), 3.77 (dd, J
=12.9,6.4Hz, 6H), 2.88 (dd, J=15.9,4.7Hz, 4H), 2.81-2.72 (m, 2H), 2.16-2.06 (m, 6H)
13C NMR(126MHz,CDCl3)δ164.92,164.11,152.62,133.97,133.37,131.91,
131.17,130.99,128.53,126.62,126.13,125.62,122.97,122.55,122.50,110.64,108.49,
55.53,55.49,53.15,50.32,38.48,28.44,26.07,25.19.
Characterization 1：Ultra-violet absorption spectrum
This experiment is tested all compounds of D series, and table 1 is the ultraviolet spectrum data of the series compound.
1. compound D1-4 ultraviolet-visible absorption spectroscopy data of table
Tab.1.UV-vis spectra data of d1-d4
The ultraviolet-visible spectrogram obtained according to test is it is found that with CT-DNA intercalation occurs for D1-D4, with CT-DNA
It mixes the spectrogram obtained later and all there is hyperchromic (losing lustre) effect or red shift (blue shift).Solid line is the D of various concentration in figure
Series compound ultraviolet absorption curve, and dotted line then represents the ultraviolet absorption curve with the compound after DNA effects.It can by Fig. 1
Seeing, D1 enhances with its hypochromic effect of the increase of compound concentration, and when this shows that concentration is high, drug molecule is accumulated on the surfaces DNA,
The pi-electron track of the π * unoccupied orbitals and base that are inserted into ligand couples, and the π * tracks after coupling make because being partially filled with electronics
It obtains π → π * transition probabilities to reduce, and generates stronger hypochromic effect.From Figure 2 it can be seen that D2 then maximum absorption wavelengths at high concentrations
Hyperchromicity nearby occurs, be the π * tracks after coupling causes because partly losing electronics and making the increase of π → π * transition probabilities
's.
Application examples 1：Activity of tumor cells Inhibition test
This experiment uses MTT colorimetric determination D series compounds for the anti tumor activity in vitro of different cell strains, selected
The cell strain taken is human breast cancer cell MCF-7, Human Gastric Cancer cell BCG-823.
2. compound D1-D4 of table is to MCF-7, the IC of BGC-823 cells50Value
Tab.2.The values of IC50of compounds D1-D4against MCF-7,BCG-823
D series compounds have tumor inhibition effect, different side chains to take MCF-7, BGC-823 cell strain IC50 values
Dai Ji causes different compounds different for the inhibiting effect of different cell strains.For human breast cancer cell MCF-7, chemical combination
Object D1 (side-chain radical is piperidyl) has optimum value (IC50=21.79 μM), and D3 (side-chain radical is morpholinyl) then inhibits
Effect is most weak, remaining D2 and D4 are respectively the compound containing thio-morpholinyl and pyrrolidinyl side chain, their IC50 value phases
Closely, i.e., antitumor action is similar.For Human Gastric Cancer cell BGC-823, the compound D4 containing pyrrolidinyl is shown most preferably
Antitumor action (IC50=24.36 μM), the inhibiting effect of remaining D1, D2, D3 three is similar, and antitumor activity shows as D2>
D1>D3。
Claims (4)
1. 1, the 8- naphthalene anhydride analog derivatives of a kind of side chain isoquinoline-containing, it is characterised in that it is the compound with general formula A structures：
2. the preparation method of 1, the 8- naphthalene anhydride analog derivatives of side chain isoquinoline-containing as described in claim 1, reaction route are as follows：
Wherein, the definition of R is identical as claim 1.
3. the 1,8- naphthalene anhydrides analog derivative of side chain isoquinoline-containing as described in claim 1 is in preparing inhibition tumour cell drug
Application.
4. application according to claim 3, it is characterised in that the tumour cell is MCF-7 Breast Cancer Cell and human body
Stomach cancer cell BCG-823 cells.
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