CN105669657A - Benzopyran-4-one substituted naphthalimide-polyamine conjugate and preparing method and usage thereof - Google Patents
Benzopyran-4-one substituted naphthalimide-polyamine conjugate and preparing method and usage thereof Download PDFInfo
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Abstract
The invention relates to a benzopyran-4-one substituted naphthalimide-polyamine conjugate and a preparing method and usage thereof. The naphthalimide-polyamine conjugate has a structure as shown in a formula I. The benzopyran-4-one substituted naphthalimide-polyamine conjugate has obvious inhibition activity for cell proliferation of multiple tumor cells such as HCT-116 (human colon cancer cell), HepG2 (human hepatoma carcinoma cell), K562 (human chronic myeloid leukemia cells) and SMMC7721 (human hepatoma carcinoma cell); the conjugate can also serve as a targeting mitochondria fluorescence probe and can effectively inhibit pulmonary metastasis of the tumor, wherein a is 0, 1 or 2, m is 1, 2 or 3, n is 1, 2, 3, or 4, R is H or CH3, and R1 is shown in the description.
Description
Technical field
The invention belongs to medicinal chemistry art, it is specifically related to a class " naphthalimide-polyamines " conjugate containing benzopyran-4-one and its production and use.
Background technology
Polyamines is a kind of biological endogenous property small molecules with complex physiologic function. Most eukaryotic cell has a polyamines running system on its cytolemma, can regulate the concentration of intracellular polyamine on demand, based on these features of polyamines make it in the medicinal designs such as antitumor and neuroprotective quite concerned. And research in recent years shows natural polyamines or the potential targeting vector developing into a kind of polyamines transporter that can effectively utilize on cytolemma of synthetic polyamine.
Naphthoyl imide compounds is quite concerned as anti-tumor agent comprising salmosin in recent years, and multiple naphthalimide derivative once entered the experimental stage of clinical I phase and II phase. But in clinical trial, also find that there is the toxic side effect such as serious central nervous system (NCS) toxicity, hematotoxicity and bone marrow depression, and clinical activity is limited.
Flavonoid compound is the compound with 2-phenyl chromone structure that a class is present in nature. Because its low poison advantage, many natural or synthesis flavonoidss as rutin, Quercetin etc. have entered the clinical I phase test, there is certain anticancer and reversing tumor resistance etc. and act on.
Summary of the invention
It is an object of the invention to provide a class " naphthalimide-polyamines " conjugate containing benzopyran-4-one and its production and use.
Based on above-mentioned purpose, the present invention takes following technical scheme:
" naphthalimide-polyamines " conjugate that benzopyran-4-ketone replaces, the structural formula of described conjugate is as follows:
Wherein a gets 0,1 or 2; M gets 1,2 or 3; N gets 1,2,3 or 4; R is H or CH3; R1For
X gets 1,2 or 3.
The preparation method of " naphthalimide-polyamines " conjugate that above-mentioned benzopyran-4-ketone replaces, comprises the steps:
One, compoundSynthesis
By following synthetic route and step synthesis (its common structure is bought by market),
(1) the triethylamine methanol solution that 1,3-propylene diamine or 1,4-butanediamine or piperazine (50mmol) are dissolved in 30mL10v% is got, by 20mmolBoc under ice bath2The methanol solution 20mL of O (4.3g) slowly drips into above-mentioned solution, drips Bi Shengzhi stirring at room temperature 12h;Decompression steams solvent after completion of the reaction, and resistates is first with dichloromethane extraction, then uses saturated Na2CO3Solution washing, collected organic layer, anhydrous Na2SO4Drying, concentrates to obtain compound 1 or compound 8;
(2) get 4.50g (23.9mmol) compound 1 or compound 8 or morpholine or n-Butyl Amine 99 and it is dissolved in 100mL acetonitrile, add Anhydrous potassium carbonate 4.5g (32mmol), after stirring at room temperature 15min, it is warming up to 45 DEG C, add 5.45 (20.4mmol) 3-bromine propyl phthalimide or 4-brombutyl phthalic imidine in batches, react 12h in 45 DEG C. Reaction terminates, and removes solvent under reduced pressure, resistates first with dichloromethane extraction, with the Na of massfraction 10% after extraction2CO3Solution washing, collected organic layer, anhydrous Na2SO4Drying, complete to a kind of raw material reaction with the reaction of 28.68mmol (6.194g) two tert.-butoxy formic anhydride in ethanol after concentrating under reduced pressure, decompression steams solvent, resistates chloroform extraction, washing; Use volume ratio sherwood oil: ethyl acetate=4:1 is eluting to be obtained product 2 and 6 or uses volume ratio methylene dichloride: methyl alcohol=20:1 is eluting obtains compound 9 and 11;
(3) 2.1g (4.3mmol) compound 2 or compound 6 or compound 9 or compound 11 is got in 100mL dehydrated alcohol, add hydrazine hydrate 1.27g (25mmol), stirring at room temperature 12h, remove solvent under reduced pressure, resistates is first with dichloromethane extraction, then the Na with massfraction 10%2CO3Solution washing, collected organic layer, concentrated compound 3 or compound 7 or compound 10 or compound 12, do not need separation to be directly used in the next step.
(4) 8mmol compound 3 is dissolved in 50mL acetonitrile, add Anhydrous potassium carbonate 2.25g (16mmol), after stirring at room temperature 15min, it is warming up to 45 DEG C, add 2.14g (8mmol) N-(3-bromine propyl group) phthalic imidine in batches, react 12h in 45 DEG C. Reaction terminates, and removes solvent under reduced pressure, and resistates is first with dichloromethane extraction, then uses massfraction 10%Na2CO3Solution washing, collected organic layer, anhydrous Na2SO4Drying, reacts with 9.6mmol (2.07g) two tert.-butoxy formic anhydride after concentrating under reduced pressure in ethanol, and decompression steams solvent, resistates chloroform extraction, washing, obtains product 4 with volume ratio sherwood oil ethyl acetate=4:1 is eluting; Being dissolved in 50mL dehydrated alcohol by compound 4, add hydrazine hydrate 1.27g (25mmol), stirred overnight at room temperature, removes solvent under reduced pressure, and resistates is first with dichloromethane extraction, then the Na with massfraction 10%2CO3Solution washing, collected organic layer, concentrates to obtain compound 5, does not need separation to be directly used in the next step.
Two, the synthesis of target compound
(1) compound 13 and phosphorus oxychloride, N, dinethylformamide is after 90～95 DEG C of reaction 3h in impouring water, and decompress filter obtains compound 14;
(2) compound 14 in massfraction 50%KOH solution withThe obtained orange solid of reaction, this solid obtains compound 15 at vitriol oil effect ShiShimonoseki ring in methyl-sulphoxide;
(3) compound 15 prepares compound 16 with potassium dichromate oxidation in Glacial acetic acid liquid;
(4) compound 16 and compound 5 or compound 7 or compound 10 compound 12 reflux in dehydrated alcohol, and product column separating purification obtains compound 17;
(5) compound 17 stirs with 4M hydrochloric acid in dehydrated alcohol and spends the night, and filters absolute ethanol washing and namely obtains target compound 18.
In step (4), compound 16 is 11 with the mol ratio of compound 5 or compound 7 or compound 10 compound 12.
" naphthalimide-polyamines " conjugate that described benzopyran-4-ketone replaces is preparing the application in antitumor drug.
" naphthalimide-polyamines " conjugate that described benzopyran-4-ketone replaces is preparing the application in antitumor drug lead compound.
Described " the application of " naphthalimide-polyamines " conjugate that benzopyran-4-ketone replaces in the antitumor Lung metastases medicine of preparation.
" naphthalimide-polyamines " conjugate that described benzopyran-4-ketone replaces is in the application of the Mitochondrially targeted property fluorescent probe of preparation.
Embodiment
Below in conjunction with specific embodiment, the technical scheme of the present invention is described in further details, but protection scope of the present invention is not limited thereto.
Embodiment 1
6-(2-4H-1-benzopyran-4-one)-{ 2-[(2-dimethylamino)-ethyl] }-1H-benzisoquinoline-1,3 (2H)-diketone } preparation of hydrochloride (18a):
(1) the triethylamine methanol solution that 1,3-propylene diamine (50mmol) is dissolved in 30mL10v% is got, by 4.3gBoc under ice bath2The methanol solution 20mL of O (20mmol) slowly drips into above-mentioned solution, drips Bi Shengzhi stirring at room temperature 12h; Decompression steams solvent after completion of the reaction, and resistates is first with dichloromethane extraction, then uses saturated Na2CO3Solution washing, collected organic layer, anhydrous Na2SO4Drying, concentrates to obtain compound 1;
(2) get 4.50g (23.9mmol) compound 1 and it is dissolved in 100mL acetonitrile, add Anhydrous potassium carbonate 4.5g (32mmol), after stirring at room temperature 15min, it is warming up to 45 DEG C, add 5.45g (20.4mmol) N-(3-bromine propyl group) phthalic imidine in batches, react 12h in 45 DEG C. Reaction terminates, and decompression steams solvent, and resistates is first with dichloromethane extraction, then the Na with massfraction 10%2CO3Solution washing, collected organic layer, anhydrous Na2SO4Dry, reacting with 28.68mmol (6.19g) two tert.-butoxy formic anhydride in dehydrated alcohol after concentrating under reduced pressure, decompression steams solvent, resistates chloroform extraction, washing, organic layer is through volume ratio sherwood oil: ethyl acetate=4:1 is eluting obtains compound 2;
(3) getting 2.1g (4.3mmol) compound 2 in 100mL dehydrated alcohol, add hydrazine hydrate 1.27g (25mmol), stirring at room temperature 12h, decompression steams solvent, and resistates is first with dichloromethane extraction, then the Na with massfraction 10%2CO3Solution washing, collected organic layer, concentrates to obtain compound 3, does not need separation to be directly used in the next step;
(4) 8mmol compound 3 is dissolved in 50mL acetonitrile, add Anhydrous potassium carbonate 2.25g (16mmol), after stirring at room temperature 15min, it is warming up to 45 DEG C, add 2.14g (8mmol) N-(3-bromine propyl group) phthalic imidine in batches, react 12h in 45 DEG C. Reaction terminates, and decompression steams solvent, and resistates is first with dichloromethane extraction, then uses 10wt%Na2CO3Solution washing, collected organic layer, anhydrous Na2SO4Dry, reacting with 9.6mmol (2.07g) two tert.-butoxy formic anhydride in ethanol after concentrating under reduced pressure, after reaction terminates, decompression steams solvent, resistates chloroform extraction, washing, organic layer obtains product 4 through volume ratio sherwood oil ethyl acetate=4:1 wash-out separation and purification; Compound 4, in 50mL dehydrated alcohol, adds hydrazine hydrate 1.27g (25mmol), stirring at room temperature 12h, and decompression steams solvent, and resistates is first with dichloromethane extraction, then the Na with massfraction 10%2CO3Solution washing, collected organic layer, concentrates to obtain compound 5, does not need separation to be directly used in the next step;
(5) get 9mmoL (1.38g) compound 13 to mix with 1.35mL phosphorus oxychloride, N is slowly added by dropping funnel, dinethylformamide 1.35mL, finish and pour in 27mL frozen water after reacting 3h with 90～95 DEG C, stirring has a large amount of brown sticky solid to generate, decompress filter, washes to obtain compound 14;
(6) 15mmol (2.04g) o-hydroxyacetophenone is got in flask, add 19mmoL (3.55g) compound 14, dehydrated alcohol 11mL, under ice-water bath stirs, constant voltage dropping liquid drip adds massfraction 50%KOH aqueous solution 12g, and react 5.5h in 52 DEG C, reaction end is poured in frozen water, with about concentrated hydrochloric acid adjust pH to 3～4, has a large amount of red flocculent precipitation to generate, decompress filter, collects to obtain orange solid.
Getting step gained Exocarpium Citri Rubrum solid in 27mL methyl-sulphoxide, low-grade fever is dissolved, and adds the 3.5mL vitriol oil, after 110 DEG C of stirring 20min, adds 1 iodine grain, continues reaction 5.5h, react complete, poured into by reaction solution in frozen water, and decompress filter obtains compound 15.
(7) get 7.5mmoL (2.25g) compound 15 and in flask, add Glacial acetic acid 18mL, potassium bichromate 6.8g, 90～100 DEG C of reaction 2h, then pour in frozen water after naturally cooling 0.5h, have a large amount of sap green flocks to produce, decompress filter, obtains compound 16.
(8) get 2mmoL (0.68g) compound 16 and, in flask, add N, N-dimethyl-ethylenediamine 2mmol, adding dehydrated alcohol 20mL, reflux, TLC monitors reaction, after about 3h, decompression steams solvent, and volume ratio sherwood oil ethyl acetate=2:1 is eluting obtains sterling 17. Getting and walk gained compound 17 on 1mmol in 10mL dehydrated alcohol, ice bath stirs the lower ethanol (V adding 4MHCl4M hydrochloric acid:VEthanol=1:2) solution 0.5mL, drip and finish, stirring at room temperature 12h occurs to a large amount of solid, filters, and collects solid, with heavy steamed absolute ethanol washing three times, dry compound 18a product rate: 86%,1HNMR(400MHz,D2O) δ: 7.98～8.05 (m, 3H, Ar-H); 7.62 (d, J=7.60Hz, 1H, Ar-H); 7.46 (t, J=7.88Hz, 1H, Ar-H); 7.24 (d, J=6.80Hz, 1H, Ar-H); 7.19 (d, J=6.88Hz, 1H, Ar-H); 7.10 ((t, J=7.48Hz, 1H, Ar-H); 5.87 (s, 1H, Ar-H); 4.43 (t, J=6.54Hz, 2H, 1 × N-CH2); 3.52 (t, J=6.62Hz, 2H, 1 × N-CH2); 3.13 (s, 6H, 2 × CH3); ESI-MIm/z:427.21 [M+H-HCl]+.Anal.calcdforC26H23Cl1N2O4·1.45H2O:C63.85%, H5.34%, N5.73%; FoundC63.90%, H5.51%, N5.48%.
Embodiment 2
The preparation of 6-(2-4H-1-benzopyran-4-one)-{ 2-[3-(3-aminopropyl) aminopropyl] 1H-benzisoquinoline-1,3 (2H)-one } dihydrochloride (18b):
Replace N except in (8) step with 3a, N-dimethyl-ethylenediamine, drip and add 2mL4MHCl ethanol (V4M hydrochloric acid:VEthanol=1:2) outside solution, other synthesizing progress method is with embodiment 1. Product rate: 86%,1HNMR(400MHz,D2O) δ: 8.15～8.26 (m, 3H, Ar-H); (7.82 d, 1H, J=8.8Hz, Ar-H); 7.63～7.67 (m, 1H, Ar-H); 7.51～7.56 (m, 2H, Ar-H); 7.29 (t, J=7.78Hz, 1H, Ar-H), 7.12 (d, J=4.28Hz, 1H, Ar-H); 6.26 (s, 1H, Ar-H); 4.18 (t, J=6.96Hz, 2H, 1 × N-CH2); 3.21～3.26 (m, 4H, 2 × N-CH2); 3.15 (t, J=7.82Hz, 2H, 1 × N-CH2); 2.12～2.20 (m, 4H, 2 × CH2); ESI-MSm/z:456.2 [M+1 2HCl]+.Anal.calcdforC27H27Cl2N3O4·1.85H2O:C57.73%, H5.51%, N7.48%; FoundC57.64%, H5.50%, N7.42%.
Embodiment 3
The preparation of 6-(2-4H-1-benzopyran-4-one)-{ 2-[3-(4-amino butyl) aminopropyl] 1H-benzisoquinoline-1,3 (2H)-one } dihydrochloride (18c):
Replace N except in (8) step with 3b, N-dimethyl-ethylenediamine, drip and add 2mL4MHCl ethanolic soln (V4M hydrochloric acid:VEthanol=1:2) outward, other synthesizing progress method is with embodiment 1.Product rate: 86%, white solid1HNMR(400MHz,D2O) δ: 7.74～7.78 (m, 3H, Ar-H); 7.42 (t, 1H, J=3.70Hz, Ar-H); 7.26～7.29 (m, 2H, Ar-H); 7.05 (s, 2H, Ar-H); 6.74 (t, J=4.08Hz, 1H, Ar-H), 5.64 (d, 1H, J=4.68Hz, Ar-H); 3.98 (t, J=6.78Hz, 2H, 1 × N-CH2); 3.16～3.22 (m, 4H, 2 × N-CH2); 3.10 (t, 2H, J=7.12Hz1 × N-CH2); 2.06 (t, 2H, J=7.02Hz1 × CH2); 1.78-1.89 (4H, 2 × CH2).ESI-MIm/z:470.21[M+H-2HCl]+.Anal.calcdforC28H29Cl2N3O4·1.6H2O:C58.87%, H5.68%, N7.36%; FoundC58.97%, H5.57%, N7.45%.
Embodiment 4
The preparation of 6-(2-4H-1-benzopyran-4-one)-{ 2-[(4-butyl) amino butyl] 1H-benzisoquinoline-1,3 (2H)-one } dihydrochloride (18d):
Replace N except in (8) step with compound 7, N-dimethyl-ethylenediamine, drip and add 1.0mL4MHCl ethanolic soln (V4M hydrochloric acid:VEthanol=1:2) outward, other synthesizing progress method is with embodiment 1. Product rate: 86%, white solid1HNMR(400MHz,D2O) δ: 7.77～7.86 (m, 3H, Ar-H); (7.46 d, 1H, J=7.28Hz, Ar-H); (7.35 t, 2H, J=7.84Hz, Ar-H); (7.16 d, J=6.76Hz, 1H, Ar-H); (7.07 t, 1H, J=7.44Hz, Ar-H); (6.84 d, J=7.72Hz, 1H, Ar-H); 5.83 (s, 1H, Ar-H); 3.89 (t, J=8.0Hz, 1 × N-CH2); 3.06～3.13 (m, 4H, 2 × N-CH2); 1.75～1.79 (m, 2H, 1 × CH2); 1.65～1.73 (m, 4H, 2 × CH2); 1.39～1.45 (m, 2H, 1 × CH2); 0.95 (t, 3H, J=7.36Hz, 1 × CH3).ESI-MIm/z:469.2[M+H-3HCl]+.Anal.calcdforC29H29Cl1N2O4·0.6H2O:C67.53%, H5.90%, N5.43%; FoundC67.36%, H5.90%, N5.49%.
Embodiment 5
The preparation of 6-(2-4H-1-benzopyran-4-one)-{ 2-[4-(4-amino butyl) amino butyl] 1H-benzisoquinoline-1,3 (2H)-one } dihydrochloride (18e):
Replace N, N-dimethyl-ethylenediamine except in (8) step with compound 3d, drip and add 2mL4MHCl ethanolic soln (V4M hydrochloric acid:VEthanol=1:2) outward, other synthesizing progress method is with embodiment 1. Product rate: 86%, white solid1HNMR(400MHz,D2O) δ: 7.68～7.76 (m, 3H, Ar-H); (7.37 d, 1H, J=8.0Hz, Ar-H); 7.20～7.30 (m, 2H, Ar-H); (6.98-7.06 m, 2H, Ar-H); 6.73 (d, J=8.0Hz, 1H, Ar-H), 5.71 (s, 1H, Ar-H); 3.83 (t, 2H, J=6.0Hz, 1 × N-CH2); 3.04～3.12 (m, 6H, 3 × N-CH2); ; 1.76-1.78 (m, 6H, 3 × CH2); 1.63-1.65 (m, 2H, 1 × CH2)(ESI-MIm/z:484.2[M+H-2HCl]+.Anal.calcdforC29H31Cl2N3O4·3.35H2O:C56.47%, H6.16%, N6.81%; FoundC56.86%, H6.24%, N6.43%.
Embodiment 6
6-(2-4H-1-benzopyran-4-one)-{ 2-[3-(3-(3-aminopropyl) aminopropyl)-aminopropyl]-amine } 1H-benzisoquinoline-1,3 (2H)-one } preparation of tri hydrochloride (18f):
Replace N, N-dimethyl-ethylenediamine except in (8) step with compound 5a, drip and add 3mL4MHCl ethanolic soln (V4M hydrochloric acid:VEthanol=1:2) outward, other synthesizing progress method is with embodiment 1. Product rate: 86%,1HNMR(400MHz,D2O) δ: 7.98～8.06 (m, 3H, Ar-H); (7.65 d, 1H, J=7.68Hz, Ar-H); (7.51 t, 1H, J=7.92Hz, Ar-H); (7.41-7.45 m, 1H, Ar-H); 7.31 (d, J=7.72Hz, 1H, Ar-H), 7.19 (t, 1H, J=7.6Hz, Ar-H); (6.95 d, 1H, J=8.32Hz, Ar-H); (6.00 s, 1H, Ar-H);4.10 (t, 2H, J=6.68Hz, 1 × N-CH2); 3.21～3.27 (m, 8H, 4 × N-CH2); 3.14 (t, 2H, J=7.86Hz, 1 × N-CH2); 2.09-2.25 (m, 6H, 3 × CH2).ESI-MIm/z:513.25[M+H-3HCl]+.Anal.calcdforC30H35Cl3N4O4·1.0H2O:C56.30%, H5.83%, N8.75%; FoundC56.03%, H5.84%, N8.88%.
Embodiment 7
The preparation of 6-(2-4H-1-benzopyran-4-one)-{ 2-[(3-piperazinyl) propyl group] 1H-benzisoquinoline-1,3 (2H)-one } dihydrochloride (18g):
Replace N, N-dimethyl-ethylenediamine except in (8) step with compound 10a, drip and add 1.5mL4MHCl ethanolic soln (V4M hydrochloric acid:VEthanol=1:2) outward, other synthesizing progress method is with embodiment 1. Product rate: 86%, white solid1HNMR(400MHz,D2O) δ: 7.61～7.85 (m, 3H, Ar-H); (7.29 d, J=5.16Hz, 1H, Ar-H); 7.17～7.19 (m, 2H, Ar-H); 6.96 (s, 1H, Ar-H); 6.64 (d, J=6.32Hz, 1H, Ar-H), 6.84～6.87 (m, 1H, Ar-H); 5.55 (s, 1H, Ar-H); 3.71～3.82 (t, J=10Hz, 5 × N-CH2); 3.40 (t, J=8.2Hz, 1H, 1 × N-CH2); 1.87～1.88 (m, 2H, 1 × CH2); 1.63～1.65 (m, 2H, 1 × CH2).ESI-MIm/z:468.19[M+H-2HCl]+.Anal.calcdforC28H27Cl2N3O4·3.0H2O:C56.57%, H5.60%, N7.07%; FoundC56.65%, H5.34%, N7.03%.
Embodiment 8
The preparation of 6-(2-4H-1-benzopyran-4-one)-{ 2-[(4-piperazinyl) butyl] 1H-benzisoquinoline-1,3 (2H)-one }-dihydrochloride (18h):
Replace N, N-dimethyl-ethylenediamine except in (8) step with compound 10b, drip and add 1.5mL4MHCl ethanolic soln (V4M hydrochloric acid:VEthanol=1:2) outward, other synthesizing progress method is with embodiment 1. Product rate: 86%, white solid1HNMR(400MHz,D2O) δ: 7.61～7.65 (m, 3H, Ar-H); (7.29 d, 1H, J=5.16Hz, Ar-H); 7.18～7.20 (m, 2H, Ar-H); 6.96 (s, 2H, Ar-H); 6.64 (d, J=6.32Hz, 1H, Ar-H), 5.55 (s, 1H, Ar-H); 3.70-3.82 (m, 8H, 4 × N-CH2); 3.39 (t, J=8.2Hz, 2H, 1 × N-CH2); 1.86-1.88 (m, 2H, 1 × CH2); 1.63-1.65 (m, 2H, 1 × CH2)(ESI-MIm/z:482.2[M+H-2HCl]+.Anal.calcdforC29H29Cl2N3O4·3.0H2O:C57.24%, H5.80%, N6.91%; FoundC57.53%, H5.64%, N6.95%.
Embodiment 9
The preparation of 6-(2-4H-1-benzopyran-4-one)-{ 2-[(3-morpholinyl) propyl group] 1H-benzisoquinoline-1,3 (2H)-one } hydrochloride (18i):
Replacing N except in (8) step with compound 12, outside N-dimethyl-ethylenediamine, other synthesizing progress method is with embodiment 1. Product rate: 86%, white solid1HNMR(400MHz,D2O) δ: 7.85 (d, J=7.56Hz, 2H, Ar-H); (7.78 d, 1H, J=7.12Hz, Ar-H); (7.49 d, J=7.16Hz, 1H, Ar-H); 7.37～7.40 (m, 1H, Ar-H); (7.31 t, 1H, J=7.82Hz, Ar-H); 7.11～7.18 (m, 2H, Ar-H); (6.87 d, J=8.28Hz, 1H, Ar-H); 5.66 (s, 1H, Ar-H); 4.19 (t, J=5.82Hz, 1 × N-CH2); 4.04 (t, J=6.68Hz, 1 × N-CH2); 3.92 (t, 2H, J=5.38Hz, 2 × N-CH2); 3.62～3.67 (m, 2H, 1 × CH2); 3.38 (t, 2H, J=7.94Hz, 1 × CH2); 3.25～3.27 (m, 2H, 1 × CH2); 2.15～2.20 (m, 2H, 1 × CH2).(ESI-MIm/z:469.17[M+H-HCl]+.Anal.calcdforC28H25Cl1N2O5·1.85H2O:C62.48%, H5.37%, N5.20%; FoundC62.41%, H5.29%, N5.17%.
Embodiment 10
The preparation of 6-(2-4H-1-benzopyran-4-one)-{ 2-[(2-hydroxyethyl) ethyl] 1H-benzisoquinoline-1,3 (2H)-one } hydrochloride (18j):
Outside replacing N, N-dimethyl-ethylenediamine with compound beta-hydroxyethyl quadrol in (8) step, other synthesizing progress method is with embodiment 1.Product rate: 86%, white solid1HNMR(400MHz,D2O) δ: 8.03～8.08 (m, 3H, Ar-H); 7.65 (d, J=7.68Hz, 1H, Ar-H); 7.46～7.51 (m, 2H, Ar-H); 7.40 (d, J=7.88Hz, 1H, Ar-H); 7.24 (t, J=7.58Hz, 1H, Ar-H); 7.04 ((d, J=8.36Hz, 1H, Ar-H); 5.97 (s, 1H, Ar-H); 4.42 (t, J=6.26Hz, 2H, 1 × CH2); 3.89 (t, J=5.16Hz, 2H, 1 × CH2); 3.47 (t, J=6.26Hz, 2H, 1 × CH2); 3.32 (t, J=5.12Hz, 2H, 1 × CH2).ESI-MIm/z:482.2[M+H-2HCl]+.Anal.calcdforC29H29Cl2N3O4·3.0H2O:C57.24%, H5.80%, N6.91%; FoundC57.53%, H5.64%, N6.95%.
Embodiment 11
6-[2-(8-methyl) 4H-1-benzopyran-4-one]-[2-(3-aminopropyl)] 1H-benzisoquinoline-1,3 (2H)-one } preparation of hydrochloride (18k):
Except replacing o-hydroxyacetophenone with compound 2-hydroxy-3-methyl methyl phenyl ketone in (6) step, other synthesizing progress method is with embodiment 1. Product rate: 86%,1HNMR(400MHz,D2O) δ: 7.98～8.05 (m, 3H, Ar-H); (7.62 d, J=7.60Hz, 1H, Ar-H); (7.46 t, J=7.88Hz, 1H, Ar-H); (7.24 d, J=6.80Hz, 1H, Ar-H); (7.19 d, J=6.88Hz, 1H, Ar-H); 7.10 ((t, J=7.48Hz, 1H, Ar-H); 5.87 (s, 1H, Ar-H); 4.43 (t, J=6.54Hz, 2H, 1 × N-CH2); 3.52 (t, J=6.62Hz, 2H, 1 × N-CH2); 3.13 (s, 6H, 2 × CH3); 2.95 (s, 3H, 1 × CH3); ESI-MIm/z:427.21 [M+H-HCl]+.Anal.calcdforC26H23Cl1N2O4·1.45H2O:C63.85%, H5.34%, N5.73%; FoundC63.90%, H5.51%, N5.48%.
Embodiment 12
6-[2-(8-methyl) 4H-1-benzopyran-4-one]-2-[2-(3-aminopropyl)] 1H-benzisoquinoline-1,3 (2H)-one } preparation of hydrochloride (18l):
Replace o-hydroxyacetophenone except in (6) step with compound 2-hydroxy-3-methyl methyl phenyl ketone, (8) step replaces N, N-dimethyl-ethylenediamine with the propylene diamine of Boc protection, drips and add 1.0mL4MHCl ethanolic soln (V4M hydrochloric acid:VEthanol=1:2) outward, other synthesizing progress method is with embodiment 1. Product rate: 86%,1HNMR(400MHz,D2O) δ: 7.97 (d, J=8.26Hz, 1H, Ar-H); (7.90 d, 2H, J=7.66Hz, Ar-H); (7.57 d, J=7.60Hz, 1H, Ar-H); (7.44 t, J=10.86Hz, 1H, Ar-H); (7.15 d, 1H, J=6.36Hz, Ar-H); (7.06 d, J=6.92Hz, 1H, Ar-H); (7.00 t, J=7.44Hz, 1H, Ar-H); 5.82 (s, 1H, Ar-H); (4.02 t, J=6.98Hz, 1 × N-CH2); 3.16 (t, 2H, J=7.32Hz, 1 × N-CH2); 2.04～2.12 (m, 2H, 1 × CH2); 1.65 (s, 3H, 1 × CH3).ESI-MIm/z:413.15[M+H-HCl]+.Anal.calcdforC25H21Cl1N2O4·0.5H2O:C65.57%, H4.84%, N6.12%; FoundC65.41%, H6.29%, N6.17%.
Evaluated biological activity:
(1) compound extracorporeal suppression tumor cell growth activity measures:
Select compound prepared by embodiment 1-12, HCT-116 (human cancer cell), HepG2 (human liver cancer cell), K562 (the former leukemia cell of the chronic marrow of people), SMMC7721 (human liver cancer cell) four kinds of tumor cell lines and the QSG-7701 (Human normal hepatocyte) taken the logarithm respectively vegetative period, 96 orifice plates are imbedded, 90 μ L/ holes with 5000-8000, every hole cell. After cultivating 24h, adding the sample of 10,50,100,300,500 μMs, to each cell strain, each concentration has four multiple holes, at 37 DEG C, and 5v%CO2After cultivating 48h under condition, adding MTT50 μ L (i.e. tetrazolium bromide), abandon supernatant after continuing to cultivate 4h, every hole adds 100 μ LDSMO, and vibrate 15min gently, surveys its absorbance A value by microplate reader at 570nm wavelength place.By formulae discovery analyte below to the inhibiting rate of different growth of tumour cell, experiment repeats three times, and obtains IC50 value by statistical software. The results are shown in Table 1.
Growth of tumour cell inhibiting rate (%)=(OD compares-OD experiment)/(it is blank that OD compares-OD) × 100%
The growth-inhibiting of tumour cell is lived by each embodiment compound of table 1
By table 1 data it may be seen that the cytotoxicity aspect of HCT-116 (human cancer cell), HepG2 (human liver cancer cell), K562 (the former leukemia cell of the chronic marrow of people), SMMC7721 (human liver cancer cell) four kinds of tumour cells is played a part to make compound have selectivity in various degree by the compound of embodiment 1 to 12 respectively. Major part embodiment compound tests tumor cell line to four kinds and positive control ammonia naphthalene Fitow has similar activity; Wherein the rejection ability of four kinds of tumor cell lines is obviously better than positive control by embodiment 10; QSG-7701 normal liver cell is demonstrated the toxicity being significantly lower than positive control by embodiment 2,5,12 compound, especially HCT-116, HepG2, SMMC7721 tri-kinds of tumour cells are had good selectivity by embodiment 5 compound, QSG-7701 normal liver cell is not had toxicity substantially simultaneously, there are the potentiality of druggability.
(2) suppression of mouse interior tumor Lung metastases is measured by compound:
Get the mouse H22 liver cancer cell of external logarithmic phase, inject H22 cell (5 × 10 by intravenous injection to 30 kunming mices6Individual/only), for guaranteeing the tumour average production of all mouse before administration, cultivate after its inoculated tumour 7 days, get the mouse model of inoculation after the 7th day, it is divided at random 3 groups (often organizing 10), it is respectively physiological saline group, embodiment 5 groups, positive control (ammonia naphthalene Fitow) group. Respectively inject embodiment 5 (5mg/kg), ammonia naphthalene Fitow (5mg/kg) and physiological saline (10mL/kg, negative control) by tail vein injections to mouse at the 8th day, and continue 7 days. Within 15th day, put to death mouse with cervical vertebra dislocation method, count the tubercle number of each lobe of the lung with dissecting microscope. With following formulae discovery Lung metastases inhibiting rate: inhibiting rate (%)=(the average Lung neoplasm number of 1-treatment group average Lung neoplasm number/negative control group) × 100%. Experimental result is in table 2.
Table 2 embodiment 5 compound suppresses mouse interior tumor Lung metastases active
The compound provided in the present invention is compared control drug ammonia naphthalene Fitow and in vitro the propagation of kinds of tumor cells is demonstrated more obvious inhibit activities and selectivity, the toxic side effect of normal liver cell QSG-7701, compared with positive control ammonia naphthalene Fitow, is obviously reduced by 12 compounds of synthesis that important is. Wherein embodiment 5 to normal liver cell QSG-7701 almost without any toxic side effect. And in experiment in vivo, embodiment 5 to the rejection ability of mouse interior tumor Lung metastases obviously higher than control drug ammonia naphthalene Fitow. Therefore the medicine for the treatment of metastases can be applied to prepare. Laser co-focusing is utilized to carry out the fluorometric assay in cell, prove that this compound and mitochondrial dye have the overlap ratio of more than 95%, so this compound is positioned in cell mitochondrial, so can be used as Mitochondrially targeted property fluorescent probe, in vivo bioactivity show this compounds can the Lung metastases of effective Tumor suppression, be potential antitumor Lung metastases medicine.
Above-described embodiment is the preferred embodiment of the present invention, but embodiments of the present invention are not restricted to the described embodiments, and the change that other any the present invention of not deviating from does all should be the substitute mode of equivalence, is included within protection scope of the present invention.
Claims (7)
1. naphthalimide-polyamines conjugate that benzopyran-4-ketone replaces, it is characterised in that, the structural formula of described conjugate is as follows:
Wherein a gets 0,1 or 2; M gets 1,2 or 3; N gets 1,2,3 or 4; R is H or CH3; R1For
、、、、Or。
2. the preparation method of naphthalimide-polyamines conjugate that benzopyran-4-ketone according to claim 1 replaces, it is characterised in that, comprise the steps:
(1) by compoundWith phosphorus oxychloride, N, dinethylformamide reacts to obtain compound;
(2) compoundIn KOH solution withThe obtained solid of reaction, this solid obtains compound at vitriol oil effect ShiShimonoseki ring in methyl-sulphoxide;
(3) compoundCompound is obtained in glacial acetic acid with potassium dichromate oxidation;
(4) compoundWithRefluxing in dehydrated alcohol, product obtains compound through chromatography purifying;
(5) by compoundNamely dehydrated alcohol obtains target compound with 4M hydrochloric acid stirring reaction.
3. the preparation method of naphthalimide-polyamines conjugate that benzopyran-4-ketone according to claim 2 replaces, it is characterised in that, compound in step (4)WithMol ratio be 11.
4. naphthalimide-polyamines conjugate that benzopyran-4-ketone as claimed in claim 1 replaces is preparing the application in antitumor drug.
5. naphthalimide-polyamines conjugate that benzopyran-4-ketone as claimed in claim 1 replaces is preparing the application in antitumor drug lead compound.
6. the application of naphthalimide-polyamines conjugate that benzopyran-4-ketone as claimed in claim 1 replaces in the antitumor Lung metastases medicine of preparation.
7. naphthalimide-polyamines conjugate that benzopyran-4-ketone as claimed in claim 1 replaces is in the application of the Mitochondrially targeted property fluorescent probe of preparation.
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