CN109574997A - Flavones-polyamines conjugate and its preparation method and application that a kind of naphthalimide replaces - Google Patents
Flavones-polyamines conjugate and its preparation method and application that a kind of naphthalimide replaces Download PDFInfo
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Abstract
The invention belongs to field of pharmaceutical chemistry technology, and in particular to flavones-polyamines conjugate and its preparation method and application that a kind of naphthalimide replaces.The present invention is using chromone as raw material, in its 2- introducing active group naphthalimide skeleton, synthesize the flavonoids pharmacophore that new naphthalimide replaces, and it is modified with polyamines chain, while such compound keeps the activity of naphthoyl imide compounds, also the characteristic of flavone compound low toxicity has been had both, improve the biological activity of original molecule, improve the anti-tumor activity of target molecule, experiment proves that finding conjugate of the present invention to HCT-116, HepG2, Hela, SMMC7721 kinds of tumor cells proliferation all shows apparent inhibitory activity.
Description
Technical field
The invention belongs to field of pharmaceutical chemistry technology, and in particular to " flavones-polyamines " conjugation that a kind of naphthalimide replaces
Object and its preparation method and application.
Background technique
Flavone compound is distributed widely in natural plants, and quantity is many kinds of, and the complicated multiplicity of structure type has wide
General pharmacological activity, such as can antitumor, anti-inflammatory antibacterial, anti-oxidant, strengthen immunity, and prevention cardiovascular and cerebrovascular disease and exhales
Desorption system disease.Just because of this, such compound is always in recent years the hot spot studied both at home and abroad, with to its structure-activity relationship
The research of further investigation, flavone compound enters a new level.
Naphthoyl imide compounds are constantly subjected to the extensive concern of researcher, multiple derivatives as anti-tumor small molecular
Clinical investigation phase, such as ammonia naphthalene Fitow, mitonafide are entered, but have failed to list mostly, main cause is such compound
With a variety of toxic side effects, such as dose limit, hematotoxicity.
Polyamines is widely present in the prokaryotic cell and eukaryocyte in biological (including human body).Research shows that quick
In the cell of growth and differentiation, the activity of the content of polyamines and enzyme relevant to their anabolism is all significantly improved,
Thus they can influence a variety of physiological processes such as the proliferation of cell, division, have a variety of important physiological functions, further grind
Study carefully display, can assign compound some new functions after polyamines modification antitumoral compounds, therefore, polyamines is in anti-tumor aspect
Research more and more causes the concern of people.
Summary of the invention
In view of this, present invention aims at " flavones-polyamines " conjugates for proposing that a kind of naphthalimide replaces.
In order to achieve the above objectives, the technical solution of the invention is achieved in that
" flavones-polyamines " conjugate that a kind of naphthalimide replaces has structure shown in Formulas I:
Wherein a takes 0,1 or 2；M takes 1,2 or 3；N takes 1,2,3 or 4；R1For X takes 1,2 or 3.
Specifically, the R1For
The synthetic route of " flavones-polyamines " conjugate that above-mentioned naphthalimide replaces is as follows:
Preparation method includes the following steps:
(1b) compound 6 and phosphorus oxychloride, n,N-Dimethylformamide are poured into water after 90~95 DEG C of reaction 1-5h, subtract
Pressure filters to obtain compound 7；
(2b) compound 7 in KOH solution withIt reacts and Chinese red solid is made, this solid exists in acetone
Compound 8 is descended to obtain in hydrogen peroxide effect；
(3b) compound 8 reacts prepare compound 9 with dimethyl suflfate in acetone；
(4b) compound 9 is in glacial acetic acid liquid with potassium dichromate oxidation prepare compound 10；
(5b) compound 10 withIt flows back in dehydrated alcohol, product column separating purification obtains compound
11；Compound 11 stirs in mixed liquor of the dehydrated alcohol with 4M hydrochloric acid, and filtering, being washed with dehydrated alcohol up to structure is Formulas I
Shown in target compound 12.
Wherein, in step (5b) compound 10 withMolar ratio be 1 ︰ (1-2).
Application of " flavones-polyamines " conjugate in terms of preparing anti-tumor drug that the naphthalimide replaces.
" flavones-polyamines " conjugate the answering in terms of preparing anti-tumor drug lead compound that the naphthalimide replaces
With.
Further, the tumour refers to human colon carcinoma, human liver cancer, human cervical carcinoma.
Compound in above-mentioned preparation method step (5b)Following (the synthetic route of synthetic route
In common structure can be bought by conven-tional channels):
CompoundPreparation method, step are as follows:
(a1) it takes 1,3- propane diamine or Putriscine to be dissolved in triethylamine methanol solution, and contains Boc2The methanol solution of O
Reaction, removes under reduced pressure, extracts, and washs, and collects, dry, is concentrated to give compound 1；
(a2) it takes compound 1 to be dissolved in acetonitrile, adds Anhydrous potassium carbonate, in 45-50 DEG C, 3- bromopropyl O-phthalic is added portionwise
Acid imide or 4- brombutyl phthalimide react 6-18h, remove under reduced pressure, extract, and wash, and collect, dry, depressurize dense
It reacts, removes under reduced pressure completely with two tert-butoxy formic anhydrides after contracting, extract, washing；With the mixed liquor of petroleum ether and ethyl acetate
Elution, purifying, obtain product 2；
(a3) it takes compound 2 in dehydrated alcohol, adds hydrazine hydrate, 6-18h is stirred at room temperature, remove under reduced pressure, extract, washing,
It collects, is concentrated to give compound 3.
(a4) it takes compound 3 to be dissolved in acetonitrile, adds Anhydrous potassium carbonate, in 45-50 DEG C, the adjacent benzene of N- (3- bromopropyl) is added portionwise
Dicarboximide reacts 6-18h；Remove under reduced pressure, extract, wash, collect, it is dry, after reduced pressure with two tert-butoxy formic acid
Anhydride reactant removes under reduced pressure, extracts, and washing is purified by flash to obtain product 4 with petroleum ether and ethyl acetate mixtures；Compound 4 is molten
In dehydrated alcohol, add hydrazine hydrate, be stirred overnight at room temperature, remove under reduced pressure, extract, wash, collects, be concentrated to give compound
Compared with the existing technology, flavones-polyamines conjugate that naphthalimide of the present invention replaces has the advantage that
The present invention is using chromone as raw material, and in its 2- introducing active group naphthalimide skeleton, synthesis is new
The flavonoids pharmacophore that replaces of naphthalimide, and it is modified with polyamines chain, design has synthesized a kind of Huang that naphthalimide replaces
Ketone-polyamines conjugate.While such compound keeps the activity of naphthoyl imide compounds, flavone compound has also been had both
The characteristic of low toxicity, improves the biological activity of original molecule, improves the anti-tumor activity of target molecule.
Specific embodiment
Below in conjunction with specific embodiment, further details of the technical solution of the present invention, but protection model of the invention
It encloses and is not limited thereto.
Embodiment 1:
6- [2- (3- methoxyl group -4H-1- benzopyran-4-one)]-{ 2- [(2- dimethylamino)-ethyl] } -1H- benzo
Isoquinolin -1,3 (2H)-diketone } hydrochloride (12a) preparation:
(a1) 1,3- propane diamine or Putriscine (25mmol) is taken to be dissolved in the triethylamine methanol solution of 15mL 10v%, in
By 10mmol Boc under ice bath2The methanol solution 10mL of O (2.15g) is slowly dropped into above-mentioned solution, and drop, which finishes, is warmed to room temperature stirring
12h；After completion of the reaction decompression steam solvent, residue is first extracted with dichloromethane, then be saturated Na2CO3Solution washing, is collected
Organic layer, anhydrous Na2SO4It is dry, it is concentrated to give compound 1；
(a2) it takes 2.25g (11.45mmol) compound 1 to be dissolved in 50mL acetonitrile, adds Anhydrous potassium carbonate 2.25g (16mmol),
After 15min is stirred at room temperature, 45 DEG C are warming up to, 2.28 (10.2mmol) 3- bromopropyl phthalimides or 4- bromine is added portionwise
Butyl phthalimide, in 45 DEG C of reaction 12h.Reaction terminates, and evaporating solvent under reduced pressure, residue is first extracted with methylene chloride
It takes, the Na of mass fraction 10% is used after extraction2CO3Aqueous solution washing, collected organic layer, anhydrous Na2SO4It is dry, after reduced pressure
It has been reacted in ethyl alcohol with a kind of two tert-butoxy formic acid anhydride reactant of 14.34mmol (3.08g) to raw material, decompression steams solvent,
The extraction of residue chloroform, washing；Product 2 is purified by flash to obtain with volume ratio petroleum ether: ethyl acetate=4:1；
(a3) it takes 1.05g (2.15mmol) compound 2 in 50mL dehydrated alcohol, adds hydrazine hydrate 0.64g (12.5mmol),
12h, evaporating solvent under reduced pressure is stirred at room temperature, residue is first extracted with dichloromethane, then with the Na of mass fraction 10%2CO3Aqueous solution
Washing, collected organic layer are concentrated to give compound 3, do not need to be separated and be directly used in the next step；
(a4) it takes 4mmol compound 3 to be dissolved in 25mL acetonitrile, adds Anhydrous potassium carbonate 1.13g (8mmol), 15min is stirred at room temperature
Afterwards, 45 DEG C are warming up to, 1.04g (4mmol) N- (3- bromopropyl) phthalimide is added portionwise, in 45 DEG C of reaction 12h.Instead
It should terminate, evaporating solvent under reduced pressure, residue is first extracted with dichloromethane, then with mass fraction 10%Na2CO3Solution washing, is collected
Organic layer, anhydrous Na2SO4It is dry, after reduced pressure in ethyl alcohol with two tert-butoxy formic acid anhydride reactant of 9.6mmol (2.07g),
Decompression steams solvent, the extraction of residue chloroform, and washing is purified by flash to obtain product 4 with volume ratio Shi You Mi ︰ ethyl acetate=4:1；
Compound 4 is dissolved in 25mL dehydrated alcohol, adds hydrazine hydrate 0.64g (12.5mmol), is stirred overnight at room temperature, remove under reduced pressure molten
Agent, residue are first extracted with dichloromethane, then with the Na of mass fraction 10%2CO3Solution washing, collected organic layer are concentrated to give N,
N- dimethyl-ethylenediamine, does not need to be separated and is directly used in the next step；
(b1) it takes 4.5mmoL (0.69g) compound 6 to mix with 0.63mL phosphorus oxychloride, N, N- is slowly added by dropping funel
Dimethylformamide 0.63mL is finished and is poured into 13.5mL ice water after reacting 3h with 90~95 DEG C, and stirring has a large amount of brown viscous
Solid generates, and decompression filters, and washes to obtain compound 7；
(b2) it takes 15mmol (2.04g) o-hydroxyacetophenone in 100mL round-bottomed flask, 19.5mmol (3.55g) is added to change
Object 7 is closed, adds ethyl alcohol 11mL, then magnetic agitation under ice bath, solution is in yellow, after its all dissolution, uses constant pressure funnel
The 50% solution 12g that is made by 6mL water and 6g potassium hydroxide solid is added dropwise, then when in bottle solid remove ice after completely dissolution
Bath, is transferred to oil bath, and under stiring, 52 DEG C of reaction 5.5h of maintaining reaction temperature, after reaction, reaction solution are in brownish red, so
After steam part ethyl alcohol, reaction solution after cooling is poured into and is about filled in 200mL ice water, orange red flocculent deposit is generated, with HCL tune
PH to 3-4 or so has a large amount of peony flocculent deposits to generate, and stands decompression and filters, collects Chinese red solid；
(b3) 11.5mmol (3.45g) Orange red solid obtained above is taken to be put in 250mL round-bottomed flask, then successively
35.5mmol (2.0g) KOH and 150mL methanol is added, adds and is ground block-like solid with mortar when potassium hydroxide, make
Preferably dissolution in a solvent, under ice bath stirring after solid is completely dissolved in bottle, is slowly added dropwise with constant pressure funnel for it
30% hydrogen peroxide of 22.5mL drips off in 20min, and drop, which finishes, to be removed ice bath recovery and be stirred overnight at room temperature, and steams portion after reaction
Point methanol, about to residue 80mL solution when, rear that about 75mL ice water is added, dilute hydrochloric acid neutralizes, have a large amount of orange-yellow precipitatings generations,
Decompression filters, and obtains compound 8；
(b4) it takes the compound 8 walked on 7.96mmol (2.5g) in the round-bottomed flask of 250mL, 60mL is then added
Acetone after tepidarium is completely dissolved, sequentially adds 24mmol (2.4g) potassium carbonate and 31mmol (3.9g) dimethyl suflfate,
Flow back 5h at 56 DEG C, and after reaction, appropriate diluted sodium hydroxide solution is slowly added dropwise in solvent evaporated, is in neutrality solution or weak
Alkalinity will sufficiently rock during dropwise addition, contact solution sufficiently with unreacted dimethyl suflfate, unreacted to remove
Then dimethyl suflfate is extracted with dichloromethane, collect organic phase, and after adding anhydrous sodium sulfate dry, decompression is filtered, and uses dichloromethane
Alkane washing, until anhydrous sodium sulfate is white, collection filtrate is evaporated gains silica gel column separating purification and obtains product 9；
(b5) it takes 7.5mmol (2.45g) compound 9 obtained above to be put into 250mL round-bottomed flask, sequentially adds 33mL
Glacial acetic acid, 12.4g potassium bichromate, are eventually adding 0.5mL sulfuric acid, at this point, solution is in orange-yellow, it is cooling after being heated to reflux 5h
0.5h pours into reaction solution in 100mL ice water, has a large amount of dirty-green flocculent deposits to generate, and stands, and decompression filters, washing.By institute
It obtains solid to collect, vacuum oven is sufficiently dry, obtains compound 10；Take compound 10 obtained by 2mmol (0.75g) in 100mL circle
In the flask of bottom, 2.8mmol N is then added, N- dimethyl-ethylenediamine is added appropriate dehydrated alcohol, makes it completely dissolved, and heats
Flow back 3h, and solution is brown, and solvent is evaporated by the yellow mercury oxide that reaction flask bottom has part insoluble, rear silica gel column separating purification
(volume ratio Er Lv Jia Wan ︰ methanol=100:5 is purified by flash to obtain sterling 11a；Take compound 11a obtained by 1mmol in the anhydrous second of 10mL
In alcohol, the ethyl alcohol (V of 4M HCl is added dropwise under ice bath stirring4M hydrochloric acid:VEthyl alcohol=1:2) solution 0.5mL, drop finishes, and 12h is stirred at room temperature to big
It measures solid to occur, solid is collected in filtering, is washed three times with the steamed dehydrated alcohol of weight, dry compound 12a, yield:
86%:1H NMR (300MHz, DMSO) δ: 8.56~8.64 (m, 2H, Ar-H), 8.04 (d, J=5.60Hz, 1H, Ar-H),
8.19 (t, J=8.62Hz, 1H, Ar-H)；7.82~7.93 (m, 2H, Ar-H), 7.68 (d, J=5.68Hz, 1H, Ar-H),
7.59 ((t, J=8.23Hz, 1H, Ar-H), 4.21 (t, J=6.28Hz, 1H, Ar-H), 3.06 (s, 3H, 1 × O-CH3),2.61
~2.64 (m, 2H, 1 × CH2)；2.29(s,6H,2×CH3).13C NMR(75MHz,DMSO)δ179.00,168.65,
168.39,160.60,159.64,147.01,139.56,139.18,137.13,136.47,138.08,134.41,134.05,
133.51,132.74,130.62,130.38,129.37,129.22,127.74,123.78,65.31,61.15,
49.84.ESI-MI m/z:443.3[M+H-HCl]+.Anal.calcd for C26H23ClN2O5: C 65.20, H 4.84%, N
5.85；Found C 65.38%, H 5.01%, N5.49%.
Embodiment 2:
6- [2- (3- methoxyl group -4H-1- benzopyran-4-one)] -2- [(4- amino)-butyl] -1H- benzisoquinoline -
1,3 (2H)-diketone } hydrochloride (12b) preparation:
Except (b5) Bu Zhongyong 1b replaces N, 2mL 4M HCl ethyl alcohol (V is added dropwise in N- dimethyl-ethylenediamineHydrochloric acid:VEthyl alcohol=1:2)
Outside solution, other synthesizing progress methods are the same as embodiment 1.Yield: 86%:1H NMR (300MHz, DMSO) δ: 8.62 (d, J=
7.53Hz, 1H, Ar-H), 8.55 (d, J=6.75Hz, 1H, Ar-H), 8.37 (d, J=8.31Hz, 1H, Ar-H), 8.16 (t, J
=7.23Hz, 2H, Ar-H), 8.01 (s, 2H, NH-H), 7.81~7.92 (m, 2H, Ar-H), 7.66 (d, J=8.40Hz, 1H,
), Ar-H 7.54 (t, J=7.51Hz, 1H, Ar-H), 4.10 (t, J=6.39Hz, 2H, 1 × N-CH2),3.65(s,3H,1×O-
CH3),2.83(s,2H,1×NH2-CH2), 1.65~1.74 (m, 4H, 2 × CH2).13C NMR(75MHz,DMSO+D2O)δ
174.53,163.87,163.58,155.61,155.05,142.11,135.02,134.15,132.09,131.80,130.39,
129.59,129.04,128.74,127.68,125.97,125.50,124.15,124.09,122.55,118.80,60.70,
24.56.ESI-MS m/z:430.2[M+1-HCl]+.Anal.calcd for C26H24Cl2N2O55: C 60.59%, H
4.69%, N 5.44%；Found C 60.64%, H4.50%, N 5.42%.
Embodiment 3:
6- [2- (3- methoxyl group -4H-1- benzopyran-4-one)]-{ 2- [3- (3- aminopropyl)-aminopropyl] 1H- benzene
And isoquinolin -1,3 (2H) -one dihydrochloride (12c) preparation:
Except (b5) Bu Zhongyong 3a replaces N, 2mL 4M HCl ethanol solution (V is added dropwise in N- dimethyl-ethylenediamine4M hydrochloric acid:VEthyl alcohol
=1:2) outside, other synthesizing progress methods are the same as embodiment 1.Yield: 86%, white solid:1H NMR(300MHz,D2O)δ:
8.16 (t, J=7.59Hz, 2H, Ar-H), 7.74~7.82 (m, 2H, Ar-H), 7.65 (d, J=7.89Hz, 2H, Ar-H),
7.49 (t, J=7.80Hz, 2H, Ar-H), 7.33 (t, J=7.53Hz, 1H, Ar-H), 7.20 (t, J=7.50Hz, 1H, Ar-
H), 6.95 (d, J=8.31Hz, 1H, Ar-H), 4.15 (t, J=5.40Hz, 2H, 1 × N-CH2),3.43(s,3H,1×O-
CH3), 3.29 (t, J=7.69Hz, 4H, 2 × CH2), 3.21 (t, J=7.77Hz, 2H, 1 × CH2), 2.15~2.27 (m, 4H, 2
×CH2).13C NMR(75MHz,D2O)δ175.15,164.26,163.88,154.72,154.31,141.40,134.66,
133.12,131.84,131.67,129.98,129.23,127.82,127.69,126.75,125.37,124.33,122.54,
122.30,120.83,117.38,60.74,45.56,44.79,37.50,36.64,24.38,23.84.ESI-MI m/z:
486.20[M+H-2HCl]+.Anal.calcd for C28H29Cl2N3O5: C 60.22%, H5.23%, N 7.52%；found
C 60.37%, H 5.51%, N 7.45%.
Embodiment 4:
6- [2- (3- methoxyl group -4H-1- benzopyran-4-one)]-{ 2- [(4- aminobutyl)-aminobutyl] 1H- benzo
Isoquinolin -1,3 (2H) -one } dihydrochloride (12d) preparation:
Except (b5) Bu Zhongyong compound 3b replaces N, 1.0mL 4M HCl ethanol solution is added dropwise in N- dimethyl-ethylenediamine
(V4M hydrochloric acid:VEthyl alcohol=1:2) outside, other synthesizing progress methods are the same as embodiment 1.Yield: 86%, white solid:1H NMR
(300MHz,D2O) δ: 8.08 (d, J=7.35Hz, 2H, Ar-H), 7.78 (d, J=8.43Hz, 1H, Ar-H), 7.71 (d, J=
7.75Hz, 1H, Ar-H), 7.62 (d, J=7.98Hz, 1H, Ar-H), 7.44 (t, J=7.89Hz, 1H, Ar-H), 7.32 (t, J
=7.50Hz, 1H, Ar-H), 7.17 (t, J=7.48Hz, 1H, Ar-H), 6.94 (d, J=8.28Hz, 1H, Ar-H), 3.98 (t,
J=6.87Hz, 2H, 1 × N-CH2),3.40(s,3H,1×O-CH3), 3.13~3.15 (m, 4H, 1 × CH2), 3.04~3.08
(m,2H,1×CH2), 1.73~1.81 (m, 8H, 4 × CH2).13C NMR(75MHz,D2O)δ175.54,164.38,163.96,
154.91,154.54,141.41,134.75,132.87,131.87,131.51,129.91,129.28,127.84,127.70,
126.76,125.42,124.45,122.69,122.35,120.98,117.45,60.78,47.18,46.94,39.80,
38.83,24.39,23.97,23.27,22.82.ESI-MI m/z:514.23[M+H-2HCl]+.Anal.calcd for
C30H33Cl2N3O5: C 61.44%, H 5.67%, N 7.16%；Found C 61.36%, H 5.90%, N 7.49%.
Embodiment 5:
6- [2- (3- methoxyl group -4H-1- benzopyran-4-one)]-{ 2- [3- (3- (3- aminopropyl) aminopropyl)-ammonia
Base propyl]-amine 1H- benzisoquinoline -1,3 (2H) -one tri hydrochloride (12e) preparation:
Except (b5) Bu Zhongyong compound 5a replaces N, 2mL 4M HCl ethanol solution is added dropwise in N- dimethyl-ethylenediamine
(V4M hydrochloric acid:VEthyl alcohol=1:2) outside, other synthesizing progress methods are the same as embodiment 1.Yield: 86%, white solid:1H NMR
(300MHz,D2O) δ: 8.19 (d, J=3.30Hz, 2H, Ar-H), 7.79~7.87 (m, 2H, J=8.0Hz, Ar-H), 7.67
(d, J=8.46Hz, 1H, Ar-H), 7.53 (t, J=7.38Hz, 1H, Ar-H), 7.38 (t, J=5.54Hz, 1H, Ar-H),
7.23 (t, J=7.29Hz, 1H, Ar-H), 6.98~7.00 (m, 1H, Ar-H), 4.17 (t, J=6.85Hz, 2H, 1 × N-CH2,
3.43(s,3H,1×O-CH3), 3.24~3.30 (m, 8H, 4 × CH2), 3.16 (t, J=7.77Hz, 2H, 1 × CH2), 2.10~
2.29(m,6H,3×CH2).13C NMR(75MHz,D2O)δ175.23,164.26,163.87,154.75,154.33,
141.41,134.65,133.12,131.84,131.67,130.00,129.24,127.83,127.70,126.74,125.39,
124.39,122.54,122.31,120.83,117.39,60.77,45.62,44.79,44.72,37.58,36.59,24.40,
23.79,22.80.ESI-MI m/z:543.3[M+H-3HCl]+.Anal.calcd for C31H37Cl3N4O5: C 57.11%, H
5.72%, N 8.59%；Found C 56.86%, H 6.01%, N 8.43%.
Embodiment 6:
6- [2- (3- methoxyl group -4H-1- benzopyran-4-one)]-{ 2- [3- (4- (3- aminopropyl) aminobutyl)-ammonia
Base propyl]-amine 1H- benzisoquinoline -1,3 (2H) -one tri hydrochloride (12f) preparation:
Except (b5) Bu Zhongyong compound 5c replaces N, 3mL4M HCl ethanol solution is added dropwise in N- dimethyl-ethylenediamine
(V4M hydrochloric acid:VEthyl alcohol=1:2) outside, other synthesizing progress methods are the same as embodiment 1.Yield: 86%:1H NMR(300MHz,D2O)δ:
8.24~8.27 (m, 2H, Ar-H), 7.95 (d, 1H, J=8.52Hz, Ar-H), 7.88 (d, J=7.68Hz, 1H, Ar-H),
7.72 (d, J=7.71Hz, 1H, Ar-H), 7.60 (t, J=7.85Hz, 1H, Ar-H), 7.44 (t, 1H, J=7.31Hz, Ar-
), H 7.28 (t, J=7.69Hz, 1H, Ar-H), 7.05 (t, J=8.40Hz, 1H, Ar-H), 4.20 (t, J=6.39Hz, 2H, 1
×N-CH2),3.42(s,3H,1×O-CH3), 3.09~3.25 (m, 10H, 5 × CH2), 2.05~2.18 (m, 4H, 2 × CH2),
1.83-1.85(m,4H,2×CH2).13C NMR(75MHz,D2O)δ175.84,164.83,164.40,155.41,154.63,
141.49,134.88,134.81,133.17,132.23,131.97,130.08,129.43,127.96,127.80,126.97,
125.39,124.40,122.76,122.33,121.01,117.64,60.83,57.36,47.00,45.34,44.51,
37.48,36.48,24.36,23.71,22.80,16.72.ESI-MI m/z:557.4[M+H-3HCl]+.Anal.calcd
for C32H39Cl3N4O5: C 57.71%, H 5.90%, N 8.41%；Found C 58.00%, H 5.84%, N
8.58%.
Embodiment 7:
6- [2- (3- methoxyl group -4H-1- benzopyran-4-one)]-{ 2- [4- (4- (4- aminobutyl) aminobutyl)-ammonia
Base butyl]-amine 1H- benzisoquinoline -1,3 (2H) -one tri hydrochloride (12g) preparation:
Except (b5) Bu Zhongyong compound 5b replaces N, 1.5mL 4M HCl ethanol solution is added dropwise in N- dimethyl-ethylenediamine
(V4M hydrochloric acid:VEthyl alcohol=1:2) outside, other synthesizing progress methods are the same as embodiment 1.Yield: 86%, white solid:1H NMR
(300MHz,D2O) δ: 8.25 (t, J=6.03Hz, 2H, Ar-H), 7.94 (d, J=7.92Hz, 1H, Ar-H), 7.87 (d, J=
6.96Hz, 1H, Ar-H), 7.75 (d, J=7.98Hz, 1H, Ar-H), 7.61 (t, J=7.77Hz, 1H, Ar-H), 7.44 (t, J
=6.99Hz, 1H, Ar-H), 7.30 (t, J=7.50Hz, 1H, Ar-H), 7.09 (t, J=8.22Hz, 1H, Ar-H), 4.10 (s,
2H,1×N-CH2),3.45(s,3H,1×O-CH3), 3.07~3.20 (m, 10H, 5 × N-CH2), 1.81~1.84 (m, 2H, 1
×CH2).13C NMR(75MHz,D2O)δ175.28,164.08,163.70,154.84,154.42,141.52,134.63,
133.07,131.76,131.61,129.89,129.19,127.79,127.58,126.71,125.42,124.47,122.64,
122.38,120.94,117.40,60.77,47.23,46.97,39.81,38.84,24.40,23.95,23.31,22.91,
22.88,22.79.ESI-MI m/z:584.4[M+H-3HCl]+.Anal.calcd for C34H43Cl3N4O5: C 58.83%, H
6.24%, N 8.07%；Found C 58.65%, H 6.34%, N 8.03%.
Biological evaluation
(1) Compound ira vitro inhibits tumor cell growth activity measurement:
The compound of selection example 1-7 preparation, the HCT-116 (human colon cancer cell) of difference logarithmic growth phase,
HepG2 (human liver cancer cell), Hela (human cervical carcinoma cell), four kinds of tumor cell lines of SMMC7721 (human liver cancer cell) and QSG-
7701 (Human normal hepatocytes) are embedded to 96 orifice plates, 90 holes μ L/ with 5000-8000, every hole cell.After culture for 24 hours, addition 10,
50,100,300,500 μM of sample, to each cell strain, each concentration is there are four multiple holes, at 37 DEG C, 5v%CO2Under the conditions of
After cultivating 48h, add 50 μ L (i.e. thiazolyl blue) of MTT, continues to abandon supernatant after cultivating 4h, every hole is added 100 μ L DSMO, gently vibrates
15min surveys its absorbance A value with microplate reader at 570nm wavelength.Measured object is calculated to different tumour cells by following formula
The inhibiting rate of growth, experiment in triplicate, and find out IC50 value by statistical software.It the results are shown in Table 1, wherein growth of tumour cell
Inhibiting rate (%)=(OD control-OD experiment)/(OD control-OD blank) × 100%.
The growth inhibitory activity of each embodiment compound on tumor cell of table 1.
The compound of embodiment 1 to 7 is respectively to HCT-116 (human colon cancer cell), HepG2 it can be seen from 1 data of table
The cytotoxicity of (human liver cancer cell), Hela (human cervical carcinoma cell), SMMC7721 (human liver cancer cell) four kinds of tumour cells
Aspect plays different degrees of effect, shows more to the proliferation of kinds of tumor cells in vitro compared to control drug ammonia naphthalene Fitow
Apparent inhibitory activity.Wherein the rejection ability of 1,3,6 pair of four kinds of tumor cell line of embodiment is better than positive control；Embodiment 7
Sample control is weaker than to the rejection ability of hepatocellular carcinoma H22 and SMMC7721, but is had preferably to Hela and HCT-116 cell
Selection selectivity；Especially 6 compound of embodiment has preferable selectivity to tri- kinds of tumour cells of HCT-116, HepG2, Hela,
Show that such compound can effectively inhibit the proliferation of tested tumor cell line, the potentiality with druggability.
Above-described embodiment be embodiment of the present invention for example, embodiments of the present invention not by above-described embodiment
Limitation, it is other any without departing from made changes, modifications, substitutions, combinations, simplifications under spirit of the invention and principle,
It should be equivalent substitute mode, be included within the scope of the present invention.
Claims (6)
1. flavones-polyamines conjugate that a kind of naphthalimide replaces, which is characterized in that have structure shown in Formulas I:
Wherein a takes 0,1 or 2；M takes 1,2 or 3；N takes 1,2,3 or 4；R1For X takes 1,2 or 3.
2. flavones-polyamines conjugate that naphthalimide according to claim 1 replaces, which is characterized in that the R1For
3. flavones-polyamines conjugate preparation method that naphthalimide of any of claims 1 or 2 replaces, which is characterized in that packet
Include following steps:
(b1) compound 6 and phosphorus oxychloride, n,N-Dimethylformamide reaction are placed in water, and decompression filters to obtain compound 7；
(b2) compound 7 in KOH solution withSolid is reacted to obtain, solid is reacted in acetone with hydrogen peroxide
Compound 8；
(b3) compound 8 reacts prepare compound 9 with dimethyl suflfate in acetone；
(b4) compound 9 is in glacial acetic acid liquid with potassium dichromate oxidation prepare compound 10；
(b5) compound 10 withIt flows back in dehydrated alcohol, product column separating purification obtains compound 11；
Compound 11 stirs in dehydrated alcohol with the mixed liquor of hydrochloric acid, and the compound up to Formulas I structure is washed in filtering；
The structural formula of compound 6 isThe structural formula of compound 7 isThe structural formula of compound 8 isThe structural formula of compound 9 isThe structural formula of compound 10 is
4. preparation method according to claim 3, which is characterized in that in step (5b) compound 10 withMolar ratio be 1 ︰ (1-2).
5. flavones-polyamines conjugate that naphthalimide of any of claims 1 or 2 replaces answering in preparation tumor therapeutic agent
With.
6. application according to claim 5, which is characterized in that the tumour refers to human colon carcinoma, human liver cancer or people's uterine neck
Cancer.
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| LI, XIANG: "3-O-Substituted-3",4",5"-trimethoxyflavonols: Synthesis and cell-based evaluation as anti-prostate cancer agents", 《BIOORGANIC & MEDICINAL CHEMISTRY》 * |
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