CN109020857A - Plumbagin selenide analog derivative and its preparation and application - Google Patents
Plumbagin selenide analog derivative and its preparation and application Download PDFInfo
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- CN109020857A CN109020857A CN201811300122.7A CN201811300122A CN109020857A CN 109020857 A CN109020857 A CN 109020857A CN 201811300122 A CN201811300122 A CN 201811300122A CN 109020857 A CN109020857 A CN 109020857A
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- 0 CC(C(c1cccc(OCCS*)c11)=O)=CC1=O Chemical compound CC(C(c1cccc(OCCS*)c11)=O)=CC1=O 0.000 description 10
- WSCIDIDGVSKNDO-YMEBTKBKSA-N C/C(/C(/C=C/C=C\C(\OCCSc1ccccc1)=C1)=O)=C/C1=O Chemical compound C/C(/C(/C=C/C=C\C(\OCCSc1ccccc1)=C1)=O)=C/C1=O WSCIDIDGVSKNDO-YMEBTKBKSA-N 0.000 description 1
- YRNJEIGNLYDKQJ-UHFFFAOYSA-N CCC1C=CC=CC1 Chemical compound CCC1C=CC=CC1 YRNJEIGNLYDKQJ-UHFFFAOYSA-N 0.000 description 1
- NPDACUSDTOMAMK-UHFFFAOYSA-N Cc(cc1)ccc1Cl Chemical compound Cc(cc1)ccc1Cl NPDACUSDTOMAMK-UHFFFAOYSA-N 0.000 description 1
- QZLOQERDALCPPX-UHFFFAOYSA-N Cc1cccc([SiH2]CCOC(C2C(C=C3C)=O)C=CC=C2C3=O)c1 Chemical compound Cc1cccc([SiH2]CCOC(C2C(C=C3C)=O)C=CC=C2C3=O)c1 QZLOQERDALCPPX-UHFFFAOYSA-N 0.000 description 1
- JQLPZBNYQCHXSI-UHFFFAOYSA-N Fc(cc1)ccc1SCCBr Chemical compound Fc(cc1)ccc1SCCBr JQLPZBNYQCHXSI-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C391/00—Compounds containing selenium
- C07C391/02—Compounds containing selenium having selenium atoms bound to carbon atoms of six-membered aromatic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
- A61P39/06—Free radical scavengers or antioxidants
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C391/00—Compounds containing selenium
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/04—One of the condensed rings being a six-membered aromatic ring
- C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline
Abstract
The present invention provides plumbagin selenide analog derivatives and the preparation method and application thereof shown in a kind of formula (V), the plumbagin selenide analog derivative synthesis technology is simple, there are preferable antioxidant activity and anti-tumor activity, there is good application value；
Description
(1) technical field
The present invention relates to plumbagin selenide analog derivative and its preparation and application.
(2) background technique
Plumbagin (IV) is the root extract of medicinal plant Plumbago zeylanica, is a kind of natural naphthoquinone compound, tool
There are many biological activities, including anti-oxidant, antiatherosclerosis, antitumor, antibacterium and fungi etc., are especially in the whole world
One band of Southeast Asia is widely used.
Selenium is the essential trace elements of the human body, has irreplaceable role.Storage of the organic selenium in human body inner tissue,
Absorption is easier to；It can be utilized rapidly after absorption of human body selenium, blood selenium situation in human body can be effectively improved.Selenium can directly act on
Virus inhibits the duplication of virus in vivo, and can participate in the reparation of cell, prevents a variety of viruses and disease (such as hepatitis B, carditis
Deng).More than the 40 kinds of diseases of the mankind are all too low related to human body Se content, as cancer, pancreatic disease, cardiovascular disease, cataract,
Diabetes, hepatopathy, genital system diseases etc. can make human immunological competence decline when selenium deficiency, threaten human health
And life.Therefore, biological active selenium is introduced to plumbagin structure, it would be possible to anti-oxidant and anti-tumor activity can be greatly improved,
As the new plumbagin drug derivative with potential medical value.
The present invention is to obtain plumbagin selenide class by having carried out chemical modification to the hydroxyl in plumbagin structure and spread out
Biology has detected its antioxidant activity, and detect its to human pancreatic cancer cell (CFPAC-1), human lung carcinoma cell (A549), in
The rejection ability of state's hamster pneumonocyte (CHL), it is good anti-oxidant that result of study shows that plumbagin selenide analog derivative has
Activity and anti-tumor activity, can be developed into as relevant drug.
(3) summary of the invention
It is an object of the present invention to provide a kind of plumbagin selenide analog derivatives and preparation method thereof and the analog derivative to exist
The application in anti-oxidant and anti-tumor activity medicine is prepared, the analog derivative synthesis technology is simple, there is preferable antioxidant activity
And anti-tumor activity, there is good application value.
Technical scheme is as follows:
Plumbagin selenide analog derivative shown in a kind of formula (V):
In formula (V), R be C1-C10 alkyl, aryl, naphthalene, benzyl orThe aryl is benzene
The phenyl that base or o-, m- or p- position replace, the substituent group on phenyl are selected from C1-C3 alkyl or halogen；
Further, plumbagin selenide analog derivative preferably of the present invention is one of following:
It is described the present invention also provides a kind of preparation method of plumbagin selenide analog derivative shown in formula (V)
Method are as follows:
(1) under the conditions of anhydrous and oxygen-free, by compound shown in formula (I), a hydronium(ion) cesium oxide, 4A molecular sieve and solvent DMF
(n,N-Dimethylformamide) mixing, (20~30 DEG C) stirrings (1h) of room temperature obtain mixed liquor, gained mixed liquor are added drop-wise to formula
(II) it in the DMF solution of compound shown in, dripping off rear room temperature and is stirred to react, TLC is monitored to fully reacting (usually 8~12h),
Reaction solution is post-treated later, obtains compound shown in formula (III)；
The ratio between amount of substance of compound shown in the formula (I), compound, a hydronium(ion) cesium oxide shown in formula (II) is 1:
5~8:1~3, preferably 1:6:1；
The quality dosage of the 4A molecular sieve is calculated as 0.1~0.5g/mmol with the amount of the substance of compound shown in formula (I),
It is preferred that 0.2g/mmol；
The volumetric usage of the solvent DMF is calculated as 2~6mL/mmol with the amount of the substance of compound shown in formula (I), preferably
3mL/mmol；
The concentration of compound shown in formula (II) is in 5~10mmol/mL in the DMF solution of compound shown in the formula (II),
It is preferred that 6mmol/mL；
The method of the post-processing are as follows: after reaction, through filtering, filter cake is washed reaction solution with ether, merging filtrate and
Cleaning solution is evaporated off solvent and carries out column chromatography for separation successively after washing, saturated common salt water washing, anhydrous sodium sulfate are dry, with
200~300 mesh silica gel are column packing, and petroleum ether is eluant, eluent, collect the eluent containing target compound, solvent is evaporated off and does
It is dry, obtain compound shown in formula (III)；
(2) under the conditions of anhydrous and oxygen-free, compound shown in formula (III), silver nitrate, plumbagin (IV) and solvent acetonitrile is mixed
It closes, reaction is stirred at room temperature, TLC is monitored to fully reacting (usually 1~3h), and reaction solution is post-treated later, obtains formula (V) institute
Show product；
The ratio between amount of substance of compound shown in the formula (III), silver nitrate, plumbagin (IV) is 1:1~3:1~3,
It is preferred that 1:1:1；
The volumetric usage of the solvent acetonitrile is calculated as 5~10mL/mmol with the amount of the substance of compound shown in formula (III),
It is preferred that 6mL/mmol；
The method of the post-processing are as follows: after reaction, through filtering, filter cake is washed reaction solution with ether, merging filtrate and
Cleaning solution is evaporated off solvent and carries out column chromatography for separation successively after washing, saturated common salt water washing, anhydrous sodium sulfate are dry, with
200~300 mesh silica gel are column packing, and the mixed liquor of petroleum ether and ethyl acetate volume ratio 8:1 are eluant, eluent, collect and contain targeted
The eluent for closing object, is evaporated off solvent and drying, obtains product shown in formula (V)；
Reaction equation is as follows:
In formula (I) or (III), the definition of R is identical with formula (V).
In addition, compound shown in Chinese style (V-10) of the present invention can also be prepared as follows:
Under the conditions of anhydrous and oxygen-free, compound shown in formula (VI), silver nitrate, plumbagin (IV) and solvent acetonitrile are mixed,
Reaction is stirred at room temperature, TLC is monitored to fully reacting (usually 3h), and reaction solution is post-treated later, is obtained shown in formula (V-10)
Product；
Wherein, compound shown in formula (VI) can refer to Potapov, the preparation method of the reports such as V.A.: Russian
Journal of Organic Chemistry,2014,50(2),291-292.
The ratio between amount of substance of compound shown in the formula (VI), silver nitrate, plumbagin (IV) is 1:2~4:2~4,
It is preferred that 1:2:2；
The volumetric usage of the solvent acetonitrile is calculated as 5~10mL/mmol with the amount of the substance of compound shown in formula (VI), excellent
Select 8mL/mmol；
The method of the post-processing are as follows: after reaction, through filtering, filter cake is washed reaction solution with ether, merging filtrate and
Cleaning solution is evaporated off solvent and carries out column chromatography for separation successively after washing, saturated common salt water washing, anhydrous sodium sulfate are dry, with
200~300 mesh silica gel are column packing, and the mixed liquor of petroleum ether and ethyl acetate volume ratio 8:1 are eluant, eluent, collect and contain targeted
The eluent for closing object, is evaporated off solvent and drying, obtains product shown in formula (V-10)；
Reaction equation is as follows:
Plumbagin selenide analog derivative of the present invention can be used for preparing anti-tumor activity medicine, thin to human pancreas cancer
Born of the same parents (CFPAC-1), human lung carcinoma cell (A549), CHL cells (CHL) have preferable inhibitory activity.
Plumbagin selenide analog derivative of the present invention can be also used for preparing anti-oxidation medicine, the plumbagin selenium
Ether derivative can remove DPPH, ABTS and superoxide radical (O2 -)。
Compared with prior art, the beneficial effects are mainly reflected as follows:
(1) present invention is reacted by selenide (III) with plumbagin (IV), and it is derivative to be prepared for new plumbagin selenide class
Object；
(2) such plumbagin derivative has antioxidant activity and anti-tumor activity, and wherein plumbagin selenide class is spread out
Biological (V-3), (V-4), (V-6), (V-7), (V-10) have good antioxidant effect, can remove DPPH, ABTS and super oxygen
Free radical (O2 -)；Formula (V-3), (V-7), plumbagin selenide analog derivative shown in (V-10) are to human pancreatic cancer cell (CFPAC-
1), human lung carcinoma cell (A549) has good inhibitory activity, much higher than the inhibitory activity of plumbagin itself；
(3) resulting through the invention to go out plumbagin derivative as the result is shown in drug development system with wide
Application prospect provides new broader thinking and method to synthesize and screening plumbagin drug derivative, to be correlation
The treatment of disease provides significantly more efficient approach.
(4) specific embodiment
The present invention is described further combined with specific embodiments below, but protection scope of the present invention is not limited in
This.
Embodiment 1: the preparation of plumbagin phenyl selenide (V-1)
(1) by taking the preparation method of bromo selenide (III-1) as an example, illustrate bromo selenide (III) used in the present invention
Preparation method, the specific method is as follows:
Reaction equation is as follows:
Under dry nitrogen atmosphere, be added into 30mL anhydrous DMF 2g just dried powdered 4A molecular sieve,
1.679g (10mmol) hydronium(ion) cesium oxide, 1.571g (10mmol) phenyl selenium phenol (I-1), open that be stirred to react 1 small at room temperature
Shi Hou is quickly transferred to constant pressure titration funnel, and is slowly dropped into 11.268g (60mmol) 1, the 2- Bromofume (II) that stirred
In DMF (10mL) solution.About 5 hours drop finish (if during dropwise addition solid powder blocking titration funnel, should be in a nitrogen atmosphere
Carefully dredged with minute hand), then react at room temperature 10 hours.Stop reacting, filter, with 300mL washed with ether；Organic layer is washed with water
(200mL × 3), saturated common salt water washing (120mL × 2), anhydrous sodium sulfate are dry；Boil off solvent ether and excessive 1,2- bis-
Bromoethane, obtained grease uses column chromatography, and (petroleum ether purifies to obtain bromo selenide (III- as eluant, eluent, Rf=0.5-0.7)
1), yield 79%.Its structural characterization is as follows:
HRMS(ESI)calcd for C8H9BrSe m/z:263.9053；Found:263.9061.
(2) preparation of plumbagin phenyl selenide (V-1)
Reaction equation is as follows:
Under dry nitrogen atmosphere, into 30mL anhydrous acetonitrile be added 1.320g (5mmol) bromo selenide (III-1),
0.770g (5mmol) silver nitrate, 0.941g (5mmol) plumbagin (IV), open after being stirred to react 1 hour at room temperature, stop reacting,
Filtering, with 100mL washed with ether；Organic layer is washed with water (100mL × 3), saturated common salt water washing (80mL × 2), anhydrous slufuric acid
Sodium is dry；Solvent ether is boiled off, obtained white flower is purified with column chromatography (petroleum ether: ethyl acetate=8:1, Rf=0.5-0.7)
Red element phenyl selenide (V-1) 1.50g, yield 81%.Its structural characterization is as follows:
HRMS(ESI)calcd for C19H16O3Se m/z:372.0265；Found:372.0256.1H NMR
(500MHz,CDCl3)δ7.71-7.56(m,4H),7.29-7.17(m,3H),6.81-6.77(m,1H),6.74(s,1H),
4.23-4.21(m,2H),2.92-2.86(m,2H),2.21(s,3H)；13C NMR(125MHz,CDCl3)δ188.2,182.7,
160.1,149.2,136.0,135.8,133.7,131.8,128.3,126.9,123.3,122.8,119.6,115.9,65.8,
29.5,16.5.
Embodiment 2: the preparation of plumbagin p-methylphenyl selenide (V-2)
(1) in addition to formula (I-1) is replaced with formula (I-2) 1.711g (10mmol), the preparation method of bromo selenide (III-2)
With step (1), yield 78% in embodiment 1.Its structural characterization is as follows:
HRMS(ESI)calcd for C9H11BrSe m/z:277.9209；Found:277.9211.
Reaction equation is as follows:
(2) preparation of plumbagin p-methylphenyl selenide (V-2)
Reaction equation is as follows:
Under dry nitrogen atmosphere, into 30mL anhydrous acetonitrile be added 1.390g (5mmol) bromo selenide (III-2),
0.770g (5mmol) silver nitrate, 0.941g (5mmol) plumbagin (IV), operate step (2) in same embodiment 1, finally below
Obtain plumbagin p-methylphenyl selenide (V-2) 1.540g, yield 80%.Its structural characterization is as follows:
HRMS(ESI)calcd for C20H18O3Se m/z:386.0421；Found:386.0429.1H NMR
(500MHz,CDCl3) δ 7.70-7.69 (d, J=7.4Hz, 1H), 7.56-7.54 (d, J=7.2Hz, 1H), 7.48-7.46 (d,
J=8.0Hz, 2H), 6.97-6.95 (d, J=8.0Hz, 2H), 6.79-6.75 (m, 1H), 6.76 (s, 1H), 4.24-4.22 (m,
2H),2.93-2.87(m,2H),2.24(s,3H),2.21(s,3H)；13C NMR(125MHz,CDCl3)δ188.4,182.8,
160.7,149.0,136.3,135.2,131.8,129.4,128.3,123.5,122.7,120.6,119.8,116.2,65.7,
29.6,20.9,16.5.
Embodiment 3: the preparation of plumbagin p-fluorophenyl selenide (V-3)
(1) in addition to formula (I-1) is replaced with formula (I-3) 1.751g (10mmol), the preparation method of bromo selenide (III-3)
With step (1), yield 69% in embodiment 1.Its structural characterization is as follows:
HRMS(ESI)calcd for C8H8BrFSe m/z:281.8959；Found:281.8951.
Reaction equation is as follows:
(2) preparation of plumbagin p-methylphenyl selenide (V-3)
Reaction equation is as follows:
Under dry nitrogen atmosphere, into 30mL anhydrous acetonitrile be added 1.410g (5mmol) bromo selenide (III-3),
0.770g (5mmol) silver nitrate, 0.941g (5mmol) plumbagin (IV), operate step (2) in same embodiment 1, finally below
Obtain plumbagin p-fluorophenyl selenide (V-3) 1.440g, yield 74%.Its structural characterization is as follows:
HRMS(ESI)calcd for C19H15FO3Se m/z:390.0170；Found:390.0182.1H NMR
(500MHz,CDCl3) δ 7.71-7.70 (d, J=7.2Hz, 1H), 7.59-7.54 (m, 3H), 6.80-6.77 (m, 1H), 6.76
(s,1H),6.59-6.55(m,2H),4.24-4.22(m,2H),2.91-2.86(m,2H),2.21(s,3H).
Embodiment 4: the preparation of plumbagin rubigan selenide (V-4)
(1) in addition to formula (I-1) is replaced with formula (I-4) 1.915g (10mmol), the preparation method of bromo selenide (III-4)
With step (1), yield 70% in embodiment 1.Its structural characterization is as follows:
HRMS(ESI)calcd for C8H8BrClSe m/z:297.8663；Found:297.8671.
Reaction equation is as follows:
(2) preparation of plumbagin rubigan selenide (V-4)
Reaction equation is as follows:
Under dry nitrogen atmosphere, into 30mL anhydrous acetonitrile be added 1.492g (5mmol) bromo selenide (III-4),
0.770g (5mmol) silver nitrate, 0.941g (5mmol) plumbagin (IV), operate step (2) in same embodiment 1, finally below
Obtain plumbagin rubigan selenide (V-4) 1.684g, yield 83%.Its structural characterization is as follows:
HRMS(ESI)calcd for C19H15ClO3Se m/z:405.9875；Found:405.9869.1H NMR
(500MHz,CDCl3) δ 7.72-7.66 (m, 4H), 7.25-7.23 (d, J=8.1Hz, 2H), 6.94-6.92 (m, 1H), 6.79
(s,1H),4.20-4.17(m,2H),2.90-2.84(m,2H),2.20(s,3H)；13C NMR(125MHz,CDCl3)δ188.9,
182.6,160.2,149.2,136.1,135.0,131.2,129.1,128.4,123.3,122.8,120.9,119.2,
116.0,65.8,29.5,16.4.
Embodiment 5: the preparation of chlorphenyl selenide (V-5) between plumbagin
(1) in addition to formula (I-1) is replaced with formula (I-5) 1.915g (10mmol), the preparation method of bromo selenide (III-5)
With step (1), yield 68% in embodiment 1.Its structural characterization is as follows:
HRMS(ESI)calcd for C8H8BrClSe m/z:297.8663；Found:297.8675.
Reaction equation is as follows:
(2) between plumbagin chlorphenyl selenide (V-5) preparation
Reaction equation is as follows:
Under dry nitrogen atmosphere, into 30mL anhydrous acetonitrile be added 1.492g (5mmol) bromo selenide (III-5),
0.770g (5mmol) silver nitrate, 0.941g (5mmol) plumbagin (IV), operate step (2) in same embodiment 1, finally below
Chlorphenyl selenide (V-5) 1.623g between plumbagin, yield 80%.Its structural characterization is as follows:
HRMS(ESI)calcd for C19H15ClO3Se m/z:405.9875；Found:405.9888.1H NMR
(500MHz,CDCl3)δ7.73-7.59(m,3H),7.31-7.29(m,1H),7.25-7.23(m,2H),6.95-6.78(m,
2H),4.22-4.19(m,2H),2.89-2.83(m,2H),2.19(s,3H).
Embodiment 6: the preparation of plumbagin Chloro-O-Phenyl selenide (V-6)
(1) in addition to formula (I-1) is replaced with formula (I-6) 1.915g (10mmol), the preparation method of bromo selenide (III-6)
With step (1), yield 65% in embodiment 1.Its structural characterization is as follows:
HRMS(ESI)calcd for C8H8BrClSe m/z:297.8663；Found:297.8651.
Reaction equation is as follows:
(2) preparation of plumbagin Chloro-O-Phenyl selenide (V-6)
Reaction equation is as follows:
Under dry nitrogen atmosphere, into 30mL anhydrous acetonitrile be added 1.492g (5mmol) bromo selenide (III-6),
0.770g (5mmol) silver nitrate, 0.941g (5mmol) plumbagin (IV), operate step (2) in same embodiment 1, finally below
Obtain plumbagin Chloro-O-Phenyl selenide (V-6) 1.420g, yield 70%.Its structural characterization is as follows:
HRMS(ESI)calcd for C19H15ClO3Se m/z:405.9875；Found:405.9873.1H NMR
(500MHz,CDCl3)δ7.76-7.54(m,3H),7.23-7.13(m,2H),6.85-6.74(m,3H),4.23-4.19(m,
2H),2.90-2.85(m,2H),2.20(s,3H).
Embodiment 7: the preparation of plumbagin naphthalene selenide (V-7)
(1) in addition to formula (I-1) is replaced with formula (I-7) 2.071g (10mmol), the preparation method of bromo selenide (III-7)
With step (1), yield 72% in embodiment 1.Its structural characterization is as follows:
HRMS(ESI)calcd for C12H11BrSe m/z:313.9209；Found:313.9220.
Reaction equation is as follows:
(2) preparation of plumbagin naphthalene selenide (V-7)
Reaction equation is as follows:
Under dry nitrogen atmosphere, into 30mL anhydrous acetonitrile be added 1.570g (5mmol) bromo selenide (III-7),
0.770g (5mmol) silver nitrate, 0.941g (5mmol) plumbagin (IV), operate step (2) in same embodiment 1, finally below
Obtain plumbagin naphthalene selenide (V-2) 1.685g, yield 80%.Its structural characterization is as follows:
HRMS(ESI)calcd for C23H18O3Se m/z:422.0421；Found:422.0435.1H NMR
(500MHz,CDCl3)δ7.99(s,1H),7.88-7.85(m,1H),7.77-7.69(m,3H),7.57-7.34(m,4H),
6.81-6.77(m,2H),4.21-4.18(m,2H),2.88-2.83(m,2H),2.20(s,3H).
Embodiment 8: the preparation of plumbagin benzyl selenide (V-8)
(1) in addition to formula (I-1) is replaced with formula (I-8) 1.711g (10mmol), the preparation method of bromo selenide (III-8)
With step (1), yield 73% in embodiment 1.Its structural characterization is as follows:
HRMS(ESI)calcd for C9H11BrSe m/z:277.9209；Found:277.9201.
Reaction equation is as follows:
(2) preparation of plumbagin benzyl selenide (V-8)
Reaction equation is as follows:
Under dry nitrogen atmosphere, into 30mL anhydrous acetonitrile be added 1.390g (5mmol) bromo selenide (III-8),
0.770g (5mmol) silver nitrate, 0.941g (5mmol) plumbagin (IV), operate step (2) in same embodiment 1, finally below
Obtain plumbagin benzyl selenide (V-8) 1.1.464g, yield 76%.Its structural characterization is as follows:
HRMS(ESI)calcd for C20H18O3Se m/z:386.0421；Found:386.0433.1H NMR
(500MHz,CDCl3) δ 7.69-7.68 (d, J=7.0Hz, 1H), 7.57-7.56 (d, J=7.2Hz, 1H), 7.13-7.00 (m,
5H),6.81-6.79(m,1H),6.77(s,1H),4.17-4.14(m,2H),3.71-3.68(m,2H),2.85-2.79(m,
2H),2.19(s,3H).
Embodiment 9: the preparation of plumbagin butyl selenide (V-9)
(1) in addition to formula (I-1) is replaced with formula (I-9) 1.371g (10mmol), the preparation method of bromo selenide (III-9)
With step (1), yield 66% in embodiment 1.Its structural characterization is as follows:
HRMS(ESI)calcd for C6H13BrSe m/z:243.9366；Found:243.9378.
Reaction equation is as follows:
(2) preparation of plumbagin butyl selenide (V-9)
Reaction equation is as follows:
Under dry nitrogen atmosphere, into 30mL anhydrous acetonitrile be added 1.220g (5mmol) bromo selenide (III-9),
0.770g (5mmol) silver nitrate, 0.941g (5mmol) plumbagin (IV), operate step (2) in same embodiment 1, finally below
Obtain plumbagin butyl selenide (V-9) 1.089g, yield 62%.Its structural characterization is as follows:
HRMS(ESI)calcd for C17H20O3Se m/z:352.0578；Found:352.0590.1H NMR
(500MHz,CDCl3) δ 7.70-7.69 (d, J=7.1Hz, 1H), 7.57-7.56 (d, J=7.0Hz, 1H), 6.82-6.80 (m,
1H),6.76(s,1H),4.16-4.13(m,2H),2.92-2.68(m,4H),2.21(s,3H),1.78-1.55(m,4H),
0.88(t,3H).
Embodiment 10: the preparation of double plumbagin selenides (V-10)
Reaction equation is as follows:
Under dry nitrogen atmosphere, the selenide VI (reference of 1.475g (5mmol) bromo is added into 40mL anhydrous acetonitrile
The preparation method of the reports such as Potapov, V.A.: Russian Journal of Organic Chemistry, 2014,50 (2),
291-292.), 1.540g (10mmol) silver nitrate, 1.881g (10mmol) plumbagin (IV), open that be stirred to react 3 small at room temperature
Shi Hou stops reacting.Step (2) in same embodiment 1 is operated below, finally obtains double plumbagin selenide (V-10) 1.477g, yield
58%.Its structural characterization is as follows:
HRMS(ESI)calcd for C26H22O6Se m/z:510.0582；Found:510.0591.1H NMR
(500MHz,CDCl3)δ7.65(m,2H),7.64(m,2H),7.25(m,2H),6.80(s,2H),4.24-4.21(m,4H),
2.80-2.76(m,4H),2.21(s,6H).13C NMR(125MHz,CDCl3)δ190.2,184.2,161.0,149.3,
136.0,135.2,131.7,124.0,119.4,115.3,64.8,28.7,16.4.
11 plumbagin selenide compounds (V-1) of embodiment to (V-10) antioxidant activity measurement
(1) sample preparation
Sample V-1, V-2, V-3, V-4, V-5, V-6, V-7, V-8, V-9, V-10, tocopherol (vitamin E) are weighed respectively
Each 3mg, is dissolved in anhydrous methanol respectively, and preparation sample concentration is 300 μ g/mL.It is purged DPPH (1,1- diphenyl-respectively
2- trinitrophenyl-hydrazine) measurement of free radical ability, the measurement of total reducing power ability, superoxide radical (O2 -) clearance rate measurement with
And remove the measurement of ABTS (2,2- joins nitrogen-two (3- ethyl-benzothiazole -6- sulfonic acid) di-ammonium salts) free radical ability.Each reality
It tests group and all carries out three groups of parallel laboratory tests, be averaged.
(2) measurement of scavenging ability of DPPH free radical
It is divided into experimental group, control group, blank zeroing group in continuous mode.The 200 μ L of DPPH methanol solution of 1mmol/L is taken to add
Enter in test tube, the anhydrous methanol for adding 800 μ L is diluted, and prepares the DPPH methanol solution of 0.2mmol/L.Experimental group (OD
Value is denoted as Ai) the DPPH methanol solution of 2mL sample liquid and 2mL0.2mmol/L is added in every test tube；(OD value is denoted as A to control groupj) every
2mL sample liquid and 2mL anhydrous methanol is added in test tube；(OD value is denoted as A to blank zeroing group0) every test tube is added 2mL0.2mmol/L's
DPPH methanol solution and 2mL anhydrous methanol.60min, suction of the measurement sample when ultraviolet wavelength is 517nm are protected from light at 25 DEG C
Luminosity.
Calculation formula of the sample to DPPH free radical scavenging ability are as follows:
R%=[1- ((Ai-Aj)/A0)] × 100%
(3) measurement of total reducing power ability
Continuous mode only needs experimental group.In every test tube, the pH=6.6's of the 0.2mol/L of the sample liquid and 2mL of 2mL
After the potassium ferricyanide buffer of PBS buffer solution and the mass concentration of 2mL 1% mixes, 30min is reacted in 50 DEG C of water-baths, then
It is separately added into TCA (trichloroacetic acid) aqueous solution that the mass concentration of 2mL is 10%, 3000rpm is centrifuged 10min.Take supernatant 2mL
With the anhydrous methanol of 2mL and the FeCl of 0.4mL mass concentration 0.1%3Aqueous solution mixes.It is protected from light 10min, measures sample
Absorbance when ultraviolet wavelength is 700nm.OD700Value is bigger, illustrates that its reducing power i.e. oxidation resistance is stronger.
(4) superoxide radical (O2 -) clearance rate measurement
It is divided into experimental group, control group, blank zeroing group in continuous mode.The PBS buffer solution of 0.2mol/L is taken (to use NaOH
(1.0M) adjusts pH to 8.0) 1mL, the anhydrous methanol of 99mL is added, constant volume is diluted to 2mmol/L, pH=8.35, then takes this buffering
Every test tube is added in liquid 4.5mL, preheats 20min at room temperature at 25 DEG C.(OD value is denoted as A to experimental groupx) 0.1mL sample is added in every test tube
The 25mmol/L pyrogallol aqueous solution of product liquid and 0.4mL mix；(OD value is denoted as A to control groupi) 0.1mL sample is added in every test tube
The anhydrous methanol of liquid and 0.4mL mix；(OD value is denoted as A to blank zeroing group0) 0.1mL anhydrous methanol and 0.4mL is added in every test tube
25mmol/L pyrogallol aqueous solution mix；React 5min at 25 DEG C, every test tube drip concentrated hydrochloric acid (material concentration:
12mol/L) to terminate reaction.Measure absorbance of the sample when ultraviolet wavelength is 325nm.
Superoxide radical (O2 -) clearance rate calculation formula are as follows:
R%=[(A0-(Ax-Ai))/A0] × 100%
(5) measurement of ABTS free radical ability is removed
It is divided into experimental group, control group in continuous mode.(2,2- joins (the 3- ethyl-benzothiazole -6- sulphur of nitrogen-two to 5mLABTS
Acid) di-ammonium salts) reagent and 88 μ L of potassium peroxydisulfate be protected from light after 12-16h prepares ABTS free radical stock solution, buffered using PBS
It is 0.70 ± 0.02 standby that stock solution is diluted to its absorbance when ultraviolet wavelength is 734nm by liquid (10mmol/L, pH=7.4)
With.1mL sample solution and 3mL ABTS free radical stock solution is added in the every test tube of experimental group (OD value is denoted as Ax)；Control group (OD value
It is denoted as A0) 1mL anhydrous methanol and 3mLABTS free radical stock solution is added in every test tube.It is protected from light 5min at 25 DEG C, measures sample
Absorbance when ultraviolet wavelength is 734nm.
Calculation formula of the sample to ABTS free radical scavenging ability are as follows:
R%=[(A0-Ax)/A0] × 100%
Experimental result is shown in Tables 1 and 2s.
The measurement of 1 each sample scavenging ability of DPPH free radical of table is measured with total reducing power
Note: 1) * indicates that sample is too small to DPPH free radical scavenging ability, can not calculate；
2) A is measured in scavenging ability of DPPH free radical measurement experiment0Value is 0.298.
2 each sample of table removes superoxide radical (O2 -) ability measures and ABTS free radical ability measures
Note: superoxide radical (O is removed2 -) A in ability measurement experiment0Value is 0.347.
As it can be seen from table 1 compound (V-1)~(V-10) has certain Scavenging activity to DPPH free radical,
Middle compound (V-3), (V-4), (V-6), the Scavenging activity of (V-10) are stronger, and are higher than VE Scavenging activity, especially compound
(V-10) there is very strong Scavenging activity；Compound (V-3), (V-10) total reducing power be higher than VE.
From table 2 it can be seen that compound (V-1)~(V-10) is to superoxide radical (O2 -) all there is certain removing energy
Power, wherein compound (V-3), (V-4), (V-6), (V-7), (V-10) are to removing superoxide radical (O2 -) ability is stronger, (V-
4), (V-6), the Scavenging activity of (V-7) and VE are close, and the Scavenging activity of (V-3), (V-10) are higher than VE.Compound (V-1)~
(V-10) removing ABTS free radical ability is all stronger, wherein the Scavenging activity of (V-3), (V-10) are especially strong, is much higher than VE
Scavenging activity.
Measurement of 12 each sample of embodiment to cell growth inhibition ability
Human pancreatic cancer cell (CFPAC-1), human lung carcinoma cell (A549), CHL cells (CHL), purchased from Chinese section
Institute's cell bank.
(1) human pancreatic cancer cell (CFPAC-1)
Condition of culture: 90%/IMDM culture medium (GIBCO is purchased from Cell Bank of Chinese Academy of Sciences, article No. 12200036)+
10%/high-quality fetal calf serum, 37 DEG C, gas phase: air (95%), carbon dioxide (5%).
Conditions of cryopreservation: IMDM+10%/fetal calf serum of culture solution+10%DMSO.
Propagating method: cell grows into 80-90% in culture bottle and is passed on when being still single layer.Old liquid is discarded, to
2mLPBS buffer (pH value is 7.2 ± 0.1) is added in culture bottle, cleans, discards, be repeated twice.Digestive juice is added
(0.25% trypsase+0.03%EDTA) 1mL digestion, microscopically observation cell completely disengage bottle wall and are separated into 3-5 armfuls
2mL (+10%/cow's serum of IMDM culture solution) culture solution is added after group's cell and terminates digestion, blows and beats under cell to microscope in single
Cell state, cell suspension move into centrifuge tube, and 1000r/min is centrifuged 5min, abandon supernatant, and IMDM culture solution is resuspended cell and repeats
Twice.Culture solution is resuspended after cell mixes and is dispensed into T25 culture bottle, adds culture solution to 4-5mL, and 37 DEG C, 5%CO2Culture
It is cultivated in case.
(2) human lung carcinoma cell (A549) is cultivated
Condition of culture: RPMI1640+10%/cow's serum of culture solution, 37 DEG C, 5%CO2Incubator.
Conditions of cryopreservation: RPMI1640+10%/fetal calf serum of culture solution+10%DMSO.
Propagating method: cell grows into 80-90% in culture bottle and is passed on when being still single layer.Old liquid is discarded, to
2mLPBS buffer (pH value is 7.2 ± 0.1) is added in culture bottle, cleans, discards, be repeated twice.Digestive juice is added
(0.25% trypsase+0.03%EDTA) 1mL digestion, microscopically observation cell completely disengage bottle wall and are separated into 3-5 armfuls
2mL (+10%/cow's serum of RPMI1640 culture solution) culture solution is added after group's cell and terminates digestion, blows and beats under cell to microscope
In unicellular, cell suspension is moved into centrifuge tube, and 1000r/min is centrifuged 5min, abandons supernatant, and RPMI1640 culture solution is resuspended
Cell is repeated twice.Culture solution is resuspended after cell mixes and is dispensed into T25 culture bottle, adds culture solution to 4-5mL, and 37 DEG C, 5%
CO2It is cultivated in incubator.
(3) CHL cells (CHL) are cultivated
Condition of culture: RPMI1640+10%/cow's serum of culture solution, 37 DEG C, 5%CO2Incubator.
Conditions of cryopreservation: RPMI1640+10%/fetal calf serum of culture solution+10%DMSO.
Propagating method: cell grows into 80-90% in culture bottle and is passed on when being still single layer.Old liquid is discarded, to
2mLPBS buffer (pH value is 7.2 ± 0.1) is added in culture bottle, cleans, discards, be repeated twice.Digestive juice is added
(0.25% trypsase+0.03%EDTA) 1mL digestion, microscopically observation cell completely disengage bottle wall and are separated into 3-5 armfuls
2mL (+10%/cow's serum of RPMI1640 culture solution) culture solution is added after group's cell and terminates digestion, blows and beats under cell to microscope
In unicellular, cell suspension is moved into centrifuge tube, and 1000r/min is centrifuged 5min, abandons supernatant, and RPMI1640 culture solution is resuspended
Cell is repeated twice.Culture solution is resuspended after cell mixes and is dispensed into T25 culture bottle, adds culture solution to 4-5mL, and 37 DEG C, 5%
CO2It is cultivated in incubator.
(4) anti-tumor activity experiment (mtt assay)
Respectively by CFPAC-1, A549 cell it is adherent to T25 bottles about 90% when, cell suspending liquid is made through digestion, uniformly spreads
In 96 orifice plates, concentration is 1.6-2 × 104A/hole.It tests and sets 6 concentration gradient dosing groups, 1 control group, 1 zeroing group, often
Group 3 parallel, and for control group with cosolvent alternatives to medication, zeroing group adds the corresponding culture solution of same volume, and 96 orifice plate rims add PBS
Buffer.Cell is in 37 DEG C, 5%CO2Incubator culture for 24 hours, until the adherent merisis of cell adds to after accounting for bottle wall 70-80%
Various concentration gradient is added in medicine group, and [compound (IV) and (V-1)~(V-10) are corresponding with 80 μ L cosolvent DMSO+920 μ L
Culture solution is prepared, final concentration of 2.5 μM, 1.875 μM, 1.25 μM, 0.625 μM, 0.3125 μM, 0.15625 μM] medicine
The solution (i.e. the corresponding culture solution of 80 μ L cosolvent DMSO+920 μ L) of corresponding same volume, zeroing group is added in object, control group
Corresponding culture solution is then added, all groups every hole liquid volume added in 96 orifice plates is 200 μ L.In 37 DEG C, 5%CO2Culture
Case culture is for 24 hours.Dosing group, control group and zeroing group are added 20 μ L MTT (5mg/mL, PBS now matched film use) and act on 4h, small
Culture solution is sucked out in the heart, adds 200 μ L DMSO, and oscillator plate shakes up 10min or so to precipitating sufficiently dissolution；Using microplate reader in
Absorbance is measured at 570nm, calculates respective inhibiting rate, calculates IC50 value using SPSS20.0 software.
(5) anti-tumor activity control experiment (mtt assay)
CHL cell it is adherent to T25 bottles about 90% when, cell suspending liquid is made through digestion, is uniformly laid on 96 orifice plates, concentration is
1.6-2×104A/hole.Experiment sets 6 concentration gradient dosing groups, and 1 control group, 1 zeroing group, every group 3 parallel, control
For group with cosolvent alternatives to medication, zeroing group adds same volume culture medium, and 96 orifice plate rims add PBS buffer solution.Cell is in 37 DEG C, 5%
CO2For 24 hours, until the adherent merisis of cell is to after accounting for bottle wall 70-80%, various concentration gradient is added in dosing group for incubator culture
[compound (IV) and (V-1)~(V-10) are prepared with 80 μ L cosolvent DMSO+920 μ L RPMI1640 culture solutions, dense eventually
Degree be 2.5 μM, 1.875 μM, 1.25 μM, 0.625 μM, 0.3125 μM, 0.15625 μM] drug, control group be added correspondence it is identical
The solution (i.e. 80 μ L cosolvent DMSO+920 μ LRPMI1640 culture solutions) of volume, RPMI1640 culture solution is then added in zeroing group,
All groups every hole liquid volume added in 96 orifice plates is 200 μ L.In 37 DEG C, 5%CO2Incubator culture is for 24 hours.Dosing group, control
Group and zeroing group are added 20 μ L MTT (5mg/mL, PBS now matched film use) and act on 4h, and culture solution is carefully sucked out, adds 200 μ L
DMSO, oscillator plate shake up 10min or so to precipitating sufficiently dissolution；Absorbance is measured at 570nm using microplate reader, is calculated
Respective inhibiting rate calculates IC50 value using SPSS20.0 software.
Sample experiments the results are shown in Table 3.
3 plumbagin selenide analog derivative of table to CFPAC-1, A549 and CHL cell inhibitory activity
Note: 1), * indicate that no inhibitory activity or inhibitory activity are far longer than 500 μM.
2)、SICFPAC-1=IC50 (CFPAC-1)/IC50 (CHL), SIA549=IC50 (A549)/IC50 (CHL), SI is got over
Small, drug is higher to the selectivity of tumour cell.
As shown in table 3, plumbagin selenide analog derivative is to human pancreatic cancer cell (CFPAC-1), human lung carcinoma cell
(A549) there is inhibitory activity.Wherein, compound (V-1), (V-2), (V-3), (V-4), (V-7), (V-8), (V-10) have compared with
Strong anti-human pancreatic cancer cell (CFPAC-1) effect, activity are all larger than plumbagin (IV)；Especially (V-3), (V-7), (V-10)
With extremely strong anti-human pancreatic cancer cell (CFPAC-1) effect, (V-3) and (V-10) is also very good to the selectivity of tumour cell.
In addition, compound (V-1), (V-2), (V-3), (V-4), (V-6), (V-7), (V-10) are with relatively strong anti-human lung carcinoma cell
(A549) it acts on, activity is all larger than plumbagin (IV)；Especially (V-2), (V-3), (V-7), (V-10) are with extremely strong anti-human
Lung carcinoma cell (A549) effect, (V-3) and (V-10) is also very good to the selectivity of tumour cell.
Claims (9)
1. plumbagin selenide analog derivative shown in a kind of formula (V):
In formula (V), R be C1-C10 alkyl, aryl, naphthalene, benzyl orThe aryl be phenyl or
The phenyl that the o-, m- or p- position of person replaces, the substituent group on phenyl are selected from C1-C3 alkyl or halogen.
2. plumbagin selenide analog derivative shown in formula (V) as described in claim 1, which is characterized in that the Plumbago zeylanica
Plain selenide analog derivative is one of following:
3. the preparation method of plumbagin selenide analog derivative shown in formula (V) as described in claim 1, which is characterized in that
The method are as follows:
(1) under the conditions of anhydrous and oxygen-free, compound shown in formula (I), a hydronium(ion) cesium oxide, 4A molecular sieve and solvent DMF are mixed,
It is stirred at room temperature to obtain mixed liquor, gained mixed liquor is added drop-wise in the DMF solution of compound shown in formula (II), drip off rear room temperature and stir
Reaction is mixed, TLC is monitored to fully reacting, and reaction solution is post-treated later, obtains compound shown in formula (III)；
The ratio between amount of substance of compound shown in the formula (I), compound, a hydronium(ion) cesium oxide shown in formula (II) be 1:5~
8:1~3；
(2) under the conditions of anhydrous and oxygen-free, compound shown in formula (III), silver nitrate, plumbagin (IV) and solvent acetonitrile are mixed,
Reaction is stirred at room temperature, TLC is monitored to fully reacting, and reaction solution is post-treated later, obtains product shown in formula (V)；
The ratio between amount of substance of compound shown in the formula (III), silver nitrate, plumbagin (IV) is 1:1~3:1~3；
Reaction equation is as follows:
In formula (I) or (III), the definition of R is identical with formula (V).
4. preparation method as claimed in claim 3, which is characterized in that in step (1), the quality dosage of the 4A molecular sieve with
The amount of the substance of compound shown in formula (I) is calculated as 0.1~0.5g/mmol.
5. preparation method as claimed in claim 3, which is characterized in that in step (1), the volumetric usage of the solvent DMF with
The amount of the substance of compound shown in formula (I) is calculated as 2~6mL/mmol.
6. preparation method as claimed in claim 3, which is characterized in that in step (1), compound shown in the formula (II)
The concentration of compound shown in formula (II) is in 5~10mmol/mL in DMF solution.
7. preparation method as claimed in claim 3, which is characterized in that in step (2), the volumetric usage of the solvent acetonitrile with
The amount of the substance of compound shown in formula (III) is calculated as 5~10mL/mmol.
8. plumbagin selenide analog derivative shown in formula (V) as described in claim 1 is in preparation anti-tumor activity medicine
Application.
9. plumbagin selenide analog derivative shown in formula (V) as described in claim 1 is preparing answering in anti-oxidation medicine
With.
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