CN107021945B - One kind analog derivative of myricetin containing piperazine acidamide and preparation method thereof - Google Patents
One kind analog derivative of myricetin containing piperazine acidamide and preparation method thereof Download PDFInfo
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- CN107021945B CN107021945B CN201710299940.9A CN201710299940A CN107021945B CN 107021945 B CN107021945 B CN 107021945B CN 201710299940 A CN201710299940 A CN 201710299940A CN 107021945 B CN107021945 B CN 107021945B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
- C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
- C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
- C07D311/32—2,3-Dihydro derivatives, e.g. flavanones
Abstract
The invention discloses a kind of analog derivatives of myricetin containing piperazine acidamide, it is characterised in that: its general formula is as follows:Wherein, R1To contain more than one hydrogen atom, methoxyl group, nitro, methyl, trifluoromethyl or halogen atom on position o-, m- or p- on phenyl ring.The compounds of this invention has certain inhibitory activity to hepG2 cell and SGC7901 cell, and itself is to normal cell small toxicity, can be used for preparing anti-tumor drug.
Description
Technical field
The present invention relates to chemical technology fields, relate in particular to a kind of system of analog derivative of myricetin containing piperazine acidamide
Preparation Method and its application in anti-tumor aspect.
Background technique
Tumour is a kind of cause of disease, pathology, clinical manifestation and treats more complicated common disease, especially malignant tumour
It is the health for seriously threatening the mankind.The formation of tumour is the process of multifactor, multi-step and polygenic mutation, it is known that manyization
The formation of tumour can be induced and promote by learning carcinogenic substance.In vitro test shows that myricetin has apparent suppression to mankind's kinds of tumor cells
Production is used.
Myricetin (3', 4', 5', 3,5,7- quercetagetin alcohol, Myricetin (Myr)), different name myricetin, poplar
Plum flavones, myricetin, are a kind of natural flavone and polyphenol compound, be typically found in our daily consumptions water fruits and vegetables,
In tealeaves and beverage.It is most of to exist in the form of glucoside, rather than exist in the form of free glycosides.Simultaneously because myricetin has
Multiple biological activities, such as: antibacterial, antiviral and antitumor, anti-oxidant, antiallergy, hypoglycemic, liver protecting, anti-inflammatory and anti-mutation
Deng receiving the concern of extensive researcher.
2010, (Wei Wei, Jiang Qing myricetin induced bladder cancer cell line BIU-87 Apoptosis mechanism to study [J] to Wei Wei etc.
Medical University Of Chongqing's journal, 2010,12 (7): 1791-1794.) using MTT and 33258 decoration method of Hoechst have studied poplar
Syphilis induces the mechanism of bladder cancer cell line BIU-87 apoptosis, by culture human bladder cancer cell strain BIU-87, is added thereto
Cytomorphology variation is observed in the interference of various concentration myricetin under inverted microscope.Result of study shows: myricetin can lure
The Apoptosis for leading bladder cancer cell BIU-87 has apparent inhibiting effect to the transcript and expression of survivin, right
Caspase-3 also has up-regulation effect.
2011, (Kang, the N.J. such as Kang；Jung,S.K.；Lee,K.W.；Lee,H.J.Myricetin is a
potent chemopreventive phytochemical in skin carcinogenesis[J]
.Ann.N.Y.Acad.Sci., 2011,1229 (1): 124-132.) myricetin is had studied to the inhibition work of mouse skin cancer cell
With research is found: myricetin is the expression of COX-2 to be induced, to inhibit cutaneum carcinoma apoptosis by weakening Ultraviolet B；Pass through work
The angiogenesis induced with target bacteriostasis PI3-K, therefore, myricetin are that the promising chemistry for inhibiting cutaneum carcinoma is pre-
Anti- dose.The same year, (Zhang, the X.H. such as Zhang；Zou,Z.Q.；Xu,C.W.；Shen,Y.Z.；Li,D.Myricetin
induces G2/M phase arrest in HepG2cells by inhibiting the activity of the
Cyclin B/Cdc2complex [J] .Mol.Med.Report., 2011,4:273-277.) further study myricetin pair
The mechanism of action of liver cancer cells, discovery myricetin are the levels by reducing Cdc2 and Cyclin B1 in liver cancer cells, thus
Inhibit the growth and breeding of liver cancer cells.
2013, (Shiomi, the K. such as Kazuaki Shiomi；Kuriyama,I.；Yoshida,H.；Mizushina,
Y.Inhibitory effects of myricetin on mammalian DNA polymerase,topoisomerase
And human cancer cell proliferation [J] .Food Chem., 2013,139 (1-4): 910-918.) research
Archaeal dna polymerase of the myricetin to the mankind, topoisomerase and the value-added inhibiting effect of human cancer cell, as a result, it has been found that: red bayberry
Element has certain inhibitory activity to mammalian polymerases α, β and κ and human DNA topoisomerase II, wherein to human DNA
The IC of topoisomerase II50Value is 27.5 μm of ol/L, prevents the increment of human colon's HCT116 tumour cell, LD50Value is
28.2μmol/L.And myricetin is by directly acting on enzyme, to inhibit the activity of enzyme；By inducing cell apoptosis, Jin Eryin
The death of cancer cell is played, mechanism is by inhibiting topoisomerase II.
2013, Xu Rongrong etc. (Xu Rongrong, Zhang Ying myricetin and myricetrin to the external inhibition of some tumour cells and
Apoptosis-induced Effect study [J] Journal of Nutrition, 2013,35 (3): 303-306.) have studied myricetin, myricetrin and myricetin
The increasing to human hepatoma cell line HepG2, human bladder cancer cell line YTS-1 and human prostate cancer cell line PC-3 is combined with myricetrin
It grows and inhibits and apoptosis-induced effect.The study found that in 72h, myricetin, myricetrin, myricetin and myricetrin molar ratio 1:1
It is combined the 503nhibiting concentration IC to YTS-150Value is respectively 207.7,209.2,249.4 μm of ol/L；Myricetin, myricetrin and poplar
Syphilis myricetrin is combined the 503nhibiting concentration IC to PC-350Value is respectively 110.2,423.8,43.13 μm of ol/L；Three kinds of samples pair
The effect of HepG2 is most weak.Myricetin has preferable apoptosis-induced effect, red bayberry to tri- kinds of cancer cells of HepG2, YTS-1, PC-3
The apoptosis-induced effect of glycosides is relatively weak, to the apoptosis-induced of HepG2 and PC-3 when myricetin and myricetrin are combined with 1:1 molar ratio
Effect is most strong, this may be more related in 3 few hydroxyls than the chemical structure of myricetin with myricetrin.
2014, (Zang, the W.Q. such as Zang；Wang,T.；Wang,Y.Y.；Li,M.；Xuan,X.Y.；Ma,Y.Y.；Du,
Y.W.；Liu,K.D.；Dong,Z.M.；Zhao,G.Q.Myricetin exerts anti-proliferative,anti-
invasive,and pro-apoptotic effects on esophageal carcinoma EC9706 and KYSE30
Cells via RSK2 [J] .Tumor Biol., 2014,35:12583-12592.) pass through CCK-8 experimental method, vitro invasion
Experiment, wound healing assay, the methods of cell cycle analysis and Apoptosis, to test myricetin to esophageal cancer cell EC9706
The inhibiting effect of external increment, Apoptosis and invasion with KYSE30.Result of study shows: myricetin is led by amido kinases
RSK2 is bound to inhibit proliferation, invasion and the Apoptosis of EC9706 and KYSE30 cell in domain.Prevention and treatment to the cancer of the esophagus
Provide new reagent.
2014, (Maggioni, the D. such as Maggioni；Nicolini,G.；Rigolio,R.；Biffi,L.；
Pignataro,L.；Gaini,R.；Garavello,W.Myricetin and Naringenin Inhibit Human
Squamous Cell Carcinoma Proliferation and Migration In Vitro[J].Nutr.Cancer,
2014,66 (7): 1257-1267.) it has studied myricetin and has to oral squamous cell carcinoma (OSCC), SCC-25 and HaCaT cell
Potential inhibiting effect.Inhibit the growth of SCC-25 cell.Myricetin inhibits cell Proliferation not close with inducing cell apoptosis
System, but it is related with cell cycle obstacle.Western blot analysis shows: myricetin is induction of cyclin D1 in SCC-25
In cell and reduction of the cell periodic protein B 1 in HaCaT cell.Healing and cell entry test prove: myricetin may subtract
The motility of SCC-25 and HaCaT cell is lacked.The result shows that: myricetin is that inhibition cell is played by block cell process
The effect of growth.
2015, (Feng, the J.F. such as Feng；Chen,X.N.；Wang,Y.Y.；Du,Y.W.,Sun,Q.Q.；Zang,
W.Q.；Zhao,G.Q.Myricetin inhibits proliferation and induces apoptosis and cell
cycle arrest in gastric cancer cells[J].Mol.Cell.Biochem.,2015,408:163-170.)
Effect of the myricetin to the increment of GCHGC-27 and SGC7901 cell, Apoptosis and cell cycle is had studied, cytometer is used
Calculation tool (CCK) test, the methods of Western blot, cell cycle analysis method and Apoptosis assay test myricetin to thin
The effect of born of the same parents proliferation, Apoptosis and cell cycle.Result of study shows: myricetin inhibits GC cell Proliferation, induction of thin
Born of the same parents' apoptosis and cell-cycle arrest affect the Apoptosis and cell-cycle arrest of GC.Further relating to myricetin has inhibition
The effect of cell Proliferation, Apoptosis, cell cycle and cell-cycle arrest.
2015, (Xue, the W. such as Xue；Song,B.A.；Zhao,H.J.；Qi,X.B.；Huang,Y.J.；Liu,
X.H.Novel myricetin derivatives:Design,synthesis and anticancer activity[J]
.Eur.J.Med.Chem., a series of myricetin of class containing acylhydrazone derivatives 2015,97:155-163.) are reported, are with myricetrin
Raw material, iodomethane protect hydroxyl, successively with bromoacetate, hydrazine hydrate, and the fragrant formaldehyde reaction that difference replaces finally synthesizes poplar
Syphilis acylhydrazone.Using mtt assay, the body of mankind mastopathy cell MDA-MB-231 has been carried out to synthesized compound
Outer proliferation inhibition activity test, result of study show: myricetin acylhydrazone is to mankind mastopathy cell MDA-MB-231
Preferable inhibiting rate is all showed, wherein compound 2- ((5,7- dimethoxy-4 's-oxo -2- (3,4,5- trimethoxyphenyl) -
4H- chromene -3- base) oxygroup)-N'- (furans -2- methylene) acethydrazide hydrazides shows preferable inhibitory activity, IC50Value
For 0.91 μm of ol/L.
In conclusion myricetin and its derivative have certain researching value in anti-tumor aspect, and toxic side effect is small.
It is to study itself, and structural modification is carried out to myricetin to myricetin majority at present, research myricetin derivative is anti-
The research of tumor promotion is less.
Summary of the invention
The technical problem to be solved by the present invention is provide a kind of red bayberry chlorins compound in structure containing piperazine amide and its
Preparation method is found to have preferable anti-tumor activity red bayberry chlorins compound, and compound itself is to the secondary work of the poison of normal cell
With less.
The technical scheme is that a kind of analog derivative of myricetin containing piperazine acidamide, general formula are as follows:
Wherein, R1To contain more than one hydrogen atom, methoxyl group, nitro, methyl, trifluoro on position o-, m- or p- on phenyl ring
Methyl or halogen atom.
A kind of preparation method of the analog derivative of myricetin containing piperazine acidamide, with 1- (4- substituted benzyl piperazine) -2- chloroethene
Alkane -1- ketone and 3- hydroxyl -5,7- dimethoxy -2- (3,4,5- trimethoxyphenyl) -4H- chromene -4- ketone are that raw material preparation contains
Piperazine acidamide myricetin analog derivative:
The piperazine acidamide myricetin analog derivative the preparation method comprises the following steps: (1) using piperazine and replace benzyl chloride as raw material,
Preparation 1- substituted benzyl piperazine is heated to reflux under alkaline condition:
(2) using substituted 1- benzyl diethylenediamine and chloracetyl chloride as raw material, 1- (4- substituted benzyl piperazine) -2- chloroethene is prepared
Alkane -1- ketone:
(3) using myricetrin and iodomethane as raw material, 3- hydroxyl -5,7- dimethoxy -2- (3,4,5- trimethoxy-benzenes are prepared
Base) -4H- chromene -4- ketone:
(4) with 3- hydroxyl -5,7- dimethoxy -2- (3,4,5- trimethoxyphenyl) -4H- chromene -4- ketone and 1-, (4- is taken
For benzyl diethylenediamine) -2- chloroethanes -1- ketone be raw material, prepare 3- (substituted benzyl piperazine) -2- oxoethyl) -5,7- dimethoxy
- 4 ketone of base -2- (3,4,5- trimethoxyphenyl) -4H- chromene:
Beneficial effects of the present invention: the piperazine amide structure with excellent activity is introduced into myricetin structure by the present invention,
Design has synthesized a series of chlorins compound of red bayberry containing piperazine acidamide in structures, and by synthesized red bayberry containing piperazine acidamide
Chlorins compound is applied to the research of anti-tumor aspect, it is found that such compound not only has certain suppression to tumour cell for test
Outside production, and it is also very small to the toxic side effect of normal cell, and part of compound is inhibiting tumor cell proliferation
Inhibitory activity is more than its comparison medicament epirubicin, has certain application value.
Specific embodiment
Total embodiment:
(1) using piperazine and substitution benzyl chloride as raw material, preparation 1- substituted benzyl piperazine is heated to reflux under alkaline condition:
(2) using substituted 1- benzyl diethylenediamine and chloracetyl chloride as raw material, 1- (4- substituted benzyl piperazine) -2- chloroethene is prepared
Alkane -1- ketone:
(3) using myricetrin and iodomethane as raw material, 3- hydroxyl -5,7- dimethoxy -2- (3,4,5- trimethoxy-benzenes are prepared
Base) -4H- chromene -4- ketone:
(4) with 3- hydroxyl -5,7- dimethoxy -2- (3,4,5- trimethoxyphenyl) -4H- chromene -4- ketone and 1-, (4- is taken
For benzyl diethylenediamine) -2- chloroethanes -1- ketone be raw material, prepare 3- (substituted benzyl piperazine) -2- oxoethyl) -5,7- dimethoxy
- 4 ketone of base -2- (3,4,5- trimethoxyphenyl) -4H- chromene:
Specific embodiment is graphically listed below, is seen below:
Wherein, R1=2-Cl, 2-CH3, 2-F, 3-CH3, 2,4-di-Cl, H；.
Embodiment 1
3- (2- (4 (2- chlorphenyl) piperazinyl) -2- oxoethyl) -5,7- dimethoxy -2- (3,4,5- trimethoxy-benzene
Base) -4H- chromene -4- ketone synthesis (compound number I1), comprising the following steps:
(1) synthesis of 1- (2- chlorobenzyl) piperazine:
Piperazine anhydrous 2.59g (30mmol) is added into 50mL single-necked flask, sodium hydroxide 1.20g (30mmol) and 25mL
Dehydrated alcohol, stirring is added after it is completely dissolved and replaces benzyl chloride 1.27g (10mmol) under room temperature, and is warming up to reflux, until
Benzyl chloride completely disappears about 5~7h.Stop reaction, solvent is removed under reduced pressure, is dissolved in water, adjust pH > 12, with methylene chloride (3 ×
It 30mL) extracts, merges the drying of organic layer anhydrous sodium sulfate, filter, solvent is removed under reduced pressure, obtain the not purified direct use of crude product
In in next step.
(2) synthesis of 1- (4- (2- chlorobenzyl) piperazine) -2- chloroethanes -1- ketone:
Into 50mL single-necked flask, crude product, the 1.44g tri- of 1.00g 1- (2- chlorobenzyl) piperazine (4.75mmol) is added
Reaction system is transferred in ice bath, slowly by ethamine (14.24mmol) and 25mL methylene chloride after stirring 30min at normal temperature
The dichloromethane solution (10mL) of chloracetyl chloride is added dropwise, and keeps this temperature the reaction was continued 3h, TLC monitoring reaction (petroleum ether: second
Acetoacetic ester=1:1, V/V).After stopping reaction, reaction solution washed with water (3 × 40mL), anhydrous Na2SO4Solvent is removed under reduced pressure in drying,
The crude product of 1- (4- (2- chlorobenzyl) piperazine) -2- chloroethanes -1- ketone is obtained, it is not purified, it is directly used in next step.
(3) synthesis of 3- hydroxyl -5,7- dimethoxy -2- (3,4,5- trimethoxyphenyl) -4H- chromene -4- ketone:
4.64g myricetrin (10mmol), 22.09g K are sequentially added in 250mL round-bottomed flask2CO3(160mmol) and
7.50mL iodomethane (120mmol) is slowly added dropwise after stirring 0.5~1h under room temperature in 120mL DMF, and 48h, TLC prison is stirred at room temperature
Survey reaction (methanol: ethyl acetate=1:4, V/V).After stopping reaction, filtering precipitating, filter residue is with ethyl acetate (or methylene chloride)
Washing, merging filtrate are diluted with 100mL water, three times with ethyl acetate (or methylene chloride) extraction, are merged organic layer, are depressurized dense
Concentrate, is then dissolved in 30mL dehydrated alcohol, is warming up to reflux by contracting, and after solution clarification, flow back the lower addition dense salt of 16mL
Acid then has yellow solid precipitation, the reaction was continued 2h, cooling, and filtering obtains crude product 3- hydroxyl -5,7- dimethoxy -2-
(3,4,5- trimethoxyphenyl) -4H- chromene -4- ketone.
(4) 3- (2- (4 (2- chlorphenyl) piperazinyl) -2- oxoethyl) -5,7- dimethoxy -2- (3,4,5- trimethoxy
Base) dilute -4- ketone of -4H- synthesis:
In 50mL round-bottomed flask, 3- hydroxyl -5,7- dimethoxy -2- (3,4,5- trimethoxyphenyl)-is sequentially added
4H- chromene -4- ketone (1.30mmol), Anhydrous potassium carbonate (3.90mmol) and 15mL DMF stir 0.5~1h under room temperature, slowly
DMF (10mL) solution of 1- (4- (2- chlorobenzyl) piperazine) -2- chloroethanes -1- ketone (1.56mmol) is added dropwise, is warming up to 100 DEG C,
The reaction was continued at this temperature 5~7h, TLC tracking reaction (ethyl acetate: methanol=10:1, V/V) stop reaction, are cooled to
Room temperature is added ice water and stands, solid is such as precipitated, for solid through filtering, recrystallizing methanol obtains target compound.It is as solid in not being precipitated
Body is extracted with methylene chloride (3 × 30mL), merges organic layer, dry with saturated common salt water washing (3 × 40mL), anhydrous sodium sulfate
It is dry, solvent is removed under reduced pressure, obtain crude product, through column chromatography (ethyl acetate: methanol=15:1~10:1, V/V) purification obtain target
Compound, yield: 55.3%.
Embodiment 2
3- (2- (4 (2,4 dichloro benzene base) piperazinyl) -2- oxoethyl) -5,7- dimethoxy -2- (3,4,5- trimethoxy
Base phenyl) -4H- chromene -4- ketone synthesis (compound number I2), comprising the following steps:
(1) synthesis of 1- (2,4- dichloro benzyl) piperazine:
Such as 1 (1) step of embodiment, difference is with 2,4- dichloro benzyl chloride for raw material.
(2) synthesis of 1- (4- (2,4- dichloro benzyl) piperazine) -2- chloroethanes -1- ketone:
Such as 1 (2) step of embodiment, difference is with 1- (2,4- dichloro benzyl) piperazine for raw material.
(3) synthesis of 3- hydroxyl -5,7- dimethoxy -2- (3,4,5- trimethoxyphenyl) -4H- chromene -4- ketone:
Such as 1 (3) step of embodiment.
(4) 3- (2- (4 (2,4 dichloro benzene base) piperazinyl) -2- oxoethyl) -5,7- dimethoxy -2- (3,4,5- tri-
Methoxyphenyl) -4H- chromene -4- ketone synthesis:
Such as 1 (4) step of embodiment, difference is with 1- (4- (2,4- dichloro benzyl) piperazine) -2- chloroethanes -1- ketone for original
Material.
Embodiment 3
3- (2- (4 (3- aminomethyl phenyl) piperazinyl) -2- oxoethyl) -5,7- dimethoxy -2- (3,4,5- trimethoxy
Phenyl) -4H- chromene -4- ketone synthesis (compound number I3), comprising the following steps:
(1) synthesis of 1- (3- methylbenzyl) piperazine:
Such as 1 (1) step of embodiment, difference is using 3- methyl benzyl chloride as raw material.
(2) synthesis of 1- (4- (3- methylbenzyl) piperazine) -2- chloroethanes -1- ketone:
Such as 1 (2) step of embodiment, difference is using 1- (3- methylbenzyl) piperazine as raw material.
(3) synthesis of 3- hydroxyl -5,7- dimethoxy -2- (3,4,5- trimethoxyphenyl) -4H- chromene -4- ketone:
Such as 1 (3) step of embodiment.
(4) 3- (2- (4 (3- aminomethyl phenyl) piperazinyl) -2- oxoethyl) -5,7- dimethoxy -2- (3,4,5- front three
Phenyl) -4H- chromene -4- ketone synthesis:
Such as 1 (4) step of embodiment, difference is with 1- (4- (3- methylbenzyl) piperazine) -2- chloroethanes -1- ketone for original
Material.
Embodiment 4
3- (2- (4 (2- fluorophenyl) piperazinyl) -2- oxoethyl) -5,7- dimethoxy -2- (3,4,5- trimethoxy-benzene
Base) -4H- chromene -4- ketone synthesis (compound number I4), comprising the following steps:
(1) synthesis of 1- (2- luorobenzyl) piperazine:
Such as 1 (1) step of embodiment, difference is using 2- fluorine benzyl chloride as raw material.
(2) synthesis of 1- (4- (2- luorobenzyl) piperazine) -2- chloroethanes -1- ketone:
Such as 1 (2) step of embodiment, difference is using 1- (2- luorobenzyl) piperazine as raw material.
(3) synthesis of 3- hydroxyl -5,7- dimethoxy -2- (3,4,5- trimethoxyphenyl) -4H- chromene -4- ketone:
Such as 1 (3) step of embodiment.
(4) 3- (2- (4 (2- fluorophenyl) piperazinyl) -2- oxoethyl) -5,7- dimethoxy -2- (3,4,5- trimethoxy
Base phenyl) -4H- chromene -4- ketone synthesis:
Such as 1 (4) step of embodiment, difference is using 1- (4- (2- luorobenzyl) piperazine) -2- chloroethanes -1- ketone as raw material.
Embodiment 5
3- (2- (4 (2- aminomethyl phenyl) piperazinyl) -2- oxoethyl) -5,7- dimethoxy -2- (3,4,5- trimethoxy
Phenyl) -4H- chromene -4- ketone synthesis (compound number I3), comprising the following steps:
(1) synthesis of 1- (2- methylbenzyl) piperazine:
Such as 1 (1) step of embodiment, difference is using 2- methyl benzyl chloride as raw material.
(2) synthesis of 1- (4- (2- methylbenzyl) piperazine) -2- chloroethanes -1- ketone:
Such as 1 (2) step of embodiment, difference is using 1- (2- methylbenzyl) piperazine as raw material.
(3) synthesis of 3- hydroxyl -5,7- dimethoxy -2- (3,4,5- trimethoxyphenyl) -4H- chromene -4- ketone:
Such as 1 (3) step of embodiment.
(4) 3- (2- (4 (2- aminomethyl phenyl) piperazinyl) -2- oxoethyl) -5,7- dimethoxy -2- (3,4,5- front three
Phenyl) -4H- chromene -4- ketone synthesis:
Such as 1 (4) step of embodiment, difference is with 1- (4- (2- methylbenzyl) piperazine) -2- chloroethanes -1- ketone for original
Material.
Embodiment 6
3- (2- (4- benzyl) piperazinyl) -2- oxoethyl) -5,7- dimethoxy -2- (3,4,5- trimethoxyphenyl) -
Synthesis (the compound number I of 4H- chromene -4- ketone6), comprising the following steps:
(1) synthesis of 1- benzyl diethylenediamine:
Such as 1 (1) step of embodiment, difference is using benzyl chloride as raw material.
(2) 1- (4- benzyl) piperazine) -2- chloroethanes -1- ketone synthesis:
Such as 1 (2) step of embodiment, difference is using 1- benzyl diethylenediamine as raw material.
(3) synthesis of 3- hydroxyl -5,7- dimethoxy -2- (3,4,5- trimethoxyphenyl) -4H- chromene -4- ketone:
Such as 1 (3) step of embodiment.
(4) 3- (2- (4 (3- aminomethyl phenyl) piperazinyl) -2- oxoethyl) -5,7- dimethoxy -2- (3,4,5- front three
Phenyl) -4H- chromene -4- ketone synthesis:
Such as 1 (4) step of embodiment, difference is using 1- (4- benzyl) piperazine) -2- chloroethanes -1- ketone is raw material.
The physicochemical property and mass spectrometric data of the analog derivative of myricetin containing piperazine acidamide of synthesis are shown in Table 1, hydrogen nuclear magnetic resonance
Spectrum (1H NMR) and carbon spectrum (13C NMR) data are shown in Table 2 and table 3.
1 target compound physicochemical property of table and its analytical data of mass spectrum
| Compound | Yield | Character | Fusing point (DEG C) | HRMS(ESI)m/z(calcd.) |
| I1 | 55.3 | White solid | 134~136 | 639.2105(639.2104[M+H]+) |
| I2 | 65.8 | White solid | 132~134 | 673.1686(673.1714[M+H]+) |
| I3 | 48.2 | White solid | 103~105 | 619.2652(619.2650[M+H]+) |
| I4 | 53.7 | White solid | 192~194 | 623.2399(623.2399[M+H]+) |
| I5 | 61.3 | White solid | 189~191 | 619.2654(619.2650[M+H]+) |
| I6 | 43.8 | White solid | 209~211 | 605.2494(605.2494[M+H]+) |
2 target compound hydrogen nuclear magnetic resonance modal data of table
3 target compound carbon-13 nmr spectra data of table
Inhibitory activity of the target compound to hepG2 cell and SGC7901 cell:
(1) test method
A. experimental principle
MTT full name is 3- (4,5-Dimethylthiazol-2-yl) -2,5-diphenyltetrazolium
Bromide, entitled 3- (4,5- dimethylthiazole -2) -2, the 5- diphenyltetrazolium bromide bromide of Chinese, trade name: thiazolyl blue.It is one
Kind receive hydrionic dyestuff, may act on the respiratory chain in living cells mitochondria, in succinate dehydrogenase and cytochrome c
Lower tetrazolium ring opening is acted on, the first a ceremonial jade-ladle, used in libation crystallization of bluish violet is generated.The production quantity of first a ceremonial jade-ladle, used in libation crystallization is directly proportional to number of viable cells, and dead
Cell is without this function.Dimethyl sulfoxide, SDS can dissolve the crystallization, using microplate reader measurement 595nm at absorbance, can between
The reversed quantity for reflecting living cells.Within certain cell context, the quantity for the crystal that MTT is formed is directly proportional to cell number.
This method can be used for large-scale screening anti-tumor medicine, cytotoxicity experiment and tumor radiosensitivity measurement etc..
B. experimental procedure
By the uplink and downlink of 96 orifice plates sterilizing secondary water edge sealing, every 200 μ L of hole.Logarithmic growth phase cell, conventional digestion
Afterwards, it is resuspended in 1640 culture medium of RPMI containing 10%FBS, with 4 × 104The final concentration of a/mL is inoculated in 96 well culture plates,
Every 100 μ L of hole, the rightmost side one are classified as blank control group, and adding cell-free has 1640 culture medium of serum RPMI.It is placed in 37 DEG C, 5%
CO2Saturated humidity incubator in cultivate and make cell adherent for 24 hours.Culture medium is sopped up, the concentration containing different pharmaceutical is added has serum
Culture medium, every 200 μ L of hole notice that for DMSO final concentration no more than 0.1%, the every hole of blank control group adds 200 μ L complete in culture medium
Full culture medium.The requirement of experiment time is handled respectively, is removed supernatant, is added the MTT of 100 μ L/well concentration 0.5mg/mL.After cultivating 4h
10% SDS of 100 μ L/well is added again.10h takes out crystal after completely dissolution at 37 DEG C, and 5min, holding chamber are swung in microseism
The lower 30min of temperature, surveys OD value, and calculate cell activity, inhibiting rate and P value under A595 wavelength.
Using drug concentration or processing time as horizontal axis, OD value or inhibiting rate are the longitudinal axis, draw curve.Every concentration of specimens repeats
Six holes, each experiment in triplicate, are averaged as final result.
Experimental result carries out variance analysis with SPSS software, is significant difference when p < 0.05, extremely aobvious for difference when p < 0.01
It writes.The inhibiting rate calculation formula of cell Proliferation is as follows:
(2) biological activity test result
Inhibitory activity of 4 target compound of table to hepG2 cell
Note: * compound is in the case where setting concentration to the inhibiting rate otherness of the inhibiting rate of hepG2 and negative control group (DMSO)
Analysis has significant difference (P < 0.05).
Inhibitory activity of 5 target compound of table to SGC7901 cell
Note: suppression of the * compound in the case where setting concentration to the inhibiting rate of gastric cancer SGC7901 cell and negative control group (DMSO)
System
Rate difference analysis has significant difference (P < 0.05).
Using mtt assay, using epirubicin as comparison medicament, under institute's test concentrations, institute test compound I1~I6It is right
The inhibitory activity (being shown in Table 4 and table 5) of hepG2 cell and SGC7901 cell.Test result shows: institute's test compound is to two kinds
Tumour cell has certain inhibitory activity.When concentration is 1 μm of ol/L, inhibitory activity of all compounds to hepG2 cell
More than 50%, and it is relatively low to the inhibitory activity of gastric cancer SGC7901 cell；When concentration is 10 μm of ol/L, compound I3
Inhibitory activity to hepG2 cell and gastric cancer SGC7901 cell is more than comparison medicament epirubicin (81.64,78.38%),
Its inhibitory activity is respectively 97.90,87.53%.
The above described is only a preferred embodiment of the present invention, being not intended to limit the present invention in any form, appoint
What is to the above embodiments according to the technical essence of the invention any simply to repair without departing from technical solution of the present invention content
Change, equivalent variations and modification, all of which are still within the scope of the technical scheme of the invention.
Claims (3)
1. a kind of analog derivative of myricetin containing piperazine acidamide, it is characterised in that: its general formula is as follows:
Wherein, R1For hydrogen atom, methoxyl group, nitro, methyl, trifluoromethyl or the halogen atom contained on o-, m- or p- position.
2. a kind of preparation method of the analog derivative of myricetin containing piperazine acidamide as described in claim 1, it is characterised in that: with
Containing 1- (4- substituted benzyl piperazine) -2- chloroethanes -1- ketone and 3- hydroxyl -5,7- dimethoxy -2- (3,4,5- trimethoxy-benzene
Base) -4H- chromene -4- ketone be raw material prepare the analog derivative of myricetin containing piperazine acidamide:
3. a kind of preparation method of analog derivative of myricetin containing piperazine acidamide according to claim 2, it is characterised in that:
(1) to replace benzyl chloride and piperazine as raw material, 1- substituted benzyl piperazine is prepared under alkaline condition:
(2) using 1- substituted benzyl piperazine and chloracetyl chloride as raw material, 1- (4- substituted benzyl piperazine) -2- chloroethanes -1- ketone is prepared:
(3) it using myricetrin and iodomethane as raw material, prepares 3- hydroxyl -5,7- dimethoxy -2- (3,4,5- trimethoxyphenyl) -
4H- chromene -4- ketone:
(4) with 3- hydroxyl -5,7- dimethoxy -2- (3,4,5- trimethoxyphenyl) -4H- chromene -4- ketone and 1-, (4- replaces benzyl
Base piperazine) -2- chloroethanes -1- ketone be raw material, prepare 3- (substituted benzyl piperazine) -2- oxoethyl) -5,7- dimethoxy -2-
- 4 ketone of (3,4,5- trimethoxyphenyl) -4H- chromene:
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