CN109350741A - 3,7- bis- (di-n-propylamine base)-phenthazine -5- iodide and supersonic synergic inhibit the application of tumor cell proliferation - Google Patents
3,7- bis- (di-n-propylamine base)-phenthazine -5- iodide and supersonic synergic inhibit the application of tumor cell proliferation Download PDFInfo
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- CN109350741A CN109350741A CN201811264478.XA CN201811264478A CN109350741A CN 109350741 A CN109350741 A CN 109350741A CN 201811264478 A CN201811264478 A CN 201811264478A CN 109350741 A CN109350741 A CN 109350741A
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- phenthazine
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- iodide
- bis
- prb
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0028—Disruption, e.g. by heat or ultrasounds, sonophysical or sonochemical activation, e.g. thermosensitive or heat-sensitive liposomes, disruption of calculi with a medicinal preparation and ultrasounds
- A61K41/0033—Sonodynamic cancer therapy with sonochemically active agents or sonosensitizers, having their cytotoxic effects enhanced through application of ultrasounds
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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
Abstract
The invention belongs to field of medicaments, the application of open one kind 3,7- bis- (di-n-propylamine base)-phenthazine -5- iodide (PRB) and supersonic synergic inhibition tumor cell proliferation.Using K562 cell as research object, in conjunction with low frequency ultrasound, experiments have shown that can significantly inhibit the proliferation of K562 cell after PRB and supersonic synergetic effect, provide strong theories integration for the structure activity study of sound sensitiser, and push SDT for antitumor clinic.
Description
Technical field
The invention belongs to field of medicaments, and in particular to one kind 3,7- bis- (di-n-propylamine base)-phenthazine -5- iodide
(PRB) inhibit the application of tumor cell proliferation with supersonic synergic.
Background technique
SDT is a kind of method of promising non-intrusive treatment tumour, and ultrasonic irradiation treatment can focus on tumor focus
Area, and what normal tissue damage substantially without, while having stronger penetrability than light radiation.Since SDT is with relatively small
Adverse reaction, and have the advantages that it is noninvasive, SDT once propose the great attention by whole world scholar at once.Due to the party
Method has treatment tumour cell the non-invasive of stronger specific aim and normal tissue, so for treating tumour, it is special
It is not that tissue deep tumor has preferable application prospect.Sound motivation therapy (SDT) is that biological tissue's depth can be penetrated using ultrasound
Portion activates the quick substance of sound for being enriched with and can completely being stayed in tumor tissues for a long time, and generates synergistic effect killing tumor cell
Treatment method.Unique advantage of the sound motivation therapy in antitumor field has obtained the extensive of domestic and foreign scholars with clinical application potentiality
Concern, wherein sound sensitiser research is the key that SDT is pushed to be applied to clinical antineoplastic early.
Methylenum careuleum (MB) be used as a kind of phenothiazine compound, sound power anti-tumor activity it is verified that.This project
Group synthesizes multiple derivatives on the basis of MB, and wherein PRB has preferable sound photodynamic activity.The research is expected to as screening sound power
More preferably sound sensitiser provides reference to activity, and to push SDT to be widely used in antitumor clinical based theoretical early.
Summary of the invention
It is an object of that present invention to provide one kind 3,7- bis- (di-n-propylamine base)-phenthazine -5- iodide (PRB) and ultrasound
Collaboration inhibits the application of tumor cell proliferation.
The technical solution adopted by the present invention are as follows:
1.3,7- bis- (di-n-propylamine base)-phenthazine -5- iodide (PRB) and supersonic synergic inhibit tumor cell proliferation
Application.
The application, the tumour cell are K562 cell.
The application, the supersonic frequency are 40KHz.
The application, the ultrasonic power 450W.
The application, the ultrasonic temperature are 20 DEG C.
The application, the ultrasonic procedure carry out under the conditions of being protected from light.
The application, the concentration of the PRB are 12.5 μm of ol/L.
The preparation method of the application, the PRB includes the following steps:
(1) at room temperature, it weighs phenthazine 2.0860g to be dissolved in the dichloromethane solution of 100mL, weighs iodine solid
8.4056g is dissolved in 400mL methylene chloride, and the dichloromethane solution of iodine is slowly dropped to the dichloromethane solution of phenthazine
Afterwards, stirring for 24 hours, filters, and gained precipitating, which adds methylene chloride, to be continuously stirred 16h and washed, and obtains intermediate product phenthazine -5- four
Iodide；
(2) at room temperature, the methanol solution of di-n-propylamine is slowly dropped to the methanol solution of the phenthazine -5- tetraiodide
In, the molar ratio of the phenthazine -5- tetraiodide and di-n-propylamine is 1:14, continues to stir, be judged with thin-layered chromatography
Reaction end, suction filtration obtain filtrate, crude product after revolving, and 50mL methylene chloride is added and 5% dilute hydrochloric acid is extracted, collects
Lower layer's solution is washed with distilled water, and obtains 3,7- bis- (di-n-propylamine base)-phenthazine -5- iodide crude product.
The application, product purification include: first to be eluted with column chromatographic grade, and eluant, eluent is respectively methanol: methylene chloride
=1:100 and methanol: methylene chloride=1:50；Thin-layer chromatography is used again, and solvent is methanol: methylene chloride=1:30 can obtain
To 3,7- bis- (di-n-propylamine base)-phenthazine -5- iodide sterling.
The invention has the following advantages:
The present invention, in conjunction with low frequency ultrasound, discloses 3,7- bis- (di-n-propylamine base)-pheno thiophene using K562 cell as research object
Piperazine -5- iodide (PRB) inhibit the application of tumor cell proliferation as sound sensitiser and supersonic synergic, and PRB itself has certain
Inhibition tumor cell proliferation effect can become apparent from and effective inhibit tumour thin experiments have shown that after PRB and supersonic synergetic effect
The proliferation of born of the same parents' K562 cell, inhibitory effect, which is substantially better than, is used alone PRB or ultrasound, living for phenothiazine compound sound power
Property and for the structure activity study of more high activity sound sensitiser provide strong theories integration, and push SDT for antitumor clinic.
Detailed description of the invention
Fig. 1 is independent ultrasound, PRB, PRB and supersonic synergetic effect is used alone in the inhibiting effect comparison diagram of K562 cell
Specific embodiment
The following describes the present invention in detail with reference to examples.
By PRB and supersonic synergetic effect, the purpose for effectively inhibiting tumor cell proliferation can achieve.
The preparation of embodiment 1:3,7- bis- (di-n-propylamine base)-phenthazine -5- iodide (PRB)
Include the following steps:
1) synthesis of the intermediate phenthazine -5- tetraiodide
It weighs 2.0860g phenthazine to be placed in a beaker, 100ml methylene chloride is added into beaker and is stirred dissolution, obtains
To the dichloromethane solution of yellow green phenthazine, then transfer them in 1000ml eggplant-shape bottle.
8.4056g iodine solid is weighed in beaker, 400ml methylene chloride is added into beaker and is stirred dissolution, obtains
The dichloromethane solution of aubergine iodine is added in dropping funel by several times.
At room temperature, the dichloromethane solution of iodine is slowly added dropwise into the dichloromethane solution of phenthazine, is stirred when being added dropwise
It mixes.It drips and continues stirring under room temperature for 24 hours, yellow green reactant solution color can be observed and gradually change, be finally in
Dark-brown.It is detected and is reacted with lamellae, solvent selects methanol: methylene chloride=1:30, clearly green spot, that is, anti-occurs
It should be complete.After reaction, solution is filtered to obtain dark gray solid.Dichloro containing 100ml is added in this dark gray solid
In the eggplant-shape bottle of methane, continuously stirs 16h and washed.It is filtered later, obtains silver gray solid, it is dry, obtain intermediate
Phenthazine -5- the tetraiodide, yield 82%.
2) 3,7- bis- (di-n-propylamine base)-phenthazine -5- iodide synthesis
The 2.1945g intermediate phenthazine -5- tetraiodide is weighed in beaker, is made it dissolve with 200ml methanol, obtains pheno
The methanol solution of the thiazine -5- tetraiodide.
The di-n-propylamine for weighing 4.2420g is dissolved with 30ml methanol, obtains the methanol solution of di-n-propylamine.
At room temperature, the methanol solution of di-n-propylamine is slowly added dropwise into the methanol solution of the phenthazine -5- tetraiodide, adopts
Whether complete with lamellae detection reaction, the solvent selected is volume ratio for the methanol and methylene chloride of 1:30, if having reacted
Complete visible clear blue spot.Reaction mixture is filtered after the reaction was completed, filtrate rotates to obtain solids, then with 50ml dichloro
Methane dissolves this solids, is placed in separatory funnel, and the dilute hydrochloric acid solution that 50ml volume fraction is 5% is added and washes twice, shakes
It is stood after swinging, makes its layering, the lower layer's solution being collected into washed twice with appropriate distilled water, and it is appropriate that anhydrous sodium sulfate is added
Dry, avoid light place is for 24 hours.It is finally filtered, filtrate rotates to obtain navy blue 3,7- bis- (di-n-propylamine base)-phenthazine -5-
Iodide crude product.
3) product purification
Column chromatographic grade is first used to elute 3,7-- bis- (di-n-propylamine base)-phenthazine -5- iodide crude product, elution
Agent is respectively methanol: methylene chloride=1:100 and methanol: methylene chloride=1:50 uses thin-layer chromatography again, and solvent is methanol: two
Chloromethanes=1:30.3,7- bis- (di-n-propylamine base)-phenthazine -5- iodide sterling can be obtained.
Embodiment 2:3,7- bis- (di-n-propylamine base)-phenthazine -5- iodide (PRB) inhibit tumour thin with supersonic synergic
The application of born of the same parents' proliferation
K562 cell strain is inoculated in containing in 15% fetal calf serum, 1% dual anti-RPMI1640 culture medium, in 37 DEG C, 5%
CO2, saturated humidity incubator in cultivate, experiment used is logarithmic growth phase cell.
The K562 cell of logarithmic growth phase, discards supernatant after centrifugation, and culture medium 3ml is taken to blow outstanding cell.Cell is hanged
Liquid is randomly divided into blank group, simple ultrasonic group, simple medicine group (PRB) and combination of ultrasound medicine group (ultrasound+PRB), every group thin
Born of the same parents' suspension final densities are 5 × 104cells/ml.Aseptically, simple medicine group and combination of ultrasound medicine group cell are outstanding
Liquid is dispensed respectively into 5ml EP pipe, dilutes drug concentration to 12.5 μm of ol/L with culture medium, and with the dilution of this pastille culture medium
Cell, obtaining appropriate density is 5 × 104The cell suspension of cells/ml；Blank group and simple ultrasound group cell suspension equally divide
It is not filled in 5ml EP pipe, with culture medium diluting cells, obtaining appropriate density is 5 × 104The cell suspension of cells/ml.More than
Four groups of cells, which are protected from light, is incubated for 30min.Ultrasound group and combination of ultrasound medicine group are subjected to ultrasonic treatment 1min, EP is effective when ultrasonic
Sealed membrane sealing.After ultrasound, above-mentioned group of cells is seeded to 96 porocyte culture plates, every 200 μ of hole under aseptic condition
L, 4 multiple holes of every group of setting.It is placed in incubator after being incubated for for 24 hours, after every hole adds 20 μ l MTT, 96 porocyte culture plates is placed in
Continue to be incubated for 4h in incubator.Centrifugation removal supernatant, every hole add the DMSO of 150 μ l of people, measure after vibrating 8min in microplate reader
Wavelength 490nm measures the light absorption value (OD value) in each hole, calculates inhibition rate of tumor cell using formula (1).
Experimental result shows that individually ultrasound is 13.4% ± 1.83% to the inhibiting rate of K562 cell Proliferation, individual PRB
Proliferation inhibition rate to K562 cell is 57.7% ± 2.10%, and PRB collaboration ultrasound is to the proliferation inhibition rate of K562 cell
78.5% ± 2.19%, hence it is evident that higher than independent ultrasonic and drug alone to the inhibiting effect of K562 cell Proliferation.
Claims (9)
1.3,7- bis- (di-n-propylamine base)-phenthazine -5- iodide (PRB) inhibit answering for tumor cell proliferation with supersonic synergic
With.
2. application as described in claim 1, which is characterized in that the tumour cell is K562 cell.
3. application as described in claim 1, which is characterized in that the supersonic frequency is 40KHz.
4. application as described in claim 1, which is characterized in that the ultrasonic power 450W.
5. application as described in claim 1, which is characterized in that the ultrasonic temperature is 20 DEG C.
6. application as described in claim 1, which is characterized in that the ultrasonic procedure carries out under the conditions of being protected from light.
7. application as described in claim 1, which is characterized in that the concentration of the PRB is 12.5 μm of ol/L.
8. application as described in claim 1, which is characterized in that the preparation method of the PRB includes the following steps:
(1) at room temperature, it weighs phenthazine 2.0860g to be dissolved in the dichloromethane solution of 100mL, it is molten to weigh iodine solid 8.4056g
In 400mL methylene chloride, after the dichloromethane solution of iodine is slowly dropped to the dichloromethane solution of phenthazine, stir for 24 hours,
It filters, gained precipitating, which adds methylene chloride, to be continuously stirred 16h and washed, and the intermediate product phenthazine -5- tetraiodide is obtained；
(2) at room temperature, the methanol solution of di-n-propylamine is slowly dropped in the methanol solution of the phenthazine -5- tetraiodide,
The molar ratio of the phenthazine -5- tetraiodide and di-n-propylamine is 1:14, continues to stir, and judges to react with thin-layered chromatography
Terminal, suction filtration obtain filtrate, crude product after revolving, and 50mL methylene chloride is added and 5% dilute hydrochloric acid is extracted, collects lower layer
Solution is washed with distilled water, and obtains 3,7- bis- (di-n-propylamine base)-phenthazine -5- iodide crude product.
9. application as claimed in claim 8, which is characterized in that product purification includes: first to be eluted with column chromatographic grade, eluant, eluent
Respectively methanol: methylene chloride=1:100 and methanol: methylene chloride=1:50；Thin-layer chromatography is used again, and solvent is methanol: two
3,7- bis- (di-n-propylamine base)-phenthazine -5- iodide sterling can be obtained in chloromethanes=1:30.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811264478.XA CN109350741A (en) | 2018-10-29 | 2018-10-29 | 3,7- bis- (di-n-propylamine base)-phenthazine -5- iodide and supersonic synergic inhibit the application of tumor cell proliferation |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811264478.XA CN109350741A (en) | 2018-10-29 | 2018-10-29 | 3,7- bis- (di-n-propylamine base)-phenthazine -5- iodide and supersonic synergic inhibit the application of tumor cell proliferation |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN109350741A true CN109350741A (en) | 2019-02-19 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN201811264478.XA Pending CN109350741A (en) | 2018-10-29 | 2018-10-29 | 3,7- bis- (di-n-propylamine base)-phenthazine -5- iodide and supersonic synergic inhibit the application of tumor cell proliferation |
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2018
- 2018-10-29 CN CN201811264478.XA patent/CN109350741A/en active Pending
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Application publication date: 20190219 |
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