CN106074556B - L-type cytimidine alanine is preparing the application in anticancer drug - Google Patents
L-type cytimidine alanine is preparing the application in anticancer drug Download PDFInfo
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- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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Abstract
The invention discloses a kind of L-type cytimidine alanine to prepare the application in anticancer drug, belongs to technical field of new application of medicine.The wherein chemical structural formula of L-type cytimidine alanine, and specifically disclose the L-type cytimidine alanine and preparing the application in medicines resistant to liver cancer.L-type cytimidine alanine produced by the present invention has significant inhibiting effect to liver cancer cells, it can be used for the exploitation of medicines resistant to liver cancer, it is also contemplated that for being used as chemotherapy ancillary drug, to which the clinical treatment to improve the malignant tumours such as liver cancer provides a kind of new effective treatment method, with good development and application prospects.
Description
Technical field
The invention belongs to technical field of new application of medicine, and in particular to the new application of L-type cytimidine alanine, i.e. L-type born of the same parents
Pyrimidine alanine is preparing the application in anticancer drug.
Background technique
Malignant tumour is always to endanger one of serious problems of human health, the reason is that intracellular proto-oncogene and suppression cancer
Gene expression is out of control as a result, general can all undergo one section of very long pathogenic course.Intracellular oncogene expression imbalance, makes cell
It uncontrollably grows and breeds, and can transport and shift with body body fluid.Apoptosis Mechanism is to holding Equilibrium ten
Point important, the growth rate of tumour is difficult to control, this is closely related with the decrease of apoptosis capacity and the promotion of proliferative capacity.
Hepatocellular carcinoma（Hepatocellular carcinoma, HCC）It is global the fifth-largest kinds of tumor, there is prognosis
The features such as severe and death rate is high seriously threatens the life and health of the mankind.Although recently as diagnostic imaging and operation skill
Being constantly progressive for art and emerging using Sorafenib as the hepatoma-targeting therapeutic agent of representative, for liver cancer early diagnosis with control
Treatment, which provides, so that the treatment level of liver cancer has been obtained certain raising with more and more effective therapeutic choice.However, comprehensive
Current liver cancer clinical treatment status is seen, still lacks really effective and few side effects cancer treatment drug now, is answered after Liver Cancer Operation
The hair rate of transform still remains high, and postoperative 5 years survival rates are still hovered 30% or so, seriously constrains liver cancer overall therapeutic level
It improves, can not be allowed to obtain the improvement of essence.
At present in the treatment method of malignant tumour, chemotherapy is one of essential therapeutic arsenals of malignant tumour.With chemotherapy
Medicine be widely used and the appearance of the following multi-drug resistance phenomenon, the sensibility of tumours of chemotherapeutic agents is lower and lower,
The antitumor action of certain chemotherapeutics increasingly declines, and the treatment rate of patient is caused to further decrease.In view of this, urgently opening at present
The drug for being able to suppress tumor cell proliferation and promoting apoptosis of tumor cells for sending out selectively targeted.At present clinically for treating
The toxic and side of liver cancer is larger.Therefore, the anticancer drug for developing and developing new and effective low toxicity has become treatment
With the new hope for capturing cancer.
Summary of the invention
The object of the present invention is to provide the new applications of L-type cytimidine alanine, i.e., L-type cytimidine alanine is in preparation anticancer
Application in drug.
The technical scheme is that L-type cytimidine alanine is preparing the application in anticancer drug, wherein L-type born of the same parents are phonetic
The chemical structural formula of pyridine alanine。
Further preferably, the L-type cytimidine alanine is preparing the application in medicines resistant to liver cancer.
Further preferably, the drug is chemotherapy ancillary drug.
Further preferably, the specific synthesis process of the L-type cytimidine alanine is：
（1）The Serine of importing amino protecting group is under the action of diethylazodicarboxylate and triphenylphosphine by nucleophilic
Reagent replaces, while Walden overturning occurs with the connected carbon atom configuration of hydroxyl and generates N- (tert- butoxy carbonyl 1)-L- ammonia
Acid-lactone；
（2）Sodium hydride is added in the organic solution of cytimidine, amido protecting examination is added in gained suspension after standing in 0 DEG C
Then agent is neutralized with hydrochloric acid solution, the solid product of generation is filtered, washing, and the born of the same parents for being dried to obtain importing amino protecting group are phonetic
Acridine compound monomer；
（3）Under the action of organic alkali catalyst, step（2）Products therefrom and N- (tert- butoxy carbonyl 1)-Serine-
Lactone compound reaction generates the alanine derivatives of cytimidine；
（4）By step（3）Reaction products therefrom sloughs amino protecting group, is filtered, and washs, is dried to obtain L-type cytimidine
Alanine.
Further preferably, step（1）In amino protecting group Wei Benzyl oxygen carbonyl（Cbz）, tertbutyloxycarbonyl（Boc）, fluorenes first
Oxygroup（Fmoc）, allyloxycarbonyl（Alloc）, trimethylsilyl ethoxycarbonyl（Teoc）, methoxycarbonyl group or carbethoxyl group.
Further preferably, step（2）The organic solvent of middle dissolution cytimidine is dimethylformamide, tetrahydrofuran or diformazan
Base sulfoxide, amido protecting agent are benzyl chloroformate, chloro-carbonic acid -9- fluorenyl methyl ester, allyl chlorocarbonate, N- [2- (trimethyl silicane
Base) ethoxy carbonyloxy group] succinimide or 2,2,2 trichloroethyl chloroformate.
Further preferably, step（3）In organic alkali catalyst be 1,8- diazabicylo (5,4,0) -7- alkene（DBU）Or
Tetramethylguanidine（TMG）.
The present invention detects the influence that L-type cytimidine alanine survives BRL-3A and RH35 with MTT method.The result shows that by
The activity of the RH35 of both L-type cytimidine alanine processing is than control decline 58%, and the BRl-3A activity being subject to processing is sequentially than control
Decline 33%, statistical analysis show that L-type cytimidine alanine has apparent inhibiting effect to the activity of RH35, and living to BRL-3A
The inhibiting effect of property is not significant, and L-type cytimidine alanine has higher toxicity and selectivity to liver cancer cells.
With various concentration L-type cytimidine alanine（1-8mmol/L）After handling BRL-3A and RH35 cell 48h respectively, use
Enzyme-linked immunosorbent assay instrument measures absorbance value under 570nm wavelength（OD）, and calculate cell proliferation inhibition rate.L-type after measured
Cytimidine alanine has significant inhibiting effect, and this suppression to the growth of BRL-3A cell between 1-8mmol/L in concentration
Production is in dose-dependence.
Show L-type cytimidine alanine to RH35's with the half lethal dose of SPSS software analysis L-type cytimidine alanine
Half lethal dose is 9.8mM, and the half lethal dose to BRL-3A is 13.7mM（As shown in Figure 1）, the results showed that L-type cytimidine alanine
There are higher toxicity and selectivity to liver cancer cells.
L-type cytimidine alanine produced by the present invention has significant inhibiting effect to liver cancer cells, can be used for anti-liver cancer and anti-
The exploitation of drug, it is also contemplated that for being used as chemotherapy ancillary drug, thus to improve the clinical treatment of the malignant tumours such as liver cancer
A kind of new effective treatment method is provided, with good development and application prospects.
Detailed description of the invention
Fig. 1 is toxic effect curve of the L-type cytimidine alanine of the present invention to cell；
Fig. 2 is the influence curve of L-type cytimidine alanine cell cycle of the present invention, and wherein A is L-type cytimidine alanine
The BRL-3A cell of processing, B are control BRL-3A cell, and C is the RH35 cell of L-type cytimidine alanine processing, and D is control
RH35 cell；
Fig. 3 is L-type cytimidine alanine of the present invention to the influence curve of natural death of cerebral cells, and wherein A is L-type cytimidine alanine
The BRL-3A cell of processing, B are control BRL-3A cell, and C is the RH35 cell of L-type cytimidine alanine processing, and D is control
RH35 cell；
Fig. 4 is L-type cytimidine alanine pair of the present inventionCCNA2、MYC、CASP3、CASP9、BAXWithBCL2The influence of expression
Curve.
Specific embodiment
Above content of the invention is described in further details by the following examples, but this should not be interpreted as to this
The range for inventing above-mentioned theme is only limitted to embodiment below, and all technologies realized based on above content of the present invention belong to this hair
Bright range.
Embodiment 1
The synthesis of L-type cytimidine alanine
Step 1）Synthesize N- (tert- butoxy carbonyl 1)-Serine-lactone 2：By anhydrous tetrahydro furan（THF）（100mL）
It is added dropwise to azo ethyl diacetate（3.8mL, 24.22mmol）With triphenyl phosphorus（Ph3P）（6.3g, 24.00mmol）It is molten
In liquid object, and stir more than 10min.Thus obtained reaction mixture is stirred for 10min.At N- (tert- butoxy carbonyl 1)-L-
Propylhomoserin（5g, 24.36mmol）In the mixed solution of above-mentioned tetrahydrofuran is added dropwise（25mL）, stir more than 20min.It obtains
Solution stirs 20min under the conditions of -78 DEG C.Futher stir 2.5h under normal temperature conditions again.Use chromatographic column（Volume ratio is 3:1
Normal hexane/ethyl acetate）Solvent purification semifinished product is removed, finally recrystallizes and is further purified from ethyl acetate/normal hexane
Obtain compound as white solid 2（2.4g, yield 53%）.
Step 2）Synthesize N-CBZ- cytimidine 6：In sodium hydride（NaH）（60% disperses in the oil, 1.35g, 33.8mmol）It is molten
Cytimidine 5 is added in liquid（2g, 8.2mmol）Dimethylformamide（DMF）Solution.Suspension stirs 45min at 0 DEG C, uses
Benzyl chloroformate（ClCO2Bn）（50.7mL 355mmol）The mixed solution that above-mentioned dimethylformamide is added dropwise is more than 1h.Gained
16h is stirred at room temperature in solution.Resulting yellow solution pours into ice water, is neutralized with hydrochloric acid solution.It is obtained by filtration solid
Body product is washed through water and ether, obtains white powdery solids compound 6 after dry（1.5g, yield 75%）.
Step 3）Synthesize N- tertiary butyloxycarbonyl-β-(N4- benzyloxycarbonyl group -1- cytimidine)-l-Alanine 3：Under an argon atmosphere
By diazabicylo（DBU）（0.48g, 3.10mmol）It is added to N-CBZ- cytimidine 6（1.07g 4.37mmol）Dimethyl
Formamide（4mL）In suspension.It is added in 15min into the mixed solution of above-mentioned dimethylformamide and is dissolved in dimethyl formyl
Amine（4mL）N- (tert- butoxy carbonyl 1)-Serine-lactone 2（0.41g, 2.18mmol）.Reaction 3h is stirred at room temperature
Afterwards, dimethylformamide, gained crude product purified by silica gel column chromatography are removed under vacuum conditions（Eluent：DCM/MeOH/
AcOH =9:1:0.1）Obtain solid chemical compound 3（500mg, yield 53%）.
Step 4）Synthesize 1- cytimidine-l-Alanine 4：Compound 3（0.53g, 1.23mmol）It is added to trifluoroacetic acid
（TFA）（34mmol）Thioanisole（6mmol）3h is stirred in solution.After the reaction was completed, it is heavy that hydrochloric acid solution is added in the product
It forms sediment and removes solvent in a vacuum.Resulting solid is filtered and is washed with ether to obtain white solid product L-type born of the same parents
Pyrimidine alanine 4（0.11g, yield 45%）.
The synthetic route of L-type cytimidine alanine is as follows：
Embodiment 2
Cell culture：Prepare the complete of fetal calf serum containing 10wt%, the streptomysin of 100mg/L and 1 × 105U/L penicillin
Culture solution is in 37 DEG C, saturated humidity, the CO containing volume fraction 5%2Incubator in cultivated.
Embodiment 3
MTT detection：Logarithmic phase growth period cell is taken to be inoculated in 96 well culture plates, every hole 5 × 10 respectively3A cell, culture
It is incubated in case and replaces the alanine of cytimidine containing L-type afterwards for 24 hours（0,1,2,3,4,6,8mmol/L）Complete culture solution, each concentration
Group 3 multiple holes of setting, to use the cell for the complete medium culture for not adding compound as control group, and are arranged and contain only training
The zeroing group of nutrient solution.After cultivating 48h, 20 μ L MTT are added（5mg/mL）, continue slowly to absorb supernatant after cultivating 4h, add 150 μ
L DMSO, 10min is rocked in oscillation makes crystallization detect 570nm absorbance with microplate reader after completely dissolution（A）Value.It calculates relatively living thin
Born of the same parents' inhibiting rate（IR）：IR=[1-（ATest class mean-AReturn to zero class mean）/（ACompare class mean- AReturn to zero class mean）] × 100%, it is non-linear with SPSS software
Return calculation of half inhibitory concentration（IC 50 ）.
Experimental result is with the concentration L-type cytimidine alanine processing rat normal liver cell BRL-3A that is 4mmol/L and big
Hepatoma cells RH35 48h detects the influence that they survive BRL-3A and RH35 with MTT method.The result shows that the work of RH35
Property than control decline 58%, BRl-3A activity than control decline 33%, statistical analysis show L-type cytimidine alanine to RH35 activity
Inhibiting effect it is significant, and it is not significant (P > 0.05) to the active inhibiting effect difference of BRL-3A.Two kinds are analyzed with SPSS software
The half lethal dose of compound shows that L-type cytimidine alanine is 9.8mM to the half lethal dose of RH35, to the semilethal of BRL-3A
Amount is 13.7mM（As shown in Figure 1）, as a result illustrate that L-type cytimidine alanine has higher toxicity and selectivity to liver cancer cells
（It the results are shown in Table 1）.
1 MTT of table detects the effect of L-type cytimidine alanine
Embodiment 4
The Flow cytometry cell cycle：Logarithmic growth phase cell inoculation is in 6 orifice plates, every hole 2 × 105A cell,
After being incubated for for 24 hours, 12h is synchronized with the culture solution containing 0.1% fetal calf serum, replaces the complete of the cytimidine of L-type containing 4mM/L alanine
Culture solution.48h, collected by trypsinisation cell are cultivated, PBS is washed twice, and the ethyl alcohol for being 70% with pre-cooling volume fraction is solid at -20 DEG C
Determine for 24 hours.Centrifugation removal ethyl alcohol, PBS are washed twice, and 500 μ L are added and contain 1% RNase（DNasefree）Buffer, 37 DEG C incubation
30min.Then 5 μ L PI dyestuffs are added, 4 DEG C are protected from light 15min, flow cytomery DNA content are used in 1h, data are used
The analysis of Modfit software.
Experimental result handles BRL-3A and RH35 48h with the L-type cytimidine alanine that concentration is 4mM, uses flow cytometry
Detect its influence to BRL-3A the and RH35 cell cycle.The result shows that after L-type cytimidine alanine processing RH35, the G0/G1 phase
Cell rises 13.12% than control, and after handling BRL-3A, G0/G1 phase cell rises 22.45% than control.To two kinds of cell cycles
It has a significant impact（P≤0.05）（As shown in Figure 2）.The specific timetable for analyzing two kinds of cell cycles of the compounds affect is bright, L-type
Cytimidine alanine mainly inhibits cell G0/G1 phase process.
Embodiment 5
Annexin V-FITC/7-AAD method detects Apoptosis：Logarithmic growth phase cell inoculation is in 6 orifice plates, every hole 2
×105A cell after being incubated for for 24 hours, replaces the complete culture solution of the cytimidine of L-type containing 4mM/L alanine.48h is cultivated, pancreatin disappears
Change and collect cell, pre-cooling PBS is washed twice, is resuspended with Binding buffer and is adjusted cell density extremely（0.25×107）-（1.0
×107）It is mixed that 5 μ L 7-AAD are added after taking 100 μ L cell suspensions that 5 μ L Annexin V-FITC mixing is added in a cells/ml
Even, room temperature is protected from light 5-10min, and sample, which is added, uses flow cytomery cell in Binding buffer to 500 μ L, 1h
Apoptosis, data are analyzed with Flowjo software.
Experimental result handles BRL-3A and RH35 48h with the L-type cytimidine alanine that concentration is 4mM, uses flow cytometry
Detect their influences to Apoptosis.The result shows that apoptosis rate is than in control after L-type cytimidine alanine processing RH35
3.55% is risen, after handling BRL-3A, apoptosis rate rises 1.06% than control.Statistical analysis shows that the compound induces liver cancer
The effect of Apoptosis is significant（P≤0.05）, but induce the effect of normal liver cell apoptosis not significant（P > 0.05）（Such as Fig. 3 institute
Show）.
Embodiment 6
Real-time quantitative PCR detects changes in gene expression：Logarithmic growth phase cell inoculation is in 6 orifice plates, every hole 2 × 105It is a
Cell after being incubated for for 24 hours, replaces the complete culture solution of the cytimidine of L-type containing 4mM/L alanine.48h is cultivated, collected by trypsinisation is thin
Born of the same parents, pre-cooling PBS are washed twice, and 1mL Trizol is added after centrifugation removal PBS.It is total that cell is extracted by Trizol reagent specification method
RNA carries out reverse transcription reaction using Reverse Transcriptase kit and synthesizes cDNA, is carried out using cDNA as template using SYBR Green technology
MRNA is quantitative.Amplification condition：94 DEG C, 2min, 94 DEG C, 20s, 52-56 DEG C, 20s, 60 DEG C, 30s, 45 circulations.Acquisition is every in real time
The variation of fluorescence intensity in one reaction tube obtains recurring number experienced when sample to be tested fluorescence signal reaches given threshold
（Cycle threshold, Ct）Value, using 2- △△ CtMethod is for statistical analysis.
Experimental result handles BRL-3A and RH35 48h with the L-type cytimidine alanine that concentration is 4mM, is examined with qRT-PCR
Survey the influence of their cell proliferations and the expression of apoptosis-associated genes.The result shows that after L-type cytimidine alanine processing RH35, it
Proliferation-associated genes CCNA2 and MYC expression successively than control decline 80.7% and 70.5%, apoptosis-related genes CASP3,
CASP9, BAX and BCL2 expression successively rise 81.5%, 178.9%, 100% and 158.5% than control, after handling BRL-3A, they
CCNA2 and MYC expression successively than control decline 83.5% and 65.9%, significant changes do not occur for apoptosis-related genes（Such as Fig. 4 institute
Show）.
Embodiment above describes basic principles and main features of the invention and advantage, the technical staff of the industry should
Understand, the present invention is not limited to the above embodiments, and the above embodiments and description only describe originals of the invention
Reason, under the range for not departing from the principle of the invention, various changes and improvements may be made to the invention, these changes and improvements are each fallen within
In the scope of protection of the invention.
Claims (5)
1.L type cytimidine alanine is preparing the application in medicines resistant to liver cancer, wherein the chemical structural formula of L-type cytimidine alanine
For。
2. L-type cytimidine alanine according to claim 1 is preparing the application in medicines resistant to liver cancer, it is characterised in that：
The drug is chemotherapy ancillary drug.
3. L-type cytimidine alanine according to claim 1 is preparing the application in medicines resistant to liver cancer, it is characterised in that institute
The specific synthesis process for the L-type cytimidine alanine stated is：
（1）The Serine of importing amino protecting group is under the action of diethylazodicarboxylate and triphenylphosphine by nucleopilic reagent
Replace, while interior with connected carbon atom configuration generation Walden overturning generation N- (tert- the butoxy carbonyl)-Serine-of hydroxyl
Ester；
（2）Sodium hydride is added in the organic solution of cytimidine, amido protecting agent is added after standing in 0 DEG C in gained suspension,
Then it is neutralized with hydrochloric acid solution, the solid product of generation is filtered, and washing is dried to obtain the cytimidine for importing amino protecting group
Monomer adduct；
（3）Under the action of organic alkali catalyst, step（2）Products therefrom and N- (tert- butoxy carbonyl)-Serine-lactone
The alanine derivatives of combination reaction generation cytimidine；
（4）By step（3）Reaction products therefrom sloughs amino protecting group, is filtered, and washs, is dried to obtain the third ammonia of L-type cytimidine
Acid.
4. L-type cytimidine alanine according to claim 3 is preparing the application in medicines resistant to liver cancer, it is characterised in that：
Step（2）The organic solvent of middle dissolution cytimidine is dimethylformamide, tetrahydrofuran or dimethyl sulfoxide, amido protecting agent
For benzyl chloroformate, chloro-carbonic acid -9- fluorenyl methyl ester, allyl chlorocarbonate, N- [2- (trimethyl silicon substrate) ethoxy carbonyloxy group] amber
Acid imide or 2,2,2 trichloroethyl chloroformate.
5. L-type cytimidine alanine according to claim 3 is preparing the application in medicines resistant to liver cancer, it is characterised in that：
Step（3）In organic alkali catalyst be 1,8- diazabicylo (5,4,0) -7- alkene or tetramethylguanidine.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1880737A1 (en) * | 1994-08-19 | 2008-01-23 | La Region Wallonne | Compounds, pharmaceutical composition and diagnostic device comprising same and their use |
| CN103351383A (en) * | 2013-07-29 | 2013-10-16 | 中国人民解放军第四军医大学 | 5-fluorouracil nitroxyl-free-radical anti-tumor drug |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1880737A1 (en) * | 1994-08-19 | 2008-01-23 | La Region Wallonne | Compounds, pharmaceutical composition and diagnostic device comprising same and their use |
| CN103351383A (en) * | 2013-07-29 | 2013-10-16 | 中国人民解放军第四军医大学 | 5-fluorouracil nitroxyl-free-radical anti-tumor drug |
Non-Patent Citations (1)
| Title |
|---|
| Characteristics of pyrimidine nucleobases through inter-base interactions on the crystals of the ternary copper(II) complexes;Koichiro Jitsukawa等;《Chemistry Letters》;20041231;第33卷(第10期);第1302-1303页 * |
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