CN107019689A - A kind of application of fluoro thiosemicarbazones compound in antineoplastic - Google Patents
A kind of application of fluoro thiosemicarbazones compound in antineoplastic Download PDFInfo
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- CN107019689A CN107019689A CN201710305700.5A CN201710305700A CN107019689A CN 107019689 A CN107019689 A CN 107019689A CN 201710305700 A CN201710305700 A CN 201710305700A CN 107019689 A CN107019689 A CN 107019689A
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
- A61K31/175—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine having the group, >N—C(O)—N=N— or, e.g. carbonohydrazides, carbazones, semicarbazides, semicarbazones; Thioanalogues thereof
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Abstract
The present invention relates to a kind of pharmaceutical usage of fluoro thiosemicarbazides compound 2 (3,4 difluoro benzylidene) thiosemicarbazides (I).The experiments such as the present invention breeds through cell, Apoptosis and cell cycle prove that institute's invention compound can effectively suppress the propagation of tumour cell, inducing apoptosis of tumour cell, and influence tumour cell cycle, with significant antitumor activity.Described 2 (3,4 difluoro benzylidene) thiosemicarbazides (I) can be subject to pharmaceutically acceptable carrier, prepare antitumor medicine composition as effective ingredient.
Description
Technical field
The invention belongs to technical field of pharmaceuticals, specifically, it is related to 2- (3,4- difluoro benzylidene) thiosemicarbazides chemical combination
Thing (I) its pharmacological activity and pharmaceutical use.The compound can be used for preventing and/or treat tumour caused by various factors or cancer
The diseases such as disease.
Background technology
It is to cause the second largest cause of disease of human death that tumour, which has a strong impact on the healthy of people,.Counted according to World Health Organization,
The tumor patient that the whole world is newly made a definite diagnosis every year is more than 10,000,000, and annual whole world tumor mortality is total up to 7,000,000 people.2012
Year, newly-increased 3,070,000 cancer patients of China simultaneously cause about 2,200,000 people dead, and the 21.9% and 26.8% of global total amount, cancer are accounted for respectively
Disease has become the dead first cause of urban and rural residents of China.Tumour not only seriously threatens the healthy of the people, gives
Patient and patient family bring economic loss, but also can cause white elephant to country and society.Find efficiently, low toxicity,
The new type antineoplastic medicine of the novel mechanism of alternative killing or suppression tumour cell has turned into what antineoplastic was researched and developed
Important directions.
(thiosemicarbazone) compound has extensive bioactivity, has multiple compounds at present as clinical antineoplastic medicine
Thing uses or carries out preclinical study, such as 2-formylpyridine, 5-HP and 3-AP, has in antitumor field of medicaments
Good application prospect.Fluorine atom or fluoro-containing group are incorporated into small-molecule drug, are the important of pharmaceutical chemistry structure of modification
Research strategy.The pharmacokinetic property of small molecule can not only be changed by introducing fluorine atom, improve the bioavilability of medicine, also
It is able to can also be led in addition by influenceing be combined with each other ability and the selectivity of the conformation of compound, enhancing part and target proteinses
Cross blocking easily metabolism site and then improve drug metabolism stability etc..Therefore, fluoro medicine occupies very big proportion in medicine, rises
Important function.
The present invention relates to application of the fluoro thiosemicarbazides compound (I) in drug field, in the prior art without this hair
The fluoro thiosemicarbazides compound (I) and its report of the medicine as active ingredient of bright offer, also not the compound thing or
Its pharmaceutical composition applies the report in preparing or treating the disease medicament such as tumour caused by various factors.
The content of the invention
It is an object of the invention to provide 2- (3,4- difluoro benzylidene) thiosemicarbazides (I) pharmaceutical usage, and in particular to
Application in antineoplastic is prepared；
2- (3,4- difluoro benzylidene) thiosemicarbazides (I) of the present invention is this laboratory chemical synthesis gained,
Its chemical mechanical formula is as follows：
It is real that above-mentioned 2- (3,4- difluoros benzylidene) thiosemicarbazides (I) has been carried out anti-tumour cell proliferative activity by the present invention
Test, inducing apoptosis of tumour cell experiment and influence tumour cell cycle are tested, test result indicates that, described 2- (3,4- difluoros
Benzylidene) thiosemicarbazides (I) can significantly inhibit tumor cell proliferation, and inducing apoptosis of tumour cell can simultaneously influence tumour cell week
Phase, with notable antitumor activity；
Described 2- (3,4- difluoro benzylidene) thiosemicarbazides (I) can be subject to pharmaceutically as effective ingredient
Acceptable carrier, prepares antineoplastic pharmaceutical compositions.Particularly for preparing the antitumor medicine for having a related disorders.The fluoro ammonia
The chemistry of base thiourea compound, the pharmaceutically acceptable salt of fluoro thiosemicarbazides compound and fluoro thiosemicarbazides compound
One or two or more kinds in equivalent can be used directly, or be used in the form of pharmaceutical composition.The pharmaceutical composition
Contain 0.1-99%, preferably 0.5-90% fluoro base thiourea compound, the materia medica of fluoro thiosemicarbazides compound
One or two or more kinds in the chemical equivalent of upper acceptable salt and fluoro thiosemicarbazides compound, remaining is pharmaceutically
Acceptable pharmaceutical carrier and/or excipient.
The invention has the advantages that：
The present invention proves that compound can significantly inhibit tumor cell proliferation through antitumor activity experiment, and induced tumor cell withers
Die and tumour cell cycle can be influenceed, with notable antitumor activity.
Brief description of the drawings
Fig. 1 is compound 2- (3,4- difluoros benzylidene) thiosemicarbazides (I) to A549 inhibitory action figures.
Fig. 2 is compound 2- (3,4- difluoros benzylidene) thiosemicarbazides (I) to A549 apoptotic effect figures.
Fig. 3 compounds 2- (3,4- difluoros benzylidene) thiosemicarbazides (I) is to A549 apoptotic effect morphologic detection figures.
Fig. 4 is influence figure of compound 2- (the 3,4- difluoros benzylidene) thiosemicarbazides (I) to the A549 cell cycles.
Embodiment
The research of the 2- of embodiment 1 (3,4- difluoros benzylidene) thiosemicarbazides (I) cell proliferation activity
1. experimental drug
Weigh 1mmol3,4- difluorobenzaldehydes (3.07g) and 1.1mmol thiosemicarbazides (2.16g) is placed in 200mL reaction bulbs
In, add after 20mL ethanol (95%) stirs, 1mL glacial acetic acid be added dropwise, then 65-70 DEG C of return stirring about 10 hours,
Remove 20 milliliters of frozen water of addition after most of ethanol under reduced pressure, filtering to be precipitated, and ice water washing and precipitating (20mL is in three times) ethanol is tied again
It is brilliant to obtain 2- (3,4- difluoro benzylidene) thiosemicarbazides, white solid.2- (3,4- difluoros benzylidene) thiosemicarbazides is used
DMSO hydrotropies, are configured to 50mg/ml storing liquids and preserve for a long time, and experiment Cmax is 12.5,25,50 μ g/ml.
2. cell line
Non-small cell lung carcinoma cell (A549) is purchased from Chinese Academy of Sciences's Shanghai cell bank.With containing the peptide ox of mass concentration 10%
The DMEM culture mediums of serum are 5%CO in 37 DEG C, volume fraction2, cellar culture, 48h in air under fully saturated damp condition
Culture medium is changed, when cell growth reaches saturation state, is passed on 0.25% Trypsin Induced, is passed on 1 time within 2-3 days, experiment choosing
Use exponential phase cell.
3. cytoactive detection
It is right using tetramethyl azo azoles salt (MTT) method detection compound 2- (3,4- difluoros benzylidene) thiosemicarbazides (I)
The influence of lung cell A549 cell proliferation activity.Take the logarithm the lung cell A549 of phase, pancreatin digestion is resuspended, and adjustment cell is dense
Spend for 5 × 104/ ml, is inoculated with after 96 orifice plates, adherent growth 24h with 100 μ L/ holes, and culture medium is abandoned in suction, adds the 2- of various concentrations
(3,4- difluoros benzylidene) thiosemicarbazides (I) (5,10,20 μ g/mL).Each concentration sets three multiple holes, and sets corresponding dense
The PBS Vehicle controls of degree and acellular zeroing group.Cell is in 37 DEG C, 5%CO2Under the conditions of cultivate 48h, then add 20 μ L,
5mg/mL MTT, in 37 DEG C, 5%CO2Under the conditions of be incubated 4h, supernatant is abandoned in suction, and 150 μ L DMSO are added per hole, is shaken 10 minutes,
OD values are detected under ELIASA 490nm wavelength.And calculate cell inhibitory rate and half-inhibition concentration (IC50).
As a result show：2- (3,4- difluoros benzylidene) thiosemicarbazides (I) has stronger Proliferation Ability to A549 cells
Effect, its IC50For 22.74 μ g/ml.Cell inhibitory effect activity See Figure 1.
Research of the 2- of embodiment 2 (the 3,4- difluoros benzylidene) thiosemicarbazides (I) to A549 apoptosis
1. experimental cell：
Be the same as Example 1
2. Experimental agents：
Be the same as Example 1
3. experimental method：
Apoptosis detection uses AnnexinV/PI decoration methods.To take the logarithm phase A549 cell, adjustment cell concentration is 5 ×
105/ mL, is inoculated in six orifice plates, in 37 DEG C, 5%CO2Cultivate 24h in incubator, add various concentrations concentration compound 2- (3,
4- difluoros benzylidene) thiosemicarbazides (I) (5,10,20 μ g/mL), 48h is acted on, blank group (PBS) is concurrently set.Cell is not with
Pancreatin digestion containing EDTA, PBS is washed three times, collects 1~5 × 105Cell, the Binding Buffer for adding 500 μ L suspend
Cell is into 5 μ L Annexin V-FITC and 5 μ L Propidium Iodide are added after cell suspension, and room temperature lucifuge is anti-after mixing
15min is answered, is detected in flow cytometer.
As a result show, compound 2- (3,4- difluoro benzylidene) thiosemicarbazides (I) can induce A549 apoptosis,
High concentration group apoptosis ratio is up to 51.8%, and its apoptosis-promoting effect is in dose dependent, its inhibitory activity See Figure 2.
The 2- of embodiment 3 (3,4- difluoros benzylidene) thiosemicarbazides (I) is to A549 apoptosis Senile Mouses
1. experimental cell：
Be the same as Example 1
2. Experimental agents：
Be the same as Example 1
3. experimental method：
Morphologic detection to Apoptosis uses Hoechst decoration methods.Take the logarithm phase A549 cell, adjust cell concentration
For 5 × 105/ mL, is inoculated in six orifice plates, in 37 DEG C, 5%CO2Cultivated in incubator after 24h, add the 2- of various concentrations concentration
(3,4- difluoro benzylidene) thiosemicarbazides (I) (5,10,20 μ g/mL), acts on 48h, concurrently sets blank group (PBS).Cell
Washed with PBS three times, 4% paraformaldehyde room temperature fixes 15min, PBS adds Hoechst33258 dyestuff lucifuges after washing three times
Dye after 15min with being observed under fluorescence microscope.
As a result show, 2- (3,4- difluoro benzylidene) thiosemicarbazides (I) is acted on after A549 cells, cell occurs obvious
Apoptosis feature, such as there is obvious pyknosis and small fragment, its morphological observation See Figure 3.
Research of the 2- of embodiment 4 (the 3,4- difluoros benzylidene) thiosemicarbazides (I) to the A549 cell cycles
1. experimental cell：
Be the same as Example 1
2. Experimental agents：
Be the same as Example 1
3. experimental method：
The method that the analysis of cell cycle uses the mono- dyes of PI.To take the logarithm phase A549 cell, adjustment cell concentration is 5 ×
105/ mL, is inoculated in six orifice plates, in 37 DEG C, 5%CO2Cultivated in incubator after 24h, add the 2- (3,4- bis- of various concentrations concentration
Fluorobenzylidene) thiosemicarbazides (I) (5,10,20 μ g/mL), 48h is acted on, blank group (PBS) is concurrently set.It is collected by centrifugation thin
Born of the same parents, PBS is washed twice, and cell is resuspended with 75% cold ethanol and is placed in -20 DEG C overnight.Cell is centrifuged and washed twice with PBS,
30min are incubated in 37 DEG C with 20 μ g/mL of PBS resuspension cell additions RNase A, then cell adds 50 μ g/mL PI room temperatures
Lucifuge is incubated 30min and detected after flow cytometer.
As a result show, compound 2- (3,4- difluoro benzylidene) thiosemicarbazides (I) can induce A549 cells and occur the G1 phases
Cycle Arrest, it is to A549 Cycle Arrests See Figure 4.
Comparative example 2- (the 3,5- difluoros benzylidene) research of thiosemicarbazides to tumour cell A549 proliferation activities
1. experimental cell：
Be the same as Example 1
2. Experimental agents：
Synthetic method be the same as Example 1
3. experimental method：
Be the same as Example 1
Experimental result shows compound 2- (3,5- difluoros benzylidene) thiosemicarbazides to tumour cell A549 Proliferation Abilities
IC50Value is more than 50 μ g/ml.
Claims (6)
1. a kind of fluoro thiosemicarbazones Compound Compound is applied in antineoplastic is prepared, it is characterised in that：
The fluoro thiosemicarbazones compound has antitumor activity, can be used to prepare antineoplastic as active ingredient
And/or for preparing in the antitumor medicine for having a related disorders.
2. according to the application described in claim 1, it is characterised in that：The fluoro thiosemicarbazones compound is 2- (3,4- bis-
Fluorobenzylidene) thiosemicarbazides (I), it has the chemical constitution such as Formula I：
3. according to the application described in claim 2, it is characterised in that：
Described 2- (3,4- difluoro benzylidene) thiosemicarbazides (I) is antitumor relevant for preparing as effective ingredient
The medicine of disease.
4. according to the application described in claim 3, it is characterised in that：
It is described it is antitumor have related disorders for prevent and/or the relevant disease and symptom such as treatment tumour, cancer in one kind or two
More than kind, particularly relate to and tumour and/or the cancer disease such as lung cancer, liver cancer, stomach cancer, breast cancer, cancer of pancreas, intestinal cancer, prostate cancer
One or two or more kinds in disease.
5. according to the application described in claim 1, it is characterised in that：
The pharmaceutically acceptable salt and fluoro amino sulphur of the fluoro thiosemicarbazides compound, fluoro thiosemicarbazides compound
One or two or more kinds in the chemical equivalent of carbamide compound can be used directly, or be made in the form of pharmaceutical composition
With.
6. according to the application described in claim 5, it is characterised in that：Described pharmaceutical composition contains 0.1-99%, is preferably
0.5-90% fluoro base thiourea compound, the pharmaceutically acceptable salt and fluoro ammonia of fluoro thiosemicarbazides compound
One or two or more kinds in the chemical equivalent of base thiourea compound, remaining for pharmaceutically acceptable pharmaceutical carrier and/
Or excipient.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710305700.5A CN107019689A (en) | 2017-05-03 | 2017-05-03 | A kind of application of fluoro thiosemicarbazones compound in antineoplastic |
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| CN201710305700.5A CN107019689A (en) | 2017-05-03 | 2017-05-03 | A kind of application of fluoro thiosemicarbazones compound in antineoplastic |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20040014801A1 (en) * | 2002-05-08 | 2004-01-22 | The Regents Of The University Of California | Thio semicarbazone and semicarbazone inhibitors of cysteine proteases and methods of their use |
| WO2015157242A1 (en) * | 2014-04-07 | 2015-10-15 | H. Lee Moffitt Cancer Center And Research Institute, Inc. | Thiosemicarbazones inhibitors of lysophosphatidic acid acyltransferase and uses thereof |
-
2017
- 2017-05-03 CN CN201710305700.5A patent/CN107019689A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20040014801A1 (en) * | 2002-05-08 | 2004-01-22 | The Regents Of The University Of California | Thio semicarbazone and semicarbazone inhibitors of cysteine proteases and methods of their use |
| WO2015157242A1 (en) * | 2014-04-07 | 2015-10-15 | H. Lee Moffitt Cancer Center And Research Institute, Inc. | Thiosemicarbazones inhibitors of lysophosphatidic acid acyltransferase and uses thereof |
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Application publication date: 20170808 |