CN108926551A - Application of the dichloroacetyl bromide phenol (thiosemicarbazone) compound in anti-tumor drug - Google Patents

Application of the dichloroacetyl bromide phenol (thiosemicarbazone) compound in anti-tumor drug Download PDF

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Publication number
CN108926551A
CN108926551A CN201810753792.8A CN201810753792A CN108926551A CN 108926551 A CN108926551 A CN 108926551A CN 201810753792 A CN201810753792 A CN 201810753792A CN 108926551 A CN108926551 A CN 108926551A
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compound
thiosemicarbazone
cancer
cell
dichloroacetyl
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史大永
郭传龙
王立军
江波
李祥乾
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Institute of Oceanology of CAS
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • 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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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

The present invention relates to a kind of dichloroacetyl bromide phenol (thiosemicarbazone) compounds to prepare the application in antineoplastic, is especially preparing the application in drugs against colon cancer.The present invention experiments have shown that the proliferation of tumour cell, inducing apoptosis of tumour cell can be effectively suppressed in institute's invention compound, and influences tumour cell cycle through cell Proliferation, Apoptosis, cell cycle and molecular biology etc., has significant anti-tumor activity.The present invention provides experimental basis for development of new anti-tumor drug, has good clinical application prospect.The dichloro-acetyl heterozygote can be used as effective ingredient, is subject to pharmaceutically acceptable carrier, prepares antitumor medicine composition.

Description

Application of the dichloroacetyl bromide phenol (thiosemicarbazone) compound in anti-tumor drug
Technical field
The invention belongs to technical field of pharmaceuticals, specifically, being related to dichloroacetyl bromide phenol (thiosemicarbazone) compound (I) its pharmacological activity and pharmaceutical use.The compound can be used for preventing and/or treating tumour or cancer caused by various factors Etc. diseases.
Background technique
Colon cancer is one of big common cancer in China nine.In 30 years of past, the morbidity of China's colon cancer Rate is in rising trend.Colon cancer died, male occupy the 5th of mortality of malignant tumors, and women occupies the 6th.From epidemiology Viewpoint sees, the morbidity of colon cancer and social environment, life style (especially eating habit, lack physical exertion), inherent cause It is related.Age, colorectal polypus history, ulcerative colitis and gallbladder removal history are also the high risk factor of colon cancer.But it is overall and Speech, the cause of disease of colon cancer is not like fully aware of.
Colon cancer is more common in the middle-aged and the old, accounts within 30~69 years old the overwhelming majority, and male is more than women, and it is swollen that disease incidence accounts for gastrointestinal tract The 3rd of tumor.Colon cancer is mainly gland cancer, mucinous adenocarcinoma, undifferentiated carcinoma.General form is in polypoid, ulcer type etc..Colon cancer Can along intestinal wall go in ring development, along intestinal tube indulge diameter up and down spread or to intestinal wall deep layer infiltrate, except through lymphatic vessel, blood flow transfer and part It, can also be to intraperitoneal plantation or along suture, cut sides diffusion transfer outside invading.Patients with chronic colitis, polyp of colon patient, male Property overweight people it is equal be Susceptible population.
The treatment of colon cancer is still the basis of radical cure with surgical operation, and having Operation indication, person is still first choice with surgical operation Therapeutic modality.Effective complex treatment or adjuvant radiotherapy appropriate, chemotherapy are the aspects of clinical pay attention to day by day, especially take peace Complete effective drugs against colon cancer, can effectively improve the life quality of patient.But current clinically available safe, low toxicity, Effective antitumour drug is considerably less.Therefore, efficient, low toxicity, alternative killing or the new role for inhibiting tumour cell are found The new type antineoplastic medicine of mechanism has become the important directions of anti-tumor drug research and development.
Dichloroacetic acid is a kind of mitochondrial pyruvate acidohydrogenase kinase inhibitor, can be with the work of pyruvic dehydrogenase (PDH) Property, control the adapter phospho between oxidative stress and glycolysis.Dichloroacetic acid class compound can pass through modulate tumor cell Metabolic alterations play anti-tumor activity, are more paid close attention in recent years.By dichloroacetic acid in conjunction with contracting amido thiourea compound, The biological activity of compound can be effectively improved, adjusting of the compound to oxidative stress is improved, plays more excellent resist Tumor promotion.
It is existing the present invention relates to application of the dichloroacetyl bromide phenol (thiosemicarbazone) compound (I) in drug field There is no dichloroacetyl bromide phenol (thiosemicarbazone) compound (I) provided by the invention and its medicine as effective component in technology The report of object is also applied without the compound object or its pharmaceutical composition and is preparing or treating the diseases such as tumour caused by various factors Report in medicine.
Summary of the invention
The purpose of the present invention is to provide the dichloroacetyl bromide phenol (thiosemicarbazone), that is, chloro- N- of 2,2- bis- (2- (2,3- bis- Bromo-4,5-dimethoxy benzylidene) hydrazine thiocarbonyl) acetamide (I) pharmaceutical usage, and in particular to preparing anti-tumor drug Or the application in the antitumor drug for having related disorders；
The chloro- N- of 2,2- bis- of the present invention (2- (the bromo- 4,5- dimethoxybenzyliden of 2,3- bis-) thio carbonyl of hydrazine Base) acetamide (I) is this laboratory chemical synthesis gained, chemical structural formula is as follows:
The dichloroacetyl bromide phenol (thiosemicarbazone) compound is the chloro- N- of 2,2- bis- (2- (the bromo- 4,5- bis- of 2,3- bis- Methoxybenzylidene) hydrazine thiocarbonyl) acetamide (2,2-dichloro-N- (2- (2,3-dibromo-4,5- dimethoxybenzylidene)hydrazinecarbonothioyl)acetamide)。
The dichloroacetyl bromide phenol (thiosemicarbazone) compound can be used as effective ingredient, be used to prepare anti- Tumour has the drug of related disorders.
Described antitumor have related disorders to prevent and/or one of the related diseases and symptom such as treatment tumour, cancer Or two kinds or more, it particularly relates to and the tumours such as intestinal cancer, lung cancer, liver cancer, gastric cancer, breast cancer, cancer of pancreas, prostate cancer and/or cancer One of disease or two kinds or more.
The pharmaceutically acceptable salt and dichloro-acetyl of the dichloroacetyl bromide phenol (thiosemicarbazone) compound One of chemical equivalent of bromine phenol (thiosemicarbazone) compound or two kinds or more can be used directly, or with medicine group The form for closing object uses.
Described pharmaceutical composition contains 0.1-99%, preferably 0.5-90% dichloroacetyl bromide phenol contracting amino sulphur The pharmaceutically acceptable salt of carbamide compounds and the chemical equivalent of dichloroacetyl bromide phenol (thiosemicarbazone) compound One of or two kinds or more, remaining is pharmaceutically acceptable pharmaceutical carrier and/or excipient.
Pharmaceutically acceptable salt is K salt and/or Na salt.
The present invention is by the chloro- N- of above-mentioned 2,2- bis- (2- (the bromo- 4,5- dimethoxybenzyliden of 2,3- bis-) hydrazine thiocarbonyl) Acetamide (I) has carried out anti-tumour cell proliferative activity experiment, morphological observation experiment, inducing apoptosis of tumour cell reality It tests, influences tumour cell cycle experiment, influences the experiment of cell activity oxygen, the experimental results showed that, the chloro- N- (2- of 2,2- bis- (2,3- bis- bromo- 4,5- dimethoxybenzyliden) hydrazine thiocarbonyl) acetamide (I) can significantly inhibit tumor cell proliferation, it lures It leads apoptosis of tumor cells and tumour cell cycle can be influenced, and tumour cell is induced to generate active oxygen, there is significant antitumor work Property.
Described chloro- N- of 2,2- bis- (2- (the bromo- 4,5- dimethoxybenzyliden of the 2,3- bis-) hydrazine thiocarbonyl) acetamide (I) it can be used as effective ingredient, be subject to pharmaceutically acceptable carrier, prepare antineoplastic pharmaceutical compositions.Particularly for Prepare the antitumor drug for there are related disorders.
The present invention has the advantage that
Through anti-tumor activity experiments have shown that compound can significantly inhibit tumor cell proliferation, induction tumour cell withers the present invention It dies, influences tumour cell cycle, it is significant that tumour cell is induced to generate active oxygen.With significant anti-tumor activity.
Detailed description of the invention
Fig. 1 is the chloro- N- of 2,2- bis- (2- (the bromo- 4,5- dimethoxybenzyliden of 2,3- bis-) hydrazine thiocarbonyl) acetamide (I) to colon cancer cell HCT-116 increment inhibiting effect figure.
Fig. 2 is the chloro- N- of 2,2- bis- (2- (the bromo- 4,5- dimethoxybenzyliden of 2,3- bis-) hydrazine thiocarbonyl) acetamide (I) to the influence of colon cancer cell HCT-116 apoptotic effect.
Fig. 3 is the chloro- N- of 2,2- bis- (2- (the bromo- 4,5- dimethoxybenzyliden of 2,3- bis-) hydrazine thiocarbonyl) acetamide (I) to the influence diagram of colon cancer cell HCT-116 cell cycle.
Fig. 4 is the chloro- N- of 2,2- bis- (2- (the bromo- 4,5- dimethoxybenzyliden of 2,3- bis-) hydrazine thiocarbonyl) acetamide (I) to the influence of colon cancer cell HCT-116 active oxygen.
Fig. 5 is the chloro- N- of 2,2- bis- (2- (the bromo- 4,5- dimethoxybenzyliden of 2,3- bis-) hydrazine thiocarbonyl) acetamide (I) to the influence of colon cancer cell HCT-116 apoptotic proteins.
Specific embodiment
The synthesis of 1 compound of embodiment and Structural Identification
The chloro- N- of 2,2- bis- of the present invention (2- (the bromo- 4,5- dimethoxybenzyliden of 2,3- bis-) hydrazine thiocarbonyl) acetamide Preparation step it is as follows: weigh 1mmol2- (the bromo- 4,5- dimethoxybenzyliden of 2,3- bis-) thiosemicarbazides and 1mmol2,2- Dichloroacetyl chloride (97 μ L) is placed in a reaction flask, and adds 30mL methylene chloride, and 500 μ LNaOH (2M) are then added and are stirred at room temperature About 12 hours, 30 milliliters of ice water are added afterwards, filter to obtain precipitating, ice water washing and precipitating (30mL is in three times) obtains compound I.1H-NMR (500MHz,DMSO-d6) δ: 11.62 (1H, s), 8.44 (1H, s), 8.34 (1H, s), 8.20 (1H, s), 7.80 (1H, s), 5.92 (s,2H),3.91(3H,s),3.76(3H,s)；13C-NMR(125MHz,DMSO-d6)δ:178.5,165.7,153.0,148.9, 142.1,131.2,121.6,117.5,110.6,66.1 60.7,57.
Chloro- N- (2- (the bromo- 4,5- dimethoxybenzyliden of the 2,3- bis-) hydrazine thiocarbonyl) acetyl of 2 2,2- of embodiment bis- Amine (I) is to the active research of cell proliferation
1. experimental drug
The chloro- N- of 2,2- bis- (2- (the bromo- 4,5- dimethoxybenzyliden of 2,3- bis-) hydrazine thiocarbonyl) acetamide (I) is by this Laboratory is synthetically prepared, and using DMSO hydrotropy, is configured to 20mM storing liquid long-term preservation, experiment maximum concentration is 20 μM.
2. cell strain
Human colon cancer cell (HCT-116) is purchased from Shanghai Cell Bank of the Chinese Academy of Sciences.With the 10% tire ox blood containing mass concentration Clear DMEM culture medium is in 37 DEG C, volume fraction 5%CO2, routine culture in air under fully saturated damp condition, 48h is more It changes culture medium, when cell growth is up to saturation state, is passed on 0.25% trypsin digestion, 3-4d is passed on 1 time, and experiment is selected pair Number growth period cell.
3. cytoactive detection
Using tetramethyl azo azoles salt (MTT) method detection compound (I) to colon cancer cell HCT-116 cell proliferation activity Influence.The colon cancer cell HCT-116 of logarithmic phase is taken, pancreatin digestion is resuspended, and adjustment cell concentration is 3 × 105/ mL, with 100 The hole μ L/ be inoculated with 96 orifice plates, adherent growth for 24 hours after, inhale abandon culture medium, compound (I) (2.5,5,10,20 μ of various concentration are added M), three multiple holes are arranged in each concentration, and set respective concentration PBS Vehicle controls and cell-free zeroing group.Cell 37 DEG C, 5%CO2Under the conditions of cultivate 48h, the MTT of 20 μ L, 5mg/mL is then added, in 37 DEG C, 5%CO2Under the conditions of be incubated for 4h, inhale on abandoning Clearly, 150 μ L DMSO are added in every hole, shake 10 minutes, and OD value is detected under microplate reader 490nm wavelength.And calculate cell inhibitory rate and Half-inhibitory concentration (IC50).
As the result is shown: compound (I) has stronger inhibited proliferation to colon cancer cell HCT-116, and IC50 is 7.19μM.Cell inhibitory effect activity See Figure 1.
Chloro- N- (2- (the bromo- 4,5- dimethoxybenzyliden of the 2,3- bis-) hydrazine thiocarbonyl) acetyl of 3 2,2- of embodiment bis- Research of the amine (I) to colon cancer cell HCT-116 apoptosis
1. experimental cell:
With embodiment 1
2. experimental drug:
With embodiment 1
3. experimental method:
Apoptosis detection uses AnnexinV/PI decoration method.Logarithmic phase colon cancer cell HCT-116 is taken, cell is adjusted Concentration is 5 × 105/ mL is inoculated in six orifice plates, in 37 DEG C, 5%CO2It is cultivated in incubator for 24 hours, the change of various concentration concentration is added It closes object (I) (5,10,20 μM), acts on 48h, concurrently set blank group (PBS).Cell uses the pancreatin without EDTA to digest, and PBS is washed It washs three times, collects 1~5 × 105The Binding Buffer suspension cell of 500 μ L is added at 5 μ L are added after cell suspension in cell Annexin V-FITC and 5 μ L Propidium Iodide, room temperature is protected from light 15min after mixing, carries out in flow cytometer Detection.
The results show that compound (I), which can induce colon cancer cell HCT-116, occurs apoptosis, high concentration group apoptosis ratio can Up to 59%, apoptosis-promoting effect is in dose dependent, inhibitory activity See Figure 2.
Chloro- N- (2- (the bromo- 4,5- dimethoxybenzyliden of the 2,3- bis-) hydrazine thiocarbonyl) acetyl of 4 2,2- of embodiment bis- Research of the amine (I) to the A549 cell cycle
1. experimental cell:
With embodiment 1
2. experimental drug:
With embodiment 1
3. experimental method:
The analysis of cell cycle uses the mono- method contaminated of PI.Logarithmic phase HCT-116 cell is taken, adjustment cell concentration is 5 ×105/ mL is inoculated in six orifice plates, in 37 DEG C, 5%CO2After cultivating for 24 hours in incubator, the compound (I) of various concentration is added (5,10,20 μ g/mL) acts on 48h, concurrently sets blank group (PBS).Cell is collected by centrifugation, PBS is washed twice, and cell is used 75% cold ethyl alcohol resuspension is placed in -20 DEG C overnight.Cell is centrifuged and is washed twice with PBS, cell is resuspended with PBS, 20 μ are added In 37 DEG C of incubation 30min, the PI room temperature that then 50 μ g/mL are added in cell is protected from light to be incubated for after 30min in streaming the RNase A of g/mL Cell instrument is detected.
The results show that compound (I), which can induce HCT-116 cell, occurs G1 phase Cycle Arrest, to A549 Cycle Arrest See Figure 3.
Chloro- N- (2- (the bromo- 4,5- dimethoxybenzyliden of the 2,3- bis-) hydrazine thiocarbonyl) acetyl of 5 2,2- of embodiment bis- Research of the amine (I) to colon cancer cell HCT-116 active oxygen
1. experimental cell:
With embodiment 1
2. experimental drug:
With embodiment 1
3. experimental method:
Taking logarithmic phase A549 cell adjustment cell concentration is 5 × 105/ mL is inoculated in six orifice plates, in 37 DEG C, 5%CO2Culture After cultivating for 24 hours in case, the compound (I) (5,10,20 μ g/mL) of various concentration is added, acts on 48h, concurrently sets blank group (PBS).Cell culture fluid is removed, the fluorescence probe DCFH-DA that 1mL concentration is 10 μM is added, is put into incubator and is incubated for 20min.Cell is washed three times with serum-free cell culture medium, and intracellular Fluorescence probe DCFH-DA is not entered with abundant removal.Carefully Born of the same parents digest centrifugation with 0.25% pancreatin, and cell precipitation is detected after being resuspended with the PBS of 500 μ L in flow cytometer.
The results show that inducing cell generates active oxygen, with blank control group phase after compound (I) stimulation HCT-116 cell Than the compound (I) of high concentration can make intracellular reactive oxygen concentration increase 240.67%.As a result see Fig. 4.
Chloro- N- (2- (the bromo- 4,5- dimethoxybenzyliden of the 2,3- bis-) hydrazine thiocarbonyl) acetyl of 6 2,2- of embodiment bis- Research of the amine (I) to HCT-116 apoptosis protein
1. experimental cell:
With embodiment 1
2. experimental drug:
With embodiment 1
3. experimental method:
Taking logarithmic phase HCT-116 cell adjustment cell concentration is 5 × 105/ mL is inoculated in six orifice plates, in 37 DEG C, 5%CO2 After cultivating for 24 hours in incubator, the compound (I) (5,10,20 μM) of various concentration is added, acts on 48h, concurrently sets blank group (PBS), group of cells total protein is extracted with RIPA fine melt liquid.SDS-PAGE polyacrylamide gel electrophoresis (concentration glue 80V, Separation gel 120V) and transferring film, pvdf membrane infiltration closed 1h in the TBST containing 5% skimmed milk power by transfer protein to pvdf membrane, It is added specificity primary antibody PARP, Bcl-2, Bax, caspase-3 (1:1000).4 DEG C overnight, and TBST buffer is washed film 3 times, is added The secondary antibody (1:10000) of HRP label is incubated at room temperature 1h, and TBST buffer is washed film 3 times, finally developed the color with ECL, X sensitive film is photosensitive Afterwards, developing fixing.β-actin is used as internal reference albumen.
The results show that induction Bax protein expression raises and lowers Bcl-2's after compound (I) stimulation HCT-116 cell Expression, while activating PARP and caspase-3.As a result see Fig. 5.

Claims (7)

1. a kind of dichloroacetyl bromide phenol (thiosemicarbazone) compound is applied in the preparation of antitumor drugs, it is characterised in that:
The dichloroacetyl bromide phenol (thiosemicarbazone) compound has following chemical structure:
(I),
It can be used as an active ingredient in the preparation of in the antitumor and/or antitumor drug for having related disorders with anti-tumor activity.
2. application described in accordance with the claim 1, it is characterised in that:
The dichloroacetyl bromide phenol (thiosemicarbazone) compound is the chloro- N- of 2,2- bis- (2- (the bromo- 4,5- dimethoxy of 2,3- bis- Base benzylidene) hydrazine thiocarbonyl) acetamide (2,2-dichloro-N- (2- (2,3-dibromo-4,5- dimethoxybenzylidene)hydrazinecarbonothioyl)acetamide)。
3. application described in accordance with the claim 1, it is characterised in that:
The dichloroacetyl bromide phenol (thiosemicarbazone) compound can be used as effective ingredient, be used to prepare antitumor There is the drug of related disorders.
4. application described in accordance with the claim 3, it is characterised in that:
Described antitumor have related disorders to prevent and/or one of the related diseases and symptom or two such as treatment tumour, cancer Kind or more, it particularly relates to and the tumours such as intestinal cancer, lung cancer, liver cancer, gastric cancer, breast cancer, cancer of pancreas, prostate cancer and/or cancer disease One of disease or two kinds or more.
5. application described in accordance with the claim 1, it is characterised in that:
The pharmaceutically acceptable salt and dichloroacetyl bromide phenol of the dichloroacetyl bromide phenol (thiosemicarbazone) compound One of chemical equivalent of (thiosemicarbazone) compound or two kinds or more can be used directly, or with pharmaceutical composition Form use.
6. applying according to claim 5, it is characterised in that:
Described pharmaceutical composition contains 0.1-99%, preferably 0.5-90% dichloroacetyl bromide phenol (thiosemicarbazone) In the pharmaceutically acceptable salt of compound and the chemical equivalent of dichloroacetyl bromide phenol (thiosemicarbazone) compound One or two or more kinds, remaining is pharmaceutically acceptable pharmaceutical carrier and/or excipient.
7. applying according to claim 5, it is characterised in that:
Pharmaceutically acceptable salt is K salt and/or Na salt.
CN201810753792.8A 2018-07-10 2018-07-10 Application of the dichloroacetyl bromide phenol (thiosemicarbazone) compound in anti-tumor drug Pending CN108926551A (en)

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Citations (2)

* Cited by examiner, † Cited by third party
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
CN106748939A (en) * 2016-11-29 2017-05-31 中国科学院海洋研究所 The new bromine phenol thiosemicarbazide compound of one class and its preparation and medicine and purposes

Patent Citations (2)

* Cited by examiner, † Cited by third party
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
CN106748939A (en) * 2016-11-29 2017-05-31 中国科学院海洋研究所 The new bromine phenol thiosemicarbazide compound of one class and its preparation and medicine and purposes

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
ARIJIT BASU等: "Effect of substitution at N’’-position of N’-hydroxy-N-amino guanidines on tumor cell growth", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 *
NING WU等: "Marine Bromophenol Bis (2,3-Dibromo-4,5-dihydroxy-phenyl)-methane Inhibits the Proliferation, Migration, and Invasion of Hepatocellular Carcinoma Cells via Modulating β1-IntegrinFAK Signaling", 《MAR. DRUGS》 *
四川医学院主编: "《药物化学》", 30 November 1979, 四川医学院主编 *

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Application publication date: 20181204