CN103550208A - Application of thiazolidone derivative in preparing anti-colon-cancer medicines - Google Patents
Application of thiazolidone derivative in preparing anti-colon-cancer medicines Download PDFInfo
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Abstract
The invention discloses application of a thiazolidone derivative in preparing broad-spectrum anticancer medicines. The thiazolidone derivative is 2-(4-hydroxyphenylimido)-5-(3-metoxyphenylmethylene)-4-thiazolidone. The broad-spectrum anticancer medicines are preferably medicines with favorable anticancer activity for cervical carcinoma, colon cancer and rhabdomyosarcoma. The test proves that the thiazolidone compound can effectively inhibit proliferation of cervical carcinoma Hela cells, colon cancer HCT-116 cells and rhabdomyosarcoma RD cells and induce apoptosis; and the inspection on the action target spot detects that the obviously inhibits the formation of microtubules when acting on microtubulins and is hopeful to be developed into broad-spectrum anticancer medicines.
Description
The application is dividing an application of publication number CN103054859A application, the applying date of original application: 2013-01-16, and application number: 201310016506.7, denomination of invention: the application of a kind of thiazolidinone derivatives in preparing broad-spectrum anti-cancer drug.
Technical field
The present invention relates to the application of a kind of novel thiazole alkane ketone derivatives in preparing broad-spectrum anti-cancer drug, relate in particular to a kind of 2-(4-hydroxy benzenes imido grpup)-5-(3-methoxybenzene methylene) application of-4-thiazolidone in preparing broad spectrum anticancer (anti-cervical cancer, colon cancer, rhabdomyosarcoma) medicine.
Background technology
Cancer, malignant tumor or vegetation also called in other term, is the disease that a class can affect any position of health.A defined feature of cancer is to produce fast abnormal cell, and these cells surmount its normal growth border, and can attack health and adjoin position and be diffused into other organ.Cancer is the mankind's important death cause, in 7,600,000 dead people in 2008, account for 13% of all death tolls, and wherein about 70% cancer mortality occur in as China low income and middle income country (data Yin Zi international cancer research institution, IARC).According to World Health Organization (WHO): world's cancer mortality number estimates will continue rising, to the year two thousand thirty will be over 1,310 ten thousand.For treatment cancer, need one or more intervening measures of careful selection, as surgical operation, radiotherapy and chemotherapy etc., with cure diseases, or significant prolongation life improve patients ' life quality.Chemotherapy is in treatment cancer, and treatment means is absolutely necessary.But chemotherapeutics faces serious bottleneck at present: the one, and can select at present chemotherapeutics few, and drug resistance phenomenon is serious.Cancer incidence improves constantly and chemotherapeutics slower development and generation several drug resistance cancer.The 2nd, chemotherapeutics exists serious untoward reaction, ubiquity digestive tract reaction, bone marrow depression, neurotoxicity etc. (draw from Song Enfeng etc., the toxicity of chemical anticarcinogenic drug and Chinese medicine are processed, the journal > > of < < Guiyang College of Traditional Chinese Medicine, 01 phase in 2008).Be badly in need of the new determined curative effect of exploitation and safe and reliable cancer therapy drug.
Thiazolidone compounds is that a class has multiple bioactive lead compound.The clinical medicine of existing listing is the thiazolidine dione compounds that contains two carbonyls, for oral blood sugar lowering.Current research finds that thiazolidinone compound also has the multiple biological effect (R.B.Lesyk such as antibiotic, antiviral, anti-inflammatory; B.S.Zimenkovsky.4-Thiazolidones:Centenarian History, Current Status and Perspectives for Modern Organic and Medicinal Chemistry.Current Organic Chemistry, 2004,8,1547-1577).In recent years; active anticancer for thiazolidone has also progressively caused people's attention; research finds that it has good active anticancer (Amit Verma.et al.4-Thiazolidinone e A biologically active scaffold.European Journal of Medicinal Chemistry.2008 to multiple cancerous cell; 43,897-905; Dmytro Havrylyuk.et al.Synthesis of novel thiazolone-based compounds containing pyrazoline moiety and evaluation of their anticancer activity.European Journal of Medicinal Chemistry, 2009,44,1396 – 1404).Yet 4-thiazolidone is used for developing broad-spectrum anti-cancer drug, the research of evaluate efficacy and pharmacology, through authoritative institution (SCI/SSCI/A & HCI/ESI, BIOSIS/Inspec/JCR data base and CNKI data base) retrieval, look into newly, not yet report at present both at home and abroad.Therefore the thiazolidinone derivatives medicine that, research and development has a broad spectrum anticancer activity is extremely important.
Summary of the invention
For at present clinical in kinds cancer Treatment need, the object of the present invention is to provide a kind of 2-(4-hydroxy benzenes imido grpup)-5-(3-methoxybenzene methylene) application of-4-thiazolidone in preparing broad spectrum anticancer (anti-cervical cancer, colon cancer, rhabdomyosarcoma) medicine.
The present invention utilizes pharmaceutical chemistry combinational chemistry, a series of 4-thiazolidinone derivatives have been synthesized, use cervical cancer, colon cancer, rhabdomyosarcoma cancerous cell as main screening model, described compound is carried out to external high flux screening to Hela, HCT-116, RD cancerous cell, obtained compound 2-(4-hydroxy benzenes imido grpup)-5-(3-methoxybenzene methylene)-4-thiazolidone, later experiments confirms that this compound can cause this three kinds of Cancer Cell cycles retardance apoptosis-induced, effectively the growth of anticancer and without obvious toxic-side effects.
Thiazolidone compounds 2-(4-hydroxy benzenes imido grpup provided by the invention)-5-(3-methoxybenzene methylene)-4-thiazolidone chemical constitution is as shown in general formula I:
2-(4-hydroxy benzenes imido grpup of the present invention)-5-(3-methoxybenzene methylene)-application of 4-thiazolidone in preparing broad-spectrum anti-cancer drug, wherein, described broad-spectrum anti-cancer drug preferably refers to medicine cervical cancer, colon cancer and rhabdomyosarcoma to high anti-cancer activity.
In above-mentioned application: can effectively suppress s, colon cancer HCT-116 cell, Rhabdomyosarcoma RD Cells propagation apoptosis-induced 2-(4-hydroxy benzenes imido grpup)-5-(3-methoxybenzene methylene)-4-thiazolidone half growth inhibitory concentration is respectively 1.62 μ M, 1.12 μ M and 0.79 μ M.
Below in conjunction with concrete pharmacodynamic action and its mechanism of action of discussing thiazolidone compounds of the present invention of test.
With conventional method, cultivate people source cancerous cell, and collect the good and cell in logarithmic (log) phase of growth conditions for experimental study.Adopt Celluar and Molecular Biology method to test as follows, take and investigate thiazolidone compounds 2-(4-hydroxy benzenes imido grpup of the present invention)-5-(3-methoxybenzene methylene) (hereinafter referred is the Compound I) biological activity to cervical cancer, colon cancer, three kinds of cancerous cell of rhabdomyosarcoma to-4-thiazolidone.
1. cancerous cell adds that compared with normal contrast form after Compound I changes, number tails off
Collect respectively logarithmic (log) phase Hela, HCT-116, tri-kinds of cancerous cell of RD, in culture medium, add Compound I to process 48h, using DMSO as solvent control, examine under a microscope the variation of cancerous cell morphology and number, found that the cell number that Compound I is processed after 48h is obviously less than solvent control group cell number, and after drug treating there is obvious morphological change (see figure 1) in cell.
2. dosage-the medicine efficacy relation of quantitative analysis Compound I effect cancerous cell
Collect respectively logarithmic (log) phase Hela, HCT-116, tri-kinds of cancerous cell of RD, be inoculated in 96 orifice plates, through the compound (I) of variable concentrations (20,10,5,1,0.1,0.01 μ M), process after 48h, by SRB method, detect respectively the number of living cells, calculate survival rate.Survival rate=(absorbance during experimental group absorbance-dosing 0h) ÷ (absorbance during matched group OD value-dosing 0h) (take not celliferous culture fluid as absorbance measurement blank background), experimental result shows that Compound I can suppress the growth of three kinds of cancerous cell under lower drug level, and half growth inhibitory concentration is respectively 1.62 μ M, 1.12 μ M and 0.79 μ M.(seeing Fig. 2,3,4).
3. Compound I causes growth of cancer cells Cycle Arrest, blocks normal birth process
Collect respectively logarithmic (log) phase Hela, HCT-116, tri-kinds of cancerous cell of RD, be inoculated in culture dish, add Compound I, after effect a period of time, with PI dyeing, with flow cytometry, found that after three kinds of combined thing I of cancerous cell process 24h and be arrested in G
2/ M phase (see figure 5).
4. Compound I inducing cancer cell produces apoptosis
Collect logarithmic (log) phase RD cancerous cell, add Compound I, after effect a period of time, carry out Annexin V-FITC/7-AAD dyeing, by flow cytometry, produce significant apoptosis phenomenon (see figure 6) after found that the combined thing I of RD cancerous cell effect 48h.
5. experiment in vitro proof Compound I suppresses tubulin polymerization
Microtubule is the framing structure that maintains cell normal morphology, by tubulin polymerization, is formed.Suppress the formation of microtubule, can play the even effect of cell killing of cell proliferation that suppresses.The medicine of exploitation has vincristine, Colchicine etc. thus.Compound I is hatched altogether with tubulin in vitro, by fluorescence signal, detect the polymerization situation of tubulin, result demonstration, under low concentration, Compound I can suppress the polymerization of tubulin, can infer that tubulin is one of the important action target spot of Compound I (see figure 7).
By above-mentioned experiment and result thereof, can obtain drawing a conclusion:
Thiazolidone compounds 2-(4-hydroxy benzenes imido grpup of the present invention)-5-(3-methoxybenzene methylene)-4-thiazolidone is at the lower growth inhibitory effect that can cause Hela, HCT-116, tri-kinds of cancerous cell 50% of RD of low concentration (1.62 μ M, 1.12 μ M and 0.79 μ M), and under 5 μ M concentration, cause that obvious Cancer Cell cycle retardance is also apoptosis-induced, and investigate its action target spot and find, this compound effects is in tubulin, suppress the formation of microtubule, we tentatively grasp its pharmacological mechanism of action thus.
Above-mentioned experimental result indication 2-(4-hydroxy benzenes imido grpup)-5-(3-methoxybenzene methylene)-4-thiazolidone, after continual exploitation, is expected to become the effective cancer therapy drug of wide spectrum, has good development prospect.
Accompanying drawing explanation
Fig. 1 2-(4-hydroxy benzenes of the present invention imido grpup)-5-(3-methoxybenzene methylene)-4-thiazolidone acts on respectively after Hela, HCT-116, RD cancerous cell, examines under a microscope cellular morphology and changes and number change situation.Wherein, the compound treatment time is 48 hours, and concentration used is 0 μ M(DMSO), 1 μ M, 5 μ M.
SRB methods analyst 2-(4-hydroxy benzenes imido grpup for Fig. 2)-5-(3-methoxybenzene methylene)-4-thiazolidone acts on the dosage-cell survival rate relation after 48h after Hela cancerous cell.Wherein, abscissa is concentration (unit: negative logarithm mol/L), vertical coordinate is cell survival rate, calculates and gets with formula (absorbance during experimental group absorbance-dosing 0h) ÷ (absorbance during matched group OD value-dosing 0h).
SRB methods analyst 2-(4-hydroxy benzenes imido grpup for Fig. 3)-5-(3-methoxybenzene methylene)-4-thiazolidone acts on the dosage-cell survival rate relation after 48h after HCT-116 cancerous cell.Wherein, abscissa is concentration (unit: negative logarithm mol/L), vertical coordinate is cell survival rate, calculates and gets with formula (absorbance during experimental group absorbance-dosing 0h) ÷ (absorbance during matched group OD value-dosing 0h).
SRB methods analyst 2-(4-hydroxy benzenes imido grpup for Fig. 4)-5-(3-methoxybenzene methylene)-4-thiazolidone acts on the dosage-cell survival rate relation after 48h after RD cancerous cell.Wherein, abscissa is concentration (unit: negative logarithm mol/L), vertical coordinate is cell survival rate, calculates and gets with formula (absorbance during experimental group absorbance-dosing 0h) ÷ (absorbance during matched group OD value-dosing 0h).
Fig. 5 Flow cytometry 2-(4-hydroxy benzenes imido grpup)-5-(3-methoxybenzene methylene)-4-thiazolidone causes Hela, HCT-116, the retardance of RD Cancer Cell cycle.Wherein, compound used therefor I concentration 5.0 μ M effect 24 hours, abscissa is cell DNA content, vertical coordinate is cell number.Line segment 1,2 and 3 has indicated respectively G
1, S and G
2/ M period.
The two methods of dying of Fig. 6 Annexin V-FITC/7-AAD detect 2-(4-hydroxy benzenes imido grpup)-5-(3-methoxybenzene methylene)-4-thiazolidone induction RD cancerous cell generation phenomena of apoptosis.Wherein compound concentration used is 5.0 μ M, action time 48h.Fourth quadrant is normal living cells.Second and third quadrant is apoptotic cell.
Fig. 7 variable concentrations 2-(4-hydroxy benzenes imido grpup)-5-(3-methoxybenzene methylene)-4-thiazolidone inhibition tubulin polymerization becomes microtubule process.Abscissa is the time, and vertical coordinate is the amount (indicating with fluorescence intensity) that microtubule forms.DMSO is solvent control group, and Nocodole is the positive drug of known inhibition tubulin polymerization.
The specific embodiment
The instrument that synthetic compound and analysis and characterization are used: Fourier's infrared spectrum, Nicolet380FTIR; LC-MS, Waters2795 (Waters2996PDA detector/MicromassZQ mass dete ctor, C
18post, 2.0 μ m * 50mm); Calculate molecular characterization: TSAR software Accelrys(SanDiego, CA) and PipelinePilotSciTegic(SanDiego, CA).
Embodiment 1:2-(4-hydroxy benzenes imido grpup)-5-(3-methoxybenzene methylene) the preparation of-4-thiazolidone
Press HCl:H
2o(1:4) ratio is made into hydrochloric acid solution.Taking 11.4g(150mmol) ammonium thiocyanate is dissolved in 50mL hydrochloric acid solution, add 10.9mL(100mmol) 4-hydroxyanilines, under stirring condition, be heated to 85 ℃, mixture becomes clarification, after reaction 12 as a child, TLC monitors reaction, after reaction finishes, by mixture cool to room temperature, there is sticky oily liquids to occur, be extracted with ethyl acetate extract 10% hydrochloric acid solution, sodium chloride saturated solution, water washs successively, extract removes solvent under reduced pressure, obtains sticky oily liquids, 4-hydroxy benzenes thiourea.
By 4-hydroxy benzenes thiourea 4.24g, anhydrous sodium acetate 9.15g, joins in 35mL ethanol, under stirring condition, adds ethyl chloroacetate 5.13g, then at 60 ℃, heats 6 hours, and TLC detection reaction, is cooled to 4 ℃ after reaction finishes, and occurs precipitation.By reactant liquor sucking filtration, solid washing with alcohol, then precipitation is suspended in water, dissolving unreacting material, sucking filtration, uses washing with alcohol again.Obtain product 2-(4-hydroxy benzenes imino group)-1,3-thiazoles-4-ketone.
Taking 2-(4-hydroxy benzenes imino group)-1,3-thiazoles-4-ketone 1.7g is dissolved in 50mL ethanol, adds to m-methoxybenzaldehyde 1.58g piperidinyl-1 .65mL, 60 ℃ of isothermal reactions 24 hours.Reaction is monitored by TLC, and cool to room temperature has a large amount of faint yellow precipitations to generate in course of reaction after completion of the reaction, characterizes by analysis, and precipitation is finished product.Filter, with ethyl acetate, ethanol, petroleum ether washs successively, obtains compared with neat compounds 2-(4-hydroxy benzenes imido grpup)-5-(3-methoxybenzene methylene)-4-thiazolidone.
Product is pale yellow powder, ESI-MS:m/z324.1(M+1).
Above-mentioned 2-(4-hydroxy benzenes imido grpup)-5-(3-methoxybenzene methylene)-reaction equation prepared by 4-thiazolidone is as follows:
Embodiment 2:SRB method mensuration 2-(4-hydroxy benzenes imido grpup)-5-(3-methoxybenzene methylene)-4-thiazolidone is to growth of cancer cells half-inhibition concentration
At 37 ℃, contain 5%CO
2environment under, with DMEM/10% hyclone culture medium culturing Hela, HCT-116, tri-kinds of cancerous cell of RD.Three kinds of cancerous cell collecting logarithmic (log) phase are inoculated in respectively in 96 orifice plates, hatch 24h.The 2-(4-hydroxy benzenes imido grpup that adds variable concentrations (20,10,5,1,0.1,0.01 μ M))-5-(3-methoxybenzene methylene)-4-thiazolidone (Compound I) is hatched after 48h, add 50 μ L trichloroacetic acid solution (30%), fix one hour for 4 ℃.Get rid of solution, high purity water rinses five times, adds 100 μ L sulphonyl rhodamine B dyeing 30 minutes after drying, and after drying, with 1% acetum, rinses five times.After drying, add Tris solution 100 μ L fully to dissolve, in microplate reader, under 540nm wavelength, measure absorbance.According to absorbance, calculate survival rate, survival rate=(absorbance during experimental group absorbance-dosing 0h) ÷ (absorbance during matched group OD value-dosing 0h) (take not celliferous culture fluid as absorbance measurement blank background), the results are shown in Figure 2,3 and 4.
Embodiment 3:PI dyeing cells were tested by flow cytometry 2-(4-hydroxy benzenes imido grpup)-5-(3-methoxybenzene methylene)-4-thiazolidone affects Cancer Cell cycle
Take the logarithm tri-kinds of cancerous cell of Hela, HCT-116, RD of trophophase, the amount by every 3mL culture volume containing 200,000 cell number is inoculated in respectively in 6cm culture dish.Cultivate grouping after 24 hours, every kind of cancerous cell is used respectively DMSO and 5.0 μ M2-(4-hydroxy benzenes imido grpups)-5-(3-methoxybenzene methylene) processing of-4-thiazolidone (Compound I).Hatch after 24h, at peptic cell on ice, collecting cell suspension, centrifugal rear with PBS washing 2 times.Add 70% ice ethanol 10mL suspendible, at-20 ℃, spend the night.Centrifuge cell suspension, rinses 2 times with PBS, and cell mass adds at 4 ℃ of 500 μ L PI/5 μ L RNAaseA lucifuges and dyes half an hour.With DMSO, organize negative contrast and with standardization program, detect cell cycle with flow cytometer.
Result shows: Compound I effect cancerous cell was all arrested in the G2/M phase by Hela, HCT-116, tri-kinds of cancerous cell of RD after 24 hours, and blocking-up cancerous cell birth process the results are shown in Figure 5.
The two method detection compound 2-(4-hydroxy benzenes imido grpups that dye of embodiment 4:Annexin V-FITC/7-AAD)-5-(3-methoxybenzene methylene)-4-thiazolidone induction RD cancerous cell generation phenomena of apoptosis
Anticarcinogen is brought into play its effect by inducing apoptosis of tumour cell conventionally.For preliminary assessment thiazolidinone compound 2-(4-hydroxy benzenes imido grpup)-5-(3-methoxybenzene methylene) ability of-4-thiazolidone inducing apoptosis of tumour cell, with Annexin-V/7-AAD staining and flow cytometry thiazolidinone compound, act on the apoptosis induction situation to cell after cell.
The take the logarithm RD cell of trophophase, by every 3mL culture volume, containing the amount of 200,000 cell number, be inoculated in 6cm culture dish, use respectively DMSO and 5.0 μ M compound 2-(4-hydroxy benzenes imido grpups)-5-(3-methoxybenzene methylene)-4-thiazolidone effect 48 hours.Then at peptic cell on ice, collecting cell suspension, centrifugal rear with PBS washing 2 times.To cell mass, add 100 μ L PBS and 100 μ L Annexin-V/7-AAD dyeing liquors, jolting mixes, lucifuge room temperature dyeing 30 minutes.With DMSO, organize negative contrast flow cytometry, found that 5.0 μ M compound 2-(4-hydroxy benzenes imido grpups)-5-(3-methoxybenzene methylene) there is significant apoptosis phenomenon (the results are shown in Figure 6) in-4-thiazolidone induction RD cancerous cell.
Embodiment 5: compound 2-(4-hydroxy benzenes imido grpup)-5-(3-methoxybenzene methylene)-4-thiazolidone suppresses tubulin polymerization, thereby affect the normal function of cytoskeletal microtubule
Under the reaction condition of setting, tubulin meeting polymerization reaction take place, forms microtubule.
Adopt Tubulin polymerization experiment test kit (U.S. Cytoskelecton company) to test, in reaction system, add variable concentrations (0, 0.1, 1.0, 3.0, 10.0, 30.0, 100.0 μ M) compound 2-(4-hydroxy benzenes imido grpup)-5-(3-methoxybenzene methylene) the positive drug Nocodole10.0 μ M of-4-thiazolidone and known inhibition tubulin polymerization, in 60 minutes, the variation of test reaction system fluorescence intensity, formation volume (being directly proportional to fluorescence intensity) with reflection microtubule, result shows, 2-(4-hydroxy benzenes imido grpup under low concentration)-5-(3-methoxybenzene methylene)-4-thiazolidone (Compound I) can suppress the polymerization of tubulin, can infer that tubulin is one of important action target spot of Compound I, the results are shown in Figure 7.
Claims (2)
1.2-(4-hydroxy benzenes imido grpup)-5-(3-methoxybenzene methylene)-application of 4-thiazolidone in preparing inhibitor against colon carcinoma cells medicine.
2. application as claimed in claim 1, is characterized in that: can effectively suppress colon cancer HCT-116 cell proliferation apoptosis-induced 2-(4-hydroxy benzenes imido grpup)-5-(3-methoxybenzene methylene)-4-thiazolidone half growth inhibitory concentration is 1.12 μ M.
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