CN103992289B - Substituted tetrahydrothiazole dithiocarbamic acid bismuth title complex and uses thereof - Google Patents
Substituted tetrahydrothiazole dithiocarbamic acid bismuth title complex and uses thereof Download PDFInfo
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- CN103992289B CN103992289B CN201410215809.6A CN201410215809A CN103992289B CN 103992289 B CN103992289 B CN 103992289B CN 201410215809 A CN201410215809 A CN 201410215809A CN 103992289 B CN103992289 B CN 103992289B
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- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/04—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D277/06—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
The invention discloses a kind of substituted tetrahydrothiazole dithiocarbamic acid bismuth title complex and uses thereof, six kinds of structure titles of described title complex are respectively: thiazolidine dithiocarbamic acid bismuth, 2-methylthiazol alkane dithiocarbamic acid bismuth, 2-carboxyl thiazolidine dithiocarbamic acid bismuth, 2-ethoxycarbonyl thiazolidine dithiocarbamic acid bismuth, S-4-carboxyl thiazolidine dithiocarbamic acid bismuth, 4-ethoxycarbonyl thiazolidine dithiocarbamic acid bismuth; Described title complex can be used for treating the disease in individual body or illness, and described disease or illness can be cancers, comprise human colon cancer, Human Breast Cancer, human bone marrow's cancer, human hepatocellular, Human Lung Cancer and human white blood disease etc.; Described title complex purity is high, antitumous effect good, and effect bacterial strain wide spectrum, adds the kind of antitumor drug, have wide market outlook.
Description
Technical field
The invention belongs to cancer therapy drug research field, be specifically related to a kind of substituted tetrahydrothiazole dithiocarbamic acid bismuth title complex and uses thereof.
Background technology
The health of the mankind in malignant tumour (cancer) serious threat, and the patient dying from cancer every year accounts for 1/4th of total death toll, and sickness rate is in rising tendency gradually, and the control of cancer becomes one of problem that medical science and life science worker mainly study.China's cancer morbidity is very surprising, has become second-biggest-in-the-world cancer state occurred frequently, and statistic data (WHOGLOBOCAN2008) shows: all tumour new cases of China are 2,800,000, are 2 times (U.S. are 1,400,000) that tumor cases is newly sent out by the U.S.; The same year, China's tumor mortality case was 1,960,000, and the death of the U.S. is 570,000, and the two gap is 3.4 times.As can be seen here, Science in Future in China has a high potential with global cancer therapy drug market growth, and research and development new generation anti-cancer medicament must have huge market.But the cancer therapy drug at present for cancer therapy has tens kinds, but still lacks active drug to most common solid tumors, and many antitumour drugs create resistance in various degree in process of clinical application.Thus, the antitumor drug that exploitation filters out high-efficiency low-toxicity becomes anti-cancer agent and researches and develops of paramount importance task.
Bismuth has long medicinal history.Bismuth belongs to period 6 VA race heavy metal element in periodictable, is positioned at metal and nonmetal intersection, has special physico-chemical property.Due to nontoxicity, the non-carinogenicity of bismuth, be called as green metal.Through years of researches and development, bismuth compound has been widely used in the aspects such as medical science, chemical industry and biology, the field be wherein most widely used is medical science, as for Surgery Treatment wound and hemostasis, as the pharmaceutical cpd killing Eradication Therapy of Helicobacter pylori Infection stomach ulcer and gastrointestinal disturbance, separately studies have found that bismuth title complex can anticancer growth and have no side effect.
Hong Kong University professor Sun Hongzhe conducts in-depth research in effect medically bismuth preparation.Bismuth compound not only shows to have on antitumour activity in the effect of field of cancer, and they can also alleviate the toxic side effect caused by other anticancer chemotherapeutic agent.Experimentation on animals shows, Bismuth trinitrate and citric acid coupling can be alleviated effectively along platinum medicine kidney damage caused in anticancer therapy process.Nearest research finds, bismuth agent can suppress the growth of sars coronavirus, and its process may with Bi(III) suppress the helicase (helicase) in SARS virus relevant.Bismuth can combine with the different kinds of molecules in organism.Research finds that gsh (GSH) can prevent CBS from precipitating.Bismuth also can by combining with Transferrins,iron complexes (transderrin) object reaching biological transmission.
At present, in pharmacology, medical science and biological chemistry etc., dialkyl amino dithioacid salt compounds is used for promoting agent more.In addition, because some dialkyl amino Sulfonates compounds have interesting biological effect, as anti-alkylation, AntiHIV1 RT activity characteristic etc.Therefore, it is used as the treatment of carcinostatic agent and acquired immune deficiency syndrome (AIDS) widely.Dialkyl amino dithioacid salt compounds structural formula as:
Wherein: R
1, R
2for groups such as identical or different hydrogen atom, alkyl, aryl, cycloalkyl, high molecular polymer skeleton and heterocycles, M is metal ion, as bismuth and sulphur just have stronger affinity, easily forms covalent linkage.
Within 2006, NUS EdwardRTTiekink has taught at U. S. application the patent (US2006/0142621Al) of Bismuth dibutyldithiocarbamate compound, inquired into the anti-tumor activity of dialkyl amino dithioacid bismuth compound, disclosed in this patent, molecular structure of compounds is as follows:
R and R in this structural formula
1identical or different, each is that alkyl or alkyl replacement, aryl or aryl replace, X is halogenide or pseudohalide, n is 2 or 3, as antineoplastic agent, although this compound can reduce the survival coefficient of tumour cell to a certain extent, but there is following shortcoming in this compound: although 1. mention in literary composition " this compound can act on animals or humans tumour; tumour is that to comprise be not be confined to mammary cancer, ovarian cancer, melanoma, kidney disease and nonsmall-cell lung cancer ", but the antitumor cell bacterial strain of a certain specific compound effect is few; 2. compound stability is little, R and R
1for alkyl replaces or aryl replacement, its molecule is extended longer, molecular structure is comparatively large, inhibits the activity of molecule to a certain extent, and be unfavorable for playing antitumour activity in process of clinical application, clinical value is lower.
Dithiocarbamic acid bismuth title complex not only has special biological activity, but also has good anti-tumor activity.Therefore, exploitation, the bismuth title complex that efficient, the low toxicity, side effect of synthesizing new is little, antitumour activity is strong, to treatment neoplastic hematologic disorder and noumenal tumour, alleviate patient's misery, improves the health level of the people, have important actual application value and realistic meaning.
Summary of the invention
The object of the invention is to make up above-mentioned deficiency, provide a kind of substituted tetrahydrothiazole dithiocarbamic acid bismuth title complex and uses thereof, this compound purity is high, antitumous effect good, and effect bacterial strain wide spectrum, adds the kind of antitumor drug.
A kind of substituted tetrahydrothiazole dithiocarbamic acid bismuth title complex, comprise medically acceptable salt and hydrate, it is characterized in that, described complex structure formula is: a kind of substituted tetrahydrothiazole dithiocarbamic acid bismuth title complex, comprise its medically acceptable salt and hydrate, it is characterized in that, described complex structure formula is:
, wherein R
1=R
2=H.
R in described complex structure formula
1can also be-CH
3,-COOH or-CO
2c
2h
5, structural formula is as follows:
R in described complex structure formula
2can also be-COOH or-CO
2c
2h
5, structural formula is as follows:
The purposes of described title complex is: described substituted tetrahydrothiazole dithiocarbamic acid bismuth title complex preparation treatment individual body in disease or illness medicine in application, described disease or illness can be cancer, various medicable cancer, include but not limited to: cancer, comprise bladder cancer, breast cancer, colorectal carcinoma, kidney, liver cancer, lung cancer, ovarian cancer, prostate cancer, carcinoma of testis, genitourinary cancer, lymphsystem cancer, the rectum cancer, laryngocarcinoma, carcinoma of the pancreas, the esophageal carcinoma, cancer of the stomach, carcinoma of gallbladder, cervical cancer, thyroid carcinoma and skin carcinoma, lymphatic cells system tumor; Described bladder cancer comprises and worsening and the bladder cancer of transfer, and described colorectal carcinoma comprises colorectal carcinoma, and described lung cancer comprises small cell lung cancer and nonsmall-cell lung cancer and adenocarcinoma of lung, and described carcinoma of the pancreas comprises exocrine pancreas cancer, and described skin carcinoma comprises squamous cell carcinoma.
Below in conjunction with beneficial effect, the invention will be further described.
(1) compared with traditional dialkyl amino dithioacid bismuth compound, complex structure of the present invention is novel, and the structure activity relationship of Molecular Structure Design is more reasonable, and molecule extends shorter, and molecular volume is less, good stability, convenient drug administration; Substituted thiazole alkyl sterically hindered little, the ability penetrating cancer cells is high, improves medicine turn-over capacity in vivo and tumor tissues to the picked-up ability of medicine.
(2) title complex of the present invention has very high chemical purity, and antitumour activity is strong, and antitumor curative effect is good; Described title complex good water solubility, is conducive to medicine running in vivo, is easy to metabolism, and medicine can be removed rapidly from healthy tissues, and tumour cell is good to the uptake ratio of this compound, and medicine is detained in the tissue selectively, and low toxicity, side effect is little.
(3) this complex preparation is simple, and namely adopt conventional means first to synthesize new part, resynthesis novel complexes, after separation and purification, can obtain described title complex, produce simple, expense is low, and purity is high, improves title complex quality and the market competitiveness.
(4) by finding the research of dithiocarbamic acid bismuth title complex for a long time, substituted tetrahydrothiazole dithiocarbamic acid bismuth compound has good anti-tumor activity, and antitumous effect is good, and that applies clinically as medicine has a extensive future.Title complex Antitumor test of the present invention is wide, and the illness for the treatment of tumour is many, and the tumour that can be used for treating comprises human colon carcinoma, Human Breast Cancer, human bone marrow's cancer, human hepatocellular, Human Lung Cancer and human white blood disease etc., once drop into clinical application, will produce huge economic benefit and social benefit.
Embodiment
Below in conjunction with embodiment, the invention will be further described.
In following embodiment,
The structural formula of thiazolidine dithiocarbamic acid bismuth (A) is:
The structural formula of 2-methylthiazol alkane dithiocarbamic acid bismuth (B) is:
The structural formula of 2-carboxyl thiazolidine dithiocarbamic acid bismuth (C) is:
The structural formula of 2-ethoxycarbonyl thiazolidine dithiocarbamic acid bismuth (D) is:
The structural formula of S-4-carboxyl thiazolidine dithiocarbamic acid bismuth (E) is:
The structural formula of 4-ethoxycarbonyl thiazolidine dithiocarbamic acid bismuth (F) is:
Embodiment one
The preparation of thiazolidine dithiocarbamic acid bismuth (A)
0.445g(5mmol is added in 50mL round-bottomed flask) thiazolidine, 0.25g(6mmol) sodium hydroxide, 15mL anhydrous methanol, after magnetic agitation is dissolved in 0 ~ 5 DEG C of cooling bath, drips 0.76g(10mmol) CS
2, low-temperature magnetic stirring reaction 2h, normal temperature lower magnetic force stirring reaction 4h.
By 0.53g(1.7mmol) BiCl
3dissolve in 15mL anhydrous methanol, instill in above-mentioned reaction solution, stirring at room temperature 3h, suction filtration, anhydrous methanol is washed, vacuum-drying.Solids methylene dichloride and ethyl alcohol recrystallization, obtain 0.94g yellow powder solid, yield 80.3%, fusing point: 137 ~ 138 DEG C (carbonization blackening).
Structural characterization: utilize nuclear magnetic resonance analyser carry out proton resonance (
1hNMR), the relevant signals of atom under resonance is recorded as follows:
1HNMR(CDCl
3,400MHz),δ:3.184-3.215(6H,t,S-CH
2,J=6.4Hz),
4.262-4.294(6H,t,N-CH
2,J=6.4Hz),4.937(6H,s,N-CH
2-S)。
Ultimate analysis is carried out according to above-mentioned signal, analytical results is (be the calculated value according to structure in bracket, unit: Wt%): C20.49(20.53), H2.47(2.59), N5.76(5.99), results of elemental analyses conforms to substantially with calculated value, illustrates that obtained title complex purity is high.
Embodiment two
The preparation of 2-methylthiazol alkane dithiocarbamic acid bismuth (B)
0.516g(5mmol is added in 50mL round-bottomed flask) 2-methylthiazol alkane, 0.25g(6mmol) sodium hydroxide, 15mL anhydrous methanol, after magnetic agitation is dissolved in 0 ~ 5 DEG C of cooling bath, drips 0.76g(10mmol) CS
2, low-temperature magnetic stirring reaction 2h, normal temperature lower magnetic force stirring reaction 4h.
By 0.53g(1.7mmol) BiCl
3dissolve in 15mL anhydrous methanol, instill in above-mentioned reaction solution, stirring at room temperature 4h.Separate out yellow mercury oxide, suction filtration, anhydrous methanol is washed, dry.Solids recrystallized from acetonitrile, obtains 1.15g yellow solid, yield 92.7%, fusing point: 139 ~ 140 DEG C (carbonization blackening).
Structural characterization: utilize nuclear magnetic resonance analyser carry out proton resonance (
1hNMR), the relevant signals of atom under resonance is recorded as follows:
1HNMR(CDCl
3,400MHz),δ:1.699-1.715(9H,d,-CH
3,J=6.4Hz),
3.158-3.214(3H,m,S-CH
2,J=3.6-6.4Hz),3.285-3.353(3H,m,S-CH
2,J=3.6-6.4Hz),4.094-4.152(3H,m,N-CH
2,J=3.6-6.8Hz),4.481-4.551(3H,m,N-CH
2,J=3.6-6.8Hz),5.865-5.913(3H,q,N-CH-,J=6.4Hz)。
Ultimate analysis is carried out according to above-mentioned signal, analytical results is (be the calculated value according to structure in bracket, unit: Wt%): C24.19(24.22), H3.21(3.26), N5.58(5.65), results of elemental analyses conforms to substantially with calculated value, illustrates that obtained title complex purity is high.
Embodiment three
The preparation of 2-carboxyl thiazolidine dithiocarbamic acid bismuth (C)
0.666g(5mmol is added in 50mL round-bottomed flask) 2-thiaproline, 0.40g(10mmol) sodium hydroxide, 15mL anhydrous methanol, after magnetic agitation is dissolved in 0 ~ 5 DEG C of cooling bath, drips 0.76g(10mmol) CS
2, low-temperature magnetic stirring reaction 2h, normal temperature lower magnetic force stirring reaction 4h.
By 0.53g(1.7mmol) BiCl
3dissolve in 15mL anhydrous methanol, instill in above-mentioned reaction solution, stirring at room temperature 4h.With 1:1 hydrochloric acid soln adjust pH to 5-6, suction filtration, with deionized water wash, drains, vacuum-drying.Obtain 1.09g yellow solid, yield 78.4%, fusing point 136-138 DEG C (carbonization decomposition).
Structural characterization: utilize nuclear magnetic resonance analyser carry out proton resonance (
1hNMR), the relevant signals of atom under resonance is recorded as follows:
1HNMR(DMOS-d
6,400MHz),δ:3.174-3.219(3H,q,S-CH,J=6.4Hz),
3.468-3.517(3H,q,S-CH,J=6.4Hz),4.286-4.336(3H,q,N-CH,J=6.4Hz),4.452-4.496(3H,q,N-CH,J=6.4Hz),5.903(3H,s,S-CH-N)。
Ultimate analysis is carried out according to above-mentioned signal, analytical results is (be the calculated value according to structure in bracket, unit: Wt%): C21.56(21.60), H2.16(2.18), N4.49(5.04), results of elemental analyses conforms to substantially with calculated value, illustrates that obtained title complex purity is high.
Embodiment four
The preparation of 2-ethoxycarbonyl thiazolidine dithiocarbamic acid bismuth (D)
0.828g(5mmol is added in 50mL round-bottomed flask) 2-ethoxycarbonyl thiazolidine hydrochloride, 0.44g(11mmol) sodium hydroxide, 15mL anhydrous methanol, after magnetic agitation is dissolved in 0 ~ 5 DEG C of cooling bath, drips 0.76g(10mmol) CS
2, low temperature lower magnetic force stirring reaction 2h, stirring at room temperature reaction 4h.
By 0.53g(1.7mmol) BiCl
3dissolve in 15mL anhydrous methanol, instill in above-mentioned reaction solution, stirring at room temperature 5h, suction filtration, anhydrous methanol is washed, dry.Solids uses recrystallized from acetonitrile again, obtains 1.18g yellow solid, yield 77.1%, fusing point 93-95 DEG C.
Structural characterization: utilize nuclear magnetic resonance analyser carry out proton resonance (
1hNMR), the relevant signals of atom under resonance is recorded as follows:
1HNMR(CDCl
3,400MHz),δ:1.277-1.326(9H,t,-CH
3,J=7.2Hz),
3.172-3.218(3H,q,S-CH-,J=6.4Hz),3.466-3.516(3H,q,S-CH,J=6.4Hz),
4.217-4.268(6H,q,O-CH
2,J=6.8Hz),4.286-4.336(3H,q,N-CH-,J=6.4Hz),4.452-4.496(3H,q,N-CH-,J=6.4Hz),5.903(3H,s,S-CH-N)。
Ultimate analysis is carried out according to above-mentioned signal, analytical results is (be the calculated value according to structure in bracket, unit: Wt%): C27.36(27.47), H3.23(3.30), N4.49(4.58), results of elemental analyses conforms to substantially with calculated value, illustrates that obtained title complex purity is high.
Embodiment five
The preparation of S-4-carboxyl thiazolidine dithiocarbamic acid bismuth (E)
0.666g(5mmol is added in 50mL round-bottomed flask) S-4-carboxyl thiazolidine, 0.44g(11mmol) sodium hydroxide, 15mL anhydrous methanol, after magnetic agitation is dissolved in 0 ~ 5 DEG C of cooling bath, drips 0.76g(10mmol) CS
2, low-temperature magnetic stirring reaction 2h, room temperature magnetic agitation reaction 4h.
By 0.53g(1.7mmol) BiCl
3dissolve in 15mL anhydrous methanol, instill in above-mentioned reaction solution, stirring at room temperature 4h.With 1:1 hydrochloric acid soln adjust pH to 5-6, suction filtration, with deionized water wash, drains, vacuum-drying.Obtain 1.16g yellow solid, yield 83.5%, fusing point 153-155 DEG C of carbonization is decomposed,
=-120 ° (DMF).
Structural characterization: utilize nuclear magnetic resonance analyser to carry out proton resonance (HNMR), record the relevant signals of atom under resonance as follows:
1HNMR(DMOS-d
6,400MHz),δ:3.233-3.268(6H,dd,S-CH
2,J=2.4-9.2Hz),4.671-4.697(3H,t,N-CH-,J=6.2Hz),5.201-5.226(3H,d,S-CH-N,J=6.4Hz),5.358-5.371(3H,d,S-CH-N,J=6.4Hz)。
Ultimate analysis is carried out according to above-mentioned signal, analytical results is (be the calculated value according to structure in bracket, unit: Wt%): C21.56(21.60), H2.16(2.18), N4.49(5.04), results of elemental analyses conforms to substantially with calculated value, illustrates that obtained title complex purity is high.
Embodiment six
The preparation of 4-ethoxycarbonyl thiazolidine dithiocarbamic acid bismuth (F)
0.828g(5mmol is added in 50mL round-bottomed flask) 4-ethoxycarbonyl thiazolidine hydrochloride, 0.44g(11mmol) sodium hydroxide, 15mL anhydrous methanol, after magnetic agitation is dissolved in 0 ~ 5 DEG C of cooling bath, drips 0.76g(10mmol) CS
2, low temperature lower magnetic force stirring reaction 2h, stirring at room temperature reaction 4h.
By 0.53g(1.7mmol) BiCl
3dissolve in 15mL anhydrous methanol, instill in above-mentioned reaction solution, stirring at room temperature 3h, suction filtration, anhydrous methanol is washed, dry.Solids methylene chloride-methanol recrystallization, obtains 1.21g yellow crystals, yield 79.1%, fusing point 116-118 DEG C.
Structural characterization: utilize
nuclear magnetic resonance analysercarry out proton resonance (HNMR), record the relevant signals of atom under resonance as follows:
1HNMR(CDCl
3,400MHz),δ:1.292-1.328(9H,t,-CH
3,J=7.2Hz),
3.361-3.390(3H,q,S-CH,J=6.4Hz),3.542-3.603(3H,q,S-CH,J=6.4Hz),
4.254-4.287(6H,q,O-CH
2-,J=6.8Hz),4.816-4.853(3H,t,N-CH-C,J=6.8Hz),5.304-5.326(3H,d,N-CH-S,J=8.8Hz),5.651-5.673(3H,d,S-CH-N,J=8.8Hz).
Carry out ultimate analysis (being calculated value in bracket) %:C27.36(27.47), H3.23(3.30), N4.49(4.58) and, results of elemental analyses and calculated value conform to substantially, and obtained title complex purity is high.
Following experiment be the compounds of this invention in application medically, the external Primary Screening Test of anti-tumor biological is carried out in this experiment.
1. screening method: Sulforhodamine B protein staining method and MTT reduction method.
2. tumor cell line: Human Large Intestine Carcinoma Cells strain (HTC-116), JEG-3 U(266 in people's marrow), human hepatoma cell strain (BEL-7402), human lung carcinoma cell line (A-549), human leukemia cell line (HL60), human stomach cancer cell line (AGS).
3. cell cultures
Inoculating cell: digestion is in the cell of exponential phase of growth, is made into suspension with the RPM1640 containing 10% calf serum.Assigned to by cell in 96 orifice plates, every hole contains 5000 ~ 40000 cells, at 37 DEG C, and 5%CO
224h is cultivated in incubator.
The cell that propagation is well in logarithmic phase counting after the Digestive system dispersion of 0.25% pancreatin and EDTA half and half, makes cell suspension, is inoculated in 96 orifice plates, 180 μ L/ holes, after 24h is cultivated in hole.Every hole adds medicine 20 μ L, every hole total liquid measure 200 μ L, and each drug level establishes 6 multiple holes, and establishes blank control wells (RPMI1640 nutrient solution) and normal control hole (do not add medicine, add normal saline), is placed in 37 DEG C, 5%CO
2incubator cultivates 72h under complete wet condition, and it is RPMI1640 that Tumor suppression tests nutrient solution used, includes 5% calf serum, 100IU/mL penicillin and 100 μ g/mL Streptomycin sulphates.
4. two kinds of extracorporeal anti-tumor drug screenings
MTT reduction method extracorporeal anti-tumor drug screening: depend on Exponential growth stage cell kind (cell concn 20000/mL in 96 orifice plates, 100 μ L/ holes), cultivate 24h and make cell attachment, remove supernatant, add 200 μ L/ pore area medicine fresh cultures: compound dissolves DMSO or physiological saline in advance, be finished substratum dilution desired concn when tested, notice that DMSO final concentration can not more than 0.1%.Each concentration establishes 6 multiple holes, and establishes blank control wells (only adding substratum) and negative control, establishes 6 multiple holes equally.The culture experiment time on request carries out, and removes supernatant, adds the MTT of 100 μ L/ hole concentration 0.5mg/mL.The SDS of 10% of 100 μ L/ holes is added again after cultivating 4h.Take out after 10h at 37 DEG C, 5min is swung in microseism, and 30min under placement room temperature, surveys OD value (densitometric) by microplate reader, and calculate inhibiting rate under A595 wavelength.Obtained growth of tumour cell inhibiting rate is defined as the extracorporeal inhibiting rate of drug on tumor cell.
SRB development process extracorporeal anti-tumor drug screening: get and be in Exponential growth stage cell kind (cell concn is 20000/mL in 96 orifice plates, 100 μ L/ holes), cultivate 24h and make cell attachment, remove supernatant, add 200 μ L/ pore area medicine fresh cultures: compound is dissolved in DMSO or physiological saline in advance, be diluted to desired concn with perfect medium when tested, notice that DMSO final concentration can not more than 0.1%.Each concentration establishes 6 multiple holes, and establishes blank control wells (only adding substratum) and negative control, establishes 6 multiple holes equally.Continue to be cultured to the test design time, stop cultivating, remove supernatant, every hole adds 10%TCA200 μ L, and 4 DEG C of conditions fix 1h.Rinse 5 times with redistilled water, naturally dry rear every hole and add 4mg/mLSRB solution, dye under room temperature 15min, abandons supernatant, rinses 5 times to remove the dyestuff of non-specific binding with 1% acetic acid.Every hole adds 100 μ L10mMTris solution, surveys OD value by microplate reader under A490 wavelength, and calculates inhibiting rate (method of calculation are with MTT reduction method), and test-results is as shown in the table.
This test will get the cancer cells of human body 6 different sites as study subject, and using title complex A, B, C, D, E, the F obtained by six embodiments as test medicine, test drug concentrations is 10
-4mol/L, Zorubicin is as reference medicine, and often kind of medicine is divided into two groups, adopts MT reconnaissance T reduction method and SRB development process respectively, and measure medicine to 6 kinds of inhibition of cancer cell rates (%), data results statistical average is as follows:
As seen from the above table, tested medicine all has good restraining effect to the cancer cells of people, wherein, A gives prominence to human liver cancer cell and human lung carcinoma cell action effect, F is particularly outstanding to cancer cells in Human Large Intestine Carcinoma Cells, people's marrow, human lung carcinoma cell, gastric carcinoma cells inhibition, and to human leukemia cell, there is good restraining effect, suppress bacterial strain wide spectrum, other drug also reaches good restraining effect, different medicines can be selected for the cancer cells of different steps, different sites, there is important actual application value and important realistic meaning.
Claims (10)
1. a substituted tetrahydrothiazole dithiocarbamic acid bismuth title complex, comprises the salt that it is medically acceptable, it is characterized in that, described complex structure formula is:
, wherein R
1=R
2=H.
2. substituted tetrahydrothiazole dithiocarbamic acid bismuth title complex as claimed in claim 1, is characterized in that, R in described complex structure formula
1can also be-CH
3,-COOH or-CO
2c
2h
5, structural formula is as follows:
。
3. substituted tetrahydrothiazole dithiocarbamic acid bismuth title complex as claimed in claim 1, is characterized in that, R in described complex structure formula
2can also be-COOH or-CO
2c
2h
5, structural formula is as follows:
。
4. the purposes of a substituted tetrahydrothiazole dithiocarbamic acid bismuth title complex as claimed in claim 1, it is characterized in that: described substituted tetrahydrothiazole dithiocarbamic acid bismuth title complex preparation treatment individual body in disease or illness medicine in application, described disease or illness are cancers.
5. the purposes of substituted tetrahydrothiazole dithiocarbamic acid bismuth title complex as claimed in claim 4, is characterized in that: described cancer is bladder cancer, breast cancer, colorectal carcinoma, kidney, liver cancer, lung cancer, ovarian cancer, prostate cancer, carcinoma of testis, genitourinary cancer, lymphsystem cancer, the rectum cancer, laryngocarcinoma, carcinoma of the pancreas, the esophageal carcinoma, cancer of the stomach, carcinoma of gallbladder, cervical cancer, thyroid carcinoma, skin carcinoma or lymphatic cells system tumor.
6. the purposes of substituted tetrahydrothiazole dithiocarbamic acid bismuth title complex as claimed in claim 5, is characterized in that: described bladder cancer is the bladder cancer worsening or shift.
7. the purposes of substituted tetrahydrothiazole dithiocarbamic acid bismuth title complex as claimed in claim 5, is characterized in that: described colorectal carcinoma is colorectal carcinoma.
8. the purposes of substituted tetrahydrothiazole dithiocarbamic acid bismuth title complex as claimed in claim 5, is characterized in that: described lung cancer is small cell lung cancer, nonsmall-cell lung cancer or adenocarcinoma of lung.
9. the purposes of substituted tetrahydrothiazole dithiocarbamic acid bismuth title complex as claimed in claim 5, is characterized in that: described carcinoma of the pancreas is exocrine pancreas cancer.
10. the purposes of substituted tetrahydrothiazole dithiocarbamic acid bismuth title complex as claimed in claim 5, is characterized in that: described skin carcinoma is squamous cell carcinoma.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410215809.6A CN103992289B (en) | 2014-05-22 | 2014-05-22 | Substituted tetrahydrothiazole dithiocarbamic acid bismuth title complex and uses thereof |
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