CN103980174B - Substituted pyrrolidin dithiocarbamic acid bismuth (III) title complex and preparation method thereof and preparing the application in antitumor drug - Google Patents
Substituted pyrrolidin dithiocarbamic acid bismuth (III) title complex and preparation method thereof and preparing the application in antitumor drug Download PDFInfo
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- CN103980174B CN103980174B CN201410235209.6A CN201410235209A CN103980174B CN 103980174 B CN103980174 B CN 103980174B CN 201410235209 A CN201410235209 A CN 201410235209A CN 103980174 B CN103980174 B CN 103980174B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/06—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with radicals, containing only hydrogen and carbon atoms, attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or 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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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or 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
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
Abstract
The present invention relates to a kind of substituted pyrrolidin dithiocarbamic acid bismuth (III) title complex, skeleton symbol is as follows, this substituted pyrrolidin dithiocarbamic acid bismuth (III) title complex has good anti-tumor activity, to malignant tumours such as cancer of the stomach, lung cancer, liver cancer, large bowel cancer, cervical cancer, ovarian cancer, mammary cancer, leukemia, colorectal carcinomas, there is significant antitumor activity, be developed as new antitumoral new drug and be with a wide range of applications.
。
Description
Technical field
The present invention relates to antitumor drug technical field, be specifically related to substituted pyrrolidin dithiocarbamic acid bismuth (III) title complex and preparation method thereof and preparing the application in antitumor drug.
Background technology
The health and lives of the mankind in malignant tumour (cancer) serious threat, the patient dying from cancer every year accounts for 1/4th of total death toll, and sickness rate is in growing trend year by year, 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 gap of the two 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.Therefore, the antitumor drug developing screening 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 medicine, as for Surgery Treatment wound and hemostasis, as killing Helicobacter pylori treatment stomach ulcer and the pharmaceutical cpd of 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 application 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 suppress the helicase (helicase) in SARS virus relevant by same Bi (III).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 (transferrin) object reaching biological transmission.
Within 2006, NUS EdwardRTTiekink has taught at U. S. application the patent (US2006/0142621A1) of Bismuth dibutyldithiocarbamate compound, has inquired into the anti-tumor activity of dialkyl amino dithioacid bismuth compound.But it is single to there is structure, the antitumor cell strain of effect is few, the problem that clinical value is lower, also has larger distance apart from clinical application.
Summary of the invention
The object of the invention is to open a kind of substituted pyrrolidin dithiocarbamic acid bismuth (III) title complex and preparation method thereof and preparing the application in antitumor drug, substituted pyrrolidin dithiocarbamic acid bismuth (III) title complex has good anti-tumor activity, has significant antitumor activity to malignant tumours such as cancer of the stomach, lung cancer, liver cancer, large bowel cancer, cervical cancer, ovarian cancer, mammary cancer, leukemia, colorectal carcinomas.
For achieving the above object, the technical scheme adopted is in the present invention: substituted pyrrolidin dithiocarbamic acid bismuth (III) title complex, and skeleton symbol is as follows:
,
R
2and R
3for H, R
1for
;
or
;
Or, R
1and R
3for H, R
2for F;
Or, R
1and R
2for H, R
3for F;
Or, R
1for H, R
2and R
3for F.
The preparation method of substituted pyrrolidin dithiocarbamic acid bismuth (III) title complex:
Get (2R)-2-crassitude and NaOH adds anhydrous methanol, after stirring and dissolving, drip CS
2, obtain reaction solution, get BiCl
3instill in above-mentioned reaction solution with the mixing solutions of anhydrous methanol, carry out suction filtration, alcohol wash, drying, solids recrystallization after reaction terminates, obtain (2R)-2-crassitude dithiocarbamic acid bismuth;
Or: get L-PROLINE and triethylamine adds anhydrous methanol, after stirring and dissolving, drip CS
2, obtain reaction solution, get BiCl
3instill in above-mentioned reaction solution with the mixing solutions of anhydrous methanol, reaction terminates rear adjust pH, carries out suction filtration, alcohol wash, drying, solids recrystallization, obtain (S)-2-carboxy pyrrole alkane dithiocarbamic acid bismuth after washing out precipitation;
Or: get L-PROLINE carbethoxy hydrochloride and NaOH adds anhydrous methanol, after stirring and dissolving, drip CS
2, obtain reaction solution, get BiCl
3instill in above-mentioned reaction solution with the mixing solutions of anhydrous methanol, after reaction terminates, carry out suction filtration, alcohol wash, drying, solids recrystallization, (S)-2-ethoxycarbonyl tetramethyleneimine dithiocarbamic acid bismuth;
Or: get R-3-Fluoropyrrolidine hydrochloride salt and NaOH adds anhydrous methanol, after stirring and dissolving, drip CS
2, obtain reaction solution, get BiCl
3instill in above-mentioned reaction solution with the mixing solutions of anhydrous methanol, carry out suction filtration, alcohol wash, drying after reaction terminates, solids on a silica gel column purifies and separates obtains (3R)-3-fluoropyrrolidine dithiocarbamic acid bismuth;
Or: get S-3-Fluoropyrrolidine hydrochloride salt and NaOH adds anhydrous methanol, after stirring and dissolving, drip CS
2, obtain reaction solution, get BiCl
3instill in above-mentioned reaction solution with the mixing solutions of anhydrous methanol, carry out suction filtration, alcohol wash, drying after reaction terminates, solids on a silica gel column purifies and separates obtains (3S)-3-fluoropyrrolidine dithiocarbamic acid bismuth;
Or: get 3,3-difluoropyrrolidine hydrochloride and NaOH adds anhydrous methanol, after stirring and dissolving, drip CS
2, obtain reaction solution, get BiCl
3instill in above-mentioned reaction solution with the mixing solutions of anhydrous methanol, carry out suction filtration, alcohol wash, drying after reaction terminates, solids on a silica gel column purifies and separates obtains 3,3-difluoropyrrolidin dithiocarbamic acid bismuth;
Substituted pyrrolidin dithiocarbamic acid bismuth (III) title complex has significant antitumor activity to malignant tumours such as cancer of the stomach, lung cancer, liver cancer, large bowel cancer, cervical cancer, ovarian cancer, mammary cancer, leukemia, colorectal carcinomas.
beneficial effect
Salt and the hydrate of substituted pyrrolidin dithiocarbamic acid bismuth (III) title complex of the present invention and described title complex have good anti-tumor activity, preparation method is simple, to malignant tumours such as cancer of the stomach, lung cancer, liver cancer, large bowel cancer, cervical cancer, ovarian cancer, mammary cancer, leukemia, colorectal carcinomas, there is significant antitumor activity, be developed as new antitumoral new drug and be with a wide range of applications.
Accompanying drawing explanation
Fig. 1-Fig. 4 is that the title complex (numbering N048) of embodiment three suppresses test result for tumor cell extracorporeal growth;
Fig. 5-Fig. 7 is that the title complex (numbering N055) of embodiment four suppresses test result for tumor cell extracorporeal growth;
Fig. 8-Figure 10 is that the title complex (numbering N060) of embodiment five suppresses test result for tumor cell extracorporeal growth;
Figure 11-Figure 13 is that the title complex (numbering N061) of embodiment six suppresses test result for tumor cell extracorporeal growth;
Figure 14-Figure 16 is that the title complex (numbering N062) of embodiment one suppresses test result for tumor cell extracorporeal growth;
Figure 17 is that the title complex (numbering N048) of embodiment three is to the growth inhibition test result of solid tumor model;
Figure 18 is that the title complex (numbering N060) of embodiment five is to the growth inhibition test result of solid tumor model.
Embodiment
Below by way of specific embodiment, the present invention is further illustrated, but not as restriction.
embodiment one:(2R)-2-crassitude dithiocarbamic acid bismuth and preparation thereof
0.426g (5mmol) (2R)-2-crassitude is added in round-bottomed flask, 0.25g (6mmol) sodium hydroxide, 15mL anhydrous methanol, after magnetic agitation is dissolved, 0-5 DEG C of cooling bath, drips 0.76g (10mmol) CS
2, magnetic agitation reaction 5h.
By 0.53g (1.7mmol) BiCl
3be dissolved 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 0.82g yellow powder solid, yield 71.3%.Fusing point: 224-226 DEG C, specific rotatory power
=-205
°(HCl
3), be numbered N062.
1HNMR(400MHz,CDCl
3),δ:1.362～1.378(9H,d,-CH
3,J=6.4Hz),1.692～1.731(3H,m,Cy-CH，J=5.2Hz),2.035～2.071(3H,m,Cy-CH,J=4.0-4.8Hz),2.088～2.161(6H,m,Cy-CH
2-,J=4.0-6.8Hz),3.890～3.952(6H,q,N-CH
2,J=7.6-9.2Hz),4.725～4.782(3H,m,N-CH,J=6.4-6.8Hz)。
Molecular formula: C
18h
30n
3s
6bi, results of elemental analyses (being calculated value % in bracket): C31.29 (31.34), H4.30 (4.39), N6.06 (6.09).
embodiment two:(S)-2-carboxy pyrrole alkane dithiocarbamic acid bismuth and preparation thereof
In 50mL round-bottomed flask, add 0.576g (5mmol) L-PROLINE, 0.759g (7.5mmol) triethylamine, 15mL anhydrous methanol, after magnetic agitation is dissolved, 0-5 DEG C of cooling bath, drips 0.76g (10mmol) CS
2, magnetic agitation reaction 1h, stirring at room temperature reaction 3h.
By 0.53g (1.7mmol) BiCl
3be dissolved in 15mL anhydrous methanol, instill in above-mentioned reaction solution, stirring at room temperature 4h.Be 5-6 with glacial acetic acid adjust pH, separate out yellow mercury oxide, suction filtration, anhydrous methanol is washed, dry.Solids recrystallizing methanol, obtains 1.05g yellow solid.Yield 80.8%.Fusing point: 186-188 DEG C, specific rotatory power
=-103
°(DMSO).
1HNMR(400MHz,DMSO-
d 6),δ:1.971～2.014(6H,m,Cy-CH
2,J=6.4～7.2Hz),2.272～2.318(6H,m,Cy-CH
2，J=6.4-7.6Hz),3.818～3.848(6H,t,N-CH
2,J=7.6Hz),4.761～4.805(3H,t,N-CH,J=8.8Hz)。
Molecular formula: C
18h
24n
3o
6s
6bi, results of elemental analyses (being calculated value % in bracket): C27.69 (27.72), H3.01 (3.11), N5.32 (5.39).
embodiment three:(S)-2-ethoxycarbonyl tetramethyleneimine dithiocarbamic acid bismuth and preparation thereof
0.898g (5mmol) L-PROLINE carbethoxy hydrochloride is added in 50mL round-bottomed flask, 0.44g (11mmol) sodium hydroxide, 15mL anhydrous methanol, after magnetic agitation is dissolved, 0-5 DEG C of cooling bath, drips 0.76g (10mmol) CS
2, magnetic agitation reaction 2h, stirring at room temperature reaction 4h.
By 0.53g (1.7mmol) BiCl
3be dissolved in 15mL anhydrous methanol, instill in above-mentioned reaction solution, stirring at room temperature 3h, suction filtration, anhydrous methanol is washed, vacuum-drying.Solids recrystallized from acetonitrile, obtains 1.15g aureus crystal.Yield 79.9%.Fusing point: 89-91 DEG C, specific rotatory power
=-393
°(CHCl
3), be numbered N048.
1HNMR(400MHz,CDCl
3),δ:1.261～1.297(9H,t,-CH
3,J=7.2Hz),2.069～2.091(3H,m,Cy-CH，J=4.4-6.8Hz),2.092～2.155(6H,m,Cy-CH
2,J=5.6-8.2Hz),2.314～2.400(3H,m,Cy-CH，J=6.4-8.0Hz),3.929～3.998(3H,m,N-CH,J=4.4-7.6Hz),4.061～4.108(3H,m,N-CH,J=3.2-5.2Hz),4.185～4.238(2H,q,O-CH
2,J=7.2Hz),4.997～5.031(3H,dd,N-CH,J=3.2-7.6Hz)。
Molecular formula: C
24h
36n
3o
6s
6bi, results of elemental analyses (being calculated value % in bracket): C33.28 (33.36), H4.16 (4.21), N4.69 (4.86).
embodiment four:(3R)-3-fluoropyrrolidine dithiocarbamic acid bismuth and preparation thereof
In round-bottomed flask, add 0.628g (5mmol) R-3-Fluoropyrrolidine hydrochloride salt, 0.44g (11mmol) sodium hydroxide, 15mL anhydrous methanol, after magnetic agitation is dissolved, 0-5 DEG C of cooling bath, drips 0.76g (10mmol) CS
2, magnetic agitation reaction 2h, stirring at room temperature reaction 4h.
By 0.53g (1.7mmol) BiCl
3be dissolved in 15mL anhydrous methanol, instill in above-mentioned reaction solution, stirring at room temperature 3h, suction filtration, anhydrous methanol is washed, dry.Solids is purifying on post, eluent: ethyl acetate-light petrol=1:2, is separated and obtains 1.02g yellow powder solid.Yield 87.2%, fusing point: 156-158 DEG C, specific rotatory power
=+10.5
°(CHCl
3), be numbered N048.
1HNMR(400MHz,CDCl
3),δ:2.349～2.442(6H,m,Cy-CH
2,J=6.0-8.0Hz),3.883～3.960(6H,m,N-CH
2,J=7.4Hz),4.285～4.315(3H,m,F-CH，J=8.0Hz),5.255～5.286(3H,q,N-CH,J=5.6～7.6Hz)，5.388～5.416(3H,q,N-CH,J=4.8～6.8Hz)。
Molecular formula: C
15h
21n
3f
3s
6bi, results of elemental analyses (being calculated value % in bracket): C25.68 (25.67), H3.01 (3.02), N5.89 (5.99).
embodiment five:(3S)-3-fluoropyrrolidine dithiocarbamic acid bismuth and preparation thereof
In round-bottomed flask, add 0.628g (5mmol) S-3-Fluoropyrrolidine hydrochloride salt, 0.44g (11mmol) sodium hydroxide, 15mL anhydrous methanol, after magnetic agitation is dissolved, 0-5 DEG C of cooling bath, drips 0.76g (10mmol) CS
2, magnetic agitation reaction 2h, stirring at room temperature reaction 4h.
By 0.53g (1.7mmol) BiCl
3be dissolved in 15mL anhydrous methanol, instill in above-mentioned reaction solution, stirring at room temperature 3h, suction filtration, anhydrous methanol is washed, dry.Solids is purifying on post, eluent: ethyl acetate-light petrol=1:2, is separated and obtains 0.97g yellow powder solid.Yield 82.9%, fusing point: 156-158 DEG C, specific rotatory power
=-10.5
°(CHCl
3), be numbered N060.
1HNMR(400MHz,CDCl
3),δ:2.349～2.442(6H,m,Cy-CH
2,J=6.0-8.0Hz),3.883～3.960(6H,m,N-CH
2,J=7.4Hz),4.285～4.315(3H,m,F-CH，J=8.0Hz),5.255～5.286(3H,q,N-CH,J=5.6～7.6Hz)，5.388～5.416(3H,q,N-CH,J=4.8～6.8Hz)。
Molecular formula: C
15h
21n
3f
3s
6bi, results of elemental analyses (being calculated value % in bracket): C25.63 (25.67), H2.98 (3.02), N5.88 (5.99).
embodiment six:3,3-difluoropyrrolidin dithiocarbamic acid bismuth and preparation thereof
In round-bottomed flask, add 0.718g (5mmol) 3,3-difluoropyrrolidine hydrochloride, 0.44g (11mmol) sodium hydroxide, 15mL anhydrous methanol, after magnetic agitation is dissolved, 0-5 DEG C of cooling bath, drips 0.76g (10mmol) CS
2, magnetic agitation reaction 2h, stirring at room temperature reaction 4h.
By 0.53g (1.7mmol) BiCl
3be dissolved in 15mL anhydrous methanol, instill in above-mentioned reaction solution, stirring at room temperature 5h, suction filtration, anhydrous methanol is washed, dry.Solids is purifying on post, eluent: ethyl acetate-light petrol=1:3, is separated and obtains 1.11g yellow powder solid.Yield 88.1%, fusing point: 228-230 DEG C, is numbered N061.
1HNMR(CDCl
3,400MHz),δ:2.521～2.557(6H,t,Cy-CH
2,J=7.2Hz),4.220～4.262(6H,t,N-CH
2,J=8.4Hz),5.405(6H,s,N-CH
2)。
Molecular formula: C
15h
18n
3f
6s
6bi, results of elemental analyses (being calculated value % in bracket): C23.73 (23.84), H2.38 (2.41), N5.48 (5.56).
antitumor cytolytic activity
one, anti tumor activity in vitro research
1. cell strain and cultivation
The cancer cell such as cancer cell leukemia cell line (HL-60), lung cancer cell line (A-549), hepatoma cell strain (BEL-7402), colorectal cancer cell lines (SW-1116), cervical cancer cell lines (HELA), Ovarian Cancer Cells (3AO), breast carcinoma cell strain (MCF-7), stomach cancer cell line (MKN-28) are incubated at 10% inactivated fetal bovine serum, 100U/mL penicillin, in RPMI1640 or the DMEM substratum of 100 μ g/mL Streptomycin sulphates, in the 10%CO of 37 DEG C
2cultivate under incubator and saturated humidity condition.For normal cultivation, attached cell is all with carrying out in the trypsinase-EDTA of 1 times of concentration after tryptic digestion takes off wall, every for cell 3 ~ 4 days being gone down to posterity once (when institute's area coverage is 80-90% to cell in culture dish) by the ratio of 1:5 ~ 1:20.
2. Antitumor Activity of Drugs measures
Test the day before yesterday, described cell carries out tryptic digestion about 5 minutes (in 37 DEG C of incubators) in 1 times of concentration trypsin-EDTA solutions, is suspended in DMEM or the RPMI nutrient solution of 10mL, is then inoculated into 96 orifice plates.Cell is 1 ~ 2 × 10 by density
4/ hole is inoculated in standard DMEM or RPMI substratum, and volume is 50 μ L.
Second day, prepare a series of 2x concentration dilutions storage liquid (0.003 μM ~ 60 μMs) of tested metal complexes with standard DMEM medium.50 μ L being diluted storage liquid joins in corresponding plate well, and the tested title complex ultimate density that the cell in test slab accepts be (0.0015 μM ~ 30 μMs) a series of 9 different dosage groups, often group 3 parallel holes.Therefore 2 kinds of compounds (such as X and Y) can carry out testing (table 1) in a plate simultaneously.Except test compound, each plate also comprises positive control (0.5 μM of Zorubicin) and negative control (DMSO).
Table 1: the testing scheme of 96 orifice plates and tested compounds final concentration in test
96 orifice plate culture plates are put in 37 DEG C of incubators and are cultivated after 48 hours, and abandoning supernatant adds the serum-free medium of the 0.5mg/mLMTT solution (0.5%MTT) containing 20 μ L of the 200 fresh configurations in μ L/ hole, and 37 DEG C are continued cultivation 5 hours.Abandoning supernatant, add 150 μ LDMSO, after concussion mixing, the light absorption value in each hole is measured at enzyme-linked immunosorbent assay instrument OD490nm place, calculate inhibitory rate of cell growth, formula is: inhibitory rate of cell growth=[(negative control group OD value-experimental group OD value)/negative control group OD value] × 100%.And by inhibitory rate of cell growth and corresponding concentration, go out IC50 value (half inhibiting rate IC50, inhibitory rate of cell growth is the drug level of 50%) by computed in software.For each compound, this mensuration repeats twice all in addition, once complete three mensuration, just calculates IC50 value by raw data.
3. experimental result
Measure the numbering N048 of different concns, N055, N060, N061, N062 etc. for tumor cell growth activity impact through mtt assay, result is as shown in Fig. 1-Figure 16.Numbering N048, N055, N060, N061, N062 etc. are to various tumor cell extracorporeal growth inhibit activities IC50 value (table 2) as shown in the table.
Table 2. title complex is to tumor cell extracorporeal growth inhibit activities
two, anti-tumor in vivo activity research
1. experiment material
1.1. laboratory animal and knurl strain
8-12 health Balb/c in age in week mouse, male and female half and half (body weight 22-25g), each cage fills 5 mouse, is placed between clean animal raising, drinking-water of freely ingesting.
Mouse colonic cell C26 is used to make allos solid tumor model Balb/c mouse both sides are subcutaneous.
1.2. testing drug
All title complexs are all formulated in 20%DMSO carrier soln, and to numbering N048, concentration is 4mg/mL; To numbering N060, concentration is 4mg/mL.
2. experimental procedure
2.1. animal model and grouping
By subcutaneous injection 5 × 10 under tucking in before mouse both sides
6individual culturing cell establishes C26 solid tumor models, treats that 80% gross tumor volume is greater than 80mm
3time, all mouse are divided at random embodiment treatment group and vehicle Control group.
2.2. medication
All described title complexs are all with intraperitoneal injection, and 30mg/kg/ days, control group accepts, without drug carrier injection, within one week 5 days, to continue 3 weeks, have a rest one week, or until mouse is had to due to large tumour and puts to death.
2.3. measurement of tumor
Two axles (mm) (L, the most major axis of vernier caliper measurement tumour; W, most minor axis).With formula: gross tumor volume V=0.5 × L × W
2estimate gross tumor volume V(cubic millimeter, mm
3).While pharmacological agent, every day carries out measurement of tumor, one week 3-4 time after treatment is finished.
2.4. the evaluation of antitumous effect
Anti-tumor activity is evaluated by drawing tumor growth curve and calculating maximum inhibition rate of tumor growth (maximum tumour inhibiting rate, MTGI): maximum Tumor growth inhibition (MTGI)=[(vehicle Control group mean tumour volume-administration group mean tumour volume)/vehicle Control group mean tumour volume] × 100%.
2.5. experimental result
Result statistical analysis, the maximum tumour inhibiting rate of numbering N048 is 16%, p<0.05; The maximum tumour inhibiting rate of numbering N060 is 10%, p<0.05.The tumor growth curve drawn after one-wayANOVA analyzes is as Figure 17 and Figure 18.
3. conclusion
Experimental data shows, metal complexes has significant antitumor activity to malignant tumours such as cancer of the stomach, lung cancer, liver cancer, large bowel cancer, cervical cancer, ovarian cancer, mammary cancer, leukemia, colorectal carcinomas, is developed as new antitumoral new drug and is with a wide range of applications.
Claims (2)
1. substituted pyrrolidin dithiocarbamic acid bismuth (III) title complex, is characterized in that: the skeleton symbol of described substituted pyrrolidin dithiocarbamic acid bismuth (III) title complex is as follows:
,
R
2and R
3for H, R
1for
or
;
Or, R
1and R
3for H, R
2for F;
Or, R
1and R
2for H, R
3for F;
Or, R
1for H, R
2and R
3for F.
2. the preparation method of substituted pyrrolidin dithiocarbamic acid bismuth (III) title complex as claimed in claim 1, is characterized in that:
Get (2R)-2-crassitude and NaOH adds anhydrous methanol, after stirring and dissolving, drip CS
2, obtain reaction solution, get BiCl
3instill in above-mentioned reaction solution with the mixing solutions of anhydrous methanol, carry out suction filtration, alcohol wash, drying, solids recrystallization after reaction terminates, obtain (2R)-2-crassitude dithiocarbamic acid bismuth;
Or: get L-PROLINE carbethoxy hydrochloride and NaOH adds anhydrous methanol, after stirring and dissolving, drip CS
2, obtain reaction solution, get BiCl
3instill in above-mentioned reaction solution with the mixing solutions of anhydrous methanol, after reaction terminates, carry out suction filtration, alcohol wash, drying, solids recrystallization, (S)-2-ethoxycarbonyl tetramethyleneimine dithiocarbamic acid bismuth;
Or: get R-3-Fluoropyrrolidine hydrochloride salt and NaOH adds anhydrous methanol, after stirring and dissolving, drip CS
2, obtain reaction solution, get BiCl
3instill in above-mentioned reaction solution with the mixing solutions of anhydrous methanol, carry out suction filtration, alcohol wash, drying after reaction terminates, solids on a silica gel column purifies and separates obtains (3R)-3-fluoropyrrolidine dithiocarbamic acid bismuth;
Or: get S-3-Fluoropyrrolidine hydrochloride salt and NaOH adds anhydrous methanol, after stirring and dissolving, drip CS
2, obtain reaction solution, get BiCl
3instill in above-mentioned reaction solution with the mixing solutions of anhydrous methanol, carry out suction filtration, alcohol wash, drying after reaction terminates, solids on a silica gel column purifies and separates obtains (3S)-3-fluoropyrrolidine dithiocarbamic acid bismuth;
Or: get 3,3-difluoropyrrolidine hydrochloride and NaOH adds anhydrous methanol, after stirring and dissolving, drip CS
2, obtain reaction solution, get BiCl
3instill in above-mentioned reaction solution with the mixing solutions of anhydrous methanol, carry out suction filtration, alcohol wash, drying after reaction terminates, solids on a silica gel column purifies and separates obtains 3,3-difluoropyrrolidin dithiocarbamic acid bismuth.
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| PCT/CN2015/080495 WO2015180693A1 (en) | 2014-05-30 | 2015-06-01 | Bismuth(iii)dithiocarbamate complex and preparation method and use thereof |
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