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WO2004067505A2 - Composes a base de dithiocarbamate de bismuth et leur utilisation - Google Patents

Composes a base de dithiocarbamate de bismuth et leur utilisation Download PDF

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Publication number
WO2004067505A2
WO2004067505A2 PCT/SG2004/000028 SG2004000028W WO2004067505A2 WO 2004067505 A2 WO2004067505 A2 WO 2004067505A2 SG 2004000028 W SG2004000028 W SG 2004000028W WO 2004067505 A2 WO2004067505 A2 WO 2004067505A2
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compound
halide
substituted
aryl
alkyl
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WO2004067505A3 (fr
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Edward R.T. Tiekink
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National University of Singapore
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National University of Singapore
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/94—Bismuth compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C333/00—Derivatives of thiocarbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C333/14—Dithiocarbamic acids; Derivatives thereof
    • C07C333/16—Salts of dithiocarbamic acids

Definitions

  • the present invention relates to bismuth dithiocarbamate compounds.
  • bismuth dithiocarbamate compounds for use in therapy.
  • Chemotherapy is at the forefront of tackling cancer. Chemotherapeutic agents currently employed suffer from a lack of efficacy and are known to cause deleterious side-effects in patients. Amongst the important drugs used to treat cancer, some of the most effective are metal-based.
  • Metal-containing compounds may offer certain advantages over purely organic compounds in drug therapy. For example, co-ordination of an organic molecule to a metal centre may alter the normal metabolic pathway and/or may lead to a slow release mechanism for delivery of the organic molecule i.e. the metal complex may function as a pro-drug.
  • cisplatin [(NH 3 ) 2 PtCI 2 ]
  • cisplatin is effective against certain cancers such as head, neck and testicular cancers, it lacks selectivity for tumour tissue, which leads to severe side effects.
  • platinum anticancer drugs there is still a large need for the development of novel metal-based compounds with unprecedented features.
  • Some known metal-based compounds have been proven to have effect only on limited types of cancer while other known metal-based compounds have not been used in therapy.
  • bismuth compounds are generally only used to relieve diaper (nappy) rash, treat burns as well as to treat gastric disorders such as diarrhoea and even ulcers.
  • bismuth subcitrate and bismuth subsalycilate are used to treat such medical conditions, of which both are Bi (III) ions.
  • Their empirical formulae are often given as K 3 (NH) 4 [Bi 6 ⁇ 3(OH) 5 (H ci t) ] (Merck Index, 1989, 11 th edition, p197) and OC 6 H 4 COOBiO (Sun, Li et. al., 1997, Chem. Ber. / Recueil. Vol 130, p675) respectively.
  • bismuth compounds such as bismuth tris(methyl-/ hexyl- dithiocarbamate), Bi(S 2 CN(Me)Hex) 3 and bismuth (III) tris(n,n- diethyldithiocarbamate), Bi(S 2 CNEt 2 ) 3 have only been described for crystallographic studies (Koh et. al., 2003, Chem. Mater., 15, 4544-4554; Monteira et. al., 2001 , Chem. Mater., 13, 2103-2111 ) and their use as precursors for Bi 2 S 3 nanoparticles.
  • the invention provides a compound of general formula I:
  • R and R 1 are the same or different, and each is an alkyl, substituted alkyl, aryl or a substituted aryl; X is a halide or a pseudo-halide; and n is either 2 or 3; for use as an active pharmaceutical substance.
  • the invention also provides a compound of formula I, wherein n is 3 and R and R 1 are both ethyl, for use as an active pharmaceutical substance.
  • the compound of general formula I can be used in the manufacture of a medicament for therapeutic application as an anti-tumour agent.
  • the compound having general formula I, wherein n is 3, R and R 1 are both ethyl.
  • the compounds may be used for the treatment of tumor including but not limited to breast cancer, ovarian cancer, melanoma, renal cancer and non- small cell lung cancer.
  • the tumor can be animal or human tumor.
  • a pharmaceutical composition comprising the bismuth dithiocarbamate compounds of general formula I is provided.
  • a pharmaceutical composition comprising the compound Bi(S 2 CNEt 2 ) 3 .
  • the pharmaceutical compositions optionally comprise a pharmaceutical acceptable diluent and/or carrier.
  • Another aspect of the invention is a method for treating tumor comprising the administration of compound of general formula I:
  • R and R are the same or different, and each is an alkyl, substituted alkyl, aryl or a substituted aryl; X is a halide or a pseudo-halide; and n is either 2 or 3. In particular, n is 3 and R and R 1 are both ethyl.
  • the above-mentioned method wherein the tumor is animal or human tumor and includes but is not limited to breast cancer, ovarian cancer, melanoma, renal cancer and non-small cell lung cancer.
  • the invention provides novel compounds of the general formula I:
  • R and R 1 are the same or different, and each is an alkyl, substituted alkyl, aryl or a substituted aryl; X is a halide or a pseudo-halide; and n is either 2 or 3, with the proviso that when n is 3, R and R 1 are not ethyl (Et), and that when n is 3, R is not methyl (Me) and R 1 is not hexyl (Hex) or vice versa.
  • the invention provides new compounds included in the general formula I, wherein n is 2. These compounds are indicated with general formula II:
  • R and R' are both (CH 2 ) 2 and X is Cl.
  • the compounds of formula II may be used in therapy as well as in other fields such as the preparation of nanoparticles.
  • Another aspect of the present invention is the process for preparing the compound of formula II, which comprises mixing a bismuth salt, alcohol and carbodithioic acid to obtain a mixture and then dissolving the precipitate obtained from the mixture in a halogen-substituted alkane and organic nitrile to further obtain a solution, followed by drying the said solution to recover an amorphous form of compound of formula II.
  • the bismuth salt is anhydrous bismuth (III) chloride
  • the alcohol is ethanol
  • the acid is 1-pyrrolidinecarbodithioic acid
  • NH 4 S 2 CNC H 8 the halogen-substituted alkane is chloroform, CHCI 3
  • the organic nitrile is acetonitrile, C 2 H 3 N.
  • the halogen-substituted alkane and organic nitrile are mixed in a 1 :1 volume ratio.
  • FIG 1a The cytotoxic effects of Bi(SCNEt 2 ) 3 (referred to as Bi(dedtc) 3 in figure) on the ovarian cancer cell line (OVCAR).
  • Bi(dedtc) 3 ovarian cancer cell line
  • Figure 1 b The cytotoxic effects of Bi(S 2 CN(CH 2 ) 4 ) 2 CI (referred to as Bi(pydtc) 2 CI in figure) on the ovarian cancer cell line (OVCAR).
  • Bi(pydtc) 2 CI ovarian cancer cell line
  • FIG. 2a The cytotoxic effects of Bi(SCNEt 2 ) 3 (referred to as Bi(dedtc) 3 in figure) on A-498 cell line.
  • Figure 2b The cytotoxic effects of Bi(S 2 CN(CH 2 ) 4 ) 2 CI (referred to as Bi(pydtc) 2 CI in figure) on A-498 cell line.
  • Figure 3a The cytotoxic effects of Bi(SCNEt 2 ) 3 (referred to as Bi(dedtc) 3 in figure) on HF cell line.
  • Figure 3b The cytotoxic effects of Bi(S 2 CN(CH 2 ) 4 ) 2 CI (referred to as Bi(pydtc) 2 CI in figure) on HF cell line.
  • FIG 4a The cytotoxic effects of Bi(SCNEt 2 ) 3 (referred to as Bi(dedtc) 3 in figure) on NCI-H1299 cell line.
  • Figure 4b The cytotoxic effects of Bi(S 2 CN(CH 2 ) ) 2 CI (referred to as Bi(pydtc) 2 CI in figure) on NCI-H1299 cell line.
  • Figure 5a The cytotoxic effects of Bi(SCNEt )3 (referred to as Bi(dedtc)3 in figure) on HT-29 cell line.
  • Figure 5b The cytotoxic effects of Bi(S CN(CH 2 ) 4 ) 2 CI (referred to as Bi(pydtc) 2 CI in figure) on HT-29 cell line.
  • Figure 6a The cytotoxic effects of Bi(SCNEt 2 )3 (referred to as Bi(dedtc) 3 in figure) on MRC-5 cell line.
  • Figure 6b The cytotoxic effects of Bi(S 2 CN(CH 2 ) 4 ) 2 CI (referred to as Bi(pydtc) 2 CI in figure) on MRC-5 cell line.
  • Figure 7a The cytotoxic effects of Bi(SCNEt 2 )3 (referred to as Bi(dedtc) 3 in figure) on MCF-7 cell line.
  • Figure 7b The cytotoxic effects of Bi(S 2 CN(CH 2 ) 4 ) 2 CI (referred to as Bi(pydtc) 2 CI in figure) on MCF-7 cell line.
  • Figure 8 Plot of relative tumour volume (mm 3 ) versus days after administration of Bi(S 2 CNEt ) 3 (test group) and DMSO only (control group) for nude Balb/C mice inoculated with OVCAR (human ovarian cancer).
  • One aspect of the present invention relates to the use of bismuth dithiocarbamate compounds for use as an active pharmaceutical substance.
  • the general formula of these compounds is as follows:
  • R and R 1 are the same or different, and each is an alkyl, substituted alkyl, aryl or a substituted aryl;
  • X is a halide or a pseudo-halide; and
  • n is either 2 or 3.
  • 'alkyl' refers to a straight or branched, monovalent, saturated aliphatic chain of 1-20 carbon atoms, including normal, iso, neo and tertiary.
  • 'Alkyl' includes but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec butyl, tert butyl, amyl, isoamyl, neoamyl, hexyl, isohexyl, neohexyl, heptyl, isoheptyl, neoheptyl, octyl, isooctyl, neooctyl, and the like; cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like, the cycloalkyl group may
  • aryl' refers to organic compounds including but not limited to phenyl, biphenyl, naphthyl, furanyl, pyrrolyl, thiophenyl, pyridinyl, indolyl, benzofuranyl, benzothiophenyl, quinolinyl, isoquinolinyl, imidazolyl, thiazolyl, pyrazinyl, primidinyl, purinyl and pteridinyl.
  • the aryl group may be substituted and may include the following compounds:
  • 'halide' refers to a family of non-metallic, generally electronegative, elements of group VII of the periodic table. They are all multivalent and have oxidation numbers of -1 (the most common), 1 , 3, 5, and 7. Examples of halides are fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).
  • pseudo-halide refers to SCN, CN, NCO and the like.
  • the compound of general formula I wherein n is 3 and R and R 1 are both ethyl, for use as an active pharmaceutical substance.
  • This compound is known as bismuth (III) tris(N,N-diethyldithiocarbamate), Bi(S 2 CNEt ) 3 .
  • Bi(S 2 CNEt ) 3 bismuth (III) tris(N,N-diethyldithiocarbamate), Bi(S 2 CNEt ) 3 .
  • This is a known compound (Howard et. al., 1975, Ada Crystallographica., 31.S141 and Raston et. al., 1976, J. Chem. Soc, Dalton Trans., 791 )
  • its previous uses are non-medical uses. It has most commonly been used in crystallographic studies.
  • the properties of this compound are as follows based on the preparation of the compound as described in Koh et.
  • a further embodiment of the invention is the use of the compound of general formula I in the manufacture of a medicament for therapeutic application as an anti-tumour agent.
  • These compounds are found to be highly effective with minimal deleterious side effects owing to the high mammalian tolerance of bismuth.
  • the known compound Bi(S 2 CNEt 2 )3) is also used in the manufacture of a medicament for therapeutic application as an anti-tumour agent.
  • tumours which can be animal or human tumours.
  • the compounds can also be used to treat tumours including but not limited to breast cancer, ovarian cancer, melanoma, renal cancer and non-small cell lung cancer.
  • the compound of general formula I can also be used as a pharmaceutical composition for use in therapy. For example, it is useful for the prevention or reduction of tumours.
  • the invention encompasses the preparation and use of pharmaceutical compositions comprising the compound of general formula I as an active ingredient.
  • Such a pharmaceutical composition may consist of the active ingredient alone, in a form suitable for administration to a subject, or alternatively the pharmaceutical composition may comprise the active ingredient and one or more pharmaceutically acceptable carrier, excipient and/or diluent.
  • compositions described herein may be prepared by any method known or hereafter developed in the art.
  • preparatory methods include the step of bringing the active ingredient into association with a carrier, excipient and/or diluent, and then, if necessary or desirable, shaping or packaging the product into a desired single- or multi-dose unit.
  • compositions are principally directed to pharmaceutical compositions that are suitable for administration to humans, the person skilled in the art will understand that such compositions are generally suitable for administration to animals of all sorts. Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and perform such modifications. Subjects to which administration of the pharmaceutical compositions of the invention is contemplated include, but are not limited to, humans and other primates.
  • R and R 1 are the same or different, and each is an alkyl, substituted alkyl, aryl or a substituted aryl; X is a halide or a pseudo-halide; and n is either 2 or 3.
  • Tumour as stated in the above-mentioned method includes breast cancer, ovarian cancer, melanoma, renal cancer and non-small cell lung cancer. Further, the tumour is animal and/or human tumour.
  • Another aspect of the invention is compounds of general formula I:
  • a further embodiment of the above aspect is novel bismuth dithiocarbamate compounds of general formula II:
  • R and R 1 are the same or different, and each is an alkyl, substituted alkyl, aryl or a substituted aryl and X is a halide or a pseudo-halide.
  • alkyl, aryl, halide and pseudo-halide are as previously defined.
  • a novel compound of general formula II, wherein R and R 1 are both (CH 2 ) 2 and X is Cl.
  • the carbodithioic acid is dissolved in distilled water and added to a suspension containing the bismuth salt and alcohol.
  • the resulting mixture is stirred to ensure that reaction between the reagents is complete.
  • the precipitate that is obtained is then separated from the rest of the mixture and washed with distilled water several times.
  • the precipitate that is collected is then dissolved in a halogen-substituted alkane.
  • the solvent is then evaporated and the crude precipitate that remains is recrystallised by using an organic nitrile, with further addition of the halogen-substituted alkane.
  • the end product is crystals of the desired compound.
  • the starting materials were obtained commercially such as anhydrous bismuth (III) chloride, BiC (Strem Chemicals Co), sodium diethyldithiocarbamate trihydrate, (CH 3 CH 2 ) 2 NCS 2 Na.3H 2 ⁇ , bismuth nitrate pentahydrate, Bi(N0 3 ) 3 .5H 2 0 and 1-pyrr ⁇ lidinecarbodithioic acid ammonium salt, NH 4 [S 2 CN(CH 2 ) 4 ] (Aidrich Chemical Co).
  • 1 H and ⁇ 1 H ⁇ 13 C NMR spectra were recorded on a Bruker ACF 300MHz FT NMR spectrometer. Infrared spectra were recorded as KBr discs on an Excalibur Series Bio-Rad Merlin
  • FTS 3000 spectrophotometer in the range of 400 - 4000 cm "1 . Mass spectra were recorded on FINNIGAN TSQ 7000 spectrometer. Elemental analysis was carried out on a Perkin-Elmer PE 2400CHN and CHNS Elemental
  • the compound, Bi(S 2 CNEt 2 )3. is a known and well-characterised species and the crystal structure is known (J.A. Howard et. al., 1975, Acta Crystallogr. A31 , S141 and C. L. Raston & A. H. White, 1976, J. Chem. Soc, Dalton Trans, 791) and can be prepared readily and in high purity in the following fashion. All reactions were carried out under a nitrogen atmosphere and at room temperature. All reagent grade solvents were used without further purification.
  • Table 1 ID 50 values (ng/ml) of Bi(S 2 CNEt 2 ) 3 , Bi(S 2 CN(CH 2 ) 4 ) 2 CI, plus those for standard compounds, doxorubicin (DOX), cisplatin (CPT), 5-fluorouracil (5-FU), methotrexate (MTX), etoposide (ETO) and taxol (TAX) in vitro using SRB as cell viability test
  • the codes for the cell lines are as follows: A498: renal cancer; EVSA-T: breast cancer, estrogen receptor (ER)-/progesterone receptor (PgR)-; H226: non-small cell lung cancer; IGROV: ovarian cancer; M19 MEL: Melanoma; MCF-7: breast cancer, estrogen receptor (ER)+/progesterone receptor (PgR)+; WIDR: colon cancer.
  • Table 1 The results shown in Table 1 were obtained in the following manner.
  • the test and reference compounds were dissolved to a concentration of 250 000 ng/ml in full medium, by 20 fold dilution of a stock solution which contained 1 mg compound/200 ⁇ l.
  • the trial complexes were taken into DMSO. Cytotoxicity was estimated by the microculture sulforhodamine B (SRB) test (Keepers, Pizao, et. al., 1991 , Eur. J. Cancer, 27, 897).
  • SRB microculture sulforhodamine B
  • the experiment was started on day 0. On day 0, 150 ⁇ l of trypsinized tumour cells (1500 - 2000 cells/well) were plated in 96-well flatbottom microtiter plates (falcon 3072, DB). The plates were pre-incubated 48 hrs at 37°C, 8.5
  • % C0 2 to allow the cells to adhere.
  • a three-fold dilution sequence of ten steps was made in full medium, starting with the 250 000 ng/ml stock solution. Every dilution was used in quadruplicate by adding 50 ⁇ l to a column of four wells. This resulted in a highest concentration of 62 5000 ng/ml being reached in column 12.
  • Column 2 was used as a blank.
  • PBS was added to column 1 to diminish interfering evaporation.
  • the incubation was terminated by washing the plate twice with PBS. Subsequently, the cells were fixed with 10 % trichloroacetic acid in PBS and placed at 4 °C for one hour.
  • the cells were stained for at least 15 minutes with 0.4 % SRB dissolved in 1 % acetic acid. After staining, the cells were washed with 1 % acetic acid to remove the unbound stain. The plates were air-dried and the bound stain was dissolved in 150 ⁇ l 10 mM Tris-base. The absorbance was read at 540 nm using an automated microplate reader (Labsystems Multiskan MS). The data obtained was used for the construction of concentration-response curves and the determination of the ID 50 value using the Deltasoft 3 software.
  • SI survival index
  • the reported in vitro potency is maintained in nude Balb/C mice inoculated with a human ovarian cancer cell line, OVCAR.
  • the Maximum Tolerated Dose (MTD) in Balb/C mouse model was determined.
  • the MTD of Bi(S 2 CNEt )3 was determined in the following manner. Male and female BALB/c mice obtained from the Laboratory Animal Centre, (National University of Singapore), were used for the study. The mice used were about 4 - 5 weeks old with a mean body weight of 20 ⁇ 2 g. The 5 mice per cage were kept at room temperature and under standard light conditions. They received standard mouse chow and water.
  • the compound Bi(S 2 CNEt 2 ) 3 was dissolved in sterile DMSO and 0.1 ml was given intraperitoneal (i.p.) for a 20 g mouse.
  • the mice in the control group were administered with DMSO only.
  • the concentrations of Bi(S 2 CNEt 2 ) 3 were calculated in terms of mg Bi/kg of mouse.
  • An initial concentration of 20 mg Bi/kg was used for a small sampling population of two mice, one of each gender. If both mice died, the complex concentration was decreased, and the experiment was repeated for another two mice. If one of the mice died but the other survived, the experiment was repeated for a larger sampling population of ten mice, five of each gender, for the same complex concentration. The observation period lasted 14 days.
  • the objective of the experiment was to plot a graph of percent of live mice (number of survivors / ten x 100%) against compound dosage (in mg Bi / kg). This procedure enabled the determination of the Maximum Tolerated Dose (at MTD 90 % survival of mice).
  • mice Female BALB/C-nude mice, obtained from the Animal Resources Centre in Queensland, Australia were used for this experiment. The mice used were about 5 - 6 weeks old and had a mean body weight of 20 ⁇ 2g. Throughout this experiment, the mice were housed in filtered air laminar-flow cabinets and were manipulated following standard aseptic procedures.
  • OVCAR Human ovarian cancer
  • a suspension of OVCAR cells (10 7 cells) were injected subcutaneously (s.c.) in the flank of each animal (0.1 ml per mice). When the volume of the tumour reached approximately 50-100 mm 3 , the mice were randomly divided into 2 groups, the test group and the control group, comprising 6 mice in each group.
  • Bi(S 2 CNEt 2 ) 3 was prepared as a 20 mg Bi/kg stock solution in dimethylsulphoxide, DMSO, and further diluted with DMSO immediately before administration.
  • the compound was given subcutaneously to mice in amounts of 0.1 ml/20 g three times every two days in the first week.
  • the dose applied was at the level of the MTD, i.e. 0.14 mg Bi/kg mouse.
  • the appropriate vehicle (DMSO) was injected into the mice in the control group, using the same schedule and route of injection as the drug therapies.
  • tumour growth was monitored and the volume of the tumour was determined by measuring its diameter with a vernier calliper every 2-4 days.
  • the above experiment shows that three weeks after multiple administration of Bi(S 2 CNEt 2 ) 3 to nude Balb/C mice afflicted with OVCAR human ovarian cancer at 0.14 mg Bi/kg animal weight, the average volume of a tumour in a mouse in the test group was 30 % that of a mouse in the control group. This shows that Bi(S 2 CNEt 2 ) 3 demonstrates significant anti- tumour activity.

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  • Organic Chemistry (AREA)
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Abstract

La présente invention concerne des composés à base de dithiocarbamate de bismuth correspondant à la formule générale I, dans laquelle R et R1 sont identiques ou différents, chacun d'eux étant un alkyle, un alkyle substitué, un aryle ou un aryle substitué; X est un halogénure ou un pseudo-halogénure, et n est 2 ou 3; il est destiné à être utilisé en tant que substance pharmaceutique active. Il peut notamment être utilisé en tant qu'agent anti-tumoral et pour traiter de diverses formes de tumeurs. L'invention concerne aussi certains nouveaux composés de dithiocarbamate de bismuth et le procédé de fabrication de ces composés.
PCT/SG2004/000028 2003-01-29 2004-01-29 Composes a base de dithiocarbamate de bismuth et leur utilisation Ceased WO2004067505A2 (fr)

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006023714A3 (fr) * 2004-08-20 2006-08-10 Aaipharma Inc Derives de dithiocarbamate et leur utilisation pour le traitement du cancer
CN103588687A (zh) * 2012-11-21 2014-02-19 复旦大学附属肿瘤医院 一种一价铜金属配合物及其制备方法和用途
CN103980174A (zh) * 2014-05-30 2014-08-13 天津博美开泰生物医药科技有限公司 取代吡咯烷氨荒酸铋(ⅲ)配合物及其制备方法和在制备抗肿瘤药物中的应用
CN104072443A (zh) * 2014-05-30 2014-10-01 南阳师范学院 N-取代哌嗪氨荒酸铋(ⅲ)配合物及其制备方法和在制备抗肿瘤药物中的应用
CN104876893A (zh) * 2015-05-25 2015-09-02 南阳师范学院 一类取代高哌嗪氨荒酸铋配合物、配合物的可药用盐以及配合物的制备方法和抗肿瘤应用

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3322802A (en) * 1963-05-27 1967-05-30 Vanderbilt Co R T Metal salts of organodithiocarbamateorganothiocarbamoyl sulfinates and the preparation thereof
JPS63174926A (ja) * 1987-01-09 1988-07-19 Nitto Kasei Kk 家禽用抗コクシジウム剤

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006023714A3 (fr) * 2004-08-20 2006-08-10 Aaipharma Inc Derives de dithiocarbamate et leur utilisation pour le traitement du cancer
CN103588687A (zh) * 2012-11-21 2014-02-19 复旦大学附属肿瘤医院 一种一价铜金属配合物及其制备方法和用途
CN103588687B (zh) * 2012-11-21 2016-07-06 复旦大学附属肿瘤医院 一种一价铜金属配合物及其制备方法和用途
CN103980174A (zh) * 2014-05-30 2014-08-13 天津博美开泰生物医药科技有限公司 取代吡咯烷氨荒酸铋(ⅲ)配合物及其制备方法和在制备抗肿瘤药物中的应用
CN104072443A (zh) * 2014-05-30 2014-10-01 南阳师范学院 N-取代哌嗪氨荒酸铋(ⅲ)配合物及其制备方法和在制备抗肿瘤药物中的应用
CN104876893A (zh) * 2015-05-25 2015-09-02 南阳师范学院 一类取代高哌嗪氨荒酸铋配合物、配合物的可药用盐以及配合物的制备方法和抗肿瘤应用

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