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WO2008147242A1 - Utilisation d'un complexe fer-tétranitrosyle avec du thiophénol comme médicament antitumoral - Google Patents

Utilisation d'un complexe fer-tétranitrosyle avec du thiophénol comme médicament antitumoral Download PDF

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Publication number
WO2008147242A1
WO2008147242A1 PCT/RU2007/000285 RU2007000285W WO2008147242A1 WO 2008147242 A1 WO2008147242 A1 WO 2008147242A1 RU 2007000285 W RU2007000285 W RU 2007000285W WO 2008147242 A1 WO2008147242 A1 WO 2008147242A1
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WIPO (PCT)
Prior art keywords
thiophenol
complex
iron
tetranitrosyl
pharmaceutical composition
Prior art date
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Ceased
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PCT/RU2007/000285
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English (en)
Russian (ru)
Inventor
Natalia Alexeevna Sanina
Olga Stepanovna Zhukova
Sergei Mikhailovich Aldoshin
Nina Sergeevna Emelyanova
Galina Konstantinovna Gerasimova
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INSTITUT PROBLEM KHIMICHESKOI FIZIKI ROSSIISKOI AKADEMII NAUK
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INSTITUT PROBLEM KHIMICHESKOI FIZIKI ROSSIISKOI AKADEMII NAUK
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Priority to PCT/RU2007/000285 priority Critical patent/WO2008147242A1/fr
Publication of WO2008147242A1 publication Critical patent/WO2008147242A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/095—Sulfur, selenium, or tellurium compounds, e.g. thiols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/28—Compounds containing heavy metals
    • A61K31/295—Iron group metal compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia

Definitions

  • the invention relates to tetranitrosyl binuclear iron complexes and can be used in medical practice to create a new generation drug for the treatment of cancer. Specifically, the present invention relates to the use of a tetranitrosyl binuclear complex of iron with thiophenol as a new generation antitumor drug.
  • NO donors as a new class of antitumor agents is associated with the important role of NO in the growth of malignant tumors [Wipk D., Vodóvoz J.,
  • Nitrogen monoxide has been shown to alter the level of tumor cell apoptosis, p53 gene activity, and neoangiogenesis [Vrupe V., Scheneiderhan N., Nitrirete okhide evoked p53-accsnulation apd aportosis, Toxol Letters, 2003, 193, 2, pp.19-23], inhibits the activity of the key repair protein of mammalian Ob-methyl guanine DNA methyl transferase [Li Liu, M. Hu-Welliveg, S.
  • An object of the present invention is to expand the arsenal of antitumor agents and to provide an antitumor drug based on transition metal complexes with an improved activity spectrum and reduced side effects, in particular, a drug based on a tetranitrosyl binuclear iron complex acting as an NO donor with increased activity and reduced toxicity .
  • the invention relates to the use of a tetranitrosyl binuclear iron complex with a thiophenol of the formula [Fe 2 (SC 6 Hs) 2 (NO) 4 ] as an antitumor drug.
  • the invention relates to the use of a tetranitrosyl binuclear iron complex with a thiophenol of the formula [Fe 2 (SC 6 Hs) 2 (NO) 4 ] for the preparation of an antitumor drug.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising an effective amount tetranitrosyl binuclear complex of iron with a thiophenol of formula [Fe 2 (SC 6 Hs) 2 (NO) 4] and a pharmaceutically acceptable carrier.
  • the present invention provides a kit useful for the treatment of cancer, comprising: (1) a pharmaceutical composition comprising a tetranitrosyl binuclear a complex of iron with thiophenol of the formula [Fe 2 (SCeHs) 2 (NO) 4 ], in a sealed package; and (2) auxiliaries.
  • the present invention relates to the use of a tetranitrosyl binuclear iron complex with a thiophenol of the formula [Fe 2 (SC 6 Hs) 2 (NO) 4 ] as an antitumor drug.
  • the tetranitrosyl binuclear complex of iron with thiophenol of the formula [Fe 2 (SC 6 H 5 ) 2 (NO) 4 ] is known in the art.
  • the preparation of a tetranitrosyl iron complex with a thiophenol of the formula [Fe 2 (SC 6 Hs) 2 (NO) 4 ] from Fe 2 (I) 2 (NO) 4 and PhSH in the presence of Et 3 N is described in T.V. Rausshfuss, T.D. W Canalth réellerill, Ipoorg. Chem., 1982, 21, pp. 827-830.
  • the tetranitrosyl iron-thiophenol complex of the formula [Fe 2 (SC 6 Hs) 2 (NO) 4 ] can be obtained using known synthesis methods, for example, by the method disclosed in article C. Glidewell, RJ. Lambert, M.E. Narmap and M. B. Nursthause, J. Chem. Sos, Daltop Tgaps., 1990, 10, pp.2685-2690, for similar tetranitrosyl complexes [Fe 2 (SR) 2 (NO) 4 ], where R is alkyl (CrC 8 ), CH 2 CO 2 Me, CH 2 CH 2 OH or 2-pyrimidinyl.
  • the method consists in the interaction of bis ( ⁇ -thiocylphato-S) -bis-
  • the tetranitrosyl complex of iron with thiophenol [Fe 2 (SC 6 Hs) 2 (NO) 4 ] is an effective NO donor, releasing NO spontaneously when decomposed in proton media (such as water, blood and its components, physiological solutions etc.), and this does not require thermal or photoactivation, as for other known nitrosyl iron complexes.
  • the authors of the present invention also showed that the tetranitrosyl binuclear complex of iron with thiophenol inhibits the growth of tumor cells in mammals, in particular humans.
  • the present invention relates to the use of a tetranitrosyl binuclear iron complex with a thiophenol of the formula [Fe 2 (SC 6 Hs) 2 (NO) 4 ] as an antitumor drug.
  • the tetranitrosyl binuclear complex of iron with thiophenol can be used to treat myeloid leukemia.
  • the tetranitrosyl binuclear iron-thiophenol complex of the present invention is suitable for inhibiting tumor growth in mammals and is preferably administered as a pharmaceutical composition comprising an effective antitumor amount of the compound of the present invention in combination with at least one pharmaceutically or pharmacologically acceptable carrier.
  • a carrier also known in the art as an excipient, excipient, excipient, additive or diluent, is any substance that is pharmaceutically inert, gives the appropriate consistency or form of the composition and does not impair the therapeutic efficacy of the antitumor compounds.
  • a carrier is “pharmaceutically or pharmacologically acceptable” if it does not cause an adverse, allergic or other adverse reaction when administered to a mammal or human, respectively.
  • the invention relates to the use of a tetranitrosyl binuclear iron complex with a thiophenol of the formula [Fe 2 (SC 6 Hs) 2 (NO) 4 ] for the manufacture of an antitumor drug.
  • the present invention also provides pharmaceutical compositions comprising an effective amount of a tetranitrosyl binuclear iron complex with a thiophenol of the formula [Fe 2 (SC 6 Hs) 2 (NO) 4 ] and a pharmaceutically acceptable carrier.
  • a pharmaceutically acceptable carrier Preferably, a proton-containing medium, more preferably a mixture of proton-containing medium and dimethyl sulfoxide, is used as a pharmaceutically acceptable carrier.
  • water, physiological saline, and water-soluble biopolymers are preferably used as a proton-containing medium.
  • the tetranitrosyl iron-thiophenol complex is present in the pharmaceutical composition in an amount of 50-100 ⁇ M.
  • compositions containing an antitumor compound of the present invention can be prepared by any conventional method. The required formulation is selected depending on the chosen route of administration. Compositions according to the invention can be prepared for any route of administration, so that the target tissue is accessible with this route of administration.
  • Suitable routes of administration include, but are not limited to, oral, parenteral (e.g., intravenous, intraarterial, subcutaneous, rectal, intramuscular, intraorbital, intracapsular, intraspinal, intraperitoneal or intrasternal), local (nasal, percutaneous, intraocular, intraocular) into the small intestine, pulmonary, intralymphatic, intracavitary, vaginal, trasurethral, intradermal, auricular, intramammary, buccal, orthotopic, intratracheal, intrafocal, percutaneous, endoscopic, transmucosal, sublingual and intestinal administration.
  • parenteral e.g., intravenous, intraarterial, subcutaneous, rectal, intramuscular, intraorbital, intracapsular, intraspinal, intraperitoneal or intrasternal
  • local (nasal, percutaneous, intraocular, intraocular) into the small intestine pulmonary, intralymphatic, intracavit
  • compositions of the present invention are well known to those skilled in the art and are selected depending on a number of factors: the particular antitumor compound used and its concentration, stability and expected bioavailability; the disease, disorder or condition of the person being treated with the composition; subject, his age, weight and general condition; and method of administration. Suitable carriers are readily determined by a person skilled in the art (JG Nairp at: Remiptop's Pharmacutil Sciepse (ed. A. Geppago), Mass Publishing Co., Eastop, Pa, (1985), pp. 1492-1517).
  • compositions are preferably prepared in the form of tablets, dispersible powders, pills, capsules, gelatin capsules, coated droplets, gels, granules, solutions, suspensions, emulsions, syrups, elixirs, troches, dragees, lozenges, or any other dosage form that may be administered orally.
  • Technologies and compositions for the preparation of oral dosage forms suitable according to the present invention are described in the literature (Model Pharmacutis, chapters 9 and 10 (ed. Wapker and Rhodes, 1979); Liebegmap et al., Pharmacut Dosage Fogm: Tablets (1981); Iprodustiopo Pharmaceutil Formes, second edition (1976)).
  • compositions of the present invention for oral administration comprise an effective antitumor amount of a compound of the invention and a pharmaceutically acceptable carrier.
  • suitable carriers for solid dosage forms include sugars, starches, and other common substances including lactose, talc, sucrose, gelatin, carboxymethyl cellulose, agar, mannitol, sorbitol, calcium phosphate, calcium carbonate, sodium carbonate, kaolin, alginic acid, gum arabic, corn starch , potato starch, sodium saccharinate, magnesium carbonate, tragacanth, microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium, talc, magnesium stearate and stearic acid.
  • such solid dosage forms may be uncoated or may be coated by known methods, for example, to delay fracture and absorption.
  • the antitumor compound of the present invention is also it is preferably used for the preparation of a parenteral dosage form, for example, in the form of a dosage form for injection by the intravenous, intraarterial, subcutaneous, rectal, intramuscular, intraorbital, intracapsular, intraspinal, intraperitoneal or intrasterial routes.
  • Compositions according to the invention for parenteral administration include an effective antitumor amount of an antitumor compound in a pharmaceutically acceptable carrier.
  • Formulations suitable for parenteral administration include solutions, suspensions, dispersions, emulsions, or any other dosage form that can be administered parenterally. Techniques and compositions for preparing parenteral dosage forms are known in the art.
  • compositions of the invention may be included in the compositions of the invention for various purposes. These components for the most part give properties that increase the retention time of the antitumor compound at the injection site, contribute to the stability of the composition, provide pH control, facilitate the incorporation of the antitumor compound into pharmaceutical compositions, and the like. Each of these components is individually present in an amount, preferably, less than about 15 mass%, more preferably less than about 5 mass%, and most preferably less than about 0.5 mass%, based on the total weight of the composition. Some components, such as fillers or diluents, can be up to 90 mass%, based on the total weight of the composition, as is well known in drug technology.
  • Such additives include cryoprotective component to prevent precipitation of the iron complex with thiophenol, surfactants, wetting or emulsifying agents (e.g. lecithin, policopbat-80, Tween ® 80, plyuponik-60, polyoxyethylene stearate), preservatives (e.g., ethyl-n- hydroxybenzoate), anti-microbial agents (e.g. benzyl alcohol, phenol, m-cresol, chlorobutanol, sorbic acid, thimerosal and paraben), agents for pH adjustments or buffering agents (e.g. acids, bases, sodium acetate, sorbitan monolaurate), components for controlling osmolarity (e.g.
  • glycerin e.g. aluminum monostearate, stearic acid, cetyl alcohol, stearyl alcohol, guar gum, methyl cellulose, hydroxypropyl cellulose, tristearin, wax cetyl esters, polyethylene glycol), pigments, dyes, fluidity additives, non-volatile silicones (e.g. cyclomethicone), clays (e.g. bentonites), adhesives, uve bulking agents, flavors, sweeteners, adsorbents, fillers (e.g. water, saline, electrolyte solutions), binders (e.g.
  • starches such as corn starch, wheat starch, rice starch or potato starch, gelatin, tragacanth, methyl cellulose , hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, polyvinyl pyrrolidone, sugars, polymers, gum arabic), disintegrating agents (e.g. starches, such as corn starch, wheat starch, rice starch, potato starch hop or carboxymethyl starch, structured polyvinylpyrrolidone, agar, alginic acid or a salt thereof, such as sodium alginate, croscarmellose sodium or crospovidone), lubricants (e.g.
  • the pharmaceutical composition of the invention comprises at least one non-aqueous pharmaceutically acceptable solvent and an antitumor compound having a solubility therein of at least about 10-60 mg / ml.
  • the solubility of the antitumor compound in dimethyl sulfoxide can be directly related to its effectiveness. It is also preferred that the antitumor compound has an ID 10O value (i.e. the concentration of the drug, causing 100% inhibition of colony formation) is at least 4 times lower than cisplatin when measured in accordance with the procedure described in the book ((Experimental Evaluation of Antitumor Drugs in the USSR and the USA), ed. Z. P. Sof'ina, A. B. Syrkin (USSR), A. Goldin, A. Klein (USA) M .: "Medicine", 1979, p. 71-105.
  • ID 10O value i.e. the concentration of the drug, causing 100% inhibition of colony formation
  • the administration of the dosage form in the indicated ways can be continuous or periodic, depending, for example, on the physiological state of the patients, on whether the purpose of the administration is therapeutic or prophylactic, and other factors known or evaluated by the practitioner.
  • the dose and route of administration of the pharmaceutical compositions of the invention can be easily determined by an oncologist. It is understood that the dose of antitumor compounds depends on the age, gender, health status and weight of the recipient, the type of treatment being carried out simultaneously, if any, the frequency of treatment and the nature of the desired effect. For any route of administration, the exact amount of the antitumor compound used, as well as the prescribed dose necessary to achieve the beneficial effects described here, also depends, in particular, on factors such as the bioavailability of the antitumor compound, the human disease being treated, the desired therapeutic dose, and others factors that are obvious to the specialist.
  • concentration of the antitumor compound of the present invention in a liquid pharmaceutical composition is, most preferably, 50-100 ⁇ M. Relatively low concentrations are generally preferred, since the antitumor compound is most soluble at low concentrations.
  • Emulsions for parenteral administration can be prepared by dissolving the antitumor compound in any pharmaceutically acceptable solvent capable of dissolving the compound (e.g., DMSO, dichloromethane) to form a solution.
  • a pharmaceutically acceptable solvent capable of dissolving the compound (e.g., DMSO, dichloromethane)
  • To the solution with stirring, add the appropriate volume of the carrier, which is an emulsion, such as an emulsion Liposyn II or Lirosup III, to obtain a pharmaceutically acceptable emulsion for parenteral administration to a patient.
  • an emulsion such as an emulsion Liposyn II or Lirosup III
  • such emulsions can be prepared with or without a minimal amount of Cegorhor ® solution.
  • Solutions for parenteral administration can be prepared by dissolving the antitumor compound in any pharmaceutically acceptable solvent capable of dissolving the compound (e.g., DMSO) to form a solution.
  • DMSO a pharmaceutically acceptable solvent capable of dissolving the compound
  • To the solution with stirring, add the appropriate volume of the carrier, which is a proton-containing medium (saline solutions, sugars, water-soluble polymers, proteins, electrolyte solutions) for parenteral administration to the patient.
  • a proton-containing medium saline solutions, sugars, water-soluble polymers, proteins, electrolyte solutions
  • non-aqueous pharmaceutically acceptable polar solvents are usually used as a carrier, such as oils, alcohols, amides, esters, ethers, ketones, hydrocarbons and mixtures thereof, as well as water, saline solutions, dextrose solutions (e.g. DW5), electrolyte solutions, or any other proton, pharmaceutically acceptable medium.
  • a carrier such as oils, alcohols, amides, esters, ethers, ketones, hydrocarbons and mixtures thereof, as well as water, saline solutions, dextrose solutions (e.g. DW5), electrolyte solutions, or any other proton, pharmaceutically acceptable medium.
  • Suitable non-aqueous, pharmaceutically acceptable polar solvents include, but are not limited to, amides (e.g., dimethylacetamide (DMA), dimethylacetamide benzyl benzoate, dimethylformamide, N- ( ⁇ -hydroxyethyl) lactamide, N, N-dimethylacetamide, 2-pyldimetholidamide - pyrrolidinone or polyvinylpyrrolidone); esters (e.g., 1-methyl-2-pyrpolyldinone, 2-pyrpolyldinone, acetic acid esters such as monoacetin, diacetin and triacetin; aliphatic or aromatic esters such as ethyl caprylate or ethyl octanoate, alkyl oleate, benzyl benzoate, DMSO), glycerol esters such as mono-, di- or triglyceryl citrates or tartrates, ethyl benzoate,
  • sucrose, maltose, lactose and trehalose or an oligosaccharide or mixtures thereof with a fatty acid (s) with 4-22 carbon atoms (e.g. saturated fatty acids such as caprylic acid, capric acid , lauric acid, myristic acid, palmitic acid and stearic acid, and saturated fatty acids, such as palmitoleic acid, oleic acid, elaidic acid, erucic acid and linoleic acid)), or steroidal esters); alkyl, aryl or cyclic ethers with 2-30 carbon atoms (for example, diethyl ether, tetrahydrofuran, dimethyl isosorbite, diethylene glycol monoethyl ether); glycofurol (ether of polyethylene glycol and tetrahydrofurfuryl alcohol); ketones with 3-30 carbon atoms (e.g.
  • aliphatic, cycloaliphatic or aromatic hydrocarbons with 4-30 carbon atoms e.g. benzene, cyclohexane, dichloromethane, dioxolanes, hexane, n-decane, n-dodecane, n-hexane, sulfolane, tetramethylene sulfone, tetramethylene sulfoxide, toluene, dimethyl sulfoxide) tetramethylene sulfoxide); alkyl or aryl halides containing 1-30 carbon atoms and optionally more than one halogen atom as a substituent; dichloromethane; monoethanolamine; petroleum ether; trolamine; omega-3 polyunsaturated fatty acids (for example, alpha-linolenic acid, eicosapentaeno
  • a proton-containing medium such as water, saline solutions, water-soluble polymers, proteins, dextrose solutions (eg, DW5), solutions of electrolytes or alcohols from the PAA Labotor's catalog, p. 26, 2006, as a pharmaceutically acceptable carrier in the present invention.
  • compositions for example, are 0.2% solutions of dimethyl sulfoxide in RPMI 1640 nutrient medium with a tetranitrosyl binuclear complex of iron with thiophenol with a concentration of 50-100 ⁇ M dissolved in it.
  • a pharmaceutically acceptable carrier, RPMI 1640 nutrient medium can be replaced with saline, starch, and other carriers selected by one skilled in the art depending on the route of administration, the type of tumor disease, and the subject being treated.
  • kits for treating cancer which comprises: (1) a pharmaceutical composition comprising a tetranitrosyl binuclear complex of iron with a thiophenol of the formula [Fe 2 (SC 6 Hs) 2 (NO) 4 ], in a sealed package; and (2) auxiliaries.
  • the kit may contain the composition in the form of a single dosage form or in the form of multiple doses.
  • the kit may include forms for oral or parenteral administration.
  • the pharmaceutical composition in the kit can be placed in glass or polymer vials, ampoules, vials, metered dose cartridges for injectors, blisters, capsules, sachets with the composition, used respectively for oral or parenteral form.
  • Aids include reconstitution fluids a composition administered parenterally if it is presented in a kit in concentrated form, for example, in the form of a dry substance, a dried preparation, and the like; Means for the preparation of oral liquid forms and forms for injection ex-troter. Water for injection, physiological saline, lidocaine solution, etc., can be used as a recovery fluid. To restore the composition used in liquid form orally, a solution of glucose, sugars, syrups, etc. can be used.
  • Optional kit aids include openings for closures, means for sealing opened reusable closures, instruction inserts.
  • the pharmaceutical composition which is a solid dosage form for oral administration, can be presented in a kit in the form of tablets, capsules in blisters, ampoules, vials, vials, sachets, and the like.
  • the pharmaceutical composition which is a liquid dosage form for parenteral or oral administration, may be presented in a kit in bottles, capsules, ampoules, cartridges, and the like.
  • kits for parenteral administration includes a package that contains instructions for use, ampoules or vials with a dry composition and ampoules with saline for injection. A device for opening ampoules is inserted into the package. Ampoules are packed in blisters of 10 ampoules.
  • the structure of the obtained iron complex was studied by the following methods. Elemental analysis for Fe 2 S 2 C 12 H 10 N 4 O 4 . Found,%: Fe 24.82; S 14.20; N
  • the IR spectrum of the sample was recorded on a SPECTRUM BX-II Fourier spectrometer.
  • a sample was prepared in the form of tablets with KBr (1 mg of the analyte per 300 mg of KBr).
  • IR spectrum (cm "1 ): 1778, 1763, 1723, 1583, 1478, 1441, 1303, 1181, 1118, 1092, 1071, 1024, 999, 916, 834, 734, 694, 688.
  • the Mössbauer absorption spectra were recorded on a WissEl setup operating in a constant acceleration mode. Co 57 in the Rh matrix served as a source. Spectra were measured at low temperatures using a flow-controlled helium cryostat CF-506 (Oxford Ipstumepts) with a controlled temperature. The Mössbauer spectra were processed using the least squares method under the assumption of the Lorentzian shape of individual spectral components. Parameters of NGR spectroscopy:
  • the following human tumor cell lines were used for the study: SKO V3 ovarian carcinoma, K562 myeloid leukemia, MCF7 breast carcinoma, A549 non-small cell lung cancer.
  • Cells were grown in a monolayer in RPMI 1640 medium containing 10% fetal calf serum at 37 ° C and 5% CO 2 .
  • cells were seeded in 96-well plates and grown under the same conditions.
  • the compound was dissolved in 200 ⁇ l of DMSO, and then adjusted to the desired concentration with RPMI 1640 nutrient medium.
  • the final concentration of DMSO in the samples did not exceed 0.2% and did not affect cell growth.
  • the cytotoxic effect was tested using the MTT test based on the ability of living cell dehydrogenase to restore the unpainted tetrazolium salt into blue formazan crystals soluble in dimethyl sulfoxide (DMSO).
  • DMSO dimethyl sulfoxide
  • the compound was added to the wells in a volume of 20 ⁇ l at 4 final concentrations ( ⁇ M) of 100, 50, 25 and 10.
  • the total incubation volume was 200 ⁇ l.
  • Cells with the drug were incubated under the above conditions for 72 hours.
  • MTT reagent was added to the cells and incubated under the same conditions for 2 hours. Then, the formed crystals of formazan were dissolved in 100 ⁇ l of DMSO at 37 ° C for 20 minutes.
  • the optical absorption of DMSO solutions was measured on an optical counter for multi-well plates at a wavelength of 540 nm. The results were expressed as mean values for 4 parallel measurements as inhibition of cell growth in%: (1 - experiment / control) x 100. A compound was considered active if a concentration of 100 ⁇ M in one of the 3 cell lines caused growth inhibition by 50 % or more (IRso ⁇ 100 ⁇ M). The measurement error did not exceed 5%.
  • cisplatin cis-DDP
  • carmustine bischlorethylnitrosourea
  • the nitrosyl complex of iron with thiophenol showed cytotoxic activity on all cell lines (table 1).
  • the most resistant to the action of the studied complex was the cell line of lung cancer A549 and ovarian carcinoma SCO V3.
  • the complex [Fe 2 (SC 6 Hs) 2 (NO) 4 ] exerts a cytotoxic effect on human tumor cells of various origins: myeloid leukemia K562, breast carcinoma MCF7, non-small cell lung cancer A549 and ovarian carcinoma SKVZ.
  • mice were carried out on transplantable tumors of mice on Ca-755 and melanoma B-16 (on first-generation hybrid mice BDFi (Cs 7 Bl / 6 x DBA / 2 ) and DBA / 2 weighing 18–25 g obtained from the laboratory animal department of the State Research Center for NN Blokhin RAMS).
  • a moderate statistically significant antitumor effect of the claimed preparation was revealed in doses of 10-75 mg / kg with daily intraperitoneal administration for 5 days.

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Abstract

La présente invention concerne l'utilisation d'un complexe fer-tétranitrosyle avec du thiophénol représenté par la formule [Fe2(SC6H5)2(NO)4] comme médicament antitumoral pour produire un médicament servant au traitement de maladies oncologiques. Cette invention concerne également une composition pharmaceutique et une trousse contenant ce complexe.
PCT/RU2007/000285 2007-05-30 2007-05-30 Utilisation d'un complexe fer-tétranitrosyle avec du thiophénol comme médicament antitumoral Ceased WO2008147242A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
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RU2437667C1 (ru) * 2010-04-05 2011-12-27 Учреждение Российской Академии Наук Институт Проблем Химической Физики Ран (Ипхф Ран) Применение биядерного сера-нитрозильного комплекса железа анионного типа в качестве вазодилататорного лекарственного средства
RU2460531C2 (ru) * 2010-04-05 2012-09-10 Учреждение Российской Академии Наук Институт Проблем Химической Физики Ран (Ипхф Ран) Применение биядерного сера-нитрозильного комплекса железа катионного типа в качестве вазодилататорного лекарственного средства

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Publication number Priority date Publication date Assignee Title
RU2437667C1 (ru) * 2010-04-05 2011-12-27 Учреждение Российской Академии Наук Институт Проблем Химической Физики Ран (Ипхф Ран) Применение биядерного сера-нитрозильного комплекса железа анионного типа в качестве вазодилататорного лекарственного средства
RU2460531C2 (ru) * 2010-04-05 2012-09-10 Учреждение Российской Академии Наук Институт Проблем Химической Физики Ран (Ипхф Ран) Применение биядерного сера-нитрозильного комплекса железа катионного типа в качестве вазодилататорного лекарственного средства

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