WO2018024172A1 - Complexes de platine et leurs procédés d'utilisation - Google Patents

Complexes de platine et leurs procédés d'utilisation Download PDF

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WO2018024172A1
WO2018024172A1 PCT/CN2017/095150 CN2017095150W WO2018024172A1 WO 2018024172 A1 WO2018024172 A1 WO 2018024172A1 CN 2017095150 W CN2017095150 W CN 2017095150W WO 2018024172 A1 WO2018024172 A1 WO 2018024172A1
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optionally substituted
group
platinum
complex
complexes
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Chi Ming Che
Di HU
Lai Fung CHAN
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University of Hong Kong
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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
    • C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/001—Preparation for luminescence or biological staining
    • A61K49/0013—Luminescence
    • A61K49/0017—Fluorescence in vivo
    • A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
    • A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
    • 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
    • C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
    • C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
    • C07F15/0086—Platinum compounds
    • C07F15/0093—Platinum compounds without a metal-carbon linkage
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2500/00—Screening for compounds of potential therapeutic value
    • G01N2500/10—Screening for compounds of potential therapeutic value involving cells

Definitions

  • platinum (II) complexes More particularly, the platinum (II) complexes can include emissive 1- (3-hydroxybenzo [b] thiophen-2-yl) ethanone ligands. Also disclosed are methods for using the platinum (II) complexes in the treatment of cancer and in the monitoring of cells.
  • Cisplatin cis-diamminedichlorophlatinum
  • platinum (II) complexes used in the treatment of cancer. It is one of the more effective anti-cancer drugs; however, cisplatin can have drawbacks. For example, patients can show drug resistance or can have serious side-effects.
  • Carboplatin cis-diammine (1, 1-cyclobutanedicarboxylato) platinum
  • Carboplatin is another anti-cancer drug in the family of platinum (II) complexes.
  • Carboplatin has an amine non-leaving ligand like cisplatin, but has a different leaving ligand.
  • platinum (II) complexes and methods for use thereof.
  • the platinum (II) complexes can include complexes of a Formula I,
  • R 1 and R 2 are independently selected from the group consisting of an amine, an optionally substituted amine, and an optionally substituted heterocyclic amine; or the pair of R 1 and R 2 are joined together to form a bidentate ligand containing nitrogen atoms;
  • R 3 is selected from the group consisting of H, alkyl optionally substituted, aryl optionally substituted, thienyl optionally substituted, and polyethylene glycol;
  • R 4 , R 5 , R 6 , and R 7 are independently selected from the group consisting of H, halide, –OR, alkyl optionally substituted and polyethylene glycol, or each pair of R 4 and R 5 , R 5 and R 6 , R 6 and R 7 is joined together to form
  • Y is selected from a group consisting of a sulfur atom, oxygen atom, and NR (wherein R is selected from the group consisting of H and alkyl optionally substituted) ; Z is selected from a group consisting of a carbon atom and a nitrogen atom; and X is selected from a group consisting of fluoride, chloride, bromide, iodide, trifluoromethanesulfonate, acetate, nitrate, perchlorate, hexafluorophosphate, sulfate and phosphate.
  • the method for treating a subject having cancer can include administering a therapeutically effective amount of at least one platinum (II) complex of Formula I.
  • the method of monitoring cells can include administering an effective amount of at least one platinum (II) complex of Formula I, and detecting a fluorescence signal of the platinum (II) complex.
  • FIG. 1 shows chemical structures of non-limiting examples of platinum (II) complexes containing the 1- (3-hydroxybenzo [b] thiophen-2-yl) ethanone (Hbt) ligand, according to some embodiments.
  • FIG. 1a shows chemical structures of platinum (II) complexes containing the Hbt ligand as a labile leaving group.
  • FIG. 2 shows the synthetic method for preparing the Hbt ligand, and non-limiting examples of synthetic methods for preparing platinum (II) complexes, according to some embodiments.
  • FIG. 2a shows in vivo tumor growth inhibition effects of 1a, 2a and 3a, examined using nude mice bearing NCI-H460 xenografts through intravenous injection.
  • B Body weight ofnude mice in the 1a, 2a, 3a treatment groups and solvent control group.
  • C Representative photographs of tumors obtained from nude mice in the 1a, 2a, 3a treatment groups and solvent control group.
  • FIG. 3 shows UV-visible absorption spectra of some exemplary platinum (II) complexes and the Hbt ligand in PBS solutions, according to some embodiments.
  • FIG. 3a shows body weight of nude mice in cispaltin (1mg/kg and 3 mg/kg) and complex 1a (10 mg/kg and 20 mg/kg) treatment groups.
  • the mice treated with cispaltin at 3 mg/kg lost total body weight by more than 10%.
  • the mice treated with 1a at 20 mg/kg had consistant body weight and non signs of noticebale adverse effects were observed.
  • FIG. 4 shows the emission spectra of some exemplary platinum (II) complexes and the Hbt ligand in CH 2 Cl 2 , according to some embodiments.
  • FIG. 4a shows a series of platinum (II) complexes containing different substituted Hbt ligand.
  • FIG. 5 shows a) the UV-visible absorption spectra of some exemplary platinum (II) complexes in PBS solutions at different time intervals, and b) the UV-visible absorption spectra of some exemplary platinum (II) complexes in the presence of GSH in PBS solutions at different time intervals, according to some embodiments.
  • FIG. 6 shows the emission spectra of some exemplary platinum (II) complexes in the presence of GSH in PBS solutions, according to some embodiments.
  • a) emission spectra of complexes 1 and 2 in the presence of GSH were recorded at different time points with the excitation wavelength at ⁇ ex 381 nm.
  • FIG. 7 shows a) the emission spectra of some exemplary platinum (II) complexes in the presence of ctDNA at different molar ratios. b) the emission intensity enrichment of some exemplary platinum (II) complexes by ctDNA.
  • FIG. 8 shows luminescence imaging of some exemplary platinum (II) complexes and the Hbt ligand inside cells, according to some embodiments.
  • FIG. 9 shows luminesce imaging time-series of some exemplary platinum (II) complexes inside live cells, according to some embodiments.
  • FIG. 10 shows cellular uptake and DNA binding fractions of some exemplary platinum (II) complexes and oxaliplatin in cells, according to some embodiments.
  • FIG. 11 shows a) average tumor volumes of nude mice bearing HeLa xenografts after treatment with some exemplary platinum (II) complexes or solvent though intraperitoneal injection. b) body weight of nude mice bearing HeLa xenografts in the platinum (II) complex treatment groups and solvent control group, according to some embodiments.
  • FIG. 12 shows a) representative photographs of tumors obtained from nude mice in the platinum (II) complex treatment groups and solvent control group. b) representative photographs of nude mice in the platinum (II) complex treatment groups and solvent control group, according to some embodiments.
  • alkyl refers to a linear, branched, or cyclic saturated hydrocarbon group typically although not necessarily containing 1 to about 20 carbon atoms, preferably 1 to about 12 carbon atoms, 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, octyl, decyl, and the like, as well as cycloalkyl groups such as cyclopentyl, cyclohexyl and the like.
  • cycloalkyl intends a cyclic alkyl group, typically having 4 to 8, preferably 5 to 7, carbon atoms.
  • substituted alkyl refers to alkyl substituted with one or more substituent groups
  • heteroatom-containing alkyl and “heteroalkyl” refer to alkyl in which at least one carbon atom is replaced with a heteroatom. If not otherwise indicated, the term “alkyl” includes linear, branched, cyclic, unsubstituted, substituted, and/or heteroatom-containing alkyl.
  • bidentate ligand containing nitrogen atoms refers to bidentate ligand containing 10-to 64-, preferably a 10-to 48-or 10-to 36-, membered heterocyclic molecules, which consists of carbon atoms and from one to six, preferably 1, 2, 3, 4 or 5, heteroatoms selected from the group consisting of nitrogen, oxygen, and sulphur where such heterocyclic molecules contain at least one nitrogen atoms.
  • heterocyclic molecules comprise but are not limited to pyrazole, triazole, tetrazole, pyridine, pyrazine, azepine, benzimidazole, benzothiazole, isothiazole, imidazole, indole, piperidine, piperazine, purine, quinoline, thiadiazole, oxazoline, isoxazoline, thiazoline, morpholine, bipyridine, bipyrazine, terpyridine, phenanthroline, bathophenanthroline, bisoxazoline, bisthiazoline, bisquinoline, bisisoquinoline, quinolinylpyridine, quinolinylphenanthroline and the like.
  • heterocyclic in the context of the invention refers to a stable 5-to 32-, preferably a 5-to 24-or 5-to 18-, membered heterocyclic group, which consists of carbon atoms and from one to six, preferably 1, 2 or 3, heteroatoms selected from the group consisting of nitrogen, oxygen, and sulphur.
  • 5-to 32-membered heterocyclic group as used herein means a heterocyclic radical having a skeleton of from 5 to 32 atoms.
  • the heterocycle may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include bonded or fused ring systems; and the heterocyclyl radical may be partially or fully saturated or aromatic (heteroaryl) .
  • heterocyclic groups include, but are not limited to pyrazole, triazole, tetrazole, pyridine, pyrazine, azepine, benzimidazole, benzothiazole, isothiazole, imidazole, indole, piperidine, piperazine, purine, quinoline, thiadiazole, oxazoline, isoxazoline, thiazoline, morpholine, bipyridine, bipyrazine, terpyridine, phenanthroline, bathophenanthroline, bisoxazoline, bisthiazoline, bisquinoline, bisisoquinoline, quinolinylpyridine, quinolinylphenanthroline and the like.
  • These heterocyclic ligands may be optionally substituted.
  • alkenyl and alkynyl refer to linear or branched hydrocarbon chain radical having one or more carbon-carbon double bonds or one or more carbon-carbon triple bonds, respectively, and having from two to twelve carbon atoms, and which are attached to the rest of the molecule by a single bond.
  • the alkenyl or the alkynyl has two to eight, two to six, two or three carbon atoms.
  • the double bond of an alkenyl or the triple bond of an alkynyl group can be unconjugated or conjugated to another unsaturated group.
  • Suitable alkenyl groups include, but are not limited to alkenyl groups such as vinyl, allyl, butenyl, butadienyl, or pentadienyl.
  • Suitable alkynyl groups include, but are not limited to alkynyl groups such as-CCH, -CH 2 CCH, -CCCH 3 , -CH 2 CCCH 3 .
  • aryl refers to an aromatic group having between 6 and 24, preferably between 6 and 18, more preferably between 6 and 16, even more preferably between 6 and 10 carbon atoms, comprising 1, 2, 3 or 4 aromaticrings, bound by means of a carbon-carbon bond or fused, including for example and in a non-limiting sense, phenyl, naphthyl, diphenyl, indenyl, anthryl, phenanthryl, pyrenyl, etc.
  • aryl refers to phenyl.
  • halogen refers to bromo, chloro, iodo or fluoro.
  • the above mentioned groups may be optionally substituted at one or more available positions by one or more suitable groups such as OR', O - , SR', SOR', SO 2 R', OSO 2 R', SO 3 R', SO 3 - , NO 2 , N (R') 2 , N (R') 3 + , N (R') COR', N (R') SO 2 R', CN, halogen, COR', CO 2 R', CO 2 - , OCOR', OCO 2 R', OCONHR', OCON (R') 2 , CONHR', CON (R') 2 , substituted or unsubstituted C 1 -C 18 alkyl, substituted or unsubstituted C 2 -C 12 alkenyl, substituted or unsubstituted C 2 -C 12 alkynyl, substituted or unsubstituted aryl, and substituted or unsubstituted heterocyclic group, wherein each of the
  • platinum (II) complexes can include, but are not limited to, complexes of Formula I:
  • R 1 and R 2 are independently selected from the group consisting of an amine, such as–NH 3 , an optionally substituted amine, and an optionally substituted heterocyclic amine; or the pair of R 1 and R 2 are joined together to form a bidentate ligand containing nitrogen atoms;
  • R 3 is selected from the group consisting of H, alkyl optionally substituted, aryl optionally substituted, thienyl optionally substituted, and polyethylene glycol;
  • R 4 , R 5 , R 6 , and R 7 are independently selected from the group consisting of H, halide, –OR, alkyl optionally substituted and polyethylene glycol, or each pair of R 4 and R 5 , R 5 and R 6 , R 6 and R 7 is joined together to form
  • Y is selected from a group consisting of a sulfur atom, oxygen atom, and–NR, wherein R is selected from the group consisting of H and alkyl optionally substituted;
  • Z is selected from a group consisting of a carbon atom and a nitrogen atom
  • X is a counter-ion that can include, but is not limited to: halogens ions, including fluoride, chloride, bromide and iodide; trifluoromethanesulfonate; acetate; nitrate; perchlorate; hexafluorophosphate; sulfate and phosphate.
  • halogens ions including fluoride, chloride, bromide and iodide
  • trifluoromethanesulfonate acetate; nitrate; perchlorate; hexafluorophosphate; sulfate and phosphate.
  • the platinum (II) complexes can include, but are not limited to, complexes with a 1- (3-hydroxybenzo [b] thiophen-2-yl) ethanone (Hbt) ligand.
  • the 1- (3-hydroxybenzo [b] thiophen-2-yl) ethanone (Hbt) ligand can be fluorescent, and can be a suitable leaving group for luminescent platinum (II) complexes. Modification of substituents on the Hbt ligand can allow for the optimization of the anti-cancer activity of platinum (II) complexes, such as by regulating their lipophilicity and/or their reaction kinetics.
  • the platinum (II) complexes containing the Hbt ligand can display both anti-cancer activity and photoluminescent properties.
  • the 1- (3-hydroxybenzo [b] thiophen-2-yl) ethanone ligand can include, but are not limited, ligands of Formula II:
  • R 3 is selected from the group consisting of H, alkyl optionally substituted, aryl optionally substituted, thienyl optionally substituted and polyethylene glycol
  • R 4 , R 5 , R 6 and R 7 are independently selected from the group consisting of–H, halide, –OR, alkyl optionally substituted and polyethylene glycol, or each pair ofR 4 and R 5 ; R 5 and R 6 ; R 6 and R 7 is joined together to form and
  • Y is selected from a group consisting of a sulfur atom, oxygen atom, and NR, wherein R is selected from the group consisting of H and alkyl optionally substituted.
  • the 1- (3-Hydroxybenzo [b] thiophen-2-yl) ethanone ligand can form a single positively charged complex with the platinum (II) ion.
  • the platinum (II) complex can include, but is not limited to, a counter-anion to coordinate to the platinum (II) complex to balance the charge.
  • platinum (II) complexes can include, but are not limited, ligands of Formula III:
  • X is a counter-ion that can include, but is not limited to: halogens ions, such as fluoride, chloride, bromide and iodide, trifluoromethanesulfonate, acetate, nitrate, perchlorate, hexafluorophosphate, sulfate, and phosphate.
  • halogens ions such as fluoride, chloride, bromide and iodide
  • trifluoromethanesulfonate such as fluoride, chloride, bromide and iodide
  • trifluoromethanesulfonate such as fluoride, chloride, bromide and iodide
  • trifluoromethanesulfonate such as fluoride, chloride, bromide and iodide
  • trifluoromethanesulfonate such as fluoride, chloride, bromide and iodide
  • platinum (II) complexes can include, but are not limited to, complexes of Formula IV:
  • X is a counter-ion that can include, but is not limited to: halogens ions (including fluoride, chloride, bromide and iodide) , trifluoromethanesulfonate, acetate, nitrate, perchlorate, hexafluorophosphate, sulfate, and phosphate.
  • halogens ions including fluoride, chloride, bromide and iodide
  • trifluoromethanesulfonate acetate, nitrate, perchlorate, hexafluorophosphate, sulfate, and phosphate.
  • the method of treatment of a subject with cancer can include, but is not limited to, administering therapeutically effective amount of at least one platinum (II) complex of Formula I.
  • the method can induce cancer cell death and/or inhibit cellular proliferation in vitro and/or in vivo.
  • the platinum (II) complex can administered intravenously as short-term infusion in normal saline for treatment of solid malignancies.
  • the platinum (II) complexes can have similar therapeutic functioning to the cisplatin class of drugs.
  • one or more of the platinum (II) complexes can bind to DNA strands, which can cause the DNA strands to crosslink and ultimately result in apoptosis.
  • platinum (II) complexes including sterile aqueous solutions or dispersions or sterile powders comprising the platinum (II) complexes. These platinum (II) complexes are adapted for facile preparation of sterile injectable or infusible solutions or dispersions.
  • the dosage can be sterile, fluid and stable under the conditions of manufacture and storage.
  • the liquid carrier or vehicle can be a solvent or liquid dispersion medium comprising, for example, water, ethanol, a polyol, vegetable oil, nontoxic glyceryl esters and suitable mixtures thereof.
  • the method of treatment can be used for many kinds of cancer.
  • the method can be used for sarcomas, such as small cell lung cancer, squamous cell carcinoma of the head and neck and ovarian cancer; lymphomas; bladder cancer; testicular cancer; cervical cancer; and germ cell tumors.
  • the method of monitoring of cells can include administering at least one platinum (II) complex of Formula I, and detecting the fluorescence signals of the platinum (II) complex.
  • the monitoring can include, but is not limited to, monitoring the cellular distribution and/or structural changes of the platinum (II) complexes in live cells.
  • the structural changes of the platinum (II) complexes can include, but are not limited to, a release of the ligand 1- (3-hydroxybenzo [b] thiophen-2-yl) ethanone ligand from the platinum (II) complex.
  • the method of monitoring cells can include real-time monitoring.
  • the present application includes the following embodiments:
  • a platinum (II) complex comprising:
  • R 1 and R 2 are independently selected from the group consisting of an amine, an optionally substituted amine, and an optionally substituted heterocyclic amine; or the pair of R 1 and R 2 are joined together to form a bidentate ligand containing nitrogen atoms;
  • R 3 is selected from the group consisting of H, alkyl optionally substituted, aryl optionally substituted, thienyl optionally substituted, and polyethylene glycol;
  • R 4 , R 5 , R 6 , and R 7 are independently selected from the group consisting of H, halide, –OR, alkyl optionally substituted and polyethylene glycol, or each pair of R 4 and R 5 , R 5 and R 6 , R 6 and R 7 is joined together to form
  • Y is selected from a group consisting of a sulfur atom, oxygen atom, and NR (wherein R is selected from the group consisting of H and alkyl optionally substituted) ;
  • Z is selected from a group consisting of a carbon atom and a nitrogen atom
  • X is selected from a group consisting of fluoride, chloride, bromide, iodide, trifluoromethanesulfonate, acetate, nitrate, perchlorate, hexafluorophosphate, sulfate and phosphate.
  • Z is a carbon atom
  • R 1 and R 2 are independently selected from the group consisting of ammonia (-NH 3 ) , an optionally substituted amine, and an optionally substituted heterocyclic amine, or the pair of R 1 and R 2 is joined together to form a bidentate ligand containing nitrogen atom;
  • R 3 is selected from the group consisting of–H, alkyl optionally substituted, aryl optionally substituted, thienyl optionally substituted and polyethylene glycol;
  • R 4 , R 5 , R 6 and R 7 are independently selected from the group consisting of–H, halide, -OR, alkyl optionally substituted and polyethylene glycol, or each pair of R 4 and R 5 ; R 5 and R 6 ; R 6 and R 7 is joined together to form
  • Y is selected from a group consisting of a sulfur atom, oxygen atom, and NR (wherein R is selected from the group consisting of–H and alkyl optionally substituted) ;
  • X is selected from a group consisting of fluoride, chloride, bromide, iodide, trifluoromethanesulfonate, acetate, nitrate, perchlorate, hexafluorophosphate, sulfate and phosphate.
  • Y is a sulfur atom
  • Z is a carbon atom
  • R 1 and R 2 are independently selected from the group consisting of ammonia (-NH 3 ) , an optionally substituted amine, and an optionally substituted heterocyclic amine, or the pair of R 1 and R 2 is joined together to form a bidentate ligand containing nitrogen atom;
  • R 3 is selected from the group consisting of–H, alkyl optionally substituted, aryl optionally substituted, thienyl optionally substituted and polyethylene glycol;
  • R 4 , R 5 , R 6 and R 7 are independently selected from the group consisting of–H, halide, -OR, alkyl optionally substituted and polyethylene glycol, or each pair of R 4 and R 5 ; R 5 and R 6 ; R 6 and R 7 is joined together to form
  • X is selected from a group consisting of fluoride, chloride, bromide, iodide, trifluoromethanesulfonate, acetate, nitrate, perchlorate, hexafluorophosphate, sulfate and phosphate.
  • Y is a sulfur atom
  • Z is a nitrogen atom
  • R 1 and R 2 are independently selected from the group consisting of ammonia (-NH 3 ) , an optionally substituted amine, and an optionally substituted heterocyclic amine, or the pair of R 1 and R 2 is joined together to form a bidentate ligand containing nitrogen atom;
  • R 3 is selected from the group consisting of–H, alkyl optionally substituted, aryl optionally substituted, thienyl optionally substituted and polyethylene glycol;
  • R 5 , R 6 and R 7 are independently selected from the group consisting of–H, halide, -OR, alkyl optionally substituted and polyethylene glycol, or each pair of R 4 and R 5 ; R 5 and R 6 ; R 6 and R 7 is joined together to form
  • X is selected from a group consisting of fluoride, chloride, bromide, iodide, trifluoromethanesulfonate, acetate, nitrate, perchlorate, hexafluorophosphate, sulfate and phosphate.
  • Y is a sulfur atom
  • Z is a carbon atom
  • R 3 is—CH3
  • R 4 , R 5 , R 6 and R 7 are each H;
  • R 1 and R 2 are independently selected from the group consisting of ammonia (-NH 3 ) , an optionally substituted amine, and an optionally substituted heterocyclic amine, or the pair of R 1 and R 2 is joined together to form a bidentate ligand containing nitrogen atom; and
  • X is selected from a group consisting of fluoride, chloride, bromide, iodide, trifluoromethanesulfonate, acetate, nitrate, perchlorate, hexafluorophosphate, sulfate and phosphate.
  • Y is a sulfur atom
  • Z is a nitrogen atom
  • R 3 is–CH 3 ;
  • R 5 , R 6 and R 7 are each–H;
  • R 1 and R 2 are independently selected from the group consisting of ammonia (-NH 3 ) , an optionally substituted amine, and an optionally substituted heterocyclic amine, or the pair of R 1 and R 2 is joined together to form a bidentate ligand containing nitrogen atom; and
  • X is selected from a group consisting of fluoride, chloride, bromide, iodide, trifluoromethanesulfonate, acetate, nitrate, perchlorate, hexafluorophosphate, sulfate and phosphate.
  • Y is a sulfur atom
  • Z is a carbon atom
  • R 1 and R 2 are joined together to form (1R, 2R) -1, 2-cyclohexanediamine;
  • R 3 is–CH 3 ;
  • R 4 , R 5 , R 6 and R 7 are each–H;
  • X is selected from a group consisting of fluoride, chloride, bromide, iodide, trifluoromethanesulfonate, acetate, nitrate, perchlorate, hexafluorophosphate, sulfate and phosphate.
  • Y is a sulfur atom
  • Z is a carbon atom
  • R 1 and R 2 are each–NH 3 ;
  • R 3 is–CH 3 ;
  • R 4 , R 5 , R 6 and R 7 are each–H;
  • X is selected from a group consisting of fluoride, chloride, bromide, iodide, trifluoromethanesulfonate, acetate, nitrate, perchlorate, hexafluorophosphate, sulfate and phosphate.
  • Y is a sulfur atom
  • Z is a carbon atom
  • R 1 and R 2 are joined together to form 2, 2’-bipyridine
  • R 3 is–CH 3 ;
  • R 4 , R 5 , R 6 and R 7 are each–H;
  • X is selected from a group consisting of fluoride, chloride, bromide, iodide, trifluoromethanesulfonate, acetate, nitrate, perchlorate, hexafluorophosphate, sulfate and phosphate.
  • a method for treating a subject having a cancer comprising:
  • R 1 and R 2 are independently selected from the group consisting of an amine, an optionally substituted amine, and an optionally substituted heterocyclic amine; or the pair of R 1 and R 2 are joined together to form a bidentate ligand containing nitrogen atoms,
  • R 3 is selected from the group consisting of H, alkyl optionally substituted, aryl optionally substituted, thienyl optionally substituted, and polyethylene glycol;
  • R 4 , R 5 , R 6 , and R 7 are independently selected from the group consisting of H, halide, –OR, alkyl optionally substituted and polyethylene glycol, or each pair of R 4 and R 5 , R 5 and R 6 , R 6 and R 7 is joined together to form
  • Y is selected from a group consisting of a sulfur atom, oxygen atom, and NR (wherein R is selected from the group consisting of H and alkyl optionally substituted) ;
  • Z is selected from a group consisting of a carbon atom and a nitrogen atom
  • X is selected from a group consisting of fluoride, chloride, bromide, iodide, trifluoromethanesulfonate, acetate, nitrate, perchlorate, hexafluorophosphate, sulfate and phosphate.
  • Z is a carbon atom
  • R 1 and R 2 are independently selected from the group consisting of ammonia (-NH 3 ) , an optionally substituted amine, and an optionally substituted heterocyclic amine, or the pair of R 1 and R 2 is joined together to form a bidentate ligand containing nitrogen atom;
  • R 3 is selected from the group consisting of–H, alkyl optionally substituted, aryl optionally substituted, thienyl optionally substituted and polyethylene glycol;
  • R 4 , R 5 , R 6 and R 7 are independently selected from the group consisting of–H, halide, -OR, alkyl optionally substituted and polyethylene glycol, or each pair of R 4 and R 5 ; R 5 and R 6 ; R 6 and R 7 is joined together to form
  • Y is selected from a group consisting of a sulfur atom, oxygen atom, and NR (wherein R is selected from the group consisting of–H and alkyl optionally substituted) ;
  • X is selected from a group consisting of fluoride, chloride, bromide, iodide, trifluoromethanesulfonate, acetate, nitrate, perchlorate, hexafluorophosphate, sulfate and phosphate.
  • Y is a sulfur atom
  • Z is a carbon atom
  • R 1 and R 2 are independently selected from the group consisting of ammonia (-NH 3 ) , an optionally substituted amine, and an optionally substituted heterocyclic amine, or the pair of R 1 and R 2 is joined together to form a bidentate ligand containing nitrogen atom;
  • R 3 is selected from the group consisting of H, alkyl optionally substituted, aryl optionally substituted, thienyl optionally substituted and polyethylene glycol;
  • R 4 , R 5 , R 6 and R 7 are independently selected from the group consisting of H, halide, –OR, alkyl optionally substituted and polyethylene glycol, or each pair of R 4 and R 5 ; R 5 and R 6 ; R 6 and R 7 is joined together to form
  • X is selected from a group consisting of fluoride, chloride, bromide, iodide, trifluoromethanesulfonate, acetate, nitrate, perchlorate, hexafluorophosphate, sulfate and phosphate.
  • Y is a sulfur atom
  • Z is a nitrogen atom
  • R 1 and R 2 are independently selected from the group consisting of ammonia (-NH 3 ) , an optionally substituted amine, and an optionally substituted heterocyclic amine, or the pair of R 1 and R 2 is joined together to form a bidentate ligand containing nitrogen atom;
  • R 3 is selected from the group consisting of–H, alkyl optionally substituted, aryl optionally substituted, thienyl optionally substituted and polyethylene glycol;
  • R 5 , R 6 and R 7 are independently selected from the group consisting of–H, halide, -OR, alkyl optionally substituted and polyethylene glycol, or each pair of R 4 and R 5 ; R 5 and R 6 ; R 6 and R 7 is joined together to form
  • X is selected from a group consisting of fluoride, chloride, bromide, iodide, trifluoromethanesulfonate, acetate, nitrate, perchlorate, hexafluorophosphate, sulfate and phosphate.
  • Y is a sulfur atom
  • Z is a carbon atom
  • R 3 is—CH3
  • R 4 , R 5 , R 6 and R 7 are each–H;
  • R 1 and R 2 are independently selected from the group consisting of ammonia (-NH 3 ) , an optionally substituted amine, and an optionally substituted heterocyclic amine, or the pair of R 1 and R 2 is joined together to form a bidentate ligand containing nitrogen atom; and
  • X is selected from a group consisting of fluoride, chloride, bromide, iodide, trifluoromethanesulfonate, acetate, nitrate, perchlorate, hexafluorophosphate, sulfate and phosphate.
  • Y is a sulfur atom
  • Z is a nitrogen atom
  • R 3 is–CH 3 ;
  • R 5 , R 6 and R 7 are each–H;
  • R 1 and R 2 are independently selected from the group consisting of ammonia (-NH 3 ) , an optionally substituted amine, and an optionally substituted heterocyclic amine, or the pair of R 1 and R 2 is joined together to form a bidentate ligand containing nitrogen atom; and
  • X is selected from a group consisting of fluoride, chloride, bromide, iodide, trifluoromethanesulfonate, acetate, nitrate, perchlorate, hexafluorophosphate, sulfate and phosphate.
  • Y is a sulfur atom
  • Z is a carbon atom
  • R 1 and R 2 are joined together to form (1R, 2R) -1, 2-cyclohexanediamine;
  • R 3 is–CH 3 ;
  • R 4 , R 5 , R 6 and R 7 are each–H;
  • X is selected from a group consisting of fluoride, chloride, bromide, iodide, trifluoromethanesulfonate, acetate, nitrate, perchlorate, hexafluorophosphate, sulfate and phosphate.
  • a method of monitoring cells comprising:
  • R 1 and R 2 are independently selected from the group consisting of an amine, an optionally substituted amine, and an optionally substituted heterocyclic amine; or the pair of R 1 and R 2 are joined together to form a bidentate ligand containing nitrogen atoms;
  • R 3 is selected from the group consisting of H, alkyl optionally substituted, aryl optionally substituted, thienyl optionally substituted, and polyethylene glycol;
  • R 4 , R 5 , R 6 , and R 7 are independently selected from the group consisting of H, halide, –OR, alkyl optionally substituted and polyethylene glycol, or each pair of R 4 and R 5 , R 5 and R 6 , R 6 and R 7 is joined together to form
  • Y is selected from a group consisting of a sulfur atom, oxygen atom, and NR (wherein R is selected from the group consisting of H and alkyl optionally substituted) ; Z is selected from a group consisting of a carbon atom and a nitrogen atom; and
  • X is selected from a group consisting of fluoride, chloride, bromide, iodide, trifluoromethanesulfonate, acetate, nitrate, perchlorate, hexafluorophosphate, sulfate and phosphate; and
  • the present invention further comprises the embodiment of the platinum (II) complex according to the present invention, wherein the bidentate ligand containing nitrogen atoms comprises bidentate ligand containing 10-to 64-membered heterocyclic molecules, which consists of carbon atoms and from one to six heteroatoms selected from the group consisting of nitrogen, oxygen, and sulphur, where such heterocyclic molecules contain at least one nitrogen atoms.
  • the bidentate ligand containing nitrogen atoms comprises bidentate ligand containing 10-to 64-membered heterocyclic molecules, which consists of carbon atoms and from one to six heteroatoms selected from the group consisting of nitrogen, oxygen, and sulphur, where such heterocyclic molecules contain at least one nitrogen atoms.
  • the present invention further comprises the embodiment of the use of the platinum (II) complex according to the present invention in the manufacture of medicament for treating a subject having a cancer.
  • the present invention further comprises the embodiment of the use of the platinum (II) complex according to the present invention in the manufacture of a compound for the method of monitoring cells according to the present invention.
  • Example 1 is the synthesis and characterization of non-limiting examples of the platinum (II) complexes containing the 1- (3-hydroxybenzo [b] thiophen-2-yl) ethanone (Hbt) ligand.
  • the Hbt ligand was prepared according to a reported procedure (Chan, Low et al. 2011) .
  • a complex Fe (acac) 3 (0.20 mmol) and 2-Thiosalicylic acid (0.20 mmol) were added to a round bottom flask with a stir bar, followed by addition of ethylene glycol (4 mL) . The mixture was heated under nitrogen atmosphere at 120°C for 4-24 h.
  • the synthesis of complex 1, was performed by adding cis- [PtI 2 (NH 3 ) 2 ] (245mg, 0.51mmol) to a solution of MeOH/H 2 O (20ml; Volumn: 1: 1) with AgNO 3 (170mg, 1.0mmol) in a 50 mL of two-neck flask. A yellow precipitate formed immediately. The reaction was stirring for 1h, then filtered through celite to remove yellow precipitate.
  • Synthesis of complex 2 was performed by adding (bpy) PtCl 2 (210 mg, 0.5 mmol) to a solution of MeOH/H 2 O (20 ml; Volumn: 1: 1) with AgOTf (257 mg, 1.0 mmol) in a 50 mL of two-neck flask. A white precipitate formed immediately. The reaction was stirring for 1 h, and then filtered through celite to remove precipitate.
  • Example 1a Synthesis and characterization of additional platinum (II) complexes
  • Example 2 is the stability of non-limiting examples of the platinum (II) complexes containing the 1- (3-hydroxybenzo [b] thiophen-2-yl) ethanone ligand towards GSH in PBS solutions.
  • Complexes 1 and 2 were dissolved in DMSO/PBS solutions (1: 9, v/v) to give the complex at a final concentration of 20 ⁇ M, respectively.
  • the UV-visible absorption spectra were recorded at different time intervals.
  • Complexes 1 and 2 were separately incubated with GSH (final 2 mM) in DMSO/PBS solutions (1: 9, v/v) .
  • the UV-visible absorption spectra were recorded at different time intervals.
  • the rate of increase in emission intensity at 450 nm may be taken to correlate with release of the 1- (3-hydroxybenzo [b] thiophen-2-yl) ethanone ligand from the platinum (II) complexes.
  • Example3 Luminescence of platinum (II) complexes in the presence of ctDNA
  • Complexes 1 and 2 are weakly emissive in aqueous solution with ⁇ max at 600 nm for complex 1, and 580 nm for complex 2.
  • II luminescent platinum
  • the emission intensity of complexes 1 and 2 in the presence of DNA was examined. As depicted in FIG. 7, the emission intensity of complex 2 is increased by 3.1-fold upon addition of 0.5 equivalent of ctDNA and by 32-fold upon addition of 10 equivalents of ctDNA. In contrast, for complex 1, only 1.5-fold increase in emission intensity was found upon addition of 10 equivalents of ctDNA.
  • Example 4 Fluorescence imaging of platinum (II) complexes and the 1- (3- hydroxybenzo [b] thiophen-2-yl) ethanone ligand in live cells
  • Example 4 is the fluorescence imaging of non-limiting examples of the platinum (II) complexes and the 1- (3-hydroxybenzo [b] thiophen-2-yl) ethanone ligand in live cells.
  • the differences in photoluminescent properties of the platinum (II) complexes and the 1- (3-hydroxybenzo [b] thiophen-2-yl) ethanone ligand affords possibility to determine the fate of these complexes in vitro and even in vivo.
  • SW480 human colorectal carcinoma cells were seeded in a glass bottom dish (MatTek corporation) and allowed to grow for 24 h prior to treatment with 25 ⁇ M complexes 1, 2 or the 1- (3-hydroxybenzo [b] thiophen-2-yl) ethanone ligand for 30 min, respectively. After removing the medium, cells were washed with Hank’s balanced salt solution (HBSS) and then covered with 2 mL of HBSS. A Carl Zeiss LSM700 inverted confocal microscope with a Plan-Apochromat 40 ⁇ 1.40NA oil-immersion objective was used to capture the fluorescence and phase contrast images.
  • HBSS Hank’s balanced salt solution
  • a time series experiment was performed using a confocal microscope conjugated with a LCI TC-L stage-top incubator.
  • SW480 cells were seeded in a glass bottom dish (MatTek corporation) and allowed to grow for 24 h.
  • a solution of complex 2 (25 ⁇ M) in HBSS was prepared.
  • Cells were washed with HBSS, and then incubated with complex 2 (25 ⁇ M in HBSS) in the stage-top incubator containing 5%(v/v) CO 2 at 37°C.
  • a Carl Zeiss LSM700 inverted confocal microscope with a Plan-Apochromat 40 ⁇ 1.40NA oil-immersion objective was used to capture the fluorescence and phase contrast images.
  • Imaging was captured immediately after treatment with complex 2. For time series experiment, the interval time was set to 2.5 min and total 20 cycles were captured. Both complex 2 and the 1- (3-hydroxybenzo [b] thiophen-2-yl) ethanone ligand were excited using 405 nm laser. Emission over 580 nm was collected for complex 2, and emission within 400-500 nm was collected for the 1- (3-hydroxybenzo [b] thiophen-2-yl) ethanone ligand.
  • the photoluminescent properties of complexes 1, 2 and the 1- (3-hydroxybenzo [b] thiophen-2-yl) ethanone ligand allows real time tracking inside live cells. These include tracing subcellular localization, monitoring the structural changes as well as biotransformation pathways of these platinum (II) complexes under cellular conditions.
  • Example 5 In vitro cytotoxicity of platinum (II) complexes and the 1- (3- hydroxybenzo [b] thiophen-2-yl) ethanone ligand against cancer cells
  • Example 5 is the in vitro cytotoxicity of non-limiting examples of the platinum (II) complexes and the 1- (3-hydroxybenzo [b] thiophen-2-yl) ethanone ligand against various human cancer cell lines.
  • Non-limiting examples of human carcinoma include cervical epithelioid carcinoma, colorectal carcinoma, hepatocellular carcinoma, lung carcinoma and ovarian carcinoma.
  • the cytotoxicity of each complex was measured by plotting the dose-dependent cell viability curve and the concentration of complex decreasing cellular viability by 50%was determined as IC 50 value (Table 1) .
  • Complexes 1 and 2 can exhibit dose-and time-dependent cytotoxicity towards these cancer cell lines.
  • Complex 2 display higher anti-cancer potency and it is less cytotoxic towards the normal human fibroblast-like CCD-19Lu cells with an IC 50 value around 30 ⁇ M.
  • Complex 1 display comparable cytotoxicity to the reference complex cisplatin and it is less cytotoxic towards CCD-19Lu cells with an IC 50 value over 60 ⁇ M.
  • Complexes 1 and 2 are cytotoxic towards ovarian carcinoma cell lines and they displayed comparable IC 50 values towards both cisplatin-sensitive A2780 cells and cisplatin-resistant A2780 cis cells.
  • cisplatin and oxaliplatin display higher anti-cancer activity towards A2780 cells than A2780 cis cells, with IC 50 values that are 30-fold lower than that towards A2780 cis cells.
  • the Hbt ligand is not cytotoxic against cancer cells and normal cells with the IC 50 values larger than 100 ⁇ M.
  • Table 1 shows the in vitro cytotoxic IC 50 values of complexes 1 and 2, cisplatin, oxaliplatin and the Hbt ligand against human colorectal cancer cells (SW480 and HCT116) , human hepatocellular cancer cells (Hep G2) human non-small lung cancer cells (NCI-H460) , human cervical epithelioid cancer cells (HeLa) , human ovarian cancer cells (A2780) and its cisplatin-resistant variant (A2780 cis) , and normal human fibroblast-like cells (CCD-19Lu) , 72h.
  • Table 1a in vitro cytotoxic IC 50 values of complexes 1a, 2a, 3a and the Hbt ligand towards various human cancer cell lines and normal cell lines.
  • SW480 and HCT116 colorectal carcinoma
  • NCl-H460 non-small-cell lung carcinoma
  • Hep G2 hepatocellular carcinoma
  • HeLa cervical epithelioid carcinoma
  • NCM460 normal human colon mucosal epithelial cells
  • CCD-19Lu normal human fibroblast-like cells
  • Example 6 is the cellular uptake and nuclear DNA binding of non-limiting examples of platinum (II) complexes in cancer cells.
  • one exemplary human cancer cell line is colorectal SW480 cancer cell line.
  • the time-dependent cellular uptake of some exemplary platinum (II) complexes was determined by inductively coupled plasma-mass spectrometry (ICP-MS) .
  • SW480 cells were seeded in a 6-well plate with DMEM and allowed to grown for 24 h in a humidified 5%CO 2 (v/v) incubator at 37 °C. The culture medium was removed and replaced with medium containing 10 ⁇ M complexes 1 and 2 or oxaliplatin, respectively.
  • Cells were incubated with each complex for 0.5 h, 1 h, 2 h, 4 h and 8 h. At each time point, cells were harvested by trypsinisation, followed by resuspending in H 2 O and sonication to obtain a homogenous cell lysate. The protein concentrations were quantified using Bradford protein assay and cell lysates were digested in 68%HNO 3 at 60 °C for 2 h and then at room temperature, overnight.
  • the time-dependent binding of platinum to nuclear DNA was also determined by ICP-MS.
  • SW480 cells were incubated with 10 ⁇ M complexes 1 and 2 or oxaliplatin for 1 h, 2 h, 4 h and 8 h.
  • cells were harvested by trypsinisation, followed by resuspending in 300 ⁇ L lysing buffer (100 mM NaCl, 25 mM EDTA, 0.5% (w/v) SDS, 0.1 mg/mL proteinase K and 10 mM Tris-HCl, pH 8.0) and incubating at 50 °C, overnight.
  • 300 ⁇ L phenol: CHCl 3 mixture (1: 1, v/v) was added to the cell lysates.
  • the DNA was dissolved in TE buffer (1 mM EDTA and 10 mM Tris-HCl, pH 7.4) .
  • the DNA concentration was quantified by measuring the absorbance at 260 nm. DNA was digested in concentrated HNO 3 , overnight.
  • the digested cell lysates or digested DNA solutions were further diluted in H 2 O to make the final concentration of HNO 3 less than 5%.
  • Platinum contents were quantified with an ICP- MS by measuring the most abundant isotope of platinum at m/z 195 and corrected with respect to a calibration curve from a series of concentrations of platinum standards.
  • the cellular platinum uptake is expressed as ng platinum/mg protein and the binding of platinum to nuclear DNA is expressedas ng platinum/mg DNA.
  • FIG. 10 shows the intracellular uptake of platinum and Pt-DNA covalent binding fractions afterexposure of SW480 cells to complexes 1 and 2.
  • Complexes 1 and 2 accumulate in SW480 cells at higher levels than oxaliplatin, reflecting the favorable cellular uptake efficiency due to the lipophilic the Hbt ligand in these complexes.
  • Higher quantities of platinum are found to bind to nuclear DNA in the cases of complexes 1 and 2, which were about 7-fold higher than clinically used oxaliplatin after an 8 h incubation.
  • Example 7 is the in vivo tumor growth inhibition effects of non-limiting examples of platinum (II) complexes in nude mice bearing HeLa xenograft.
  • Female BALB/cAnN-nu (Nude) mice were purchased from the Charles River Laboratories (Wilmington, MA) . Mice were maintained according to the requirements of the Laboratory Animal Unit of the University of Hong Kong (HKU) and experiments were conducted based on the guidelines approved by the Committee on the Use of Live Animals in Teaching and Research of HKU.
  • HKU Laboratory Animal Unit of the University of Hong Kong
  • mice were randomly divided into the following three groups with four mice per group: solvent control, complex 1 (10 mg/kg) and complex 2 (2.5 mg/kg) .
  • Complex 1 was reconstituted inPET (60%polyethylene glycol 400, 30%ethanol and 10%Tween 80) to a final concentration of 20 ⁇ g/ ⁇ L
  • complex 2 was reconstituted in PET to a final concentration of 5 ⁇ g/ ⁇ L.
  • Complexes 1 and 2 in PET were then diluted in PBS and PBS containing the same amount ofPET was also prepared.
  • Complexes 1, 2 and solvent were separately injected into mice by intraperitoneal injections twice or thrice per weekuntilthe micewere sacrificed.
  • Tumor sizes were measured twice or thrice per week and the tumor volume (V) was calculated by the following equation:
  • a and b were the longest and the shortest diameters of the tumor, respectively.
  • V o was the initial tumor size of group of 1 or 2 treatment
  • V was the final tumor size of group 1 or 2 treatment
  • V′ 0 was the initial tumor size of group of solvent control
  • V′ was the final tumor size of group of solvent control.
  • an optional component in a system means that the component may be present or may not be present in the system.
  • Luminescent cyclometalated platinum (II) complex forms emissive intercalating adducts with double-stranded DNA and RNA: differential emissions and anticancer activities.

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Abstract

L'invention concerne des complexes de platine (II) qui peuvent comprendre des complexes de la formule, ou des sels pharmaceutiquement acceptables de ceux-ci, dans lesquels : R1 et R2 sont indépendamment choisis dans le groupe constitué par une amine, une amine éventuellement substituée et une amine hétérocyclique éventuellement substituée; ou la paire de R1 et R2 sont réunis pour former un ligand bidenté contenant des atomes d'azote; R3 est choisi dans le groupe constitué par un H, un alkyle éventuellement substitué, un aryle éventuellement substitué, un thiényle éventuellement substitué, et un polyéthylène glycol; R4, R5, R6, et R7 sont indépendamment choisis dans le groupe constitué par H, halogénure, -OR, alkyle éventuellement substitué et polyéthylène glycol, ou chaque paire de R4 et R5, R5 et R6, R6 et R7 sont réunis ensemble pour former Y est choisi dans un groupe constitué par un atome de soufre, un atome d'oxygène et NR (où R est choisi dans le groupe constitué par H et un alkyle éventuellement substitué); Z est choisi dans le groupe constitué par un atome de carbone et un atome d'azote; et X est choisi dans le groupe constitué par le fluorure, le chlorure, le bromure, l'iodure, le trifluorométhanesulfonate, l'acétate, le nitrate, le perchlorate, l'hexafluorophosphate, le sulfate et le phosphate. L'invention concerne également des procédés d'utilisation des complexes de platine (II) dans le traitement du cancer et dans la visualisation dans les cellules.
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021034405A1 (fr) * 2019-08-19 2021-02-25 Diverse Biotech, Inc. Agents antinéoplasiques complexes de platine comprenant un ligand cannabinoïde

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1197798A (zh) * 1997-04-30 1998-11-04 中国科学院大连化学物理研究所 新铂抗癌药物及合成
CN1680384A (zh) * 2004-04-08 2005-10-12 香港中文大学 去甲基斑蟊素铂配合物及其用途
WO2010087976A2 (fr) * 2009-01-31 2010-08-05 Igf Oncology, Llc Conjugués anticancéreux protéine-platine
WO2014165782A2 (fr) * 2013-04-05 2014-10-09 Massachusetts Institute Of Technology Compositions, méthodes et nécessaires impliquant des composés platine associés à un ligand comportant une fraction de ciblage

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SK16352000A3 (sk) * 1998-05-04 2002-07-02 Zentaris Ag Indolové deriváty, spôsob ich výroby, ich použitie na liečivá obsahujúce tieto zlúčeniny
FR2825278A1 (fr) * 2001-05-30 2002-12-06 Sod Conseils Rech Applic Produit comprenant du mikanolide, du dihydromikanolide ou un analogue de ceux-ci en association avec un autre agent anti-cancereux pour une utilisation therapeutique dans le traitement du cancer
CN101400661A (zh) * 2006-03-14 2009-04-01 马林克罗特公司 四氮杂大环衍生物的金属络合物

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1197798A (zh) * 1997-04-30 1998-11-04 中国科学院大连化学物理研究所 新铂抗癌药物及合成
CN1680384A (zh) * 2004-04-08 2005-10-12 香港中文大学 去甲基斑蟊素铂配合物及其用途
WO2010087976A2 (fr) * 2009-01-31 2010-08-05 Igf Oncology, Llc Conjugués anticancéreux protéine-platine
WO2014165782A2 (fr) * 2013-04-05 2014-10-09 Massachusetts Institute Of Technology Compositions, méthodes et nécessaires impliquant des composés platine associés à un ligand comportant une fraction de ciblage

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021034405A1 (fr) * 2019-08-19 2021-02-25 Diverse Biotech, Inc. Agents antinéoplasiques complexes de platine comprenant un ligand cannabinoïde
US12453711B2 (en) 2019-08-19 2025-10-28 Diverse Biotech, Inc. Platinum complex anti-neoplastic agents comprising a cannabinoid ligand

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