WO2003078386A1 - Derives de naphthyl(thio)semicarbazone et leur utilisation therapeutique - Google Patents

Derives de naphthyl(thio)semicarbazone et leur utilisation therapeutique Download PDF

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WO2003078386A1
WO2003078386A1 PCT/AU2003/000328 AU0300328W WO03078386A1 WO 2003078386 A1 WO2003078386 A1 WO 2003078386A1 AU 0300328 W AU0300328 W AU 0300328W WO 03078386 A1 WO03078386 A1 WO 03078386A1
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compound
formula
substituted
group
unsubstituted
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Des R. Richardson
David Benn Lovejoy
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Unisearch Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/88—Nicotinoylhydrazones
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
    • A61K31/175—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine having the group, >N—C(O)—N=N— or, e.g. carbonohydrazides, carbazones, semicarbazides, semicarbazones; Thioanalogues thereof
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • 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
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
    • C07C251/72—Hydrazones
    • C07C251/86—Hydrazones having doubly-bound carbon atoms of hydrazone groups bound to carbon atoms of six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C281/00—Derivatives of carbonic acid containing functional groups covered by groups C07C269/00 - C07C279/00 in which at least one nitrogen atom of these functional groups is further bound to another nitrogen atom not being part of a nitro or nitroso group
    • C07C281/06—Compounds containing any of the groups, e.g. semicarbazides
    • C07C281/08—Compounds containing any of the groups, e.g. semicarbazides the other nitrogen atom being further doubly-bound to a carbon atom, e.g. semicarbazones
    • C07C281/14—Compounds containing any of the groups, e.g. semicarbazides the other nitrogen atom being further doubly-bound to a carbon atom, e.g. semicarbazones the carbon atom being further bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C337/00—Derivatives of thiocarbonic acids containing functional groups covered by groups C07C333/00 or C07C335/00 in which at least one nitrogen atom of these functional groups is further bound to another nitrogen atom not being part of a nitro or nitroso group
    • C07C337/06—Compounds containing any of the groups, e.g. thiosemicarbazides
    • C07C337/08—Compounds containing any of the groups, e.g. thiosemicarbazides the other nitrogen atom being further doubly-bound to a carbon atom, e.g. thiosemicarbazones

Definitions

  • the present invention relates to novel naphthyl semicarbazone, naphthyl hydrazone, naphthyl thiosemicarbazone, and naphthyl thiohydrazone compounds.
  • the invention also relates to therapeutic uses of such compounds and/or their iron complexes.
  • the invention further relates to methods of treating diseases associated with cell proliferation, iron overload disorders, and diseases associated with microbial infection.
  • Iron is an indispensable requirement for the activity of many essential metabolic processes.
  • Fe-containing proteins catalyse key reactions involved in energy metabolism, respiration, and DNA synthesis (eg. ribonucleotide reductase (RR), is the rate-limiting step in DNA synthesis).
  • RR ribonucleotide reductase
  • Neoplastic cells have a high Fe requirement relative to normal cells due to their greater ribonucleotide reductase activity and higher rates of proliferation. This is reflected by an increase in the expression in neoplastic cells of the transferrin receptor (TfR), which binds the serum Fe-transport protein, transferrin (Tf).
  • TefR transferrin receptor
  • Neoplastic cells are more sensitive to perturbations in cellular iron concentrations and the role of Fe in cellular proliferation and ribonucleotide reductase activity, means Fe is an important therapeutic target.
  • Iron is also an essential component for the functioning or regulation of a number of plasmoidial enzymes, such as ribonucleotide reductase, delta aminovulinate synthetase, and dihydroorotate dehydrogenase.
  • ribonucleotide reductase ribonucleotide reductase
  • delta aminovulinate synthetase delta aminovulinate synthetase
  • dihydroorotate dehydrogenase iron chelating agents inhibit parasite growth and proliferation by depriving the intracellular parasites of this essential nutrient.
  • Desferrioxamine DFO
  • a key factor regarding the clinical use of Fe chelators for the treatment of cancer is their selectivity at inhibiting the growth of neoplastic compared to normal cells.
  • NB Neuroblastoma
  • DFO desferrioxamine
  • DFO is capable of a cytotoxic effect on NB cells in vitro while having little effect on other cell types.
  • DFO has also shown activity against leukemia cells both in vitro and in vivo .
  • DFO suffers from a number of serious problems that limit its therapeutic use.
  • DFO is extremely expensive, has poor membrane permeability, and is not orally available.
  • DFO requires long subcutaneous infusions (12-24 hours/day, 5-7 day/week) to produce significant iron excretion, resulting in poor patient compliance.
  • the short plasma half-life of DFO and its low efficacy at permeating cell membranes limits its anti-proliferative activity.
  • E is O or S
  • X is OH or SH
  • R 4 is selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, and substituted amino, wherein an R 4 substituent can be at any available position on the naphthyl ring; and n is 1, 2, 3, 4, 5 or 6;
  • R' is hydrogen or a group that does not prevent the compound chelating iron ions
  • R 8 is hydrogen or Ci ⁇ alkyl
  • Rj is N, or CR 5 , wherein the bond between C and R 5 may be a single, double or triple bond; and wherein when the bond between C and R 5 is a double bond, one of R 2 and R 3 is absent, and wherein when the bond between C and R 5 is a triple bond, R 2 and R 3 are both absent;
  • R 2 and R 3 are the same or different and are individually selected from the following: hydrogen, halogen, substituted or unsubstituted C 1-8 alkyl group, substituted or unsubstituted C 2-8 alkenyl group, substituted or unsubstituted C 2-8 alkynyl group, substituted or unsubstituted amino group, substituted or unsubstituted heterocyclic group eg, 5- or 6-membered heterocyclic group, substituted or unsubstituted bicyclic group, and substituted or unsubstituted aromatic group;
  • R 5 is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C 1-8 alkyl group, substituted or unsubstituted C 2-8 alkenyl group, substituted or unsubstituted C 2-8 alkynyl group, substituted or unsubstituted amino group, substituted or unsubstituted heterocyclic group, eg 5- or 6-membered heterocyclic group, substituted or unsubstituted bicyclic group, and substituted or unsubstituted aromatic group; or -G is a substituted or unsubstituted heterocyclic group, eg 5- or 6-membered heterocyclic group, a substituted or unsubstituted bicyclic group, a substituted or unsubstituted aromatic group, a substituted or unsubstituted C 1-8 alkyl group; or a C 3-8 substituted or unsubstituted cycloalkyl group; with the provisos that:
  • G is not -NH 2 , -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 2 CH 3 ,
  • the compound according to the first aspect of the invention is a compound of Formula 2:
  • E is O or S
  • R' and -G are as defined above, including the provisos.
  • the compound according to the first aspect of the invention is a compound of Formula 3:
  • the compound of Formula 1 is 2-hydroxy- l-naphthylaldehyde-4-methyl-3 -thiosemicarbazone (abbreviated N4mT), 2-hydroxy-l- naphthylaldehyde-4-allyl-3 -thiosemicarbazone (abbreviated N4aT), 2-hydroxy-l- naphthylaldehyde-4,4-dimethyl-3 -thiosemicarbazone (abbreviated N44mT), 2-hydroxy-l- naphthylaldehyde-4,4-diphenyl-3-semicarbazone (abbreviated N44pH), 2-hydroxy-l- naphthylaldehyde-4-octoylhydrazone (abbreviated NoctH), as depicted in Figure 1.
  • N4mT 2-hydroxy-l-naphthylaldehyde-4-methyl-3 -thiosemicarbazone
  • N4aT 2-hydroxy
  • the compound of Formula la, 2 or 3 may be suitable for use as an iron chelator.
  • the compound of Formula la, 2 or 3 may form a complex with Fe(II) or Fe(M).
  • the compound of Formula la, 2 or 3 may be suitable for therapeutic use as an iron chelator in vivo.
  • a pharmaceutical composition comprising a pharmaceutically acceptable diluent or carrier and at least one compound according to Formula lb
  • E is O or S
  • X is OH or SH
  • R 4 is selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, and substituted amino; and n is 1, 2, 3, 4, 5 or 6;
  • R' is hydrogen or a group that does not prevent the compound chelating iron ions
  • R 8 is hydrogen or C alkyl
  • Ri is N, or CR 5 , wherein the bond between C and R 5 may be a single, double or triple bond; and wherein when the bond between C and R 5 is a double bond, one of R 2 and R 3 is absent, and wherein when the bond between C and R 5 is a triple bond, R 2 and R 3 are both absent;
  • R 2 and R 3 are the same or different and are individually selected from the following: hydrogen, halogen, substituted or unsubstituted C 1-8 alkyl group, substituted or unsubstituted C 2-8 alkenyl group, substituted or unsubstituted C 2-8 alkynyl group, substituted or unsubstituted amino group, substituted or unsubstituted heterocyclic group eg, 5- or 6-membered heterocyclic group, substituted or unsubstituted bicyclic group, and substituted or unsubstituted aromatic group;
  • R 5 is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted Cj -8 alkyl group, substituted or unsubstituted C 2-8 alkenyl group, substituted or unsubstituted C 2-8 alkynyl group, substituted or unsubstituted amino group, substituted or unsubstituted heterocyclic group, eg 5- or 6-membered hetero
  • the pharmaceutical composition according to the invention comprises a pharmaceutically acceptable diluent or carrier and at least one compound according to Formula la as defined above.
  • the pharmaceutical composition according to the invention comprises a pharmaceutically acceptable diluent or carrier and at least one compound of Formula 2 or Formula 3:
  • composition according to the invention may comprise one or more iron complex of a compound according to Formula la, lb, 2 or 3.
  • the pharmaceutical composition according to the invention may be suitable for iron chelation therapy, treating iron-overload disorders, inhibiting cellular proliferation, or treating proliferative disorders.
  • the pharmaceutical composition according to the invention may be formulated for subcutaneous or intravenous injection, oral administration, inhalation, transdermal application, or rectal administration.
  • a pharmaceutical composition of the invention may be made by mixing a compound of Formula la, lb, 2 or 3 with a pharmaceuticallyacceptable carrier and or diluent and/or adjuvant.
  • the present invention provides a method of iron chelation therapy in a mammal comprising administering to said mammal a therapeutically effective amount of at least one compound selected from the group consisting of a compound of
  • the present invention provides a method of treating an iron- overload disorder in a mammal comprising administering to said mammal a therapeutically effective amount of at least one compound selected from the group consisting of a compound of Formula la, a compound of Formula lb, a compound of
  • the present invention provides a method of inhibiting cellular proliferation in a mammal comprising administering to said mammal a therapeutically effective amount of at least one compound selected from the group consisting of a compound of Formula la, a compound of Formula lb, a compound of Formula 2 and a compound of Formula 3, as defined above, or an iron complex of said compound, or a pharmaceutical composition according to the invention.
  • the present invention provides a method of treating a proliferative disorder in a mammal comprising administering to said mammal a therapeutically effective amount of at least one compound selected from the group consisting of a compound of Formula la, a compound of Formula lb, a compound of Formula 2 and a compound of Formula 3, as defined above, or an iron complex of said compound, or a pharmaceutical composition according to the invention.
  • the present invention provides the use of at least one compound selected from the group consisting of a compound of Formula la, a compound of Formula lb, a compound of Formula 2 and a compound of Formula 3, as defined above, for the preparation of a medicament for iron chelation therapy.
  • the present invention provides the use of at least one compound selected from the group consisting of a compound of Formula la, a compound of Formula lb, a compound of Formula 2 and a compound of Formula 3, as defined above, for the manufacture of a medicament for treating an iron-overload disorder.
  • the present invention provides the use of at least one compound selected from the group consisting of a compound of Formula la, a compound of Formula lb, a compound of Formula 2 and a compound of Formula 3, as defined above, or an iron complex of said compound, for the manufacture of a medicament for inhibiting cellular proliferation.
  • the present invention provides the use of at least one compound selected from the group consisting of a compound of Formula la, a compound of Formula lb, a compound of Formula 2 and a compound of Formula 3, as defined above, or an iron complex of said compound, for the manufacture of a medicament for treating a proliferative disorder.
  • the present invention provides at least one compound selected from the group consisting of a compound of Formula la, a compound of Formula lb, a compound of Formula 2 and a compound of Formula 3, as defined above, or a pharmaceutical composition of the invention, when used for iron chelation therapy, treating an iron-overload disorder, inhibiting cellular proliferation, or treating a proliferative disorder in a mammal.
  • the mammal may be a human.
  • the proliferative disorder may be selected from the group consisting of angiogenesis-dependent diseases, cellular proliferative diseases, inflammatory disorders, and cancer.
  • the proliferative disorder may be psoriasis or arthritis.
  • the cancer may be a metastatic tumour or benign tumour.
  • the cancer may be a solid tumour.
  • a process for identifying a compound having anti-proliferative activity comprising: contacting a cell or cellular extract having DNA encoding one or more cell cycle inhibitors, with a compound, determining the level of expression of said DNA, and thereby determining whether said compound has anti-proliferative activity, wherein said anti-proliferative activity is determined by the ability of the compound to up-regulate expression of said DNA encoding one or more cell cycle inhibitors.
  • the present invention provides a process for screening a plurality of compounds to identify a compound having anti-proliferative activity, said process comprising: contacting a cell or cellular extract having DNA encoding one or more cell cycle inhibitors, with a plurality of compounds, determining whether any of said compounds modify the level of expression of said DNA, and if so, separately determining the level of expression of a DNA for each compound, and thereby identifying a compound having anti-proliferative activity, wherein said anti-proliferative activity is determined by the ability of said compound to up-regulate expression of said DNA encoding one or more cell cycle inhibitors.
  • the compound may be a compound of Formula la, lb, 2 or 3 as defined herein, or an iron complex thereof.
  • the DNA expressing cell cycle inhibitor may be GADD45.
  • a fourteenth aspect of the invention there is provided a method of treating viral, bacterial, or fungal infection in a mammal, said method comprising administering to said mammal a therapeutically effective amount of at least one compound selected from the group consisting of a compound of Formula la, a compound of Formula lb, a compound of Formula 2, and a compound of Formula 3, as defined above, or a metal ion complex of said compound, or a pharmaceutical composition according to the invention.
  • the compounds according to the present invention include substituted or unsubstituted naphthyl semicarbazone, naphthylhydrazone, naphthyl thiosemicarbazone, and naphthyl thiohydrazone derivatives.
  • the compounds are sometimes referred to herein as "NT analogues" or the "NT series”.
  • alkyl group refers to a saturated aliphatic hydrocarbon radical including straight-chain, branched chain, cyclic groups, and combinations thereof.
  • the alkyl radical may be a C ⁇ . % , C 1-7 , C 1-6 , C 1-5 , C , C 1-3 , C 1-2 or CH 3 radical, or in the case of a cycloalkyl group, a C 3-8 , C -7 , C 3-6 , C -5 , or C -4 radical.
  • Typical alkyl groups include but are not limited to methyl, ethyl, 1-propyl, isopropyl, 1 -butyl, 2-butyl, tert- butyl, amyl, isoamyl, sec-amyl, 1,2-dimethylpropyl, 1,1-dimethylpropyl, pentyl, isopentyl, hexyl, 4-methylpentyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1- dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1 ,2-dimethylbutyl, 1,3- dimethylbutyl, 1,2,2-trimethylpropyl, 1,1,2-trimethylpropyl, heptyl, 5-methylhexyl, 1- methylhexyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 4,4-dimethylpentyl, 1,2- di
  • alkenyl group refers to an unsaturated aliphatic hydrocarbon radical including straight, branched chain, cyclic groups, and combinations thereof, having at least one double bond, of either E or Z stereochemistry where applicable.
  • alkenyl groups include but are not limited to ethenyl, 1-propenyl, 2-propenyl, 2-methyl-2- propenyl, 1-butenyl, 1,3-butadienyl, hexenyl, pentenyl, heptenyl and octenyl, cyclohexenyl, cyclopentenyl.
  • alkynyl group refers to an unsaturated aliphatic hydrocarbon group including straight, branched chain, cyclic groups and combinations thereof, having at least one triple bond.
  • the alkynyl group may be a C 2-8 , C 2- , C 2-6 , C 2-5 , C 2-4 , C 2- or C C radical.
  • alkynyl groups include but are not limited to ethynyl, 1-propynyl, 1- and 2-butynyl, and l-methyl-2-butynyl.
  • amino refers to the group -N eR 7 wherein R and R 7 are individually selected from the group including but not limited to H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, and substituted or unsubstituted heterocyclic group.
  • aryl or "aromatic” as used herein refers to single, polynuclear, conjugated and fused residues of aromatic hydrocarbons having from 6 to 12 carbon atoms. Examples of these groups include phenyl, biphenyl, naphthyl, tetrahydronaphthyl, fluorenyl, indenyl, indanyl, pyrenyl, and the like.
  • bicyclic refers to two fused cyclic rings, wherein the rings are individually selected from C -8 aliphatic and C 5-6 aromatic rings.
  • halide or "halo atom” as used herein refers to fluorine, chlorine, bromine or iodine.
  • heteroatom refers to any atom other than carbon or hydrogen and preferably means oxygen, nitrogen or sulfur.
  • heterocyclic refers to any saturated or unsaturated 3-12 membered, e.g 5- or 6-membered, aliphatic or aromatic ring systems containing from 1 to 3 heteroatoms selected from oxygen, nitrogen and sulfur.
  • Examples include substituted and unsubstituted piperidinyl, morpholinyl, pyrrolyl, furanyl, imidazolyl, thienyl, pyridyl, pyradizinyl, lH-indazolyl, quinoxalinyl, quinolinyl, indolinyl, oxazolidinyl, benzimidazolyl, benzisothiazolyl, tetrazolyl, benzofuranyl, purinyl and indolyl.
  • substituted or unsubstituted alkyl means the respective alkyl, alkenyl, alkynyl, amino, aromatic, bicyclic, heterocyclic, or cycloalkyl group may be unsubstituted, or substituted with one or more groups selected from C 1-8 alkyl, C 3-8 cycloalkyl, C 3-8 heterocycloalkyl, C 2-8 acyl, C 5-1 o aryl, C 5-1 o heteroaryl, amino, amide,
  • therapeutically effective amount is intended to include within its meaning a non-toxic but sufficient amount of a compound or composition of the invention to provide the desired therapeutic effect.
  • the exact therapeutically effective amount of the analogue will vary according to factors such as the type of disease of the animal, the age, sex, and weight of the animal, mode of administration, and the ability of the analogue to permeate cell membranes and chelate iron in cells of the animal. Dosage procedures can be adjusted to provide the optimum therapeutic response. For example, several divided doses can be administered daily or the dose can be proportionally reduced as indicated by the exigencies of the therapeutic situation.
  • a "mammal” includes a primate or non- human primate or other non-human mammal, a marsupial or a reptile.
  • the mammal may be selected from the group consisting of human, non-human primate, equine, murine, bovine, leporine, ovine, caprine, feline and canine.
  • the mammal may be selected from a human, horse, cattle, sheep, goat, dog, cat, llama, rabbit and a camel.
  • N2mT 2-hydroxy- 1 -naphthylaldehyde-2-methyl-3-thiosemicarbazone
  • N4mT 2-hydroxy- 1 -naphthylaldehyde-4-methyl-3-thiosemicarbazone
  • N44mT 2-hydroxy-l-naphthylaldehyde-4,4-dimethyl-3-thiosemicarbazone
  • N4eT 2-hydroxy-l-naphthylaldehyde-4-ethyl-3-thiosemicarbazone
  • N4aT 2-hydroxy- 1 -naphthylaldehyde-4-allyl-3-thiosemicarbazone
  • N4pT 2-hydroxy- 1 -naphthylaldehyde-4-phenyl-3-thiosemicarbazone
  • N44pH 2-hydroxy-l-naphthylaldehyde-4,
  • Figure 1 Structures of representative NT Analogues.
  • Figure 2 X-Ray crystal structure of NT showing 30% thermal ellipsoids
  • Figure 3 X-Ray crystal structure of N44mT showing 30% thermal ellipsoids (dimethyl sulfoxide molecule of crystallisation not shown).
  • Figure 4 X-Ray crystal structure of N4eT showing 30% thermal ellipsoids.
  • Figure 5 X-Ray crystal structure of N4pT showing 30% thermal ellipsoids.
  • Figure 6 The effect of NT chelators on 59 Fe mobilisation from prelabelled SK-N- MC neuroepithehoma cells.
  • Cells were labelled with 59 Fe-Tf (0.75 ⁇ M) for 3 h at 37°C, washed, and then reincubated, (A) for 3 h at 37°C in the presence of medium alone (control) or medium containing DFO (25 ⁇ M) or the other chelators (25 ⁇ M), or (B) reincubated as above for 3, 6, 12 and 24 h.
  • Results are expressed as the mean + SD of 3 replicates in a typical experiment of 2 experiments performed.
  • Figure 7 The effect of NT chelators on 59 Fe uptake from 59 Fe-transferrin ( 59 Fe-Tf) by SK-N-MC neuroepithehoma cells.
  • the cells were incubated for: (A) 3 h at 37°C in media containing 59 Fe-Tf (0.75 ⁇ M) and either DFO (25 ⁇ M) or the other chelators (25 ⁇ M), washed, and then incubated with pronase (1 mg/ml) for 30 min at 4°C, or (B) incubated as described in (A) for 3, 6, 12 and 24 h at 37°C and internalised 59 Fe measured. Results are expressed as the mean ⁇ SD of 3 replicates in a typical experiment of 2 experiments performed.
  • Figure 8 The effect of NT analogue concentration on the proliferation of SK-N- MC neuroepithehoma cells.
  • Cells were incubated in the presence and absence of an NT analogue (0-12.5 ⁇ M) for 72 h at 37°C. After this incubation period, cellular density was measured via the MTT assay. Each data point represents the mean of 2 replicates in a typical experiment of 3 experiments performed.
  • Figure 9 Antiproliferative effects of NT chelators in neoplastic and normal cells.
  • Cells were incubated in the presence and absence of the chelators (0-25 ⁇ M) for 72 h at 37°C. After this incubation period, cellular density was measured via the MTT assay. Each data point represents the mean of 2 replicates in a typical experiment of 3 experiments performed.
  • Figure 10 Comparison of the effect of NNH, NT and N44mT and the clinically used anti-tumour agents cisplatin and doxorubicin on the inhibition of normal granulocyte-macrophage (GM) stem cell colonies of normal human bone marrow.
  • Normal bone marrow stem cells (1 x 10 5 cells/ml) were incubated for 14 days at 37°C with the agents (0.005-0.4 ⁇ M), and the colonies were then counted. Results are from a typical experiment of 3 experiments performed.
  • Figure 11 The relationship between the anti-proliferative activity of the chelators using SK-N-MC neuroepithehoma cells (IC 50 values) and their lipophilicity (calculated log P eak values).
  • FIG. 13 The effect of NT chelators on the mRNA levels of TfR, GADD45, and ⁇ - actin (loading control) in SK-N-MC neuroepithehoma cells.
  • Total RNA was extracted from cells after a 20 h incubation with medium alone (control) or medium containing DFO (150 ⁇ M) or the other chelators (25 ⁇ M).
  • the isolated RNA underwent electrophoresis on a 1.2% agarose-formaldehyde gel, transferred to a hybridisation membrane, and probed under high stringency conditions as described in Example 8. The result illustrated is a typical experiment from 3 experiments performed.
  • Figure 14 Effect of NT analogues on the expression of cell-cycle control molecules.
  • Western analysis was performed as described in Example 8. The results shown are typical of 2 experiments performed.
  • Figure 15 The effect of EDTA, NNH, Triapine, and the cytotoxic NT analogues NT and N4mT on (A) the Fe(III)-induced oxidation of ascorbate, and (B) the Fe(IT)- induced hydroxylation of benzoate. Ascorbate oxidation and benzoate hydroxylation were assessed as described in Example 9(a) and 9(b). The results are mean ⁇ SEM of 3 experiments.
  • Figure 16 The effect of EDTA, NNH, Triapine, and the cytotoxic NT analogues NT and N4mT on integrity of the plasmid pGEM-7Z (+) when incubated in the presence of Fe(II) and hydrogen peroxide.
  • Reagents were added in the following order: purified sterile water, chelator (1, 10, and 30 ⁇ M), FeSO 4 (10 ⁇ M), H 2 O 2 (1 mM), and plasmid (10 ⁇ g/ml), and incubated at room temperature for 30 min before loading onto a 1% agarose gel (Example 9(c)). Results are a typical experiment from at least 8 performed.
  • the present invention is directed to novel substituted naphthyl semicarbazone, naphthylhydrazone, naphthyl thiosemicarbazone, and naphthyl thiohydrazone compounds of Formula la which are capable of chelating iron ions.
  • the invention also encompasses pharmaceutical formulations comprising at least one compound of Formula la, Formula lb, Formula 2, or Formula 3 as defined herein, or an iron complex of said compound, and the therapeutic uses thereof.
  • NT analogues the compounds are sometimes referred to herein as "NT analogues".
  • the NT analogues in accordance with the present invention have a substituted or unsubstituted naphthyl moiety and a thiosemicarbazone, semicarbazone, thiohydrazone or hydrazone moiety.
  • the naphthyl moiety may be substituted with one or more lipophilic and/or electron donating groups, such as substituted or unsubstituted Cj -8 alkyl, C 2-8 alkenyl, C 2- alkynyl, C ⁇ -8 alkoxy, aromatic, heterocyclic, cycloalkyl, cycloaromatic groups, alkyl-substituted amines, and the like.
  • the thiosemicarbazone, semicarbazone, thiohydrazone or hydrazone moiety is substituted with one or more lipophilic groups, such as C ⁇ -8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, aromatic, cycloaromatic, heterocycloalkyl, heteroaromatic, alkyl substituted amines and the like.
  • the lipophilicity of the NT series of compounds according to the present invention is such that the NT compounds may be capable of permeating cell membranes. Inside cells, NT compounds are capable of chelating intracellular Fe.
  • naphthyl semicarbazone, naphthylhydrazone, naphthyl thiosemicarbazone, and naphthyl thiohydrazone derivatives disclosed herein may be prepared by means of a Schiff base condensation reaction in which a substituted or unsubstituted 2- hydroxynaphthaldehyde is condensed with either an acid hydrazide or acid thiosemicarbazide of choice to produce the corresponding thiosemicarbazone, semicarbazone, hydrazone or thiohydrazone derivative having the desired substitution pattern.
  • NoctH The condensation reactions represented above may be carried out under conditions known to those skilled in the art.
  • suitable solvent systems include ethanol, methanol, ethanol/water, methanol/water, or other common organic solvents such as acetone, benzene, toluene, etc.
  • Preferred NT analogues suitable for use in accordance with the present invention include the following:
  • N4aT 2-hydroxy-l-naphthylaldehyde-4-allyl-3-thiosemicarbazone
  • N4pT 2-hydroxy- 1 -naphthylaldehyde-4-phenyl-3 -thiosemicarbazone
  • N44pH 2-hydroxy- 1 -naphthylaldehyde-4-octoyl-3-hydrazone
  • NoctH 2-hydroxy-l-naphthylaldehyde-4-allyl-3-thiosemicarbazone
  • the NT series of compounds in accordance with the present invention include compounds which have iron chelation and anti-proliferative properties.
  • the NT series of compounds are effective Fe(III) and Fe(II) chelators.
  • Iron complexes in accordance with the present invention include: Fe[NT] 2 , Fe[N4aT] 2 , Fe[N4eT] 2 , Fe[N4mT] 2 , Fe[N44mT] 2 , Fe[N4pT] 2 , Fe[N44pH] 2 and Fe[N4octH] 2 .
  • the iron ion is Fe(II) or Fe(III).
  • Iron complexes of NT analogues in accordance with the invention may be readily prepared using techniques and reagents well known to those skilled in the art.
  • Suitable iron salts include, but are not limited to, halides, nitrates, sulfates, perchlorates, acetates, and triflates.
  • Suitable iron salts for forming iron complexes include, but are not limited to,
  • FeCl 3 Fe(NO 3 ) 3 , FeSO 4 , Fe(OAc) 3 , and Fe 2 (ClO 4 ) 3 (Richardson & Bernhardt, 1999).
  • NT derivatives in accordance with the present invention can function as tridentate ligands capable of forming iron complexes.
  • a general example of an iron complex is represented below for an NT analogue of Formula la or lb. where E is O or S, and G is as defined above.
  • an iron complex of the ligand N44mT is illustrated below.
  • the NT analogues disclosed herein have a range of activities, including iron chelation.
  • the inventors have examined the effect of a range of NT analogues on cellular proliferation, iron chelation efficacy, the expression of cell cycle control molecules, iron-regulatory protein-RNA-binding activity, 3 H-thymidine incorporation, and the effect of the NT analogues on iron-mediated free radical damage.
  • NT analogues in accordance with the present invention may be capable of permeating cell membranes.
  • iron complexes of NT ligands in accordance with the invention may be neutral or charged.
  • NT analogues especially for example, more lipophilic members of the NT series of compounds, may be potent Fe(ffl) and/or Fe(II) chelators and may exhibit anti-proliferative activity. Accordingly, the NT series of compounds are potentially useful as anti-tumour agents.
  • Fe-NT complexes suitable for use in accordance with the present invention may exhibit anti-proliferative activity.
  • NT analogues disclosed herein may exhibit antimicrobial activity.
  • NT analogues disclosed herein may be capable of treating bacterial, viral and fungal infection.
  • NT analogues in accordance with the invention may inhibit DNA synthesis, and preferred analogues may induce an increase of the mRNA levels of molecules vital for cell cycle arrest.
  • expression of GADD45 mRNA may provide a useful indicator of the anti-proliferative potential of Fe chelators.
  • preferred NT analogues may exhibit anti-proliferative activity. Accordingly, NT analogues disclosed herein have potential therapeutic applications, including for example, the treatment of iron-overload disease, and the treatment of proliferative diseases, such as cancer. Methods of measuring DNA synthesis are well known by persons skilled in the art.
  • DNA synthesis can be measured indirectly by quantitating [ 3 H]- hypoxanthine incorporation into the nucleic acids in the presence or absence of the agents to be tested.
  • ribonucleotide reductase can interfere with the cellular synthesis of DNA
  • one useful anti-viral treatment strategy is the use of an Fe chelator to inhibit the replication of viral DNA.
  • One method of assessing viral activity includes infecting human monocyte-derived macrophages and peripheral blood lymphocytes with HIV-l B a- L - The cells are then incubated in the absence or presence of the chelator for a suitable period. Virus replication is monitored by assessing the level of p24 core antigen in virus-inactivated supernatants by ELISA techniques (Georgiou et al., 2000).
  • a microplate alamar blue assay (MABA) procedure can be used (Stevens et al., 2001).
  • MABA microplate alamar blue assay
  • an appropriate strain of Mycobacterium tuberculosis eg, H37Rv strain
  • Bactec 12 B medium in the presence or absence of the test compounds.
  • the reduction in fluorescence produced by the treated cultures is proportional to the inhibition of inoculum growth.
  • Anti-fungal activity of the NT analogues can be assessed by methods known to those skilled in the art, for example, the recommendations of the National Committee for Clinical Laboratory Standards (U.S.A). 16 Briefly, the standardised test compares the turbidity of treated vs untreated control cultures. An inoculum of test yeast is grown at 35°C and adjusted to a concentration of approximately 1 x 10 3 CFU/mL, and then reincubated (35°C) for a suitable time period before turbidity is measured.
  • NT analogues when used for the treatment of disease or infection, may be administered alone. However, it is generally preferable that the analogues be administered as a pharmaceutical formulation which comprises at least one NT analogue, or a metal ion complex thereof.
  • the NT analogues may also be present as suitable pharmaceutically acceptable salts.
  • pharmaceutically acceptable salt it is meant those salts which, within the scope of sound medical judgement, are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art.
  • suitable pharmaceutically acceptable salts of NT analogues in accordance with the present invention may be prepared by mixing a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, methanesulfonic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, phosphoric acid, acetic acid, oxalic acid, carbonic acid, tartaric acid, or citric acid with the compounds of the invention.
  • a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, methanesulfonic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, phosphoric acid, acetic acid, oxalic acid, carbonic acid, tartaric acid, or citric acid.
  • Suitable pharmaceutically acceptable salts of the compounds of the present invention therefore include acid addition salts.
  • Representative acid addition salts include acetate, adipate, alginate, ascorbate, asparate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pe
  • alkali or alkaline earth metal salts include sodium, lithium potassium, calcium, magnesium, and the like, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like.
  • Convenient modes of administration include injection (subcutaneous, intravenous, etc.), oral administration, inhalation, transdermal application, or rectal administration.
  • the analogue may be coated with a material to protect the analogue from the action of enzymes, acids and other natural conditions which may inactivate the therapeutic activity of the analogue.
  • the analogue may also be administered parenterally or intraperitoneally.
  • Dispersions of NT analogues can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, pharmaceutical preparations may contain a preservative to prevent the growth of microorganisms.
  • compositions suitable for injection include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.
  • the composition is stable under the conditions of manufacture and storage and may include a preservative to stabilise the composition against the contaminating action of microorganisms such as bacteria and fungi.
  • the analogue is administered orally, for example, with an inert diluent or an assimilable edible carrier.
  • the analogue and other ingredients can also be enclosed in a hard or soft shell gelatin capsule, compressed into tablets, or incorporated directly into an individual's diet.
  • the analogue can be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.
  • such compositions and preparations may contain at least 1% by weight of active compound.
  • the percentage of the NT analogue in pharmaceutical compositions and preparations can, of course, be varied and, for example, can conveniently range from about 2% to about 90%, about 5% to about 80%, about 10% to about 75%, about 15% to about 65%; about 20% to about 60%, about 25% to about 50%, about 30% to about 45%, or about 35% to about 45%, of the weight of the dosage unit.
  • the amount of analogue in therapeutically useful compositions is such that a suitable dosage will be obtained.
  • pharmaceutically acceptable carrier is intended to include solvents, dispersion media, coatings, anti-bacterial and anti-fungal agents, isotonic and absorption delaying agents, and the like.
  • the use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the analogue, use thereof in the therapeutic compositions and methods of treatment is contemplated.
  • Supplementary active compounds can also be incorporated into the compositions according to the present invention. It is especially advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage.
  • Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the individual to be treated; each unit containing a predetermined quantity of analogue is calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • the specification for the novel dosage unit forms of the invention are dictated by and directly dependent on (a) the unique characteristics of the analogue and the particular therapeutic effect to be achieve, and (b) the limitations inherent in the art of compounding such an analogue for the treatment of iron-related or iron overload diseases in individuals.
  • the principal analogue is compounded for convenient and effective administration in effective amounts with a suitable pharmaceutically acceptable carrier in an acceptable dosage unit. In the case of compositions containing supplementary active ingredients, the dosages are determined by reference to the usual dose and manner of administration of the said ingredients.
  • the carrier is an orally administrable carrier.
  • a particularly suitable form of a pharmaceutical composition is a dosage form formulated as enterically coated granules, tablets or capsules suitable for oral administration.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyetheylene glycol, and the like), suitable mixtures thereof, and vegetable oils.
  • the proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • Prevention of the action of microorganisms can be achieved by including various anti-bacterial and/or anti-fungal agents.
  • Suitable agents are well known to those skilled in the art and include, for example, parabens, chlorobutanol, phenol, benzyl alcohol, ascorbic acid, thimerosal, and the like.
  • isotonic agents for example, sugars, polyalcohols such as mannitol, sorbitol, sodium chloride in the composition.
  • Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminium monostearate and gelatin.
  • Sterile injectable solutions can be prepared by incorporating the analogue in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilisation.
  • dispersions are prepared by incorporating the analogue into a sterile vehicle which contains a basic dispersion medium and the required other ingredients from those enumerated above.
  • Tablets, troches, pills, capsules and the like can also contain the following: a binder such as gum gragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin or a flavouring agent such as peppermint, oil of wintergreen, or cherry flavouring.
  • a binder such as gum gragacanth, acacia, corn starch or gelatin
  • excipients such as dicalcium phosphate
  • a disintegrating agent such as corn starch, potato starch, alginic acid and the like
  • a lubricant such as magnesium stearate
  • a sweetening agent such as sucrose, lactose or saccharin or a flavouring agent such as peppermint, oil of wintergreen, or
  • tablets, pills, or capsules can be coated with shellac, sugar or both.
  • a syrup or elixir can contain the analogue, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavouring such as cherry or orange flavour.
  • any material used in preparing any dosage unit form should be pharmaceutically pure and substantially non-toxic in the amounts employed.
  • the analogue can be incorporated into sustained-release preparations and formulations.
  • the pharmaceutical composition may further include a suitable buffer to minimise acid hydrolysis.
  • suitable buffer agent agents are well known to those skilled in the art and include, but are not limited to, phosphates, citrates, carbonates and mixtures thereof.
  • Single or multiple administrations of the pharmaceutical compositions according to the invention can be carried out.
  • One skilled in the art would be able, by routine experimentation, to determine effective, non-toxic dosage levels of the compound and/or composition of the invention and an administration pattern which would be suitable for treating the disorders or diseases to which the compounds and compositions are applicable.
  • an effective dosage of NT analogue per 24 hours may be in the range of about 0.0001 mg to about 1000 mg per kg body weight; suitably, about 0.001 mg to about 750 mg per kg body weight; about 0.01 mg to about 500 mg per kg body weight; about 0.1 mg to about 500 mg per kg body weight; about 0.1 mg to about 250 mg per kg body weight; or about 1.0 mg to about 250 mg per kg body weight.
  • an effective dosage per 24 hours may be in the range of about 1.0 mg to about 200 mg per kg body weight; about 1.0 mg to about 100 mg per kg body weight; about 1.0 mg to about 50 mg per kg body weight; about 1.0 mg to about 25 mg per kg body weight; about 5.0 mg to about 50 mg per kg body weight; about 5.0 mg to about 20 mg per kg body weight; or about 5.0 mg to about 15 mg per kg body weight.
  • an effective dosage may be up to about 500 mg/m 2 .
  • an effective dosage may be in the range of about 25 to about 500 mg/m 2 , about 25 to about 350 mg/m 2 , about 25 to about 300 mg/m 2 , about 25 to about 250 mg/m 2 , about 50 to about 250 mg/m 2 , or about 75 to about 150 mg/m 2 .
  • suitable dosage forms in accordance with the present invention include the following:
  • NT Analogue 0.01 to 20 mg, generally 0.1 to 10 mg
  • DFO was purchased from Ciba-Geigy Pharmaceutical Co., Summit, NJ, USA. Representative structures of the NT series of compounds, DFO and "311" are provided in Figure 1.
  • Example 1(a) - General Synthesis of NT Analogues Representative NT analogues were synthesised by Schiff base condensation using standard procedures. Equimolar amounts of 2-hydroxy-l-naphthylaldehyde was heated with an appropriate acid hydrazide or thiosemicarbazide in refluxing ethanol. The product was collected by filtration. Other suitable solvents for the Schiff base condensation include methanol, ethanol/water, methanol/water, acetone, benzene, and toluene. The NT compounds were characterised by a combination of elemental analysis, l H-NMR spectroscopy, infrared spectroscopy, and X-ray crystallography using. Representative structures of NT analogues are provided in Figure 1.
  • Example Kb - Synthesis of 2-hydroxy-l-naphthylaldehyde thiosemicarbazone (NT) Equimolar amounts of 2-hydroxy-l-naphthaldehyde and thiosemicarbazide were refluxed in ethanol. The compound was collected by filtration and crystals suitable for X-ray crystallography were obtained by slow evaporation of an ethanolic solution of the compound. The crystal structure and data of NT is provided in Figure 2.
  • N44mT is provided in Figure 3.
  • Example 1(d) Synthesis of 2-hydroxy-l-naphthylaldehyde-4-ethyl-3- thiosemicarbazone (N4eT)
  • N4eT 2-hydroxy-l-naphthaldehyde and 4-ethylthiosemicarbazide were refluxed in ethanol.
  • the title compound was collected by filtration and crystals suitable for X-ray crystallography were obtained by slow evaporation of an ethanolic solution of the compound.
  • the crystal structure and data of N4eT is provided in Figure 4.
  • Example 1(e) Synthesis of 2-hydroxy-l-naphthyladehyde-4-phenyl-3- thiosemicarbazone (N4pT)
  • N4pT 2-hydroxy-l-naphthaldehyde and 4-phenylthiosemicarbazide were refluxed in ethanol.
  • the title compound was collected by filtration and crystals suitable for X-ray crystallography were obtained by slow evaporation of an ethanolic solution of the compound.
  • the crystal structure and data of N4pT is provided in Figure 5.
  • Iron complexes of NT analogues were prepared using techniques described by
  • NT chelators were dissolved in dimethyl sulfoxide (DMSO) as 10 mM stock solutions immediately prior to an experiment and then diluted in 10% fetal calf serum (FCS; Commonwealth Serum Laboratories, Melbourne, Australia) so that the final DMSO concentration was equal to or less than 0.5 % (v/v).
  • DMSO dimethyl sulfoxide
  • Human K562 erythroleukemia, SK-Mel-28 melanoma, SK-N-MC neuroepithehoma cells, MCF-7 breast cancer cells and the normal cell lines MRC-5 and L8 rat skeletal muscle were from the American Type Culture Collection (ATCC), Rockville, MD, USA.
  • the cell lines were grown in Eagle's modified minimum essential medium (MEM; Gibco BRL, Sydney, Australia) containing 10 % FCS, 1 % (v/v) non-essential amino acids (Gibco), 2 mM L-glutamine (Sigma Chemical Co., St.
  • HEVECs human umbilical vein endothelial cells
  • HMDM human monocyte derived macrophages
  • Bone marrow stem cell cultures were prepared using established methods (Eaves, 1995) to study the effect of the chelators on the growth of granulocyte-macrophage (GM) colonies. Cellular growth and viability were monitored using phase-contrast microscopy and trypan blue staining.
  • NT chelators to mobilise 59 Fe from SK-N-MC neuroepithehoma cells was studied using standard procedures (Richardson et al., 1995). Briefly, cells were prelabelled with 59 Fe-transferrin (0.75 ⁇ M) for 3 h at 37°C. The cells were then placed on ice and washed 4 times with ice-cold BSS, and then (A) reincubated for 3 h at 37°C in the presence and absence of the internal standard DFO (100 ⁇ M) or the NT chelators (50 ⁇ M); or (B) reincubated for 3, 6, 12 and 24 h.
  • DFO was used at a concentration of 100 ⁇ M due to the low efficacy of this chelator at mobilising 59 Fe from cells and preventing 59 Fe uptake from 5 Fe-Tf.
  • the overlying medium was then removed and placed into ⁇ - counting tubes.
  • the cells were removed from the petri dishes in 1 ml of BSS using a plastic spatula and transferred to a separate set of ⁇ -counting tubes.
  • the ligands can be grouped into two classes depending upon their ability to mobilise 59 Fe.
  • the first class exhibit activity similar to DFO, and include the chelators ST, NT, and N2mT, which mobilise 3-13% of total cellular 59 Fe (Fig. 6A).
  • the second class of chelators are the remaining NT analogues which are significantly (p ⁇ 0.0001) more effective than DFO, resulting in the release of 28-43% of cellular 59 Fe (Fig. 6 A).
  • N44mT is the most efficient analogue having activity that is comparable to 311 and NNH, resulting in the release of 43% of cellular 59 Fe (Fig. 6A).
  • N44mT shows significant antiproliferative activity, resulting in 43% release of cellular 59 Fe (Fig 6 A).
  • the parent analogue, NT only mobilised 13% of cellular 59 Fe and is markedly less efficient than the other NT analogues (Fig. 6A).
  • NT has high anti-proliferative efficacy (Fig. 8 and Table 1), but relatively low activity at mobilising 5 Fe from cells (Fig. 6A), time-course experiments were performed in an attempt to understand its mechanism of action (Fig. 6B).
  • N44mT was also assessed as it has high activity at both inhibiting proliferation and mobilising cellular 59 Fe.
  • NT analogues to inhibit cellular uptake of 59 Fe from 59 Fe-Tf by SK- N-MC Neuroepithehoma Cells was examined using standard procedures (Richardson et al., 1995).
  • SK-N-MC Cells were incubated for 3 h at 37°C in media containing 59 Fe-Tf (0.75 ⁇ M) in the presence or absence of an NT chelator (25 ⁇ M) or in the presence of DFO (lOO ⁇ M) (Fig 7A-B).
  • the cells were then placed on ice and washed four times with ice-cold Hank's balanced salt solution (BSS) to remove non-specifically bound 59 Fe-Tf.
  • BSS Hank's balanced salt solution
  • the amount of 59 Fe internalised by cells was measured by incubation with the general protease, pronase (1 mg/ml), for 30 min at 4°C to remove membrane-bound 59 Fe and Tf.
  • NT and DFO reduced 59 Fe uptake by SK-N-MC cells to 82% and 85% of the control, respectively.
  • NT and DFO reduce 59 Fe uptake to 61% and 48% of the control, respectively (Fig. 7B).
  • 59 Fe Delivery From Tf The ability of the NT chelators to prevent cellular 59 Fe uptake from 59 Fe-Tf (Fig. 7A) was examined to determine whether it was due to direct removal of 59 Fe from transferrin.
  • the most effective chelators at inhibiting proliferation namely 311, 311m, NT, N4mT and N44mT were ineffective at removing 59 Fe from Tf over the duration of an uptake experiment (3 h), resulting in the release of 0.1-0.3% of the bound 59 Fe, while DFO removed 0.7% (data not shown).
  • These results demonstrate that the chelators have very little effect on direct 59 Fe release from 59 Fe-Tf. Further, these data suggest that the ligands inhibit 59 Fe uptake only after intracellular delivery from Tf.
  • NNH, NT, N4mT and N44mT active analogues against SK-N-MC cells
  • NNH, NT, N4mT and N44mT were also assessed against K562 erythroleukemia, SK-Mel-28 melanoma and MCF-7 breast cancer cell lines.
  • the NNH, NT, N4mT and N44mT ligands were far more active than DFO at inhibiting the growth of K562 and MCF-7 cells (Table 1).
  • chelator NNH demonstrated significant broad spectrum activity against all neoplastic cells examined (Table 1).
  • the chelators and the iron complex of NT were Incubated with cells for 72 h. At the end of this incubation period, cell density was determined by the MTT assay, as described In Material and Methods. Results are mean ⁇ SD (3 experiments) except HMDM (mean of 2 experiments).
  • cytotoxic NT analogues (311, NNH, NT, N4mT,
  • N44mT was assessed for a range of neoplastic and normal cells (Fig. 9 and Table 1). In these experiments, N2mT was included as a negative control since the methyl group at the
  • N4mT and N44mT which have one and two methyl groups at N4, and IC 5 o values of 0.5 and 1.0 ⁇ M, respectively, in SK-N- MC cells.
  • N4pT and N44pH both more lipophilic than N4mT and N44mT; Table 2 have one and two phenyl groups at N4 and IC 50 values of 3.3 ⁇ M and 5.2 mM, respectively.
  • anti-proliferative activity against SK-N-MC cells decreased when substituents on the terminal nitrogen atom became increasingly lipophilic.
  • Table 2 Calculated n-octanol partition coefficients (log P ca i c ) for NT chelators.
  • chelator 311 0.6 ⁇ M
  • N44mT also showed the highest Fe chelation efficacy of the NT series in terms of its ability to increase 59 Fe mobilisation from cells (Fig. 6A,B) and inhibiting 59 Fe uptake from 59 Fe-Tf (Fig. 7A,B).
  • Table 3 The effect of the NT ligands on [ 3 H]thymidine incorporation into SK-N-MC neuroepithelioma cells.
  • IC 50 indicates 50% inhibitory concentration
  • RNA Isolation Reagent Advanced Biotechnologies Ltd, Surrey, United Kingdom
  • the RNA was then cross-linked to the membrane using a UV-crosslinker (UV Stratalinker 1800, Stratagen Ltd, USA).
  • UV-crosslinker UV Stratalinker 1800, Stratagen Ltd, USA
  • the membranes were hybridised with probes specific for human GADD45, and ⁇ -actin.
  • the GADD45 probe consisted of a 760 bp fragment from human GADD45 cDNA cloned into pHul45B2 (kindly supplied by Dr. Albert Fornace, National Cancer Institute, NLH, Maryland, USA).
  • the ⁇ -actin probe consisted of a 1.4 kb fragment from human ⁇ -actin cDNA cloned into pBluescript SK- (ATCC; Cat. No. 37997). Hybridisation of probes to the membranes and their subsequent washing were performed as described previously. 5 The membranes were then exposed to Kodak XAR films at - 70°C with an intensifying screen. Densitometric data were collected with a Laser Densitometer and analysed by Kodak Biomax I Software (Kodak Ltd, USA).
  • Monoclonal antibody against ⁇ -actin (clone AC-15; used at a dilution 1:5000) was obtained from Sigma. The remaining antibodies were from Santa Cruz (CA, USA). These are listed below in two sections: mouse anti-human MoAbs or rabbit anti-human polyclonal antibodies. The catalogue number and working concentrations ( ⁇ g/ml) are listed next to each antibody.
  • MoAbs cyclin A (BF683/SC239; 2 ⁇ g/ml); cyclin DI (R124/SC6281: 2 ⁇ g/ml); cyclin E (HE12/SC247; 1 ⁇ g/ml); cdk2 (D12/SC6248; 2 ⁇ g/ml); Rb (LF8/SC102; 2 ⁇ g/ml).
  • Polyclonal antibodies cyclin D2 (H289/SC754; 2 ⁇ g/ml); cyclin D3 (C16/SC182; 0.2 ⁇ g/ml); cdk4 (C22/SC260; 1 ⁇ g/ml).
  • TfR plays a crucial role in Fe uptake while GADD45 plays a key role in cell-cycle arrest.
  • NT analogues were assessed in order to determine whether they up-regulated these genes.
  • DFO 150 ⁇ M
  • 311 25 ⁇ M
  • both up-regulated TfR and GADD45 mRNA levels Fig. 13
  • N44mT 25 ⁇ M
  • N4mT and particularly N2mT
  • the Fe complex of NT did not increase the level of TfR or GADD45 mRNA (Fig. 13)
  • the chemotherapeutic drugs, doxorubicin and bleomycin partly mediate their cytotoxic effects by forming metal ion complexes that generate free radicals.
  • the ascorbate oxidation, benzoate hydroxylation, and plasmid DNA cleavage assays were used to assess the redox-activity of the Fe-complexes of NT analogues which exhibited the greatest anti-proliferative activity in the SK-N-MC cells, namely, NNH, NT, and N4mT.
  • the redox-active Fe complexes of EDTA and Triapine were used as internal controls (Dean & Nicholson, 1994).
  • IBEs iron-binding equivalents
  • an IBE of 1 is equivalent to the complete filling of the coordination shell of the Fe atom by the ligand(s).
  • a hexadentate chelator i.e., DFO or EDTA
  • an IBE ratio of 1 represents 1 ligand to 1 Fe atom
  • a tridentate chelator i.e., Triapine, NT, or 311
  • An IBE of 0.1 represents an excess of Fe to chelator i.e., 1 hexadentate chelator or 2 tridentate chelators in the presence of 10 Fe atoms.
  • An LBE of 3 represents an excess of chelator to Fe, and is equal to 3 hexadentate chelators or 6 tridentate chelators in the presence of 1 Fe atom.
  • This assay was performed in accordance with methods known in the art (Dean & Nicholson, 1994). Briefly, ascorbic acid (0.1 mM) was prepared immediately prior to an experiment and incubated in the presence of Fe(III) (10 ⁇ M) and a 50-fold molar excess of citrate (500 ⁇ M) and the chelator (1-60 ⁇ M). Absorbance at 265 nm was measured after 10 and 40 min incubation at room temperature and the decrease between these time points calculated.
  • this assay is based on the ability of hydroxyl radicals to hydroxylate benzoate to fluorescent products (308 nm excitation and 410 nm emission) (Dean & Nicholson, 1994).
  • Benzoic acid (1 mM) was incubated for 1 h at room temperature in 10 mM sodium phosphate (pH 7.4) with 5 mM hydrogen peroxide, the chelator (3-180 ⁇ M), and ferrous sulfate (30 ⁇ M).
  • 10 mM sodium phosphate pH 7.4
  • ferrous sulfate 30 ⁇ M
  • Escherichia. coli (DH-5 ⁇ ) were transformed with the plasmid pGEM-7Zf(+) (Promega Inc.) and were grown in LB medium.
  • the plasmid DNA was then purified using the Qiagen plasmid purification kit (Qiagen Inc., USA). Reagents were added to sterile Eppendorf tubes in the following order: purified sterile water, chelator (1, 10, and 30 ⁇ M), FeSO 4 (10 ⁇ M), H 2 O 2 (1 mM), and plasmid DNA (10 ⁇ g/ml).
  • NT analogues to prevent Fe-mediated hydroxyl radical damage to plasmid DNA was assessed.
  • Untreated plasmid and plasmid treated with H 2 O 2 that both run on gels as a single band of supercoiled (SC) DNA were used as one control (Fig. 16).
  • Plasmid treated with the restriction enzyme BamHl was used as a another control.
  • SC DNA was partially converted to the open circular (OC) form (Fig. 16).
  • EDTA was redox active in both the ascorbate oxidation (Fig. 15 A) and benzoate hydroxylation assays (Fig.
  • CAD-4 software (Enraf-Nonius, 1989) ,-cell refinement: SET4 in CAD-4 software; data reduction: Xtal (Hall et al . , 1992); programs used to solve structure: SHELX86 (Sheldrick, 1990) ; Program used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphic: PLATON (Spek, 1990; software used to generate crystallographic data: SHELXL 97.
  • Occupancy sum of asymmetric unit 13.00 for non-hydrogen and 0.00 for hydrogen atoms
  • Occupancy sum of asymmetric unit 23.00 for non-hydrogen and 21.00 for hydrogen atoms
  • Occupancy sum of asymmetric unit 19.00 for non-hydrogen and 15.00 for hydrogen atoms
  • Occupancy sum of asymmetric unit 23.00 for non-hydrogen and 15.00 for hydrogen atoms

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Abstract

Cette invention se rapporte à de nouveaux composés de naphthyle semicarbazone, de naphthylhydrazone, de naphthylthiosemicarbazone, et de naphthylthiohydrazone. Cette invention se rapporte également aux utilisations thérapeutiques de ces composés et à leurs complexes avec du fer. Cette invention concerne en outre des procédés servant à traiter des maladies associées à la prolifération cellulaire et les maladies associées à des infections microbiennes.
PCT/AU2003/000328 2002-03-19 2003-03-19 Derives de naphthyl(thio)semicarbazone et leur utilisation therapeutique WO2003078386A1 (fr)

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AUPS1209A AUPS120902A0 (en) 2002-03-19 2002-03-19 Iron chelators as anti-proliferative agents against tumour cells
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EP2046122A2 (fr) * 2006-07-24 2009-04-15 University of Maryland, Baltimore Inhibiteurs de l'hème oxygénase et procédés d'utilisation thérapeutique
CN102127106A (zh) * 2010-12-30 2011-07-20 聊城大学 一种二苯基二氯化锡配合物及其制备方法与应用
US8207205B2 (en) 2008-04-21 2012-06-26 Institute For Oneworld Health Compounds, compositions and methods comprising oxadiazole derivatives
CN102625795A (zh) * 2009-09-04 2012-08-01 分子发现系统公司 细胞毒性化合物
US8236838B2 (en) 2008-04-21 2012-08-07 Institute For Oneworld Health Compounds, compositions and methods comprising isoxazole derivatives
US8283351B2 (en) 2007-04-02 2012-10-09 Institute For Oneworld Health Cyclic and acyclic hydrazine derivatives compositions including them and uses thereof
US8343976B2 (en) 2009-04-20 2013-01-01 Institute For Oneworld Health Compounds, compositions and methods comprising pyrazole derivatives
WO2014078898A1 (fr) * 2012-11-22 2014-05-30 The University Of Sydney Chimiothérapie pour des cellules cancéreuses résistantes aux médicaments
WO2015180583A1 (fr) * 2014-05-30 2015-12-03 中国人民解放军军事医学科学院毒物药物研究所 Dérivés d'acétohydrazide substitué, procédé de préparation associé et utilisation correspondante

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Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2046122A2 (fr) * 2006-07-24 2009-04-15 University of Maryland, Baltimore Inhibiteurs de l'hème oxygénase et procédés d'utilisation thérapeutique
EP2046122A4 (fr) * 2006-07-24 2009-12-23 Univ Maryland Inhibiteurs de l'hème oxygénase et procédés d'utilisation thérapeutique
US8450368B2 (en) 2006-07-24 2013-05-28 University Of Maryland, Baltimore Heme oxygenase inhibitors, screening methods for heme oxygenase inhibitors and methods of use of heme oxygenase inhibitors for antimicrobial therapy
US8283351B2 (en) 2007-04-02 2012-10-09 Institute For Oneworld Health Cyclic and acyclic hydrazine derivatives compositions including them and uses thereof
US8236838B2 (en) 2008-04-21 2012-08-07 Institute For Oneworld Health Compounds, compositions and methods comprising isoxazole derivatives
US8207205B2 (en) 2008-04-21 2012-06-26 Institute For Oneworld Health Compounds, compositions and methods comprising oxadiazole derivatives
US8343976B2 (en) 2009-04-20 2013-01-01 Institute For Oneworld Health Compounds, compositions and methods comprising pyrazole derivatives
CN102625795A (zh) * 2009-09-04 2012-08-01 分子发现系统公司 细胞毒性化合物
CN102127106B (zh) * 2010-12-30 2013-05-22 聊城大学 一种二苯基二氯化锡配合物及其制备方法与应用
CN102127106A (zh) * 2010-12-30 2011-07-20 聊城大学 一种二苯基二氯化锡配合物及其制备方法与应用
WO2014078898A1 (fr) * 2012-11-22 2014-05-30 The University Of Sydney Chimiothérapie pour des cellules cancéreuses résistantes aux médicaments
WO2015180583A1 (fr) * 2014-05-30 2015-12-03 中国人民解放军军事医学科学院毒物药物研究所 Dérivés d'acétohydrazide substitué, procédé de préparation associé et utilisation correspondante
CN105218399A (zh) * 2014-05-30 2016-01-06 中国人民解放军军事医学科学院毒物药物研究所 一种取代乙酰肼类衍生物、其制备方法及用途
CN105218399B (zh) * 2014-05-30 2018-02-09 中国人民解放军军事医学科学院毒物药物研究所 一种取代乙酰肼类衍生物、其制备方法及用途
US10196346B2 (en) 2014-05-30 2019-02-05 Institute Of Pharmacology And Toxicology Academy Of Military Medical Sciences P.L.A. China Substituted acethydrazide derivative, preparation method and use thereof

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