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WO2010000008A1 - Composés thiosemicarbazones et leur utilisation - Google Patents

Composés thiosemicarbazones et leur utilisation Download PDF

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WO2010000008A1
WO2010000008A1 PCT/AU2008/000961 AU2008000961W WO2010000008A1 WO 2010000008 A1 WO2010000008 A1 WO 2010000008A1 AU 2008000961 W AU2008000961 W AU 2008000961W WO 2010000008 A1 WO2010000008 A1 WO 2010000008A1
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compounds
compound
formula
bpt
bp4et
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Desi Raymond Richardson
David Benn Lovejoy
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—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
    • A61K31/4402—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 2, e.g. pheniramine, bisacodyl
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
    • C07D213/53—Nitrogen atoms

Definitions

  • the present invention relates to thiosemicarbazone compounds, more particularly 2-benzoylpyridine thiosemicarbazone compounds.
  • the invention also relates to pharmaceutical compositions comprising these compounds and to their use in the treatment of diseases and disorders, including proliferative diseases and disorders, such as cancer.
  • Rapidly proliferating cancer cells have an increased requirement for Fe, compared with normal cells, as illustrated by the increased expression of transferring receptor 1 (TfR1).
  • This membrane protein is necessary for Fe uptake from the serum Fe-transport protein, transferring (Tf). Therefore, cellular Fe pools and Fe uptake are a potential therapeutic target for inhibiting proliferation of rapidly proliferating cells, such as cancer cells.
  • the present invention relates to a method of treating a proliferative disease in a vertebrate, the method comprising administering to the vertebrate a therapeutically effective amount of at least one compound of formula (I):
  • R 1 is selected from H, C 1-6 alkyl, C 2-6 alkenyl and phenyl;
  • alkenyl groups include but are not limited to ethenyl, vinyl, allyl, 1-methylvinyl, 1-propenyl, 2-propenyl, 2-methyl- 1-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butentyl, 1 ,3-butadienyl, 1-pentenyl, 2-pententyl, 3-pentenyl, 4-pentenyl, 1 ,3-pentadienyl, 2,4-pentadienyl, 1,4-pentadienyl, 3-methyl-2-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1 ,3-hexadienyl, 1 ,4-hexadienyl, and the like.
  • formula (I) should be understood to include, for example, E, Z, cis, trans, (R), (S), (L), (D), (+), and/or (-) forms of the compounds, as appropriate in each case.
  • administering includes contacting, applying, delivering or providing a compound or composition of the invention to an organism, or a surface by any appropriate means.
  • treatment refers to any and all uses which remedy a disease state or symptoms, prevent the establishment of disease, or otherwise prevent, hinder, retard, or reverse the progression of disease or other undesirable symptoms in any way whatsoever.
  • terapéuticaally effective amount includes within its meaning a sufficient but non-toxic amount of a compound or composition of the invention to provide the desired therapeutic effect.
  • the exact amount required will vary from subject to subject depending on factors such as the species being treated, the age and general condition of the subject, the severity of the condition being treated, the particular agent being administered, the mode of administration, and so forth. Thus, it is not possible to specify an exact "effective amount”. However, for any given case, an appropriate "effective amount” may be determined by one of ordinary skill in the art using only routine experimentation.
  • the present invention relates to 2-benzoylpyridine thiosemicarbazone compounds and their iron complexes. More particularly, the invention relates to the use of 2-benzoylpyridine thiosemicarbazone compounds and their iron complexes as antiproliferative agents.
  • 2-benzoylpyridine thiosemicarbazone compounds of general formula (I) may be referred to as "BpT compounds", “BpT analogues”, “BpT ligands” or “BpT chelators”. Unless specifically indicated otherwise, these terms should be considered synonymous.
  • the present invention relates to the use of at least one compound of formula (I) as defined herein, or a salt, hydrate or iron complex thereof, in the manufacture of a medicament for inhibiting proliferation of rapidly proliferating cells.
  • Preferred embodiments relate to inhibition proliferation of rapidly proliferating cells in a vertebrate.
  • the vertebrate is a human.
  • compounds of formula (I) selectively target rapidly proliferating cells relative to normal cells.
  • compounds of formula (I) may selectively target rapidly proliferating cells relative to MRC-5 fibroblasts.
  • compounds of formula (I) as defined herein may be taken up by rapidly proliferating cells at a higher rate than normal cells.
  • R 1 is selected from H, C 1-6 alkyl, C 2-6 alkenyl and phenyl
  • R 2 is selected from H, C 1-6 alkyl, C 2-6 alkenyl and phenyl; wherein R 1 and R 2 may be the same or different.
  • R 1 and R 2 are the same. In another embodiment, R 1 and R 2 are different. In one embodiment, R 1 is selected from H, C 1-4 alkyl, C 2-4 alkenyl and phenyl; and R 2 is selected from H, Ci -4 alkyl, C 2-4 alkenyl and phenyl. In another embodiment, R 1 is selected from H, Ci -3 alkyl and C 2-3 alkenyl; and R 2 is selected from H, Ci -3 alkyl and C 2-3 alkenyl.
  • Another aspect of the invention relates to a subset of compounds of formula (I) having structural formula (Ia):
  • R 1 is methyl and R 2 is propyl. In a further embodiment R 1 is methyl and R 2 is isopropyl. In another embodiment R 1 is methyl and R 2 is vinyl. In a further embodiment R 1 is methyl and R 2 is allyl. In another embodiment R 1 is ethyl and R 2 is propyl. In a further 12
  • 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.
  • the reaction is carried out in the presence of a catalytic amount of acid.
  • Suitable acids include, for example, glacial acetic acid.
  • Compounds of formula (I) may be purified using standard techniques, such as recrystallisation from a suitable solvent system, or column chromatography.
  • Fe complexes of compounds of formula (I) may be prepared using standard techniques known to those skilled in the art.
  • ferrous (Fe")complexes of compounds of formula (I) may be prepared by dissolving the ligand in a polar solvent, such as an alcohol (e.g., ethanol), followed by addition of a base (e.g., Et 3 N) and an Fe(II) salt, e.g., Fe(CIO 4 ) 2 .6H 2 O, then heating the mixture at reflux to form the Fe" complex.
  • a polar solvent such as an alcohol (e.g., ethanol)
  • an Fe(II) salt e.g., Fe(CIO 4 ) 2 .6H 2 O
  • the complex may be purified by filtering and washing with a suitable solvent, and/or recrystallisation.
  • the Fe" complex may be in the form of a hydrate.
  • Ferric (Fe” 1 ) complexes of compounds of formula (I) may be prepared using a similar method which involives dissolving the ligand in a polar solvent, such as an alcohol (e.g., ethanol), then adding a base (e.g., Et 3 N) and an Fe(III) salt, e.g., Fe(CIO 4 ) 3 .6H 2 O, then heating the mixture at reflux to form the Fe(II) complex.
  • a polar solvent such as an alcohol (e.g., ethanol)
  • a base e.g., Et 3 N
  • an Fe(III) salt e.g., Fe(CIO 4 ) 3 .6H 2 O
  • the complex may be purified by filtering and washing with a suitable solvent, and/or recrystallisation.
  • the Fe 1 " complex may be in the form of a salt and/or hydrate. 11
  • R 1 is ethyl and R 2 is isopropyl. In another embodiment R 1 is ethyl and R 2 is vinyl. In a further embodiment R 1 is ethyl and R 2 is allyl.
  • Compounds of general formula (I) are tridentate Iigands that are able to chelate transition metal ions, including Fe(II) and Fe(III).
  • the present invention also includes iron complexes of compounds of formula (I).
  • the iron complex may be an Fe(II) or an Fe(III) complex.
  • a preferred embodiment of the invention relates to Fe complexes of compounds of formula (Ia).
  • the Fe complex is selected from Fe"[(Bp44mT) 2 ], Fe"'[(Bp44mT) 2 ], Fe"[(Bp4eT) 2 ] and Fe'"[(Bp4eT) 2 ], or a salt or hydrate thereof.
  • Compounds of general formula (I) are capable of modifying cellular Fe levels e.g., by releasing or 'mobilizing' intracellular pools of Fe, and inhibiting Fe-uptake from transferring (Tf), which may contribute to the antiproliferative and cytotoxic properties of these compounds.
  • Other properties of compounds of formula (I) and their Fe complexes that may contribute to the antiproliferative and cytotoxic properties include cellular uptake (e.g., the lipophilicity of the compounds which is linked to their ability to cross cell membranes), and redox cycling.
  • compounds of formula (I) may be prepared using methods well known to those skilled in the art and as described, for example, in J. March, Advanced Organic Chemistry, 4 th Edition (John Wiley & Sons, New York, 1992); and Vogel's Textbook of Practical Organic Chemistry, 5 th Edition (John Wiley & Sons, New York, 1989).
  • compounds of formula (I) may be prepared by a Schiff base condensation reaction in which a ketone or aldehyde is condensed with either an acid thiosemicarbazide to produce a Therapeutic properties
  • Compounds of formula (I) and/or their Fe complexes are particularly advantageous and show surprising in vitro and in vivo efficacy for rapidly proliferating cells and thus, may be useful for treating proliferative diseases such as cancer, e.g., solid tumours.
  • compounds of formula (I) and/or their Fe complexes may be selectively taken up by rapidly proliferating cells relative to normal cells.
  • Compounds of general formula (I) and/or their Fe complexes may have up to 100-times, 500-times, 1000-times, 1500-times, 2000-times, 2500-times, 3000-times, or 3500-times greater selectivity for rapidly proliferating cells relative to normal cells.
  • compounds of formula (I) are approximately 2000-3500-times more selective for rapidly proliferating cells relative to normal cells.
  • a compound of formula (I) is approximately 3000-times more selective for rapidly proliferating cells relative to normal cells.
  • a further particular advantage of compounds of formula (I) and/or their iron complexes is that they show surprising clinical efficacy in vivo.
  • compounds of formula (I) according to the present invention may be less cardiotoxic than other anti-cancer agents.
  • compound(s) of the invention may be administered alone.
  • the compounds may be administered as a pharmaceutical or veterinarial formulation which comprises at least one compound according to the invention.
  • the compound(s) may also be present as suitable salts, including pharmaceutically acceptable salts, or hydrates.
  • the thiosemicarbazone compounds of formula (I), and/or their iron complexes may be used in combination with other known therapies, including surgery, chemotherapeutics and radiotherapeutics.
  • chemotherapeutic agents include alkylating agents such as nitrogen mustards (e.g., mechlorethamine, cyclophosphamide, melphalan (L-sarcolysin), chlorambucil), ethylenimines and methylmelamines (e.g.
  • salt By 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 compounds according to 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.
  • the percentage of the compound(s) of formula (I) and/or (II) in pharmaceutical compositions and preparations may, of course, be varied and, for example, may 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 compound in therapeutically useful compositions is such that a suitable dosage will be obtained.
  • Dosage unit form refers to physically discrete units suited as unitary dosages for the individual to be treated; each unit containing a predetermined quantity of compound(s) is calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • the compound(s) may be formulated for convenient and effective administration in effective amounts with a suitable pharmaceutically acceptable carrier in an acceptable dosage unit.
  • the dosages are determined by reference to the usual dose and manner of administration of the said ingredients.
  • prodrug is an inactive form of a compound which is transformed in vivo to the active form.
  • Suitable prodrugs include esters, phosphonate esters etc, of the active form of the compound.
  • the compound may be administered by injection.
  • 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.
  • 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.
  • Bp4mT 2-Benzoylpyridyl 4-methyl-3-thiosemicarbazone
  • Bp4eT 2-Benzoylpyridyl 4-ethyl-3-thiosemicarbazone
  • Bp4aT 2-Benzoylpyridyl 4-allyl-3-thiosemicarbazone
  • IR (crr ⁇ 1 ) 337Ow, 1642w, 1582w, 1516s, 1468w, 1442w, 1422w, 130Ow, 1247m, 1205m, 1179m, 115Ow, 1114m, 1072w, 1047w, 991w, 962w, 921s, 836m, 796s, 770s, 734m, 699s, 664m, 619s, 567m.
  • Bp4pT 2-Benzoylpyridyl 4-phenyl-3-thiosemicarbazone
  • Bp4e4mT 2-Benzoylpyridyl 4-ethyl-4-methyl-3-thiosemicarbazone
  • Ferrous complexes of BpT compounds were prepared by the following general method.
  • the appropriate 2-benzoylpyridine thiosemicarbazone (3.5 mmol) was dissolved in EtOH (15 mL), and Et 3 N (0.35 g, 3.4 mmol) was added followed by Fe(CIO 4 ) 2 .6H 2 O (0.64 g, 1.7 mmol).
  • EtOH EtOH
  • Et 3 N 0.35 g, 3.4 mmol
  • Fe(CIO 4 ) 2 .6H 2 O 0.64 g, 1.7 mmol
  • Fe(Bp44mT) 2 Yield 76%.
  • Anal, calcd. for C 30 H 30 FeN 8 S 2 C, 57.9; H, 4.9; N, 18.0; S, 10.3%. Found: C, 57.1; H, 4.9; N, 18.0; S 1 10.3%.
  • IR (crrf 1 ) 2917w, 1586w, 1515s, 1446w, 1421w, 1386s, 1297s, 1234s, 1140s, 1012m, 963w, 920s, 817w, 770s, 741s, 695s, 632s.
  • Electronic spectrum (MeOH) ⁇ max (nm) ( ⁇ L mol "1 cm “1 ) 644 (7900), 395 (25900).
  • Fe(Bp4eT) 2 Yield 67%.
  • Anal, calcd. for C 30 H 30 FeN 8 S 2 C, 57.9; H, 4.9; N, 18.0; S, 10.3. Found: C, 57.5; H, 4.8; N, 18.0; S, 9.7%.
  • IR (cm "1 ) 3023w, 159Ow, 1527s, 1503w, 1449w, 1423m, 1380s, 1333w, 1283w, 1254s, 1198w, 115Ow, 1113w, 1087s, 1047m, 1014m, 963w, 92Ow, 874w, 826w, 771s, 741s, 691s, 645s.
  • the electrochemical properties of the Fe complexes of the BpT analogues may be significant to their anti-proliferative activity as anti-proliferative efficacy is linked with the capability of the chelator to undergo Fenton chemistry upon complexation with intracellular Fe. (References 2-4). In all cases, totally reversible Fe""" couples were identified at sweep rates between 50 and 500 mV s "1 .
  • the redox potentials of the Fe complexes are presented in Table 1.
  • the Fe ⁇ / " complexes of Bp4pT with a -NHPh terminal group showed by far the highest redox potential, while the remaining complexes cluster around a similar potential.
  • Ascorbic acid (0.1 mM) was prepared immediately prior to an experiment and incubated in the presence of Fe'" (10 ⁇ M; added as FeCI 3 ), a 50-fold molar excess of citrate (500 ⁇ M) and the chelator (1-60 ⁇ M). The excess of citrate was used to prevent hydrolytic polymerization of Fe'". Absorbance at 265 nm was measured after 10 and 40 min at room temperature and the decrease between these time points calculated. The reaction was started by the addition of ascorbic acid. The absorbance of the chelator at 265 nm was accounted for by the addition of the compound in the blank. The Fe 111 stock solution was prepared in HCI (0.1 M) to prevent hydrolytic polymerization, and then immediately added to the chelators.
  • the electrochemical data for the BpT compounds shown in Table 1 illustrate the facile interconversion between the ferric and ferrous states at potentials accessible to biological oxidants and reductants.
  • the ability of the BpT compounds to catalyse the oxidation of a physiological substrate was important to determine if redox activity played a role in anti-proliferative activity.
  • the oxidation of ascorbate mediated by the Fe complexes of the BpT compounds was examined.
  • the positive control, EDTA increased ascorbate oxidation to 357% and 382% of the control at an IBE of 1 and 3, respectively, while showing little activity at an IBE of 0.1 ( Figure 2A).
  • the BpT ligands were generally found to be significantly (p ⁇ 0.05) more effective at oxidizing ascorbate.
  • the compounds Bp4aT and Bp4pT were comparable to Dp4aT and Dp4pT respectively (WO 2004/069801). While the compounds BpT, Bp4mT, and Bp4aT showed ascorbate oxidation activity comparable to that of EDTA, Bp4eT exhibited significantly (p ⁇ 0.01) higher ascorbate oxidative activity than EDTA at an IBE of 1 and 3.
  • the human SK-N-MC neuroepithelioma cell line, MIAPaCa-2, PANC-1 and AsPC-1 prostate cancer cells were purchased from the American Type Culture Collection (ATCC), Rockville, MD, USA.
  • the normal cell type MRC-5 fibroblasts were also obtained from the American Type Culture Collection (ATCC), Rockville, MD, USA.
  • the cells were grown in Eagle's modified minimum essential medium (MEM; Gibco BRL, Sydney, Australia) containing 10% FCS (Commonwealth Serum Laboratories, Melbourne, Australia), 1% (v/v) non-essential amino acids (Gibco), 2 mM L-glutamine (Sigma Chemical Co., St.
  • MTT 3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyl tetrazolium
  • MEM MEM medium containing all supplements as described above (complete medium) and also 1.25 ⁇ M human diferric Tf. This seeding density resulted in exponential growth of the cells for the duration of the assay.
  • the cells were grown overnight and the compounds to be tested were then added in 0.1 mL of complete medium containing 1.25 ⁇ M diferric transferrin. The final concentration of the compounds was 0.39-50 ⁇ M. Control samples contained complete medium and 1.25 ⁇ M diferric Tf.
  • Example 6.1 Anti-proliferative Activity of BpT Ligands against Tumour Cells
  • the ability of the BpT compounds to inhibit cellular proliferation was assessed using SK-N-MC neuroepithelioma cells.
  • the BpT compounds were compared to a number of relevant positive controls, including DFO, which is used for the treatment of Fe overload, the ligand 2-hydroxy-1-napthylaldehyde isonicotinoyl hydrazone (NIH), and the clinically trialed chelator 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (Triapine ® ; 3-AP) that has been designed for cancer therapy (Figure 1). These results are presented in Table 1.
  • BpT analogues have high anti-proliferative activity (Table 1).
  • the BpT compounds are a surprisingly effective series of chelators having anti-proliferative activity.
  • the compound Bp4eT was shown to have marked activity against the human prostate cancer cell lines MIAPaCa-2, PANC-1 and AsPC-1 with IC 50 values ⁇ 0.002 ⁇ M; Table 2). Significantly, the activity of Bp4eT was far greater than that observed for gemcitabine and 5-flurouracil, current treatments of prostate cancer, with IC 50 values for these agents ranging from 0.012-76 ⁇ M and 24.3-112 ⁇ M respectively.
  • the formation of the Fe complex may result in a more lipophilic species because of the inaccessibility of the donor atoms to the solvent, and is therefore better able to penetrate cellular membranes in comparison to the free ligand. Therefore, pre-complexation may lead to higher concentrations of the redox-active Fe complexes within cells, resulting in greater anti-proliferative effects.
  • lipophilic metal complexes may act as transport vehicles, dissociating after entry into the cell and as a consequence, delivering the toxic metal ion to the cell, acting as lipid soluble delivery shuttles.
  • BpT was found to be one of the most hydrophilic members of the BpT series, its Fe complex may act as a lipophilic shuttle, allowing intracellular access of the ligand and metal, mediating their cytotoxic effects simultaneously.
  • BpT compound Selectivity for neoplastic cells relative to normal cells is important for anti-cancer therapies. Therefore, for a BpT compound to be an effective anti-tumour agent in vivo, it must exhibit potent anti-proliferative activity against neoplastic cells while leaving normal cells unaffected.
  • the chelator-mediated increase in cellular Fe mobilization was not mediated by their cytotoxic effects as the cells remained viable within the short 3 h of incubation used.
  • Example 7.2 Inhibition of Cellular 59 Fe Uptake from 59 Fe Transferrin by BpT Chelators
  • Tf serum Fe-binding protein transferrin
  • the positive controls NIH and PIH were found to effectively reduce 59 Fe uptake to 9 ⁇ 1% and 21 ⁇ 1% of the control, respectively ( Figure 3B).
  • net tumour size was 313% of the initial volume.
  • mice treated with 0.4 mg/kg Dp44mT or 0.4 mg/kg Bp4eT experienced weight loss of 18% and 12% of initial body weight, respectively, (Figure 4B) after 49 days of treatment. Control mice in this experiment lost 8% of initial body weight ( Figure 4B).

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Abstract

L'invention porte sur un procédé de traitement d'une maladie proliférative chez un vertébré, le procédé comprenant l'administration au vertébré d'une quantité thérapeutiquement efficace d'au moins un composé de formule (I) (I) dans laquelle R1 est choisi parmi H, alkyle en C1-6, alcényle en C2-6 et phényle ; R2 est choisi parmi H, alkyle en C1-6, alcényle en C2-6 et phényle ; R1 et R2 étant les mêmes ou différents, ou d'un sel, hydrate ou complexe du fer de celui-ci, ou d'une composition pharmaceutique comprenant ledit composé, sel, hydrate ou complexe du fer et un véhicule, diluant ou excipient pharmaceutiquement acceptable.
PCT/AU2008/000961 2008-06-30 2008-06-30 Composés thiosemicarbazones et leur utilisation Ceased WO2010000008A1 (fr)

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8128929B2 (en) 2005-06-17 2012-03-06 Imclone Llc Antibodies against PDGFRa
WO2013169361A1 (fr) * 2012-05-09 2013-11-14 Howard University Chélateurs du fer en tant qu'inhibiteurs du vih-1
EP2651894A4 (fr) * 2010-12-17 2014-07-09 Des R Richardson Composés de thiosemicarbazone et utilisation dans le traitement du cancer
CN111233837A (zh) * 2020-02-05 2020-06-05 李本 一种缩氨基硫脲的化合物及其制备方法和用途
CN112500447A (zh) * 2020-12-15 2021-03-16 天津市第一中心医院 新型糖基化二价铂抗肿瘤化合物制备方法

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8128929B2 (en) 2005-06-17 2012-03-06 Imclone Llc Antibodies against PDGFRa
EP2651894A4 (fr) * 2010-12-17 2014-07-09 Des R Richardson Composés de thiosemicarbazone et utilisation dans le traitement du cancer
EP3287442A1 (fr) * 2010-12-17 2018-02-28 Des R Richardson Composés de thiosémicarbazone et leur utilisation dans le traitement du cancer
WO2013169361A1 (fr) * 2012-05-09 2013-11-14 Howard University Chélateurs du fer en tant qu'inhibiteurs du vih-1
CN111233837A (zh) * 2020-02-05 2020-06-05 李本 一种缩氨基硫脲的化合物及其制备方法和用途
CN112500447A (zh) * 2020-12-15 2021-03-16 天津市第一中心医院 新型糖基化二价铂抗肿瘤化合物制备方法

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