WO2012160337A1 - Oligosaccharides sulfatés à utiliser dans le traitement de maladies neurodégénératives - Google Patents

Oligosaccharides sulfatés à utiliser dans le traitement de maladies neurodégénératives Download PDF

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Publication number
WO2012160337A1
WO2012160337A1 PCT/GB2012/000468 GB2012000468W WO2012160337A1 WO 2012160337 A1 WO2012160337 A1 WO 2012160337A1 GB 2012000468 W GB2012000468 W GB 2012000468W WO 2012160337 A1 WO2012160337 A1 WO 2012160337A1
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compound
fucose
alkyi
nitro
hydroxy
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PCT/GB2012/000468
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English (en)
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Colin Campion
Adrian Peter John PINI
Robindra Nathan GOGOI
Jonathan GILTHORPE
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Kings College London
Carbohydrate Synthesis Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H11/00—Compounds containing saccharide radicals esterified by inorganic acids; Metal salts thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
    • C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
    • C07H13/04—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids having the esterifying carboxyl radicals attached to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/02—Acyclic radicals, not substituted by cyclic structures
    • C07H15/04—Acyclic radicals, not substituted by cyclic structures attached to an oxygen atom of the saccharide radical

Definitions

  • the present invention relates to novel compounds, pharmaceutical compositions comprising the compounds, processes for their preparation, as well as to the use of the compounds in the inhibition of histories, in particular histone HI.
  • the invention also relates to the compounds for use in medicine and particularly in the prevention and/or treatment of a disease, selected from: a neurodegenerative disease including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), neurodegeneration, dementia, vascular dementia, multiple sclerosis, a neuroinflammatory or inflammatory condition, or a disease state associated with aberrant histone levels.
  • a disease selected from: a neurodegenerative disease including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), neurodegeneration, dementia, vascular dementia, multiple sclerosis, a neuroinflammatory or inflammatory condition, or a disease state associated with aberrant histone levels.
  • the present invention also relates to use in the prevention and/or treatment of conditions that affect any organ or tissue that results in cellular damage and the release of histones due to pathology, infection, trauma, infarct/ischaemia, or sequelae arising from bacterial, fungal or viral infection or sepsis.
  • conditions include neurological disorders and conditions.
  • Histones are highly basic proteins that function in the nucleus to package chromatin and regulate transcription, It is usually assumed that they are restricted to the nucleus but a growing body of evidence indicates that certain histones and histone-derived peptides have cytoplasmic and extracellular locations, reviewed In [1]. When brain cells die they release histones into the extracellular environment where it is most probable that they exert toxic effects on neighbouring nerve cells.
  • histones can be cytotoxic to a variety of microorganisms and mammalian cells [5-8].
  • histones can be toxic to malignant cells when applied exqgenously and it has been suggested that this extracellular action could have therapeutic implications [9].
  • histones are toxic to cortical neurons [ 14-16 ⁇ . Under cold stress, cortical slices lose their ability to increase respiration in response to electrical stimulation. This is accompanied by migration of histones from the nucleus into the cytoplasm where they associate with microsomes and mitochondria (which swell). The loss of response is most likely to result from inhibition of oxidative metabolism of ATP and is completely reproduced by addition of soluble histones to the culture medium. Thus, under certain conditions histones can be liberated from the nucleus and taken up with both events leading to neuronal toxicity.
  • Histones are also implicated in the formation of insoluble protein deposits. They bind to the Parkinson's disease-associated protein o-synuclein and increase its fibrillation rate [21-23] , Histones also bind Alzheimer ⁇ - amyloid precursor protein (APP) and to ⁇ -amyloid with high affinity [23, 24]. Since histones are found extraceilulariy within amyloid plaques in AO brain [25] an increase in their expression could be a catalyst for neuronal death and would be consistent with the findings of raised antibody titres. As such histones are likely to be important and overlooked therapeutic targets that can be used to delay the progression of AD.
  • APP Alzheimer ⁇ - amyloid precursor protein
  • the target(s) can be members of the highly conserved histone family of proteins (HI, H2A, H2B, H3, H4) and their isoforms.
  • Histones are highly basic and are normally present in the nucleus where they form the major protein components of eukaryotic chromatin.
  • Histones H2A, H2B, H3 and H4 are 'core' histones, have relatively similar structures and form an octameric arrangement termed the nucleosome, which packages genomic DNA.
  • the linker histone Hi binds between nucleosomes and are much more variable in their sequences.
  • Histones which are released following apoptosis or necrosis of neurons and other cells are released into the extracellular space where they are neurotoxic and induce reactive gliosis, a hallmark of AD. Very little is known of the mechanisms by which extracellular histones mediate neurotoxicity/neuroinflammation but a requirement for glycosaminoglycan-containing ceil surface molecules has now been found for their endocytosis and toxicity.
  • GAGs such as low molecular weight heparin (L WH) derivatives are neuroprotective In vivo and in vitro [26- 30].
  • Histones appear to bind to cell surface receptors that contain CSPG/HSPG modifications since ceils that are defective in these receptors do not take up histones.
  • microglia In all neurodegenerative diseases neurons die and cells of the immune system called microglia become activated and also contribute to neuronal death. It has now been found that nanomolar concentrations of extracellular histones, especially HI which is released on cell death, kill neurons and activate microglia and that certain heparin and chondroitin carbohydrates can reduce these effects in culture.
  • histone inhibitors may be useful in the treatment of a variety of neurodegenerative diseases
  • the development of inhibitors with good activity, selectivity and pharmacokinetic profiles is needed to fully exploit the clinical potential of this target.
  • the present invention provides compounds which interact selectively with at. least one histone, in particular histone HI.
  • the histone is selected from mammalian histones,- more preferably human histones, including at least one of histone HI, H2A, H2B y 3 OF 4 or a- combination thereof.
  • the invention provides a compound selected from the group of compounds represented by the genera! formula :
  • Ri is H, alkyl, or cydoalkyi; alkyl or cydoalkyi optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogen, alkoxy, alkenyl, alkynyl, nitro, amino, an amino acid or a polypeptidyl residue, or by aryl or heteroary!
  • one to three non-adjacent CH 2 groups may be optionally replaced by NR', S or 0, where R" is H or alkyl, cydoalkyi or a sugar residue; or one to three non-adjacent CH 2 groups may be optionally replaced by aryl or heteroaryi optionally substituted with aikyl, hydroxy, chloro, bromo, alkoxy, alkenyl, alkynyl, nitro, or an amino group;
  • Rz has the general formula:
  • R 3 is alkyi, or cycloalkyi; alkyi or cycloalkyi optionally substituted with one or more substituents selected from the group consisting of hydroxy, chloro, bromo, alkoxy, alkenyl, alkynyl, nitro, amino, an amino acid or a pclypeptidyl residue, or by aryl, heteroaryl optionally substituted with alkyi, hydroxy, halogen, alkoxy, alkenyl, alkynyl, nitro, or an amino group; and when R 3 is alky!
  • one to three non-adjacent CH 2 groups may be optionally replaced by NfV, S or 0 where - is H or a!kyl or cycloalkyi; or when ⁇ is alkyi or cycloalkyi, one to three non-adjacent CH 2 groups may be optionally replaced by aryl or heteroaryl substituted with alkyi hydroxy, halogen, alkoxy, alkenyl, aikynyl, nitro, or an amino group;
  • Me is methyl
  • Sulfation is preferred at at least one of the arrowed positions, more preferably at at least two of the arrowed positions, more preferably at at least three of the arrowed positions, more preferably at at least four of the arrowed positions, even more preferably at all five of the arrowed positions; or a pharmaceutically acceptable salt, hydrate, solvate, geometrical isomer, tautomer, optical isomer, or prodrug form thereof.
  • X is sulfate (-S0 3 H) or phosphate (-P0 3 H);
  • Ri is H, alkyi, or cycloalkyi; alkyi or cycloalkyi optionally substituted with one or more substituents selected from the group consisting of hydroxy, chloro, bromo, alkoxy, nitro, amino, an amino acid or a poiypeptidyl residue, cr by phenyl substituted with lower alkyi hydroxy, chloro, bromo, alkoxy, nitro, or an amino group; and when i is alkyi or cycioalkyl, one to three non-adjacent CH 2 groups may be optionally replaced by IMR', S or 0, where R' is H or alkyi, cycioalkyl or a sugar residue; or one to three non-adjacent CH 2 groups may be optionally replaced by phenyl or phenyl substituted with lower alkyi hydroxy, chloro, bromo, alkoxy, nitro r or an amino group;
  • R 2 has the general formula ;
  • R 3 is alkyi, or cycioalkyl; alkyi or cycioalkyl optionally substituted with one or more substituents selected from the group consisting of hydroxy, chloro, bromo, alkoxy, nitro, amino, an amino acid or a polypeptidyl residue, or by phenyl optionally substituted with alkyi, hydroxy, chloro, bromo, alkoxy, nitro, or an amino group; and when R 3 is alkyi or cycioalkyl, one to three non-adjacent CH 2 groups may be optionally replaced by NR ⁇ S or O where R' is H or alkyi or cycioalkyl; or when 3 is alkyi or cycioalkyl, one to three non-adjacent CH 2 groups may be optionally replaced by phenyl or phenyl substituted with lower alkyi hydroxy, chloro, bromo, alkoxy, nitro, or an amino group.
  • the invention provides a compound selected from the group consisting of compounds represented by the general forumula:
  • the compounds of the invention possess the ability to inhibit the activity of at least one histone.
  • the histone is preferably selected from a mammalian histone, more preferably a human histone, even more preferably HI, H2A, H2B, H3 or H4 or a combination thereof.
  • Such compounds may be useful in the treatment of a wide variety of conditions including a neurodegenerative disease including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), neurodegeneratlon, dementia, vascular dementia, multiple sclerosis, a neuroinflammatory or inflammatory condition, or a disease state associated with aberrant histone levels.
  • a neurodegenerative disease including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), neurodegeneratlon, dementia, vascular dementia, multiple sclerosis, a neuroinflammatory or inflammatory condition, or a disease state associated with aberrant histone levels.
  • the present invention also relates to use in the prevention and/or treatment of conditions that affect any organ or tissue that results in cellular damage and the release of histories due to pathology, infection, trauma, infarct/ischaemia, or sequelae arising from bacterial, fungal or viral infection or sepsis.
  • conditions include neurological disorders and conditions.
  • compounds of the invention may be useful in the prevention of medical conditions described above either when used alone or in combination with other chemotherapeutic agents.
  • Figure 1 shows the appearance of histones in AD
  • the right and far left panels show the abnormal appearance of histones in human AD.
  • the middle panel shows histone HI in glia and in amyloid plaques in a transgenic AD mouse.
  • Phosphory!ated histone H3 is a nuclear marker for the M-phase of normal cell division but becomes activated and re-localised to the cytoplasm of neurons in AD [18] see far left panel in Fig. 2. There is compelling evidence that aberrant re-entry into the cell cycle may be a significant cause of neuronal cell death in AD [19]. Moreover, following UV-induced damage, the histone isoform, HI.2, translocates from the nucleus to the cytoplasm and triggers apoptosis [20]. Thus, (consistent with 14-16) one source of extracellular histones might be those re-localised in the cytoplasm while another could be that released from the nuclei of disintegrating cells. Potentially, extracellular histones could act both at the cell surface and within the cytoplasm following uptake.
  • Figure 2 has three panels which show cultures of mixed cartica! neurons and glia which have been exposed to 7.5 nM of fluorescently labelled histone protein HI for 24 hrs.
  • the left hand panel shows trafficking of histone Hi to ER surrounding the nucleus in neuron (this route is taken by numerous toxins and viruses).
  • the chromatin ⁇ DAPI blue) is condensing, the neuron is under ER stress and is dying.
  • histone HI fluorescently labelled histone HI is taken up b/ neurons, astrocytes, HeLa and CHO cells but that only neurons die. Hence an accumulation of extracellular histones could exacerbate neurotoxicity and as cell death increases ou!d produce an auto-catalytic cascade of neuronal cell death.
  • Figure -3 has three panels. On the left is a confocal z-projection of a section of temporal cortex stained for histone HI that came from a 68 year old neurologically normal woman who died from a perforated ulcer. There is no extranuclear expression of histone.
  • the middle panel shows temporal cortex of a 70 year old woman who died from AD and demonstrates extensive extracellular deposits of histone Hi.
  • the right hand panel shows that histone HI is also distributed extracellu!arly in a transgenic AD model (Swedish and London point mutations to human Amyloid Precursor Protein) expressed under the Thy 1 promoter.
  • Figure 4 has two panels. Both panels show mixed neuronal and glial cultutes of rat neocortex.
  • the left hand panel shows the effects of 30nM fluorescently labelled histone H I (red) application for 24hrs. Histone has killed the majority of the neurons whose disintegrating nuclei are labelled with fluorescent HI. Glial cells are seen in blue.
  • the right hand panel shows that histone toxicity is prevented by a GAG, chondroitin sulphate C.
  • FIG. 5 shows possible points of attack in an histone amplification cascade using drugs and humanised antibodies.
  • Histones are present abnormally in AD and contribute to disease progression through the amplification cascade.
  • Histones bind to Alzheimer ⁇ -amyloid precursor protein (APP) and to ⁇ -amyioid with high affinity and are found within amyloid plaques in AD brain.
  • APP Alzheimer ⁇ -amyloid precursor protein
  • ⁇ -amyioid with high affinity and are found within amyloid plaques in AD brain.
  • an increase in their expression could be a catalyst for neuronal death and gliosis.
  • Figure 6 shows a schematic representation of likely cell surface glycoprotein histohe receptors.
  • Histones bind to CSPG/HSPG glycan decorations (wavy lines) on cell- suface proteoglycan receptors. It has now been shown that co-application of histones and soluble sulphated GAGs prevent histone binding and uptake, whereas pre-treatment with a GAG does not (indicating that the . GAG acts as decoy receptor and binds direct!y to the histone) . Furthermore, histones do not bind to a CSPG/HSPG-defident cell-line or cells that have had their GAG decorations stripped away using heparinase or chondroitinase.
  • the major candidate receptors are members of the glypican (GPI-linked, orange circle) or syndecan (transmembrane, blue rectangle) families.
  • Another strong candidate is APP, which contains a single HSPG modification and is a known histone-binding protein. Rece tor- mediated uptake in neurons results in cell death but elicits proliferation and differentiation of glial cells (astrocytes), which contribute to neuropathogenesis.
  • a therapeutic compound according to the invention targets histones in the extracellular space and prevents receptor binding.
  • the invention provides a compound selected from the group of compounds represented by the general formula :
  • Ri is H, alkyl, or cycloaikyi; alkyl or cycloaikyi optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogen, alkoxy, alkenyl, alkynyl, nitro, amine, an amino acid or a polypeptidyl residue, or by aryl ar heteroaryl optionally substituted with alkyl, hydroxy, halogen, alkoxy, alkenyl, alkynyl, nitro, or an amino group; and when Ri is alkyl or cycloaikyi, one to three non-adjacent CH 2 groups may be optionally replaced by NR', S or 0, where R' is H or alkyl, cycloaikyi or a sugar residue; or one to three non-adjacent CH 2 groups may be optionally replaced by aryl or heteroaryl optionally substituted with alkyl, hydroxy, chloro, bromo, alkoxy, alkenyl, alky
  • R 2 has the general formula :
  • R 3 is alky!, or cycloalkyl; alkyl or cydoalkyl optionaliy substituted with one or more substituents selected from the group consisting of hydroxy, chloro, bromo, alkoxy, alkenyl, alkynyl, nitro, amino, an amino acid or a po!ypeptidyl residue, or by aryl, heteroaryl optionally substituted with alkyl, hydroxy, halogen, atkoxy, alkenyl, alkynyl, nitro, or an amino group; and when j is alkyl or cycloalkyl, one to three non-adjacent CHj groups may be optionally replaced by NR', S or 0 where R' is H cr alkyl or cycloalkyl; or when R 3 is alkyl or cycloalkyl, one to three non-adjacent CH 2 groups may be optionally replaced by aryl or heteroaryl substituted with alkyl hydroxy, hal
  • Me is methyl
  • Sulfation is most likely at the arrowed positions or a pharmaceutically acceptable derivative, analogue, salt, hydrate, solvate, geometrical isomer, tautomer, optical isomer, or prodrug form thereof.
  • X is sulfate (-50 3 ⁇ ) or phosphate ( -P0 3 H);
  • Rj is H, alkyl, or cycloalkyl; alkyl or cycloalkyl optionally substituted with one or more substituents selected from the group consisting of hydroxy, chloro, bromo, alkoxy, nitro, amino, an amino acid or a polypeptidyl residue, or by phenyl substituted with lower alkyl hydroxy, chloro, bromo, alkoxy, nitro, or an amino group; and when i is alkyl or cycloalkyl, one to three non-adjacent CH 2 groups may be optionally replaced by NR', S or O, where R' is H or alkyl, cycloalkyl or a sugar residue; or one to three non-adjacent CH 2 groups may be optionally replaced by phenyl or phenyl substituted with lower alkyl hydroxy, chloro, bromo, alkoxy, nitro, or an amino group;
  • R 2 has the general formula:
  • R 3 is alkyl, or cycloalkyl; alkyl or cycloalkyl optionaliy substituted with one or more substituents selected from the group consisting of hydroxy, chloro, rom , alkoxy,, nitro, amino, an amino acid or a polypeptidyl residue, or by phenyl optionally substituted with alkyl, hydroxy, chloro, bromo, alkoxy, nitro, or an amino group; and when R 3 is alkyl or cycloalkyl, one to three non-adjacent CH 2 groups may be optionally replaced by NR' ( S or O where R' is H or alkyl or cycloalkyl; or when R3 is alkyl or cycloalkyl, one to three non-adjacent CH 2 groups may be optionally replaced by phenyl or phenyl, substituted with lower alkyl hydroxy, chloro, bromo, alkoxy, nitro, or an amino group.
  • Preferred compounds comprise less than about 10 sugars, more
  • sugars are selected from L-Fticose alpha linked, D-Glucosamine beta linked, D-Glucose alpha or beta linked, D- Mannose alpha linked, D-Galactose alpha or beta linked to other sugars.
  • the invention provides a pharmaceutical formulation comprising a compound of the invention and a pharmaceutically acceptable diluent or carrier.
  • a pharmaceutical formulation comprising a compound of the invention and a pharmaceutically acceptable diluent or carrier.
  • the invention provides a process for the preparation of a compound of the invention as described below, which comprises at least one of the steps of:
  • the process comprises all of steps a) to c).
  • the invention provides a method for the prophylaxis or treatment of a disorder associated with aberrant histone level which comprises administering to a subject in need of such treatment an effective amount of a compound or a pharmaceutical formulation of the invention.
  • the condition is selected from a neurodegenerative disease including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), ; neurodegeneration, dementia, vascular dementia, multiple sclerosis, a neuroinflammatory or inflammatory condition, or a disease state associated with aberrant histone levels.
  • a neurodegenerative disease including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), ; neurodegeneration, dementia, vascular dementia, multiple sclerosis, a neuroinflammatory or inflammatory condition, or a disease state associated with aberrant histone levels.
  • the present invention also relates to use in the prevention and/or ' treatment , of conditions that affect any organ or tissue that results in cellufer damage and the release of histones due to pathology, infection, trauma, infarct/ischaemia, or sequelae arising from bacterial, fungal or viral infection or sepsis.
  • conditions include neurological disorders and conditions.
  • the compound, or the pharmaceutical formulation of the invention is administered in combination with other chemotherapeuttc agents.
  • the invention provides a method for modulating histone activity which comprises administering to a subject in need of such treatment an effective amount of a compound or a pharmaceutical formulation of the Invention.
  • the invention provides a compound of the invention for use in therapy, especially for use in the prophylaxis or treatment of a disorder associated with aberrant histone levels.
  • a further aspect of the invention is the use of a compound as mentioned above for the manufacture of a medicament for use in the prophylaxis or treatment of a disorder associated with aberrant histone !evel.
  • the compound may be administered in combination, with other chemotherapeutic agents.
  • disorders associated with aberrant histone level include a disease or condition selected from a neurodegenerative disease including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), neurodegeneration, dementia, vascular dementia, multiple sclerosis, a neuroinflarnmatory or inflammatory condition, or a disease state associated with aberrant histone levels.
  • a neurodegenerative disease including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), neurodegeneration, dementia, vascular dementia, multiple sclerosis, a neuroinflarnmatory or inflammatory condition, or a disease state associated with aberrant histone levels.
  • the present invention also relates to use in the prevention and/or treatment of conditions that affect any organ or tissue that results in cellular damage and the release of histones due to pathology, infection, trauma, infarct/tschaemia, or sequelae arising from bacterial, fungal or viral infection or sepsis.
  • conditions include neurological disorders and conditions,
  • alkyl denotes a straight or branched alky! group.
  • said alkyl group is a "lower alkyl” having from 1 to 5 carbon atoms (“G-s-alkyl”).
  • Examples of said lower alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl and straight- and branched-chain pentyl and hexyl.
  • Ci.5-alkyl, C ⁇ -alky C 1- alkyi, C J-2 -alkyl, C 2 -6-alkyl, C 2 .s-alkyi, C z . ⁇ -alkyl, C 2- j-alkyl, C 3 . 6 -alkyl, C4.5-alk.yl, etc
  • Halo-C ⁇ -alkyl means a C 1-6 - alkyl group substituted with one or more halogen atoms.
  • aryl- Cx. f i-alkyi means a C 1-6 -alkyl group substituted with one or more aryl groups.
  • cycloalkyl denotes a cyclic alkyl group preferably having a ring size from 3 to 8 carbon atoms (' , C 3 .g-cyc!oa!ky!' r ⁇ .
  • examples of said cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclohexy!, cycloheptyl, and cyclooctyl.
  • C 3 . $ -cycloalkyl all subgroups thereof are contemplated such as C 3 .7-cycioalkyl, C 3 .
  • alkoxy denotes a straight or branched alkoxy group.
  • said alkoxy group is a "lower alkoxy” group having from 1 to 6 carbon atoms ("G. 6 alkoxy”).
  • Examples of said lower alkoxy include methoxy, ethoxy, n-propoxy, iso-propoxy, n- butoxy, iso-butoxy, sec-butoxy, t-butoxy and straight- and branched- chain pentoxy and- hexoxy.
  • Ci -$ -alkoxy For parts of the range 3 ⁇ 4 Ci -$ -alkoxy" all subgroups thereof are contemplated such as C 1-5 -alkoxy, C ⁇ -a!koxy, Ci-3- alkoxy, G ⁇ -alkoxy, C 2 .6-alkoxy, G-s-alkoxy, C 2 ⁇ -aikoxy, Cz-3-alkoxy, C 3 -6- alkoxy, Gt -5 -alkoxy ; etc.
  • alkenyl means a straight chain or branched a!kenyl radical preferably of 2 to 6 carbon atoms and containing one or more carbon-carbon double bonds and includes but is net limited to ethylene, n-propyi-l-ene, n-propyl-2-ene, isopropylene, etc.
  • alkynyl means a straight chain or branched alkynyl radical preferably of 2 to 6 carbon atoms and containing one or more carbo -carbon triple bonds and includes but is not limited to ethynyl, 2-methylethynyl etc. -
  • aryl refers to a hydrocarbon ring system, which is preferably a 3-10, membered ring system, having at least one aromatic ring or being fused to one or more saturated or unsaturated rings including, but not limited to phenyl, pentaienyl, indenyl, indanyl, isoindolinyl, chromanyl, na ' phthyl, fluorenyl, anthryl, phenanthryl and pyrenyl,
  • the aryl rings may optionally be substituted with G. 6 -alkyl. Examples of substituted aryl groups are benzyl and 2-methylphenyl.
  • aryloxy refers to an aryl group banded to an oxygen atom .
  • heteroaryl refers to a hydrocarbon ring system having at least one aromatic ring which contains at least one heteroatom such as 0, N, or S, Preferably the hydrocarbon ring system is a 3-10 membered ring system.
  • heteroaryl groups include furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, thia2olyl, isothiazolyl, pyridinyl, pyrimidinyl, quinazolinyi, indoiyl, pyrazolyl, pyridazinyl, quinolinyl, benzofuranyl, dihydrobenzofuranyl, benzodioxolyl, benzodioxinyi, benzothiazclyl, , benzothiadiazolyl, and benzotriazolyl groups.
  • Heterocyclyl means a preferably 3-10 membered ring system containing one or more heteroatoms selected from N, 0 or S and includes heteroaryl.
  • the heterocyclyl system can contain one ring or may be fused to one or more saturated or unsaturated rings; the heterocyclyl can be fully saturated, partially saturated or unsaturated and includes but is not limited to heteroaryl and heterocarbocyclyl.
  • carbocyclyl or heterocyclyl groups include but are not limited to cyclohexyl, phenyl, acridlne, benzimidazole, benzofuran, benzothiophene, benzoxazole, benzothiazole, carbazole, cinnoiine, dioxln, dioxane, dioxolane, dithiane, dithia2ine, dithiazoie, dithiolane, furan, imidazole, imidazoline, imidazolidine, indole, indoline, indolizine, indazole, isoindole, isoquinoline, isoxazole, isothiazole, morpholine, napthyridine, oxazole, oxadiazole, oxathiazole, oxathiazolidine, oxazine, oxadiazine, phenazine, phenothiazine,
  • halogen shall mean fluorine, chlorine, bromine or iodine.
  • leaving group refers to a group to be displaced from a molecule during a nudeophiiic displacement reaction.
  • leaving groups are bromide, chloride and methanesulfonate, especially bromide and methanesulfonate
  • interact means affecting the binding or activity of a molecule. This includes competitive binding, agonism and antagonism .
  • “Pharmaceutically acceptable” means being useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable and includes being useful for veterinary use as well as human pharmaceutical use, "Treatment” as used herein includes prophylaxis of the named disorder or condition, or amelioration or elimination of the disorder once it has been established,
  • “An effective amount” refers to an amount of a compound that confers a therapeutic effect on the treated subject
  • the therapeutic effect may be objective (i.e. , measurable by some test or marker) or subjective (i.e., subject gives an indication of or feels an effect).
  • prodrug forms means a pharmacologically acceptable derivative, such as an ester or an amide, which derivative is biotransformed in the body to form the active drug.
  • pharmacologically acceptable derivative such as an ester or an amide
  • ACN means acetonitrile
  • DEA diethylamide
  • DEPT means distortion enhancement polarisation transfer
  • D SO means dimethyl sulfoxide
  • ELS electron light scattering
  • HPLC means high performance liquid chromatography
  • TFA means trifluoroacetic acid
  • THF means tetrahydrofuran
  • TLC means thin layer chromatography
  • Neurodegenerative diseases are chronic degenerative diseases of the Central Nervous System (CNS) that often cause dementia, Although for the most part the causes and mechanisms of this collection of brain diseases are not well known, they are increasing in incidence in the developed as well as the underdeveloped world and are often found in the aging population. These diseases are characterized by molecular changes in nerve cells that result in nerve cell degeneration and ultimately nerve dysfunction and cell death, resulting in neurological signs and symptoms and in extreme cases dementia. There appears to be a genetic link to neurodegenerative diseases, but the genetic changes that occur and the changes in gene expression that are found in these diseases are complex. One of the types of change found in essentially all neurological degenerative diseases is the over-expression of oxidative free radical compounds (oxidative stress) that cause lipid, protein and genetic structural changes.
  • oxidative free radical compounds oxidative stress
  • the compounds of the invention may be used as such or, where appropriate, as pharmacologically acceptable salts (acid or base addition salts) thereof.
  • pharmacologically acceptable addition salts mentioned above are meant to comprise the therapeutically active non-toxic acid and base addition salt forms that the compounds are able to form.
  • Compounds that have basic properties can be converted to their pharmaceutically acceptable acid addition salts by treating the base form with an appropriate acid.
  • Exemplary acids include inorganic acids, such as hydrogen chloride, hydrogen bromide, hydrogen iodide, sulfuric, acid, phosphoric acid; and organic acids such as formic acid, acetic acid, propanoic acid, hydroxyacetic acid, lactic acid, pyruvic acid, glycolic acid, maleic acid, malonic acid, oxalic acid, benzenesulfonic acid, to!uenesulfonlc acid, methanesulfonic acid, trifluoroacetic acid, fumaric acid, succinic acid, malic acid, tartaric acid, citric acid, salicylic acid, p-aminosalicylic acid, pamoic acid, benzoic acid, ascorbic acid and the tike.
  • inorganic acids such as hydrogen chloride, hydrogen bromide, hydrogen iodide, sulfuric, acid, phosphoric acid
  • organic acids such as formic acid, acetic acid, propanoic acid, hydroxyacetic acid, lactic acid,
  • Exemplary base addition salt forms are the sodium, potassium, calcium salts, and salts with pharmaceutically acceptable amines such as, for example, ammonia, alkylamines, benzathine, and amino acids, such as, e.g. arginine and lysine.
  • the term addition salt as used herein also comprises solvates which the compounds and salts thereof are able to form, such as, for example, hydrates, alcohoiates and the like.
  • the compounds of the invention are formulated into pharmaceutical formulations for oral, rectal, parenteral or other mode of administration.
  • Pharmaceutical formulations are usually prepared by mixing the active substance, or a pharmaceutically acceptable salt thereof, with a conventional pharmaceutical excipient (a pharmaceutically acceptable diluent or carrier).
  • excipients are water, gelatin, gum arabicum, lactose, microcrystalline cellulose, starch, sodium starch giycolate, calcium hydrogen phosphate, magnesium stearate, talcum, colloidal silicon dioxide, and the like.
  • Such formulations may also contain other pharmacologically active agents, and conventional additives, such as stabilizers, wetting agents, emulsifiers, flavouring agents, buffers, and the like.
  • the use of such excipients for pharmaceutical active substances is well known in the art. Except in so far as conventional excipient is incompatible with the active compound, use thereof in the pharmaceutical formulation of the invention is contemplated.
  • Such formulations may also contain other pharmacologically active agents, and conventional additives, such as stabilizers, wetting agents, emulsifiers, flavouring agents, buffers, and the like,
  • the formulations can be further prepared by known methods such as granulation, compression, microencapsulation, spray coating, etc.
  • the formulations may be prepared by conventional methods in the dosage form of tablets, capsules, granules, powders, syrups, suspensions, suppositories or injections.
  • Liquid formulations may be prepared by dissolving or suspending the active substance in water or other suitable vehicles. Tablets and granules may be coated in a conventional manner.
  • Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as ben2yl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide.
  • the parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.
  • compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion.
  • suitable carriers include physiological saline, bacteriostatic water, Cremophor ELTM (BASF, Parsippany, NJ) or phosphate buffered saline (PBS).
  • the composition must be sterile and should be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, poiyol (for example, glycerol, propylene glycol, and liquid polyetheylene glycol, and the like ⁇ , and suitable mixtures thereof.
  • 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 various antibacterial and antifungal agents, for example, parabens, 'chlorobutanol, phenol, ascorbic acid, thimerosal, and the like.
  • isotonic agents for example, sugars, polyalcoho
  • Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum mono stearate and gelatin.
  • Sterile injectable solutions can be prepared by incorporating the active compound (e.g., a compound according to an embodiment of the invention) in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the active compound into a sterile vehicle which contains a basic dispersion medium and the required other ingredients . from those enumerated above.
  • the preferred methods of preparation are vacuum drying and freeze-drying which yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile- filtered solution thereof.
  • Oral compositions generally include an inert diluent or an edible carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition.
  • the tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
  • a binder such as microcrystalline cellulose, gum tragacanth or gelatin
  • an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch
  • a lubricant such as magnesium stearate or Sterotes
  • a glidant such as colloidal silicon dioxide
  • the compounds are delivered in the form of an aerosol spray from pressured container or dispenser which contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer.
  • a suitable propellant e.g., a gas such as carbon dioxide, or a nebulizer.
  • Systemic administration can also be by transmucosal or transdermal means.
  • penetrants appropriate to the barrier to be permeated are used in the formulation.
  • penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives.
  • Transmucosal administration can be accomplished through the use of nasal sprays or suppositories.
  • the active compounds are formulated into ointments, salves, gels, or creams as generally known in the art.
  • the compounds can also be prepared in the form of suppositories (e.g., with conventional suppository bases such as cocoa butter and other glycerides) or retention enemas for rectal delivery.
  • suppositories e.g., with conventional suppository bases such as cocoa butter and other glycerides
  • retention enemas for rectal delivery.
  • the active compounds are prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems.
  • a controlled release formulation including implants and microencapsulated delivery systems.
  • Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, palyanhydrides, polyglycolic acid, collagen, polyorthoesters, and po!ylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art.
  • the materials can also be obtained commercially from Alza Corporation and Nova Pharmaceuticals, Inc.
  • Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies to viral antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art
  • Dosage unit form refers to physically discrete units suited as unitary dosages for the subject to be treated ; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • the specification for the dosage unit forms of the invention are dictated by and directly dependent on the unique characteristics of the active compound and the particular therapeutic effect to be achieved, and the iimitations inherent in the art of compounding such an active compound for the treatment of individuals.
  • Toxicity and therapeutic efficacy of such compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population) .
  • the dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD50/ED50.
  • Compounds which exhibit large therapeutic indices are preferred. While compounds that exhibit toxic side effects may be used, care should be taken to design a delivery system that targets such compounds to the site of affected tissue in order to minimize potential damage to uninfected ceils and, thereby, reduce side effects.
  • the data obtained from the cell culture assays and animal studies can be used in formulating a range of dosage for use in humans.
  • the dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with little or no toxicity.
  • the dosage may vary within this range depending upon the dosage form employed and the route of administration utilized.
  • the therapeutically effective dose can be estimated initially from cell culture assays.
  • a dose may be formulated in animai models to achieve a circulating plasma concentration range that includes the IC50 (i.e., the concentration of the test compound which achieves a half-maximal inhibition of symptoms) as determined in cell culture.
  • IC50 i.e., the concentration of the test compound which achieves a half-maximal inhibition of symptoms
  • levels in plasma may be measured, for example, by high performance liquid chromatography,
  • compositions can be included in a container, pack, or dispenser together with instructions for administration.
  • the invention relates to methods of making compounds of any of the formulae herein comprising reacting any one or more of the compounds of the formulae delineated herein, including any processes delineated herein.
  • the compounds of the invention may be prepared by, or in analogy with, conventional methods.
  • a pharmaceutically acceptable acid addition salt may be obtained by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition slats from base compounds. Examples of addition salt forming acids are mentioned above.
  • the compounds of the invention may possess one or more chiral carbon atoms, and they ma therefore be obtained in the form of optical isomers, e.g. as a pure enantiomer, or as a mixture of enantiomers (racemate) or as a mixture containing diastereomers.
  • optical isomers e.g. as a pure enantiomer, or as a mixture of enantiomers (racemate) or as a mixture containing diastereomers.
  • the separation of mixtures of optical isomers to obtain pure enantiomers is well known in the art and may, for example, be achieved by fractional crystallization of salts with optically active (chira! acids or by chromatographic separation on chiral columns.
  • the necessary starting materials for preparing the compounds of the invention are either known or may be prepared in analogy with the preparation of known compounds.
  • the dose level and frequency of dosage of the specific compound will vary depending on a variety of factors including the potency of the specific compound employed, the metabolic stability and length of action of that compound, the patient's age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the condition to be treated, and the patient undergoing therapy.
  • the daily dosage may, for example, range from about 0.001 mg to about 100 mg per kilo of body weight, administered singly or multiply in doses, e.g. from about 0.01 mg to about 25 mg each. Normally, such a dosage is given orally but parenteral administration may also be chosen.
  • the compounds can be administered alone or in combination with other anticancer agents
  • Preferred compounds of the present invention are shown in Table 1, Table 2 and Table 3.
  • X is sulfate (-S0 3 H) or phosphate (-P0 3 H);
  • R 3 is H, alkyl, or cycioalkyl; alkyl or cycioalkyl optionally substituted with , one or more substituents selected from the group consisting of hydroxy, chloro, bromo, alkoxy, nitro, amino, an amino acid or a polypeptidyl residue, or by phenyl substituted with lower alkyl hydroxy, chloro, bromo, alkoxy, nitro, or an amino group; and when Ri is alkyl or cycioalkyl, one to three non-adjacent CH ⁇ groups may be optionally replaced by NR', S or O, where R' is H or alky), cycioalkyl or a sugar residue; or one to three non-adjacent CH 2 groups may be optionally replaced by phenyl or phenyl substituted with lower alkyl hydroxy, chioro, bromo, aikoxy, nitro, or an amino group;
  • R 2 has the genera! formula:
  • R3 Is alkyl, or cycioalkyl; alkyl or cycioalkyl optionally substituted with one or more substituents selected from the group consisting af hydroxy, chloro, bromo, alkoxy, nitro, amino, an amino acid or a poiypeptidyi residue, or by phenyl optionally substituted with alkyl, hydroxy, chloro, bromo, alkoxy, nitro, or an amino group; and when R 3 is alkyl or cycioalkyl, one to three non-adjacent CH 2 groups may be optionally replaced by NR', S or 0 where R' is H or alkyl or cycioalkyl; or when R 3 is alkyl or cycioalkyl, one to three non-adjacent CH 2 groups may be optionally replaced by phenyl or phenyl substituted with lower ⁇ alkyl hydroxy, chloro, bromo, alk
  • the present invention provides compounds which interact selectively with histones and show selectivity over other molecules, more specifically the key selectivity target histone H I.
  • Novel neurotoxic factors have no been found, and available compounds have been systematically explored to reduce their toxicity in 96-well plate assays.
  • Various compound libraries have been screened including high molecular weight giycosaminoglycan (GAG) species to the identification of lower molecular weight GAG 'hits'.
  • GAG high molecular weight giycosaminoglycan
  • SAR structure activity relationships
  • HSPGs heparin/heparan sulphate proteoglycans
  • GAGs Structurally complex polysaccharides with a multitude of possible permutations to a repeating backbone.
  • GAGs commonly have a disaccharide repeat and are classified based on chemical similarities which determine their overall properties:
  • Type of glycosidic link e.g. a-(l,3), a-(i,4) links
  • GlcNAc Disaccharide repeat IM-acetyl gaiactosamine
  • GlcUA uronic acid
  • IdoUA epimer iduronic acid
  • Disaccharide repeat N-acetyl or IM sulpho-glucosamine and uronic acid (GlcUA) or the epimer iduronic acid (IdoUA)
  • O-sulphation: 2-0, 6-0 or the less common 3-0 De-N or De-0 has the selective removal of N- linked or Q-sulphate esters
  • a complex, branched polysaccharide composed of glucose monosaccharides joined by a-(l,S) glycosidic linkages with branching occurring from o-(i ; 3) linkages.
  • a 96-well plate screening assay was developed against novel neurotoxic factors and has identified high (Mw ⁇ 500,000) and lower molecular weight (Hw ⁇ S000) GAG 'hits'.
  • the heparin derived 4-mer Enoxaparin (Mw ⁇ 1500) represents the smallest saccharide length hit identified.
  • a heparin backbone substituted with the epimer, iduronic acid has similar activity to a uro.nic acid based polysaccharide; compare K50Q2 with EK5.
  • Non-heparin GAG 'hits' are preferably sulphated; e.g. fucoidan, mesoglycan, dextran sulphate (see exception below).
  • Un-sulphated GAGs were classified as ! non-hits' e.g. un-sulphated heparin K5 backbone K5001; maltooligosaccharide. MD-6-1; hyaluronic acid oligomers Hya6-12; chitin; chitosan; dextran.
  • Heparin and chondroitin sulphate disaccharides were classified as v non-rtits'.
  • the GAG kappa-carageenan is O-sulphated, however this was classified as 'non-hit' and could be due to the 3,6 anhydro bridge which affects conformation and overall stereochemistry.
  • Heparin compounds are recognized as neuroprotectants, 2 ' 3 have known safety profiles and cross the blood brain barrier 4, s . Heparin compounds are also known to reduce plaques in a mouse model of Alzheimer's disease* and to prevent both the production and aggregation of ⁇ through inhibiting BACE-1 6"8 and fibrillisation respectively 9 .
  • Glc beta 1-4 Glc beta 1-4 (3,6-dibenzyl) N-acetylglucosamine 300 mg of Methyl 3,6 dibenzyl beta N-acetyiglucosamine, 2.0 gm of hepta-O- acety) l-bromo alpha cellobiose, 2 gm of 4A molecular sieves stirred at ambient temperature in 1: 1 toluene: nitromethane then 750 mg solver carbonate followed by 770 mg silver triflate were added. The reaction mixture was stirred at ambient temperature for 1 hour. Filtered, washed twice with distilled water then purified by chromatography in 1: 1 toluene: ethyl acetate.
  • the disaccharide mixture (73 mg) plus 66 mg of 2-benzyl, 3,4 di-O-acetyl, 1- ethy!thio-L-fucose and 50 mg of 4A molecular sieves was stirred at ambient .temperature in 2 ml of dichloromethane then 0.25 ml of dimethyl thiomethyl sulfonium triflate was added.
  • reaction mixture was de-0 acetylated and worked up as for the disaccharide mixture then purified on a short column eluting with 2:1 toluene : ethyl acetate to afford 60 mg of a trisaccharide mixture.
  • the tetrasaccharide mixture (30 rng) was stirred at ambient temperature overnight in 1 ml of 1: 1 dimethylformamide: yridine with 50 mg of sulfur trioxidetrimethylamine complex, the reaction mixture was diluted with 50 ml of ethyl acetate then washed successively with 10 ml 1M hydrochloric acid, then twice with 10 ml of brine, It was dried then rotary-evaporated to an oil.
  • Results 1 mean mean control da mean 146.3182 F100 85.19048
  • JOOpi mean 9.157895 701100F1 12.85
  • control da mean 78.18182 F100 mean 84.27273
  • H30 da mean 76.76923 ⁇ 30 1 00 mean 81.75 da
  • H30 pi mean 5.923077 H30 F100 mean ' 11.25
  • control da mean 124.4737
  • control pi mean 9.055556
  • H30 da mean 133.5263 H30 FlOO mean 112.9 da
  • H30 pi mean 9.052632 H30 F100 mean 28.3
  • H100 da mean 171.2143 HI 00 mean 115,1765
  • HI 00 pi mean 30.9 HI 00 mean 25.91667
  • tetrasaccharide (table 2) and pentasaccharide (table 3) libraries were dissolved in culture medium and applied for 24hrs at concentrations of 30- 400uM.
  • Bed DA Morrison B: The spontaneous apoptotic cell death of normal human lymphocytes in vitro: the release of, and immunoproliferative response to, nucleosomes in vitro. Clin Immunol ImmunopathoS 1991, 60:13-26.
  • cl!wain H Protein interactions and metabolic response to stimulating agents in isolated cerebral tissues: histones as inhibitors. Biochem J 1959, 73:514-521.
  • Neve RL, McPhie DL The cell cycle as a therapeutic target for Alzheimer's disease. Pharmacol Ther 2006, 111:99-113.
  • Hiidebrand CE Tobey RA, Gurley L , Walters RA: Action of heparin on mammalian nuclei. II. Cell-cycle-specific changes in chromatin organization correlate temporally with histone Hi phosphorylation. Btochim Biophys Acta 1978, 517, ⁇ 486-499.
  • Demidenko O Tsvetkova S: Action of heparin on protein fractions of isolated nuclei and on their DNA content. Histochemistry 1978, 57:265-271.
  • Hiidebrand CE Gurley LR, Tobey RA, Walters RA: Action of heparin on mammalian nuclei, I. Differential extraction of histone Hi and cooperative removal of histones from chromatin. Btochim Biophys Acta 1977, 477:295-311.

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Abstract

L'invention concerne des composés interagissant avec des histones, soit les composés de Formule (I): 4'''-sulfo-fucose [alpha]1-3 (4''-sulfo)-fucose [alpha]1-3 (4'-sulfo-fucose [alpha]1-4-acide glucuronique [bêta]1-O-méthyle ou 4''''-sulfo-fucose [alpha]1-3 (4''-sulfo)-fucose [alpha]1-3 (4''-sulfo)-fucose [alpha]1-3 (4'-sulfo-fucose[alpha]1-4-acide glucuronique [bêta]1-O-méthyle, où X est sulfate (-SO3H) ou phosphate (-PO3H), Su est sulfate et la sulfatation est plus probable au niveau des positions fléchées. Les composés susmentionnés sont utiles dans l'inhibition d'histones, et notamment de l'histone H1. Ces composés peuvent être utilisés en médecine, et notamment dans la prévention et/ou le traitement d'une multitude de maladies neurodégénératives, telles que la maladie d'Alzheimer et la maladie de Parkinson.
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JP2015038061A (ja) * 2013-07-19 2015-02-26 学校法人慶應義塾 抗腫瘍剤
CN108392485A (zh) * 2018-01-17 2018-08-14 浙江工业大学 硫酸化甘露葡萄糖醛酸寡糖在制备治疗或预防神经退行性疾病药物或保健品中的应用
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JP2021517582A (ja) * 2017-12-15 2021-07-26 ジ・オーストラリアン・ナショナル・ユニヴァーシティ 細胞外ヒストンによって媒介される病理を処置及び予防するための化合物
EP3723768A4 (fr) * 2017-12-15 2021-09-01 The Australian National University Composés pour le traitement et la prévention de pathologies médiées par l'histone extracellulaire
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