[go: up one dir, main page]

WO2011029956A1 - Dérivés de flavones et flavanones en tant qu'inhibiteurs d'adn méthyltransférases - Google Patents

Dérivés de flavones et flavanones en tant qu'inhibiteurs d'adn méthyltransférases Download PDF

Info

Publication number
WO2011029956A1
WO2011029956A1 PCT/EP2010/063493 EP2010063493W WO2011029956A1 WO 2011029956 A1 WO2011029956 A1 WO 2011029956A1 EP 2010063493 W EP2010063493 W EP 2010063493W WO 2011029956 A1 WO2011029956 A1 WO 2011029956A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
chosen
formula
alkoxy
halogen
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/EP2010/063493
Other languages
English (en)
Inventor
Barbara Arimondo
Dominique Guianvarc'h
Alexandre Ceccaldi
Catherine Senamaud-Beaufort
Daniel Dauzonne
Albert Jeltsch
Renata Jurkowska
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Institut National de la Sante et de la Recherche Medicale INSERM
Institut Curie
Original Assignee
Institut National de la Sante et de la Recherche Medicale INSERM
Institut Curie
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Institut National de la Sante et de la Recherche Medicale INSERM, Institut Curie filed Critical Institut National de la Sante et de la Recherche Medicale INSERM
Publication of WO2011029956A1 publication Critical patent/WO2011029956A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
    • C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
    • C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
    • C07D311/30—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only not hydrogenated in the hetero ring, e.g. flavones
    • 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
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
    • C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
    • C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
    • C07D311/32—2,3-Dihydro derivatives, e.g. flavanones

Definitions

  • Flavones and flavanones derivates as DNA methyltransferases inhibitors
  • the present invention concerns flavones and flavanones derivates as DNA methyltransferases inhibitors.
  • the invention also concerns a method of high- throughput screening of DNA methyltransferases inhibitors.
  • Cancer cells are out of control. Throughout tumorigenesis they acquire (or are naturally selected thanks to) some key modifications that hack their natural protections against abnormal cell proliferation and boost their malignant characteristics: independence to growth signals, tissue invasion, unlimited replicative potential, etc. Proto-oncogenes and oncogenes are able to transform a normal cell into an over-clocked system: much more active but also more fragile. Indeed, cancer cells need an important nutrients and oxygen supply, triggered by a leaky and imperfect neovascular system. They are also addicted to specific metabolisms; they poorly repair their DNA damages, etc. These are various strategic options to impact the disease that chemotherapy already explores.
  • An innovative choice would be to awake the cancer cell's sleeping defences against tumor progression, for instance by reactivating the silenced tumor-suppressor genes.
  • the idea is there to revert the pathological phenotype of malignant cells, not necessarily to kill them, but to force them to adopt a more normal behavior: senescence, differentiation, cell death, etc.
  • Epigenetics is of great interest to transform this concept into reality.
  • Epigenetics describes the cellular regulations of genes expression that are heritable without being coded within the DNA sequence: DNA methylation, histones modifications (e.g. methylation and acetylation) and nucleosomes positioning.
  • Epigenetic modifications such as DNA methylation are involved in the control of gene expression and play an important role in pathologies, as for example in cancer.
  • a general disruption in the epigenetic landscape is virtually associated with every human cancer (M. Esteller, N Engl J Med 358, 1 148; Mar 13, 2008).
  • the genome of malignant cells is hypomethylated, which is responsible for aberrant expression of repeated sequences such as transposons and indeed global genomic instability.
  • most of the tumors harbor very early a specific hypermethylation in the promoter region of tumors-suppressor genes that leads to their silencing.
  • This aberrant inactivation is reversible by blocking the DNA methylation process that is managed by a super-family of enzymes called DNA methyl-transferases (DNMTs) (X. Cheng, R. M. Blumenthal, Structure 16, 341 ; Mar, 2008).
  • DNMTs DNA methyl-transferases
  • DNMTs catalyse the transfer of a methyl group from the cofactor S-Adenosyl Methionine (SAM) to the position 5 of cytosines belonging to CpG dinucleotides.
  • SAM cofactor S-Adenosyl Methionine
  • DNMTs inhibitors have already proven their ability to bring back malignant cells to a more "normal epigenetic state” and thus, to reactivate genes that are essential to fight against tumorigenesis ( C. B. Yoo, P. A. Jones, Nat Rev Drug Discov 5, 37; Jan, 2006).
  • Epigenetic drugs form a very attractive new class of chemotherapy agents.
  • Cytosine analogs have been known for twenty years. FDA has approved in 2004 and 2006 5-azacytidine (VidazaTM) and 5-aza-2'-deoxycytidine (DacogenTM), respectively, for the treatment of myelodysplasic syndromes. Cytosine analogues are currently tested against many types of solid tumors. They share a structure analogy and have a unique mode of action, by acting as suicide substrates. Active DNMTs have a catalytic cysteine that forms a transient covalent complex with DNA during its methylation: cytosine analogues block definitively the enzyme at this step of the reaction. Indeed, these molecules need to be integrated into the genome during replication to be active.
  • cytosines analogues are still highly toxic. Furthermore, some of them are chemically instable. More recently a second class of molecules, non-nucleotidic DNMT inhibitors, have been discovered (C. B. Yoo, P. A. Jones, Nat Rev Drug Discov 5, 37; Jan, 2006). Indeed, they show a much broader chemical diversity. Hydralazine is developed as a treatment against brain and ovarian tumors. Other agents like the green tea's EGCG or the RG108 (a molecule discovered through a virtual screening) are studied. All these drugs do not need to be integrated into DNA to be active but their mechanisms remains mainly unknown. Their specificity for the DNMTs is also to be demonstrated.
  • An aim of the present invention is thus to provide new DNMTs inhibitors.
  • Another aim of the present invention is to provide a new high throughput assay to screen for DNMTs inhibitors.
  • the present invention relates to a com ound of formula (I):
  • ⁇ Ri is chosen from the group consisting of:
  • Ai is an alkylene radical comprising from 1 to 12 carbon atoms
  • ⁇ R 2 is chosen from the group consisting of:
  • ⁇ R 3 is chosen from the group consisting of:
  • ⁇ — is either a single bond or a double bond; ⁇ — is either none or a single bond, provided that when— is a double bond, then— is none;
  • R 4 is OH, N0 2 or a halogen atom
  • R 5 a is a halogen atom and R 5 b is H, or none when— is a double bond;
  • ⁇ R 6 is chosen from the group consisting of:
  • R is an alkyl group comprising from 1 to 12 carbon atoms
  • ⁇ R 7 is chosen from the group consisting of:
  • ⁇ R 8 is chosen from the group consisting of:
  • ⁇ R 9 is chosen from the group consisting of:
  • ⁇ R 10 is chosen from the group consisting of:
  • alkenyl as employed herein includes partially unsaturated, nonaromatic, hydrocarbon groups having 2 to 12 carbons, preferably 2 to 6 carbons.
  • alkylene refers to a divalent radical comprising from 1 to 12 carbon atoms, and preferably from 1 to 6 carbon atoms. Said radical may be represented by the formula (CH 2 ) n wherein n is an integer varying from 1 to 12, and preferably from 1 to 6.
  • halogen refers to the atoms of the group VII of the periodic table and includes in particular fluorine, chlorine, bromine, and iodine atom.
  • alkoxy refers to an -O-alkyl radical.
  • alkyl means a saturated or unsaturated aliphatic hydrocarbon group which may be straight or branched having about 1 to about 12 carbon atoms in the chain. Preferred alkyl groups have 1 to about 6 carbon atoms in the chain.
  • Branched means that one or lower alkyl groups such as methyl, ethyl or propyl are attached to a linear alkyl chain.
  • «Lower alkyl» means about 1 to about 4 carbon atoms in the chain which may be straight or branched.
  • the alkyl may be substituted with one or more «alkyl group substituants», which may be the same or different, and include for instance halo, cycloalkyl, hydroxy, alkoxy, amino, acylamino, aroylamino, carboxy.
  • the compounds herein described may have asymmetric centers.
  • Compounds of the present invention containing an asymmetrically substituted atom may be isolated in optically active or racemic forms. It is well-known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a compound are intended, unless the stereochemistry or the isomeric form is specifically indicated.
  • “Pharmaceutically acceptable” means it is, within the scope of sound medical judgment, suitable for use in contact with the cells 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 salt refers to salts which retain the biological effectiveness and properties of the compounds of the invention and which are not biologically or otherwise undesirable.
  • the compounds of the invention are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto.
  • Pharmaceutically acceptable acid addition salts may be prepared from inorganic and organic acids, while pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases.
  • non-toxic pharmaceutically acceptable salts refers to non-toxic salts formed with nontoxic, pharmaceutically acceptable inorganic or organic acids or inorganic or organic bases.
  • the salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, and the like, as well as salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicyclic, sulfanilic, fumaric, methanesulfonic, and toluenesulfonic acid and the like.
  • treating means reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition.
  • compositions both for veterinary and for human use, useful according to the present invention comprise at least one compound having formula (I) as above defined, together with one or more pharmaceutically acceptable carriers and optionally other therapeutic ingredients.
  • active ingredients necessary in combination therapy may be combined in a single pharmaceutical composition for simultaneous administration.
  • compositions, carriers, diluents and reagents are used interchangeably and represent that the materials are capable of administration to or upon a mammal without the production of undesirable physiological effects such as nausea, dizziness, gastric upset and the like.
  • compositions that contains active ingredients dissolved or dispersed therein are well understood in the art and need not be limited based on formulation.
  • compositions are prepared as injectables either as liquid solutions or suspensions; however, solid forms suitable for solution, or suspensions, in liquid prior to use can also be prepared.
  • the preparation can also be emulsified.
  • the pharmaceutical compositions may be formulated in solid dosage form, for example capsules, tablets, pills, powders, dragees or granules.
  • excipients such as lactose, sodium citrate, calcium carbonate, dicalcium phosphate and disintegrating agents such as starch, alginic acids and certain complex silicates combined with lubricants such as magnesium stearate, sodium lauryl sulphate and talc may be used for preparing tablets.
  • lactose and high molecular weight polyethylene glycols When aqueous suspensions are used they can contain emulsifying agents or agents which facilitate suspension.
  • Diluents such as sucrose, ethanol, polyethylene glycol, propylene glycol, glycerol and chloroform or mixtures thereof may also be used.
  • compositions can be administered in a suitable formulation to humans and animals by topical or systemic administration, including oral, rectal, nasal, buccal, ocular, sublingual, transdermal, rectal, topical, vaginal, parenteral (including subcutaneous, intra-arterial, intramuscular, intravenous, intradermal, intrathecal and epidural), intracisternal and intraperitoneal. It will be appreciated that the preferred route may vary with for example the condition of the recipient.
  • the formulations can be prepared in unit dosage form by any of the methods well known in the art of pharmacy. Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.
  • Total daily dose of the compounds of the invention administered to a subject in single or divided doses may be in amounts, for example, of from about 0.001 to about 100 mg/kg body weight daily and preferably 0.01 to 10 mg/kg/day. Dosage unit compositions may contain such amounts of such submultiples thereof as may be used to make up the daily dose. It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the body weight, general health, sex, diet, time and route of administration, rates of absorption and excretion, combination with other drugs and the severity of the particular disease being treated.
  • the compounds of the invention are drugs that inhibit DNA methylation and may therefore be useful for the treatment of tumors and proliferative diseases, such as coronary restenosis and neoplastic diseases, particularly colon carcinoma, familiary adenomatous polyposis carcinoma and hereditary non-polyposis colorectal cancer, prostate carcinoma, melanoma, non-Hodgkin lymphoma, acute lymphatic leukemia (ALL), chronic lymphatic leukemia (CLL), acute myeolid leukemia (AML), chronic myeloid leukemia (CML), hepatocellular carcinoma, neuroblastoma, intestine carcinoma, rectum carcinoma, colon carcinoma, oesophageal carcinoma, labial carcinoma, larynx carcinoma, hypopharynx carcinoma, tong carcinoma, salivary gland carcinoma, gastric carcinoma, adenocarcinoma, medullary thyroidea carcinoma, papillary thyroidea carcinoma, renal carcinoma, kidney parenchyma carcinoma, ovarian carcinoma, cervix carcinoma,
  • They may be also used for the treatment of developmental disorders such as Prader-Willi-Syndrome, Angelman-Syndrome (Happy Puppet Syndrome), Beckwith- Wiedemann-Syndrome, and neurodegenerative diseases.
  • developmental disorders such as Prader-Willi-Syndrome, Angelman-Syndrome (Happy Puppet Syndrome), Beckwith- Wiedemann-Syndrome, and neurodegenerative diseases.
  • neurodegenerative disease is used throughout the specification to identify a disease which is caused by damage to the central nervous system and can be identified by neuronal death.
  • exemplary neurodegenerative diseases include HIV-associated Dementia, multiple sclerosis, Alzheimer's Disease, Parkinson's Disease, amyotrophic lateral sclerosis, schizophrenia and Pick's Disease.
  • neurodegenerative disease shall be taken to mean a disease that is characterized by neuronal cell death.
  • the neuronal cell death observed in a neurodegenerative disease is often preceded by neuronal dysfunction, sometimes by several years.
  • the term “neurodegenerative disease” includes a disease or disorder that is characterized by neuronal dysfunction and eventually neuronal cell death.
  • gliosis e.g., astrocytosis or microgliosis
  • a neurodegenerative disease often manifest as a behavioral change (e.g., deterioration of thinking and/or memory) and/or a movement change (e.g., tremor, ataxia, postural change and/or rigidity).
  • a behavioral change e.g., deterioration of thinking and/or memory
  • a movement change e.g., tremor, ataxia, postural change and/or rigidity.
  • neurodegenerative disease examples include, for example, FTLD, amyotrophic lateral sclerosis, ataxia (e.g., spinocerebellar ataxia or Friedreich's Ataxia), Creutzfeldt-Jakob Disease, a polyglutamine disease (e.g., Huntington's disease or spinal bulbar muscular atrophy), Hallervorden-Spatz disease, idiopathic torsion disease, Lewy body disease, multiple system atrophy, neuroanthocytosis syndrome, olivopontocerebellar atrophy, Pelizaeus-Merzbacher disease, progressive supranuclear palsy, syringomyelia, torticollis, spinal muscular atrophy or a trinucleotide repeat disease (e.g., Fragile X Syndrome).
  • FTLD amyotrophic lateral sclerosis
  • ataxia e.g., spinocerebellar ataxia or Friedreich's Ataxia
  • DNA methyltransferases are the enzymes responsible for DNA methylation that in mammals catalyze the transfer of a methyl group from the AdoMet co-factor to the postion 5 of cytidine in a CpG context.
  • DNA-methyltransferases The inhibition of said DNA-methyltransferases may be measured by the test as described below and alternatively as in M. Roth, A. Jeltsch, Biol Chem 381 , 269, 2000.
  • R 4 is N0 2 or a halogen atom.
  • R 2 is chosen from the group consisting of: H, CI, Br, OH, and N0 2 , and more preferably from the group consisting of: H, CI, Br, and N0 2 .
  • R 3 is H or OCH 3 .
  • R 4 is OH, N0 2 or CI, more preferably N0 2 or CI, and most preferably is N0 2 .
  • R 6 is chosen from the group consisting of: H, F, C0 2 CH 3 , and C0 2 CH 2 Ph.
  • R 7 is chosen from the group consisting of: H, CI, OH, N0 2 , and OCH 3 , and more preferably from the group consisting of: H, CI, N0 2 , and OCH 3 .
  • R 8 is chosen from the group consisting of: H, F, CI, N0 2 , OH, OCH 3 , and OCH 2 Ph, and more preferably from the group consisting of: H, F, CI, N0 2 and OCH 3 .
  • R 9 is chosen from the group consisting of: H, OCH 3 , and C 6 H 4 -C0 2 H.
  • Ri 0 is chosen from the group consisting of: H, F, CI, OH, OCH 3 , and N0 2 .
  • a preferred group of compounds according to the invention are compounds having formula (I) as defined above, wherein at most two, and preferably at most one, of the groups Ri , R 2 , and R 3 is other than H.
  • a preferred group of compounds according to the invention are compounds having formula (I) as defined above, wherein at most three, preferably two, and more preferably at most one, of the groups R 6 , R 7 , R 8 , Rg, and R 0 is other than H.
  • the present invention also relates to a compound having formula (1-1 ):
  • Ri , R 2 , R 3 , R 4 , R 6 , R 7 , Rs, Rg and Ri 0 are as defined above for formula (l),for its use as mentioned above.
  • R 4 is N0 2 or CI.
  • the present invention also relates to a compound having formula (I-2):
  • R 4 is preferably N0 2 .
  • R 5 a is preferably a halogen atom, and in particular is CI.
  • the compounds of formula (I-2) may also be represented by the following formula:
  • the compounds of formula (1-2-1 ) may also be represented by the following formula:
  • a preferred group of invention are compounds having formula (1-2-1 ) as defined above, wherein at most two, and preferably at most one, of the groups Ri , R 2 , and R 3 is other than H.
  • a preferred group of compounds according to the invention are compounds having formula (1-2-1 ) as defined above, wherein at most three, preferably two, and more preferably at most one, of the groups R 6 , R 7 , R 8 , Rg, and R 0 is other than H.
  • R 2 and R 3 are H.
  • R 1 ; R 2 and R 3 are H.
  • a subgroup of preferred compounds of the invention consists of those as defined above wherein R 2 and R 3 are H.
  • Another group of compounds of the invention consists of compounds having formula (1-2-1 ) as defined above wherein Ri and R 3 are H, and R 2 is halogen, such as CI, N0 2 or alkoxy such as OCH 3 .
  • Another group of compounds of the invention consists of compounds having formula (1-2-1 ) as defined above wherein Ri and R 2 are halogen, and in particular Br.
  • Another group of compounds of the invention consists of compounds having formula (1-2-1 ) as defined above wherein R ⁇ and R 2 are H.
  • a subgroup of this group of preferred compounds consists of compounds wherein R 3 is alkoxy, and preferably OCH 3 .
  • Another group of compounds of the invention consists of compounds having formula (1-2-1 ) as defined above wherein R ⁇ is alkoxy, and preferably OCH 3 .
  • a subgroup of this group of preferred compounds consists of compounds wherein R 2 and R 3 are H.
  • Another group of compounds of the invention consists of compounds having formula (1-2-1 ) as defined above wherein R 6 to Ri 0 are H.
  • Another group of compounds of the invention consists of compounds having formula (1-2-1 ) as defined above wherein R 6 and R 8 to Ri 0 are H.
  • a subgroup of this group of preferred compounds consists of compounds wherein R 7 is halogen such as CI, N0 2 , or alkoxy such as OCH 3 .
  • Another group of compounds of the invention consists of compounds having formula (1-2-1 ) as defined above wherein R 8 is halogen, and in particular CI, and R 6 ,
  • Another group of compounds of the invention consists of compounds having formula (1-2-1 ) as defined above wherein three of the groups R 6 to R 0 are alkoxy such as OCH 3 , the two other groups being H.
  • Another group of compounds of the invention consists of compounds having formula (1-2-1 ) as defined above wherein at most three of the groups R 6 to R 0 are alkoxy such as OCH 3 , the other groups being H.
  • Another group of compounds of the invention consists of compounds having formula (1-2-1 ) as defined above wherein two of the groups R 6 to R 0 are alkoxy such as OCH 3 , the three other groups being H.
  • Another group of compounds of the invention consists of compounds having formula (1-2-1 ) as defined above wherein one of the groups R 6 to Ri 0 are alkoxy such as OCH 3 , the other groups being H.
  • the present invention also relates to a compound having formula (I-3):
  • R 1 ; R 2 , R 3 , R 4 , R 5 a , R 5 b , R 6 , R 7 , Rs, Rg and R 0 are as defined above for formula (I), for its use as mentioned above.
  • the compounds of formula (I-3) are compounds of formula (I) wherein X is CHOH, — is a single bond, and — is a single bond.
  • a preferred group of compounds of formula (I-3) consists of compounds of formula (I-3) wherein R 5 b is H.
  • R 4 is N0 2 or CI.
  • the compounds of formula (I-3) may also be represented by the following formula:
  • the present invention also relates to the compound having formula (I-4):
  • R 1 ; R 2 , R 3 , R 6 , R 7 , R 8 , R 9 and R 0 are as defined above for formula (I), for its use as defined above.
  • the compounds of formula (I-4) are compounds of formula (1-1 ) wherein R 4 is
  • Another preferred group of compounds according to the invention are compounds having formula (I-4) as defined above, wherein at least one of the groups R 7 , R 8 , Rg and Ri 0 is a (CrC 6 )alkoxy group.
  • R 7 , R 8 , R 9 and R 0 is a (CrC 6 )alkoxy group, and preferably OCH 3 .
  • Preferred compounds having formula (I-4) as defined above are compounds having formula (1-4-1 ) as follows:
  • Ri , R 6 , R 7 , Rs, Rg and Ri 0 are as defined above.
  • a preferred group of compounds according to the invention are compounds having formula (1-4-1 ) as defined above, wherein at most two, and preferably at most one, of the groups R 6 , R 7 , Rs, Rg, and Ri 0 is other than H.
  • a preferred group of compounds of formula (1-4-1 ) consists of compounds wherein R 7i R 9 or R 0 is N0 2 .
  • Another preferred group of compounds of formula (1-4-1 ) consists of compounds wherein R 7 is N0 2 .
  • formula (1-4-1 ) is H, CH 2 CHO or CH 2 C0 2 H.
  • Preferred compounds having formula (I-4) are as follows:
  • Ri , R 2 , R 3 , Re, R 7 , Rs, Rg and Ri 0 are as defined above.
  • the compounds of formula (I-5) are compounds of formula (1-1 ) wherein R 4 is
  • a preferred group of compounds according to the invention consists of compounds having formula (I-5), wherein Ri , R 2 and R 3 are H.
  • R 8 and R 0 being as defined above.
  • R 8 is N0 2 .
  • R 0 is halogen
  • Preferred compounds having formula (I-5) are as follows:
  • the present invention also relates to the compound of formula (I-6):
  • R 1 ; R 2 , R 3 , R 6 , R 7 , R 8 , R 9 and R 0 are as defined above for formula (I), for its use as mentioned above.
  • the compounds of formula (I-6) are compounds of formula (I-3) wherein R 4 is N0 2 , R 5 a is CI and R 5 b is H.
  • a preferred group of compounds according to the invention consists of compounds of formula (I-6) as defined above, wherein Ri , R 2 and R 3 are H.
  • Another preferred group of compounds according to the invention consists of compounds having formula (I-6) as defined above, wherein R 6 , R 8 , R 9 and Ri 0 are H.
  • R 7 is as defined above for formula (I).
  • R 6 , R 8 , R 9 and R 0 are H.
  • Another preferred group of compounds according to the invention consists of compounds of formula (I-6) as defined above, wherein R 7 is N0 2 .
  • Preferred compounds having formula (I-6) are as follows:
  • the present invention also relates to the compound having the following formu
  • the present invention relates to the below preferred compounds for their use in the prevention and/or treatment of cancer, developmental disorders, neurodegenerative diseases or Trypanomiasis diseases by inhibition of DNA- methyltransferases:
  • the present invention also relates to a compound of formula (I) as defined above for its use in the prevention and/or the treatment of developmental diseases or Trypanomiasis diseases.
  • the present invention also relates to a compound of formula (1-4) as defined above for its use in the prevention and/or the treatment of neurodegenerative diseases.
  • the present invention also relates to a compound of formula (1-2) as defined above for its use in the prevention and/or the treatment of neurodegenerative diseases.
  • the present invention also relates to a com ound having formula (1-5):
  • R 1 ; R 2 , R 3, R 6 , R 7 , s, Rg, and R 0 are as defined above for formula (I), or its pharmaceutically acceptable salts, hydrates or hydrated salts or its polymorphic crystalline structures, racemates, diastereomers or enantiomers.
  • Ri , R 2 and R 3 are
  • the present invention also relates to compounds having formula (I-4-2) as follows:
  • R 6 , R 7 , R 8 , R 9 , and R 0 are as defined above for formula (I), or its pharmaceutically acceptable salts, hydrates or hydrated salts or its polymorphic crystalline structures, racemates, diastereomers or enantiomers.
  • the compounds of formula (I-4-2) are compounds of formula (1-4-1 ) as defined above wherein is CH 2 CHO.
  • a preferred group of compounds according to the invention are compounds having formula (I-4-2) as defined above, wherein at most two, and preferably at most one, of the groups R 6 , R 7 , R 8 , Rg, and Ri 0 are other than H.
  • a preferred group of compounds of formula (I-4-2) consists of compounds wherein R 7 is N0 2 .
  • Another preferred group of compounds of formula (I-4-2) consists of compounds wherein R 8 is OCH 2 Ph and/or R 9 is C 6 H 4 COOH.
  • the present invention also relates to a compound having formula (I-2-3):
  • Ai is an alkylene radical comprising from 1 to 12 carbon atoms, and - -A1 -CO2H , wherein Ai is as defined above,
  • R 2 , R 3 , Re, R7, Rs, Rg and Ri 0 are as defined above.
  • Another group of compounds of the invention consists of compounds having formula (I-2-3) as defined above wherein Ri and R 3 are H, and R 2 is halogen, such as CI, N0 2 or alkoxy such as OCH 3 .
  • Another group of compounds of the invention consists of compounds having formula (I-2-3) as defined above wherein Ri and R 2 are halogen, and in particular Br.
  • Another group of compounds of the invention consists of compounds having formula (I-2-3) as defined above wherein and R 2 are H.
  • a subgroup of this group of preferred compounds consists of compounds wherein R 3 is alkoxy, and preferably OCH 3 .
  • Another group of compounds of the invention consists of compounds having formula (I-2-3) as defined above wherein is alkoxy, and preferably OCH 3 .
  • a subgroup of this group of preferred compounds consists of compounds wherein R 2 and R 3 are H.
  • the present invention also relates to a compound having formula (I-2-2):
  • Ri , R 2 , R 3 , R 6 , R 7 , Rg and Ri 0 are as defined above,
  • R 6 , R 9 and R 0 are H.
  • R 6 , R 9 and R 0 are H and R 7 is halogen such as I.
  • At most one of the groups Ri , R 2 , and R 3 is other than H.
  • the present invention also relates to the following compounds as such: (47), (48), (50), (52), (58), (59), (60), (61 ), (62), (63), (64), (65), (66), (67), (68), (69), (70), (71 ), (72), (73), (74), (75), (76), (77), (79), (80), (81 ), (82), (83), (1 13), and (1 14).
  • the present invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound having formula (I-5), (I-4-2), (I-2-3) or (I-2-2) as mentioned above, in association with at least one pharmaceutically acceptable excipient.
  • composition comprising a compound having formula (1 1 ), (38), (59), (60), (82), (99) or (102) as mentioned above, in association with at least one pharmaceutically acceptable excipient.
  • the present invention also relates to a method for screening a DNA methyltransferase inhibitor comprising the following steps:
  • a step of coating a solid support with avidin, streptavidin or neutravidin - a step of incubating the coated solid support with a double-modified DNA duplex containing a fluorophore at the 5' or 3' end of one strand of the duplex and biotin at the 5' or 3' end of the other strand,
  • - a step of measuring the fluorescence signal being understood that said compound is a DNA methyltransferase inhibitor when the measured fluorescence signal is lower than the fluorescence signal measured in the absence of the compound to be tested.
  • This screening method is based on methylation-sensitive DNA cleaving restriction enzyme and fluorescence measurement (see Figure 1 ).
  • Each step of the above-mentioned screening method is followed by washing steps, in particular with PBS, eventually in association with Tween 20.
  • the step of incubating the support with a restriction enzyme is carried out in the presence of a restriction buffer having the appropriate pH and salt concentration.
  • the method of the invention is based on the detection of the cleavage of a fluorescence labelled DNA duplex by restriction enzymes that are active only if the substrate is not methylated in their specific recognition site containing a CpG. Therefore, a preferred embodiment is as follows: 96-well plates coated through biotin/avidin interactions with a double-modified DNA duplex containing the fluorophore, FAM, at one end and the biotin at the other end.
  • the duplex can be methylated by the DNMT on a single CpG site and then cleaved after a washing step by the appropriate restriction enzyme.
  • the set-up is such that there are washing steps after each reaction that are fundamental to eliminate all the limitations and drawbacks above and be applicable to all compounds without any restriction.
  • the assay of the invention can be understood as a high throughput method to find inhibitors of whether methyltransferase activity or a well defined DNMT.
  • the same method can also be applied to other DNA modifying enzymes (such as DNA topoisomerases).
  • the present invention also relates to a kit for screening a DNA methyltransferase inhibitor, comprising: (1 ) a solid support coated with avidin, (2) a double-modified DNA duplex containing a fluorophore at the 5' end of one strand of the duplex and biotin at the 5' end of the other strand, (3) a DNA methyltransferase and its cofactor SAM, and (4) a restriction enzyme.
  • the kit of the present invention may also contain instructions for use to carry out the method for screening DNA methyltransferase inhibitors.
  • PBS PBS
  • Tween 20 PBS " I X - 0.5% Tween 20
  • PBST PBS " I X - 0.5% Tween 20
  • a restriction buffer having the appropriate pH and salt concentration, such as a buffer comprising 10 mM Bis-Tris-Propane-HCI, 10 mM MgCI 2 , and 1 mM DTT (pH 7.0).
  • a reaction buffer such as a buffer comprising 20 mM HEPES pH 7.2, 50 mM KCI, and 1 mM EDTA).
  • the chloronitro derivative 59 has been prepared from 3-allyl-2- hydroxybenzaldehyde and (Z)-4-benzyloxy-1 -(2-chloro-2-nitroethenyl)-3-iodo- benzene via the corresponding 3-chloro-3,4-dihydro-4-hydroxy-3-nitro-2H-1 - benzopyrane (Dauzonne, D.; Demerseman P. A convenient synthesis of 3-chloro- 3,4-dihydro-4-hydroxy-3-nitro-2-phenyl-2h-1 -benzopyrans Synthesis 1990, 66-70) according to a previously published procedure (Dauzonne, D.; Grandjean, C. Synthesis of 2-aryl-3-nitro-4H-1 -benzopyran-4-ones. Synthesis 1992, 677-680).
  • the chloronitro derivative 60 has been prepared according to the same procedure as described in example 2 starting from salicylaldehyde and the same (Z)- -chloro- -nitrostyrene.
  • the chloronitro derivative 82 has been prepared according to the same procedure as described in example 2 starting from salicylaldehyde and (Z)-1 -(2- chloro-2-nitroethenyl)-2,4-dimethoxybenzene.
  • 4- carboxylic acid (38) has been carried out using a three-step procedure starting from 60 (example 3). Formation, under basic conditions, of the 2-(4-benzyloxy-3- iodophenyl)-3-nitro-4H-1 -benzopyran-4-one in 98% yield followed by Pallado- catalyzed condensation of this iodoflavone with 4-formylphenylboronic acid in the presence of potassium carbonate provided the 2'-benzyloxy-5'-(3-nitro-4-oxo-4H- chromen-2-yl)biphenyl-4-carbox-aldehyde in 75% yield. Subsequent oxidation of this latter formyl derivative with oxone in acidic medium gave the wanted acid 38 in 93% yield.
  • the 3-chloroflavones 99 and 102 have been isolated as minor by-products (4% and 5%, respectively) in large scale synthesis of the corresponding 3- nitroflavones (Dauzonne, D.; Folleas, B.; Martinez, L; Chabot, G. G. Synthesis and in vitro cytotoxicity of a series of 3-aminoflavones. Eur. J. Med. Chem. 1997, 32, 71 - 82.)
  • 5-azacytidine was bought from Calbiochem and conserved in water at -20 °C. All the drugs are dissolved in 100% DMSO and conserved at -20 °C.
  • Short DNA duplexes have been made upon hybridization of complementary oligonucleotides (Eurogentec, Belgium) bearing a FAM and a biotin, respectively at the 5' end of each strand.
  • the substrates have a single CpG site included in a flanking sequence that is simultaneously adequate for the DNA methyltransferase and the methylation-sensible restriction enzyme.
  • the substrates for the assay with DNTM3A/3L, M.Sss I and DNMT1 have respectively the following sequences (the CpG site is in bold):
  • CostarTM 96-Well high binding EIA/RIA plates (ref. 9018) have been coated with 1 ⁇ / ⁇ of avidin (Sigma) in 100 ⁇ _ of 100 mM NaHC0 3 , pH 9.60 at 4°C overnight. The plate has been then washed five times with PBST (PBS 1 X - 0.5% Tween 20), 500 mM NaCI. The plate can be stored 2 weeks at 4°C. To further coat the substrate on the plate, 100pmol/well of DNA has been incubated in 100 ⁇ _ of PBST at room temperature for at least 30 min. The plate is finally ready-to-use after being washed three times with PBST, 500 mM NaCI and three times with PBST. DNMT3a/3L methylation reactions:
  • the human GST-tagged DNMT1 was bought from BPS Bioscience. The enzyme was incubated at 350 nM in reaction buffer (20 mM HEPES pH 7.2, 50 mM KCI, 1 mM EDTA) and 20 ⁇ SAM in the presence of the tested compound in a total volume of 50 ⁇ _/ ⁇ of a testing plate. The methylation reaction was achieved at 37°C during 120 min. Each well was washed as described.
  • DNA methylation by the bacterial CpG methyltransferase M.Sss I (New England Biolabs) in the presence of the tested compound in a total volume of 50 ⁇ _/ ⁇ during 1 hour at 37°C was realized in the following conditions: 50 nM M.Sssl, 20 ⁇ SAM, 10 mM Tris-HCI pH 7.9, 50 mM NaCI, 10 mM MgCI 2 , 1 mM DTT. Each well was washed as described.
  • DNMT3a/3L assay and M.Sssl assay 2 units/well of the methylation-sensible restriction enzyme HpyCH4 IV (New Englands Biolabs) have been incubated in total 50 ⁇ _ volume of restriction buffer (10 mM Bis-Tris-Propane-HCI, 10 mM MgCI 2 , 1 mM DTT, pH 7.0) during 1 hour at 37 ⁇ C. The plate has been then washed three times with PBST, 500 mM NaCI and three times with PBST.
  • restriction buffer 10 mM Bis-Tris-Propane-HCI, 10 mM MgCI 2 , 1 mM DTT, pH 7.0
  • M.Sssl assay 2 units/well of the methylation-sensible restriction enzyme Hpa II (New Englands Biolabs) have been incubated in 50 ⁇ _ total of the same restriction buffer. Washing conditions are the same as above.
  • DNMT1 assay 2 units/well of the methylation-sensible restriction enzyme BfuCI (New Englands Biolabs) have been incubated in 50 ⁇ _ total of the same restriction buffer. Washing conditions are the same as above.
  • the fluorescence signal of the DNA substrate has been measured on a TyphoonTM scanner (AmershamTM). Fluorescence has been measured after the microplate coating with DNA to check if the amount of substrate is adequate, after methylation and after completion of the reaction. Up to ten plates can be scanned in a single scan. Quantification has been done automatically by measuring the sum of pixels in each well.
  • the first one is the global percentage of methylation defined as 100 * ((average signal of methylation controls - average signal of restriction controls)/( average signal of DNA controls)).
  • IC 50 concentration of drug needed to obtain 50% of inhibition
  • Mean IC 5 o are given ⁇ the standard error defined as— , where SD sam pie is the
  • DNA methylation activity of the complex is measured by the incorporation of tritiated methyl groups from labeled S-[methyl- 3 H] AdoMet (specific activity 370 GBq / mmol, Perkin Elmer) into a biotinylated, hemi-methylated oligonucleotide substrate (biotin - GAAGCT GGACAG TAMeCGTC AAGAGA GTGCAA / TTGCAC TCTT GACGTA CTGTCC AGCTTC)(SEQ ID NO: 5 / SEQ ID NO: 6) using the avidin-biotin methylation kinetic assay as described (M.
  • the methylation reactions were carried out in the methylation buffer (20 mM HEPES, pH 7.5, 50 mM KCI, 1 mM EDTA, 25 ⁇ g/mL bovine serum albumin (BSA)), using 2 ⁇ DNA, 5.5 ⁇ of labeled AdoMet and 0.5 ⁇ of both proteins. Decreasing amounts of inhibitor in DMSO (500 ⁇ , 250 ⁇ , 100 ⁇ , 50 ⁇ , 20 ⁇ , 1 ⁇ , no inhibitor) were pre-incubated with Dnmt3a/C and Dnmt3L/C at room temperature for 30 min.
  • DMSO 500 ⁇ , 250 ⁇ , 100 ⁇ , 50 ⁇ , 20 ⁇ , 1 ⁇ , no inhibitor
  • Human cancer cells (DU145, LNCaP, PC3, HCT1 16 and MCF7) were purchased from ATCC. These cell lines were grown in the RPMI1640, DMEM or MEM medium (Invitrogen) supplemented with 10% heat-inactivated fetal calf serum, 2 mM L-glutamine, 100 units/mL penicillin, 100 ⁇ g mL streptomycin at 37 ⁇ C with 5% C0 2 .
  • DNA methylation activity of the DNMT3a/3L complex was measured by the incorporation of tritiated methyl groups from labeled S-[methyl- 3 H] SAM (specific activity 2.9 TBq/mmol, Perkin Elmer) into a DNA duplex substrate containing 8 CpG sites, with the following sequence 5 'AGGGGACGAAGGAGGGAAGGAAGGGC- AAGGCGGGGGGGGCTCTGCGAGAGCGCGCCCAGCCCCGCCTTCGGGCCCCA CAG (SEQ ID NO: 12).
  • the methylation reactions were carried out in the methylation buffer (20 mM HEPES pH 7.2, 50 mM KCI, 1 mM EDTA), using 200 nM DNA, 280 nM of radiolabeled SAM and 0.5 ⁇ of both proteins.
  • Fertilized eggs were obtained from natural mating of adult zebrafish maintained under standard conditions (Westerfield, M. The Zebrafish Book. A Guide for the Laboratory Use of Zebrafish (Danio rerio), 3rd Edition, (Eugene, OR, University of Oregon Press, 385 (Book), 1 995)). Embryos were incubated in an aqueous solution of the various substrates (from stage 1 6 cells to analysis). Embryos were manually dechorionated before malformation scored or 5mC detected with a specific antibody (anti-5-methylcytosine antibody, Calbiochem).
  • Vp the percentage of embryos exhibiting a phenotype
  • the C-terminal domains of the murine DNMT3a and DNMT3L have been preincubated together with each tested compound in a transfer 96 well microplate for 25 minutes. Next the wells have been transferred into the testing plate that has been previously coated with the DNA fluorescent substrate. SAM has finally been added to start the methylation reaction. After one hour of incubation at 37 °C, plates have been washed to avoid drugs interference with next steps of the assay. Then a restriction mix has been added in each well. After 30 min of incubation at 37°C, plates have been washed again and final signal has been measured and quantified by a TyphoonTM scanner.
  • Genistein is an inhibitor of several enzymatic activities: tyrosine kinases, topoisomease II and DNMTs.
  • the screen of the first 52 molecules at 500 ⁇ detected several active compounds against the DNMT3a/3L complex.
  • the IC 50 of ten hit molecules have been evaluated (in triplicate at least) through the same assay but using drugs concentration ranges in each line of the 96 well plate.
  • Compounds n °46 and 47 were the most active inhibitors of this first screening with promising submicromolar IC 50 (concentration at which 50% of inhibition is observed) of 417 nM and 169 nM, respectively.
  • the chemical structures of these two compounds and other hit molecules share the same chloro-nitro motif at the C3 position in the ring B of the flavanone skeleton.
  • the HTS was applied to the human DNMT1 and the bacterial methyltransferase M. Sssl.
  • the chemical library was screened at 5 ⁇ . Globally, a similar profile was observed on DNMT1 and M.Sssl as on the catalytic DNMT3a/3L complex with little differences.
  • the DNMTs inhibitors of the invention are not pure SAM competitors. Since SAM is the common cofactor that provides the methyl group of all methyltransferase activities in the cell, SAM competition would be unfavorable for selectivity. Second, the mixed inhibition profile is characteristic for a binding inside the active site of the enzyme.
  • DNMT inhibitors of the invention have a mix inhibition profile, since they interact both with the DNA and SAM pocket.
  • kinetics experiments with the methyltransferase G9a HMTK and the bacterial DNMT EcoDam showed a good specificity of compound 11 for the DNMT3a/3L complex, a specificity of compound 62 for the DNA methyltransferases and a poorer selectivity of compounds 47 and 70.
  • nitro-flavone 11 is the most specific compound for DNMT3a/3L and its minimal energy conformation is found mainly in the DNA pocket, differently from what is observed with all the other compounds. However it is also the less potent inhibitor with an IC50 of 9.5 ⁇ .
  • zebrafish is getting more and more used as a cancer model (Feitsma, H. & Cuppen, E. Zebrafish as a cancer model. Mol Cancer Res 6, 685-94 (2008)).
  • great epigenetic changes occur in the first steps of development of the zebrafish embryo (Mhanni, A. A. & McGowan, R.A. Global changes in genomic methylation levels during early development of the zebrafish embryo. Dev Genes Evol 214, 412-7 (2004)).
  • the screening method of the invention is robust, versatile and can be applied to all types of methyltransferases.
  • This method has several technical improvements compared to the HTS of the literature. It does not use radioactivity and allows direct readout of the fluorescent signal, after washing and restriction digest.
  • Woo et al. (Woo, Y.H., Rajagopalan, P.T. & Benkovic, S.J. A nonradioactive DNA methyltransferase assay adaptable to high-throughput screening.
  • Anal Biochem 340, 336-40 (2005) have developed a non-radioactive ELISA assay for Hhcl DNA MTase activity that is however less efficient, more expensive and more laborious to perform. Li et al.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention porte sur un composé de formule (I) ou ses sels, hydrates ou sels hydratés pharmaceutiquement acceptables ou ses structures cristallines polymorphes, racémates, diastéréoisomères ou énantiomères pour son utilisation dans la prévention et/ou le traitement du cancer, de maladies développementales, de maladies neurodégénératives ou de maladies de trypanosomose par l'inhibition d'ADN méthyltransférases.
PCT/EP2010/063493 2009-09-14 2010-09-14 Dérivés de flavones et flavanones en tant qu'inhibiteurs d'adn méthyltransférases Ceased WO2011029956A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP09305840.2 2009-09-14
EP09305840 2009-09-14

Publications (1)

Publication Number Publication Date
WO2011029956A1 true WO2011029956A1 (fr) 2011-03-17

Family

ID=41351723

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2010/063493 Ceased WO2011029956A1 (fr) 2009-09-14 2010-09-14 Dérivés de flavones et flavanones en tant qu'inhibiteurs d'adn méthyltransférases

Country Status (1)

Country Link
WO (1) WO2011029956A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3207932A1 (fr) 2016-02-19 2017-08-23 Universität Stuttgart Inhibiteurs de méthyltransférase d'adn pour la thérapie du syndrome de rett
CN114560837A (zh) * 2022-02-09 2022-05-31 五邑大学 一种色酮类化合物及其制备方法与应用

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0341104A2 (fr) * 1988-04-06 1989-11-08 MERCK PATENT GmbH Composés flavonoides substitués, leurs sels, procédé de leur préparation et compositions pharmaceutiques les contenant
WO1997027177A2 (fr) * 1996-01-29 1997-07-31 The United States Of America, Represented By The Secretary, Department Of Health And Human Services Derives de dihydropyridine-, pyridine-, benzopyrane- mono- et triazoloquinazoline, leur preparation, et utilsation comme antagonistes des recepteurs de l'adenosine
WO2000012496A1 (fr) * 1998-09-01 2000-03-09 Lg Chemical Ltd. Nouveaux inhibiteurs de kinase dependante des cyclines (cdk) presentant une structure flavone
WO2001021608A2 (fr) * 1999-09-23 2001-03-29 Vereniging Voor Christelijk Wetenschappelijk Onderwijs Nouveaux flavonoides
WO2001080855A1 (fr) * 2000-04-27 2001-11-01 Geron Corporation Inhibiteurs de la telomerase et procedes pour les utiliser
WO2004007475A1 (fr) * 2002-07-13 2004-01-22 Rowett Research Institute Composes flavonoides en tant qu'antioxydants therapeutiques
US20060025337A1 (en) * 2003-07-01 2006-02-02 President And Fellows Of Harvard College Sirtuin related therapeutics and diagnostics for neurodegenerative diseases
WO2007082178A2 (fr) * 2006-01-06 2007-07-19 Abgenomics Corporation Inhibiteurs de prostaglandine réductases
US20090118310A1 (en) * 2005-08-09 2009-05-07 University Of Medicine And Dentistry Of New Jersey Activated Cdc42-associated kinase (ACK) as a therapeutic target for Ras-induced cancer

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0341104A2 (fr) * 1988-04-06 1989-11-08 MERCK PATENT GmbH Composés flavonoides substitués, leurs sels, procédé de leur préparation et compositions pharmaceutiques les contenant
WO1997027177A2 (fr) * 1996-01-29 1997-07-31 The United States Of America, Represented By The Secretary, Department Of Health And Human Services Derives de dihydropyridine-, pyridine-, benzopyrane- mono- et triazoloquinazoline, leur preparation, et utilsation comme antagonistes des recepteurs de l'adenosine
WO2000012496A1 (fr) * 1998-09-01 2000-03-09 Lg Chemical Ltd. Nouveaux inhibiteurs de kinase dependante des cyclines (cdk) presentant une structure flavone
WO2001021608A2 (fr) * 1999-09-23 2001-03-29 Vereniging Voor Christelijk Wetenschappelijk Onderwijs Nouveaux flavonoides
WO2001080855A1 (fr) * 2000-04-27 2001-11-01 Geron Corporation Inhibiteurs de la telomerase et procedes pour les utiliser
WO2004007475A1 (fr) * 2002-07-13 2004-01-22 Rowett Research Institute Composes flavonoides en tant qu'antioxydants therapeutiques
US20060025337A1 (en) * 2003-07-01 2006-02-02 President And Fellows Of Harvard College Sirtuin related therapeutics and diagnostics for neurodegenerative diseases
US20090118310A1 (en) * 2005-08-09 2009-05-07 University Of Medicine And Dentistry Of New Jersey Activated Cdc42-associated kinase (ACK) as a therapeutic target for Ras-induced cancer
WO2007082178A2 (fr) * 2006-01-06 2007-07-19 Abgenomics Corporation Inhibiteurs de prostaglandine réductases

Non-Patent Citations (51)

* Cited by examiner, † Cited by third party
Title
AKAISHI TATSUHIRO ET AL: "Structural requirements for the flavonoid fisetin in inhibiting fibril formation of amyloid beta protein", NEUROSCIENCE LETTERS, vol. 444, no. 3, October 2008 (2008-10-01), pages 280 - 285, XP002558574, ISSN: 0304-3940 *
B. BAUVOIS ET AL., J MED CHEM, vol. 46, 28 August 2003 (2003-08-28), pages 3900
BAURES P W ET AL: "Discovering transthyretin amyloid fibril inhibitors by limited screening.", BIOORGANIC & MEDICINAL CHEMISTRY AUG 1998, vol. 6, no. 8, August 1998 (1998-08-01), pages 1389 - 1401, XP002558573, ISSN: 0968-0896 *
BAUVOIS BRIGITTE ET AL: "Synthesis and biological evaluation of novel flavone-8-acetic acid derivatives as reversible inhibitors of aminopeptidase N/CD13.", JOURNAL OF MEDICINAL CHEMISTRY, vol. 46, no. 18, 28 August 2003 (2003-08-28), pages 3900 - 3913, XP002558569, ISSN: 0022-2623 *
BAUVOIS ET AL., J. MED. CHEM., vol. 46, 2003, pages 3900 - 3913
BAUVOIS, B.; PUIFFE M. L.; BONGUI J. B.; PAILLAT S.; MONNERET C.; DAUZONNE D., J. MED. CHEM., vol. 46, no. 18, 2003, pages 3900 - 3913
BERGE ET AL., J. PHARM. SD, vol. 66, 1977, pages 1
BEUTLER JOHN A ET AL: "Structure-activity requirements for flavone cytotoxicity and binding to tubulin", JOURNAL OF MEDICINAL CHEMISTRY, vol. 41, no. 13, 18 June 1998 (1998-06-18), pages 2333 - 2338, XP002558570, ISSN: 0022-2623 *
C. B. YOO; P. A. JONES, NAT REV DRUG DISCOV, vol. 5, January 2006 (2006-01-01), pages 37
CARDENAS M ET AL: "Antitumor activity of some natural flavonoids and synthetic derivatives on various human and murine cancer cell lines", BIOORGANIC & MEDICINAL CHEMISTRY, ELSEVIER SCIENCE LTD, GB, vol. 14, no. 9, 1 May 2006 (2006-05-01), pages 2966 - 2971, XP025133187, ISSN: 0968-0896, [retrieved on 20060501] *
CHANG HUI ET AL: "Structurally related cytotoxic effects of flavonoids on human cancer cells in vitro", ARCHIVES OF PHARMACAL RESEARCH (SEOUL), vol. 31, no. 9, September 2008 (2008-09-01), pages 1137 - 1144, XP002558571, ISSN: 0253-6269 *
D. DAUZONNE; B. FOLLÉAS; L. MARTINEZ; G. G. CHABOT, EUR. J. MED. CHEM., vol. 32, 1997, pages 71
DAUZONNE D ET AL: "A new synthesis of flavanones", SYNTHESIS 1997 DE, no. 11, 1997, pages 1305 - 1308, XP002606927, ISSN: 0039-7881 *
DAUZONNE D FOLLEAS B MARTINEZ L CHABOT GG: "Synthesis and in vitro cytotoxicity of a series of 3-aminoflavones", EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, EDITIONS SCIENTIFIQUE ELSEVIER, PARIS, FR LNKD- DOI:10.1016/S0223-5234(97)84363-2, vol. 32, no. 1, 1 January 1997 (1997-01-01), pages 71 - 82, XP004034181, ISSN: 0223-5234 *
DAUZONNE DANIEL ET AL: "Synthesis of 2-aryl-3-nitro-4H-1-benzopyran-4-ones", SYNTHESIS, GEORG THIEME VERLAG, STUTTGART, DE LNKD- DOI:10.1055/S-1992-26198, no. 7, 1 July 1992 (1992-07-01), pages 677 - 680, XP009121862, ISSN: 0039-7881 *
DAUZONNE ET AL., EUR J MED CHEM, vol. 32, 1997, pages 71 - 82
DAUZONNE, D.; DEMERSEMAN P.: "A convenient synthesis of 3-chloro-3,4-dihydro-4-hydroxy-3-nitro-2-phenyl-2h-1-benzopyrans", SYNTHESIS, 1990, pages 66 - 70
DAUZONNE, D.; FOLLÉAS, B.; MARTINEZ, L.; CHABOT, G. G.: "Synthesis and in vitro cytotoxicity of a series of 3-aminoflavones", EUR. J. MED. CHEM., vol. 32, 1997, pages 71 - 82
DAUZONNE, D.; GRANDJEAN, C.: "Synthesis of 2-aryl-3-nitro-4H-1-benzopyran-4-ones", SYNTHESIS, 1992, pages 677 - 680
EDWARDS J M ET AL: "ANTINEOPLASTIC ACTIVITY AND CYTOTOXICITY OF FLAVONES, ISOFLAVONES, AND FLAVANONES", JOURNAL OF NATURAL PRODUCTS, AMERICAN CHEMICAL SOCIETY, US, vol. 42, no. 1, 1 January 1979 (1979-01-01), pages 85 - 91, XP009035912, ISSN: 0163-3864 *
FEITSMA, H.; CUPPEN, E.: "Zebrafish as a cancer model", MOL CANCER RES, vol. 6, 2008, pages 685 - 94
HORTON, J.R.; LIEBERT, K.; BEKES, M.; JELTSCH, A.; CHENG, X.: "Structure and substrate recognition of the Escherichia coli DNA adenine methyltransferase", J MOL BIOL, vol. 358, 2006, pages 559 - 70
ISHIGE KUMIKO ET AL: "Flavonoids protect neuronal cells from oxidative stress by three distinct mechanisms", FREE RADICAL BIOLOGY AND MEDICINE, vol. 30, no. 4, 15 February 2001 (2001-02-15), pages 433 - 446, XP002558572, ISSN: 0891-5849 *
J. H. ZHANG; T. D. CHUNG; K. R. OLDENBURG, J BIOMOL SCREEN, vol. 4, 1999, pages 67
J. LI; H. YAN; K. WANG; W. TAN; X. ZHOU, ANAL CHEM, vol. 79, 2007, pages 1050
J. R. HORTON; K. LIEBERT; M. BEKES; A. JELTSCH; X. CHENG, J MOL BIOL, vol. 358, 2006, pages 559
JIA, D.; JURKOWSKA, R.Z.; ZHANG, X.; JELTSCH, A.; CHENG, X., NATURE, vol. 449, 2007, pages 248 - 51
JIA, D.; JURKOWSKA, R.Z.; ZHANG, X.; JELTSCH, A.; CHENG, X.: "Structure of Dnmt3a bound to Dnmt3L suggests a model for de novo DNA methylation", NATURE, vol. 449, 2007, pages 248 - 51
KARTON Y ET AL: "SYNTHESIS AND BIOLOGICAL ACTIVITIES OF FLAVONOID DERIVATIVES AS A3 ADENOSINE RECEPTOR ANTAGONISTS", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, WASHINGTON, US, vol. 39, 1 January 1996 (1996-01-01), pages 2293 - 2301, XP000877118, ISSN: 0022-2623 *
LEE ET AL: "3-Hydroxychromones as cyclin-dependent kinase inhibitors: Synthesis and biological evaluation", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, PERGAMON, ELSEVIER SCIENCE, GB, vol. 17, no. 5, 14 February 2007 (2007-02-14), pages 1284 - 1287, XP005888465, ISSN: 0960-894X *
LEE WON JUN ET AL: "Mechanisms for the inhibition of DNA methyltransferases by tea catechins and bioflavonoids", MOLECULAR PHARMACOLOGY, vol. 68, no. 4, October 2005 (2005-10-01), pages 1018 - 1030 URL, XP002558566, ISSN: 0026-895X *
LI, J.; YAN, H.; WANG, K.; TAN, W.; ZHOU, X.: "Hairpin fluorescence DNA probe for real-time monitoring of DNA methylation", ANAL CHEM, vol. 79, 2007, pages 1050 - 6
M. ESTELLER, N ENGL J MED, vol. 358, 13 March 2008 (2008-03-13), pages 1148
M. PHAM ET AL., DRUG METAB. DISPOS., vol. 35, 2007, pages 2023
M. ROTH; A. JELTSCH, BIOL CHEM, vol. 381, 2000, pages 269
MACKAY, A.B.; MHANNI, A.A.; MCGOWAN, R.A.; KRONE, P.H.: "Immunological detection of changes in genomic DNA methylation during early zebrafish development", GENOME, vol. 50, 2007, pages 778 - 85
MARTIN, C.C.; LAFOREST, L.; AKIMENKO, M.A; EKKER, M. A: "role for DNA methylation in gastrulation and somite patterning", DEV BIOL, vol. 206, 1999, pages 189 - 205
MHANNI, A.A.; MCGOWAN, R.A.: "Global changes in genomic methylation levels during early development of the zebrafish embryo", DEV GENES EVOL, vol. 214, 2004, pages 412 - 7
P. RATHERT; A. DHAYALAN; H. MA; A. JELTSCH, MOL BIOSYST, vol. 4, 2008, pages 1186
QUINEY CLAIRE ET AL: "Flavones and polyphenols inhibit the NO pathway during apoptosis of leukemia B-cells", LEUKEMIA RESEARCH, vol. 28, no. 8, August 2004 (2004-08-01), pages 851 - 861, XP002558567, ISSN: 0145-2126 *
RATHERT, P.; CHENG, X.; JELTSCH, A.: "Continuous enzymatic assay for histone lysine methyltransferases", BIOTECHNIQUES, vol. 43, 2007, pages 602,604,606
ROTH, M.; JELTSCH, A.: "Biotin-avidin microplate assay for the quantitative analysis of enzymatic methylation of DNA by DNA methyltransferases", BIOL CHEM, vol. 381, 2000, pages 269 - 72
STEELE VERNON E ET AL: "Correlation between electron-donating ability of a series of 3-nitroflavones and their efficacy to inhibit the onset and progression of aberrant crypt foci in the rat colon", CANCER RESEARCH, vol. 62, no. 22, 15 November 2002 (2002-11-15), pages 6506 - 6509, XP002558568, ISSN: 0008-5472 *
URIG, S. ET AL.: "The Escherichia coli dam DNA methyltransferase modifies DNA in a highly processive reaction", J MOL BIOI, vol. 319, 2002, pages 1085 - 96
VALENTI P ET AL: "SYNTHESIS AND ANTITUMOR ACTIVITY OF SOME ANALOGUES OF FLAVONE ACETIC ACID", ANTI-CANCER DRUG DESIGN, OXFORD UNIVERSITY PRESS, BASINGSTOKE, vol. 11, no. 3, 1 January 1996 (1996-01-01), pages 243 - 252, XP008070261, ISSN: 0266-9536 *
WESTERFIELD, M; EUGENE, OR: "The Zebrafish Book. A Guide for the Laboratory Use of Zebrafish (Danio rerio)", vol. 385, 1995, UNIVERSITY OF OREGON PRESS
WOO, Y.H.; RAJAGOPALAN, P.T.; BENKOVIC, S.J.: "A nonradioactive DNA methyltransferase assay adaptable to high-throughput screening", ANAL BIOCHEM, vol. 340, 2005, pages 336 - 40
X. CHENG; R. M. BLUMENTHAL, STRUCTURE, vol. 16, March 2008 (2008-03-01), pages 341
Y. H. WOO; P. T. RAJAGOPALAN; S. J. BENKOVIC, ANAL BIOCHEM, vol. 340, 2005, pages 336
YAMAKOSHI, K.; SHIMODA, N.: "De novo DNA methylation at the CpG island of the zebrafish no tail gene", GENESIS, vol. 37, 2003, pages 195 - 202
YE, Y.; STIVERS, J.T.: "Fluorescence-based high-throughput assay for human DNA (cytosine-5)-methyltransferase 1", ANAL BIOCHEM, vol. 401, 2010, pages 168 - 72

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3207932A1 (fr) 2016-02-19 2017-08-23 Universität Stuttgart Inhibiteurs de méthyltransférase d'adn pour la thérapie du syndrome de rett
CN114560837A (zh) * 2022-02-09 2022-05-31 五邑大学 一种色酮类化合物及其制备方法与应用
CN114560837B (zh) * 2022-02-09 2023-11-24 五邑大学 一种色酮类化合物及其制备方法与应用

Similar Documents

Publication Publication Date Title
JP2793195B2 (ja) ベンゾチアゾール誘導体
Ashraf et al. Structure-based designing and synthesis of 2-phenylchromone derivatives as potent tyrosinase inhibitors: In vitro and in silico studies
CN108530310B (zh) 2-(取代苯杂基)芳香甲酸类fto抑制剂，其制备方法及其应用
Soni et al. Synthesis and antimicrobial evaluation of amide derivatives of benzodifuran-2-carboxylic acid
KR20140068243A (ko) 대사 질환 및 관련 장애의 치료를 위한 모노아실글리세롤 리파제 억제제
Perner et al. Synthesis and biological evaluation of 6, 7-disubstituted 4-aminopyrido [2, 3-d] pyrimidines as adenosine kinase inhibitors
EP3284743B1 (fr) Composés d'imidazole hétérocycliques, compositions pharmaceutiques les contenant, leur procédé de préparation et utilisation
JP2020158520A (ja) ラクタム化合物誘導体およびその応用
WO2023144450A1 (fr) Composés destinés à être utilisés dans le traitement du cancer et d'états inflammatoires
MXPA02012657A (es) Derivados de coumarina con actividad inhibidora de comt.
WO2011029956A1 (fr) Dérivés de flavones et flavanones en tant qu'inhibiteurs d'adn méthyltransférases
WO2002074036A2 (fr) Benzopyranones substitues utilises en tant qu'inhibiteurs de telomerase
ES2354114T3 (es) Nuevos compuestos farmacéuticos.
AU2014374601B2 (en) 1,2-naphthoquinone derivative and method for preparing same
WO2012038417A1 (fr) Dérivés d'acide aminobenzoïque substitués comme inhibiteurs de méthyltransférases de l'adn
Hassan et al. Design, synthesis and anti-ulcerogenic effect of some of furo-salicylic acid derivatives on acetic acid-induced ulcerative colitis
Kiss et al. Design, synthesis, and structure–activity relationships of 1, 3, 4-oxadiazol-2 (3 H)-ones as novel FAAH inhibitors
ES2570452B1 (es) Compuestos derivados de acrilato de 3-Alquilamino-1H-Indolilo y su uso en el tratamiento de enfermedades neurodegenerativas
US7863323B1 (en) Flavonols
Tobinaga et al. Pyrrolinone derivatives as a new class of P2X3 receptor antagonists. Part 3: Structure-activity relationships of pyrropyrazolone derivatives
Kamal et al. Synthesis, biological evaluation of 5-carbomethoxymethyl-7-hydroxy-2-pentylchromone, 5-carboethoxymethyl-4′, 7-dihydroxyflavone and their analogues
US20090029975A1 (en) 1,3-benzothiazinone derivative and use thereof
KR20030018800A (ko) 시토크롬 피450 1비1 억제활성을 갖는 페닐환 유도체 및약학적으로 허용가능한 그의 염, 그의 제조방법 및 이를함유하는 조성물
Le et al. Design, Synthesis, and Biological Activity Evaluation of Novel AZT and Adenosine‐Derived 1, 2, 3‐Triazoles
CN102584764B (zh) 2′-氯-4′-硝基黄酮及其衍生物以及它们的制备与应用

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 10755136

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 10755136

Country of ref document: EP

Kind code of ref document: A1