WO2012052596A1 - Dérivés de gangliosides et leur utilisation en tant qu'inhibiteurs de la division des cellules tumorales - Google Patents

Dérivés de gangliosides et leur utilisation en tant qu'inhibiteurs de la division des cellules tumorales Download PDF

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WO2012052596A1
WO2012052596A1 PCT/ES2011/070732 ES2011070732W WO2012052596A1 WO 2012052596 A1 WO2012052596 A1 WO 2012052596A1 ES 2011070732 W ES2011070732 W ES 2011070732W WO 2012052596 A1 WO2012052596 A1 WO 2012052596A1
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group
formula
reaction
propionyl
compound
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Manuel Nieto Sampedro
Lorenzo ROMERO RAMÍREZ
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Consejo Superior De Investigaciones Científicas (Csic)
Fundación Del Hospital Nacional De Parapléjicos Para La Investigación Y La Integración (Fuhnpaiin)
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    • 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
    • C07H15/10—Acyclic radicals, not substituted by cyclic structures attached to an oxygen atom of the saccharide radical containing unsaturated carbon-to-carbon bonds
    • 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
    • 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
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P19/00—Preparation of compounds containing saccharide radicals
    • C12P19/44—Preparation of O-glycosides, e.g. glucosides
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y203/00—Acyltransferases (2.3)
    • C12Y203/01—Acyltransferases (2.3) transferring groups other than amino-acyl groups (2.3.1)
    • C12Y203/01045—N-Acetylneuraminate 7-O (or 9-O)-acetyltransferase (2.3.1.45)

Definitions

  • the present invention relates to new inhibitors of tumor cell division.
  • Said inhibitors are semi-synthetic derivatives of neurostatin.
  • the present invention relates to a new synthesis procedure.
  • inhibitors and neurostatin refers to a procedure for obtaining O-acylated gangliosides specifically in terminal sialics. It also refers to the use of these inhibitors for the manufacture of a medicament for the treatment of brain tumors.
  • the invention is part of the pharmaceutical sector, and is applicable in the medical sector for the treatment of brain tumors.
  • Glioblastoma multiforme is the most common primary brain tumor in adults and also the most deadly. In the United States, only half of the patients receiving standard treatment survive one year after diagnosis. Less than one in ten survives more than five years. Usually
  • Brain tumors are the first cause of death
  • Treatment depends on the location and grade of the tumor; Surgery is applied when the tumor is accessible and there is no danger of damaging vital structures. Radiation therapy is used to stop tumor growth or to
  • Gangliosides are glycolipids formed by a ceramide chain (which is composed of a residue of the aminoalcoholesphingosine bound to a fatty acid) linked to an oligosaccharide chain. Gangliosides have as their structural characteristic, the presence of one or more sialic acid residues in the oligosaccharide chain.
  • Neurostatin is characterized by being a ganglioside of the series b, GD1 b, with a modification in the form of O-acetylation in one of the hydroxyls of its terminal sialic (Romero-Ramirez L, Nieto-Sampedro M. Inhibiting human astrocytomagrowth: structure - activityrelationships in neurostatinrelatedglycolipids. Journal of Medicinal Chemistry 2004; 47 (21): 4983-4.).
  • the position of this O-acetylation is preferably in the hydroxyl of carbon 9, since although O-acetylations in carbons 7 and 8 have also been described, under physiological pH conditions the O-acetyls in those carbons migrate to position 9 O-acetylation is the most frequent modification in nature and is preferably found in the sialics of gangliosides linked in links to (2,8) and (2,3) to the glycidic chain.
  • Neurostatin is a natural ganglioside that is expressed in very low concentration in the central nervous system of mammals (Abad-Rodr ⁇ guez J, Bernabé M, Romero-Ramirez L, Vallejo-Cremades M, Fernandez- Mayoralas A, Nieto-Sampedro M. Purification and structure of neurostatin, an inhibitor of astrocyted vision of mammalianbrain, Journal of Neurochemistry 2000; 74 (6): 2547-56.).
  • the present invention describes a new series of gangliosides with inhibitory activity (of the neurostatin family) of tumor cell division and glioma growth.
  • the present invention describes a novel method of obtaining O-acetylated gangliosides and neurostatin which is characterized by its simplicity, specificity and high performance. This procedure has a commercial interest in the field of glycobiology for the production of these O-acetylated gangliosides in large quantities.
  • O-propionylated and O-malonylated gangliosides are very interesting products for clinical use as antitumor agents.
  • a first aspect of the present invention relates to a method of synthesizing a compound, specifically a ganglioside, of the general formula.
  • Z is selected from a group of formula Zi:
  • Z 2 is a group of formula (Z 2 ):
  • Xi is selected from -CH 2 -O-CO-X 2 and -CH 2 OH;
  • X 2 is selected from a Ci-C 2 and -CH 2 COOH alkyl group
  • X3 is selected from H, OH, a group of formula (II) or a group of formula
  • X5 is selected from an OH group or a -0-COXe group
  • Xese selects from a C 1 -C 2 or -CH 2 COOH alkyl group; Except when:
  • - Z is a group of formula (Z 1 ) or (Z 2 ), X 1 is -CH 2 -OH and X 3 is H;
  • - Z is a group of formula (Zi) or (Z 2 ), Xi is -CH 2 -OH, X 3 is the group of formula (III) and X4 is H;
  • - Z is a group of formula (Z1) or (Z 2 ), X1 is -CH 2 -OH, X 3 is the group of formula (III) and X4 is the group of formula (IV) and X 5 is OH;
  • - Z is a group of formula (Z1) or (Z 2 ), X1 is -CH 2 -OH, X 3 is the group of formula (III) and X4 is the group of formula (V) and X 5 is OH; comprising the steps of: a) dissolving a ganglioside in a buffer solution; b) add an emulsifier to the mixture of step a) c) add to the mixture of step b) the enzyme o-acetyltransferase; and d) stop the reaction by adding methanol to the mixture obtained in step c).
  • the ganglioside of the general formula (I) is selected from the group consisting of O-acetyl-GM3, O-acetyl-GM2, O-acetyl-GD3, O-acetyl-GD2, Neurostatin, AO-acetyl-GT1 b, AO-acetyl-GQ1 b, O-propionyl-GD1 b, O-propionyl-GD3, O-propionyl-GD2, AO-propionyl-GT1 b, BO-propionyl-GT1 b, BO-acetyl-GT1 b, di -O-acetyl-GT1 b, O-Propionyl-GM3, O-Malonil-GM3, O- Propionyl-GM2, O-Malonil-GM2, O-Malonyl-GD3, O-Malonil-GD2, O-Propionyl- GD1 a , O-Malonil-GD1
  • Y is any ceramide, which is composed of a sphingosine and a fatty acid.
  • sphingosine comprises 18 to 20 carbon atoms and has a number of unsaturations of 0 to 2.
  • the fatty acid may contain 8 to 24 carbon atoms and with a number of unsaturations of 0 to 4;
  • GD1 b, GD3, GD2, GT1 b, GQ1 b, GM3, GM2, GM1 a or GD1 a refer to gangliosides of the same name known in the state of the art by any person skilled in the art.
  • these gangliosides comprise among other elements, a ceramide (Y) which in turn comprises a sphingosine and a fatty acid.
  • Sphingosine is preferably 18 carbon atoms with an unsaturation or 20 carbon atoms with an unsaturation.
  • the fatty acid is 18 carbon atoms without any unsaturation or unsaturation.
  • the compound of general formula I has the formula (la):
  • Xi is -CH 2 -O-CO-X 2 ;
  • X2 is a C1-C2 alkyl group
  • X3 is selected from H, OH, a group of formula (II) or a group of formula (III):
  • X 5 is selected from an OH group or a - ⁇ -COXe group; and ⁇ is a C1-C2 alkyl group;
  • - Xi is -CH2-O-CO-X2, X2 is a group CH 3 , X3 is the group of formula (III) and X4 is H;
  • - Xi is -CH2-O-CO-X2, X2 is a CH 3 group, X3 is the group of formula (II);
  • - Xi is -CH2-O-CO-X2
  • X2 is a group CH 3
  • X3 is the group of formula (III)
  • X4 is the group of formula (IV)
  • X 5 is OH
  • - Xi is -CH2-O-CO-X2, X2 is a group CH 3 , X3 is the group of formula (la) and X4 is OH; comprising the steps of: a) dissolving a ganglioside in a buffer solution; b) add an emulsifier to the mixture of step a) c) add to the mixture of step b) the enzyme o-acetyltransferase; and d) stop the reaction by adding methanol to the mixture obtained in step c).
  • the ganglioside is selected from the group consisting of GD1 b, GD3, GD2 and GT1 b, as they have been defined above.
  • Said gangliosides GD1 b, GD3, GD2 and GT1 b, as mentioned above, comprise among other elements, a ceramide (Y) as defined above, which in turn comprises a sphingosine and a fatty acid.
  • Sphingosine is preferably 18 carbon atoms with an unsaturation or 20 carbon atoms with an unsaturation.
  • the fatty acid is 18 carbon atoms without any unsaturation or unsaturation.
  • a ganglioside concentration between 50 to 600 pmoles / L reaction, preferably between 300 and 600 pmoles / L and more preferably 500 moles / L is added
  • the buffer solution is added in a concentration from 1 to 250 mmol / L of reaction preferably from 0 to 100 mM, more preferably at a concentration of 50 mM, at a pH from 6 to 9 , preferably at a pH between 7 and 8, more preferably at a pH of 7.0.
  • the buffer solution is from TRIS (tris (hydroxymethyl) aminomethane), MES (2- (N-morpholino) ethanesulfonic acid), phosphate, etc., preferably from MES.
  • MgC buffer (10 mmol / L) and DTT (Dithiothreitol) (1 mmol / L) are added to the solution.
  • a buffer and a coenzyme A derivative selected from Acetyl-Coenzyme A, Propionyl-Coenzyme A and Malonyl-Coenzyme A, more preferably Acetyl-Coenzyme A or Propionyl-Coenzyme A are added to the solution at a concentration from 0.1 to 10 mmol / L reaction, preferably between 0.5 and 2 mmol / L more preferably at 1 mmol / L.
  • the emulsifier is a bile acid or bile salt at a preferable concentration between 0.05% and 0.2% total weight / volume of the reaction, more preferably 0.1% in Total weight / volume of the reaction. That is, the emulsifier is a bile acid or bile salt at a preferable concentration between 0.05% and 0.2% by weight with respect to the total volume of the reaction, more preferably 0.1% by weight with respect to the total volume of the reaction.
  • the bile acid is selected from the group consisting of colic acid, deoxycholic acid, taurocolic, glycocolic, ursodeoxycholic, lithocolic acid, etc. as its sodium and potassium salts, (example: cholate, taurocholate, deoxycholate, ursodeoxycholate, glycocholate, etc. ).
  • the emulsifier is the sodium bile colata salt.
  • the emulsifier reduces the micellation of gangliosides, increasing the accessibility of terminal sialics to the enzyme O-acetyltransferase.
  • the enzyme O-acetyltransferase is added at a concentration of between 2 and 30 pg / ⁇ reaction, preferably between 15 and 25 pg / ⁇ , more preferably at 20 Mg / ⁇ -
  • the process of the present invention uses as an catalyst an O-acetyltransferase obtained from the bacteria Campylobacterjejunni, whose cloning, sequencing and activity have been patented (WO 2007016792 20070215) and published by Houliston R. et al (Houliston RS, Endtz HP, Yuki N, et al. The Journal of Biological Chemistry 2006; 281 (17): 11480-6).
  • the reaction of step c) was performed between 30-40 ° C, preferably between 35-38 ° C, more preferably at a temperature of 37 ° C.
  • the reaction of step c) was carried out during a reaction time between 1 hour and 24 hours, preferably between 5 and 12 hours, more preferably for 7 hours, and with stirring. After stopping the reaction with methanol in step d), the following steps were carried out:
  • the procedure described in the present invention is a specific protocol for ganglioside O-acetylation. Unlike the procedure described in (Houliston RS, Endtz HP, Yuki N, et al. Identification of a sialate O-acetyltransferase from Campylobacter jejuni: demonstration of direct transfer to the C-9 position of terminalalpha-2, 8-linked sialic acid The Journal of Biological Chemistry 2006; 281 (17): 11480-6) and in the patent (WO 2007016792), in the process of the present invention an emulsifier, which can be a bile acid or a salt, is added to the reaction mixture bile, which in combination of the pH reduces the micellation of the gangliosides, increasing the accessibility of the terminal sialics to the enzyme O-acetyltransferase.
  • the pH of the reaction must be equal to or greater than 6.5 for the sodium colata to be soluble in the buffer and can act on gangliosides
  • the procedure has a much higher performance than those described above.
  • the yield is 90%, compared to the scarce 10-15% of other procedures described in the prior art. Thanks to this performance, neurostatin can now be considered as an interesting product as an antitumor in patients and, therefore, with possible commercial use.
  • the process described in the present invention also allows to obtain natural O-acetylated products of the neurostatin family, such as O-acetyl-GD2 and O-acetyl-GT1 b, which have not been described in the scientific literature as antitumor; and others, such as di-O-acetyl-GT1 b, which have not been described in nature, nor as antitumor agents.
  • O-acetylated gangliosides the process described in the present invention can be used to prepare O-propionylated and O-malonylated gangliosides.
  • Both the O-acetylated, O-propionylated or O-malonylated products may refer to derivatives with one or two acyl groups (acetyl, propionyl or malonyl).
  • These O-propionylated products such as O-propionyl-GM3, O-propionyl-GM2, O-propionyl-GD3, O-propionyl-GD2, O-propionyl-GD1 b, O-propionyl-GT1 by O-propionyl-GQ1 b , and their respective O-malonylates have never been described in the literature, nor are they found in nature.
  • these O-propionylated products have greater inhibitory activity of the proliferation of the C6 glioma line (Table 1) and could be more resistant to hydrolysis by glycosidases, so that their effect would be more lasting.
  • a second aspect of the present invention relates to a compound (in hereinafter also referred to as ganglioside or compound of the invention), which has the general formula (I) according to as defined above, except when:
  • - Z is a group of formula (Zi), Xi is -CH2-O-CO-X2, X2 is a group CH 3 , X3 is the group of formula (III) and X4 is H;
  • - Z is a group of formula (Z1), X1 is -CH2-O-CO-X2, X2 is a group CH 3 , X3 is the group of formula (II);
  • - Z is a group of formula (Z1), X1 is -CH2-O-CO-X2, X2 is a group CH 3 , X3 is the group of formula (III), X4 is the group of formula (IV) and X 5 is OH;
  • - Z is a group of formula (Z1), X1 is -CH2-O-CO-X2, X2 is a group CH 3 , X3 is OH;
  • - Z is a group of formula (Z1), X1 is -CH2-O-CO-X2, X2 is a group CH 3 , X3 is the group of formula (III), X4 is the group of formula (V), X 5 is -OH;
  • - Z is a group of formula (Z 2 ), X1 is -CH2-O-CO-X2, X2 is a group CH 3 , X3 is OH;
  • - Z is a group of formula (Z 2 ), X1 is -CH2-O-CO-X2, X2 is a group CH 3 , X3 is the group of formula (II);
  • - Z is a group of formula (Z 2 )
  • X1 is -CH 2 -OH
  • X 3 is the group of formula (III)
  • X4 is the group of formula (IV)
  • X 5 is -O-CO-X6 and ⁇ is a CH 3 group.
  • the compound of the invention has the formula
  • X2 is a C1-C2 alkyl group
  • X3 is selected from H, OH, a compound of general formula (II) or a compound of general formula (III)
  • X ⁇ is selected from H and a compound of general formula (IV):
  • X 5 is selected from an OH group or a -0-COXe group; ⁇ is a C1-C2 alkyl group;
  • - Xi is -CH 2 -O-CO-X2, X2 is methyl, X3 is the compound of general formula (III) and X4 is hydrogen;
  • Xies -CH2-O-CO-X2, X2 is methyl
  • X3 is the compound of general formula (III) where X4 is the compound of general formula (IV) where X 5 is OH;
  • - X1 is - CH2-O- CO-X2,
  • X 2 is a methyl,
  • X 3 is OH;
  • - Xi is -CH2-O-CO-X2, X 2 is methyl, X 3 is OH;
  • - Xi is -CH2-O-CO-X2, X2 is methyl, X3 is the group of formula (II);
  • - Xi is -CH2-O-CO-X2, X2 is methyl, X3 is the group of formula (III), X4 is the group of formula (V) and X 5 is OH;
  • Y is a ceramide comprising a sphingosine and a natural or synthetic fatty acid.
  • sphingosine comprises 18 to 20 carbon atoms and has an unsaturation number of 0 to 2.
  • the fatty acid comprises 8 to 24 carbon atoms and has an unsaturation number of 0 to 4;
  • X 2 is a methyl group.
  • X 2 is an ethyl group.
  • X 2 is a -CH 2 COOH group.
  • X 3 is H.
  • X 3 is OH.
  • X 3 is a group of formula (II).
  • X 3 is a compound of general formula (III)
  • X4 is H.
  • X4 is a compound of general formula (IV)
  • X4 is a compound of general formula (V).
  • X 5 is an OH group.
  • X 5 is a group - ⁇ -COXe.
  • ⁇ is a methyl. According to another preferred embodiment, ⁇ is an ethyl.
  • ⁇ is a -CH 2 COOH group.
  • the compounds of the present invention are selected from the following list: O-propionyl-GD1b, O-propionyl-GD3, O-propionyl-GD2, AO-propionyl-GT1b, BO-propionyl-GT1b, di-O -propionyl-GT1b, BO-acetyl-GT1b, di-O-acetyl-GTIb, O-Propionyl-GM3, O-Malonyl-GM3, O- Propionyl-GM2, O-Malonyl-GM2, O-Malonil-GD3, O -Malonil-GD2, O-Propionyl- GD1a, O-Malonil-GD1a, O-Malonil-GD1b, AO-Malonil-GT1b, BO-Malonil- GT1b, di-O-Malonil-GT1b, BO
  • B-0-propionyl-GT1 b where Y is any ceramide, which is composed of a sphingosine and a fatty acid.
  • sphingosine comprises 18 to 20 carbon atoms and has a number of unsaturations of 0 to 2.
  • the fatty acid may contain 8 to 24 carbon atoms and with a number of unsaturations of 0 to 4;
  • GD1 b, GD3, GD2, GT1 b, GQ1 b, GM3, GM2, GM1 a or GD1 a refer to gangliosides of the same name known in the state of the art by any person skilled in the art.
  • these gangliosides comprise among other elements, a ceramide (Y) which in turn comprises a sphingosine and a fatty acid.
  • Sphingosine is preferably 18 carbon atoms with a unsaturation or 20 carbon atoms with unsaturation.
  • the fatty acid is 18 carbon atoms without any unsaturation or unsaturation.
  • Another aspect of the invention relates to a compound synthesized according to the process of the invention.
  • Another aspect of the present invention relates to the compound of general formula (I) for use as a medicament.
  • a third aspect of the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising at least the compound of general formula (I), or a compound of formula (la), and at least one pharmaceutically acceptable carrier, adjuvant and / or vehicle.
  • the pharmaceutical composition further comprises another active ingredient.
  • a fourth aspect of the present invention relates to the use of the ganglioside of general formula (I), or a ganglioside of formula (la), or any of its salts, isomers or solvates, wherein; Y, Ac, Xi, X2, X3 , X4, X5 and ⁇ are defined as defined above for the preparation of a medicine.
  • a preferred embodiment refers to the use for the preparation of a medicament for the treatment or prevention of tumors, preferably for the treatment or prevention of astrocytomas, glioblastomas, oligodendrogliomas, neuroblastomas or meningiomas.
  • a fifth aspect of the present invention relates to the use of the ganglioside of general formula (I), or of the ganglioside of formula (la), or any of its salts, isomers or solvates, where: Y, Ac, X1, X2, X3 , X4, X5 and ⁇ are defined as defined above, as a reagent in biological assays.
  • the compound described in the present invention, its salts, prodrugs and / or solvates as well as the pharmaceutical, cosmetic and nutritional compositions containing them can be used together with other drugs, or active ingredients, additional to provide a combination therapy.
  • Said additional drugs may be part of the same pharmaceutical composition or, alternatively, they may be provided in the form of a separate composition for simultaneous or non-simultaneous administration to the pharmaceutical composition comprising the compound described above, or a salt, prodrug or solvate. of the same.
  • the pharmaceutical compositions are suitable for oral administration, in solid or liquid form.
  • Possible forms for oral administration are tablets, capsules, syrups or solutions and may contain conventional excipients known in the pharmaceutical field, as aggregating agents (eg syrup, acacia, gelatin, sorbitol, tragacanth or polyvinylpyrrolidone), fillers (eg lactose, sugar , corn starch, calcium phosphate, sorbitol or glycine), disintegrants (eg starch, polyvinylpyrrolidone or microcrystalline cellulose) or a pharmaceutically acceptable surfactant such as sodium lauryl sulfate.
  • aggregating agents eg syrup, acacia, gelatin, sorbitol, tragacanth or polyvinylpyrrolidone
  • fillers eg lactose, sugar , corn starch, calcium phosphate, sorbitol or glycine
  • disintegrants eg starch, polyvinyl
  • compositions for oral administration can be prepared by conventional methods of Galenic Pharmacy, as mixing and dispersion.
  • the tablets can be coated following methods known in the pharmaceutical industry.
  • compositions can be adapted for parenteral administration, as sterile solutions, suspensions, or lyophilized products of the invention, using the appropriate dose.
  • Suitable excipients such as pH buffering agents or surfactants, can be used.
  • the aforementioned formulations can be prepared using conventional methods, such as those described in the Pharmacopoeias of different countries and in other reference texts.
  • the administration of the compounds or compositions of the present invention can be performed by any suitable method, such as intravenous infusion and oral, intraperitoneal or intravenous routes. Oral administration is preferred for the convenience of patients and for the chronic nature of the diseases to be treated.
  • the amount administered of a compound of the present invention will depend on the relative efficacy of the compound chosen, the severity of the disease to be treated and the weight of the patient. However, the compounds of this invention will be administered one or more times a day, for example 1, 2, 3 or 4 times daily, with a total dose between 0.1 and 1000 mg / kg / day. It is important to keep in mind that it may be necessary to introduce variations in the dose, depending on the age and condition of the patient, as well as modifications in the route of administration.
  • the compounds and compositions of the present invention can be used together with other medicaments in combination therapies.
  • the other drugs may be part of the same composition or of a different composition, for administration at the same time or at different times.
  • alkyl refers in the present invention to aliphatic, linear or branched chains, having 1 to 3 carbon atoms or 1 to 2 carbon atoms, for example, methyl, ethyl, n-propyl, i-propyl , etc.
  • the alkyl group has between 1 and 2 carbon atoms or preferably the alkyl group is a methyl.
  • the alkyl radicals may be optionally substituted by one or more substituents such as halogen, hydroxyl, azide, carboxylic acid or a substituted or unsubstituted group selected from amino, amido, carboxylic ester, ether, thiol, acylamino or carboxamido.alkoxide, thiol , amino, acylamino, cyano, carboxylate, carboxamide, carboxy ester, aryl or heteroaryl or combinations of these groups.
  • substituents such as halogen, hydroxyl, azide, carboxylic acid or a substituted or unsubstituted group selected from amino, amido, carboxylic ester, ether, thiol, acylamino or carboxamido.alkoxide, thiol , amino, acylamino, cyano, carboxylate, carboxamide, carboxy ester, aryl or heteroaryl or combinations of these groups.
  • the O-acetylation reaction of GD1 b resulted in a reaction product whose mobility in thin layer chromatography (TLC) was different from GD1 b.
  • TLC thin layer chromatography
  • MALDI TOF-MS Through flight time spectrometry
  • Electrospray it was characterized as Neurostatin, for presenting a single O-acetylation in the terminal sialic.
  • the reaction yield was 90%.
  • the O-acetylation reaction of GT1 b gave rise to two reaction products whose mobility in thin layer chromatography was different from that of GT1 b.
  • the compound with the greatest mobility in thin layer chromatography presented 2 O-acetylations, each in one of the two terminal sialics and was called di-O-acetyl-GT1 b.
  • the second product presented a single O-acetylation.
  • A-O-acetyl-GT1 b which presents the O-acetylation in the terminal sialic which is bound to another sialic
  • B-O-acetyl-GT1 b which is mono-O-acetylated in the sialic not bound to another sialic.
  • the reaction yield was 60% for mono-O-acetylated species and 20% for di-O-acetylated species.
  • the O-propionylation reaction of GD1 b resulted in a reaction product whose mobility in thin layer chromatography was different from that of GD1 b.
  • the reaction yield was 10%.
  • Table 1 Inhibition of division in C6 cells (48 h) in average values of ID 50 (nM). The symbol "-" indicates that the compound weakly inhibited proliferation at the maximum concentration tested (4 ⁇ ), but not enough to calculate the value of your ID 5 or-
  • Table 1 we present the activity of gangliosides GD1 b, GT1 b, and their modified derivatives.
  • Ganglioside GD1 b has no proliferative inhibitory activity of the C6 glioma line. While the compounds derived from GD1 b, Neurostatin (O-acetyl-GD1 b), and O-propionyl-GD1 b have activity in the nanomolar range. The ganglioside O-propionyl-GD1 b is slightly more active than Neurostatin.
  • Ganglioside GT1 b has a proliferation inhibitory activity.
  • the compound O-acetyl-GT1 b almost twice improves its inhibitory activity with respect to GT1 b.
  • the ganglioside GT1 b is modified with two O-acetylations (di-O-acetyl-GT1 b) it also improves its activity twice as much as the O-acetyl-GT1 b and 4 times with respect to the GT1 b.
  • the addition of O-acetyls to the ganglioside GT1 b progressively increases its proliferation inhibitory activity in C6 cells.
  • O-propionylated gangliosides have higher inhibitory activity (O-propionyl-GD1 b and O-propionyl-GT1 b) than their respective mono-O-acetylated gangliosides (O-acetyl-GD1 b and O-acetyl-GT1 b). These O-propionylated compounds could be more resistant to hydrolysis by glycosidases, so their effect would be more lasting.
  • the O-acetylation reaction of GM3 resulted in a reaction product whose mobility in thin layer chromatography was different from that of GM3.
  • MALDITOF-MS flight time spectrometry
  • electrospray it was characterized as an O-acetylated mono derivative in the sialic we call O-acetyl-GM3.
  • the reaction yield was 90%.
  • the O-acetylation reaction of GD3 resulted in a reaction product whose mobility in thin layer chromatography was different from that of GD3.
  • the reaction yield was 80%.
  • the enzyme O-acetyltransferase was added at a concentration of 20 ⁇ g ⁇ l in a total reaction volume of 432 ⁇ . The reaction was carried out at 37 ° C for 7 hours with stirring (300 rpm). After time, the reaction was stopped by the addition of methanol.
  • the O-acetylation reaction of GD1 a resulted in a reaction product whose mobility in thin layer chromatography was different from that of GD1 a.
  • MALDITOF-MS Through flight time spectrometry
  • electrospray it was characterized as an O-acetylated mono derivative in the sialic linked in alpha (2-3) to the galactose-N-acetyl-galactosamine radical that we call O-acetyl-GD1 to.
  • the reaction yield was 70%.

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Abstract

La présente invention concerne des nouveaux inhibiteurs de la division de cellules tumorales. Lesdits inhibiteurs sont des dérivés semi-synthétiques de la neurostatine. En outre, la présente invention concerne un nouveau procédé de synthèse des inhibiteurs et de la neurostatine, ainsi que l'utilisation de ces inhibiteurs dans la fabrication d'un médicament destiné au traitement des tumeurs cérébrales.
PCT/ES2011/070732 2010-10-22 2011-10-21 Dérivés de gangliosides et leur utilisation en tant qu'inhibiteurs de la division des cellules tumorales WO2012052596A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2662697A1 (fr) * 1990-06-01 1991-12-06 Snow Brand Milk Products Co Ltd Nouveau ganglioside provenant du lait et son procede d'obtention.
US5102663A (en) * 1988-10-18 1992-04-07 Sloan-Kettering Instutute For Cancer Research Vaccine for stimulating or enhancing production of antibodies against 9-O-acetyl GD3
WO1994014825A1 (fr) * 1992-12-18 1994-07-07 Merck Patent Gmbh Procede de preparation du ganglioside gd2 et du glanglioside o-acetyl-gd2
US5766887A (en) * 1996-08-26 1998-06-16 The Scripps Research Institute Synthesis of 9-0-acetyl N-acetylneuraminic acid oligosaccharides

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5102663A (en) * 1988-10-18 1992-04-07 Sloan-Kettering Instutute For Cancer Research Vaccine for stimulating or enhancing production of antibodies against 9-O-acetyl GD3
FR2662697A1 (fr) * 1990-06-01 1991-12-06 Snow Brand Milk Products Co Ltd Nouveau ganglioside provenant du lait et son procede d'obtention.
WO1994014825A1 (fr) * 1992-12-18 1994-07-07 Merck Patent Gmbh Procede de preparation du ganglioside gd2 et du glanglioside o-acetyl-gd2
US5766887A (en) * 1996-08-26 1998-06-16 The Scripps Research Institute Synthesis of 9-0-acetyl N-acetylneuraminic acid oligosaccharides

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Title
ABAD-RODRIGUEZ, J. ET AL.: "Purification and structure of neurostatin, an inhibitor of astrocyte division of mammalian brain.", JOURNAL OF NEUROCHEMISTRY., vol. 74, no. 6, 2000, pages 2547 - 2556 *
HOULISTON, R.S. ET AL.: "Identification of a Sialate O-Acetyltransferase from Campylobacter jejuni. Demonstration of direct transfer to the C-9 position of terminal -2, 8-linked sialic acid.", J. BIOL. CHEM., vol. 281, no. 17, 2006, pages 11480 - 11486, XP003008560, DOI: doi:10.1074/jbc.M512183200 *
IGARASHI, M. ET AL.: "Characteristics of gangliosides including O-acetylated species in growth cone membranes at several developmental stages in rat forebrain.", DEVELOPMENTAL BRAIN RESEARCH., vol. 78, no. 1, 1994, pages 17 - 24, XP024334455, DOI: doi:10.1016/0165-3806(94)90004-3 *
NIETO-SAMPEDRO, M. ET AL.: "Inhibitors of Glioma Growth that Reveal the Tumour to the Immune System.", CLINICAL MEDICINE INSIGHTS ONCOLOGY., vol. 5, 21 September 2011 (2011-09-21), pages 265 - 314 *
ROMERO-RAMIREZ, L. ET AL.: "Inhibiting Human Astrocytoma Growth: Structure -Activity Relationships in Neurostatin Related Glycolipids.", J. MED. CHEM., vol. 47, no. 21, 2004, pages 4983 - 4984 *
VALLE-ARGOS. B ET AL.: "Synthesis and characterization of neurostatin-related compounds with high inhibitory activity of glioma growth.", EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, vol. 45, no. 5, May 2010 (2010-05-01), pages 2034 - 43, XP026976527 *

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