WO2009002203A1 - Dérivés d'acides aminés polyfonctionnels du fullerène c60 - Google Patents

Dérivés d'acides aminés polyfonctionnels du fullerène c60 Download PDF

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Publication number
WO2009002203A1
WO2009002203A1 PCT/RU2007/000337 RU2007000337W WO2009002203A1 WO 2009002203 A1 WO2009002203 A1 WO 2009002203A1 RU 2007000337 W RU2007000337 W RU 2007000337W WO 2009002203 A1 WO2009002203 A1 WO 2009002203A1
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WO
WIPO (PCT)
Prior art keywords
fullerene
nitroxyalkyl
fullerenyl
amino acid
amino acids
Prior art date
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PCT/RU2007/000337
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English (en)
Russian (ru)
Other versions
WO2009002203A8 (fr
Inventor
Alexandr Ivanovich Kotelnikov
Valentina Semenovna Romanova
Gennady Nikolaevich Bogdanov
Nina Petrovna Konovalova
Oleg Ivanovich Pisarenko
Raisa Alekseevna Kotelnikova
Irina Igorevna Faingold
Elena Sergeevna Frog
Yury Nikolaevich Bubnov
Sergei Mikhailovich Aldoshin
Mikhail Ivanovich Davydov
Original Assignee
Institut Problem Khimicheskoi Fiziki Rossiiskoi Akademii Nauk (Ipkhf Ran)
Federalnoe Gosudarstvennoe Uchrezhdenie Rossysky Kardiologichesky Nauchno-Proizvodstvenny Kompleks Federalnogo Agenstva Po Zdravookhraneniyu I Sotsialnomu Razvitiyu Roszdrava
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.)
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Application filed by Institut Problem Khimicheskoi Fiziki Rossiiskoi Akademii Nauk (Ipkhf Ran), Federalnoe Gosudarstvennoe Uchrezhdenie Rossysky Kardiologichesky Nauchno-Proizvodstvenny Kompleks Federalnogo Agenstva Po Zdravookhraneniyu I Sotsialnomu Razvitiyu Roszdrava filed Critical Institut Problem Khimicheskoi Fiziki Rossiiskoi Akademii Nauk (Ipkhf Ran)
Priority to CA002687557A priority Critical patent/CA2687557A1/fr
Priority to PCT/RU2007/000337 priority patent/WO2009002203A1/fr
Publication of WO2009002203A1 publication Critical patent/WO2009002203A1/fr
Publication of WO2009002203A8 publication Critical patent/WO2009002203A8/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/542—Carboxylic acids, e.g. a fatty acid or an amino acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/44—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members
    • C07D207/444—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members having two doubly-bound oxygen atoms directly attached in positions 2 and 5
    • C07D207/448—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members having two doubly-bound oxygen atoms directly attached in positions 2 and 5 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms, e.g. maleimide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the invention relates to new multifunctional amino acid derivatives of C 60 fullerene having biological activity, as well as to methods for their preparation and a method for covalently linking fullerene derivatives to SH-containing proteins.
  • the invention relates to the use of nitroxyalkyl-N- (fullerenyl) amino acids as donors of nitrogen monoxide, as well as the use of nitroxyalkyl-N- (fullerenyl) amino acids as quick-acting vasodilators for antihypertensive therapy.
  • the invention also relates to a method for inhibiting the metastasis process and a method for enhancing the antileukemic activity of cyclophosphamide.
  • ACE amino acid derivatives of fullerene
  • fullerene C 60 is considered in chemical pharmacology as a very promising carrier of functional groups with one or another type of biological activity. These include alkyl groups of a cytotoxic effect, anthracyclines, as well as donors of nitric monoxide.
  • Nitric oxide is a unique intracellular multifunctional regulator of metabolism, blood vessel homeostasis, blood pressure and organ perfusion. Most exogenous nitric oxide donors recommended for the treatment of myocardial ischemia and acute heart failure are widely used as vasodilators and platelet aggregation inhibitors.
  • ACE polyfunctional amino acid derivatives of fullerene
  • the present invention is the creation of new multifunctional amino acid derivatives of fullerene (ACE),
  • SUBSTITUTE SHEET possessing inhibitory activity against tumor metastases, as well as enhancing the antileukemic activity of cyclophosphamide, and which may be suitable as donors of nitric oxide or as vasodilators of rapid action for antihypertensive therapy.
  • the multifunctional amino acid derivatives of fullerene C 60 in accordance with the invention have the formula (1)
  • R H, mono - or dihydroxyalkyl, aminoalkyl, haloalkyl, mono - or dinitroxyalkyl, maleimide; NZ is a fragment of ⁇ , ⁇ , ⁇ , ⁇ -amino acids of the general formula -NH-
  • M represents a nitroxyalkyl group, an alkyl group or an alkali metal salt, or a dipeptide, wherein the alkyl groups contain 1-6 carbon atoms.
  • the inventors of the present invention first developed methods for producing ACE by substituting a mobile proton in monohydrofullerenyl amino acids, as well as by esterifying the carboxyl monohydrofullerenyl amino acid.
  • NZ a fragment of synthetic or natural ⁇ , ⁇ , ⁇ , ⁇ -amino acids (glycine, alanine, arginine, serine, ⁇ -aminobutyric, ⁇ -aminocaproic
  • SUBSTITUTE SHEET (RULE 26) acids, proline, etc.), its alkali metal salt or lower ester.
  • M represents a nitroxyalkyl group, an alkyl group where the alkyl groups include 1-6 carbon atoms, or an alkaline earth metal salt, and in the case of alkali metal salts of amino acids, the reaction of monohydrofullerenyl amino acids with nitroxylalkyl halides proceeds according to two reaction centers according to the equation:
  • SUBSTITUTE SHEET (RULE 26) therefore, on the potential biological activity of synthesized NO donors.
  • ACE Since the structure of ACE can be classified as a class of antimetabolites, we have proposed methods for the directed synthesis of fullerene derivatives covalently linked to biologically active peptides and proteins.
  • Carnosine ( ⁇ -alanyl histidine), which is a natural antioxidant of muscle and nerve tissues, was used as one of them.
  • N- (monohydrofullerenyl) alanyl histidine a direct analogue of carnosine containing the fullerene sphere, was synthesized.
  • the resulting compound is characterized by increased membranotropy and the ability to inhibit the process of peroxide oxidation of lipids of biological membranes.
  • This method is universal in nature and is suitable for the introduction of a SUBSTITUTE SHEET (RULE 26) the fullerene spheroid into any SN-containing proteins, ensuring its transmembrane transfer to the cell.
  • nitrates based on the amino acid derivatives of fullerene C 60 generate nitrogen monoxide during their biotransformation, as evidenced by their inhibitory effect on the catalytic activity of mitochondrial cytochrome C oxidase.
  • HAPF-1 and HAPF-2 the structural formulas of which are presented below, exhibit moderate antitumor activity and pronounced antimetastatic activity.
  • HAPF-1 is a fast-acting vasodilator that reduces blood pressure and heart rate and causes relaxation coronary vessels with less depressive effect on myocardial function in comparison with nitroglycerin (NG) SUBSTITUTE SHEET (RULE 26)
  • NG nitroglycerin
  • SUBSTITUTE SHEET RULE 26
  • the resulting heterogeneous system was stirred under heating at 7O 0 C in argon for 8 hours. Then the organic layer was separated, the solvent was distilled off, the residue was dissolved in 100 ml of water, and 100 ml of a saturated solution of sodium chloride was added to it. The resulting solution was dialyzed until sodium chloride was completely removed (reaction of the absence of chlorine ion in the washings). The resulting aqueous solution was evaporated, and 130 mg of N- [monohydrofullerenyl] -carnosine sodium salt was obtained (quantitative yield).
  • Example 5 Covalent attachment of the maleimide derivative of Cp proline to protein macromolecules
  • a special procedure was developed for the covalent attachment of the maleimide derivative of fullerenylproline to SH-groups of proteins.
  • such an attachment is made to the SH groups of human hemoglobin and albumin.
  • the maleimide derivative of C 60 proline was added to the reactive CH group of human albumin.
  • To a solution of albumin at a concentration of 5XlO "4 M in OD M phosphate buffer at pH 6.5 was added the maleimide derivative C 60 -
  • SUBSTITUTE SHEET (RULE 26) proline in threefold excess in relation to protein.
  • the reaction was carried out for 30 minutes at 2 ° C.
  • the excess water-soluble maleimide derivative of fullerene was separated on a Serhadex G-25 column using phosphate buffer as an eluent. Column chromatography was performed twice to exclude the sorption of the fullerene derivative on albumin due to hydrophobic interactions. In the fraction with zero volume, the addition of the maleimide derivative to albumin was controlled by spectrophotometric method.
  • FIG. 1 shows an increase in antileukemic activity (increase in life expectancy (ILS,%) of BDF-I mice with P-388 leukemia) cyclophosphamide (SOMg / kg; 1; 6 days) when combined with HAPP-1 (30 mg / kg; 1 -6 days) and HAPF-2 (ZOMg / kg; 1-6 days).
  • Figure 2 shows the results of an increase in the chemosensitizing effect of HAPF-1 and HAPF-2 (% of cured BDF-I mice with P-388 leukemia) when combined with cyclophosphamide (single doses and administration modes as in Fig. 1).
  • HAPF-1 or NG nitroglycerin
  • HR heart rate
  • nitroxy derivative of fullerene in a wide range of concentrations weakly affects the duration of a decrease in blood pressure and significantly (two to three times) reduces this indicator compared to nitroglycerin.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Epidemiology (AREA)
  • Cardiology (AREA)
  • Molecular Biology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Peptides Or Proteins (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne de nouveaux dérivés d'acides aminés polyfonctionnels du fullerène C(60) ayant la formule (I) dans laquelle R=H, mono- ou dihydroxyalkyle, aminoalkyle, haloïdalkyle, mono- ou dinitroxyalkyle ou maleinimide; N-Z est un fragment d'acide aminé α,β,Ϝ, ω possédant la formule NH-CmH2m-COOM ou (II) -N- COOM, dans laquelle m=2-5, et M est un groupe nitroxyalkyle, groupe alkyle ou sel de métal alcalin, ou dipeptide possédant une activité biologique élevée, ainsi que des procédés de fabrication et un procédé de liaison par covalence des dérivés de fullerène avec des protéinescontenant SH. En outre, l'invention concerne l'utilisation d'acides aminés nitroxyalkyle-N-(fullerényl) en tant que donneurs de monoxyde d'azote et l'utilisation d'acides aminés nitroxyalkyle-N-(fullerényl) en tant qu'agents vas
PCT/RU2007/000337 2007-06-19 2007-06-19 Dérivés d'acides aminés polyfonctionnels du fullerène c60 WO2009002203A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
CA002687557A CA2687557A1 (fr) 2007-06-19 2007-06-19 Derives d'acides amines polyfonctionnels du fullerene c60
PCT/RU2007/000337 WO2009002203A1 (fr) 2007-06-19 2007-06-19 Dérivés d'acides aminés polyfonctionnels du fullerène c60

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/RU2007/000337 WO2009002203A1 (fr) 2007-06-19 2007-06-19 Dérivés d'acides aminés polyfonctionnels du fullerène c60

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WO2009002203A8 WO2009002203A8 (fr) 2009-04-02

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9221746B2 (en) 2011-02-01 2015-12-29 Lev Davidovich Rasnetsov Homo- and hetero-polyamino-acid derivatives of fullerene C60, method for producing same, and pharmaceutical compositions based on said derivatives
US9246104B2 (en) 2013-09-25 2016-01-26 Showa Denko K.K. Fullerene derivative, method of manufacturing fullerene derivative and solar cell

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015138819A1 (fr) * 2014-03-14 2015-09-17 Livepet, Llc. Améliorations cellulaires par l'intermédiaire de combinaisons de groupes lipofullerènes et peptidiques

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2002212197A (ja) * 2001-01-19 2002-07-31 Sanei Gen Ffi Inc フラーレン誘導体およびそれからなる組成物
RU2213049C1 (ru) * 2002-07-08 2003-09-27 Закрытое акционерное общество "ДЕСКО" Способ получения водорастворимых аминокислотных производных фуллерена
RU2236852C1 (ru) * 2003-06-23 2004-09-27 Закрытое акционерное общество "ДЕСКО" Средство для ингибирования репродукции оболоченных вирусов, способ его получения, фармацевтическая композиция и способ ингибирования вирусных инфекций
WO2005070827A2 (fr) * 2004-01-14 2005-08-04 William Marsh Rice University Acides amines a base de fullerenes

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2002212197A (ja) * 2001-01-19 2002-07-31 Sanei Gen Ffi Inc フラーレン誘導体およびそれからなる組成物
RU2213049C1 (ru) * 2002-07-08 2003-09-27 Закрытое акционерное общество "ДЕСКО" Способ получения водорастворимых аминокислотных производных фуллерена
RU2236852C1 (ru) * 2003-06-23 2004-09-27 Закрытое акционерное общество "ДЕСКО" Средство для ингибирования репродукции оболоченных вирусов, способ его получения, фармацевтическая композиция и способ ингибирования вирусных инфекций
WO2005070827A2 (fr) * 2004-01-14 2005-08-04 William Marsh Rice University Acides amines a base de fullerenes

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
KOTELNIKOVA R.A. ET AL.: "Membranotropic properties of the water soluble amino acid and peptide derivatives of fullerene C60", FEBS LETTERS, vol. 389, 1996, pages 111 - 114 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9221746B2 (en) 2011-02-01 2015-12-29 Lev Davidovich Rasnetsov Homo- and hetero-polyamino-acid derivatives of fullerene C60, method for producing same, and pharmaceutical compositions based on said derivatives
US9246104B2 (en) 2013-09-25 2016-01-26 Showa Denko K.K. Fullerene derivative, method of manufacturing fullerene derivative and solar cell

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WO2009002203A8 (fr) 2009-04-02
CA2687557A1 (fr) 2008-12-31

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