WO2010090541A1 - Dérivés boranes de l'adénosine - Google Patents

Dérivés boranes de l'adénosine Download PDF

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Publication number
WO2010090541A1
WO2010090541A1 PCT/PL2010/050004 PL2010050004W WO2010090541A1 WO 2010090541 A1 WO2010090541 A1 WO 2010090541A1 PL 2010050004 W PL2010050004 W PL 2010050004W WO 2010090541 A1 WO2010090541 A1 WO 2010090541A1
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WO
WIPO (PCT)
Prior art keywords
dicarba
closo
carborane
nucleoside derivative
adenosine
Prior art date
Application number
PCT/PL2010/050004
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English (en)
Inventor
Zbigniew LEŚNIKOWSKI
Agnieszka Olejniczak
Zofia Sulowska
Katarzyna Bednarska
Original Assignee
Instytut Biologii Medycznej Polskiej Akademii Nauk
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 Instytut Biologii Medycznej Polskiej Akademii Nauk filed Critical Instytut Biologii Medycznej Polskiej Akademii Nauk
Publication of WO2010090541A1 publication Critical patent/WO2010090541A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H23/00—Compounds containing boron, silicon, or a metal, e.g. chelates, vitamin B12
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A61K41/009—Neutron capture therapy, e.g. using uranium or non-boron material
    • A61K41/0095—Boron neutron capture therapy, i.e. BNCT, e.g. using boronated porphyrins
    • 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
    • A61K47/549—Sugars, nucleosides, nucleotides or nucleic acids

Definitions

  • the subject of the present invention are derivatives of adenosine for use in medicine in the design of drugs or as drugs.
  • the nucleoside adenosine is an endogenous factor which regulates the activity of leukocytes.
  • Adenosine is an internal purine nucleoside which diffuses through the cell membrane into surrounding cells where it binds with surface receptors, following its release from cells or through extracellular production.
  • Important cells which produce extracellular adenosine are mesothelium cells and neutrophiles.
  • Adenosine is constitutively present in the extracellular space at low concentrations, but its level significantly rises at sites of metabolic stress such as hypoxia, coronary hypoxia, inflammation or infection.
  • Adenosine is characterized by a short half- life in the serum.
  • the physiological activity of adenosine is a combination of an appropriate receptor on the cell surface and induction of intracellular pathways.
  • Four types of receptors, belonging to the G. protein receptor family, are known: A 1 , A 2A -, A 2B , and A 3 .
  • the interaction of adenosine with receptors A 2A . and A 2B on immune cells constitutes a strong, endogenous immunosuppressive mechanism which regulates an excessive response to external negative stimuli.
  • adenosine When acting through the A 1 and A 3 receptors, adenosine exhibits inflammation- promoting and immunostimulant activity. Adenosine inhibits platelet activation through receptor A 2A , present on their surface. These receptors are important targets in the search for new drugs. Adenosine is modified in order to increase its metabolic stability and to obtain a high selectivity in relation to adenosine receptors, as well as a high affinity for them.
  • EP 1113020 discloses the use of nucleosides and oligonucleotides in borane-neutron therapy (BNCT) and other therapeutic and diagnostic uses.
  • Nucleosides and oligonucleotides according to that invention are conjugated with one or more boron clusters through alkyl groups connected to carbon atoms of an appropriate nucleic base (i.e. adenine), or through phosphate or sugar residues.
  • WO 96/14073 discloses methods and composithions for the treatment of urogenital cancer, particularly prostate, bladder and kidney cancer using boron- neutron therapy.
  • Compounds according to said invention used in the above-mentioned therapy are nucleosides and oligonucleotides containing carborane groups conjugated with an appropriate nucleic base through phosphate, thiophosphate or selenophosphate residues. These compounds are characteristic in that they are more lipophilic.
  • Another patent, US 6,838,574, discloses a drug having as its active substance a dicarba-closo-dodecaborane derivative or its pharmacologically permissible salt.
  • the borane group is conjugated with an aromatic ring either directly or through a connecting group.
  • Compounds according to the invention exhibit an affinity for RAR and RXR retinoic acid receptors, and can be used as agonists or antagonists of these receptors.
  • EP 1364954 describes a compound being a dicarba- closo-dodecaborane derivative or its pharmacologically permissible salt, which is useful as an agent modulating vitamin D activityor as an agent augmenting vitamin D activity.
  • the compound according to the cited invention may be described with the formula R1-X-R2, where X denotes a dicarba-closo-dodecaboranedyl group, whereas Rl and R2 are hydroxyl derivatives of alkyl, aryl, etc. groups.
  • Both antagonists and agonists of adenosine receptors are useful in primary research as well as being used as anticoagulants, vasodilators and antiinflammatories. They are also being tested for anticancer, anti-neurodegeneration and antiviral activity.
  • the often short half-life of adenosine and its derivatives in the blood limits the possibilities of making use of the benefits of this class of compounds.
  • a compound, a derivative of adenosine for the above mentioned uses which would have a longer a dentist seen half-life than the extant compounds.
  • the present invention relates to derivatives of adenosine, having the formula: g-[(CH 2 )n(W)m]k(CH 2 )hR 2
  • R 1 HO-, CH 3 (CH 2 )n0-, CH 3 (CH 2 )nC(O)O-, H 2 N-, H 2 N(CH 2 )nNH-,
  • R 3 OH-, H-
  • And 1 represents a carbon atom or a CH group and m represents a boron atom or a BH group.
  • a compound according to the present invention has the following formula:
  • the compound according to the present invention has the following formula:
  • the compound has the following formula:
  • the compound according to the present invention has the following formula:
  • the compound has the following formula:
  • Boron clusters constitute a novel type of pharmacophore used in the design of various types of drugs.
  • the advantage of boron clusters in this area is their structure in the form of a regular dodecahedron which is similar in volume to a rotating benzene ring, their highly lipophilic character, and orthogonality which entails stability under physiological conditions and resistance to catabolism.
  • Derivatives of adenosine modified with boron clusters have thus far not been available due to the lack of a method of synthesis. These derivatives have been used as in vitro modulators of human blood platelet functions: aggregation, secretion of granular proteins and the expression of selectin P on the platelet surface.
  • Example embodiments of the present invention are shown in the attached figure (Fig.l) which shows the effect of adenosine (10 ⁇ M) and its derivatives: 2'-0-methyl-0-propyl-/? ⁇ ra- carborane-1 -adenosine (compound 11; 0.1 ⁇ M) as well as 6-iV- ⁇ 5-[3-cobartbis(l,2- dicarbollide)-8-yl]-3-oxa-pentoxy ⁇ -2'-deoxyadenosine (compound 10; 0.1 ⁇ M) on the expression of selectin P (CD62P) in blood platelets stimulated with adenosine-5' -diphosphate (ADP, 3 ⁇ M). Average values ⁇ SEM are shown from experiments on 6 donors.
  • the substrate nucleoside, 8-bromo-deoxyadenosine was lyophilised from water (0.5 rnL).
  • DMF (1.35 mL) and TEA (980 ⁇ L) were added (in argon).
  • the reaction was performed in an argon atmosphere, on a magnetic stirrer, at a temperature of 80°C. After a half-hour, the reaction was stopped and the solvent was evaporated until dry under reduced pressure. The remainder was topped off with methylene chloride (10 mL) and extracted with distilled water (2x5 mL). The organic phases were collected and extracted with 0.5% EDTA (2x5 mL). The organic phases were separated and dried over anhydrous magnesium (VI) sulphate. The drying agent was additionally rinsed with methylene chloride. The solvent was evaporated off under reduced pressure. The raw product was purified using column chromatography on a silica gel (4 g, 230-400 mesh).
  • the dry substrate mixture was dissolved in anhydrous toluene (2.5 mL) and the entirety heated to 70°C for 5 godzin on an oil bath. Next, the reaction mixture was cooled to room temperature and the solvent was evaporated off. The raw product was purified using column chromatography on a silica gel (12 g, 230-400 mesh). The eluent used was a methanol gradient in methylene chloride (0- 20%). Efficiency: 52 mg (38%).
  • the organic phase was separated and dried using magnesium sulphate. Next, the drying agent was filtered off and the phase was rinsed with ethyl acetate (2.5 mL). The solvent was evaporated using a venturi pump. The raw product was purified using column chromatography on a silica gel (5 g, 230-400 mesh). The eluent used was a methanol gradient in methylene chloride (10-40%). Efficiency: 62%.
  • the contents of the flask were evaporated off with anhydrous toluene (3 x ImL), displacing the air in the dessicator with argon.
  • sodium hydride was added (60% suspension in oil, 12.6 mg, 0.5 mmol).
  • the dry substrate mixture was dissolved in anhydrous toluene (2.57 mL) and the entirety heated to 70°C for 6 hours on an oil bath.
  • the reaction mixture was cooled to room temperature and the solvent was evaporated off.
  • the raw product (ca. 243 mg) was purified using column chromatography on a silica gel (1O g, 230-400 mesh). A linear acetonitrile gradient in methylene chloride (0-6%) was used as the eluent.
  • the reaction was carried out over 1.5 hours at room temperature.
  • the reaction mixture was supplemented with 30 mL of ethyl acetate, and then extracted with water (3 x 20 mL) and saturated sodium chloride (20 mL).
  • the organic phase was separated and dried out with magnesium sulphate.
  • the drying agent was filtered off and washed with ethyl acetate (5 mL).
  • the solvent was evaporated off using a water venturi pump.
  • the raw product (ca. 460 mg) was purified using column chromatography on a silica gel (6g, 230-400 mesh).
  • the elution system used comprised a linear methanol gradient in methylene chloride (2-10%). Efficiency: 210.5 mg, (72%).
  • the reaction was performed at room temperature for a further 26 hours.
  • the progress of the reaction was controlled using chromatography in a CH 2 Cl 2 ZMeOH (9:1) development system.
  • the reaction mixture was diluted 1,2-dichloroethane (3 mL) and rinsed with water (3 x 3 mL).
  • the organic fraction was separated and dried with anhydrous magnesium sulphate.
  • the magnesium sulphate was filtered off, and the fraction was washed with methylene chloride, whereafter the solvent was evaporated off yielding ca.
  • Example 7 During initial research, we obtained, among others, adenosine derivatives containing a para- carborane-1-yl group attached to position 2' of the adenosine (compound 11) or C8 T- deoxyadenosine (compound 7), 50-100 times more active as platelet aggregation inhibitors than unmodified adenosine.
  • the results of platelet activation include an increase in the expression of selectin P (Schematic 1). As is shown in Fig. 1, at micromolar concentrations, adenosine inhibits platelet activation. Derivative 11 already inhibits platelet activation at nanomolar concentration. The presence of A2A on neutrophiles suggests that such a modified adenosine can also significantly affect neutrophiles via this receptor, at the site of an inflammation reaction and regulate this process in said fashion.
  • derivatives of adenosine resulting from the directed synthesis of compounds with a long half-life in serum, low cytotoxicity, being more lipophilic, as well as capable of inhibiting proinflammatory neutrophile activity can be considered as potential drugs in the future.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Medicinal Chemistry (AREA)
  • Biochemistry (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Organic Chemistry (AREA)
  • Public Health (AREA)
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  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
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  • Saccharide Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un dérivé nucléoside d'une purine comprenant un groupe bore, seul ou en complexe avec un métal (métallo-carborane), le groupe bore ou son complexe étant conjugué à au moins une base nucléique, un reste de noyau glucide, ou un analogue de reste de noyau glucide.
PCT/PL2010/050004 2009-02-06 2010-02-05 Dérivés boranes de l'adénosine WO2010090541A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
PLP387217 2009-02-06
PL387217A PL387217A1 (pl) 2009-02-06 2009-02-06 Boranowe pochodne adenozyny

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WO2010090541A1 true WO2010090541A1 (fr) 2010-08-12

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106832242A (zh) * 2017-01-17 2017-06-13 哈尔滨工业大学无锡新材料研究院 一种聚酯合成用催化剂及其制备方法
WO2016020858A3 (fr) * 2014-08-05 2017-07-06 Instytut Biologii Medycznej Polskiej Akademii Nauk Dérivé de nucléoside destiné à être utilisé en tant que médicament, en particulier pour le traitement de la leucémie lymphocytaire chronique
CN109503671A (zh) * 2019-01-03 2019-03-22 曲阜师范大学 一种两性离子型半三明治铱配合物及其制备方法和应用
JPWO2018143403A1 (ja) * 2017-02-03 2019-12-12 国立大学法人東北大学 複素環化合物

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996014073A1 (fr) 1994-11-04 1996-05-17 Emory University Traitement de cancers urogenitaux par therapie au bore et a capture de neutrons
EP1113020A2 (fr) 1993-12-02 2001-07-04 Emory University Nucléosides et oligonucléosides contenant des amas de bore
EP1364954A1 (fr) 2001-02-09 2003-11-26 Hiroyuki Kagechika Derives de dicarba-(closo)-dodecarborane
US6838574B1 (en) 1999-01-22 2005-01-04 Institute Of Medicinal Molecular Design, Inc. Dicarba-closo-dodecarborane derivatives

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1113020A2 (fr) 1993-12-02 2001-07-04 Emory University Nucléosides et oligonucléosides contenant des amas de bore
WO1996014073A1 (fr) 1994-11-04 1996-05-17 Emory University Traitement de cancers urogenitaux par therapie au bore et a capture de neutrons
US6838574B1 (en) 1999-01-22 2005-01-04 Institute Of Medicinal Molecular Design, Inc. Dicarba-closo-dodecarborane derivatives
EP1364954A1 (fr) 2001-02-09 2003-11-26 Hiroyuki Kagechika Derives de dicarba-(closo)-dodecarborane

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Title
AGNIESZKA B. OLEJNICZAK ET AL.: "DNA-Dinucleotides Bearing a 3',3'-Cobalt- or 3',3'-Iron-1,2,1',2'-dicarbollide Complex", ORGANOMETALLICS, vol. 26, no. 14, 26 May 2007 (2007-05-26), pages 3272 - 3274, XP002581214, DOI: 10.1021/om070102z *
AGNIESZKA B. OLEJNICZAK ET AL.: "Nucleoside-Metallacarborane Conjugates for Base-Specific Metal Labeling of DNA", CHEMISTRY - A EUROPEAN JOURNAL, vol. 13, no. 1, 14 November 2006 (2006-11-14) - 2007, pages 311 - 318, XP002581215, DOI: 10.1002/chem.200600740 *
BLAZEJ A. WOJTCZAK ET AL.: "Highly Lipophilic p-Carborane-Modified Adenosine Phosphates", COLLECT. CZECH. CHEM. COMMUN., vol. 73, 24 February 2008 (2008-02-24), pages 175 - 186, XP002581216, DOI: 10.1135/cccc20080175 *
LESNIKOWSKI ET AL: "Nucleoside-boron cluster conjugates - Beyond pyrimidine nucleosides and carboranes", JOURNAL OF ORGANOMETALLIC CHEMISTRY, ELSEVIER-SEQUOIA S.A. LAUSANNE, CH LNKD- DOI:10.1016/J.JORGANCHEM.2008.12.061, vol. 694, no. 11, 3 January 2009 (2009-01-03), pages 1771 - 1775, XP026063046, ISSN: 0022-328X, [retrieved on 20090103], DOI: 10.1016/j.jorganchem.2008.12.061 *
OLEJNICZAK AGNIESZKA ET AL.: "2'-Deoxyadenosine Bearing Hydrophobic Carborane Pharmacophore", NUCLEOSIDES, NUCLEOTIDES AND NUCLEIC ACIDS, vol. 26, no. 10-12, October 2007 (2007-10-01), pages 1611 - 1613, XP009133215, ISSN: 1525-7770, DOI: 10.1080/15257770701548733 *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016020858A3 (fr) * 2014-08-05 2017-07-06 Instytut Biologii Medycznej Polskiej Akademii Nauk Dérivé de nucléoside destiné à être utilisé en tant que médicament, en particulier pour le traitement de la leucémie lymphocytaire chronique
CN106832242A (zh) * 2017-01-17 2017-06-13 哈尔滨工业大学无锡新材料研究院 一种聚酯合成用催化剂及其制备方法
CN106832242B (zh) * 2017-01-17 2018-09-14 哈尔滨工业大学无锡新材料研究院 一种聚酯合成用催化剂及其制备方法
JPWO2018143403A1 (ja) * 2017-02-03 2019-12-12 国立大学法人東北大学 複素環化合物
JP7161760B2 (ja) 2017-02-03 2022-10-27 国立大学法人東北大学 複素環化合物
US11986480B2 (en) 2017-02-03 2024-05-21 Tohoku University Heterocyclic compound
CN109503671A (zh) * 2019-01-03 2019-03-22 曲阜师范大学 一种两性离子型半三明治铱配合物及其制备方法和应用
CN109503671B (zh) * 2019-01-03 2020-12-25 曲阜师范大学 一种两性离子型半三明治铱配合物及其制备方法和应用

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