WO1991009048A1 - Boronated nucleosides - Google Patents
Boronated nucleosides Download PDFInfo
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- WO1991009048A1 WO1991009048A1 PCT/US1990/007446 US9007446W WO9109048A1 WO 1991009048 A1 WO1991009048 A1 WO 1991009048A1 US 9007446 W US9007446 W US 9007446W WO 9109048 A1 WO9109048 A1 WO 9109048A1
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- boronated
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- C07D473/00—Heterocyclic compounds containing purine ring systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
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- C07—ORGANIC CHEMISTRY
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- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/18—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 one oxygen and one nitrogen atom, e.g. guanine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
- C07D473/32—Nitrogen atom
- C07D473/34—Nitrogen atom attached in position 6, e.g. adenine
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- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic System
- C07F5/02—Boron compounds
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- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
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- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/06—Pyrimidine radicals
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- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/06—Pyrimidine radicals
- C07H19/10—Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/16—Purine radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/16—Purine radicals
- C07H19/20—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H21/00—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
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- 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
Definitions
- This invention pertains to novel Boron containing compounds having pharmaceutical activity. More specifically, compounds of the present invention include nucleoside analogues having antineoplastic activity. These compounds seemingly function as anti etabolites with additional utility in Boron Neutron Capture Therapy (BNCT) .
- BNCT Boron Neutron Capture Therapy
- Antimetabolites are a well known class of antineoplastic agents that function by interfering with nucleic acid sythesis and consequently, replication within the target cells. Some of these compounds structurally mimic biosynthetic precursors of the naturally occurring nucleic acids, which are ' essential for replication and cell survival. By replacing these precursors, but without exhibiting the same biological effect, these compounds disrupt replication resulting in the demise of the the target cell. Many antimetabolites have significant antiviral and antitumor activity and are incorporated in a variety of therapeutic regimens. But despite the therapeutic benefits of such compounds, their use is often accompanied by deleterious side effects, e.g. nausea, alopecia, and bone marrow depression. Accordingly, a great deal of interest has focused on synthesizing new analogues with improved therapeutic indexes.
- boron containing nucleotides may be one class of improved nucleic acid analogues.
- Some exemplary boronated nucleotides are described in copending, commonly owned U.S. patent application Serial No. of B.
- Boron containing compounds are also useful in an antineoplastic regimen known as Boron Neutron Capture Therapy (BNCT).
- BNCT Boron Neutron Capture Therapy
- BNCT Boron Chemistry, Steinberg, H. , McCloskey, A.L., Eds.; the Macmillan Company: New York, 1964; Vol. 1, Chapter 4, 203-234.
- BNCT requires two components (Boron-10 and low energy thermal neutrons) for a radiotoxic reaction.
- the inherent advantage is that each component can be manipulated independently to produce the desired radiation effect.
- Boron-10 has a high cross section for thermal neutrons and after neutron capture, the particles generated, Li & a , are relatively large by radiation standards and thus have a relatively short track in tissue, 10-14 microns.
- the Boron-10 is non- radioactive and for use in BNCT, its compounds do not have to be cytotoxic towards tumor cells..
- Thermal neutrons have such low energy that they cannot ionize tissue components per se. Upon neutron capture, however, the energy generated is sufficient to destroy the cell.
- the problem in making this procedure clinically effective has stemmed not from the concept, per se, but from lack of knowledge in medicinal chemistry, nuclear engineering and physics, immunology, physiology and pharmacology.
- the present invention arose from our continued research on new boron- containing compounds having pharmaceutical activity.
- a first aspect of the present invention is a boronated nucleoside comprising a nucleoside which is N-boronated on the nucleoside base with a boron- containing substituent selected from the group consisting of -BH-CN, -BH 3 , and -BH 2 COOR, wherein R is Cl to C18 alkyl.
- R is Cl to C9 alkyl, and most preferably R is Cl to C4 alkyl.
- a second aspect of the present invention is a boronated nucleotide comprising a 5' phosphate ester of a boronated nucleoside as described above.
- a third aspect of the present invention is a boronated oligonucleotide comprising a chain of natural or modified ribonucleotides or deoxyribonucleotides, at least one nucleotide of said oligonucleotide comprising a boronated nucleotide as described above.
- Nucleosides of the present invention have pharmaceutical activity, including antihyperlipidemic, antiinflammatory, and antineoplastic activity.
- Nucleotides of the present invention are useful as intermediates for making oligonucleotides of the present invention. Oligonucleotides of the present invention are useful as antisense agents and probes.
- a method for synthesizing N-boronated nucleosides of the present invention from a substrate nucleoside, which substrate nucleoside is comprised of a ribose moiety covalently bound to a nitrogenous base is also disclosed. The method comprises: (a) protecting the hydroxy sub ⁇ tituents of the ribose; then (b) boronating the nitrogenous base; and then
- the nitrogenous base is boronated by reacting the substrate nucleoside with either polymeric BH 2 CN or LX, wherein L is a Lewis base and X is a boron- containing substituent selected from the group consisting of -BH-CN, -BH 3 , and -BH 2 C00R, wherein R is as given above.
- alkyl refers to linear or branched alkyl groups which may be saturated or unsaturated. Preferred alkyl groups are linear and saturated.
- the present invention provides novel pharmaceutical agents, methods for their synthesis, methods for treating patients in need of such treatment, and pharmaceutical formulations comprising such agents.
- the nucleosides of the present invention comprise nucleosides having a boron-containing substituent on the base. More specifically, the present invention provides N-boronated nucleosides wherein the boronated nitrogen is a ring nitrogen of the base covalently bonded to the boron of the boron- containing substituent.
- the base is a purine or a pyrimidine or an analog thereof (as discussed in detail below) .
- a preferred group of bases are those selected from the group consisting of adenine, cytosine, guanine, inosine, and the analogs thereof.
- nucleosides we mean a purine or pyrimidine base, and analogs thereof, linked to a pentose.
- the pentose is preferably D-ribose, 2'-deoxy-D-ribose or 2' ,3'-dideoxy-D-ribose.
- nucleosides of the present invention include both naturally occurring nucleosides and analogs thereof.
- boronation occurs preferentially at either the Nl or N7 position depending upon the purine.
- the purine is adenine
- boronation occurs at the Nl position.
- guanine boronation occurs at the N7 position. It is contemplated that boronation at other nitrogens on the nitrogenous bases will yield additional useful agents.
- the nucleoside base may generally be a natural base, such as adenine, thymine, cytosine, guanine, uracil, xanthine, or hypoxanthine, (the latter two being the natural degradation products) or an .
- Particularly preferred boronated nucleosides are: 2 '-deoxyguanosine-N7-cyanoborane, 2 '-deoxyinosine- N7-cyanoborane, 2 '-deoxyadenosine-Nl-cyanoborane, and 2 ' -deoxycytidine-N3-cyanoborane.
- the nucleosides of the present invention further comprise 5'-phosphate esters of the N-boronated nucleosides described herein, such phosphate esters are also known as nucleotides.
- Such nucleotides . particularly the monophosphates, are protected " in conventional manner and used for the synthesis of oligonucleotides, as discussed below.
- Such phosphate esters include 5' mono-, di- and triphosphates, which may be protected as esters.
- molecules and macromolecules comprising rs of two or more nucleosides, which may be linked via a 3 '-5' phosphate ester, e.g.
- oligonucleotides (the terms “oligonucleotides” and “polynucleotides” being used interchangeably herein) , and comprising one or more N- boronated nucleosides are also the subject of the present invention. Accordingly, N-boronated nucleotides, oligonucleotides, and polynucleotides may be used as therapeutic agents and otherwise useful reagents, e.g. diagnostic reagents. oligonucleotides of the present invention can be synthesized in accordance with methods that are well known in the art. Such methods include the phosphite method and the phosphotriester method.
- the oligonucleotide may for example be 2 to 3 nucleotides long, 2 to 18 nucleotides long, 2 to 30 nucleotides long, 2 to 50 nucleotides long, or 50 or more nucleotides long.
- Oligonucleotides containing N-boronated bases may alternatively be prepared, with boronation occuring randomly, in essentially the same manner as the nucleoside, but with an oligonucleotide substituted for the nucleoside.
- the 3' terminus of the oligonucleotides may be immobilized to a solid support (e.g., controlled pore glass), the ' • 5' terminus protected as the dimethyltrityl ether, and amino groups on bases protected with isobutyryl groups.
- Oligonucleotides used for such a reaction preferably contain at least one base which is not thymidine or a thy idine analog, as these are less preferred, bases for boronation.
- Derivatives of the oligonucleotides and polynucleotides may additionally be formed by modifying the internucleotide phosphodiester linkage. Internucleotide phosphodiester linkages in the chain are modified, for example, to the ethylphosphonate, the phosphotriester, the phosphorothioate, the phosphorodithioate, and the phosphoramidate, all as is known in the art;
- Additional synthetic analogues of the nucleosides, nucleotides, and oligonucleotides of the present invention may be formed by otherwise modifying the 3' or 5' end of the nucleoside, and any 2 ' hydroxyl groups. Groups that can be added to the 3' or 5' end vary widely, from relatively inert protecting groups to reactive groups or groups with special properties to obtain desireable physical, chemical, or biochemical effects.
- a wide variety of protecting groups can be substituted on the 2' , 3' , and 5' hydroxy groups, such as the triphenylmethyl (trityl) group and its derivatives on the 5' hydroxy group, and acetyl, benzoyl, or the 3'-O-succinyl group on the 3' hydroxy group, as is known in the art. See 1 Chemistry of Nucleosides and Nucleotides, 287-92 (L. Townsend ed. 1988) . In general, the 5' hydroxy group is protected with an acid labile group and the 3' hydroxy group is protected with an acyl group. Id.
- a 2' hydroxy group is protected as a methyl ether, protected with a silyl group, or the 2' and 3' hydroxy groups may be protected together as an acetal.
- Reactive groups or groups with special properties may also be attached at the 3' or 5' position.
- analogs may be formed by joining an intercalating agent to oligonucleotides and polynucleotides in the manner described in U. S. Patent No. 4,835,263 to Nguyen et al. (the disclosure of this and all other patent references cited herein is incorporated herein by reference) .
- the present invention also provides methods for preparing the compounds of the present invention.
- the boronation of a nucleoside is accomplished by first preparing a hydroxy- protected nucleoside.
- Protecting groups and methods for their use are well known in the art. See, Carey and Sundberg, Advanced Organic Chemistry, Part B, pp. 408-414 (1980) .
- Preferred protecting groups are organosilanes, e.g., chlorotriisopropyl silane will form the triisopropyl silyl ether.
- the nucleoside is 0-protected by forming a silyl ether by reaction with excess chlorotriisopropyl-silane at room temperature in the presence of imidazole.
- the exchange reaction is effected by reacting the O-protected nucleoside with an organoborane.
- the organoborane is generally either polymeric BH-CN or a compound LX, wherein L is a Lewis base and X is a boron-containing substituent as given above.
- Suitable Lewis bases include a ine, phosphine, sulfide, and ether (e.g., tetrahydrofuran) .
- the strength and steric properties of the Lewis base should be chosen so as to provide a suitable leaving group.
- exemplary organoboranes include aniline-cyanoborane, triphenylphosphine-carboalkoxyboranes (wherein the alkoxy group alkyl is R as given above) , dimethylsulfide-borane, and tetrahydrofuran-borane.
- a preferred organoborane is triphenylphosphine- cyanoborane, in which case the resulting product is an - O-protected ribonucleoside N-cyanoborane.
- the exchange reaction is effected by reaction in anhydrous tetrahydrofuran (THF) at reflux temperature using two equivalents of triphenylphosphine-cyanoborane.
- THF tetrahydrofuran
- the reaction is at equilibrium in two to three hours.
- the resulting 0-protected N-boronated ribonucleoside is deprotected by appropriate methods known in the art.
- deprotection can be effected under hydrolytic or nucleophilic conditions.
- the silyl ether is effectively removed under hydrolytic conditions in the presence of fluoride ion, e.g. , tetra-n-butylammonium fluoride.
- the compounds of the present invention have pharmaceutical activity and are useful in treating mammals (e.g., human, cat, dog, cow, horse, mouse) suffering from one or more of several maladies. These compounds show pharmaceutical activity in killing cancer cells in vitro, and may be useful in combatting corresponding tumors in vivo.
- the compounds of the present invention show cytotoxic activity against colorectal carcinoma, adenocarcinoma, osteosarco a, breast carcinoma and glioma.
- the compounds of the present invention provide a method for treating a tumor bearing mammal comprising administering to said mammal a therapeutically effective amount of a boronated nucleoside of the present invention.
- antineoplastic efficacy of these compounds can be improved or supplemented by the conjoint administration with other known antineoplastic agents, as, for- example, in a combination chemotherapy regimen.
- exemplary of such other known antineoplastic agents are: vinca alkaloids such as vincristine, vinblastine, and vindesine; epipodophyllotoxins such as etoposide and teniposide; anthracycline antibiotics such as daunorubicin, doxorubicin, mitoxantraone, .and bisanthrene; actinomycin D; and plicamycin.
- the present invention also provides methods for treating tumor-bearing mammals in which the mammal is administered a boronated nucleoside as described herein and then exposed to thermal neutron radiation.
- the thermal neutron radiation is administered in an amount and in a manner effective for 10 B located in a tumor by virtue of the administration of the compound of the present invention to the subject to capture a neutron, decay, and release an alpha particle in cells of the tumor.
- the compounds of the present invention also have pharmaceutical activity as antiinflammatory agents in mammals.
- the compounds-of the present invention provide a method for treating a mammal suffering from ' inflammation comprising administering to said mammal a therapeutically effective amount of an N-boronated nucleoside.
- the compounds of the present invention may provide additional utility when conjointly administered with other known antiinflammatory agents or pain killers or some such pharmaceutical.
- Exemplary of other known antiinflammatory agents are acetylsalicylic acid (asprin) , salicylic acid, diflunisal, phenylbutazone, oxyphenbutazone, antipyrine, aminopyrine, dipyrone, apazone, acetaminophen, indomethacin, sulindac,meclofenamate, tolmetin, zomepirac, ibuprofen, and piroxicam.
- the compounds of the present invention are useful as hypolipidemic agents.
- the compounds of the present invention provide a method for treating a mammal suffering from hyperlipidemia comprising administering to said mammal a therapeutically effective amount of an N-boronated nucleoside. Additionally, the compounds of the present invention provide a method for treating a mammal suffering from hypercholesterolemia comprising administering to said mammal a therapeutically effective amount of an N- boronated nucleoside.
- the total lipoprotein level - may be reduced or the lipoprotein profile may be improved.
- these compounds may be conjointly administered with other known hypolipedemic agents to enhance or .supplement their efficacy.
- hypolipidemic agents are nicotinic acid, clofibrate, ge fibrozil, probucol, cholestyra ine, colestipol, compactin, mevinolin, choloxin, neomycin, and beta-sitosterol.
- the compounds of the present invention may be administered in any of the variety of modes currently employed for analogous pharmaceutical agents, which modes are well known in the art.
- these compounds may be administered systemically.
- Systemic administration includes parenteral administration and gastro-enteral administration.
- the compounds of the present invention When prepared in a pharmaceutical formulation for parenteral administration the compounds of the present invention should be prepared in a pharmaceutically acceptable carrier such as substantially non-pyrogenic, sterile, parenterally acceptable, aqueous solutions.
- a pharmaceutically acceptable carrier such as substantially non-pyrogenic, sterile, parenterally acceptable, aqueous solutions.
- the compounds of the present invention may be formulated in pharmaceutical preparations for gastro-enteral administration. Such pharmaceutical preparations include tablets, capsules and suppositories.
- the pharmaceutical preparations When formulated for administration according to any of the above methods the pharmaceutical preparations may further comprise buffers, binders, and other pharmaceutically acceptable excipients as are well known in the art.
- a therapeutically effective amount of a boronated nucleoside is in the range of about 0.1-100 mg/kg/day.
- the preferred range is about 0.5-50 mg/kg/day. More preferred is an amount in the range of about 1-10 mg/kg/day.
- When administered conjointly with other pharmaceutically active agents even less of the boronated nucleoside may be therapeutically effective.
- the oligonucleotides of the present invention may be used as probes in a variety of diagnostic techniques.
- One such diagnostic technique is Magnetic Resonance Imaging (MRI) .
- MRI Magnetic Resonance Imaging
- MRI is a noninvasive technique used to detect the presence and location of tumors in a patient.
- cancer cell specific boronated compounds are administered to a patient, whereupon they concentrate in cancerous tissue.
- the MRI instrument is capable of detecting and locating regions of abnormal concentrations of Boron. By indicating the regions having high relative concentrations of Boron, MRI establishes the presence and location of tumors.
- Another diagnostic application of the oligonucleotides of the present invention is their use as molecular probes.
- a detectable oligonucleotide probe is constructed that can be used to detect the presence of complementary sequences of DNA or RNA in a sample.
- probes can be used in any suitable environment, such as Southern blotting and Northern blotting, the details of which are known. See, e.g. , R. Old and S. Primrose, Principles of Gene Manipulation, 8-10 (3d Ed. 1985) .
- the boron atom serves as a radiolabel, though it is not itself radioactive until exposed to thermal neutron radiation (low energy neutrons) .
- thermal neutron radiation low energy neutrons
- 10 B absorbs a neutron and forms n B, which rapidly decays and releases an alpha particle, thus providing a detectable signal.
- the techniques involved in the generation of the alpha particle are known. See, e.g.. A. Soloway, Borax Rev.
- Oligonucleotides of the present invention which are capable of binding to polyribonucleic acid or polydeoxyribonucleic acid are useful as antisense agents in the same manner as conventional antisense agents. See generally Antisense Molecular Biology and S-oligos, Synthesis 1 (Oct. 1988) (published by
- Antisense agents of the present invention may be used by contacting an antisense agent which is capable of selectively binding to a predetermined polydeoxyribonucleic acid sequence or polyribonucleic acid sequence to a cell containing such sequence (e.g., by adding the antisense agent to a culture medium containing the cell) so that the antisense 'agent is taken into the cell, binds to the predetermined sequence, and blocks transcription, translation, or replication thereof.
- the requirements for selective binding of the antisense agent are known (e.g., a length of 17 bases for selective binding within the human genome) .
- Cyanoborane adducts of 2 '-deoxynucleosides for example, 2'-deoxyguanosine-N7-cyanoborane (3a), 2'- deoxyinosine-N7-cyanoborane (3b), 2'-deoxyadenosine-Nl- cyanoborane (3c), and 2'-deoxycytidine-N3-cyanoborane (3d) , were prepared by an exchange reaction of triphenylphosphine-cyanoborane (Ph 3 PBH 2 CN) with 3', 5'- O-protected nucleosides.
- Ph 3 PBH 2 CN triphenylphosphine-cyanoborane
- the site of boron coordination was determined by 15 N NMR spectroscopy on a JEOL FX90Q instrument. No peak was observed for .the cooordinated nitrogen (in both coupled and decoupled spectra) due to quadrupole broadening by boron. The absence of peaks for N7 of Gua* and Ino*, Nl of Ade*, and N3 of Cyt* established these to be the sites of BH-CN coordination. When 15 N N NMR spectra of 2a and 2d were obtained on a GE GN500 system, the above quadrupole effect was not observed.
- Chlorotriisopropylsilane (51.33 mmol) was added to this mixture and it was stirred at room temperature for 24 h. After dilution with diethylether (90 ml) , it was washed with a saturated solution of sodium chloride (5 x 80 ml) . The organic layer was filtered to remove any suspended solid, dried over anhydrous sodium sulfate and solvent was removed under reduced pressure to give crude product. Purification was achieved by flash chromatography on silica gel using a mixture of solvents (vide infra) . The products were characterized by X H nmr, 13 C nmr, 15 N n r, infrared and FAB mass spectroscopic techniques.
- mice 25 g were administered test drugs at 5-40 mg/kg in 0.05% Tween 80-H-O intraperitoneally 3 hours prior to and 30 minutes prior to the injection of 0.2 ml of 1% carrageenan in 0.9% saline into the plantar surface of the right hind foot. Saline was injected into the left hind foot, which serves as a base line. After 3 hours, both feet were excised at the tibiotarsal (ankle) joint according to standard procedures. See C. ' Winter et al., Proc. Soc. Expt. Biol Med. 544 , 111 (1962); A. Roszkawski et al., J. Pharm. Exp. Ther. 179, 114 (1971) . Control mice afforded a 78 ⁇ 3 mg increase in paw weight. Data on the percent inhibition of the inflammatory response for a dose of 8 mg/kg are reported in Table III below. TABLE III
- Step 1 Preparation of 5'-DMT-3'-TIPSI-N z -isobutyryl-2'- deoxyguanosine.
- Starting nucleoside I 930 mg
- imidazole 1.188 g
- chlorotriisopropylsilane 1.5 ml
- TLC CH 2 Cl 2 /MeOH 9:1 after 1 hour indicated very little reaction.
- the mixture was allowed to stir for 22 hours.
- TLC of the reaction mixture (CH 2 Cl 2 :MeOH: [:9.5:0.5]) showed only a trace amount of starting material left.
- Step 2 Preparation of 5'-DMT-3 '-TIPSI-N 2 -isobutyryl- 2'-deoxyguanosine-N 3 -cyanoborane.
- Step 3 Preparation of 5'-DMT-N 2 -isobutyryl-2'- deoxyguanosine-N- 7 -cyanoborane.
- Step 4 Preparation of N 2 -isobutyryl-5'-DMT-N 7 - cyanoborane-2'-deoxyguanosine-3' (methyldiisopropyl) phosphoramidite.
Abstract
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Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
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EP91905077A EP0506892B1 (en) | 1989-12-20 | 1990-12-17 | Boronated nucleosides |
DE69031567T DE69031567D1 (en) | 1989-12-20 | 1990-12-17 | NUCLEOSIDES CONTAINING BOR |
JP91505222A JPH05507265A (en) | 1989-12-20 | 1990-12-17 | boronated nucleosides |
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US453,311 | 1989-12-20 | ||
US07/453,311 US5130302A (en) | 1989-12-20 | 1989-12-20 | Boronated nucleoside, nucleotide and oligonucleotide compounds, compositions and methods for using same |
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WO1991009048A1 true WO1991009048A1 (en) | 1991-06-27 |
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EP (1) | EP0506892B1 (en) |
JP (1) | JPH05507265A (en) |
AT (1) | ATE159027T1 (en) |
AU (1) | AU634450B2 (en) |
CA (1) | CA2071936A1 (en) |
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Cited By (3)
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Cited By (9)
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EP0651758A1 (en) * | 1992-07-06 | 1995-05-10 | Boron Biologicals, Inc. | Phosphite-borane compounds, and method of making the same |
EP0651758A4 (en) * | 1992-07-06 | 1995-06-14 | Boron Biologicals, Inc. | Phosphite-borane compounds, and method of making the same. |
EP0649411A1 (en) * | 1992-07-07 | 1995-04-26 | Boron Biologicals, Inc. | Boronated compounds |
EP0731808A1 (en) * | 1993-12-02 | 1996-09-18 | Emory University | Nucleosides and oligonucleotides containing boron clusters |
EP0731808A4 (en) * | 1993-12-02 | 1997-04-02 | Univ Emory | Nucleosides and oligonucleotides containing boron clusters |
US6180766B1 (en) | 1993-12-02 | 2001-01-30 | Raymond F. Schinazi | Nucleosides and oligonucleotides containing boron clusters |
EP1113020A2 (en) * | 1993-12-02 | 2001-07-04 | Emory University | Nucleosides and oligonucleotides containing boron clusters |
EP1113020A3 (en) * | 1993-12-02 | 2003-04-16 | Emory University | Nucleosides and oligonucleotides containing boron clusters |
US6583122B2 (en) | 1993-12-02 | 2003-06-24 | Emory University | Nucleosides and oligonucleotides containing boron clusters |
Also Published As
Publication number | Publication date |
---|---|
JPH05507265A (en) | 1993-10-21 |
AU7344891A (en) | 1991-07-18 |
US5130302A (en) | 1992-07-14 |
ATE159027T1 (en) | 1997-10-15 |
EP0506892A4 (en) | 1993-03-31 |
EP0506892B1 (en) | 1997-10-08 |
CA2071936A1 (en) | 1991-06-21 |
EP0506892A1 (en) | 1992-10-07 |
AU634450B2 (en) | 1993-02-18 |
DE69031567D1 (en) | 1997-11-13 |
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