WO1993012129A1 - Acides nucleiques peptides et leur effet sur un materiau genetique - Google Patents

Acides nucleiques peptides et leur effet sur un materiau genetique Download PDF

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Publication number
WO1993012129A1
WO1993012129A1 PCT/US1992/010921 US9210921W WO9312129A1 WO 1993012129 A1 WO1993012129 A1 WO 1993012129A1 US 9210921 W US9210921 W US 9210921W WO 9312129 A1 WO9312129 A1 WO 9312129A1
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Prior art keywords
formula
alkyl
compound
nucleoside base
oligomer
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PCT/US1992/010921
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English (en)
Inventor
Stephen A. Thomson
Stewart A. Noble
Daniel J. Ricca
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Glaxo Inc.
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Application filed by Glaxo Inc. filed Critical Glaxo Inc.
Priority to EP93901215A priority Critical patent/EP0618923A4/fr
Priority to JP5511176A priority patent/JPH07502509A/ja
Publication of WO1993012129A1 publication Critical patent/WO1993012129A1/fr
Priority to FI942935A priority patent/FI942935A/fi
Priority to NO942327A priority patent/NO942327D0/no

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/001—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof by chemical synthesis
    • C07K14/003—Peptide-nucleic acids (PNAs)
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G69/00—Macromolecular compounds obtained by reactions forming a carboxylic amide link in the main chain of the macromolecule
    • C08G69/02—Polyamides derived from amino-carboxylic acids or from polyamines and polycarboxylic acids
    • C08G69/08—Polyamides derived from amino-carboxylic acids or from polyamines and polycarboxylic acids derived from amino-carboxylic acids
    • C08G69/10—Alpha-amino-carboxylic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • a synthetic oligodeoxynucleotide can provide absolute specificity of action since statistically the sequence defined by any linear combination of the four heterocyclic bases, adenine (A), guanine (G), cytosine (C), and thymine (T), to form an oligonucleotide of 17 residues in length, occurs just once in the entire sequence of the human genome.
  • the ODN can bind via Watson-Crick or Hoogsteen base pairing to its complementary base sequence which could, for example, be part of an oncogene implicated in tumorigenesis or an element of genetic material implicated as the dominant cause of a disease phenotype, for instance, a sequence which comprises an essential target within a viral genome.
  • complexation might lead to cleavage of the target RNA via the intermediacy of RNase H (Shuttleworth and Colman, EMBO J., 1988, 7, 427).
  • RNA splicing Interception of post-transcriptional processes such as RNA splicing is also possible by judicious choice of sequence and has proved particularly effective against viral targets, e.g. Herpes simplex Virus (HSV) (Smith et al., Proc. Natl. Acad. Sci. USA, 1986, 83, 2787) and Human Immunodeficiency Virus (HIV) (Goodchild et al., Proc. Natl. Acad. Sci. USA, 1988, 8 5, 5507), where alternative splicing of precursor RNAs is commonly used as a strategy to achieve control of viral replication.
  • HSV Herpes simplex Virus
  • HAV Human Immunodeficiency Virus
  • Oligomers having at least one peptide bond in the backbone with at least one pendant purine or pyrimidine nucleoside base are useful in affecting genetic material for diagnostic, therapeutic or analytic purposes.
  • Fig. 1 depicts a schematic representation of a process used to make a particular peptide nucleic acid (PNA) of the invention.
  • Fig.2 is a schematic of a test used to determine the degree of binding of a PNA according to the invention to genetic material.
  • Fig 3. is a graph showing the variation with increasing PNA concentration of binding to genetic material.
  • Nucleoside base oligomers which have at least one purine or pyrimidine
  • nucleoside base bound to a backbone having at least one peptide bond constitute the present invention.
  • the backbone would have 1 peptide bond for each pendant base whereby the oligomer can be formed from monomers each having an A, T, G or C nucleoside base.
  • A,T, G or C amino acid monomers By selecting the A,T, G or C amino acid monomers, each amino acid of the oligomer can be built up by successive peptide bond formations.
  • nucleoside bases in a PNA of the invention will depend on the use to which the PNA is put, i.e. the target portion of genetic material. Below 6 nucleoside bases, there will usually be too many possible different targets within the genetic material, e.g. many different chromosomes have a portion with GATT as a subsequence. Above 16 bases, the additional specificity provided is unnecessary, i.e. there will only be 1 sequence with a particular 15 base arrangement and no further purpose is provided by the additional bases.
  • the peptide oligomers of the invention may have pendant groups, usually at the termini, to stabilize the end, to act as an intercalator, to facilitate cellular uptake or to increase solubility.
  • a particular peptide oligomer of the invention is that of the following formula (I): I ) wherein
  • Q is an N-terminal blocking group
  • J is a C-terminal blocking group or Q and J may together be a single bond
  • n is at least 1 ;
  • R 1 is independently hydrogen, benzyl, -CH 2 -P-C 6 H 4 OH, -CH 2 -indol-3-yl,
  • R 3 is independently hydrogen, benzyl, -CH 2 -p-C 6 H 4 OH, -CH 2 -indol-3-yl,
  • B is independently a monovalent purine or pyrimidine nucleoside base.i.e. a base such as guanine without the hydrogen at the 9-position
  • Q is preferably an N-terminal blocking group which may stabilize that portion of the molecule, e.g. sterically hindered alkanoyl group whereby an amide is formed by the group QNH-.
  • Another function of the N-terminal blocking group Q is as an intercalator to bind within the genetic material, e.g. to actually wedge itself within the DNA double helix as described in Oligodeoxynucleotides-Antisense Inhibitors of Gene Expression, ed. by Jack S. Cohen, MacMillan Press, London (1989) (ISBN 0- 333-49211-0).
  • Q may function to increase lipophilicity, e.g.
  • Q may contain an ionizable moiety such as a carboxylic acid or an amine, e.g. the QNH moiety may be
  • J may be any of the types of groups described above for Q. Specific examples include, as the -CO-J group, -COOt-butyl as a sterically hindered stabilizing group and -CONHCH(CONH 2 )CH 2 CH 2 CH 2 CH 2 NH 2 as an ionizable moiety which functions as a solubizing moiety.
  • R 1 is preferably hydrogen, benzyl, -CH 2 -p-C 6 H 4 OH, -CH 2 -indol-3-yl
  • -CH 2 COOH, -CH 2 COO(C 1-4 alkyl), -CH 2 CH 2 COOH, -CH 2 CH 2 COO(C 1-4 alkyl), -CH 2 CONH 2 , -CH 2 CH 2 CONH 2 , -CH 2 SH, CH 2 CH 2 SCH 3 , C 1-12 alkyl, C 2-8 alkynyl, C 2-8 alkenyl, e.g. -CH 2 CH CHCH 3 , e.g. -(CH 2 ) 4 CCH, C 5-8 cycloalkyl, e.g.
  • C 1-4 alkyl in any of such definitions of R 1 , e.g. alkoxy, these may be methyl, ethyl, iso-propyl, n-propyl, n-butyl, sec-butyl, iso- butyl and tert-butyl.
  • R 3 is preferably hydrogen, benzyl, -CH 2 -p-C 6 H 4 OH, -CH 2 -indoI-3-yl,
  • -CH 2 COOH, -CH 2 COO(C 1-4 alkyl), -CH 2 CH 2 COOH, -CH 2 CH 2 COO(C 1-4 alkyl), -CH 2 CONH 2 , -CH 2 CH 2 CONH 2 , -CH 2 SH, CH 2 CH 2 SCH 3 , C 1 -12 alkyl, C 2-8 alkenyl, C 2-8 alkenyl, e.g. -CH 2 CH CHCH 3 , e.g. -(CH 2 ) 4 CCH, C 5-8 cycloalkyl, e.g. cyclopentyl, aryl, heteroaryl, or aryl or heteroaryl which is mono, di, or trisubstituted independently with halogen, nitro, C 1 -4 alkyl, C 1 - 4 alkoxy,
  • C 1 -4 alkyl in any of such definitions of R 1 , e.g. alkoxy, these may be methyl, ethyl, iso-propyl, n- propyl, n-butyl, sec-butyl, iso-butyl and tert-butyl.
  • Halogen includes chloro, bromo, iodo and fluoro.
  • B is a purine or pyrimidine nucleoside base is preferably adenine, thymine, guanine or cytosine or an equivalent thereof which binds to its complement, i.e. adenine to thymine and guanine to cytosine.
  • Examples of such equivalents are 5- methylcytosine, 5-propynyluracil, 7-propynyl-7-deaza-adenine and 7-methyl-7- deaza-adenine.
  • the peptide oligomer of the invention has at least 3 different A, T, G and C bases or their equivalent, e.g. all four of such bases.
  • R 1 is as defined for formula (I);
  • R 2 is an amino protecting group
  • R 3 is as defined for formula (I);
  • R 4 is a carboxylic acid protecting group
  • R 2 is preferably t-butyloxycarbonyl, 9-fluorenylmethoxycarbonyl, carbobenzoxy (i.e. benzyloxy carbonyl) trityl or dimethoxytrityl.
  • R 4 is preferably alkyl, e.g. methyl, ethyl, tert-butyl, or (2-trimethylsilyl)ethyl, aryl, e.g. phenyl or benzyl.
  • novel intermediates and processes e.g. the di-, tri- and tetra- peptide oligomers which are used as intermediates to produce the AS oligomers of formula (I).
  • the present invention encompasses all isomers and mixtures thereof within the scope of all the formulae provided.
  • the carbon bearing the R 1 and R 3 groups may independently each be R or S to give the isomers RR, RS, SS and SR.
  • the compounds of formula (I) may be prepared by the pathway outlined in Scheme 1.
  • step 1 an alpha-amino acid of formula (II) or a derivative thereof, wherein R 1 is as defined above for formula (I) and R 2 is defined for formula (X) is reduced by methods known in the literature (see Janusz Jurczak, Chem. Rev. 1989, 89, 149) to yield a compound of formula (III).
  • the ethyl ester of the compound of formula (I) is treated with d ⁇ sobutylaluminum hydride at -78 C to give the compound of formula (III).
  • R 1 in formula (II) and R 3 in formula (IV) may be used in a protected form to avoid reactivity of these groups during subsequent steps such as steps 1 ,2,6 and 7.
  • the starting material of formula (II) may be BocNHCH(CH 2 CH 2 CH 2 CH 2 NHCOOCH 2 C 6 H 5 )COOH, wherein the benzyloxycarbonyl group may be removed after preparation of the final compound of formula (I) by treatment with hydrogen fluoride, or hydrogenation with H 2 over a noble metal catalyst.
  • step 2 a compound of formula (III) is reacted with a compound of formula (IV) in a reductive amination to yield a compound of formula (V).
  • R 3 is as defined above for formula (I) and R 4 is a carboxylic acid protecting group as defined for formula (X) such as alkyl (e.g. methyl).
  • the carboxylic acid protecting group maintains the COO- group of formula (IV) through the reductive amination conditions of step 2 and the amide bond forming conditions of step 6.
  • the reaction of step 2 is carried out in a solvent such as methanol, in the presence of a dehydrating agent, e.g. molecular sieves, and a reducing agent such as sodium cyanoborohydride at about 25 ° C as described by Zydowsky et al in J. Org. Chem. 1988, 53, 5607.
  • This route to the compounds of formula (V) has the advantage over other possible routes in that it allows for independent selection of R 1 and R 3 and independent control of the stereochemistry at the carbon atoms which bears R 1 and R 3 . Since the starting materials for this route to compounds of formula (V) are alpha-amino acids the chiral pool of natural and unnatural alpha-amino acids can be used to produce the oligomers of the invention.
  • step 3 a compound B-H in which B is defined as in formula (X) or an
  • Step 4 depicts where, in certain cases, it is of advantage to use a masked
  • step 4 B-H is reacted with 3- bromopropene (formula (VIII)
  • Step 5 shows the conversion of (IX) to a compound of formula (VII) by oxidative cleavage of the double bond, for example by treatment with sodium periodate in the presence of ruthenium tetraoxide at about 25 ° C as described by Carlsen et al in J. Org. Chem. 1981 , 46, 3936.
  • step 6 a compound of formula (VII) in which R 5 is H is reacted with a compound of formula (V) under conditions known in the art for forming amide bonds to yield a compound of formula (X) (see Miklos Bodanszky; Peptide Chemistry, A Practical Textbook, Springer-Verlag 1988). This may involve conversion of the carboxyl moiety of a compound of formula (VII) to an activated form such as an activated ester, acid chloride, or mixed anhydride, and reaction of this activated form with a compound of formula (V) to give a compound of formula (X).
  • an activated form such as an activated ester, acid chloride, or mixed anhydride
  • a compound of formula (VII) in which R 5 is hydrogen is activated with benzotriazol-1- yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP), 1- hydroxybenzotriazole (HOBt), in dimethylformamide in the presence of
  • BOP benzotriazol-1- yloxytris(dimethylamino)phosphonium hexafluorophosphate
  • HOBt 1- hydroxybenzotriazole
  • step 7 compounds of formula (X) can be converted to a compound of formula (I) by reacting a compound of formula (X) in which R 2 is hydrogen with a compound of formula (X) in which R 4 is hydrogen under conditions known in the art for forming amide bonds (cf. Miklos Bodanszky; Peptide Chemistry, A Practical Textbook, Springer-Verlag 1988).
  • This coupling reaction can be repeated with monomers of Formula (X) with different B groups to give oligomers and polymers of a compound of formula (I).
  • step 7 can be done using standard solution phase reaction conditions, for example a compound of formula (X) in which R 4 is hydrogen, and R 2 is Boc is reacted with a compound of formula (X) in which R 2 is hydrogen, and R 4 is methyl, in dimethylformamide in the presence of the coupling reagents o-benzotriazol-1-yl-N,N,N',N',- tetramethyluronium hexafluorophosphate (HBTU), 1-hydroxybenzotriazole (HOBt), and diisopropylethylamine to yield a compound of formula (I).
  • HBTU o-benzotriazol-1-yl-N,N,N',N',- tetramethyluronium hexafluorophosphate
  • HOBt 1-hydroxybenzotriazole
  • diisopropylethylamine diisopropylethylamine
  • the coupling can also be performed by anchoring one of the reaction components on a solid support, such as a polystyrene resin and then performing a repetitive cycle of coupling and deprotection steps which allows for the rapid preparation of compounds of formula (I) in which n is greater than 1.
  • a solid support such as a polystyrene resin
  • This method is commonly known as solid phase synthesis (see Merrifield, J. Am. Chem. Soc. 1963, 85, 2149, and Science 1986, 232, 341).
  • a compound of formula (X) in which R 4 is hydrogen, and R 2 is Boc is coupled to a MBHA resin to which is anchored a lysine (with the epsilon amino group protected) through the carboxyl group in dimethylformamide in the presence of the coupling reagents HBTU, HOBt, and diisopropylethylamine.
  • the Boc group is removed by strong acid which reveals a free amino group to which a second residue can be coupled.
  • Repeating this coupling-deprotection cycle five more times and cleaving the chain from the solid support with hydrogen fluoride yields a compound of formula (I) in which n is five, J is lysine, and Q is hydrogen.
  • n five
  • J lysine
  • Q hydrogen.
  • some of the functional groups on the bases will be protected to avoid undesired side reactions during the synthesis of the compounds of formula (1).
  • Protecting groups on the nucleobases must be removed so that they will be able to bind to the target genetic material.
  • the protecting groups can be removed by methods such as treatment with fluoride ion, hydrofluoric acid, or by hydrogenation with H 2 in the presence of a noble metal catalyst. This deprotection can be
  • Scheme 2 depicts a method to make the compound of formula (V) in which R 1 and R 3 are hydrogen, R 2 is Boc, and R 4 is methyl (formula (Va)).
  • Scheme 3 is a more detailed description of steps 3 and 6 of Scheme 1 , and depicts a method for making the compound of formula (X) in which R 1 , R 3 and R 4 are hydrogen, R 2 is Boc, and B is thymine (formula (Xa)).
  • step 11 the compound of formula (VIIa) is activated with BOP in dimethylformamide and reacted with the compound of formula (Va), followed by hydrolysis of the resulting methyl ester by treatment with aqueous lithium hydroxide to give the compound of formula (Xa).
  • the compound of formula (Xa) is referred to as the Teg monomer.
  • Scheme 4 depicts a synthesis of the monomer of formula (X) in which R 1 , R 3 and R 4 are hydrogen, R 2 is Boc, and the nucleobase, B, is 4-N- benzyloxycarbonylcytosine (formula (Xc)).
  • step 12 the exocyclic amino group of cytosine, formula (XIII), is protected with the benzyloxycarbonyl group (Z) to give the compound of formula (XIV).
  • step 15 the methyl ester of the compound of formula (Xb) is hydrolyzed by treatment with aqueous lithium hydroxide to give the compound of formula (Xc), which is referred to as the Z protected Ceg monomer.
  • Scheme 5 depicts a synthesis of the monomer of formula (X) in which R 1 and R 3 are hydrogen, R 2 is Boc, R 4 is methyl, and B is 6-O-benzyl-2-N- (benzyloxycarbonyl)-guanine (formula (Xd)).
  • step 16 the commercially available 2-amino-6-chloropurine (formula (XV)) is converted to the compound of (formula (XVI)) as described by M. MacCoss et al. in Tetrahedron Lett. 1985, 26, 1815.
  • step 17 the compound of formula (XVI) is alkylated with allyl bromide at the 9 position to give the compound of formula (IX) where B is protected guanine, formula (IXa).
  • step 18 the alkene moiety of the compound of (formula (IXa)) is oxidatively cleaved by treatment with sodium periodate in the presence ruthenium tetraoxide at ca. 25°C as described by Carlsen et al in J. Org. Chem. 1981 , 46, 3936, to give the carboxylic acid which is methylated with diazomethane to give the particular compound of formula (VIIc).
  • step 19 the compound of formula (VII), i.e formula (VII), i.e.
  • formula (VIIc) is first hydrolysed to the carboxylic acid, then activated with BOP in dimethylformamide and reacted with the compound of formula (Va) to give the compound of formula (Xd).
  • the compound of formula (Xd) is referred to as the Bn-Z protected Geg monomer methyl ester. 6
  • Scheme 6 depicts a synthesis of the monomer (X) in which R 1 , R 3 and R 4 are hydrogen, R 2 is Boc and B is 6-N-benzyloxycarbonyladenine (formula (Xf)).
  • step 20 the exocyclic amine group of adenine (A-H, formula (XVII)) is protected with the benzyloxycarbonyl group (Z) to give the compound of formula (XVIII).
  • step 21 the compound of formula (XVIII) is reacted with tert-butyl bromoacetate, which is followed by removal of the t-butyl group with strong acid (trifluoroacetic acid) to give (Vlld).
  • step 22 the compound of formula (Vlld) is activated with BOP in
  • step 23 the methyl ester of the compound of formula (Xe) is hydrolysed with aqueous sodium hydroxide to give the compound of formula (Xf), which is referred to as the Z protected Aeg monomer.
  • Scheme 7 is a more detailed description of step 7 of scheme 1, and depicts a method for making the compound of formula (I) in which n is 1, and reading left to right Q is hydrogen, R 1 is hydrogen, B is guanine, R 3 is hydrogen, R 1 is hydrogen, B is thymine, R 3 is hydrogen, and J is methoxy (formula (1a)).
  • Q is hydrogen
  • R 1 is hydrogen
  • B guanine
  • R 3 hydrogen
  • R 1 is hydrogen
  • B thymine
  • R 3 is hydrogen
  • J methoxy (formula (1a)).
  • step 25 the carboxyl group of the compound of formula (Xi), the Bn-Z protected Geg monomer, is activated with HBTU and reacted with the compound of formula (Xh).
  • the protecting groups are removed by first treating with triflouroacetic acid, followed by hydrogen fluoride to give the compound of formula (la).
  • the compound of formula (la) is referred to as the Geg-Teg methyl ester.
  • the compounds of formula (I) may also be prepared by the solid phase method as described by Merrifield et al. in J. Am. Chem. Soc.
  • Figure 1 outlines a synthesis of the compound of formula (I) in which n is 5, Q is hydrogen, all R 1 an R 3 are hydrogen and all B are thymine, and J is lysine (C- terminal amide).
  • step a of figure 1 the Teg monomer is coupled to the free alpha- amino group of lysine which is bound to a MBHA resin. After coupling is complete the resin is washed.
  • step b the Boc group is removed by treatment of the resin with trifluoroacetic acid in methylene chloride. After the de-Boc reaction is complete the resin is washed and a second coupling can take place. After a total of six coupling and deprotection cycles, the resin is dried under vacuum, and in step c the resin is treated with hydrogen fluoride which cleaves the product from the resin to give the compound of formula (lb).
  • Figure 2 depicts an assay to show effective binding of a test compound nucleoside base oligomer of the invention of formula (I) to genetic material employing the enzyme RNase H.
  • 3H labeled poly rA RNA strand
  • dT complementary DNA strand
  • the enzyme RNase H (from Hela cells) is then added to the mixture.
  • RNase H will cleave the RNA strand of a RNA-DNA duplex, but not the RNA strand of a RNA-(la) duplex. Therefore only the portion of the poly rA strand which is bound to the dT strands will be cleaved into smaller fragments, and the portion of poly rA which is bound to the nucleoside base oligomer (formula (la)) will remain in tact. After ca. 30 minutes t-RNA and acid is added which precipitates the larger pieces of the poly rA, and the radioactivity remaining in the supernatant is counted. A decrease in radioactivity in the supernatant is a measure of the binding of the nucleobase oligomer of the invention over dT.
  • Figure 3 shows the results for the assay of Figure 2 for the nucleoside base oligomer of formula (la).
  • the Y axis is the radioactivity in the
  • the concentration of the compound of formula (la) is the concentration of the compound of formula (la).
  • increasing the concentration of the compound of formula (la) results in a strong decrease in the radioactivity in the supernatant.
  • the compound of formula (la) has nearly totally displaced the dT strand from the poly rA strand.
  • the addition of the compound of formula (la) had no effect on the RNase H cleavage of the RNA strand of an RNA-DNA duplex in which the RNA strand was not complementary to the base sequence of the compound of formula (la). Therefore the binding of the compound of formula (la) to RNA is sequence dependent.
  • Another assay can be used to measure the binding of the test compound
  • nucleoside base oligomer of the invention of formula (I) to double stranded (ds) DNA by measuring inhibition of a restriction enzyme which cleaves the ds DNA near or within the binding site of the test comound.
  • the test compound of formula (I) is allowed to bind to the target ds DNA which contains a complementary sequence to the test compound.
  • a restriciton enzyme is added and the amount of cleavage is measured.
  • a second restriction enzyme site removed from the test compound binding site is also within the ds DNA sequence and this site is used as an internal control.
  • a decrease in ds DNA cleavage near the test compound binding site is a measure of increased binding of the test compound.
  • compositions it will further appreciated that the amount of a compound of the invention required for use in treatment will vary not only with the particular compound selected but also with the route of administration, the nature of the condition being treated and the degree and condition of the patient and will be ultimately at the discretion of the attendant physician or veterinarian. In general however a suitable dose will be in the range of from about 1 to 75 mg/kg of bodyweight per day, such as about 0.01 to about 50 mg per kiolgram body weight of the recipient per day, preferably in the range of 0.025 to 40 mg/kg/day.
  • the desired dose may be presented in a single dose or as divided doses
  • Formulations of the present invention for medical use, comprise an active compound, i.e., a compound of formula (I), together with an acceptable carrier therefof and optionally other therapeutically active ingredients.
  • the carrier must be pharmaceutically acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • the present invention therefore, further provides a pharmaceutical formulation comprising a compound of formula (I) together with a pharmaceutically acceptable carrier thereof.
  • the formulations include those suitable for oral, rectal or parenteral (including subcutaneous, intramuscular and intravenous) administration. Preferred are those suitable for oral or parenteral administration.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active compound into association with a carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing the active compound into association with a liquid carrier or a finely divided solid carrier and then, if necessary, shaping the product into desired unit dosage form.
  • Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets, tablets or lozenges, each containing a predetermined amount of the active compound; as a powder or granules; or a suspension or solution in an aqueous liquid or non-aqueous liquid, e.g., a syrup, an elixir, an emulsion or a draught.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active compound in a free-flowing form, e.g., a powder or granules, optionally mixed with accessory ingredients, e.g., binders, lubricants, inert diluents, surface active or dispersing agents. Molded tablets may be made by molding in a suitable machine, a mixture of the powdered active compound with any suitable carrier.
  • a syrup or suspension may be made by adding the active compound to a
  • a sugar e.g., sucrose
  • accessory ingredient(s) may include flavoring, an agent to retard crystallization of the sugar or an agent to increase the solubility of any other ingredient, e.g., as a polyhydric alcohol, for example, glycerol or sorbitol.
  • Formulations for rectal or vaginal administration may be presented as a suppository with a conventional carrier, e.g., cocoa butter or Witepsol 155 (trademark of
  • Formulations suitable for parenteral administration conveniently comprise a sterile aqueous preparation of the active compound which is preferably isotonic with the blood of the recipient.
  • Such formulations suitably comprise a solution or suspension of a pharmaceutically and pharmacologically acceptable acid addition salt of a compound of the formula (I) that is isotonic with the blood of the recipient.
  • Such formulations may conveniently contain distilled water, 5% dextrose in distilled water or saline and a pharmaceutically and pharmacologically acceptable acid addition salt of a compound of the formula (I) that has an appropriate solubility in these solvents, for example the hydrochloride.
  • Useful formulations also comprise concentrated solutions or solids containing the compound of formula (1) which upon dilution with an appropriate solvent give a solution suitable for parental
  • the formulations of this invention may further include one or more optional accessory ingredient(s) utilized in the art of pharmaceutical formulations, e.g., diluents, buffers, flavoring agents, binders, surface active agents, thickeners, lubricants, suspending agents, preservatives (including antioxidants) and the like.
  • optional accessory ingredient(s) utilized in the art of pharmaceutical formulations, e.g., diluents, buffers, flavoring agents, binders, surface active agents, thickeners, lubricants, suspending agents, preservatives (including antioxidants) and the like.
  • reaction mixture is diluted with 200 mL of half saturated brine and extracted with ethyl acetate.
  • the combined organics are washed with 1 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, brine, dried over magnesium sulfate, and concentrated.
  • the resulting residue is chromatographed on silica gel (9:1 ethyl acetate:hexane) to give the title compound as a white solid: 3.65 g, 71 % yield.
  • B 6-O-benzyl-2-N-(benzyloxycarbonyl)guanine).
  • B 6-0- benzyl-2-N-(benzyloxycarbonyl)- guanine
  • sodium periodate 0.74 g, 2.21 mmol
  • ruthenium(lll) chloride hydrate 0.010 g, 0.048 mmol
  • the aqueous phase is extracted with chloroform, and the combined organic phases are washed with 30 mL of saturated brine. Upon partial concentration, crystallization occurs. The white crystals were washed with ethyl acetate and dried to afford the title
  • the residual aqueous mixture is diluted with ethyl acetate (300 mL) and brine (100 mL).
  • the pH of the aqueous phase is adjusted to ca. 2 with solid sodium bisulfate and the layers separated.
  • the aqueous layer is back extracted with ethyl acetate (150 mL).
  • the combined organics are dried over sodium sulfate, filtered then concentrated to a foam.
  • the foam is dissolved in methylene chloride then added dropwise to vigorously stirred hexane (300 mL). The resulting precipitate is filtered and dried to afford the title compound as a white powder (2.12 g, 88% yield).
  • R 1 is hydrogen
  • B is ouanine
  • R 3 is hydrogen
  • R 1 is hydrogen
  • B is thymine
  • R 3 is hydrogen
  • J is methoxy.
  • the capping solution (0.4/0.7/1.5 ratio, referred to as the capping solution). This is shaken gentl, for 0.5 hours. The resin is washed with DMF and methylene chloride, and is then treated wth 2 mL of a 1/1 trifluoroacetic acid/methylene chloride solution (referred to as teh de-Boeing solution) for 30 minutes. The reaction solution is removed by filtration and the resin is washed with a 15% solution of DIEA in methylene chloride, methylene chloride, and dried under vacuum, to give 1.101 g of dry C1Z-Iys-MBHA resin.
  • teh de-Boeing solution 1/1 trifluoroacetic acid/methylene chloride solution
  • the 3 H poly rA ⁇ T 25-30 heteroduplex was prepared as follows: 50 ml 3 H poly rA (5 ⁇ Ci, 940 pmol nucleotide) and 100 pmol T 25-30 (2500-3000 pmol nucleotide) were incubated in buffer A (40 mM Tris-HCI pH 7.5, 50 mM NaCl,
  • the reaction is incubated at 15C for 5 minutes and then terminated by the addition of 50 ⁇ l of 1 ⁇ g/ml tRNA and 100 ⁇ l of 2 M HCI, 0.2 M sodium pyrophosphate.
  • the solutions are placed on ice for ca. 10 minutes, and then centrifuged at 12,000 x g for 10 minutes at 4°C.
  • the supernatant is removed and the amount of 3 H determined by scintillation counting.
  • the extent of strand invasion is determined by comparing the 3 H in the supernatant for each time point to that of control reactions.
  • a reaction which contained none of the compound of formula (I) was performed as above to determine the maximum amount of 3 H in the supernatant.
  • a reaction in which the PNA and T25.30 were added simultaneously to the reaction, was performed to determine the minimum amount to 3 H released (an additional way to determine the minumum 3 H released was to conduct the reaction in the absence of both T25-30 and the PNA; both approaches gave essentially identical amounts of 3 H in the supernatant.

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Abstract

Oligomères d'acides nucléiques peptides ayant la formule (I) dans laquelle n = 1 ou plus, en particulier n est compris entre 5 et 20 environ, et B représente indépendamment l'une des quatre bases nucléosides ou leurs équivalents, Q et J sont des groupes extrêmes utiles dans des oligomères antisens. L'invention concerne également leur utilisation pour modifier un matériau génétique, p.ex. en tant que triplex ou antisens dans le traitement d'une maladie.
PCT/US1992/010921 1991-12-18 1992-12-17 Acides nucleiques peptides et leur effet sur un materiau genetique WO1993012129A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
EP93901215A EP0618923A4 (fr) 1991-12-18 1992-12-17 Acides nucleiques peptides et leur effet sur un materiau genetique.
JP5511176A JPH07502509A (ja) 1991-12-18 1992-12-17 ペプチド核酸と遺伝物質におけるそれらの効果
FI942935A FI942935A (fi) 1991-12-18 1994-06-17 Peptidien nukleiinihappoja ja niiden vaikutus geneettiseen materiaaliin
NO942327A NO942327D0 (no) 1991-12-18 1994-06-17 Peptid-nukleinsyrer og deres virkning på genetisk materiale

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US80966191A 1991-12-18 1991-12-18
US07/809,661 1991-12-18

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AU (2) AU3325493A (fr)
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FI (1) FI942935A (fr)
MX (1) MX9207334A (fr)
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Cited By (35)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0618925A1 (fr) * 1991-12-24 1994-10-12 Isis Pharmaceuticals, Inc. Oligonucleotides modifies en 2', a ouverture
WO1995017403A1 (fr) * 1993-12-22 1995-06-29 Perseptive Biosystems, Inc. Synthons de guanine utilises dans la synthese des acides nucleiques peptidiques et leur procede de fabrication
EP0672700A1 (fr) * 1994-03-14 1995-09-20 Hoechst Aktiengesellschaft Synthèse de PNA en utilisant un groupe aminoprotecteur labile contre des acides faibles
EP0672701A1 (fr) * 1994-03-14 1995-09-20 Hoechst Aktiengesellschaft Synthèse de PNA en utilisant un groupe aminoprotecteur labile en milieu basique
EP0672661A1 (fr) * 1994-03-14 1995-09-20 Hoechst Aktiengesellschaft Dérivés de N-éthyl-glycine substitués pour la préparation d'hybrides de PNA et PNA-/DNA
WO1996011205A1 (fr) * 1994-10-06 1996-04-18 Isis Pharmaceuticals, Inc. Conjugues d'acides nucleiques peptidiques
US5527675A (en) * 1993-08-20 1996-06-18 Millipore Corporation Method for degradation and sequencing of polymers which sequentially eliminate terminal residues
WO1996020212A2 (fr) * 1994-12-28 1996-07-04 Buchardt, Dorte Acide nucleique peptidique a squelette chiral
US5539083A (en) * 1994-02-23 1996-07-23 Isis Pharmaceuticals, Inc. Peptide nucleic acid combinatorial libraries and improved methods of synthesis
US5539082A (en) * 1993-04-26 1996-07-23 Nielsen; Peter E. Peptide nucleic acids
EP0734391A1 (fr) * 1993-11-24 1996-10-02 Isis Pharmaceuticals, Inc. Macromolecules chimeres pna-dna-pna
WO1996040685A1 (fr) * 1995-06-07 1996-12-19 Perseptive Biosystems, Inc. Synthons ameliores pour la synthese et la deprotection d'acides nucleiques peptidiques dans des conditions douces
US5612458A (en) * 1993-12-23 1997-03-18 Dako/As Antibody to PNA/nucleic acid complexes
WO1997014793A1 (fr) * 1995-10-20 1997-04-24 Trustees Of Boston University Raccords d'acide nucleique
EP0773950A1 (fr) * 1994-07-15 1997-05-21 Isis Pharmaceuticals, Inc. Acides nucleiques peptidiques lies
EP0853084A2 (fr) * 1996-12-20 1998-07-15 Hoechst Aktiengesellschaft Dérivés de purine substitués comme antagonistes du récpteur de la vitronectine
WO1998058256A1 (fr) * 1997-06-16 1998-12-23 The University Of North Carolina At Chapel Hill Peptido-oligonucleotides (pon) et leurs banques combinatoires
US5955571A (en) * 1994-08-08 1999-09-21 Bayer Aktiengesellschaft Nucleic acid-binding oligomers for therapy and diagnosis
US5977296A (en) * 1991-05-24 1999-11-02 Nielsen; Peter Chiral peptide nucleic acid monomers and oligomers
WO2000002864A1 (fr) * 1998-07-10 2000-01-20 Martens Juergen Precurseur pour monomeres de pna
US6063569A (en) * 1995-06-07 2000-05-16 Perseptive Biosystems, Inc. Methods for automated synthesis of PNA-DNA chimeras and compositions thereof
US6228982B1 (en) * 1992-05-22 2001-05-08 Benget Norden Double-stranded peptide nucleic acids
US6277603B1 (en) 1991-12-24 2001-08-21 Isis Pharmaceuticals, Inc. PNA-DNA-PNA chimeric macromolecules
US6350853B1 (en) 1993-04-26 2002-02-26 Peter E. Nielsen Conjugated peptide nucleic acids having enhanced cellular uptake
US6441130B1 (en) 1991-05-24 2002-08-27 Isis Pharmaceuticals, Inc. Linked peptide nucleic acids
US6465650B1 (en) 1995-03-13 2002-10-15 Aventis Pharma Deutschland Gmbh Substituted N-ethylglycine derivatives for preparing PNA and PNA/DNA hybrids
US6617422B1 (en) 1997-05-23 2003-09-09 Peter Nielsen Peptide nucleic acid monomers and oligomers
US6713602B1 (en) 1991-05-24 2004-03-30 Ole Buchardt Synthetic procedures for peptide nucleic acids
WO2004046331A2 (fr) 2002-11-15 2004-06-03 Idenix (Cayman) Limited Nucleoside a ramification en 2’ et mutation de flaviviridae
US6921812B1 (en) 2001-07-03 2005-07-26 Isis Pharmaceuticals, Inc. Methods of modulating pharmacokinetics of oligonucleotides
US7223833B1 (en) 1991-05-24 2007-05-29 Isis Pharmaceuticals, Inc. Peptide nucleic acid conjugates
EP2333115A1 (fr) 2005-12-22 2011-06-15 Keygene N.V. Nucléotides alternatifs pour un meilleur échange de nucléotides ciblés
WO2012113775A1 (fr) 2011-02-21 2012-08-30 University Of Zurich Ankyrine g et ses modulateurs pour le traitement de troubles neurodégénératifs
US9347095B2 (en) 2013-03-15 2016-05-24 Bio-Rad Laboratories, Inc. Digital assays for mutation detection
WO2018175927A3 (fr) * 2017-03-23 2018-11-01 Trucode Gene Repair, Inc. Monomères d'acide nucléique peptidique (anp) avec une fraction ester à protection orthogonale

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See also references of EP0618923A4 *

Cited By (65)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6441130B1 (en) 1991-05-24 2002-08-27 Isis Pharmaceuticals, Inc. Linked peptide nucleic acids
US6201103B1 (en) 1991-05-24 2001-03-13 Peter E. Nielsen Peptide nucleic acid incorporating a chiral backbone
US6713602B1 (en) 1991-05-24 2004-03-30 Ole Buchardt Synthetic procedures for peptide nucleic acids
US5773571A (en) * 1991-05-24 1998-06-30 Nielsen; Peter E. Peptide nucleic acids
US6451968B1 (en) 1991-05-24 2002-09-17 Isis Pharmaceuticals, Inc. Peptide nucleic acids
US7223833B1 (en) 1991-05-24 2007-05-29 Isis Pharmaceuticals, Inc. Peptide nucleic acid conjugates
US5977296A (en) * 1991-05-24 1999-11-02 Nielsen; Peter Chiral peptide nucleic acid monomers and oligomers
US6357163B1 (en) 1991-05-24 2002-03-19 Ole Buchardt Use of nucleic acid analogues in diagnostics and analytical procedures
US6277603B1 (en) 1991-12-24 2001-08-21 Isis Pharmaceuticals, Inc. PNA-DNA-PNA chimeric macromolecules
EP1044987A3 (fr) * 1991-12-24 2001-10-04 Isis Pharmaceuticals, Inc. Oligonucléotides modifiés en 2' à ouverture
EP0618925A1 (fr) * 1991-12-24 1994-10-12 Isis Pharmaceuticals, Inc. Oligonucleotides modifies en 2', a ouverture
EP1044987A2 (fr) * 1991-12-24 2000-10-18 Isis Pharmaceuticals, Inc. Oligonucléotides modifiés en 2' à ouverture
EP0618925A4 (en) * 1991-12-24 1997-01-02 Isis Pharmaceuticals Inc Gapped 2' modified oligonucleotides.
US6228982B1 (en) * 1992-05-22 2001-05-08 Benget Norden Double-stranded peptide nucleic acids
US5539082A (en) * 1993-04-26 1996-07-23 Nielsen; Peter E. Peptide nucleic acids
US6350853B1 (en) 1993-04-26 2002-02-26 Peter E. Nielsen Conjugated peptide nucleic acids having enhanced cellular uptake
US6686442B2 (en) 1993-04-26 2004-02-03 Peter E. Neilsen Conjugated peptide nucleic acids having enhanced cellular uptake
US5527675A (en) * 1993-08-20 1996-06-18 Millipore Corporation Method for degradation and sequencing of polymers which sequentially eliminate terminal residues
EP0734391A4 (fr) * 1993-11-24 1998-02-25 Isis Pharmaceuticals Inc Macromolecules chimeres pna-dna-pna
EP0734391A1 (fr) * 1993-11-24 1996-10-02 Isis Pharmaceuticals, Inc. Macromolecules chimeres pna-dna-pna
EP1201676A3 (fr) * 1993-11-24 2004-04-21 Isis Pharmaceuticals, Inc. Macromolécules chimères PNA-DNA-PNA
EP1201676A2 (fr) * 1993-11-24 2002-05-02 Isis Pharmaceuticals, Inc. Macromolécules chimères pna-dna-pna
WO1995017403A1 (fr) * 1993-12-22 1995-06-29 Perseptive Biosystems, Inc. Synthons de guanine utilises dans la synthese des acides nucleiques peptidiques et leur procede de fabrication
US6172226B1 (en) 1993-12-22 2001-01-09 Perseptive Biosystems, Inc. Synthons for the synthesis and deprotection of peptide nucleic acids under mild conditions
US6133444A (en) * 1993-12-22 2000-10-17 Perseptive Biosystems, Inc. Synthons for the synthesis and deprotection of peptide nucleic acids under mild conditions
US5612458A (en) * 1993-12-23 1997-03-18 Dako/As Antibody to PNA/nucleic acid complexes
US5539083A (en) * 1994-02-23 1996-07-23 Isis Pharmaceuticals, Inc. Peptide nucleic acid combinatorial libraries and improved methods of synthesis
US6756199B1 (en) 1994-02-23 2004-06-29 Isis Pharmaceuticals, Inc. Peptide nucleic acid combinatorial libraries and improved methods of synthesis
US5864010A (en) * 1994-02-23 1999-01-26 Isis Pharmaceuticals, Inc. Peptide nucleic acid combinatorial libraries
US5831014A (en) * 1994-02-23 1998-11-03 Isis Pharmaceuticals, Inc. PNA combinatorial libraries and improved methods of synthesis
US6204326B1 (en) 1994-02-23 2001-03-20 Isis Pharmaceuticals, Inc. PNA combinatorial libraries and improved methods of synthesis
US6316595B1 (en) 1994-03-14 2001-11-13 Aventis Pharma Deutschland Gmbh PNA synthesis using a base-labile amino protecting group
EP0672661A1 (fr) * 1994-03-14 1995-09-20 Hoechst Aktiengesellschaft Dérivés de N-éthyl-glycine substitués pour la préparation d'hybrides de PNA et PNA-/DNA
EP0672701A1 (fr) * 1994-03-14 1995-09-20 Hoechst Aktiengesellschaft Synthèse de PNA en utilisant un groupe aminoprotecteur labile en milieu basique
US6075143A (en) * 1994-03-14 2000-06-13 Hoechst Aktiengesellschaft Substituted N-ethylglycine derivatives for preparing PNA and PNA/DNA hybrids
US6121418A (en) * 1994-03-14 2000-09-19 Hoechst Aktiengesellschaft PNA synthesis using a base-labile amino protecting group
EP0672700A1 (fr) * 1994-03-14 1995-09-20 Hoechst Aktiengesellschaft Synthèse de PNA en utilisant un groupe aminoprotecteur labile contre des acides faibles
EP0773950A1 (fr) * 1994-07-15 1997-05-21 Isis Pharmaceuticals, Inc. Acides nucleiques peptidiques lies
EP0773950A4 (fr) * 1994-07-15 2000-05-17 Isis Pharmaceuticals Inc Acides nucleiques peptidiques lies
US5955571A (en) * 1994-08-08 1999-09-21 Bayer Aktiengesellschaft Nucleic acid-binding oligomers for therapy and diagnosis
WO1996011205A1 (fr) * 1994-10-06 1996-04-18 Isis Pharmaceuticals, Inc. Conjugues d'acides nucleiques peptidiques
WO1996020212A2 (fr) * 1994-12-28 1996-07-04 Buchardt, Dorte Acide nucleique peptidique a squelette chiral
WO1996020212A3 (fr) * 1994-12-28 1996-09-26 Buchardt Dorte & Lf Acide nucleique peptidique a squelette chiral
US6465650B1 (en) 1995-03-13 2002-10-15 Aventis Pharma Deutschland Gmbh Substituted N-ethylglycine derivatives for preparing PNA and PNA/DNA hybrids
US6063569A (en) * 1995-06-07 2000-05-16 Perseptive Biosystems, Inc. Methods for automated synthesis of PNA-DNA chimeras and compositions thereof
EP1873156A1 (fr) * 1995-06-07 2008-01-02 PerSeptive Biosystems, Inc. Procedé pour la preparation de derivés 6-[[(alkoxy)carbonyl]amino]-9H-Purine-9-acide acétique et 4-[(alkoxycarbonyl)amino]-2-oxo-1(2H)-Pyrimidine-acide acétique en tant que synthons pour la synthèse d'acides nucléiques peptidiques
WO1996040685A1 (fr) * 1995-06-07 1996-12-19 Perseptive Biosystems, Inc. Synthons ameliores pour la synthese et la deprotection d'acides nucleiques peptidiques dans des conditions douces
WO1997014793A1 (fr) * 1995-10-20 1997-04-24 Trustees Of Boston University Raccords d'acide nucleique
US6004750A (en) * 1995-10-20 1999-12-21 The Trustees Of Boston University Nucleic acid clamps
EP0853084A3 (fr) * 1996-12-20 1998-09-09 Hoechst Aktiengesellschaft Dérivés de purine substitués comme antagonistes du récpteur de la vitronectine
EP0853084A2 (fr) * 1996-12-20 1998-07-15 Hoechst Aktiengesellschaft Dérivés de purine substitués comme antagonistes du récpteur de la vitronectine
CN1101816C (zh) * 1996-12-20 2003-02-19 赫彻斯特股份公司 取代的嘌呤衍生物、其制备方法、应用以及含有它们的组合物
US6632919B1 (en) 1997-05-23 2003-10-14 Peter Nielsen Peptide nucleic acid monomers and oligomers
US6617422B1 (en) 1997-05-23 2003-09-09 Peter Nielsen Peptide nucleic acid monomers and oligomers
WO1998058256A1 (fr) * 1997-06-16 1998-12-23 The University Of North Carolina At Chapel Hill Peptido-oligonucleotides (pon) et leurs banques combinatoires
WO2000002864A1 (fr) * 1998-07-10 2000-01-20 Martens Juergen Precurseur pour monomeres de pna
US6921812B1 (en) 2001-07-03 2005-07-26 Isis Pharmaceuticals, Inc. Methods of modulating pharmacokinetics of oligonucleotides
WO2004046331A2 (fr) 2002-11-15 2004-06-03 Idenix (Cayman) Limited Nucleoside a ramification en 2’ et mutation de flaviviridae
EP2333115A1 (fr) 2005-12-22 2011-06-15 Keygene N.V. Nucléotides alternatifs pour un meilleur échange de nucléotides ciblés
WO2012113775A1 (fr) 2011-02-21 2012-08-30 University Of Zurich Ankyrine g et ses modulateurs pour le traitement de troubles neurodégénératifs
US9347095B2 (en) 2013-03-15 2016-05-24 Bio-Rad Laboratories, Inc. Digital assays for mutation detection
WO2018175927A3 (fr) * 2017-03-23 2018-11-01 Trucode Gene Repair, Inc. Monomères d'acide nucléique peptidique (anp) avec une fraction ester à protection orthogonale
CN110740994A (zh) * 2017-03-23 2020-01-31 特鲁科德基因修复公司 具有受正交保护的酯部分的肽核酸(pna)单体
EP3601237A4 (fr) * 2017-03-23 2021-01-13 Trucode Gene Repair, Inc. Monomères d'acide nucléique peptidique (anp) avec une fraction ester à protection orthogonale
AU2018240467B2 (en) * 2017-03-23 2022-09-15 Neubase Therapeutics, Inc. Peptide nucleic acid (PNA) monomers with an orthogonally protected ester moiety

Also Published As

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MX9207334A (es) 1993-08-01
NZ246473A (en) 1996-05-28
FI942935A0 (fi) 1994-06-17
FI942935A (fi) 1994-07-27
NO942327D0 (no) 1994-06-17
NO942327L (fr) 1994-08-17
CA2125966A1 (fr) 1993-06-24
EP0618923A4 (fr) 1998-05-20
AU7032596A (en) 1997-01-16
AU3325493A (en) 1993-07-19
EP0618923A1 (fr) 1994-10-12
ZA929764B (en) 1993-10-13
JPH07502509A (ja) 1995-03-16

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