WO1991019730A1 - Hydrolyse/clivage d'arn - Google Patents

Hydrolyse/clivage d'arn Download PDF

Info

Publication number
WO1991019730A1
WO1991019730A1 PCT/US1991/003880 US9103880W WO9119730A1 WO 1991019730 A1 WO1991019730 A1 WO 1991019730A1 US 9103880 W US9103880 W US 9103880W WO 9119730 A1 WO9119730 A1 WO 9119730A1
Authority
WO
WIPO (PCT)
Prior art keywords
rna
compound
group
copper
oligodeoxynucleotide
Prior art date
Application number
PCT/US1991/003880
Other languages
English (en)
Inventor
James Keane Bashkin
Anil Shrikrishna Modak
Michael Keith Stern
Original Assignee
Monsanto Company
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.)
Filing date
Publication date
Application filed by Monsanto Company filed Critical Monsanto Company
Priority to CA002083048A priority Critical patent/CA2083048A1/fr
Priority to JP51086791A priority patent/JPH05507619A/ja
Publication of WO1991019730A1 publication Critical patent/WO1991019730A1/fr

Links

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

Definitions

  • oligodeoxynucleotides each containing at least one imidazole group attached via an appropriate linker
  • imidazole group attached via an appropriate linker to a nucleoside, nucleotide or oligodeoxynucleotide in the presence of an imidazole group in solution.
  • the imidazole groups perform as synthetic analogs for the active sites of enzymes or ribozymes in the cleavage of RNA.
  • Conjugate as used herein means a compound comprised of a metal complex covalently linked to a nucleoside or nucleotide or a compound comprised of two or more imidazole groups covalently linked to a nucleoside or nucleotide, or a combination of two or more nucleosides or nucleotides each having one or more imidazole groups covalently linked thereto.
  • Oligodeoxynucleotide conjugate as used herein means a compound comprised of a metal complex covalently linked to an oligodeoxynucleotide or to a compound comprised of one or more imidazole groups covalently linked to an oligodeoxynucleotide, or a combination of two or more oligodeoxynucleotides each having one or more imidazole groups covalently linked thereto.
  • imidazole group as used herein includes imidazole and analogs of imidazole, including nitrogen-containing compounds which retain the essential properties of the imidazoles, so that they may function as either acids, bases or both, in either the Lewis (Cotton and Wilkinson, Advanced Inorganic Chemistry. 1988, Wiley, NY, p36); Orchin et al (The Vocabulary of Organic Chemistry. Wiley, 1980, p248); or Br ⁇ nsted
  • a first aspect of this invention is directed to the discovery of metal complexes useful for promoting RNA hydrolysis.
  • a second aspect of this invention is directed to a conjugate which is active for RNA
  • hydrolysis comprised of a metal complex covalently linked to a nucleoside or nucleotide.
  • a third aspect of this invention is directed to the sequence-directed hydrolytic cleavage of RNA by a metal complex covalently linked to an oligodeoxynucleotide.
  • Another aspect of this invention is directed to the discovery of two or more imidazole groups covalently linked to nucleosides, nucleotides and oligodeoxynucleotides useful for promoting RNA cleavage.
  • the oligodeoxynucleotide provides molecular recognition via Watson Crick base pairing to the target RNA sequence.
  • major objects of this invention are to provide for the hydrolysis of RNA at physiologically relevant conditions and for the cleavage of RNA.
  • other objects of this invention include (l) the discovery of metal complexes which are effective for the hydrolysis of RNA, (2) the discovery that molecules containing two or more imidazole groups show great enhancement over mono-imidazole species for the cleavage of RNA, (3) the preparation of conjugates which retain RNA cleavage behavior, (4) the preparation of oligodeoxynucleotide conjugates effective for the sequence-directed
  • FIG. 2 there is shown the titration of 3'-[4-[4'-methyl(2,2'-bipyridin)-4-yl]butyl-phosphate]-2'-deoxy-thymidine ammonium salt (5) with CuCl 2 forming 3'-[4-[4'-methyl(2,2'-bipyridin)-4-yl]butyl-phosphate]-2'-deoxy-thymidine ammonium salt copper(II) (6).
  • This Figure depicts Applicants' Example IV and demonstrates the formation of a metal complex nucleotide conjugate in accordance with Applicants' ihyehtion.
  • Figure depicts Applicants' Example XI and demonstrates that a metal complex linked to the base portion of a nucleoside is capable of hydrolyzing RNA.
  • FIG. 7 there is shown the densitometry results of polyacrylamide gel electrophoresis analysis of the sequence-directed hydrolysis of tRNA Tyr by the oligodeoxynucleotide-Cu(bpy) 2+ conjugate (32).
  • This Figure depicts Applicants' Example XV showing Densitometry scans of the polyacrylamide gel of the reaction of (32) with tRNA Tyr after 17 hours under the conditions described in Example XV and of the control reaction.
  • FIG. 9 there is shown the autoradiograph which depicts the cleavage of 32 P labeled RNA by compound (5A) and that compound (6 ⁇ ) is ineffective at cleaving RNA.
  • Figure 10 there is shown a schematic view of the use of two oligodeoxynucleotide conjugates, labeled antisense Probe 1 and Probe 2, juxtaposed in a manner to enhance cleavage of RNA.
  • Scheme 1 depicts the synthesis of compound (5) as described in Applicants' Example III.
  • Scheme 5 depicts the synthesis of compound (30) as described in Applicants' Example XIV.
  • Scheme 6 depicts the sequence-directed cleavage of tRNA Tyr by compound (32) as described in Applicants' Example XV.
  • Scheme 8 depicts the sequence-directed cleavage of RNA by compound (5A) as described in Applicants' Example XVII.
  • Scheme 9 depicts the synthesis of compound (12A) as described in Applicants' Example XVIII.
  • the hydrolytically effective oligodeoxynucleotide conjugates of this invention are comprised of a desired organic molecule, herein referred to as the ligand, a metal ion, which imparts the hydrolytic activity, and a desired oligodeoxynucleotide.
  • the effective conjugates of this invention are comprised of two or more imidazole groups which impart the RNA cleavage activity, and one or more desired nucleosides, nucleotides or oligodeoxynucleotides.
  • Applicants' invention is based on metal complexes which are effective for RNA hydrolysis, and the preparation of such metal complexes covalently linked to nucleosides, nucleotides and oligodeoxynucleotides.
  • the metal complexes covalently linked to the nucleosides, nucleotides and oligodeoxynucleotides distinguishes Applicants' invention from the speculation of the C. A. Stein et al and the teaching of the P. G. Schultz et al references described above.
  • Agents as used herein means Applicants' synthetic RNA hydrolysis compounds comprising a metal and a ligand, or metal complex, covalently linked to an oligodeoxynucleotide and conjugates and oligodeoxyconjugates as defined herein.
  • the oligodeoxynucleotide provides sequence-directed recognition of RNA targets under physiologically relevant conditions.
  • the agents of this invention are effectively artificial enzymes which mimic natural ribonucleases and ribozymes. These agents possess several advantages over ribonucleases and ribozymes in applications where sequence-directed RNA hydrolysis is desired. Such advantages include (1) enhanced specificity over ribonucleases, (2) increased chemical stability over ribozymes, (3) ease of
  • nucleic acid hydrolysis compounds of Schultz et al differ from Applicants' invention in several import aspects.
  • the nucleic acid cleavage behavior taught by Schultz et al is provided by an enzyme, not the synthetic small molecule hydrolysis agents
  • Ribonuclease S is a noncovalent complex comprised of the S-protein and S-peptide derived from ribonuclease A. This complex is subject to
  • Oligodeoxynucleotidestaphylococcal nuclease conjugates were shown to cleave DNA as well as RNA; thus, they lack the specificity of Applicants' agents for RNA hydrolysis and cleavage alone. This high activity limits the specificity of the enzyme-based systems developed by Schultz et al because nonspecific cleavage events are common. The specificity of these enzyme-based systems was artificially increased by lowering the temperature below physiologically relevant values (i.e. to 0oC).
  • oligodeoxynucleotide conjugates will not cleave their own oligodeoxy- nucleotide components at an appreciable rate. See Applicants' Example II below.
  • oligodeoxynucleotides used herein includes oligodeoxynucleotides and oligodeoxynucleotide analogs that are. effective at molecular recognition by, for example, Watson-Crick or Hoogsteen base-pairing.
  • oligodeoxynucleotide analogs include those with nonionic internucleotide linkages such as alkylphosphotriesters, alkylphosphonates and
  • oligodeoxynucleotide analogs which may be suitable include those with internucleotide linkages such as carbonate, acetate, carbamate, dialkyl and diarylsilyl groups.
  • the metal complexes which hydrolyze RNA may contain hydroxyl or aquo ligands or both. These active forms may be derived in a
  • RNA under physiologically relevant conditions 7.1 pH and 37oC.
  • a compound is determined to be active if it shows hydrolytic degradation of the substrate, as illustrated in Figure 1, to an extent greater than that which is observed for a control reaction run under identical conditions in the absence of a cleavage agent.
  • This Example shows how metal complexes and other compounds are screened for RNA hydrolysis activity.
  • RNA was hydrolytic and not oxidative. This was demonstrated by comparing the reactivity of the Cu(bpy) 2+ complexes with both DNA and RNA.
  • a stock solution of DNA [poly(dA) 12-18 ] was prepared by dissolving 25 units of the DNA in l.OmL of 20mM HEPES buffer pH - 7.1.
  • the reaction mixture contained in a total volume of 1.5mL, 63 ⁇ M of the DNA, 157 ⁇ M bipyridine, 157 ⁇ M CuCl 2 and 20mM HEPES buffer.
  • the solutions were incubated at 37'C for 48 hours after which time they were assayed by ion exchange HPLC. Identical conditions were used in the reaction of the Cu(bpy) 2+ complex with RNA [poly(A) 12+18 ].
  • Figure 6 contains the HPLC analysis of the reactions of the Cu(bpy) 2+ complexes with the DNA and RNA. After 48 hours the RNA is extensively hydrolyzed. By contrast, the DNA substrate showed no evidence of degradation. It has been reported that both RNA and DNA are oxidatively cleaved by 1,10-phenathroline-copper(II) at similar rates (C. B. Chen et al, J. Am. Chem. Soc. 1988, 110, 6570-6572). Consequently, one would expect to see extensive cleavage of the DNA by the Cu(bpy) 2+ complex if an oxidative mechanism was operative.
  • This Example shows the attachment of bipyridyl ligand (bpy) to the 3' position of 2'-deoxy-thymidine nucleotide as outline in Scheme 1.
  • nucleoside 3 '-[4-[4'-methyl(2,2'-bipyridin)-4-yl]butyl-phosphate]-2'-deoxy-thymidine ammonium salt (5) (0.192 gm., 0.354 mmol, 82%).
  • compound (6) was formed under the conditions set forth in Example IV.
  • time zero a lOO ⁇ L aliquot of the reaction mixture was removed and immediately analyzed by Applicants' HPLC Assay.
  • the reaction mixture was incubated at 37oC for 48 hours after which time a second aliquot was removed and assayed. It was found that the RNA substrate was clearly hydrolyzed by compound (6) ( Figure 3).
  • This Example shows the attachment of bipyridyl ligand (bpy) to the 5' position of 2'-deoxy-thymidine nucleotide as outlined in Scheme 2.
  • phosphoramidite (8) (0.101 gm., 0.25 mmol) and tetrazole in lmL of THF was stirred at room temperature for 10 minutes.
  • 3'-O-acetyl-2'-deoxythymidine (7) (0.071 gm., 0.25 mmol) dissolved in CH 2 Cl 2 (lmL) was added to the reaction mixture and the solution was left stirring for 60 minutes. The mixture was then filtered to remove tetrazole which precipitated out.
  • Example III The procedure described in Example III was followed. Changes in visible spectrum similar to those shown in Figure 2 and characteristic of coordination of copper(II) to bipyridine were observed. Titration of uridine showed no changes in the visible spectrum over the range 240-380nm.
  • This Example shows the preparation of various terpyridine (trpy) derivatives (Scheme 4) which can be attached to nucleotides as described in Examples IV and V and which have been previously shown in Example I to be active RNA hydrolysis catalysts.
  • trpy terpyridine
  • the mixture was poured over 10 ml brine and the aqueous layer was extracted with CH 2 Cl 2 .
  • the extracts were dried over MgSO 4 and evaporated to dryness to yield the crude acetal.
  • the acetal was hydrolyzed with 1M HCl (10mL) by heating to 50-60oC for 2 hours. The solution was then neutralized with aqueous NaHCO 3 and extracted with
  • Compound (23) can be attached to the 5' position of 2'-deoxy-thymidine by literature procedures (see B. C. F. Chu et al, DNA 1985, 4, 327-331).
  • This Example shows a variety of nucleosides and nucleotides which have groups appended on the 3' and 5' position of 2'-deoxy-thymidine and 5- position uracil in 2'-deoxy-uridine and which are not active at hydrolyzing RNA [poly(A) 12-18 ] under the conditions of the HPLC assay (Table 2).
  • This Example shows a sequence-directed cleavage of tRNA Tyr by an oligodeoxynucleotide-bipyridine
  • a 10l ⁇ M stock solution of oligodeoxynucleotidebipyridine conjugate (31) was prepared by dissolving 6.1 units of compound (31) in 500 ⁇ L of 20 mM HEPES buffer having a pH of 7.1.
  • a 25.9 ⁇ M stock solution of the tRNA Tyr substrate was prepared by dissolving 10 Units of tRNA Tyr in 500 ⁇ L of 20 mM HEPES buffer having a pH of 7.1.
  • the cleavage reaction contained in a total of 600 ⁇ L, 1.29 ⁇ M tRNA Tyr , 12.9 ⁇ M Cu(trpy) 2+ , 227 ⁇ M Cu(SO 4 ), 6.4 ⁇ M compound (31), 50mM NaCl and 50mM HEPES buffer having a pH of 7.8. Initially the tRNA Tyr , compound (31), NaCl and buffer were combined and heated to 65*C for 4 min. in a water bath. The reaction was removed and
  • Cu(trpy) 2* complex were added.
  • Applicants have shown in Example III that the copper(II) coordinates to the bipyridine ligand exclusively forming in this case the oligodeoxynucleotide-metal complex conjugate (32).
  • the reaction was heated at 37oC and 100 ⁇ L aliquots were removed at times - 0, 17 and 28 hours.
  • Analysis of the aliquots by polyacrylamide gel electrophoresis revealed three distinct cleavage sites adjacent to the targeted sequence as shown in Figure 6. These bands appeared in a time-dependent fashion and control reactions were devoid or showed significantly reduced cleavage in these regions.
  • This example shows the synthesis of the diimidazole containing nucleoside (5A) , 5-[3-[[2-[[2-[[2-amino]-1-oxo-3-[1H-imidazol-4-yl]propyl]amino]-1-oxo-3-[1H-imidazol-4-yl]propyl] amino]ethyl]amino]-3oxopropyl]-2'-deoxy-uridine, as outlined in Scheme 7.
  • the synthesis of compound (IA) has been previously described (Dervan et al., Proc. Natnl . Acad. Sci . USA 1985, 82, 968).
  • the nucleoside 5'-O-DMT-5-[3-[(2-aminoethyl)-amino]-3-oxopropyl]-2'-deoxy-uridine (IA) (1.288 g, 2.0 mmol) was dissolved in dry dichloromethane (10 mL) and was cooled to 0oC in an ice bath.
  • Fmoc-L-His(Tr)-O-pfp (3.16 g, 3.0 mmol) was added to the stirred reaction mixture.
  • Triethylamine (0.28 ml, 2.0 mol) was added to the solution and the mixture was stirred at room
  • RNA substrate was generated by runoff transcription with bacteriophage SP6 DNA-dependent RNA polymerase using standard techniques (Maniatis, T.;
  • imidazole-nucleoside conjugates into di-, tri-, and oligodeoxynucleotides. These techniques may be applied for the incorporation of suitably protected conjugates into oligodeoxynucleotides.
  • HEMS high resolution mass spectra
  • This reaction mixture was added to the phosphorylating mixture in the pear-shaped flask and stirred at room temperature for 20 minutes. The reaction was monitored on TLC, and after all of the starting material was consumed, the mixture was quenched with triethylamine (3.06 mL, 21.96 mmol) and water (10 mL) to give a homogeneous solution. The solution was stirred for 10 minutes and then concentrated. The residue was dissolved in dichloromethane (25mL) and washed with sat. NaHCO 3 (25 mL). The aqueous layer was washed with dichloromethane (2 ⁇ 20mL), and the combined organic extracts were dried over MgSO 4 and concentrated to a glass.
  • nucleoside (10A) (0.110 g, 0.143 mmol, 95% ).
  • the sample was purified on a Alltech Econosil C18 preparative RP HPLC column. Retention time for (10A) (250 OD units) was 14.6 minutes on a C18 analytical column using the same linear ternary gradient, flowing at 1.5 mL/min.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Health & Medical Sciences (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Saccharide Compounds (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention se rapporte à l'hydrolyse sélectionnée dirigée par séquences qui est effectuée sur des ARN dans des conditions physiologiquement pertinentes grâce à l'utilisation, comme agents d'hydrolyse, de conjugués comprenant des complexes métalliques liés par covalence à des oligodésoxynucléotides. Les parties oligodésoxynucléotides des agents sont sélectionnées de façon à assurer une reconnaissance moléculaire par l'intermédiaire de l'accouplement des bases Watson Cryck à la séquence d'ARN cible devant faire l'objet de l'hydrolyse. Un procédé est prévu pour déterminer l'efficacité, dans l'hydrolyse des ARN, des métaux et des ligands utilisés pour former les complexes métalliques utiles. L'invention décrit également le clivage sélectionné dirigé par séquences qui est effectué sur des ARN grâce à l'utilisation, comme agents de clivage, de conjugués comprenant deux groupes imidazole ou davantage liés par covalence à des oligodésoxynucléotides et de combinaisons de conjugués comprenant un plusieurs groupes imidazole liés par covalence à deux oligodésoxynucléotides ou davantage. Les parties oligodésoxynucléotides de ces agents sont sélectionnées pour assurer une reconnaissance moléculaire par l'intermédiaire de l'accouplement des bases Watson Crick à la séquence d'ARN cible devant faire l'objet du clivage.
PCT/US1991/003880 1990-06-04 1991-06-03 Hydrolyse/clivage d'arn WO1991019730A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
CA002083048A CA2083048A1 (fr) 1990-06-14 1991-06-03 Hydrolyse/clivage de l'arn
JP51086791A JPH05507619A (ja) 1990-06-04 1991-06-03 Ｒｎａ加水分解／開裂

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US55000190A 1990-06-14 1990-06-14
US550,001 1990-06-14
US60949790A 1990-11-05 1990-11-05
US609,497 1990-11-05

Publications (1)

Publication Number Publication Date
WO1991019730A1 true WO1991019730A1 (fr) 1991-12-26

Family

ID=27069310

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1991/003880 WO1991019730A1 (fr) 1990-06-04 1991-06-03 Hydrolyse/clivage d'arn

Country Status (4)

Country Link
EP (1) EP0533753A1 (fr)
AU (1) AU643542B2 (fr)
CA (1) CA2083048A1 (fr)
WO (1) WO1991019730A1 (fr)

Cited By (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994029316A2 (fr) * 1993-06-09 1994-12-22 Board Of Regents, The University Of Texas System Hydrolyse d'esters realisee par mediation par des complexes metalliques de texaphyrine
EP0646180A1 (fr) * 1992-04-03 1995-04-05 Abbott Laboratories Procedes permettant d'inactiver des sequences de nucleotides et chelates metalliques necessaires pour ces procedes
EP0656790A1 (fr) * 1992-03-05 1995-06-14 Isis Pharmaceuticals, Inc. Compositions et procedes de modulation d'arn
EP0693287A1 (fr) 1994-07-18 1996-01-24 Hoechst Aktiengesellschaft Oligonucléotides liant ou coupant les ARN
US5565552A (en) * 1992-01-21 1996-10-15 Pharmacyclics, Inc. Method of expanded porphyrin-oligonucleotide conjugate synthesis
US5567687A (en) * 1989-03-06 1996-10-22 University Of Texas Texaphyrins and uses thereof
US5580543A (en) * 1992-01-21 1996-12-03 Pharmacyclics, Inc. Method of magnetic resonance image enhancement
US5591422A (en) * 1995-06-02 1997-01-07 Pharmacyclics, Inc. Texaphyrin complexes having improved functionalization
US5594136A (en) * 1989-12-21 1997-01-14 Pharmacyclics, Inc. Texaphyrin solid supports and devices
US5595726A (en) * 1992-01-21 1997-01-21 Pharmacyclics, Inc. Chromophore probe for detection of nucleic acid
US5607924A (en) * 1992-01-21 1997-03-04 Pharmacyclics, Inc. DNA photocleavage using texaphyrins
US5633354A (en) * 1994-09-21 1997-05-27 Pharmacyclics, Inc. Phosphoramidite derivatives of texaphyrins
US5684149A (en) * 1993-01-22 1997-11-04 Research Foundation Of State University Of New York Metal complexes for promoting catalytic cleavage of RNA by transesterification
US5714328A (en) * 1995-06-07 1998-02-03 Board Of Regents, The University Of Texas System RNA photocleavage using texaphyrins
US5763172A (en) * 1992-01-21 1998-06-09 Board Of Regents, The University Of Texas System Method of phosphate ester hydrolysis
US5798491A (en) * 1993-06-09 1998-08-25 Board Of Regents, The University Of Texas System Multi-mechanistic chemical cleavage using certain metal complexes
US5837866A (en) * 1994-09-21 1998-11-17 Board Of Regents, The University Of Texas Phosphoramidite derivatives of macrocycles
US5888997A (en) * 1994-04-14 1999-03-30 Pharmacyclics, Inc. Radiation sensitization using texaphyrins
US5969111A (en) * 1994-04-14 1999-10-19 Board Of Regents, The University Of Texas System Texaphyrins substituted with imidazole are provided
US6022959A (en) * 1996-08-20 2000-02-08 Pharmacyclics, Inc. Nucleic acids internally-derivatized with a texaphyrin metal complex and uses thereof
US6143879A (en) * 1994-01-14 2000-11-07 Regents Of The University Of Minnesota Nucleotide cleaving agents and method
WO2002088289A2 (fr) * 2001-04-30 2002-11-07 Ciba Specialty Chemicals Holding Inc. Utilisation de composes complexes metalliques en tant que catalyseurs d'oxydation
WO2016119017A1 (fr) * 2015-01-30 2016-08-04 The University Of Sydney Composés anti-cancereux
US11040945B2 (en) 2017-12-06 2021-06-22 Lin Bioscience Pty Ltd. Tubulin inhibitors

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4795700A (en) * 1985-01-25 1989-01-03 California Institute Of Technology Nucleic acid probes and methods of using same
US4837312A (en) * 1985-01-25 1989-06-06 California Institute Of Technology Chelator-functionalized nucleosides and nucleotides and methods for making same
WO1989005853A1 (fr) * 1987-12-15 1989-06-29 Synthetic Genetics Conjugue de chelate d'acide nucleique utilise comme agent therapeutique et de diagnostic

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4795700A (en) * 1985-01-25 1989-01-03 California Institute Of Technology Nucleic acid probes and methods of using same
US4837312A (en) * 1985-01-25 1989-06-06 California Institute Of Technology Chelator-functionalized nucleosides and nucleotides and methods for making same
WO1989005853A1 (fr) * 1987-12-15 1989-06-29 Synthetic Genetics Conjugue de chelate d'acide nucleique utilise comme agent therapeutique et de diagnostic

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Journal Americain Chemical Society, vol. 110, no. 19, September 1988, Chi-Hong B. Chen et al.:" Sequence-specific scission of RNA by 1,10-phenanthroline-copper linked to deoxyoligonucleotides" pages 6570-6572, see the whole article *

Cited By (43)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5559207A (en) * 1989-03-06 1996-09-24 Board Of Regents, University Of Texas Texaphyrin metal complex mediated ester hydrolysis
US5567687A (en) * 1989-03-06 1996-10-22 University Of Texas Texaphyrins and uses thereof
US5594136A (en) * 1989-12-21 1997-01-14 Pharmacyclics, Inc. Texaphyrin solid supports and devices
US6069140A (en) * 1992-01-21 2000-05-30 The Board Of Regents University Of Texas System Pharmaceutical compositions comprising texaphyrins
US5607924A (en) * 1992-01-21 1997-03-04 Pharmacyclics, Inc. DNA photocleavage using texaphyrins
US5763172A (en) * 1992-01-21 1998-06-09 Board Of Regents, The University Of Texas System Method of phosphate ester hydrolysis
US5565552A (en) * 1992-01-21 1996-10-15 Pharmacyclics, Inc. Method of expanded porphyrin-oligonucleotide conjugate synthesis
US5632970A (en) * 1992-01-21 1997-05-27 Board Of Regents, The University Of Texas Fluoresence detection using texaphyrins
US5580543A (en) * 1992-01-21 1996-12-03 Pharmacyclics, Inc. Method of magnetic resonance image enhancement
US5595726A (en) * 1992-01-21 1997-01-21 Pharmacyclics, Inc. Chromophore probe for detection of nucleic acid
US5587371A (en) * 1992-01-21 1996-12-24 Pharmacyclics, Inc. Texaphyrin-oligonucleotide conjugates
EP0656790A4 (fr) * 1992-03-05 1997-01-22 Isis Pharmaceuticals Inc Compositions et procedes de modulation d'arn.
EP0656790A1 (fr) * 1992-03-05 1995-06-14 Isis Pharmaceuticals, Inc. Compositions et procedes de modulation d'arn
EP0646180A4 (fr) * 1992-04-03 1998-03-11 Abbott Lab Procedes permettant d'inactiver des sequences de nucleotides et chelates metalliques necessaires pour ces procedes.
EP0646180A1 (fr) * 1992-04-03 1995-04-05 Abbott Laboratories Procedes permettant d'inactiver des sequences de nucleotides et chelates metalliques necessaires pour ces procedes
US5684149A (en) * 1993-01-22 1997-11-04 Research Foundation Of State University Of New York Metal complexes for promoting catalytic cleavage of RNA by transesterification
WO1994029316A2 (fr) * 1993-06-09 1994-12-22 Board Of Regents, The University Of Texas System Hydrolyse d'esters realisee par mediation par des complexes metalliques de texaphyrine
WO1994029316A3 (fr) * 1993-06-09 1995-02-02 Univ Texas Hydrolyse d'esters realisee par mediation par des complexes metalliques de texaphyrine
US5798491A (en) * 1993-06-09 1998-08-25 Board Of Regents, The University Of Texas System Multi-mechanistic chemical cleavage using certain metal complexes
AU694737B2 (en) * 1993-06-09 1998-07-30 Board Of Regents, The University Of Texas System Texaphyrin metal complex mediated ester hydrolysis
US5622946A (en) * 1993-10-12 1997-04-22 Pharmacyclics, Inc. Radiation sensitization using texaphyrins
US5583220A (en) * 1993-10-12 1996-12-10 Pharmacyclics, Inc. Pyrole nitrogen-substituted texaphyrins
US6143879A (en) * 1994-01-14 2000-11-07 Regents Of The University Of Minnesota Nucleotide cleaving agents and method
US5888997A (en) * 1994-04-14 1999-03-30 Pharmacyclics, Inc. Radiation sensitization using texaphyrins
US5969111A (en) * 1994-04-14 1999-10-19 Board Of Regents, The University Of Texas System Texaphyrins substituted with imidazole are provided
EP0693287A1 (fr) 1994-07-18 1996-01-24 Hoechst Aktiengesellschaft Oligonucléotides liant ou coupant les ARN
US5633354A (en) * 1994-09-21 1997-05-27 Pharmacyclics, Inc. Phosphoramidite derivatives of texaphyrins
US5837866A (en) * 1994-09-21 1998-11-17 Board Of Regents, The University Of Texas Phosphoramidite derivatives of macrocycles
US5601802A (en) * 1995-06-02 1997-02-11 Pharmacyclics, Inc. Methods of MRI enhancement using compounds having improved functionalization
US5591422A (en) * 1995-06-02 1997-01-07 Pharmacyclics, Inc. Texaphyrin complexes having improved functionalization
US5714328A (en) * 1995-06-07 1998-02-03 Board Of Regents, The University Of Texas System RNA photocleavage using texaphyrins
US6022959A (en) * 1996-08-20 2000-02-08 Pharmacyclics, Inc. Nucleic acids internally-derivatized with a texaphyrin metal complex and uses thereof
WO2002088289A3 (fr) * 2001-04-30 2003-02-27 Ciba Sc Holding Ag Utilisation de composes complexes metalliques en tant que catalyseurs d'oxydation
US8044013B2 (en) 2001-04-30 2011-10-25 Basf Se Use of metal complex compounds as oxidation catalysts
US7161005B2 (en) 2001-04-30 2007-01-09 Ciba Specialty Chemicals Corporation Use of metal complex compounds as oxidation catalysts
US7456285B2 (en) 2001-04-30 2008-11-25 Ciba Specialty Chemicals Corp. Use of metal complex compounds as oxidation catalysts
US7692004B2 (en) 2001-04-30 2010-04-06 Ciba Specialty Chemicals Corporation Use of metal complex compounds as oxidation catalysts
WO2002088289A2 (fr) * 2001-04-30 2002-11-07 Ciba Specialty Chemicals Holding Inc. Utilisation de composes complexes metalliques en tant que catalyseurs d'oxydation
WO2016119017A1 (fr) * 2015-01-30 2016-08-04 The University Of Sydney Composés anti-cancereux
CN107207437A (zh) * 2015-01-30 2017-09-26 悉尼大学 抗癌化合物
US10745355B2 (en) 2015-01-30 2020-08-18 The University Of Sydney Anti-cancer compounds
AU2020205331B2 (en) * 2015-01-30 2021-03-04 The University Of Sydney Anti-cancer compounds
US11040945B2 (en) 2017-12-06 2021-06-22 Lin Bioscience Pty Ltd. Tubulin inhibitors

Also Published As

Publication number Publication date
EP0533753A1 (fr) 1993-03-31
AU8067991A (en) 1992-01-07
AU643542B2 (en) 1993-11-18
CA2083048A1 (fr) 1991-12-15

Similar Documents

Publication Publication Date Title
AU643542B2 (en) RNA hydrolysis/cleavage
US5591843A (en) 5-modified pyrimidines from palladium catalyzed carbon-carbon coupling
US5013830A (en) Compounds for the cleavage at a specific position of RNA, oligomers employed for the formation of said compounds, and starting materials for the synthesis of said oligomers
EP0135587B2 (fr) Oligonucleotides a brin unique et a sequence definie comprenant des groupes rapporteurs, procede pour effectuer leur synthese chimique, et nucleosides utiles dans une telle synthese
US5668266A (en) Synthesis of single-stranded labelled oligonucleotides of preselected sequence
US5639873A (en) Oligothionucleotides
JPH0631305B2 (ja) ヌクレオシド誘導体
JPH05504563A (ja) リン含有キラルインターサブユニットリンケージを有する非電荷モルホリノ―基体ポリマー
Seela et al. Palindromic oiigonucleotides containing 7-deaza-2'-deoxyguanosine: solid-phase synthesis of d [(p) GG* AATTCC] octamers and recognition by the endodeoxyribonnclease EcoRI
JPH01502187A (ja) α―オリゴヌクレオチド
US5684149A (en) Metal complexes for promoting catalytic cleavage of RNA by transesterification
Stutz et al. Novel fluoride‐labile nucleobase‐protecting groups for the synthesis of 3′(2′)‐O‐aminoacylated RNA sequences
Robles et al. Synthesis of modified oligonucleotides containing 4-guanidino-2-pyrimidinone nucleobases
Kuimelis et al. Synthesis of oligodeoxynucleotides containing 2-thiopyrimidine residues-a new protection scheme
Ng et al. Isoguanosine substitution of conserved adenosines in the hammerhead ribozyme
Sproat et al. Novel solid-phase synthesis of branched oligoribonucleotides, including a substrate for the RNA debranching enzyme
Jurczyk et al. Synthesis and Characterization of Oligonucleotides Containing 2′‐Deoxyxanthosine Using Phosphoramidite Chemistry
Meher et al. Nucleobase Protection of Deoxyribo‐and Ribonucleosides
Fearon et al. An improved synthesis of oligodeoxynucleotide N3′→ P5′ phosphoramidates and their chimera using hindered phosphoramidite monomers and a novel handle for reverse phase purification
US6258941B1 (en) RNA hydrolysis
Ferencic et al. Base‐Pairing Systems Related to TNA Containing Phosphoramidate Linkages: Synthesis of Building Blocks and Pairing Properties
Xu et al. Oligodeoxynucleotides containing O2-alkylthymine: synthesis and characterization
Ivanov et al. Chemical synthesis of an artificially branched hairpin ribozyme variant with RNA cleavage activity
Gaubert et al. Synthesis and RNA-selective hybridization of α-l-ribo-and β-d-lyxo-configured oligonucleotides
JPH05507619A (ja) Ｒｎａ加水分解／開裂

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AU CA JP SU

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IT LU NL SE

WWE Wipo information: entry into national phase

Ref document number: 2083048

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: 1991910937

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: 1991910937

Country of ref document: EP

WWW Wipo information: withdrawn in national office

Ref document number: 1991910937

Country of ref document: EP