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WO1996030383A1 - Polyamides de polyester d'acide nucleique - Google Patents

Polyamides de polyester d'acide nucleique Download PDF

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Publication number
WO1996030383A1
WO1996030383A1 PCT/AT1996/000056 AT9600056W WO9630383A1 WO 1996030383 A1 WO1996030383 A1 WO 1996030383A1 AT 9600056 W AT9600056 W AT 9600056W WO 9630383 A1 WO9630383 A1 WO 9630383A1
Authority
WO
WIPO (PCT)
Prior art keywords
nucleotide
carboxylic acid
formula
chlorine
hydroxyl
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/AT1996/000056
Other languages
German (de)
English (en)
Inventor
Christian Noe
Georg Haberhauer
Lucius Kaufhold
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Individual
Original Assignee
Individual
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 Individual filed Critical Individual
Priority to AU49311/96A priority Critical patent/AU4931196A/en
Publication of WO1996030383A1 publication Critical patent/WO1996030383A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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

Definitions

  • Natural nucleic acids have a 3 '-5' linkage, which is the basis for the formation of the double helix and thus for the biological function of nucleic acids. Such nucleic acids are easily cleaved by hydrolysis of the phosphoric ester bond. When using nucleotides for molecular biological, diagnostic and therapeutic purposes, the production of nuclease-resistant compounds is therefore always an important goal.
  • oligonucleotide analogs which are not linked by 3 '-5'- but 2' -5-'- are also able to pair with natural RNA or DNA, especially if the The number of atoms between the two sugar rings of the nucleosides is 3, but special attention is paid to the type of linking elements. Too great flexibility of such a link between two nucleoside units can lead to a severe restriction or even to the loss of the binding ability. On the other hand, rigidization that is too rigid or too sterically demanding can have the same negative effect.
  • the present invention relates to nucleotide carboxylic acid esters and amides of the general formula I
  • R 5 is a hydrogen, chlorine or bromine atom, a hydroxyl, amino, monomethoxytritylamino, mercapto, methylamino, dimethylamino, phenylamino or hydroxylamino group
  • R 9 hydrogen, fluorine, chlorine, or bromine or iodine atom, a methyl, trifluoro, ethyl, ethyl or hydroxymethyl group, and the salts of compounds of general form I with acids or bases.
  • the invention includes Nukleotidoligoester and -oligoamide with the above St ⁇ * ⁇ jJ structure with a number of from 2 to 200 nucleotide units.
  • oligonucleotide analogs of the subject invention can be prepared from the suitably protected monomers by conventional condensation processes after the carboxylic acid has been activated beforehand.
  • Binding experiments with natural nucleic acids show that oligonucleotides of the present invention are suitable for pairing with natural nucleic acids.
  • Molecular dynamics Studies show that esters and amide bonds are superior to other bridging compounds.
  • the invention includes the use of such nucleotide oligoesters and oligoamides as therapeutic agents, for diagnostic purposes and as research reagents.
  • the best way to investigate the binding behavior of a short Watson-Crick complementary strand is with the additional cooperative "support" of a third polymer strand that forms the pair of Hoogsteen.
  • the artificial dinucleotide 4 was thus examined under salt and buffer conditions that allow triplex formation.
  • the transformation temperature of the 2Poly-U / artificial dinucleotide system was 15 ° C. It could thus be shown that such 2'-5 'ester-linked artificial nucleotides recognize natural 3'-5'-phosphate-linked oligonucleotides and can interact with them.
  • ester modification showed the highest affinity for the complementary RNA strand. More flexible linking systems such as ether modification did not show a high affinity for the counterpart, but the hybrid double strand dissolved after a short time and the strands became entangled.

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

Abstract

L'invention concerne de nouveaux oligonucléides de structure modifiée, leur procédé de production et leur utilisation. Ces analogues d'oligonucléides se caractérisent par une liaison 2'-5' et non par la liaison 3'-5' des oligonucléotides naturels. Le nombre d'atomes entre les deux noyaux sucre est de 3 et la liaison est constituée d'un ester d'acide carboxylique ou d'un amide d'acide carboxylique. Ces oligonucléotides modifiés peuvent entrer en interaction avec de l'acide nucléique naturel. Le s oligomères décrits peuvent être utilisés comme médicaments potentiels.
PCT/AT1996/000056 1995-03-24 1996-03-25 Polyamides de polyester d'acide nucleique Ceased WO1996030383A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU49311/96A AU4931196A (en) 1995-03-24 1996-03-25 Nucleic acid polyester polyamides

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ATA538/95 1995-03-24
AT53895 1995-03-24

Publications (1)

Publication Number Publication Date
WO1996030383A1 true WO1996030383A1 (fr) 1996-10-03

Family

ID=3493275

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/AT1996/000056 Ceased WO1996030383A1 (fr) 1995-03-24 1996-03-25 Polyamides de polyester d'acide nucleique

Country Status (2)

Country Link
AU (1) AU4931196A (fr)
WO (1) WO1996030383A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8871737B2 (en) 2010-09-22 2014-10-28 Alios Biopharma, Inc. Substituted nucleotide analogs
US8916538B2 (en) 2012-03-21 2014-12-23 Vertex Pharmaceuticals Incorporated Solid forms of a thiophosphoramidate nucleotide prodrug
US8980865B2 (en) 2011-12-22 2015-03-17 Alios Biopharma, Inc. Substituted nucleotide analogs
US9012427B2 (en) 2012-03-22 2015-04-21 Alios Biopharma, Inc. Pharmaceutical combinations comprising a thionucleotide analog

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993024508A1 (fr) * 1992-06-01 1993-12-09 Gilead Sciences, Inc. Oligomeres aptes a la fixation contenant des liaisons 2', 5'
WO1994022891A1 (fr) * 1993-03-31 1994-10-13 Sterling Winthrop Inc. Oligonucleotides a liaisons d'amides remplacant les liaisons de phosphodiesters

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993024508A1 (fr) * 1992-06-01 1993-12-09 Gilead Sciences, Inc. Oligomeres aptes a la fixation contenant des liaisons 2', 5'
WO1994022891A1 (fr) * 1993-03-31 1994-10-13 Sterling Winthrop Inc. Oligonucleotides a liaisons d'amides remplacant les liaisons de phosphodiesters

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
A.D. MESMAEKER ET AL.: "Synthetic Modifications of Antisense Oligonucleotides: Novel Backbone Replacements with Improved Properties", BULL. SOC. CHIM. BELG., vol. 103, 1994, pages 705 - 17, XP002008196 *
C.R. NOE ET AL.: "Novel Three-Atom 2'-5' Linkages in Antisense Nucleotides: Synthesis and Pairing Properties of Dinucleotides with a Carboxylic Ester Linkage", ARCH. PHARM., vol. 328, 1995, pages 743 - 4, XP002008198 *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8871737B2 (en) 2010-09-22 2014-10-28 Alios Biopharma, Inc. Substituted nucleotide analogs
US9278990B2 (en) 2010-09-22 2016-03-08 Alios Biopharma, Inc. Substituted nucleotide analogs
US8980865B2 (en) 2011-12-22 2015-03-17 Alios Biopharma, Inc. Substituted nucleotide analogs
US9605018B2 (en) 2011-12-22 2017-03-28 Alios Biopharma, Inc. Substituted nucleotide analogs
US8916538B2 (en) 2012-03-21 2014-12-23 Vertex Pharmaceuticals Incorporated Solid forms of a thiophosphoramidate nucleotide prodrug
US9394330B2 (en) 2012-03-21 2016-07-19 Alios Biopharma, Inc. Solid forms of a thiophosphoramidate nucleotide prodrug
US9856284B2 (en) 2012-03-21 2018-01-02 Alios Biopharma, Inc. Solid forms of a thiophosphoramidate nucleotide prodrug
US9012427B2 (en) 2012-03-22 2015-04-21 Alios Biopharma, Inc. Pharmaceutical combinations comprising a thionucleotide analog

Also Published As

Publication number Publication date
AU4931196A (en) 1996-10-16

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