Automated Synthesis of Oligodeoxyribonucleoside Methylphosphonates Having [N-(3-Aminoprop-1-yl) -N-(2-hydroxyethyl) -2-aminoethyl] Phosphate or Methylphosphonic Acid at the 3′ End Using a Modified Controlled Pore Glass Support

John Thaden, Paul S. Miller

Research output: Contribution to journalArticlepeer-review

Abstract

To provide a solid support for automated synthesis of 3′-(aminoalkyl)-modified oligonucleoside methylphosphonates, controlled pore glass beads were functionalized with a protected N-(3-aminopropl-yl)-AT-(2-hydroxyethyl)-2-aminoethyl ester of succinic acid. This “Aha-CPG” was used for automated synthesis of oligo-2′-deoxyribonucleoside methylphosphonates having either of two distinct 3′ terminal modifications. If the first coupling to the beads was of a base-protected 5′-(dimethoxytrityl)-2′-deoxyribonucleoside 3′-(β-cyanoethyl M-N-diisopropylphosphoramidite) synthon, then, upon completion of methylphosphonate oligomer synthesis and deprotection, the 3′-[N-(3-aminoprop-l-yl)-N-(2-hydroxyethyl)-2-aminoethyl] phosphate] derivative of an oligonucleoside methylphosphonate was produced and was shown to be a stable structure which affords a primary alkylamine group suitable as a site for further conjugations. If the first coupling was of a 5′-(dimethoxytrityl)-2′-deoxyribonucleoside 3′-(N,N-diisopropylmethylphosphonamidite) synthon, the initial product of synthesis and deprotection underwent a spontaneous, regiospecific ester cleavage in aqueous solution to produce an oligonucleoside methylphosphonate 3′-(methylphosphonate). An application of the Aha-CPG to the synthesis of rhodamine-conjugated oligonucleoside methylphosphonates is described in a companion paper [Thaden, J. and Miller, P. S. (1993) Bioconjugate Chem, preceding paper in this issue].

Original languageEnglish (US)
Pages (from-to)395-401
Number of pages7
JournalBioconjugate Chemistry
Volume4
Issue number5
DOIs
StatePublished - Sep 1 1993

ASJC Scopus subject areas

  • Biotechnology
  • Bioengineering
  • Biomedical Engineering
  • Pharmacology
  • Pharmaceutical Science
  • Organic Chemistry

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