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

被引:12
作者
THADEN, J [1 ]
MILLER, PS [1 ]
机构
[1] JOHNS HOPKINS UNIV,SCH HYG & PUBL HLTH,DEPT BIOCHEM,615 N WOLFE ST,BALTIMORE,MD 21205
关键词
D O I
10.1021/bc00023a015
中图分类号
Q5 [生物化学];
学科分类号
071010 ; 081704 ;
摘要
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-aminoprop-1-yl)-N-(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'-(beta-cyanoethyl N,N-diisopropylphosphoramidite) synthon, then, upon completion of methylphosphonate oligomer synthesis and deprotection, the 3'-[N-(3-aminoprop-1-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].
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页码:395 / 401
页数:7
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