Formation of 4,4′-dimethoxytrityl-C-phosphonate oligonucleotides

被引：29

作者：

Capaldi, DC ^{[1
]}

Gaus, HJ ^{[1
]}

Carty, RL ^{[1
]}

Moore, MN ^{[1
]}

Turney, BJ ^{[1
]}

Decottignies, SD ^{[1
]}

McArdle, JV ^{[1
]}

Scozzari, AN ^{[1
]}

Ravikumar, VT ^{[1
]}

Krotz, AH ^{[1
]}

机构：

[1] ISIS Pharmaceut, Carlsbad, CA 92008 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2004年 / 14卷 / 18期

关键词：

D O I：

10.1016/j.bmcl.2004.06.088

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Incomplete sulfurization during solid-phase synthesis of phosphorothioate oligonucleotides using phosphoramidite chemistry was identified as the cause of formation of two new classes of process-related oligonucleotide impurities containing a DMTr-C-phosphonate (DMTr = 4,4'-dimethoxytrityl) moiety. Phosphite triester intermediates that failed to oxidize (sulfurize) to the corresponding phosphorothioate triester react during the subsequent acid-induced (dichloroacetic acid) detritylation with the DMTr cation or its equivalent in an Arbuzov-type reaction. This leads to formation of DMTr-C-phosphonate mono- and diesters resulting in oligonucleotides modified with a DMTr-C-phosphonate moiety located internally or at the 5' terminal hydroxy group. DMTr-C-phosphonate derivatives are not detected when optimized sulfurization conditions are employed. (C) 2004 Elsevier Ltd. All rights reserved.

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页码：4683 / 4690

页数：8

相关论文

共 33 条

[1] Efforts toward synthesis of oligonucleotides for commercialization [J].

Andrade, M ;

Scozzari, AS ;

Cole, DL ;

Ravikumar, VT .

NUCLEOSIDES & NUCLEOTIDES, 1997, 16 (7-9) :1617-1620

[2] Rhenium catalyzed sulfurization of phosphorus(III) compounds with thiiranes: New reagents for phosphorothioate ester synthesis [J].

Arterburn, JB ;

Perry, MC .

TETRAHEDRON LETTERS, 1997, 38 (44) :7701-7704

[3] Is it essential to use anhydrous acetonitrile in the manufacture of phosphorothioate oligonucleotides? [J].

Capaldi, DC ;

Scozzari, AN ;

Cole, DL ;

Ravikumar, VT .

ORGANIC PROCESS RESEARCH & DEVELOPMENT, 1999, 3 (06) :485-487

[4] Synthesis of high-quality antisense drugs. Addition of acrylonitrile to phosphorothioate oligonucleotides: Adduct characterization and avoidance [J].

Capaldi, DC ;

Gans, H ;

Krotz, AH ;

Arnold, J ;

Carty, RL ;

Moore, MN ;

Scozzari, AN ;

Lowery, K ;

Cole, DL ;

Ravikumar, VT .

ORGANIC PROCESS RESEARCH & DEVELOPMENT, 2003, 7 (06) :832-838

[5] Synthesis of antisense oligonucleotides: Replacement of 3H-1,2-benzodithiol-3-one 1,1-dioxide (Beaucage reagent) with phenylacetyl disulfide (PADS) as efficient sulfurization reagent: From bench to bulk manufacture of active pharmaceutical ingredient [J].

Cheruvallath, ZS ;

Carty, RL ;

Moore, MN ;

Capaldi, DC ;

Krotz, AH ;

Wheeler, PD ;

Turney, BJ ;

Craig, SR ;

Gaus, HJ ;

Scozzari, AN ;

Cole, DL ;

Ravikumar, VT .

ORGANIC PROCESS RESEARCH & DEVELOPMENT, 2000, 4 (03) :199-204

[6] Solid phase synthesis of phosphorothioate oligonucleotides utilizing diethyldithiocarbonate disulfide (DDD) as an efficient sulfur transfer reagent [J].

Cheruvallath, ZS ;

Kumar, RK ;

Rentel, C ;

Cole, DL ;

Ravikumar, VT .

NUCLEOSIDES NUCLEOTIDES & NUCLEIC ACIDS, 2003, 22 (04) :461-468

[7]

Crooke ST, 2000, METHOD ENZYMOL, V313, P3

[8] Molecular mechanisms of action of antisense drugs [J].

Crooke, ST .

BIOCHIMICA ET BIOPHYSICA ACTA-GENE STRUCTURE AND EXPRESSION, 1999, 1489 (01) :31-44

[9]

CROOKE ST, 2001, BASIC PRINCIPLES ANT

[10] NEW EFFICIENT SULFURIZING REAGENTS FOR THE PREPARATION OF OLIGODEOXYRIBONUCLEOTIDE PHOSPHOROTHIOATE ANALOGS [J].

EFIMOV, VA ;

KALINKINA, AL ;

CHAKHMAKHCHEVA, OG ;

HILL, TS ;

JAYARAMAN, K .

NUCLEIC ACIDS RESEARCH, 1995, 23 (20) :4029-4033

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