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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
8
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pubmed:dateCreated |
1991-6-19
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pubmed:abstractText |
Because of their nuclease resistance and ability to form substrates for RNase H, antisense oligodeoxynucleotides (ODNs) possessing several methoxyethylphosphoramidate linkages at both termini have proven effective at targeting the degradation of specific mRNAs in Xenopus embryos. The efficacy of these compounds subsequently observed in tissue culture focused our attention on the issue of cellular uptake. To investigate the extent to which phosphate backbone modifications may increase the lipophilicity of ODNs, and thereby increase passive uptake by cells, the partitioning of a series of phosphoramidate-modified compounds between aqueous and organic phases was examined. The octanol:water partition coefficient of an unmodified, mixed-sequence 16-mer was 1.75 x 10(-5). The log of the partition coefficient increased in a sigmoidal manner with the number of methoxyethylphosphoramidate internucleoside linkages, indicating a nonlinear free energy relationship. The highest level of partitioning demonstrated was approximately 4 x 10(-3) (a 230-fold increase), attained when 11 of the 15 phosphodiesters were modified. An increase in hydrophobicity was also attained with C8 and C10 alkylamines acting as phase-transfer agents. The melting temperatures of heteroduplexes formed between a phosphoramidate-modified ODN and a complementary unmodified DNA strand decreased by approximately 1.5 degrees C for every phosphate group modification. ODNs can thus be extensively derivatized without substantially compromising duplex formation under physiological conditions.
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pubmed:commentsCorrections |
http://linkedlifedata.com/resource/pubmed/commentcorrection/2030962-15421994,
http://linkedlifedata.com/resource/pubmed/commentcorrection/2030962-1668307,
http://linkedlifedata.com/resource/pubmed/commentcorrection/2030962-1692405,
http://linkedlifedata.com/resource/pubmed/commentcorrection/2030962-1697675,
http://linkedlifedata.com/resource/pubmed/commentcorrection/2030962-2154746,
http://linkedlifedata.com/resource/pubmed/commentcorrection/2030962-2447563,
http://linkedlifedata.com/resource/pubmed/commentcorrection/2030962-2549537,
http://linkedlifedata.com/resource/pubmed/commentcorrection/2030962-2726730,
http://linkedlifedata.com/resource/pubmed/commentcorrection/2030962-2836793,
http://linkedlifedata.com/resource/pubmed/commentcorrection/2030962-3277186,
http://linkedlifedata.com/resource/pubmed/commentcorrection/2030962-3280975,
http://linkedlifedata.com/resource/pubmed/commentcorrection/2030962-3387210,
http://linkedlifedata.com/resource/pubmed/commentcorrection/2030962-3772027,
http://linkedlifedata.com/resource/pubmed/commentcorrection/2030962-4084511,
http://linkedlifedata.com/resource/pubmed/commentcorrection/2030962-4215448,
http://linkedlifedata.com/resource/pubmed/commentcorrection/2030962-5030896,
http://linkedlifedata.com/resource/pubmed/commentcorrection/2030962-7013804
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
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pubmed:status |
MEDLINE
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pubmed:month |
Apr
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pubmed:issn |
0305-1048
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:day |
25
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pubmed:volume |
19
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
1805-10
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pubmed:dateRevised |
2009-11-18
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pubmed:meshHeading |
pubmed-meshheading:2030962-Amides,
pubmed-meshheading:2030962-Amines,
pubmed-meshheading:2030962-Animals,
pubmed-meshheading:2030962-Base Sequence,
pubmed-meshheading:2030962-Chromatography, High Pressure Liquid,
pubmed-meshheading:2030962-Electrophoresis, Polyacrylamide Gel,
pubmed-meshheading:2030962-Lipids,
pubmed-meshheading:2030962-Molecular Sequence Data,
pubmed-meshheading:2030962-Nucleic Acid Heteroduplexes,
pubmed-meshheading:2030962-Oligodeoxyribonucleotides,
pubmed-meshheading:2030962-Oligonucleotides, Antisense,
pubmed-meshheading:2030962-Phosphoric Acids,
pubmed-meshheading:2030962-Solubility,
pubmed-meshheading:2030962-Temperature,
pubmed-meshheading:2030962-Thermodynamics,
pubmed-meshheading:2030962-Xenopus
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pubmed:year |
1991
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pubmed:articleTitle |
Physical properties of oligonucleotides containing phosphoramidate-modified internucleoside linkages.
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pubmed:affiliation |
Department of Biochemistry, University of Iowa, Iowa City 52242.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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