Solid-phase synthesis, thermal denaturation studies, nuclease resistance, and cellular uptake of (oligodeoxyribonucleoside)methylborane phosphine-DNA chimeras.
Identifieur interne : 002432 ( Main/Exploration ); précédent : 002431; suivant : 002433Solid-phase synthesis, thermal denaturation studies, nuclease resistance, and cellular uptake of (oligodeoxyribonucleoside)methylborane phosphine-DNA chimeras.
Auteurs : Heera Krishna [États-Unis] ; Marvin H. CaruthersSource :
- Journal of the American Chemical Society [ 1520-5126 ] ; 2011.
Descripteurs français
- KwdFr :
- ADN (), Boranes (), Humains, Hybridation d'acides nucléiques, Lignée cellulaire, Oligodésoxyribonucléotides (pharmacocinétique), Oligodésoxyribonucléotides (synthèse chimique), Oligodésoxyribonucléotides (usage thérapeutique), Perméabilité de la membrane cellulaire, Phosphines (), Relation structure-activité, Techniques de chimie combinatoire.
- MESH :
- pharmacocinétique : Oligodésoxyribonucléotides.
- synthèse chimique : Oligodésoxyribonucléotides.
- usage thérapeutique : Oligodésoxyribonucléotides.
- ADN, Boranes, Humains, Hybridation d'acides nucléiques, Lignée cellulaire, Perméabilité de la membrane cellulaire, Phosphines, Relation structure-activité, Techniques de chimie combinatoire.
English descriptors
- KwdEn :
- Boranes (chemistry), Cell Line, Cell Membrane Permeability, Combinatorial Chemistry Techniques, DNA (chemistry), Humans, Nucleic Acid Hybridization, Oligodeoxyribonucleotides (chemical synthesis), Oligodeoxyribonucleotides (pharmacokinetics), Oligodeoxyribonucleotides (therapeutic use), Phosphines (chemistry), Structure-Activity Relationship.
- MESH :
- chemical , chemical synthesis : Oligodeoxyribonucleotides.
- chemical , chemistry : Boranes, DNA, Phosphines.
- chemical , pharmacokinetics : Oligodeoxyribonucleotides.
- chemical , therapeutic use : Oligodeoxyribonucleotides.
- Cell Line, Cell Membrane Permeability, Combinatorial Chemistry Techniques, Humans, Nucleic Acid Hybridization, Structure-Activity Relationship.
Abstract
The major hurdle associated with utilizing oligodeoxyribonucleotides for therapeutic purposes is their poor delivery into cells coupled with high nuclease susceptibility. In an attempt to combine the nonionic nature and high nuclease stability of the P-C bond of methylphosphonates with the high membrane permeability, low toxicity, and improved gene silencing ability of borane phosphonates, we have focused our research on the relatively unexplored methylborane phosphine (Me-P-BH(3)) modification. This Article describes the automated solid-phase synthesis of mixed-backbone oligodeoxynucleotides (ODNs) consisting of methylborane phosphine and phosphate or thiophosphate linkages (16-mers). Nuclease stability assays show that methylborane phosphine ODNs are highly resistant to 5' and 3' exonucleases. When hybridized to a complementary strand, the ODN:RNA duplex was more stable than its corresponding ODN:DNA duplex. The binding affinity of ODN:RNA duplex increased at lower salt concentration and approached that of a native DNA:RNA duplex under conditions close to physiological saline, indicating that the Me-P-BH(3) linkage is positively charged. Cellular uptake measurements indicate that these ODNs are efficiently taken up by cells even when the strand is 13% modified. Treatment of HeLa cells and WM-239A cells with fluorescently labeled ODNs shows significant cytoplasmic fluorescence when viewed under a microscope. Our results suggest that methylborane phosphine ODNs may prove very valuable as potential candidates in antisense research and RNAi.
DOI: 10.1021/ja201314q
PubMed: 21585202
Affiliations:
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Caruthers</name></author></analytic><series><title level="j">Journal of the American Chemical Society</title><idno type="eISSN">1520-5126</idno><imprint><date when="2011" type="published">2011</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Boranes (chemistry)</term><term>Cell Line</term><term>Cell Membrane Permeability</term><term>Combinatorial Chemistry Techniques</term><term>DNA (chemistry)</term><term>Humans</term><term>Nucleic Acid Hybridization</term><term>Oligodeoxyribonucleotides (chemical synthesis)</term><term>Oligodeoxyribonucleotides (pharmacokinetics)</term><term>Oligodeoxyribonucleotides (therapeutic use)</term><term>Phosphines (chemistry)</term><term>Structure-Activity Relationship</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>ADN ()</term><term>Boranes ()</term><term>Humains</term><term>Hybridation d'acides nucléiques</term><term>Lignée cellulaire</term><term>Oligodésoxyribonucléotides (pharmacocinétique)</term><term>Oligodésoxyribonucléotides (synthèse chimique)</term><term>Oligodésoxyribonucléotides (usage thérapeutique)</term><term>Perméabilité de la membrane cellulaire</term><term>Phosphines ()</term><term>Relation structure-activité</term><term>Techniques de chimie combinatoire</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemical synthesis" xml:lang="en"><term>Oligodeoxyribonucleotides</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Boranes</term><term>DNA</term><term>Phosphines</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacokinetics" xml:lang="en"><term>Oligodeoxyribonucleotides</term></keywords><keywords scheme="MESH" type="chemical" qualifier="therapeutic use" xml:lang="en"><term>Oligodeoxyribonucleotides</term></keywords><keywords scheme="MESH" qualifier="pharmacocinétique" xml:lang="fr"><term>Oligodésoxyribonucléotides</term></keywords><keywords scheme="MESH" qualifier="synthèse chimique" xml:lang="fr"><term>Oligodésoxyribonucléotides</term></keywords><keywords scheme="MESH" qualifier="usage thérapeutique" xml:lang="fr"><term>Oligodésoxyribonucléotides</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Cell Line</term><term>Cell Membrane Permeability</term><term>Combinatorial Chemistry Techniques</term><term>Humans</term><term>Nucleic Acid Hybridization</term><term>Structure-Activity Relationship</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>ADN</term><term>Boranes</term><term>Humains</term><term>Hybridation d'acides nucléiques</term><term>Lignée cellulaire</term><term>Perméabilité de la membrane cellulaire</term><term>Phosphines</term><term>Relation structure-activité</term><term>Techniques de chimie combinatoire</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">The major hurdle associated with utilizing oligodeoxyribonucleotides for therapeutic purposes is their poor delivery into cells coupled with high nuclease susceptibility. In an attempt to combine the nonionic nature and high nuclease stability of the P-C bond of methylphosphonates with the high membrane permeability, low toxicity, and improved gene silencing ability of borane phosphonates, we have focused our research on the relatively unexplored methylborane phosphine (Me-P-BH(3)) modification. This Article describes the automated solid-phase synthesis of mixed-backbone oligodeoxynucleotides (ODNs) consisting of methylborane phosphine and phosphate or thiophosphate linkages (16-mers). Nuclease stability assays show that methylborane phosphine ODNs are highly resistant to 5' and 3' exonucleases. When hybridized to a complementary strand, the ODN:RNA duplex was more stable than its corresponding ODN:DNA duplex. The binding affinity of ODN:RNA duplex increased at lower salt concentration and approached that of a native DNA:RNA duplex under conditions close to physiological saline, indicating that the Me-P-BH(3) linkage is positively charged. Cellular uptake measurements indicate that these ODNs are efficiently taken up by cells even when the strand is 13% modified. Treatment of HeLa cells and WM-239A cells with fluorescently labeled ODNs shows significant cytoplasmic fluorescence when viewed under a microscope. Our results suggest that methylborane phosphine ODNs may prove very valuable as potential candidates in antisense research and RNAi.</div></front></TEI><affiliations><list><country><li>États-Unis</li></country></list><tree><noCountry><name sortKey="Caruthers, Marvin H" sort="Caruthers, Marvin H" uniqKey="Caruthers M" first="Marvin H" last="Caruthers">Marvin H. Caruthers</name></noCountry><country name="États-Unis"><noRegion><name sortKey="Krishna, Heera" sort="Krishna, Heera" uniqKey="Krishna H" first="Heera" last="Krishna">Heera Krishna</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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