Synthesis of 2'-aminoalkyl-substituted fluorinated nucleobases and their influence on the kinetic properties of hammerhead ribozymes.
Identifieur interne : 000278 ( Ncbi/Checkpoint ); précédent : 000277; suivant : 000279Synthesis of 2'-aminoalkyl-substituted fluorinated nucleobases and their influence on the kinetic properties of hammerhead ribozymes.
Auteurs : Astrid E. Klöpffer [Allemagne] ; Joachim W. EngelsSource :
- Chembiochem : a European journal of chemical biology [ 1439-4227 ] ; 2004.
Descripteurs français
- KwdFr :
- ARN catalytique (), ARN catalytique (métabolisme), Catalyse, Cinétique, Conformation d'acide nucléique, Données de séquences moléculaires, Fluor (), Ribonucléosides (), Ribonucléosides (métabolisme), Ribonucléosides (synthèse chimique), Spécificité du substrat, Séquence nucléotidique, Thermodynamique.
- MESH :
- métabolisme : ARN catalytique, Ribonucléosides.
- synthèse chimique : Ribonucléosides.
- ARN catalytique, Catalyse, Cinétique, Conformation d'acide nucléique, Données de séquences moléculaires, Fluor, Ribonucléosides, Spécificité du substrat, Séquence nucléotidique, Thermodynamique.
English descriptors
- KwdEn :
- Base Sequence, Catalysis, Fluorine (chemistry), Kinetics, Molecular Sequence Data, Nucleic Acid Conformation, RNA, Catalytic (chemistry), RNA, Catalytic (metabolism), Ribonucleosides (chemical synthesis), Ribonucleosides (chemistry), Ribonucleosides (metabolism), Substrate Specificity, Thermodynamics.
- MESH :
- chemical , chemical synthesis : Ribonucleosides.
- chemical , chemistry : Fluorine, RNA, Catalytic, Ribonucleosides.
- chemical , metabolism : RNA, Catalytic, Ribonucleosides.
- Base Sequence, Catalysis, Kinetics, Molecular Sequence Data, Nucleic Acid Conformation, Substrate Specificity, Thermodynamics.
Abstract
Hammerhead ribozymes are ribonucleic acids that catalyse the hydrolytic cleavage of RNA. They interfere with gene expression in a highly specific manner and recognize the mRNA target through Watson-Crick base pairing. To overcome the problem of point mutations (Watson-Crick "mismatches") occurring in viral genomes, we developed 2'-aminoethyl-substituted fluorinated nucleosides, which are universal nucleobases. The highly efficient synthetic pathway, which features a direct phthaloylamination of a primary alcohol under Mitsunobu conditions, leads to modified phosphoroamidites. The 1'-deoxy-1'-(4,6-difluoro-1H-benzimidazol-1-yl)-2'-(beta-aminoethyl)-beta-D-ribofuranose nucleoside analogue does not differentiate between the four natural nucleosides and leads to a RNA duplex that is as stable as the unmodified parent duplex. Upon incorporation into a ribozyme, the analogue's catalytic activity is equal for all four possible substrates, and the cleavage rates for the modified ribozymes are significantly higher (up to a factor of 13) than for the natural Watson-Crick "mismatch" base pairs. In agreement with the thermodynamic data obtained by measurement of the T(m) values of the RNA 12-mers, the cleavage rates for the 2'-substituted fluorinated benzimidazole derivative 4 are slightly higher than for the corresponding fluorinated benzene derivative 3.
DOI: 10.1002/cbic.200300809
PubMed: 15122643
Affiliations:
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Klöpffer</name><affiliation wicri:level="3"><nlm:affiliation>Institute for Organic Chemistry and Chemical Biology, Johann Wolfgang Goethe University, Marie Curie Strasse 11, 60439 Frankfurt/Main, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute for Organic Chemistry and Chemical Biology, Johann Wolfgang Goethe University, Marie Curie Strasse 11, 60439 Frankfurt/Main</wicri:regionArea><placeName><region type="land" nuts="1">Hesse (Land)</region><region type="district" nuts="2">District de Darmstadt</region><settlement type="city">Francfort-sur-le-Main</settlement></placeName></affiliation></author><author><name sortKey="Engels, Joachim W" sort="Engels, Joachim W" uniqKey="Engels J" first="Joachim W" last="Engels">Joachim W. 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Klöpffer</name><affiliation wicri:level="3"><nlm:affiliation>Institute for Organic Chemistry and Chemical Biology, Johann Wolfgang Goethe University, Marie Curie Strasse 11, 60439 Frankfurt/Main, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute for Organic Chemistry and Chemical Biology, Johann Wolfgang Goethe University, Marie Curie Strasse 11, 60439 Frankfurt/Main</wicri:regionArea><placeName><region type="land" nuts="1">Hesse (Land)</region><region type="district" nuts="2">District de Darmstadt</region><settlement type="city">Francfort-sur-le-Main</settlement></placeName></affiliation></author><author><name sortKey="Engels, Joachim W" sort="Engels, Joachim W" uniqKey="Engels J" first="Joachim W" last="Engels">Joachim W. Engels</name></author></analytic><series><title level="j">Chembiochem : a European journal of chemical biology</title><idno type="ISSN">1439-4227</idno><imprint><date when="2004" type="published">2004</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Base Sequence</term><term>Catalysis</term><term>Fluorine (chemistry)</term><term>Kinetics</term><term>Molecular Sequence Data</term><term>Nucleic Acid Conformation</term><term>RNA, Catalytic (chemistry)</term><term>RNA, Catalytic (metabolism)</term><term>Ribonucleosides (chemical synthesis)</term><term>Ribonucleosides (chemistry)</term><term>Ribonucleosides (metabolism)</term><term>Substrate Specificity</term><term>Thermodynamics</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>ARN catalytique ()</term><term>ARN catalytique (métabolisme)</term><term>Catalyse</term><term>Cinétique</term><term>Conformation d'acide nucléique</term><term>Données de séquences moléculaires</term><term>Fluor ()</term><term>Ribonucléosides ()</term><term>Ribonucléosides (métabolisme)</term><term>Ribonucléosides (synthèse chimique)</term><term>Spécificité du substrat</term><term>Séquence nucléotidique</term><term>Thermodynamique</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemical synthesis" xml:lang="en"><term>Ribonucleosides</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Fluorine</term><term>RNA, Catalytic</term><term>Ribonucleosides</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>RNA, Catalytic</term><term>Ribonucleosides</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>ARN catalytique</term><term>Ribonucléosides</term></keywords><keywords scheme="MESH" qualifier="synthèse chimique" xml:lang="fr"><term>Ribonucléosides</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Base Sequence</term><term>Catalysis</term><term>Kinetics</term><term>Molecular Sequence Data</term><term>Nucleic Acid Conformation</term><term>Substrate Specificity</term><term>Thermodynamics</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>ARN catalytique</term><term>Catalyse</term><term>Cinétique</term><term>Conformation d'acide nucléique</term><term>Données de séquences moléculaires</term><term>Fluor</term><term>Ribonucléosides</term><term>Spécificité du substrat</term><term>Séquence nucléotidique</term><term>Thermodynamique</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Hammerhead ribozymes are ribonucleic acids that catalyse the hydrolytic cleavage of RNA. They interfere with gene expression in a highly specific manner and recognize the mRNA target through Watson-Crick base pairing. To overcome the problem of point mutations (Watson-Crick "mismatches") occurring in viral genomes, we developed 2'-aminoethyl-substituted fluorinated nucleosides, which are universal nucleobases. The highly efficient synthetic pathway, which features a direct phthaloylamination of a primary alcohol under Mitsunobu conditions, leads to modified phosphoroamidites. The 1'-deoxy-1'-(4,6-difluoro-1H-benzimidazol-1-yl)-2'-(beta-aminoethyl)-beta-D-ribofuranose nucleoside analogue does not differentiate between the four natural nucleosides and leads to a RNA duplex that is as stable as the unmodified parent duplex. Upon incorporation into a ribozyme, the analogue's catalytic activity is equal for all four possible substrates, and the cleavage rates for the modified ribozymes are significantly higher (up to a factor of 13) than for the natural Watson-Crick "mismatch" base pairs. In agreement with the thermodynamic data obtained by measurement of the T(m) values of the RNA 12-mers, the cleavage rates for the 2'-substituted fluorinated benzimidazole derivative 4 are slightly higher than for the corresponding fluorinated benzene derivative 3.</div></front></TEI><affiliations><list><country><li>Allemagne</li></country><region><li>District de Darmstadt</li><li>Hesse (Land)</li></region><settlement><li>Francfort-sur-le-Main</li></settlement></list><tree><noCountry><name sortKey="Engels, Joachim W" sort="Engels, Joachim W" uniqKey="Engels J" first="Joachim W" last="Engels">Joachim W. Engels</name></noCountry><country name="Allemagne"><region name="Hesse (Land)"><name sortKey="Klopffer, Astrid E" sort="Klopffer, Astrid E" uniqKey="Klopffer A" first="Astrid E" last="Klöpffer">Astrid E. Klöpffer</name></region></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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