Synthesis, biophysical properties, and RNase H activity of 6'-difluoro [4.3. 0] bicyclo-DNA
S Frei, AK Katolik, CJ Leumann - Beilstein journal of organic …, 2019 - beilstein-journals.org
S Frei, AK Katolik, CJ Leumann
Beilstein journal of organic chemistry, 2019•beilstein-journals.orgHere we present the synthesis, the biophysical properties, and the RNase H profile of 6'-
difluorinated [4.3. 0] bicyclo-DNA (6'-diF-bc 4, 3-DNA). The difluorinated thymidine
phosphoramidite building block was synthesized starting from an already known gem-
difluorinated tricyclic glycal. This tricyclic siloxydifluorocyclopropane was converted into the
[4.3. 0] bicyclic nucleoside via cyclopropane ring-opening through the addition of an
electrophilic iodine during the nucleosidation step followed by reduction. The gem …
difluorinated [4.3. 0] bicyclo-DNA (6'-diF-bc 4, 3-DNA). The difluorinated thymidine
phosphoramidite building block was synthesized starting from an already known gem-
difluorinated tricyclic glycal. This tricyclic siloxydifluorocyclopropane was converted into the
[4.3. 0] bicyclic nucleoside via cyclopropane ring-opening through the addition of an
electrophilic iodine during the nucleosidation step followed by reduction. The gem …
Abstract
Here we present the synthesis, the biophysical properties, and the RNase H profile of 6’-difluorinated [4.3. 0] bicyclo-DNA (6’-diF-bc 4, 3-DNA). The difluorinated thymidine phosphoramidite building block was synthesized starting from an already known gem-difluorinated tricyclic glycal. This tricyclic siloxydifluorocyclopropane was converted into the [4.3. 0] bicyclic nucleoside via cyclopropane ring-opening through the addition of an electrophilic iodine during the nucleosidation step followed by reduction. The gem-difluorinated bicyclic nucleoside was then converted into the corresponding phosphoramidite building block which was incorporated into oligonucleotides. Thermal denaturation experiments of these oligonucleotides hybridized to complementary DNA or RNA disclosed a significant destabilization of both duplex types (ΔT m/mod=− 1.6 to− 5.5 C). However, in the DNA/RNA hybrid the amount of destabilization could be reduced by multiple insertions of the modified unit. In addition, CD spectroscopy of the oligonucleotides hybridized to RNA showed a similar structure than the natural DNA/RNA duplex. Furthermore, since the structural investigation on the nucleoside level by X-ray crystallography and ab initio calculations pointed to a furanose conformation in the southern region, a RNase H cleavage assay was conducted. This experiment revealed that the oligonucleotide containing five modified units was able to elicit the RNase H-mediated cleavage of the complementary RNA strand.
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