The concept of conformational restriction leading to the preorganization of modified strands has proven to be successful and has afforded nucleic acid analogues with many interesting properties suitable for various biochemical applications. We utilized this concept to prepare a set of constrained oligonucleotides derived from 1,4-dioxane and 1,3-dioxolane-locked nucleoside phosphonates and evaluated their hybridization affinities towards their complementary RNA strands. With an increase of ΔTm per modification up to +5.2 °C, the hybridization experiments revealed the (S)-2',3'-O-phosphonomethylidene internucleotide linkage as one of the most Tm-increasing modifications reported to date. Moreover, we introduced a novel prediction tool for the pre-selection of potentially interesting chemical modifications of oligonucleotides.

Faculty of Mathematics and Physics Institute of Physics Charles University Ke Karlovu 5 12116 Prague Czech Republic

Institute of Organic Chemistry and Biochemistry of the CAS Flemingovo náměstí 2 16610 Prague Czech Republic

Institute of Organic Chemistry and Biochemistry of the CAS Flemingovo náměstí 2 16610 Prague Czech Republic and Department of Chemistry of Natural Compounds University of Chemistry and Technology Technická 5 16628 Prague Czech Republic

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