Synthesis and structure of novel conformationally constrained 1',2'-azetidine-fused bicyclic pyrimidine nucleosides: their incorporation into oligo-DNAs and thermal stability of the heteroduplexes.
[structures: see text] The synthesis of novel 1',2'-aminomethylene bridged (6-aza-2-oxabicyclo[3.2.0]heptane) "azetidine" pyrimidine nucleosides and their transformations to the corresponding phosphoramidite building blocks (20, 39, and 42) for automated solid-phase oligonucleotide synthesis is reported. The novel bicyclonucleoside "azetidine" monomers were synthesized by two different strategies starting from the known sugar intermediate 6-O-benzyl-1,2:3,4-bis-O-isopropylidene-D-psicofuranose. Conformational analysis performed by molecular modeling (ab initio and MD simulations) and NMR showed that the azetidine-fused furanose sugar is locked in a North-East conformation with pseudorotational phase angle (P) in the range of 44.5-53.8 degrees and sugar puckering amplitude (phi(m)) of 29.3-32.6 degrees for the azetidine-modified T, U, C, and 5-Me-C nucleosides. Thermal denaturation studies of azetidine-modified oligo-DNA/RNA heteroduplexes show that the azetidine-fused nucleosides display improved binding affinities when compared to that of previously synthesized North-East sugar constrained oxetane fused analogues.
Honcharenko
Dmytro
D
Department of Bioorganic Chemistry, Box 581, Biomedical Center, Uppsala University, SE-75123 Uppsala, Sweden.
Varghese
Oommen P
OP
Plashkevych
Oleksandr
O
Barman
Jharna
J
Chattopadhyaya
Jyoti
J
D001384:Azetidines / Q000737:chemistry*; D001483:Base Sequence; D002241:Carbohydrates / Q000737:chemistry; D019295:Computational Biology; D003198:Computer Simulation; D003500:Cyclization; D004247:DNA / Q000737:chemistry* / Q000235:genetics; D004988:Ethers, Cyclic / Q000737:chemistry; D009690:Nucleic Acid Conformation; D009691:Nucleic Acid Denaturation; D009943:Organophosphorus Compounds / Q000737:chemistry; D011741:Pyrimidine Nucleosides / Q000138:chemical synthesis / Q000737:chemistry*; D012313:RNA / Q000235:genetics; D013696:Temperature
D001384:Azetidines; D002241:Carbohydrates; D004988:Ethers, Cyclic; D009943:Organophosphorus Compounds; D011741:Pyrimidine Nucleosides; C434331:phosphoramidite; C082735:azetidine; D012313:RNA; D004247:DNA; C005287:oxetane