Synthesis of Seven-Membered Ring Nucleosides and Serendipitous Simmons-Smith -Glycosylation.

A series of seven-membered (oxepine) nucleosides containing various nucleobases (A, U, T, 5-FU, C) were synthesized by ring expansion of cyclopropanated glucals. We expect this new series of ring-expanded nucleic acid analogues to be useful as building blocks in the design of mixed base functional genetic systems. While exploring alternative pathways to oxepine nucleoside synthesis, we discovered an unprecedented α-stereoselective -glycosylation of 1,2-glucals under mild Simmons-Smith conditions.

8-Furylimidazolo-2'-deoxycytidine: crystal structure, packing, atropisomerism and fluorescence.

8-Furylimidazolo-2'-deoxycytidine (ImidC), CHNO, is a fluorescent analogue of 2'-deoxycytidine, also displaying the same recognition face. As a constituent of DNA, ImidC forms extraordinarily strong silver-mediated self-pairs. Crystal structure determination revealed that ImidC adopts two types of disordered residues: the sugar unit and the furyl moiety.

Nucleoside Analogues with a Seven-Membered Sugar Ring: Synthesis and Structural Compatibility in DNA-RNA Hybrids.

Herein we describe results on the pairing properties of synthetic DNA and RNA oligonucleotides that contain nucleotide analogues with a 7-membered sugar ring (oxepane nucleotides). Specifically, we describe the stereoselective synthesis of a set of three oxepane thymine nucleosides (OxT), their conversion to phosphoramidite derivatives, and their use in solid-phase synthesis to yield chimeric OxT-DNA and OxT-RNA strands. The different regioisomeric OxT phosphoramidites allowed for positional variations of the phosphate bridge and assessment of duplex stability when the oxepane nucleotides were incorporated in dsDNA, dsRNA, and DNA-RNA hybrids.

Structure-Based Design, Synthesis, and Biological Evaluation of Triazole-Based smHDAC8 Inhibitors.

Schistosomiasis is a neglected tropical disease caused by parasitic flatworms of the genus Schistosoma, which affects over 200 million people worldwide and leads to at least 300,000 deaths every year. In this study, initial screening revealed the triazole-based hydroxamate 2 b (N-hydroxy-1-phenyl-1H-1,2,3-triazole-4-carboxamide) exhibiting potent inhibitory activity toward the novel antiparasitic target Schistosoma mansoni histone deacetylase 8 (smHDAC8) and promising selectivity over the major human HDACs. Subsequent crystallographic studies of the 2 b/smHDAC8 complex revealed key interactions between the inhibitor and the enzyme's active site, thus explaining the unique selectivity profile of the inhibitor.

Exploring Atypical Fluorine-Hydrogen Bonds and Their Effects on Nucleoside Conformations.

The ability of fluorine to serve as a hydrogen-bond acceptor has been debated for many years. Short fluorine-hydrogen contacts are thought to play a key role in stabilizing some complex supramolecular systems. To directly probe the existence of fluorine-hydrogen bonds, we have performed NMR spectroscopy and computational modeling on a series of C2'-fluorinated nucleosides.

Adjusting the Structure of 2'-Modified Nucleosides and Oligonucleotides via C4'-α-F or C4'-α-OMe Substitution: Synthesis and Conformational Analysis.

We report the first syntheses of three nucleoside analogues, namely, 2',4'-diOMe-rU, 2'-OMe,4'-F-rU, and 2'-F,4'-OMe-araU, via stereoselective introduction of fluorine or methoxy functionalities at the C4'-α-position of a 4',5'-olefinic intermediate. Conformational analyses of these nucleosides and comparison to other previously reported 2',4'-disubstituted nucleoside analogues make it possible to evaluate the effect of fluorine and methoxy substitution on the sugar pucker, as assessed by NMR, X-ray diffraction, and computational methods. We found that C4'-α-F/OMe substituents reinforce the C3'-endo ( north) conformation of 2'-OMe-rU.

2'-O-Methyl- and 2'-O-propargyl-5-methylisocytidine: synthesis, properties and impact on the isoCd-dG and the isoCd-isoGd base pairing in nucleic acids with parallel and antiparallel strand orientation.

Oligonucleotides containing 2'-O-methylated 5-methylisocytidine (3) and 2'-O-propargyl-5-methylisocytidine (4) as well as the non-functionalized 5-methyl-2'-deoxyisocytidine (1b) were synthesized. MALDI-TOF mass spectra of oligonucleotides containing 1b are susceptible to a stepwise depyrimidination. In contrast, oligonucleotides incorporating 2'-O-alkylated nucleosides 3 and 4 are stable.

Robust silver-mediated imidazolo-dC base pairs in metal DNA: dinuclear silver bridges with exceptional stability in double helices with parallel and antiparallel strand orientation.

A new unprecedented metal-mediated base pair was designed that stabilizes reverse Watson-Crick DNA (parallel strand orientation, ps) as well as canonical Watson-Crick DNA (antiparallel strand orientation, aps). This base pair contains two imidazolo-dC units decorated with furan residues. Tm measurements and spectroscopic studies reveal that each silver-mediated furano-imidazolo-dC forms exceptionally stable duplexes with ps and aps chain orientation.

Stereocontrolled synthesis of four diastereomeric C-aryl manno- and talofuranosides.

In a chiral-pool synthesis starting from D-mannono-1,4-lactone 1a, the four diastereomeric C-aryl furanosides (1S,4R)-4a, (1S,4S)-4b, (1R,4R)-4c, and (1R,4S)-4d were obtained in a stereocontrolled manner. The key steps of the synthetic pathway comprise a stereoselective reduction of the diastereomeric hemiketals (4R)-2a and (4S)-2b as well as a stereospecific cycloetherification of the resulting diols (1R,4R)-5a, (1S,4R)-5c, and (1S,4S)-5d. This ring closure which led to the desired C-glycosides was achieved by a Mitsunobu reaction or by preparing the 1-O-benzoyl-4-O-methylsulfonyl derivative 7 which was then treated with sodium methoxide.