Synthesis of Nucleoside Analogs Containing Sulfur or Selenium Replacements of the Ribose Ring Oxygen or Carbon.

Nucleoside analogs have proven highly successful in many pharmaceutical intervention strategies, and continued exploration of next generation structural motifs is required. Herein we discuss recent advances toward the chemical synthesis of heteroatom-modified nucleosides, where this is constituted by the chalcogens sulfur or selenium. Paying specific focus to the organic chemistry to incorporate these heteroatoms, we consider developments toward ribose ring oxygen and ring carbon replacements alongside chalcogen-modified heterobases.

Preparation of a 4'-Thiouridine Building-Block for Solid-Phase Oligonucleotide Synthesis.

Starting from a commercially available thioether, we report a nine-step synthesis of a 4'-thiouridine phosphoramidite building-block. We install the uracil nucleobase using Pummerer-type glycosylation of a sulfoxide intermediate followed by a series of protecting group manipulations to deliver the desired phosphite. Notably, we introduce a 3',5'-O-di-tert-butylsilylene protecting group within a 4'-thiosugar framework, harnessing this to ensure regiospecific installation of the 2'-O-silyl protecting group.

Synthesis of fluorinated carbocyclic pyrimidine nucleoside analogues.

Analogues of the canonical nucleosides have a longstanding presence and proven capability within medicinal chemistry and drug discovery research. The synthesis reported herein successfully replaces furanose oxygen with CF and CHF in pyrimidine nucleosides, granting access to an alternative pharmacophore space. Key diastereoselective conjugate addition and fluorination methodologies are developed from chiral pool materials, establishing a robust gram-scale synthesis of 6'-()-monofluoro- and 6'--difluorouridines.

Recent Advances in the Chemical Synthesis and Evaluation of Anticancer Nucleoside Analogues.

Nucleoside analogues have proven to be highly successful chemotherapeutic agents in the treatment of a wide variety of cancers. Several such compounds, including gemcitabine and cytarabine, are the go-to option in first-line treatments. However, these materials do have limitations and the development of next generation compounds remains a topic of significant interest and necessity.