Synthesis of novel nucleotide analogues based on the traditional and nontraditional bioisosteres

This dissertation focuses on the development of novel synthetic approaches for incorporation of different traditional as well as untraditional bioisosteres into the structure of nucleotide analogues.;It is well known that many biologically active compounds containing polar ionic groups such as phosphates cannot be successful drag candidates because they exhibit poor bioavailability stability. One of the concepts that help to overcome these challenges called bioisosterism. According to this concept certain functional groups or a part of the molecule can be replaced with the bioisosteric group which possesses similar electronic distribution and spatial arrangement. This substitution significantly improves stability and bioavailability of the target molecule.;Chapter 1 describes the synthetic approach towards non-hydrolysable RNA-based nucleotide analogues in which bridging oxygen atoms of the triphosphate replaced by difluoromethylene group.;Chapter 2 summarizes our investigations towards replacement of the phosphate hydroxyl group with the difluoromethyl group.;Chapter 3 describes the development of new methodology for preparation of monofluoroalkenes via Julia-Kosinski reaction.;Chapter 4 explores the possibility for bioisosteric replacement one of the phosphate of trisphosphoric acid with the squaryl moiety.;Chapter 5 deals with the synthesis of phosphoramidates of 2'-deoxy-&psgr;-isocytidine.