Abstract
Efforts to develop synthetic methodologies allowing the preparation of α,α–difluorophosphonothioates, α,α–difluorophosphonodithioates, α,α–difluorophosphono-trithioates, and α,α–difluorophosphinates are reviewed in the light of applications in the field of modified oligonucleotides and cyclitol phosphates. Two successful approaches have been developed, based either on the addition of phosphorus-centered radicals onto gem–difluoroalkenes or on a process involving the addition of lithiodifluorophosphono-thioates 91 onto a ketone and the subsequent deoxygenation reaction of the adduct. The radical route successfully developed a practical route to α,α–difluoro–H–phosphinates which proved to be useful intermediates to a variety of phosphate isosters. The ionic route led to the first preparation of phosphonodifluoromethyl analogues of nucleoside–3’–phosphates.
Highlights
The ubiquitous presence of the phosphate group in molecules involved in life processes has focused the attention of many organic and medicinal chemists in their efforts to design and generate non natural molecules to interfere with biochemical transformations
Analogues targeting phospholipase C (PLC), purine nucleoside phosphorylase (PNP) and protein phosphotyrosine, phosphoserine or phosphothreonine phosphatases have been published [4]. This functional group has been successfully used to mimic the phosphate in nucleotide monophosphates and trisphosphates: analogues of adenosine monophosphate, cyclic adenosine monophosphate, adenosine triphosphate and adenosyl adenosine triphosphate, as well as structurally related potent inhibitors of the reverse transcriptase of Human Immunodeficiency Virus (HIV), have been described in literature [5]
The antisense and antigene strategies rely on the formation of a triplex between the DNA and a modified oligonucleotide (MON), and of a duplex between the messenger RNA (m– RNA) and a MON, respectively, to keep the transcription or the translation from occurring (Scheme 2) [7]
Summary
The ubiquitous presence of the phosphate group in molecules involved in life processes has focused the attention of many organic and medicinal chemists in their efforts to design and generate non natural molecules to interfere with biochemical transformations. Analogues targeting phospholipase C (PLC), purine nucleoside phosphorylase (PNP) and protein phosphotyrosine, phosphoserine or phosphothreonine phosphatases have been published [4] This functional group has been successfully used to mimic the phosphate in nucleotide monophosphates and trisphosphates: analogues of adenosine monophosphate, cyclic adenosine monophosphate, adenosine triphosphate and adenosyl adenosine triphosphate, as well as structurally related potent inhibitors of the reverse transcriptase of Human Immunodeficiency Virus (HIV), have been described in literature [5]. A very simplified view of the cycle (Scheme 3) shows how the second messenger inositol-1,4,5trisphosphate (1,4,5–IP3) released from phophatidylinositol–4,5–diphosphate (PIP2) by the action of a phospholipase C, undergoes a sequential series of phosphorylations of the hydroxyl groups and hydrolysis of the phosphates to produce, among others, three different inositol monophosphates (I–4– P, I–3–P and I–1–P) These are hydrolysed by a single enzyme, inositol monophosphatase (IMPase) to yield myo–inositol which is converted into PIP2, thereby closing the cycle. Inositol monophosphatase is a homodimeric enzyme and has been postulated as a possible target to treat manic depressive illness [9]
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