Design of Novel Derivatives of Phosphonoformate (Foscarnet) as Prodrugs and Antiviral Agents

α-Haloenamines as Reagents for the Conversion of Phosphorus Oxyacids to Their Halogenated Analogues

“…A distillation head and Liebig condenser were attached and the product was distilled (bp 120-125°C/740 torr) to produce the amine 13 (2.1 g; 79%). 1…”

“…Introduction of halogen on to phosphorus is a central aspect of phosphorus chemistry. Phosphorus halides are important intermediates in for instance medicinal, 1 polymer, 2 and pesticide chemistry 3 as well as in oligonucleotide synthesis. 4 Classical procedures for the preparation of phosphorus halides are, in general, performed under harsh conditions producing corrosive and toxic byproducts such as HCl and SO 2 .The recent development of new, more selective methods has been slow.…”

Regioselective O2′,O3′‐Deacetylations of Peracetylated Ribonucleosides by Using Tetra‐n‐butylammonium Fluoride

“…The robust, mild, efficient, and regioselective TBAF‐promoted deacetylation of 1,2‐diol diacetate provided convenient one‐step access to O 5′‐acetyl ribonucleosides in good yields. Through this procedure, a wide diversity of O 5′‐acetyl ribonucleosides are now available for the synthesis of oligoribonucleotides,4 deoxynucleosides,5 and cyclic nucleosides 6. Furthermore, this method offers the dependability and robustness of a non‐enzymatic chemical method for the selective deacetylation of peracetylated 2′‐deoxyribonucleosides.…”

“…Therefore, for the successful automated synthesis of oligonucleotides or the conventional multistep synthesis of ribonucleosides, appropriate protection of these functional groups is mandatory. The synthesis of O 5′‐acetyl ribonucleosides has gained considerable attention, as they are key intermediates in the synthesis of biomedically important molecules such as oligoribonucleotides,4 deoxynucleosides,5 and cyclic nucleosides 6. Although there are efficient methods for the selective deacetylation of the O 5′‐position while preserving the O 2′, O 3′ acyl groups, there are only a few protocols that can achieve the selective deacetylation of the O 2′, O 3′‐positions without affecting the O 5′‐acetate 7.…”

Synthesis and stability studies of phosphonoformate–amino acid conjugates: a new class of slowly releasing foscarnet prodrugs

“…6,7 Because of its multiple negative charges at physiological pH, PFA has low oral bioavailability; this poor ability to penetrate cell membranes has long been a major impediment to its overall effectiveness as an anti-viral drug. 8,9 Past efforts to address this shortcoming by prodrug strategies have included partial esterification of PFA, 8À13 including its incorporation into cyclic esters, 11 and the replacement of an oxygen atom in PFA by a sulfur atom. 14À16 It has been shown that all three acidic groups of PFA must be available for maximal nucleic acid polymerase inhibition activity, and thus the ultimate antiviral activity of PFA prodrugs wherein one or more of these groups has been derivatized by esterification (or amidation) is likely to depend on a hydrolytic activation process in vivo to release the active drug.…”