4‑Toluenesulfonyloxymethyl‑(<i>H</i>)‑phosphinate: A Reagent for the Introduction of <i>O</i>- and <i>S</i>‑Methyl‑(<i>H</i>)‑phosphinate Moieties

The straightforward synthesis of sodium 4-toluene­sulfonyl­oxymethyl-(<i>H</i>)-phosphinate and (<i>H</i>)-phosphino­methyl­isothio­uronium tosylate as new reagents for the preparation of <i>O</i>- and <i>S</i>-methyl-(<i>H</i>)-phosphinic acid derivatives, respectively, is described. The reactivity of both reagents was demonstrated by the preparation of protected 2′-deoxy­ribonucleo­side-<i>O</i>-methyl-(<i>H</i>)-phosphinates in the 5′- and 3′-series and 2′,5′-dideoxy­ribonucleo­side-5′-<i>S</i>-methyl-(<i>H</i>)-phosphinates. These compounds represent a new class of monomers compatible with the solid phase synthesis of oligonucleotides by <i>H</i>-phosphonate chemistry, as it was proved with the synthesis of a fully phosphonate heptamer

Development of Prolinol Containing Inhibitors of Hypoxanthine–Guanine–Xanthine Phosphoribosyltransferase: Rational Structure-Based Drug Design

Inhibition of hypoxanthine–guanine–xanthine phosphoribosyltransferase activity decreases the pool of 6-oxo and 6-amino purine nucleoside monophosphates required for DNA and RNA synthesis, resulting in a reduction in cell growth. Therefore, inhibitors of this enzyme have potential to control infections, caused by Plasmodium falciparum and Plasmodium vivax, Trypanosoma brucei, Mycobacterium tuberculosis, and Helicobacter pylori. Five compounds synthesized here that contain a purine base covalently linked by a prolinol group to one or two phosphonate groups have Ki values ranging from 3 nM to >10 μM, depending on the structure of the inhibitor and the biological origin of the enzyme. X-ray crystal structures show that, on binding, these prolinol-containing inhibitors stimulated the movement of active site loops in the enzyme. Against TBr in cell culture, a prodrug exhibited an EC50 of 10 μM. Thus, these compounds are excellent candidates for further development as drug leads against infectious diseases as well as being potential anticancer agents

Development of Prolinol Containing Inhibitors of Hypoxanthine–Guanine–Xanthine Phosphoribosyltransferase: Rational Structure-Based Drug Design

Inhibition of hypoxanthine–guanine–xanthine phosphoribosyltransferase activity decreases the pool of 6-oxo and 6-amino purine nucleoside monophosphates required for DNA and RNA synthesis, resulting in a reduction in cell growth. Therefore, inhibitors of this enzyme have potential to control infections, caused by Plasmodium falciparum and Plasmodium vivax, Trypanosoma brucei, Mycobacterium tuberculosis, and Helicobacter pylori. Five compounds synthesized here that contain a purine base covalently linked by a prolinol group to one or two phosphonate groups have Ki values ranging from 3 nM to >10 μM, depending on the structure of the inhibitor and the biological origin of the enzyme. X-ray crystal structures show that, on binding, these prolinol-containing inhibitors stimulated the movement of active site loops in the enzyme. Against TBr in cell culture, a prodrug exhibited an EC50 of 10 μM. Thus, these compounds are excellent candidates for further development as drug leads against infectious diseases as well as being potential anticancer agents

Straightforward Synthesis of Purine 4′-Alkoxy-2′-deoxynucleosides: First Report of Mixed Purine–Pyrimidine 4′-Alkoxyoligodeoxynucleotides as New RNA Mimics

Purine and pyrimidine 4′-alkoxy-2′-deoxynucleosides were efficiently prepared from nucleoside 4′-5′-enol acetates in three steps by <i>N</i>-iodosuccinimide promoted alkoxylation, hydrolysis, and reduction followed by conversion to phosphoramidite monomers for the solid-phase synthesis of the oligonucleotides. Fully modified 4′-alkoxyoligodeoxynucleotides, which are characterized by a prevalent <i>N</i>-type (RNA-like) conformation, exhibited superior chemical and nuclease resistance as well as excellent hybridization properties with a strong tendency for RNA-selective hybridization, suggesting a potential application of 4′-alkoxy-oligodeoxynucleotides in antisense technologies