Vicente Samano

Nucleic Acid Related Compounds. 94. Remarkably High Stereoselective Reductions of 2′- and 3′-Ketonucleoside Derivatives To Give Arabino, Ribo, and Xylofuranosyl Nucleosides with Hydrogen Isotopes at C2′ and C3′

Abstract Oxidation of 2′,5′- and 3′,5′- O -( tert -butyldimethylsilyl)-protected ribonucleosides gave the corresponding 3′-keto and 2′-keto derivatives, whose complete oxidation was assayed by total release of the heterocyclic base upon treatment with tetrabutylammonium fluoride/THF. Treatment of the protected ketones with sodium triacetoxyborohydride (generated in situ from sodium borohydride and acetic acid) in acetic acid resulted in hydride delivery at the α face with high stereoselectivity. The xylo/ribo (∼49:1) and arabino/ribo (∼49:1) diastereomers, respectively, were obtained in good to high overall yields upon deprotection. Selective removal of the TBDMS group from O5′ (trifluoroacetic acid/water, 9:1, 0 °C) and treatment of these 5′-hydroxy-(3′- and 2′)-ketones with sodium triacetoxyborohydride effected remarkably selective delivery of hydride at the β face. Deprotection gave the ribo/xylo (∼99:1) and ribo/arabino (∼99:1) nucleosides in high yields. Comparable results were obtained with sodium borodeuteride in acetic acid to give the four 2′[ 2 H] and 3′[ 2 H] arabino, ribo, and xylo isotopomers with > 95% incorporation of deuterium. Development of efficient procedures and comparison with previous methods are discussed.

Discovery of a Potent Boronic Acid Derived Inhibitor of the HCV RNA-Dependent RNA Polymerase.

A boronic acid moiety was found to be a critical pharmacophore for enhanced in vitro potency against wild-type hepatitis C replicons and known clinical polymorphic and resistant HCV mutant replicons. The synthesis, optimization, and structure-activity relationships associated with inhibition of HCV replication in a subgenomic replication system for a series of non-nucleoside boron-containing HCV RNA-dependent RNA polymerase (NS5B) inhibitors are described. A summary of the discovery of 3 (GSK5852), a molecule which entered clinical trials in subjects infected with HCV in 2011, is included.

Synthesis of 3′-deoxyadenosine-3′-spirocyclopropane, 3′-deoxy-uridine-3′-spirocyclopropane, and 5′-deoxy-4′,5′-methanoadenosine

Abstract Cycloaddition of diazomethane with 3′-deoxy-3′-methylene- and 4′,5′-didehydro-5′-deoxynucleoside derivatives followed by sensitized photochemical extrusion of nitrogen provided the previously unreported 3′- and 4′-spirocyclopropane nucleoside derivatives. Enhancement of the cycloaddition reactions by electron withdrawing benzoyl protecting groups was observed.

Ribonucleotide Reductase Targets for Chemotherapy; Mechanistic Aspects and Biologically Active Agents

Abstract Ribonucleotide reductases are essential for the de novo biosynthesis of the 2′-deoxynucleotide components of DNA. These enzymes have complex cofactors and execute novel chemistry involving C2′ via radical abstraction of H3′. Mechanistic aspects of these transformations and selected nucleotide analogues that cause mechanism-based inactivation of ribonucleotide reductases are discussed.