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Novel 4′-substituted β- d -2′-deoxy-2′-α-fluoro (2′d2′F) nucleoside inhibitors of respiratory syncytial virus (RSV) are reported. The introduction of 4′-substitution onto 2′d2′F nucleoside analogs resulted in compounds demonstrating potent cell based RSV inhibition, improved inhibition of the RSV polymerase by the nucleoside triphosphate metabolites, and enhanced selectivity over incorporation by mitochondrial RNA and DNA polymerases. Selectivity over the mitochondrial polymerases was found to be extremely sensitive to the specific 4′-substitution and not readily predictable. Combining the most potent and selective 4′-groups from N -nucleoside analogs onto a 2′d2′F C -nucleoside analog resulted in the identification of β- d -2′-deoxy-2′-α-fluoro-4′-α-cyano-5-aza-7,9-dideaza adenosine as a promising nucleoside lead for RSV. [ABSTRACT FROM AUTHOR]

Abstract: Modified purine analogs of GS-9148 [5-(6-amino-purin-9-yl)-4-fluoro-2,5-dihydro-furan-2-yloxymethyl]-phosphonic acid (2′-Fd4AP) were synthesized and their anti-HIV potency evaluated. The antiviral activity of guanosine analog (2′-Fd4GP) was comparable that of to 2′-Fd4AP in MT-2 cells, but selectivity was reduced. [Copyright &y& Elsevier]

Abstract: GS-9148 (2′-Fd4AP, 4) has been identified as a nucleoside phosphonate reverse transcriptase (RT) inhibitor with activity against wild-type HIV (EC50 =12μM). Unlike many clinical RT inhibitors, relevant reverse transcriptase mutants (M184V, K65R, 6-TAMs) maintain a susceptibility to 2′-Fd4AP that is similar to wild-type virus. The 2′-fluorine group was rationally designed into the molecule to improve the selectivity profile and in preliminary studies using HepG2 cells, compound 4 showed no measurable effect on mitochondrial DNA content indicating a low potential for mitochondrial toxicity. [Copyright &y& Elsevier]

Abstract: A series of nucleoside phosphonate reverse transcriptase (RT) inhibitors have been synthesized and their anti-HIV activity and resistance profiles evaluated. The most potent analog [5-(6-amino-purin-9-yl)-2,5-dihydro-furan-2-yloxymethyl]-phosphonic acid (d4AP) demonstrated a HIV EC50 =2.1μM, and the most favorable resistance profile against HIV-1 variants with K65R, M184V or multiple thymidine analog mutations in RT. [Copyright &y& Elsevier]

The development of potent and selective urokinase-type plasminogen activator (uPA) inhibitors based on the lead molecule 2-(2-hydroxy-3-ethoxyphenyl)-1H-benzimidazole-5-carboxamidine (3a) is described. [Copyright &y& Elsevier]

Abstract: Ribonucleoside phosphonate analogues containing 2′-α-fluoro modifications were synthesized and their potency evaluated against HCV RNA polymerase. The diphosphophosphonate (triphosphate equivalent) adenine and cytidine analogues displayed potent inhibition of the HCV polymerase in the range of 1.9–2.1μM, but only modest cell-based activity in the HCV replicon. Pro-drugs of the parent nucleoside phosphonates improved the cell-based activity. [Copyright &y& Elsevier]

Abstract: A series of purine l-ribonucleosides 2a–2i bearing diverse C-substituents (alkyl, aryl, hetaryl or hydroxymethyl) in the position 6 were prepared by Pd-catalyzed cross-coupling reactions of 6-chloro-9-(2,3,5-tri-O-acetyl-β-l-ribofuranosyl)purine with the corresponding organometallics followed by deprotection. Unlike their d-ribonucleoside enantiomers that possess strong cytostatic and anti-HCV activity, the l-ribonucleosides were inactive except for 6-benzylpurine nucleoside 2h showing moderate anti-HCV effect in replicon assay. A triphosphate of 2h did not inhibit HCV RNA polymerase. [Copyright &y& Elsevier]

The rational design and synthesis of β-amino-α-hydroxy amide derivatives as reversible inhibitors of methionine aminopeptidase-2 (MetAP2) with anti-proliferative activity against human umbilical vein endothelial cells (HUVECs) is described. [Copyright &y& Elsevier]

The structure-based design of potent and selective urokinase-type plasminogen activator (uPA) inhibitors with 4-aminoarylamidine or 4-aminoarylguanidine S1 binding groups, is described. [Copyright &y& Elsevier]