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The lack of antiviral activity of recently described (S) -3-(adenin-9-yl)-2-(phosphonomethoxy)propanoic acid, or ( S )-CPMEA in brief, has been speculated to possibly be due to the increased hydrophilicity of the molecule and, thus, by its limited cellular permeability. Efficient syntheses of novel lipophilic prodrugs of ( S )-CPMEA masking either the carboxylic group or preferably both the phosphonate and carboxylic moieties, have been developed in order to increase bioavailability of the parent compound. Two prodrugs of ( S )-CPMEA, namely phosphonate bis-amidate 15 and phenyloxy amidate 16 , exhibited pan-genotypic anti-HCV activity at submicromolar concentrations. [ABSTRACT FROM AUTHOR]

A study of the Ir-catalyzed C–H silylation of 6-phenyl-7-deazapurines or -9-deazapurines with trialkylsilanes revealed that this reaction preferentially proceeded via ortho -silylation at the aryl group due to the directing effect of the N1 nitrogen of the deazapurine, rather than C–H silylation at the heterocycle which was only a minor side-reaction. A preparative protocol for the ortho -silylation of aryldeazapurines is presented. [ABSTRACT FROM AUTHOR]

The synthesis and biological activity profiling of a large series of diverse pyrrolo[2,3- d ]pyrimidine 4′- C -methylribonucleosides bearing an (het)aryl group at position 4 or 5 is reported as well as the synthesis of several phosphoramidate prodrugs. These compounds are 4′-C-methyl derivatives of previously reported cytostatic hetaryl-7-deazapurine ribonucleosides. The synthesis is based on glycosylation of halogenated 7-deazapurine bases with 1,2-di- O -acetyl-3,5-di- O -benzyl-4- C -methyl-β- d -ribofuranose followed by cross-coupling and nucleophilic substitution reactions. The final compounds showed low cytotoxicity and several derivatives exerted antiviral activity against HCV or Dengue viruses at micromolar concentrations. [ABSTRACT FROM AUTHOR]

Glutamate carboxypeptidase II (GCPII), also known as prostate specific membrane antigen (PSMA), is an established prostate cancer marker and is considered a promising target for specific anticancer drug delivery. Low-molecular-weight inhibitors of GCPII are advantageous specific ligands for this purpose. However, they must be modified with a linker to enable connection of the ligand with an imaging molecule, anticancer drug, and/or nanocarrier. Here, we describe a structure-activity relationship (SAR) study of GCPII inhibitors with linkers suitable for imaging and drug delivery. Structure-assisted inhibitor design and targeting of a specific GCPII exosite resulted in a 7-fold improvement in Ki value compared to the parent structure. X-ray structural analysis of the inhibitor series led to the identification of several inhibitor binding modes. We also optimized the length of the inhibitor linker for effective attachment to a biotin-binding molecule and showed that the optimized inhibitor could be used to target nanoparticles to cells expressing GCPII. [ABSTRACT FROM AUTHOR]

Abstract: The six-membered saturated heterocycles—4-tert-butyl-1-methylpiperidine, 4-tert-butyl-1-methylphosphine, 4-tert-butyl-tetrahydro-2H-thiopyran, and 4-tert-butyl-tetrahydro-2H-selenopyran—were prepared as suitable model compounds with well-defined geometry for an NMR study of their oxidation products. The corresponding epimeric N-oxides, phosphinoxides, sulfoxides, and selenoxides were obtained by standard chemical preparation and also by in situ oxidation with meta-chloroperbenzoic acid directly in the NMR tube. The experimental 1H and 13C chemical shifts were compared with corresponding calculated data obtained by GIAO approach with DFT, MP2, and HF methods and various basis sets. The correlation of experimental versus calculated data showed the possibility to determine the stereochemistry of the epimeric oxidation products using fast DFT B3LYP/6-31G* method for both geometry optimization and NMR chemical shifts calculation. [Copyright &y& Elsevier]

• New acyclic nucleotide analogs with 1,2,4-thiadiazole base were synthesized. • 5-Amino-1,2,4-thiadiazol-3(2 H)-one derivatives inhibit Cathepsin K and GSK-3β. • 1,2,4-Thiadiazol-3(2 H)-one ring is stabilized by substitution at the 5-amino group. In analogy to antiviral acyclic nucleoside phosphonates, a series of 5-amino-3-oxo-1,2,4-thiadiazol-3(2 H)-ones bearing a 2-phosphonomethoxyethyl (PME) or 3-hydroxy-2-(phosphonomethoxy)propyl (HPMP) group at the position 2 of the heterocyclic moiety has been synthesized. Diisopropyl esters of PME- and HPMP-amines have been converted to the N -substituted ureas and then reacted with benzoyl, ethoxycarbonyl, and Fmoc isothiocyanates to give the corresponding thiobiurets, which were oxidatively cyclized to diisopropyl esters of 5-amino-3-oxo-2-PME- or 2-HPMP- 1,2,4-thiadiazol-3(2 H)-ones. The phosphonate ester groups were cleaved with bromotrimethylsilane, yielding N 5-protected phosphonic acids. The subsequent attempts to remove the protecting group from N 5 under alkaline conditions resulted in the cleavage of the 1,2,4-thiadiazole ring. Similarly, compounds with a previously unprotected 5-amino-1,2,4-thiadiazolone base moiety were stable only in the form of phosphonate esters. The series of twenty-one newly prepared 1,2,4-thiadiazol-3(2 H)-ones were explored as potential inhibitors of cysteine-dependent enzymes – human cathepsin K (CatK) and glycogen synthase kinase 3β (GSK-3β). Several compounds exhibited an inhibitory activity toward both enzymes in the low micromolar range. The inhibitory potency of some of them toward GSK-3β was similar to that of the thiadiazole GSK-3β inhibitor tideglusib, whereas others exhibited more favorable toxicity profile while retaining good inhibitory activity. [ABSTRACT FROM AUTHOR]