Bioisosteric deaza analogues of 6-methyl-9-β-D-ribofuranosylpurine, a hydrophobic analogue of adenosine, were synthesized and evaluated for antiviral activity. Whereas the 1-deaza and 3-deaza analogues were essentially inactive in plaque assays of infectivity, a novel 7-deaza-6-methyl-9-β-D-ribofuranosylpurine analogue, structurally related to the natural product tubercidin, potently inhibited replication of poliovirus (PV) in HeLa cells (IC 50 = 11 nM) and dengue virus (DENV) in Vero cells (IC 50 = 62 nM). Selectivity against PV over cytotoxic effects to HeLa cells was >100-fold after incubation for 7 h. Mechanistic studies of the 5'-triphosphate of 7-deaza-6-methyl-9-β-D-ribofuranosylpurine revealed that this compound is an efficient substrate of PV RNA-dependent RNA polymerase (RdRP) and is incorporated into RNA mimicking both ATP and GTP.
Nucleoside 5′-triphosphates (NTPs) play key roles in biology and medicine. However, these compounds are notoriously difficult to synthesize. We describe a one-pot method to prepare NTPs from nucleoside 5′-H-phosphonate monoesters via pyridinium phosphoramidates, and we used this approach to synthesize ATP, UTP, GTP, CTP, ribavirin-TP, and 6-methylpurine ribonucleoside-TP (6MePTP). Poliovirus RNA-dependent RNA polymerase efficiently employed 6MePTP as a substrate, suggesting that the cognate nucleoside, a poorly understood antiviral agent, may damage viral RNA.Nucleoside 5′-triphosphates (NTPs) are critical mediators of myriad biological processes including DNA replication, transcription, and translation. Correspondingly, synthetic mimics of NTPs have been widely used as molecular probes and biological assay components and represent active metabolites of certain drugs such as the antiviral agent ribavirin. Despite their importance in biology and medicine, the diversity of commercially available NTPs is limited because these compounds are often difficult to prepare and isolate in pure form. 1 Traditional approaches for the synthesis of NTPs include the "one-pot, three-step" method and the method of Ludwig and Eckstein. 2,3 Although these strategies work well for some substrates, others are plagued by low yields and difficulties in purification. 4 More recently, Ahmadibeni reported 5 a solid-phase route to NTPs, and Borch reported 6 a method for the preparation of activated phosphoramidates that can be converted to NTPs by reaction with tris(tetra-n-butylammonium) hydrogen pyrophosphate. The final coupling step employed by Borch was found to proceed in remarkably high yield, but the required four-step synthesis of We hypothesized that nucleoside 5′-H-phosphonates might provide novel and more readily synthesized precursors to NTPs. This hypothesis was based on reported syntheses of phosphates, phosphoramidates, and other phosphate derivatives from these precursors. [7][8][9][10] After conversion to silyl phosphites with TMSCl, H-phosphonate monoesters can be oxidized by elemental iodine and other reagents to generate electrophilic intermediates. 11,12 These intermediates are known to react with a variety of nucleophiles to afford addition products, but surprisingly, this strategy has not been previously investigated for the synthesis of NTPs.We report here a one-pot approach for the synthesis of NTPs from nucleoside 5′-Hphosphonate monoesters, relatively stable compounds that can be easily prepared from 2′,3′-O-isopropylidene-protected nucleosides. 13 We demonstrate that fully deprotected ribonucleoside 5′-H-phosphonate monoesters can be converted in situ to pyridinium phosphoramidate intermediates. Upon addition of nucleophilic tris(tetra-n-butylammonium) hydrogen pyrophosphate, NTPs can be isolated by use of a two-step purification protocol.As shown in Scheme 1, starting with the known 2′,3′-O-isopropylidene-protected nucleosides 1-6, 13-15 phosphitylation 16 with salicyl phosphorochlorodite or PCl 3 provi...
Inhibitors of the PI3-kinase/AKT (protein kinase B) pathway are under investigation as anticancer and antiviral agents. The benzimidazole derivative AKT inhibitor-IV (ChemBridge 5233705) affects this pathway and exhibits potent anticancer and antiviral activity. To probe its biological activity, we synthesized AKT inhibitor-IV and 21 analogues using a novel six-step route based on ZrCl4-catalyzed cyclization of 1,2-arylenediamines with α,β-unsaturated aldehydes. We examined effects on viability of HeLa carcinoma cells, viability of normal human cells (NHBE), replication of recombinant parainfluenza virus 5 (PIV5) in HeLa cells, and replication of the intracellular bacterium Mycobacterium fortuitum in HeLa cells. Replacement of the benzimidazole N-ethyl substitutent of AKT inhibitor-IV with N-hexyl and N-dodecyl groups enhanced antiviral activity and cytotoxicity against the cancer cell line, but these compounds showed substantially lower toxicity (from 6-fold to >20-fold) against NHBE cells, and no effect on M. fortuitum, suggesting inhibition of one or more host protein(s) required for proliferation of cancer cells and PIV5. The key structural elements identified here may facilitate identification of targets of this highly biologically active scaffold.
In the brain, the γ-aminobutyric acid (GABA) level is primarily controlled by the activity of its synthesizing enzyme, L-glutamate decarboxylase (GAD). At present, mechanisms responsible for regulation of GAD activity remain largely unknown. Here we report that GAD activity is inhibited by conditions favoring protein phosphorylation, and this inhibition can be reversed by phosphatase treatment. Furthermore, this inhibition appears to result from the suppression of a Ca^2+ -dependent phosphatase. Phosphorylation of GAD is demonstrated by direct incorporation of 32P into the GAD protein. These results suggest that GAD activity in the brain is inhibited by phosphorylation and activated by dephosphorylation. A model for regulation of GABA synthesis related to neuronal excitation is discussed.
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