In vitroandin vivoantiviral (RNA) evaluation of orotidine 5′-monophosphate decarboxylase inhibitors and analogues including 6-azauridine-5′-(ethyl methoxyalaninyl)phosphate (a 5′-monophosphate prodrug)

Abstract

A series of 29 pyrimidines comprising analogues of 6-azauridine (e.g. 2- and 4-thio-6-azauridine), 6-substituted uridines (including several known inhibitors of orotidine 5′-monophosphate decarboxylase, ODCase, e.g. pyrazofurin), and 6-azauridine-5′-(ethyl methoxyalaninyl) phosphate (a potential prodrug of 6-AU-5′-MP) were synthesized and evaluated in vitro and in vivo against five RNA viruses: Japanese encephalitis (JE), yellow fever (YF), sandfly fever (SF), Punta Tora (PT) and Venezuelan equine encephalomyelitis (VEE) viruses. 2-Thio-6-azauridine demonstrated the best In vitro activity against all five viruses. However, in vivo activity was not observed in JE-, PT- and VEE-infected mice. The phosphate prodrug of 6-azauridine was significantly more effective than the parent compound in the PT virus mouse model. Optimum in vivo dose/route/schedule was determined for pyrazofurin in PT-virus-infected mice.

Design of Inhibitors of Orotidine Monophosphate Decarboxylase Using Bioisosteric Replacement and Determination of Inhibition Kinetics

“…ODCase has been identified as a target for drugs directed against RNA viruses such as poxviruses and flaviviruses; the former are causing increasing concern as a potential bioterrorist weapon. − ODCase inhibitors have also been effective against West Nile virus, a recent thread to humans and birds in the United States and Canada . Plasmodia, including the malaria-causing Plasmodium falciparum , are another class of pathogens sensitive to the inhibition of this enzyme's activity .…”

Role of pH in Regulating Cancer Pyrimidine Synthesis

“…Include xanthosine, uridine 5 -phosphates, cytidine barbiturate, 5-flouro orotate [95,96] Orotidine 5 -phosphate decarboxylase approx. 7.5 Pyrazofurin and 6-aza uridine 5 -monophosphate [99,100] Cytidine monophosphate kinase 7.4 Gemcitabine [65] Nucleoside-diphosphate kinase 8 Theophylline [117] Cytosine triphosphate synthase 8 Cyclopentenyl cytosine [121] Ribonucleotide reductase enzyme 7.5-8 Cisplatin, chlorambucil, desferrioxamine, gemcitabine, and hydroxyurea [135][136][137][138][139][140][141] Tymidylate synthase 7.0 and 8.1 Capecitabine and 5 fluorouracil [154][155][156][157] Ribonucleotide reductase 7.5 to 8 with a low iron level Gemcitabine and iron chelators [160] For example, in the case of ribonucleotide reductase (RR), the key enzyme to produce nucleotides for DNA, indirect evidence shows that the optimal pH is between 7.5 and 8. These data come from the fact that at this pH range less iron is needed for the maximum activity of the enzyme [160].…”

6-Azapyrimidine-2‘-deoxy-4‘-thionucleosides: Antiviral Agents against TK+ and TK− HSV and VZV Strains

“…Purification by flash column chromatography (petroleum ether-ethyl acetate 7:3 v/v) gave 4.37 g (76%) of the product 21 as a thick orange syrup, R and β mixture of approximately 1:1: Rf 0.30 (petroleum ether-ethyl acetate 3:2); 1 H NMR (CDCl3) mixture of anomers: δ 9.69 (s, 1, NH R and β), 7.34 (m, 10, CH Ar R and β), 6.48 (dd, 1/2, J1′,2′ ) 7.1 Hz, J1′,2′ ) 5. 5 Hz, H-1′ R/β), 6.30 (t, 1/2, J ) 7. 6 Hz, H-1′ R/β), 4.58 (m, 4, CH2 Bn R and β), 4.53 (m, 1/2, H-3′ R/β), 3.98 (m, 1, H-5′ R and β), 3.88 (m, 1/2, H-3′ R/β), 3.77 (m, 1, H-5′ R and β), 3.60 (m, 1, H-4′ R and β), 2.64 (m, 3 1/2, CH2 R and β, H-2′ R/β), 2.46 (m, 1/2, H-2′ R/β), 1.68 (m, 2, CH2 R and β), 1.00 (m, 3, CH3 R and β).…”

“…4 In the 6-azapyrimidine nucleoside series, 6-azauridine monophosphate 4 is of most interest, owing to its antiviral activity which results from inhibition of orotidine 5′-monophosphate decarboxylase, an enzyme involved in the de novo pyrimidine mononucleotide biosynthesis. 5 As with all conventional glycosidic linkages, these azapyrimidine nucleosides are susceptible to cleavage by nucleoside phosphorylases. The toxicity associated with these azapyrimidine nucleosides may well result from release of the 5-or 6-azapyrimidine base, which are known to display narcotic activity and cause central nervous system disturbances in man.…”