840506-42-5Relevant articles and documents
Targeting GNE Myopathy: A Dual Prodrug Approach for the Delivery of N-Acetylmannosamine 6-Phosphate
Morozzi, Chiara,Sedláková, Jana,Serpi, Michaela,Avigliano, Marialuce,Carbajo, Rosangela,Sandoval, Lucia,Valles-Ayoub, Yadira,Crutcher, Patrick,Thomas, Stephen,Pertusati, Fabrizio
, p. 8178 - 8193 (2019/09/10)
ProTides comprise an important class of prodrugs currently marketed and developed as antiviral and anticancer therapies. The ProTide technology employs phosphate masking groups capable of providing more favorable druglike properties and an intracellular activation mechanism for enzyme-mediated release of a nucleoside monophosphate. Herein, we describe the application of phosphoramidate chemistry to 1,3,4-O-acetylated N-acetylmannosamine (Ac3ManNAc) to deliver ManNAc-6-phosphate (ManNAc-6-P), a critical intermediate in sialic acid biosynthesis. Sialic acid deficiency is a hallmark of GNE myopathy, a rare congenital disorder of glycosylation (CDG) caused by mutations in GNE that limit the production of ManNAc-6-P. Synthetic methods were developed to provide a library of Ac3ManNAc-6-phosphoramidates that were evaluated in a series of studies for their potential as a treatment for GNE myopathy. Prodrug 12b showed rapid activation in a carboxylesterase (CPY) enzymatic assay and favorable ADME properties, while also being more effective than ManNAc at increasing sialic acid levels in GNE-deficient cell lines. These results provide a potential platform to address substrate deficiencies in GNE myopathy and other CDGs.
Activation of p16 gene silenced by DNA methylation in cancer cells by phosphoramidate derivatives of 2′-deoxyzebularine
Yoo, Christine B.,Valente, Rocco,Congiatu, Costantino,Gavazza, Federica,Angel, Annette,Siddiqui, Maqbool A.,Jones, Peter A.,McGuigan, Christopher,Marquez, Victor E.
experimental part, p. 7593 - 7601 (2009/12/07)
We report herein the application of the phosphoramidate ProTide technology to improve the metabolism of the DNA methytransferase inhibitor, zebularine (Z). Zebularine is a riboside that must undergo a complex metabolic transformation before reaching the critical 2′-deoxyzebularine 5′-triphosphate (dZTP). Because 2′-deoxyzebularine (dZ) is not phosphorylated and therefore inactive, the ProTide strategy was employed to bypass the lack of phosphorylation of dZ and the inefficient reduction of zebularine 5′-diphosphate by ribonucleotide-diphosphate reductase required for zebularine. Several compounds were identified as more potent inhibitors of DNA methylation and stronger inducers of p16 tumor suppressor gene than zebularine. However, their activity was dependent on the administration of thymidine to overcome the potent inhibition of thymidylate synthase (TS) and deoxycytidine monophosphate (dCMP) deaminase by dZMP, which deprives cells of essential levels of thymidine. Intriguingly, the activity of the ProTides was cell line-dependent, and activation of p16 was manifest only in Cf-Pac-1 pancreatic ductal adenocarcinoma cells.
PHOSPHORAMIDATE PRODRUGS FOR TREATMENT OF VIRAL INFECTION
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Page/Page column 16, (2008/06/13)
The invention concerns 2'-methyl ribonucleotide phosphoramidates which are neutral prodrugs which are converted in vivo to 2'- methyl ribonucleotide triphosphates. These compounds are useful in the treatment of viral infection. Of particular interest are prodrugs of a methylsulfonylhydrazinyl purine 2'-methyl nucleotide triphosphate: 2'methyl- N6-alkyl-N6- (N-methylsulfonamide) adenosine triphosphate and its 2-amino derivative.
