Medicinal Chemistry of Nucleotide Analogues

About our group

Research projects of the group deal predominantly with development of inhibitors of enzymes involved in the metabolism of nucleosides and nucleotides. Rational design of novel types of modified nucleosides and nucleotides, acyclic nucleoside phosphonates and their prodrugs in particular, is based on the previous extensive structure-activity relationship studies carried out in our group. For the syntheses of target compounds, efficient methodology is developed using diverse methods of modern organic chemistry. Target structures are designed with respect to their anticipated antiviral, antiparasitic, antibiotic, cytostatic, and anti-inflammatory properties based on inhibition of key enzymes. The mechanism of action of prepared antimetabolites and their potential biomedicinal applications are studied in collaboration with numerous scientific groups worldwide.

Reactive cyclic intermediates in the ProTide prodrugs activation: trapping the elusive pentavalent phosphorane

E. Procházková R. Navrátil Z. Janeba J. Roithová O. Baszczyňski

Organic and Biomolecular Chemistry 17 (2): 315-320 (2019)

Nucleotide prodrugs (ProTides) based on phosphate or phosphonate compounds are potent and successfully marketed antiviral drugs. Although their biological properties are well explored, experimental evidence on the mechanism of their activation pathway is still missing. In this study, we synthesized two ProTide analogues, which can be activated by UV light. Using ³¹P and ¹³C NMR spectroscopy with in situ irradiation, we followed the ProTide activation pathway in various solvents, and we detected the first proposed intermediate and the monoamidate product. Furthermore, we used mass spectrometry (MS) coupled with infrared spectroscopy in the gas phase to detect and to characterize the elusive cyclic pentavalent phosphorane and cyclic acyl phosphoramidate intermediates. Our combined NMR and MS data provided the first experimental evidence of the cyclic intermediates in the activation pathway of ProTide prodrugs.

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Nucleobase Modified Adefovir (PMEA) Analogues as Potent and Selective Inhibitors of Adenylate Cyclases from Bordetella pertussis and Bacillus anthracis

M. Česnek J. Skácel P. Jansa M. Dračínský M. Šmídková H. Mertlíková-Kaiserová M. Soto-Velasquez V. J. Watts Z. Janeba

ChemMedChem 13 (17): 1779-1796 (2018)

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Synthesis of α‐Branched Acyclic Nucleoside Phosphonates as Potential Inhibitors of Bacterial Adenylate Cyclases

J. Frydrych J. Skácel M. Šmídková H. Mertlíková-Kaiserová M. Dračínský R. Gnanasekaran M. Lepšík M. Soto-Velasquez V. J. Watts Z. Janeba

ChemMedChem 13 (2): 199-206 (2018)

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