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

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...

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Bibliographic Details
Published in:Organic & biomolecular chemistry 2019-01, Vol.17 (2), p.315-32
Main Authors: Procházková, Eliška, Navrátil, Rafael, Janeba, Zlatko, Roithová, Jana, Baszczy ski, Ond ej
Format: Article
Language:English
Subjects:
Activation
Antiviral agents
Biological properties
Chemical compounds
Drugs
Infrared spectroscopy
Intermediates
Irradiation
Magnetic resonance spectroscopy
Mass spectrometry
Mass spectroscopy
NMR spectroscopy
Prodrugs
Spectroscopy
Ultraviolet radiation
Vapor phases
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Summary: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 31 P and 13 C 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. A combination of NMR and IRPD spectroscopy confirmed the existence of predicted cyclic phosphorus intermediates involved in ProTide prodrugs activation.
ISSN:1477-0520
1477-0539
DOI:10.1039/c8ob02870b