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

0501466 - ÚOCHB 2020 RIV GB eng J - Článek v odborném periodiku
Procházková, Eliška - Navrátil, R. - Janeba, Zlatko - Roithová, J. - Baszczyňski, Ondřej
Reactive cyclic intermediates in the ProTide prodrugs activation: trapping the elusive pentavalent phosphorane.
Organic & Biomolecular Chemistry. Roč. 17, č. 2 (2019), s. 315-320. ISSN 1477-0520. E-ISSN 1477-0539
Institucionální podpora: RVO:61388963
Klíčová slova: efficacy * acids * situ
Obor OECD: Organic chemistry
Impakt faktor: 3.412, rok: 2019
Způsob publikování: Omezený přístup
https://pubs.rsc.org/en/content/articlelanding/2019/OB/C8OB02870B#!divAbstract

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 P-31 and C-13 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.
Trvalý link: http://hdl.handle.net/11104/0296269