Design and synthesis of alpha-carboxy nucleoside phosphonate analogues and evaluation as HIV-1 reverse transcriptase-targeting agents

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Date
2014-12-22
Authors
Keane, Sarah J.
Ford, Alan
Mullins, Nicholas D.
Maguire, Nuala M.
Legigan, Thibaut
Balzarini, Jan
Maguire, Anita R.
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American Chemical Society
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Abstract
The synthesis of the first series of a new class of nucleoside phosphonate analogues is described. Addition of a carboxyl group at the α position of carbocyclic nucleoside phosphonate analogues leads to a novel class of potent HIV reverse transcriptase (RT) inhibitors, α-carboxy nucleoside phosphonates (α-CNPs). Key steps in the synthesis of the compounds are Rh-catalyzed O–H insertion and Pd-catalyzed allylation reactions. In cell-free assays, the final products are markedly inhibitory against HIV RT and do not require phosphorylation to exhibit anti-RT activity, which indicates that the α-carboxyphosphonate function is efficiently recognized by HIV RT as a triphosphate entity, an unprecedented property of nucleoside monophosph(on)ates.
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Keywords
Organophosphorus compounds , Inhibitors , Organic compounds , Nucleic acids , Reaction products , Immunodeficiency-virus type-1
Citation
Keane, S. J., Ford, A., Mullins, N. D., Maguire, N. M., Legigan, T., Balzarini, J. and Maguire, A. R. (2015) 'Design and Synthesis of α-Carboxy Nucleoside Phosphonate Analogues and Evaluation as HIV-1 Reverse Transcriptase-Targeting Agents', The Journal of Organic Chemistry, 80(5), pp. 2479-2493. doi: 10.1021/jo502549y
Copyright
© 2014 American Chemical Society. This document is the Accepted Manuscript version of a Published Work that appeared in final form in Journal of Organic Chemistry copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see https://pubs.acs.org/doi/10.1021/jo502549y