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

Keane, Sarah J.; Ford, Alan; Mullins, Nicholas D.; Maguire, Nuala M.; Legigan, Thibaut; Balzarini, Jan; Maguire, Anita R.

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

dc.contributor.author	Keane, Sarah J.
dc.contributor.author	Ford, Alan
dc.contributor.author	Mullins, Nicholas D.
dc.contributor.author	Maguire, Nuala M.
dc.contributor.author	Legigan, Thibaut
dc.contributor.author	Balzarini, Jan
dc.contributor.author	Maguire, Anita R.
dc.contributor.funder	Science Foundation Ireland	en
dc.contributor.funder	KU Leuven	en
dc.date.accessioned	2020-08-31T12:40:57Z
dc.date.available	2020-08-31T12:40:57Z
dc.date.issued	2014-12-22
dc.date.updated	2020-08-24T14:27:34Z
dc.description.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.	en
dc.description.sponsorship	KU Leuven – University of Leuven (PF-10/018)	en
dc.description.status	Peer reviewed	en
dc.description.version	Accepted Version	en
dc.format.mimetype	application/pdf	en
dc.identifier.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	en
dc.identifier.doi	10.1021/jo502549y	en
dc.identifier.endpage	2493	en
dc.identifier.issn	0022-3263
dc.identifier.journaltitle	The Journal of Organic Chemistry	en
dc.identifier.startpage	2479	en
dc.identifier.uri	https://hdl.handle.net/10468/10417
dc.identifier.volume	80	en
dc.language.iso	en	en
dc.publisher	American Chemical Society	en
dc.relation.project	info:eu-repo/grantAgreement/SFI/SFI Principal Investigator Programme (PI)/05/PICA/B802/IE/Design and Synthesis of Novel Phosphononucleosides - Potential Antiviral Agents/	en
dc.relation.uri	https://pubs.acs.org/doi/10.1021/jo502549y
dc.rights	© 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	en
dc.subject	Organophosphorus compounds	en
dc.subject	Inhibitors	en
dc.subject	Organic compounds	en
dc.subject	Nucleic acids	en
dc.subject	Reaction products	en
dc.subject	Immunodeficiency-virus type-1	en
dc.title	Design and synthesis of alpha-carboxy nucleoside phosphonate analogues and evaluation as HIV-1 reverse transcriptase-targeting agents	en
dc.type	Article (peer-reviewed)	en