Preparative Synthesis of an RP-Guanosine-3′,5′-Cyclic Phosphorothioate Analogue, a Drug Candidate for the Treatment of Retinal Degenerations
Post-print Cyclic guanosine monophosphorothioate analogue 1a is currently showing potential as a drug for the treatment of inherited retinal neurodegenerations. To support ongoing preclinical and clinical work, we have developed a diastereoselective synthesis via cyclization and sulfurization of the...
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Online Access: | https://hdl.handle.net/20.500.11815/2725 https://doi.org/10.1021/acs.oprd.1c00230 |
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ftopinvisindi:oai:opinvisindi.is:20.500.11815/2725 2023-05-15T16:51:06+02:00 Preparative Synthesis of an RP-Guanosine-3′,5′-Cyclic Phosphorothioate Analogue, a Drug Candidate for the Treatment of Retinal Degenerations Pérez, Oswaldo Schipper, Nicolaas Bollmark, Martin Lyfjafræðideild (HÍ) Faculty of Pharmaceutical Sciences (UI) Heilbrigðisvísindasvið (HÍ) School of Health Sciences (UI) Háskóli Íslands University of Iceland 2021-10-19 2453-2460 https://hdl.handle.net/20.500.11815/2725 https://doi.org/10.1021/acs.oprd.1c00230 en eng American Chemical Society info:eu-repo/grantAgreement/EC/H2020/MSCA/765441 Organic Process Research and Development;25(11) https://pubs.acs.org/doi/10.1021/acs.oprd.1c00230 Pérez, O., Schipper, N., & Bollmark, M. (2021). Preparative Synthesis of an RP-Guanosine-3′,5′-Cyclic Phosphorothioate Analogue, a Drug Candidate for the Treatment of Retinal Degenerations. Organic Process Research & Development, 25(11), 2453-2460. doi:10.1021/acs.oprd.1c00230 1083-6160 1520-586X (eISSN) https://hdl.handle.net/20.500.11815/2725 Organic Process Research and Development https://doi.org/10.1021/acs.oprd.1c00230 info:eu-repo/semantics/openAccess Organic Chemistry Physical and Theoretical Chemistry preclinical development process development retinal neurodegenerations nucleotide H-phosphonate cyclic guanosine monophosphorothioate cyclic guanosine monophosphate Lífræn efnafræði info:eu-repo/semantics/article 2021 ftopinvisindi https://doi.org/20.500.11815/2725 https://doi.org/10.1021/acs.oprd.1c00230 2022-11-18T06:52:13Z Post-print Cyclic guanosine monophosphorothioate analogue 1a is currently showing potential as a drug for the treatment of inherited retinal neurodegenerations. To support ongoing preclinical and clinical work, we have developed a diastereoselective synthesis via cyclization and sulfurization of the nucleoside 5′-H-phosphonate monoester, which affords the desired RP-3′,5′-cyclic phosphorothioate in 9:1 ratio to the undesired SP-diastereomer. This route was made viable as a result of the silyl protection sequence used, which achieved >80% selectivity for 2′,5′-hydroxyls over 3′,5′-hydroxyls. Finally, the chromatography-free process allowed for a scale-up, as intermediates and the final product were isolated by crystallization to give 125 g of 1a (13.8% total yield) with over 99.9% HPLC purity. The authors would like to thank Professor Thorsteinn Loftsson at the University of Iceland for his continued support and guidance, particularly to O.P. as academic supervisor, and Professor Jacek Stawiński at Stockholm University for fruitful discussions. We also thank Dr. Frank Schwede at BIOLOG Life Science Institute (Bremen, Germany) for discussions about synthetic strategy as well as providing material for structural comparisons to our product. This work was supported by the European Commission (H2020-MSCA-765441; HEALTH-F2-2012-304963) Peer Reviewed Article in Journal/Newspaper Iceland Opin vísindi (Iceland) Organic Process Research & Development 25 11 2453 2460 |
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Open Polar |
collection |
Opin vísindi (Iceland) |
op_collection_id |
ftopinvisindi |
language |
English |
topic |
Organic Chemistry Physical and Theoretical Chemistry preclinical development process development retinal neurodegenerations nucleotide H-phosphonate cyclic guanosine monophosphorothioate cyclic guanosine monophosphate Lífræn efnafræði |
spellingShingle |
Organic Chemistry Physical and Theoretical Chemistry preclinical development process development retinal neurodegenerations nucleotide H-phosphonate cyclic guanosine monophosphorothioate cyclic guanosine monophosphate Lífræn efnafræði Pérez, Oswaldo Schipper, Nicolaas Bollmark, Martin Preparative Synthesis of an RP-Guanosine-3′,5′-Cyclic Phosphorothioate Analogue, a Drug Candidate for the Treatment of Retinal Degenerations |
topic_facet |
Organic Chemistry Physical and Theoretical Chemistry preclinical development process development retinal neurodegenerations nucleotide H-phosphonate cyclic guanosine monophosphorothioate cyclic guanosine monophosphate Lífræn efnafræði |
description |
Post-print Cyclic guanosine monophosphorothioate analogue 1a is currently showing potential as a drug for the treatment of inherited retinal neurodegenerations. To support ongoing preclinical and clinical work, we have developed a diastereoselective synthesis via cyclization and sulfurization of the nucleoside 5′-H-phosphonate monoester, which affords the desired RP-3′,5′-cyclic phosphorothioate in 9:1 ratio to the undesired SP-diastereomer. This route was made viable as a result of the silyl protection sequence used, which achieved >80% selectivity for 2′,5′-hydroxyls over 3′,5′-hydroxyls. Finally, the chromatography-free process allowed for a scale-up, as intermediates and the final product were isolated by crystallization to give 125 g of 1a (13.8% total yield) with over 99.9% HPLC purity. The authors would like to thank Professor Thorsteinn Loftsson at the University of Iceland for his continued support and guidance, particularly to O.P. as academic supervisor, and Professor Jacek Stawiński at Stockholm University for fruitful discussions. We also thank Dr. Frank Schwede at BIOLOG Life Science Institute (Bremen, Germany) for discussions about synthetic strategy as well as providing material for structural comparisons to our product. This work was supported by the European Commission (H2020-MSCA-765441; HEALTH-F2-2012-304963) Peer Reviewed |
author2 |
Lyfjafræðideild (HÍ) Faculty of Pharmaceutical Sciences (UI) Heilbrigðisvísindasvið (HÍ) School of Health Sciences (UI) Háskóli Íslands University of Iceland |
format |
Article in Journal/Newspaper |
author |
Pérez, Oswaldo Schipper, Nicolaas Bollmark, Martin |
author_facet |
Pérez, Oswaldo Schipper, Nicolaas Bollmark, Martin |
author_sort |
Pérez, Oswaldo |
title |
Preparative Synthesis of an RP-Guanosine-3′,5′-Cyclic Phosphorothioate Analogue, a Drug Candidate for the Treatment of Retinal Degenerations |
title_short |
Preparative Synthesis of an RP-Guanosine-3′,5′-Cyclic Phosphorothioate Analogue, a Drug Candidate for the Treatment of Retinal Degenerations |
title_full |
Preparative Synthesis of an RP-Guanosine-3′,5′-Cyclic Phosphorothioate Analogue, a Drug Candidate for the Treatment of Retinal Degenerations |
title_fullStr |
Preparative Synthesis of an RP-Guanosine-3′,5′-Cyclic Phosphorothioate Analogue, a Drug Candidate for the Treatment of Retinal Degenerations |
title_full_unstemmed |
Preparative Synthesis of an RP-Guanosine-3′,5′-Cyclic Phosphorothioate Analogue, a Drug Candidate for the Treatment of Retinal Degenerations |
title_sort |
preparative synthesis of an rp-guanosine-3′,5′-cyclic phosphorothioate analogue, a drug candidate for the treatment of retinal degenerations |
publisher |
American Chemical Society |
publishDate |
2021 |
url |
https://hdl.handle.net/20.500.11815/2725 https://doi.org/10.1021/acs.oprd.1c00230 |
genre |
Iceland |
genre_facet |
Iceland |
op_relation |
info:eu-repo/grantAgreement/EC/H2020/MSCA/765441 Organic Process Research and Development;25(11) https://pubs.acs.org/doi/10.1021/acs.oprd.1c00230 Pérez, O., Schipper, N., & Bollmark, M. (2021). Preparative Synthesis of an RP-Guanosine-3′,5′-Cyclic Phosphorothioate Analogue, a Drug Candidate for the Treatment of Retinal Degenerations. Organic Process Research & Development, 25(11), 2453-2460. doi:10.1021/acs.oprd.1c00230 1083-6160 1520-586X (eISSN) https://hdl.handle.net/20.500.11815/2725 Organic Process Research and Development https://doi.org/10.1021/acs.oprd.1c00230 |
op_rights |
info:eu-repo/semantics/openAccess |
op_doi |
https://doi.org/20.500.11815/2725 https://doi.org/10.1021/acs.oprd.1c00230 |
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Organic Process Research & Development |
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25 |
container_issue |
11 |
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2453 |
op_container_end_page |
2460 |
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1766041221209260032 |