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. 2020 Nov 6;22(21):8430-8435.
doi: 10.1021/acs.orglett.0c03052. Epub 2020 Oct 21.

Cyanoamidine Cyclization Approach to Remdesivir's Nucleobase

Rachel R Knapp  1 , Veronica Tona  1 , Taku Okada  2 , Richmond Sarpong  2 , Neil K Garg  1
Affiliations

Cyanoamidine Cyclization Approach to Remdesivir's Nucleobase

Rachel R Knapp et al. Org Lett. .

Abstract

We report an alternative approach to the unnatural nucleobase fragment seen in remdesivir (Veklury). Remdesivir displays broad-spectrum antiviral activity and is currently being evaluated in Phase III clinical trials to treat patients with COVID-19. Our route relies on the formation of a cyanoamidine intermediate, which undergoes Lewis acid-mediated cyclization to yield the desired nucleobase. The approach is strategically distinct from prior routes and could further enable the synthesis of remdesivir and other small-molecule therapeutics.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Antiviral drug remdesivir (1) and nucleobase fragment 2.
Figure 2
Figure 2
Selected examples of experimental and approved drugs that possess fragment 2 or a derivative thereof.
Figure 3
Figure 3
Prior and current strategies for the synthesis of 2.
Figure 4
Figure 4
Synthetic routes to formamide 12 stemming from 15.
Figure 5
Figure 5
Synthesis of 2 on a >1 mmol scale.
See this image and copyright information in PMC

References

    1. Kupferschmidt K.‘A completely new culture of doing research.’ Coronavirus outbreak changes how scientists communicate. Science, February 26, 2020. https://www.sciencemag.org/news/2020/02/completely-new-culture-doing-res... (accessed 2020-08-30).
    2. Hao K.Over 24,000 coronavirus research papers are now available in one place. MIT Technology Review, March 16, 2020. https://www.technologyreview.com/2020/03/16/905290/coronavirus-24000-res... (accessed 2020-08-30).
    3. Hardy M. A.; Wright B. A.; Bachman J. L.; Boit T. B.; Haley H. M. S.; Knapp R. R.; Lusi R. F.; Okada T.; Tona V.; Garg N. K.; Sarpong R. Treating a global health crisis with a dose of synthetic chemistry. ACS Cent. Sci. 2020, 6, 1017–1030. 10.1021/acscentsci.0c00637. - DOI - PMC - PubMed
    1. Peplow M.Rapid COVID-19 testing breaks free from the lab. Chem. Eng. News, August 10, 2020. https://cen.acs.org/analytical-chemistry/diagnostics/Rapid-COVID-19-test... (accessed 2020-08-30).
    2. Tromberg B. J.; Schwetz T. A.; Pérez-Stable E. J.; Hodes R. J.; Woychik R. P.; Bright R. A.; Fleurence R. L.; Collins F. S. Rapid scaling up of COVID-19 diagnostic testing in the United States – The NIH RADx Initiative. N. Engl. J. Med. 2020, 383, 1071–1077. 10.1056/NEJMsr2022263. - DOI - PMC - PubMed
    3. NIH delivering new COVID-19 testing technologies to meet U.S. demand. National Institutes of Health, July 31, 2020. https://www.nih.gov/news-events/news-releases/nih-delivering-new-covid-1... (accessed 2020-08-30).
    4. La Marca A.; Capuzzo M.; Paglia T.; Roli L.; Trenti T.; Nelson S. M. Testing for SARS-CoV-2 (COVID-19): A systematic review and clinical guide to molecular and serological in-vitro diagnostic assays. Reprod. BioMed. Online 2020, 41, 483–499. 10.1016/j.rbmo.2020.06.001. - DOI - PMC - PubMed
    5. SARS-CoV-2 Diagnostic Pipeline. Foundation for Innovative New Diagnostics (FIND), 2020. https://www.finddx.org/covid-19/pipeline/ (accessed 2020-08-30).
    6. Bustin S. A.; Benes V.; Garson J. A.; Hellemans J.; Huggett J.; Kubista M.; Mueller R.; Nolan T.; Pfaffl M. W.; Shipley G. L.; Vandesompele J.; Wittwer C. T. The MIQE guidelines: Minimum information for publication of quantitative real-time PCR experiments. Clin. Chem. 2009, 55, 611–622. 10.1373/clinchem.2008.112797. - DOI - PubMed
    7. Abbott realtime SARS-CoV-2 assay. Abbott Laboratories, 2020. https://www.molecular.abbott/us/en/products/infectious-disease/RealTime-... (accessed 2020-08-30). - PubMed
    8. New Rutgers saliva test for coronavirus gets FDA approval. Rutgers University, April 13, 2020. https://www.rutgers.edu/news/new-rutgers-saliva-test-coronavirus-gets-fd... (accessed 2020-08-30).
    9. Hahn S. M.Coronavirus (COVID-19) update: serological tests. U.S. Food and Drug Administration, April, 7, 2020. https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19... (accessed 2020-08-30).
    10. Kobokovich A.; West R.; Gronvall G.. Serology-based tests for COVID-19. Center for Health Security, Johns Hopkins Bloomberg School of Public Health, 2020. https://www.centerforhealthsecurity.org/resources/COVID-19/serology/Sero... (accessed 2020-08-30).
    11. Bloom J. S.; Jones E. M.; Gasperini M.; Lubock N. B.; Sathe L.; Munugala C.; Booeshaghi A. S.; Brandenberg O. F.; Guo L.; Boocock J.; Simpkins S. W.; Lin I.; LaPierre N.; Hong D.; Zhang Y.; Oland G.; Choe B. J.; Chandrasekaran S.; Hilt E. E.; Butte M. J.; Damoiseaux R.; Cooper A. R.; Yin Y.; Pachter L.; Garner O. B.; Flint J.; Eskin E.; Luo C.; Kosuri S.; Kruglyak L.; Arboleda V. A. Swab-Seq: A high-throughput platform for massively scaled up SARS-CoV-2 testing. medRxiv 2020, 10.1101/2020.08.04.20167874. - DOI
    1. Corum J.; Grady D.; Wee S.-L.; Zimmer C.. Coronavirus Vaccine Tracker. The New York Times, August 31, 2020. https://www.nytimes.com/interactive/2020/science/coronavirus-vaccine-tra.... (accessed 2020-08-31).
    2. Deming M. E.; Michael N. L.; Robb M.; Cohen M. S.; Neuzil K. M. Accelerating development of SARS-CoV-2 vaccines—the role for controlled human infection models. N. Engl. J. Med. 2020, 383, e63.10.1056/NEJMp2020076. - DOI - PMC - PubMed
    3. Slaoui M.; Hepburn M. Developing safe and effective COVID vaccines—Operation Warp Speed’s strategy and approach. N. Engl. J. Med. 2020, 10.1056/NEJMp2027405. - DOI - PubMed
    4. Lurie N.; Saville M.; Hatchett R.; Halton J. Developing COVID-19 vaccines at pandemic speed. N. Engl. J. Med. 2020, 382, 1969–1973. 10.1056/NEJMp2005630. - DOI - PubMed
    5. Liu C.; Zhou Q.; Li Y.; Garner L. V.; Watkins S. P.; Carter L. J.; Smoot J.; Gregg A. C.; Daniels A. D.; Jervey S.; Albaiu D. Research and development on therapeutic agents and vaccines for COVID-19 and related human coronavirus diseases. ACS Cent. Sci. 2020, 6, 315–331. 10.1021/acscentsci.0c00272. - DOI - PMC - PubMed

    1. For recent studies pertaining to remdesivir, see:

    2. COVID-19 update: FDA broadens emergency use authorization of Veklury (remdesivir) to include all hospital patients for treatment of COVID-19. U.S. Food and Drug Administration, August, 28, 2020. https://www.fda.gov/news-events/press-announcements/covid-19-update-fda-... (accessed 2020-08-30).
    3. O’Day D.An open letter from our Chairman & CEO. Gilead Sciences, Inc., April 29, 2020. https://stories.gilead.com/articles/an-open-letter-from-our-chairman-and... (accessed 2020-08-30).
    4. Gilead submits new drug application to U.S. Food and Drug Administration for Veklury (remdesivir) for the treatment of COVID-19. Gilead Sciences, Inc., August 10, 2020. https://www.gilead.com/news-and-press/press-room/press-releases/2020/8/g... (accessed 2020-08-30).
    5. Beigel J. H.; Tomashek K. M.; Dodd L. E.; Mehta A. K.; Zingman B. S.; Kalil A. C.; Hohmann E.; Chu H. Y.; Luetkemeyer A.; Kline S.; Lopez de Castilla D.; Finberg R. W.; Dierberg K.; Tapson V.; Hsieh L.; Patterson T. F.; Paredes R.; Sweeney D. A.; Short W. R.; Touloumi G.; Lye D. C.; Ohmagari N.; Oh M-d.; Ruiz-Palacios G. M.; Benfield T.; Fätkenheuer G.; Kortepeter M. G.; Atmar R. L.; Creech C. B.; Lundgren J.; Babiker A. G.; Pett S.; Neaton J. D.; Burgess T. H.; Bonnett T.; Green M.; Makowski M.; Osinusi A.; Nayak S.; Lane H. C. Remdesivir for the treatment of COVID-19—Final report. N. Engl. J. Med. 2020, 10.1056/NEJMoa2007764. - DOI - PMC - PubMed
    6. Spinner C. D.; Gottlieb R. L.; Criner G. J.; Arribas López J. R.; Cattelan A. M.; Soriano Viladomiu A.; Ogbuagu O.; Malhotra P.; Mullane K. M.; Castagna A.; Chai L. Y. A.; Roestenberg M.; Tsang O. T. Y.; Bernasconi E.; Le Turnier P.; Chang S.-C.; SenGupta D.; Hyland R. H.; Osinusi A. O.; Cao H.; Blair C.; Wang H.; Gaggar A.; Brainard D. M.; McPhail M. J.; Bhagani S.; Ahn M. Y.; Sanyal A. J.; Huhn G.; Marty F. M. Effect of remdesivir vs standard care on clinical status at 11 days in patients with moderate COVID-19. JAMA 2020, 324, 1048–1057. 10.1001/jama.2020.16349. - DOI - PMC - PubMed
    7. Al-Tawfiq J. A.; Al-Homoud A. H.; Memish Z. A. Remdesivir as a possible therapeutic option for the COVID-19. Travel Med. Infect. Dis. 2020, 34, 101615.10.1016/j.tmaid.2020.101615. - DOI - PMC - PubMed
    8. Wang M.; Cao R.; Zhang L.; Yang X.; Liu J.; Xu M.; Shi Z.; Hu Z.; Zhong W.; Xiao G. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res. 2020, 30, 269–271. 10.1038/s41422-020-0282-0. - DOI - PMC - PubMed
    9. Sheahan T. P.; Sims A. C.; Leist S. R.; Schäfer A.; Won J.; Brown A. J.; Montgomery S. A.; Hogg A.; Babusis D.; Clarke M. O.; Spahn J. E.; Bauer L.; Sellers S.; Porter D.; Feng J. Y.; Cihlar T.; Jordan R.; Denison M. R.; Baric R. S. Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon β against MERS-CoV. Nat. Commun. 2020, 11, 222.10.1038/s41467-019-13940-6. - DOI - PMC - PubMed

    10. For remdesivir clinical trials for COVID-19, see:

    11. https://clinicaltrials.gov/ct2/results?cond=&term=remdesivir&cntry=&stat... (accessed 2020-08-30).

    1. For recent studies pertaining to other small-molecule therapeutics besides remdesivir that are relevant to COVID-19, see:

    2. Li G.; De Clercq E. Therapeutic options for the 2019 novel coronavirus (2019-nCoV). Nat. Rev. Drug Discov. 2020, 19, 149–150. 10.1038/d41573-020-00016-0. - DOI - PubMed
    3. Sheahan T. P.; Sims A. C.; Zhou S.; Graham R. L.; Pruijssers A. J.; Agostini M. L.; Leist S. R.; Schäfer A.; Dinnon K. H. III; Stevens L. J.; Chappell J. D.; Lu X.; Hughes T. M.; George A. S.; Hill C. S.; Montgomery S. A.; Brown A. J.; Bluemling G. R.; Natchus M. G.; Saindane M.; Kolykhalov A. A.; Painter G.; Harcourt J.; Tamin A.; Thornburg N. J.; Swanstrom R.; Denison M. R.; Baric R. S. An orally bioavailable broad-spectrum antiviral inhibits SARS-CoV-2 in human airway epithelial cell cultures and multiple coronaviruses in mice. Sci. Transl. Med. 2020, 12, eabb5883.10.1126/scitranslmed.abb5883. - DOI - PMC - PubMed
    4. Halford B.An emerging antiviral takes aim at COVID-19. Chem. Eng. News, May 5, 2020. https://cen.acs.org/pharmaceuticals/drug-development/emerging-antiviral-... (accessed 2020-08-30).
    5. Eddy J.Ridgeback Biotherapeutics announces launch of phase 2 trials testing EIDD-2801 as potential treatment for COVID-19. Bloomberg, June 19, 2020. https://www.bloomberg.com/press-releases/2020-06-19/ridgeback-biotherape... (accessed 2020-08-30).
    6. De Savi C.; Hughes D. L.; Kvaerno L. Quest for a COVID-19 cure by repurposing small-molecule drugs: mechanism of action, clinical development, synthesis at scale, and outlook for supply. Org. Process Res. Dev. 2020, 24, 940–976. 10.1021/acs.oprd.0c00233. - DOI - PubMed
    7. Maxmen A. More than 80 clinical trials launch to test coronavirus treatments. Nature 2020, 578, 347–348. 10.1038/d41586-020-00444-3. - DOI - PubMed
    8. Main protease structure and XChem fragment screen. Diamond Light Source, May 5, 2020. https://www.diamond.ac.uk/covid-19/for-scientists/Main-protease-structur... (accessed 2020-08-30).
    9. Moskal M.; Beker W.; Roszak R.; Gajewska E. P.; Wolos A.; Molga K.; Szymkuć S.; Grynkiewicz G.; Grzybowski B. A. Suggestions for second-pass anti-COVID-19 drugs based on the artificial intelligence measures of molecular similarity, shape and pharmacophore distribution. ChemRxiv 2020, 10.26434/chemrxiv.12084690.v2. - DOI
    10. Wang J. Fast identification of possible drug treatment of coronavirus disease-19 (COVID-19) through computational drug repurposing study. J. Chem. Inf. Model. 2020, 60, 3277–3286. 10.1021/acs.jcim.0c00179. - DOI - PMC - PubMed

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