3258-02-4

Basic information

• Product Name: N(4)-hydroxycytidine
• Synonyms: N(4)-hydroxycytidine;1-[(2R)-3α,4α-Dihydroxy-5β-(hydroxymethyl)oxolane-2β-yl]-4-(hydroxyamino)pyrimidine-2(1H)-one;3,4-Dihydro-1-β-D-ribofuranosyl-4-(hydroxyimino)pyrimidin-2(1H)-one;N-Hydroxycytidine;β-D-N4-Hydroxycytidine
• CAS NO: 3258-02-4
• Molecular Formula: C₉H₁₃N₃O₆
• Molecular Weight: 259.25
• Mol File: 3258-02-4.mol
• Article Data: 17

Chemical Properties

• Melting Point: 169-172 °C(Solv: methanol (67-56-1))
• Boiling Point: 576.1°Cat760mmHg
• Flash Point: 302.2°C
• Appearance: /
• Density: 1.93g/cm³
• Vapor Pressure: 1.14E-15mmHg at 25°C
• Refractive Index: 1.753
• Storage Temp.: Inert atmosphere,Store in freezer, under -20°C
• Solubility: Soluble in DMSO (up to 25 mg/ml) or in Water (up to 15 mg/ml with warming).
• PKA: 8.19±0.20(Predicted)
• Stability: Stable for 1 year from date of purchase as supplied. Solutions in DMSO or distilled water may be stored at -20° for up to 3 months.
• CAS DataBase Reference: N(4)-hydroxycytidine(CAS DataBase Reference)
• NIST Chemistry Reference: N(4)-hydroxycytidine(3258-02-4)
• EPA Substance Registry System: N(4)-hydroxycytidine(3258-02-4)

Safety Data

• Hazardous Substances Data: 3258-02-4(Hazardous Substances Data)

Usage

Description

N(4)-hydroxycytidine is a ribonucleoside analog with antiviral activity. It is an orally bioavailable broad-spectrum antiviral that inhibits SARS-CoV-2 and other multiple endemic, epidemic, and bat coronaviruses. It has the potential for seasonal and pandemic influenza treatment and is a broad-spectrum inhibitor of influenza and respiratory syncytial viruses.

Uses

Used in Antiviral Applications:
N(4)-hydroxycytidine is used as a broad-spectrum antiviral agent for inhibiting the replication of various viruses, including SARS-CoV, MERS-CoV, and SARS-CoV-2. It reduces viral titers in infected cells and has potential applications in the treatment of seasonal and pandemic influenza.
Used in Pharmaceutical Industry:
N(4)-hydroxycytidine is used as a pharmaceutical agent for the development of antiviral drugs targeting a wide range of viruses. Its broad-spectrum activity and oral bioavailability make it a promising candidate for the treatment of various viral infections.

References

1) Janion and Glickman (1980),?N4-hydroxycytidine: a mutagen specific for AT to GC transitions;?Mutat. Res.,?72?43 2) Stuyver?et al.?(2003),?Ribonucleotide analogue that blocks replication of bovine viral diarrhea and hepatitis C viruses in culture; Antimicrob. Agents Chemother.,?47?244 3) Costantini?et al.?(2012),?Antiviral activity of nucleoside analogues against norovirus; Antivir. Ther.,?17?981 4) Reynard?et al.?(2015),?Identification of a New Ribonucleoside Inhibitor of Ebola Virus Replication; Viruses,?7?6233 5) Ehteshami?et al.?(2017),?Characterization of ?-D-N4-Hydroxycytidine as a Novel Inhibitor of Chikungunya Virus; Antimicrob. Agents Chemother.,?61?e02395-16 6) Yoon?et al.?(2018),?Orally efficacious broad-spectrum ribonucleoside analog inhibitor of influenza and respiratory syncytial viruses; Antimicrob. Agents Chemother.,?62?e00766-18 7) Barnard?et al.?(2004),?Inhibition of severe acute respiratory syndrome-associated coronavirus (SARSCoV) by calpain inhibitors and beta-D-N4-hydroxycytidine; Antivir. Chem. Chemother., 15 15 8) Pyrc et al. (2006),?Inhibition of human coronavirus NL63 infection at early stages of the replication cycle; Antimicrob. Agents Chemother.,?50?2000 9) Toots et al. (2019),?Characterization of orally efficacious influenza drug with high resistance barrier in ferrets and human airway epithelia; Sci. Transl. Med.,?11?eaax5866

InChI:InChI=1/C9H13N3O6/c13-3-4-6(14)7(15)8(18-4)12-2-1-5(11-17)10-9(12)16/h1-2,4,6-8,13-15,17H,3H2,(H,10,11,16)/t4-,6-,7-,8-/m1/s1

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Relevant articles and documents

Orally efficacious broad-spectrum ribonucleoside analog inhibitor of influenza and respiratory syncytial viruses

Morbidity and mortality resulting from influenza-like disease are a threat, especially for older adults. To improve case management, next-generation broad-spectrum antiviral therapeutics that are efficacious against major drivers of influenza-like disease, including influenza viruses and respiratory syncytial virus (RSV), are urgently needed. Using a dual-pathogen high-throughput screening protocol for influenza A virus (IAV) and RSV inhibitors, we have identified N4-hydroxycytidine (NHC) as a potent inhibitor of RSV, influenza B viruses, and IAVs of human, avian, and swine origins. Biochemical in vitro polymerase assays and viral RNA sequencing revealed that the ribonucleotide analog is incorporated into nascent viral RNAs in place of cytidine, increasing the frequency of viral mutagenesis. Viral passaging in cell culture in the presence of an inhibitor did not induce robust resistance. Pharmacokinetic profiling demonstrated dose-dependent oral bioavailability of 36 to 56%, sustained levels of the active 5=-triphosphate anabolite in primary human airway cells and mouse lung tissue, and good tolerability after extended dosing at 800 mg/kg of body weight/day. The compound was orally efficacious against RSV and both seasonal and highly pathogenic avian IAVs in mouse models, reducing lung virus loads and alleviating disease biomarkers. Oral dosing reduced IAV burdens in a Guinea pig transmission model and suppressed virus spread to uninfected contact animals through direct transmission. Based on its broad-spectrum efficacy and pharmacokinetic properties, NHC is a promising candidate for future clinical development as a treatment option for influenza-like diseases.

An Engineered Cytidine Deaminase for Biocatalytic Production of a Key Intermediate of the Covid-19 Antiviral Molnupiravir

The Covid-19 pandemic highlights the urgent need for cost-effective processes to rapidly manufacture antiviral drugs at scale. Here we report a concise biocatalytic process for Molnupiravir, a nucleoside analogue recently approved as an orally available treatment for SARS-CoV-2. Key to the success of this process was the development of an efficient biocatalyst for the production of N-hydroxy-cytidine through evolutionary adaption of the hydrolytic enzyme cytidine deaminase. This engineered biocatalyst performs >85 000 turnovers in less than 3 h, operates at 180 g/L substrate loading, and benefits from in situ crystallization of the N-hydroxy-cytidine product (85% yield), which can be converted to Molnupiravir by a selective 5′-acylation using Novozym 435.

Preparation method of N4-hydroxycytidine

The invention discloses a preparation method of N4-hydroxycytidine capable of preventing and treating various virus infection including COVID-19. The preparation method comprises the following steps: taking cytosine and tetraacetyl ribose as initial raw materials, and carrying out hydroxyamination, condensation and hydrolysis reaction to prepare the N4-hydroxycytidine. The preparation method is easily available in raw materials, simple in process, economical, environment-friendly and suitable for industrial production.

N4-HYDROXYCYTIDINE AND DERIVATIVES AND ANTI-VIRAL USES RELATED THERETO

This disclosure relates to certain N4-hydroxycytidine derivatives, pharmaceutical compositions, and methods related thereto. In certain embodiments, the disclosure relates to the treatment or prophylaxis of human coronavirus 2019-nCoV.