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Cytidine

Cytidine is a pyrimidine nucleoside consisting of the nitrogenous base cytosine attached to a β-D-ribofuranose sugar via a β-N¹-glycosidic bond.^[1] With the molecular formula C₉H₁₃N₃O₅, it exists as a white crystalline powder at room temperature and serves as a fundamental building block of RNA.^[1] In RNA, cytidine base-pairs with guanine through three hydrogen bonds, contributing to the double-helical structure and functional diversity of ribonucleic acids essential for gene expression, protein synthesis, and cellular regulation.^[2] Biochemically, cytidine plays a central role in pyrimidine nucleotide metabolism through the salvage pathway, where it is phosphorylated by uridine-cytidine kinase 1 (UCK1) using ATP to form cytidine monophosphate (CMP) and ADP.^[3] CMP is further phosphorylated to cytidine diphosphate (CDP) and cytidine triphosphate (CTP), which act as substrates for RNA polymerase during transcription and as precursors in phospholipid synthesis.^[4] As a human metabolite, cytidine participates in maintaining nucleoside pools for nucleic acid biosynthesis and energy transfer processes.^[1] Beyond its structural role in RNA, cytidine derivatives exhibit broader biological significance, including regulation of nucleoside pools by cytidine deaminases that convert it to uridine, influencing DNA and RNA synthesis.^[5] Recent studies highlight modifications like N⁴-acetylcytidine (ac⁴C) on cytidine residues in mRNA, which modulate translation efficiency, stability, and immune responses, underscoring its involvement in post-transcriptional regulation.^[6] These multifaceted functions position cytidine as a critical molecule in cellular homeostasis and potential therapeutic targets in antiviral and anticancer strategies.^[7]

Chemical Properties

Molecular Structure

Cytidine is a nucleoside consisting of the pyrimidine base cytosine linked to a D-ribose sugar through a β-N¹-glycosidic bond, connecting the N¹ atom of cytosine to the C1' carbon of the ribose.^[1] The molecular formula of cytidine is C₉H₁₃N₃O₅, and its molar mass is 243.22 g/mol.^[1] The sugar component adopts a furanose ring structure, forming a five-membered β-D-ribofuranose ring with the ring oxygen between C1' and C4'. Hydroxyl groups are positioned at C2', C3', and the primary alcohol at C5' (as -CH₂OH attached to C4'). The stereochemistry features chiral centers at C1' (β-anomeric configuration), C2', C3', and C4', specified as (2R,3R,4S,5R) in the systematic IUPAC nomenclature, where the oxolane (tetrahydrofuran) ring positions correspond to C1' through C4'.^[1] The cytosine base is a planar, heterocyclic pyrimidine ring with a keto group (=O) at the C2 position and an exocyclic amino group (-NH₂) at the C4 position, enabling its tautomeric form as 4-amino-1H-pyrimidin-2-one.^[8] In structural representations such as the Haworth projection, the β-D-ribofuranose appears as a planar pentagon with the cytosine base projecting below the ring at C1', hydroxyls at C2' and C3' above the plane, and the C5'-CH₂OH above at C4'.^[1]

Physical Properties

Cytidine is a white, crystalline powder at room temperature.^[9] It decomposes at approximately 230 °C without undergoing a true melting transition.^[10] Cytidine exhibits high solubility in water, approximately 50 g/L at 25 °C, while it is only slightly soluble in ethanol and insoluble in non-polar solvents such as diethyl ether.^[11]^[12] The compound displays optical activity with a specific rotation of [\alpha]^{20}_D = +34^\circ (c = 2 in water).^[9] In terms of UV absorption, cytidine shows a maximum at 271 nm with a molar absorptivity of \epsilon = 9100 \, \mathrm{M^{-1} cm^{-1}} at pH 8.2.^[13] Cytidine remains stable under neutral aqueous conditions but decomposes via deamination in the presence of strong acids or bases.^[14]

Chemical Reactivity

Cytidine exhibits lability in its N-glycosidic bond, particularly under acidic conditions, where hydrolysis proceeds to yield cytosine and ribose as products. The process is catalyzed by both acids and bases, though it is generally slower at neutral pH. Non-enzymatic deamination of cytidine involves the conversion of the cytosine moiety to uracil, producing uridine, with rates that are pH-dependent. The reaction is acid-catalyzed below pH 5 and base-catalyzed above pH 9.5, but remains nearly constant between pH 5 and 9. This reactivity is slow under neutral conditions.^[15] The primary site of phosphorylation in cytidine is the 5'-hydroxyl group of the ribose moiety, which readily reacts with phosphorylating agents to form cytidine monophosphate (CMP), subsequently convertible to cytidine diphosphate (CDP) and cytidine triphosphate (CTP). This selectivity arises from the primary alcohol nature of the 5'-OH, which is more nucleophilic than the secondary 2'- and 3'-OH groups; chemical phosphorylation using phosphorus oxychloride in organic solvents at low temperatures (−10°C to −5°C) achieves high conversion to 5'-CMP with minimal side reactions, provided water content is controlled below 0.1 wt% to avoid glycosidic bond cleavage.^[16] Oxidation of cytidine targets the vicinal cis-diol at the 2'- and 3'-positions of the ribose ring, with the 2'-OH exhibiting high sensitivity to periodate (NaIO₄), leading to cleavage and formation of a dialdehyde derivative. This reaction proceeds rapidly, completing in 15–20 minutes for cis-glycols under standard aqueous conditions at room temperature, due to favorable steric alignment facilitating periodate coordination. Reduction of the cytosine ring occurs under electrochemical conditions, primarily at the 5,6-double bond, yielding 5,6-dihydrocytidine as the main product via a two-electron addition mechanism.^[17]^[18] The cytosine moiety in cytidine undergoes keto-enol tautomerism, with the keto-amino form (2-oxo-4-amino) predominating over the enol-hydroxy form (2-hydroxy-4-amino). In aqueous solution, the equilibrium constant for this tautomerization favors the keto form by approximately 10⁴ to 10⁵ (pK_T ≈ 4–5), as determined by experimental and semiempirical calculations, reflecting the greater stability of the carbonyl group in polar solvents.^[19]

Biosynthesis and Metabolism

Biosynthetic Pathways

Cytidine is primarily synthesized through two main biosynthetic pathways in living organisms: the de novo pathway, which constructs the pyrimidine ring from simple precursors, and the salvage pathway, which recycles pre-existing nucleosides.^[20] In the de novo synthesis, the pathway begins with the formation of carbamoyl phosphate from glutamine, bicarbonate, and ATP, catalyzed by carbamoyl phosphate synthetase II (CPSII). This is followed by the committed step where aspartate transcarbamoylase (ATCase) condenses carbamoyl phosphate with aspartate to yield carbamoyl aspartate and inorganic phosphate, as shown in the equation:

\text{Aspartate} + \text{[carbamoyl phosphate](/page/Carbamoyl_phosphate)} \rightarrow \text{carbamoyl aspartate} + \text{P}_\text{i}

Subsequent steps involve dihydroorotase (DHOase) to form dihydroorotate and dihydroorotate dehydrogenase (DHODH) to produce orotate. Orotate then reacts with phosphoribosyl pyrophosphate (PRPP) via orotate phosphoribosyltransferase to form orotidine monophosphate (OMP), which is decarboxylated by OMP decarboxylase to uridine monophosphate (UMP). UMP is further phosphorylated to uridine triphosphate (UTP), and CTP synthetase catalyzes the amination of UTP to cytidine triphosphate (CTP) using glutamine as the nitrogen donor, according to the reaction:

\text{UTP} + \text{ATP} + \text{L-glutamine} + \text{H}_2\text{O} \rightarrow \text{CTP} + \text{[ADP](/page/ADP)} + \text{L-glutamate} + \text{P}_\text{i}

CTP is then sequentially dephosphorylated to cytidine diphosphate (CDP) and cytidine monophosphate (CMP) by phosphatases, followed by conversion of CMP to free cytidine via 5'-nucleotidases. Key enzymes in the early steps, including CPSII, ATCase, and DHOase, are organized into a multifunctional complex known as CAD in eukaryotes.^[20]^[21] The salvage pathway provides an alternative route by directly utilizing exogenous or recycled cytidine. Uridine-cytidine kinase (UCK), particularly UCK1 and UCK2 isoforms, phosphorylates cytidine to CMP using ATP as the phosphate donor, in the reaction:

\text{Cytidine} + \text{ATP} \rightarrow \text{CMP} + \text{[ADP](/page/ADP)}

This step is rate-limiting in the salvage route and is crucial for maintaining nucleotide pools in rapidly dividing cells.^[22] Organism-specific variations exist in the de novo pathway. In prokaryotes, such as Escherichia coli, the enzymes CPS, ATCase, and DHOase are monofunctional and separate, with ATCase subject to feedback inhibition by CTP to prevent overproduction of pyrimidines. In contrast, eukaryotes, including mammals, feature the CAD complex for the first three steps, and feedback regulation occurs primarily at CPSII by UTP rather than CTP on ATCase, allowing finer control integrated with cellular signaling. Bacterial pathways also lack the mitochondrial localization of DHODH seen in eukaryotes, where it couples to the electron transport chain.^[21]

Metabolic Degradation

Cytidine undergoes primary metabolic degradation through deamination catalyzed by cytidine deaminase (CDA), converting it to uridine and ammonia (NH₃).^[23] This enzyme exhibits Michaelis-Menten kinetics with a K_m for cytidine approximately 10^{-4} M in human variants.^[24] CDA activity is particularly high in the liver and gastrointestinal tract, facilitating rapid clearance of cytidine in these tissues.^[25] The resulting uridine is further metabolized by uridine phosphorylase (UP), which catalyzes its reversible phosphorolysis to uracil and α-D-ribose 1-phosphate.^[26] Uracil then enters the reductive pyrimidine catabolic pathway, where it is sequentially converted to dihydrouracil by dihydropyrimidine dehydrogenase, then to N-carbamoyl-β-alanine by dihydropyrimidinase, and finally to β-alanine, carbon dioxide (CO₂), and ammonia by β-ureidopropionase.^[27] Phosphorylated forms of cytidine, such as cytidine monophosphate (CMP), diphosphate (CDP), and triphosphate (CTP), are first dephosphorylated stepwise by 5'-nucleotidases and other phosphatases to yield free cytidine, which subsequently follows the deamination pathway.^[28] The end product β-alanine can be incorporated into pantothenic acid (vitamin B5) synthesis or excreted unchanged in urine.^[29] Regulatory mechanisms include inhibition of CDA by tetrahydrouridine, a potent competitive inhibitor that prolongs cytidine availability.^[30] Cytidine is rapidly cleared from plasma primarily due to deamination.

Biological Significance

Role in Nucleic Acids

Cytidine serves as a fundamental building block in RNA through its phosphorylated form, cytidine monophosphate (CMP), which is incorporated as a residue into the phosphodiester backbone of RNA chains during transcription. RNA polymerase enzymes utilize cytidine triphosphate (CTP) as the substrate to add CMP units complementary to guanine in the DNA template, enabling the synthesis of single-stranded RNA molecules that carry genetic information from DNA.^[31]^[32] In RNA structures, the cytosine base within cytidine forms Watson-Crick base pairs with guanine via three hydrogen bonds, contributing to the stability of double-helical regions, hairpins, and other secondary motifs. This pairing is crucial for maintaining RNA integrity during processes like mRNA transport and ribosomal assembly. Cytidine residues also play key structural roles in non-helical elements, such as the anticodon loops of transfer RNA (tRNA) where they facilitate codon recognition, and in ribosomal RNA (rRNA) scaffolds that support ribosome function through base stacking and hydrogen bonding interactions.^[33]^[34] Post-transcriptional modifications, such as conversion to 5-methylcytidine (m<sup>5</sup>C), further enhance RNA stability by protecting against nuclease degradation and promoting proper folding in tRNA and rRNA. In typical cellular RNAs, cytidine accounts for approximately 25-30% of nucleotides, with variations across RNA types—for instance, higher in GC-rich rRNA compared to more variable mRNA compositions. This prevalence underscores cytidine's essential, evolutionarily conserved role in nucleic acid-based genetic information storage and transfer across all domains of life.^[35]^[36]^[37]

Physiological Functions

Cytidine plays a key role in neuronal function primarily as a precursor to cytidine diphosphate-choline (CDP-choline), which supports the synthesis of phospholipids essential for neuronal membrane integrity and signaling. CDP-choline, derived from cytidine, facilitates the regulation of glutamate cycling between neurons and glial cells by enhancing the uptake and metabolism of glutamate, thereby preventing excitotoxicity and maintaining synaptic homeostasis. ^[38] This process is critical for neuroprotection, as evidenced by studies showing that CDP-choline inhibits glutamate-mediated neuronal death in cerebellar granule cells. ^[38] Additionally, cytidine supplementation promotes brain phospholipid synthesis, contributing to the repair and maintenance of neural structures during stress or injury. ^[39] In immune modulation, cytidine participates in the pyrimidine salvage pathway, providing nucleotides necessary for the proliferation of lymphocytes during immune responses. Extracellular cytidine enhances the survival and function of activated T cells by supporting nucleotide pools required for DNA synthesis and cell division. ^[40] Cytidine is integral to glycoprotein synthesis as a component of cytidine monophosphate-sialic acid (CMP-sialic acid), the activated donor for sialylation of cell surface glycans. This sialylation process, catalyzed by sialyltransferases in the Golgi apparatus, modifies glycoproteins to regulate cell adhesion, recognition, and signaling. ^[41] CMP-sialic acid ensures proper glycosylation, which is vital for immune cell interactions and tissue homeostasis. ^[42] Research indicates potential antidepressant effects of cytidine, particularly through enhancement of glutamatergic signaling and modulation of neurotransmitter systems. In animal models, cytidine administration reduces immobility in the forced swim test, mimicking antidepressant activity by influencing brain phospholipid metabolism and synaptic plasticity. ^[43] These effects are linked to cytidine's role in increasing CDP-choline levels, which support dopamine and glutamate pathways implicated in mood regulation. ^[44] Cytidine contributes to energy metabolism via its conversion to cytidine triphosphate (CTP), which drives phospholipid synthesis through the CDP-choline and CDP-diacylglycerol pathways, essential for membrane biogenesis and cellular energy partitioning. ^[45] CTP also indirectly links to glycogen metabolism, as its synthesis is regulated by glycogen synthase kinase-3, influencing glucose storage and energy homeostasis in cells. ^[46]

Pharmacological Applications

Cytidine Analogues

Cytidine analogues are synthetic nucleoside derivatives designed to mimic the structure of cytidine while incorporating modifications to enhance their therapeutic potential in antiviral, anticancer, and epigenetic research applications. These compounds typically alter the base, sugar, or phosphate moieties to improve cellular uptake, stability, or interference with nucleic acid synthesis. Common modifications include substitutions at the 5-position of the pyrimidine ring, changes to the ribose sugar at the 2' or 3' positions, or additions to the exocyclic amino group at N4, enabling selective targeting of viral polymerases, DNA methyltransferases (DNMTs), or cellular replication machinery.^[47] Structural modifications to cytidine often focus on the pyrimidine base or furanose ring to confer specific biological activities. For instance, 5-azacytidine (azacitidine) replaces the carbon at position 5 with nitrogen, forming a triazine ring, while maintaining the ribofuranosyl moiety. Similarly, 5-aza-2'-deoxycytidine (decitabine) features the same base substitution but with a deoxyribose sugar. Another example is 2'-C-methylcytidine, which introduces a methyl group at the 2' carbon of the ribose, sterically hindering chain elongation during RNA synthesis. N4-Hydroxycytidine modifies the exocyclic amino group with a hydroxy substituent, altering base-pairing fidelity. These changes disrupt normal Watson-Crick pairing or enzyme binding, leading to therapeutic effects.^[48]^[49]^[50]^[51] The primary mechanisms of action for cytidine analogues involve incorporation into nascent RNA or DNA strands, where they cause premature chain termination, faulty base pairing, or enzyme inhibition. Upon phosphorylation to their triphosphate forms, these analogues compete with natural cytidine triphosphate for incorporation by polymerases. For example, azacitidine incorporates into both RNA and DNA; in DNA, it covalently traps DNMTs, leading to enzyme depletion and subsequent hypomethylation of cytosine residues. Decitabine, primarily a DNA analogue, similarly inhibits DNMTs after incorporation, promoting gene reactivation through demethylation. 2'-C-Methylcytidine acts as a chain terminator for viral RNA-dependent RNA polymerases by preventing further nucleotide addition due to the bulky 2' substituent. N4-Hydroxycytidine induces viral mutagenesis by promoting G-to-A and C-to-U transitions during replication. These actions collectively impair viral propagation or tumor cell proliferation without excessively affecting host nucleic acid synthesis.^[52]^[47]^[50]^[53] Notable specific analogues highlight the diversity of cytidine modifications. KP-1461, a prodrug of the deoxycytidine analogue KP-1212, functions as an RNA mutagen against HIV-1 by elevating mutation rates through ambiguous base pairing during reverse transcription. Zebularine, a pyrimidinone analogue with a simplified base structure lacking the 4-amino group, inhibits DNMTs as a demethylating agent, offering lower toxicity than azacitidine derivatives. Gemcitabine, a 2',2'-difluorodeoxycytidine structurally related to arabinosylcytosine (cytarabine), incorporates into DNA to cause chain termination and inhibits ribonucleotide reductase, reducing deoxynucleotide pools essential for replication. These compounds exemplify targeted modifications for antiviral or chemotherapeutic utility.^[54]^[55]^[56] The development of cytidine analogues began in the 1960s with the synthesis of arabinosylcytosine (cytarabine), derived from marine sponge nucleosides, which introduced an arabinose sugar configuration to inhibit DNA polymerase. Early preclinical studies in the same decade explored azacitidine and decitabine for their DNMT-inhibitory properties. Post-2016 advancements include molnupiravir, a prodrug of N4-hydroxycytidine approved in 2021, which leverages lethal mutagenesis against SARS-CoV-2. These milestones reflect iterative refinements to overcome limitations like rapid metabolism.^[57]^[58]^[59] To enhance efficacy, many cytidine analogues are engineered for resistance to cytidine deaminase (CDA), the primary enzyme metabolizing them to inactive uridine forms, thereby improving pharmacokinetics and bioavailability. For example, gemcitabine's difluoro substitution at 2' reduces CDA susceptibility, allowing sustained intracellular triphosphate levels with a half-life of approximately 0.5-1 hour in plasma. Zebularine inherently resists deamination due to its base modification, enabling oral administration and prolonged demethylation effects. Decitabine, however, remains sensitive to CDA, necessitating intravenous dosing and combination with deaminase inhibitors for better stability. These design strategies extend the therapeutic window by minimizing hepatic clearance and enhancing tissue penetration.^[60]^[56]^[55]^[61]

Clinical Uses

Cytidine analogues have found significant applications in cancer therapy, particularly as nucleoside inhibitors that disrupt DNA synthesis in malignant cells. Azacitidine, a cytidine analogue, was approved by the U.S. Food and Drug Administration (FDA) in 2004 for the treatment of adults with specific subtypes of myelodysplastic syndromes (MDS), including refractory anemia and refractory anemia with excess blasts, where it demonstrates efficacy in improving hematologic parameters and delaying progression to acute myeloid leukemia.^[62] Similarly, decitabine, another cytidine-based hypomethylating agent, received FDA approval in 2006 for MDS treatment in adults, including de novo and secondary cases, by incorporating into DNA and inhibiting DNA methyltransferases to reactivate tumor suppressor genes.^[63] Gemcitabine, a deoxycytidine analogue, is FDA-approved since 1996 as first-line therapy for locally advanced or metastatic pancreatic cancer, often in combination with other agents, and for non-small cell lung cancer; it exerts its effects by mimicking cytidine triphosphate, leading to masked chain termination during DNA synthesis and inhibition of ribonucleotide reductase, thereby halting tumor cell proliferation.^[64]^[65] In antiviral treatments, cytidine analogues target viral replication through mutagenic mechanisms. Molnupiravir, an orally bioavailable prodrug of N4-hydroxycytidine (a cytidine analogue), received FDA Emergency Use Authorization in December 2021 for mild-to-moderate COVID-19 in high-risk adults, functioning by inducing lethal mutations in SARS-CoV-2 RNA via misincorporation by the viral RNA-dependent RNA polymerase, which overwhelms the virus's error correction and leads to error catastrophe.^[66]^[67] Earlier, KP-1461, a prodrug of the mutagenic cytidine analogue KP-1212, underwent phase I/II clinical trials in the 2000s for HIV-1 treatment in antiretroviral-experienced patients, aiming to accelerate viral mutation rates and impair replication; however, development was discontinued in the 2010s due to insufficient reduction in viral load and CD4 count improvements, though it provided foundational insights into mutagenic antiviral strategies.^[68]^[69] Cytidine diphosphate-choline (citicoline), a derivative that enhances phospholipid synthesis and neurotransmitter levels, is used in neurological disorders for recovery support. In acute ischemic stroke, citicoline administration within 24 hours of onset has shown modest benefits in functional outcomes, as evidenced by meta-analyses from 2017 onward, including improved neurological scores on scales like the National Institutes of Health Stroke Scale and enhanced daily living activities, with optimal dosing around 1000 mg/day intravenously or orally.^[70]^[71] For cognitive enhancement post-stroke or in mild cognitive impairment, post-2016 meta-analyses indicate citicoline yields small but significant improvements in memory, attention, and executive function, particularly in vascular-related cases, with benefits accruing over 3-6 months of treatment at 500-2000 mg/day.^[72] Epigenetic therapies leveraging cytidine analogues focus on gene reactivation in pathological states. Zebularine, an orally available cytidine analogue and DNA methyltransferase inhibitor, has demonstrated preclinical efficacy in reactivating silenced tumor suppressor genes in various cancers, such as breast and colorectal, by reducing aberrant DNA methylation and promoting apoptosis without significant toxicity in animal models.^[73] As of 2025, zebularine remains in preclinical research for neurodegenerative diseases, with animal studies showing potential in alleviating memory deficits and neuroinflammation through epigenetic modulation, but no human trials have been conducted.^[74] Common side effects of cytidine analogue therapies include myelosuppression, manifesting as neutropenia, thrombocytopenia, and anemia, which can lead to infections or bleeding and often necessitates dose adjustments or supportive care like transfusions. For azacitidine in MDS, the standard regimen is 75 mg/m² subcutaneously or intravenously daily for 7 days every 28 days, with monitoring for cytopenias; dose reductions to 50-66% are recommended if severe myelosuppression occurs, and gastrointestinal issues like nausea are also frequent but manageable with antiemetics.^[75] Similar toxicities apply to decitabine and gemcitabine, where prophylactic growth factors may mitigate risks in cancer patients.^[76] Citicoline generally exhibits a favorable safety profile with minimal adverse events beyond mild headache or insomnia.^[70]

Dietary and Commercial Sources

Natural Dietary Sources

Cytidine, a ribonucleoside composed of cytosine and ribose, is primarily obtained through the dietary consumption of foods rich in ribonucleic acid (RNA), from which it is derived via hydrolysis. Organ meats such as liver and kidney are notable sources, containing approximately 1.5-2 g of total nucleic acids per 100 g, contributing substantially to cytidine availability through enzymatic breakdown.^[77] Similarly, brewer's yeast is particularly rich in nucleotides, with RNA levels reaching 6-12% of dry weight (equivalent to 6,000-12,000 mg/100 g), providing substantial cytidine precursors.^[78] Fish like sardines also serve as significant sources, with nucleotide contents ranging from 100-1,000 mg/100 g in aquatic products.^[79] Plant-based foods offer moderate amounts of cytidine precursors, particularly in pyrimidine-rich vegetables and fungi. Mushrooms, spinach, and broccoli contain 10-20 mg/100 g of relevant nucleotides, while beer, derived from yeast fermentation, provides additional nucleosides through its processing.^[80] In the gastrointestinal tract, dietary cytidine from RNA is hydrolyzed by nucleotidases and phosphatases into free nucleosides and bases, which are then absorbed primarily in the small intestine; free nucleosides exhibit higher bioavailability compared to intact nucleotides due to efficient transport via equilibrative and concentrative nucleoside transporters. A typical mixed diet supplies 0.5-1 g of total nucleic acids daily.^[81]^[82] This intake supports de novo synthesis and recycling, though deficiencies are rare in adults owing to robust endogenous production and salvage mechanisms. For infants, cytidine is nutritionally critical, as human breast milk contains approximately 70 mg/L of total nucleotides, including cytidine monophosphate (CMP) as a predominant form, fulfilling up to 5-10% of early pyrimidine needs.^[83] Factors influencing bioavailability include gut enzyme activity and dietary composition, with nucleoside forms absorbed more readily than polymeric RNA.

Synthesis and Production

Cytidine can be synthesized through chemical methods, with the first total synthesis achieved in 1947 by Howard, Lythgoe, and Todd via a multi-step process involving the coupling of a protected ribofuranose derivative with a cytosine precursor.^[84] Modern chemical approaches post-2000 have focused on efficient routes for analogue precursors, incorporating biotechnological refinements to improve stereoselectivity and scalability.^[85] A primary chemical synthesis route employs the Vorbrüggen glycosylation method, which involves silylation of cytosine followed by Lewis acid-catalyzed coupling with a protected ribose, typically 1-O-acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranose, yielding β-cytidine after deprotection in 50-70% overall efficiency.^[86] Another multi-step approach starts from uridine, converting the uracil base to cytosine through thiolation with Lawesson's reagent and subsequent amination, often achieving high conversion rates in the final step (up to 98%).^[87] These methods are valued for their precision in laboratory settings but are less favored industrially due to complexity and cost compared to biological routes. Enzymatic production of cytidine relies on microbial fermentation, predominantly using engineered strains of Escherichia coli or Corynebacterium ammoniagenes, where metabolic pathways are optimized to overproduce cytidine from glucose or other carbon sources.^[88] Yields have reached up to 10 g/L in optimized fermentations, such as those adapting pyrimidine salvage pathways similar to those used in ribavirin production; recent engineering efforts have achieved yields up to 18 g/L in E. coli fermentations as of 2025.^[89]^[90] Bacillus subtilis has also been employed in fermentation processes, leveraging its robust nucleotide biosynthesis for titers around 1-5 g/L.^[91] Since the 1980s, microbial biosynthesis has dominated industrial production of cytidine, driven by advances in genetic engineering that enhance flux through the de novo pyrimidine pathway.^[92] Purification typically involves ion-exchange chromatography followed by crystallization to achieve pharmaceutical-grade purity exceeding 99% by HPLC analysis.^[93] Global annual production is estimated at approximately 100 tons, primarily for pharmaceutical intermediates, with bulk costs ranging from $50-100 per kg depending on scale and supplier.^[94]

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On the Recognition of Natural Substrate CTP and Endogenous ...
Oct 11, 2022 · This study, based on molecular dynamics (MD) simulations, addresses the important aspects of the incorporation of an endogenously synthesized ...
[34]
radicals derived from the guanine·cytosine base pair cause DNA ...
May 10, 2005 · Guanine pairs with cytosine, and adenine pairs with thymine in DNA. Interstrand hydrogen bonds are responsible for this pairing. The interatomic ...
[35]
The Interaction Between C75 of tRNA and the A Loop of ... - PubMed
Here we show that the addition of this single cytidine residue (the C75 equivalent) to puromycin is sufficient to suppress the deficiencies of active site ...
[36]
RNA 5-methylcytosine modification and its emerging role as ... - NIH
m5C modification plays critical roles in diverse aspects of RNA processing, including tRNA stability, rRNA assembly, and mRNA translation. Notably, altered m5C ...
[37]
GC content shapes mRNA storage and decay in human cells - eLife
Dec 19, 2019 · The GC content of human mRNAs is key to P-body localization and protein yield, and has a major impact on their post-transcriptional control.<|control11|><|separator|>
[38]
Can the RNA World Still Function without Cytidine? - Oxford Academic
Sep 4, 2019 · Here, we assess the ability of RNA sequences formed from a three-letter AUG alphabet to perform both structural and genetic roles.
[39]
Cytidine 5′-Diphosphocholine (Citicoline): Evidence for a ...
Mar 18, 2020 · CDP-choline prevents glutamate-mediated cell death in cerebellar granule neurons. J. Mol. Neurosci. 2003;20:53–60. doi: 10.1385/JMN:20:1:53 ...
[40]
Current knowledge on the neuroprotective and neuroregenerative ...
Oct 1, 2015 · Cytidine and choline separately pass through the blood–brain barrier (BBB), enter brain cells, and act as substrates for intracellular ...
[41]
Proof-of-principle studies on a strategy to enhance nucleotide ...
First, we observed that like uridine supplementation, adding cytidine to the culture medium protects T cells from DHODH blockage. Next, we identified tumor ...
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The Role of Uridine in Health and Disease - PMC - PubMed Central
Jul 29, 2025 · Uridine can improve fibrosis progression by inhibiting the inflammatory response process. Alzheimer disease (AD), Uridine exerts positive ...
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Sialic acid metabolism and sialyltransferases: natural functions ... - NIH
They catalyze the reaction that transfers a sialic acid residue from its activated sugar nucleotide donor cytidine 5′-monophosphate sialic acid (CMP-Sia) to a ...Bacterial Sialic Acid... · Sialyltransferases · Sialyltransferase-Catalyzed...
[44]
Biological function of sialic acid and sialylation in human health and ...
Sialylation, the process of appending sialic acid units to the terminal of lipoproteins and glycoproteins, is a novel form of post-translational modification ( ...
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Antidepressant-like effects of cytidine in the forced swim test in rats
Results: Over a range of doses, citicoline did not affect behavior in the forced swim test. At molar equivalent doses, cytidine dramatically decreased ...
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Citicoline in Addictive Disorders: A Review of the Literature - PMC
Jun 20, 2014 · Citicoline influences acetylcholine, dopamine, and glutamate neurotransmitter systems; serves as an intermediate in phospholipid metabolism; and ...
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CTP synthetase and its role in phospholipid synthesis in the yeast ...
2). This review summarizes our current understanding of the regulation of CTP synthetase activity, and how this regulation influences the synthesis of membrane ...
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Regulation of human cytidine triphosphate synthetase 1 by glycogen ...
Oct 5, 2007 · Cytidine triphosphate synthetase (CTPS) catalyzes the rate-limiting step in the de novo synthesis of CTP, and both the yeast and human enzymes ...
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Concise Drug Review: Azacitidine and Decitabine - PMC - NIH
Azacitidine and decitabine (5-aza-2′deoxycytidine) are cytidine analogs in which the carbon atom at position 5 in the pyrimidine ring has been replaced by a ...Introduction · Table 2 · Mechanism Of Action
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Azacytidine | C8H12N4O5 | CID 9444 - PubChem
5-azacytidine is an N-glycosyl-1,3,5-triazine that is 4-amino-1,3,5-triazin-2(1H)-one substituted by a beta-D-ribofuranosyl residue via an N-glycosidic ...
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5-Aza-2'-deoxycytidine | C8H12N4O4 | CID 451668 - PubChem
Decitabine is a Nucleoside Metabolic Inhibitor. The mechanism of action of decitabine is as a Nucleic Acid Synthesis Inhibitor. FDA Pharm Classes. 2 of 2 items.<|control11|><|separator|>
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Fluoro-2′-C-Methylcytidine and Inhibition of Hepatitis C Virus ... - NIH
β-d-2′-Deoxy-2′-fluoro-2′-C-methylcytidine (PSI-6130) is a potent specific inhibitor of hepatitis C virus (HCV) RNA synthesis in Huh-7 replicon cells.
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N4-Hydroxycytidine | C9H13N3O6 | CID 197020 - PubChem
Molecular Weight. 259.22 g/mol. Computed by PubChem 2.2 (PubChem release ... N(4)-hydroxycytidine is a nucleoside analogue that is cytidine which carries a ...
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Azacitidine and decitabine have different mechanisms of action in ...
Both AZA and DAC are cytidine nucleoside analogs that become incorporated into newly synthesized DNA, where they bind DNA methyltransferases (DNMTs) in an ...
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Molnupiravir promotes SARS-CoV-2 mutagenesis via the RNA ... - NIH
May 11, 2021 · Molnupiravir or NHC can increase G to A and C to U transition mutations in replicating coronaviruses.
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Mutation of HIV-1 Genomes in a Clinical Population Treated with the ...
Jan 14, 2011 · Genotype and phenotype results indicated that exposure to KP-1461 did not result in increased resistance to approved antiretroviral drugs.Missing: anti- | Show results with:anti-
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Zebularine: A Novel DNA Methylation Inhibitor that Forms a ...
This novel complex provides a molecular explanation for the mechanism of action of the anti-cancer drug zebularine.
[58]
Gemcitabine and cytosine arabinoside cytotoxicity: association ... - NIH
Two cytidine analogues, gemcitabine (dFdC) and cytosine arabinoside (AraC), show significant therapeutic effect in a variety of cancers.
[59]
Cytosine Arabinoside | SpringerLink
Cytosine arabinoside (ara-c) is a synthetic antimetabolite, a structural analogue of cytidine, with a β-hydroxyl group at the 2′-position.
[60]
[PDF] Intracellular Pharmacokinetics of Pyrimidine Analogues used in ...
research for other cytidine analogues that had anti-tumour activity and led to the first preclinical studies with azaciti- dine and decitabine in the 1960s [1].<|control11|><|separator|>
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Molnupiravir and Its Antiviral Activity Against COVID-19 - PMC
On November 4, 2021, molnupiravir was approved by the U.K. Medicines and Healthcare products Regulatory Agency (MHRA) for the treatment of mild to moderate ...
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A new technique for the analysis of metabolic pathways of cytidine ...
Nov 22, 2023 · Deoxycytidine kinase (dCK) is the rate-limiting enzyme that catalyses the first phosphorylation step to form cytarabine monophosphate, which is ...<|control11|><|separator|>
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Mechanisms of resistance to 5-aza-2′-deoxycytidine in human ...
Once inside the cell, DAC is phosphorylated by deoxycytidine kinase (dCK) into the monophosphorylated derivative 5-aza-dCMP. Subsequently, 5-aza-dCMP is ...
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Search Orphan Drug Designations and Approvals - FDA
azacitidine. Trade Name: Vidaza. Marketing Approval Date: 05/19/2004. Approved Labeled Indication: Treatment of patients with the following myelodysplastic ...
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Search Orphan Drug Designations and Approvals - FDA
decitabine. Trade Name: Dacogen. Marketing Approval Date: 05/02/2006. Approved Labeled Indication: for treatment of patients with myelodysplastic syndromes ...
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[PDF] gemcitabine injection - accessdata.fda.gov
1.4 Pancreatic Cancer Gemcitabine Injection is indicated as first-line treatment for patients with locally advanced (nonresectable Stage II or Stage III) or ...
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Understanding the Mechanism of Cell Death in Gemcitabine ...
It is a deoxycytidine analogue that inhibits ribonucleotide reductase M1 and M2, preventing the replication of DNA, and thus inhibiting cancer growth. The ...
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FDA Authorizes Additional Oral Antiviral for Treatment of COVID-19 ...
Dec 23, 2021 · The FDA issued an emergency use authorization for Merck's molnupiravir for the treatment of mild-to-moderate COVID-19 in certain adults.
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Mechanism of molnupiravir-induced SARS-CoV-2 mutagenesis - PMC
The presence of M in the −gRNA then leads to mutations in the positive-strand RNA products, which do not support formation of intact new viruses, as predicted ...
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Study of KP-1461 for the Treatment of HIV Positive Patients Who ...
Jan 4, 2008 · The primary purpose of the study is to assess the safety and pharmacokinetics of KP-1461 given every 12 hours for 14 days when administered to HIV+ patients.
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Pharmacological advances in anti‐retroviral therapy for human ...
Mar 23, 2024 · The deoxycytidine analogue, KP-1212 (13), and its prodrug, KP-1461 (12), were discontinued due to a lack of effect on viral load or CD4 ...
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The efficacy of different doses of citicoline in improving ... - Frontiers
Apr 3, 2025 · Our research findings revealed that different dosages of citicoline significantly affect the neurological function, daily living activities, and adverse effect
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The efficacy of different doses of citicoline in improving the ...
Apr 4, 2025 · Our research findings revealed that different dosages of citicoline significantly affect the neurological function, daily living activities, and adverse effects
[74]
Role of Citicoline in Patients With Mild Cognitive Impairment
Feb 16, 2023 · Citicoline has shown a consistent improvement in cognitive function in patients with MCI, especially of vascular origin.
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Preferential response of cancer cells to zebularine - PubMed - NIH
Our results demonstrate that zebularine can be selective toward cancer cells and may hold clinical promise as an anticancer therapy.Missing: trials | Show results with:trials
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Inhibition of DNA Methylation With Zebularine Alters ...
Sep 18, 2018 · Zebularine is a stable nucleoside analog of cytidine that is a less toxic DNMT inhibitor and the first drug in its class that can reactivate an ...<|control11|><|separator|>
[77]
[PDF] VIDAZA (azacitidine - accessdata.fda.gov
VIDAZA® is indicated for treatment of adult patients with the following French-American-. British (FAB) myelodysplastic syndrome subtypes: refractory anemia (RA) ...
[78]
[PDF] DACOGEN® (decitabine) for injection, for intravenous use
DACOGEN is indicated for treatment of adult patients with myelodysplastic syndromes. (MDS) including previously treated and untreated, de novo and secondary MDS ...
[79]
Nucleotides as optimal candidates for essential nutrients in living ...
Fish meal, fish soluble, legumes, animal protein soluble, and yeast extracts contained high levels of NTs, while soy, vegetables, and dairy products contained ...
[80]
https://www.sciencedirect.com/science/article/pii/S175646462100147X
[81]
The proportion of total potential sources of nucleotides in the 6...
In the daily diet, the content of NTs varies among foods; for example, seafood, animal liver, and soy products are high in NTs (100-1000 mg/100 g), whereas ...Missing: 100g | Show results with:100g
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Verification for Raw and Processed Food Products
Mar 3, 2021 · At the same time, it has been suggested that a safe intake of nucleic acids by a human adult is 2 g per day (Carver and Walker 1995), with a ...
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Nucleotides: an updated review of their concentration in breast milk
Nucleotides (NTs), a significant non-protein nitrogen component in breast milk (approximately 69–72 mg/L), are consumed daily by a 3 kg infant at an estimated ...
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https://pubs.rsc.org/en/content/articlelanding/1947/jr/jr9470001052
[85]
Computer-Based Design of a Cell Factory for High-Yield Cytidine ...
Nov 28, 2022 · 1.28 g/L of cytidine with a yield of 0.26 g/g glucose was produced. The yield of cytidine produced by E. coli is higher than previous reports.
[86]
Synthesis Of Nucleosides - Vorbrüggen - Wiley Online Library
Apr 15, 2004 · The latter were gradually photoanomerized to the thermodynamically more stable compounds in overall yields of 5–6%. The furanose form of ribose ...
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Synthesis of [4-15NH2]- and [1,3-15N2]cytidine derivatives for use in ...
The conversion of 15N-enriched urea to a [1,3-15N2]cytidine derivative is accomplished in nine steps with an overall yield of 67%. Synthesis of a ...
[88]
Deoxycytidine production by metabolically engineered ...
Mar 3, 2011 · Corynebacterium ammoniagenes N424 was metabolically modified to isolate overproducers of deoxycytidine. Inosine auxotrophy (ino) was ...
[89]
High-level living cell production of cytidine-5′-diphosphocholine in ...
Nov 20, 2021 · This study develops a high-production strain with improved molar yield by metabolic engineering strategies.
[90]
Increased distribution of carbon metabolic flux during de novo ...
Feb 4, 2025 · Cytidine can be synthesized through two primary methods: enzymatic hydrolysis of ribonucleic acid (RNA) and microbial fermentation.
[91]
Enzymatic Production of Pyrimidine Nucleotides Using <italic ...
In this study, we demonstrate the possibility of the enzymatic production of CDP-choline in a one-batch mixed reaction, using C. ammoniagenes KY13505 cells and ...
[92]
High Purity 99% Cytidine CAS 65-46-3 for Pharmaceutical ...
Oct 21, 2025 · Our Cytidine (CAS 65-46-3) is guaranteed at 99% purity, meeting stringent requirements for pharmaceutical intermediates and advanced biochemical ...
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Global Cytidine Industry Growth and Trends Forecast to 2031
Sep 4, 2025 · The Cytidine market size, estimations, and forecasts are provided in terms of sales volume (tons) and revenue ($ millions), considering 2024 as ...