Application and Pharmacology of Cytidine

General description 

Cytidine is a pyrimidine nucleoside comprised of a cytosine bound to ribose via a beta-N1 glycosidic bond. Cytidine is a precursor for uridine. Both cytidine and uridine are utilized in RNA synthesis. Cytidine is a white crystalline powder. (NTP, 1992) Cytidine is a pyrimidine nucleoside in which cytosine is attached to ribofuranose via a beta-N(1)-glycosidic bond. It has a role as a human metabolite, a Saccharomyces cerevisiae metabolite, an Escherichia coli metabolite and a mouse metabolite. It derives from a cytosine.

Figure 1 the chemical structure of Cytidine

Application and Pharmacology

Cytidine participates in many reactions in vivo, and is also an important precursor for the synthesis of RNA and deoxyribonucleic acid. At the same time, it has been found that it can be used to interfere with the synthesis of RNA and develop antiviral and anti-tumor drugs through specific reaction transformation, such as zacitabine (2 ', 3' - dideoxycytidine) developed with cytidine as the main intermediate, Capecitabine (5 '- deoxy-5-fluoro-n- [(pentoxy) carbonyl] cytidine), Cyclocytidine, cytarabine, azacytidine, cytarabine hydrochloride and other commonly used drugs for the treatment of malignant diseases such as malignant tumors and acute myeloid leukemia. They are cytidine analogues, which are synthesized from cytidine as an intermediate. Therefore, cytidine is a very important intermediate for drug synthesis in modern medicine, and how to obtain cytidine in large quantities, industrialization, low cost and high efficiency to supply the huge drug synthesis market is an important problem.

1.Cytidine base editors are powerful genetic tools that catalyse cytidine to thymidine conversion at specific genomic loci, and further improvement of the editing range and efficiency is critical for their broader applications. Through insertion of a non-sequence-specific single-stranded DNA-binding domain from Rad51 protein between Cas9 nickase and the deaminases, serial hyper cytidine base editors were generated with substantially increased activity and an expanded editing window towards the protospacer adjacent motif in both cell lines and mouse embryos. Additionally, hyeA3A-BE4max selectively cata-lysed cytidine conversion in TC motifs with a broader editing range and much higher activity (up to 257-fold) compared with eA3A-BE4max. Moreover, hyeA3A-BE4max specifically generated a C-to-T conversion without inducing bystander mutations in the haemoglobin gamma gene promoter to mimic a naturally occurring genetic variant for amelioration of β-haemoglobinopathy, suggesting the therapeutic potential of the improved base editors[1].

Synthesis

Abstract:Cytidine is an important antitumor and antiviral drug intermediate. Its synthesis and industrialization process can directly affect the research and production of drug products. The synthesis methods of cytidine are mainly divided into chemical synthesis method and biological method, in which biological method is the hot spot of current research. The common methods are ribonucleic acid hydrolysis, precursor addition fermentation and direct fermentation. Direct fermentation has many advantages. such as high vield low cost and so on. The core of direct fermentation is to breed stable and high yield strains by modern molecular biotechnology.In this paper, the main methods and pathwavs of biosynthesis of cytidine were briefly summarized, and the breeding examples. Since cytidine has been widely used as a drug intermediate, the research on the synthesis of cytidine has never stopped. The synthetic methods are mainly divided into two types, namely, chemical synthesis method and biological synthesis method. The biological synthesis method is mainly divided into ribonucleic acid hydrolysis method and fermentation method, and the fermentation method is divided into adding precursor fermentation method and direct fermentation method[2].

1.chemical synthesis method the chemical synthesis method uses uridine or cytosine and ribose as the main raw materials to carry out a series of catalytic reactions to obtain cytidine [7]. After decades of research, more than a dozen synthetic routes have been improved, and the original price of cytidine tens of thousands of yuan per kilogram has been reduced to hundreds of yuan per kilogram, which can be described as "sky high" on the ground. However, the research on chemical synthesis has not yet broken through the problems of high cost of catalyst, many reaction steps, harsh reaction conditions and environmental pollution. Therefore, chemical synthesis is gradually being replaced by biological synthesis with relatively mild reaction conditions.

2. ribonucleic acid hydrolysis method ribonucleic acid hydrolysis method is to hydrolyze ribonucleic acid through the action of enzymes, and then separate and purify to obtain cytidine. Although the reaction conditions of this method are mild, it requires a large number of high-quality RNA as raw materials, and the cost is high. At the same time, the hydrolysate of RNA is not only cytidine, but also produces by-products such as thymidine, adenosine, uridine, etc. the process of separation and purification of cytidine is complex, which further increases the synthesis cost[3].

Reference

1.Ullah A., Mabood N. & Maqbool M. et al., "Cytidine deamination-induced perpetual immunity to SAR-CoV-2 infection is a potential new therapeutic target," International Journal of Medical Sciences, Vol.18, No.16(2021), pp.3788-3793.

2.Maruoshuang, fanghaitian, liuhuiyan, etc.: Research Progress in biological synthesis of cytidine, food and fermentation technology, 2019, issue 01, pp. 71-75.

3.Zhang X., Chen L. & Zhu B. et al., "Increasing the efficiency and targeting range of cytidine base editors through fusion of a single-stranded DNA-binding protein domain," Nature Cell Biology, Vol.22, No.6(2020), pp.740-750.