Medical applications of 2'-C-methyluridine

There are two main applications of 2'-C-methyluridine, which are targeted at hepatitis C and leukemia.

Nucleoside compounds are composed of glycosyl and base, and are divided into natural nucleosides and unnatural nucleosides (or nucleoside analogs). The glycosyl part of natural ribose is generally D-ribose or 2-deoxy-D-ribose, and the bases are of two types, purine and pyrimidine. Natural nucleosides have certain effects on some human diseases[1]. For example, choline citrate is closely related to the metabolism of phospholipids. It is one of the important coenzymes for the synthesis of lecithin in the body. It can treat disorders of consciousness. In recent years, with the continuous deepening of research, people have found that non-natural nucleosides obtained after some forms of structural modification or transformation of natural nucleosides have shown good efficacy in the treatment of diseases, especially antiviral and antitumor[2]. This is because they have a large structural similarity to natural nucleosides, interfere with or directly affect the metabolic process of nucleic acids, and then block the biosynthesis of proteins and nucleic acids for therapeutic purposes.

2′-C-methyluridine is one of the key intermediates in the synthesis of nucleoside anti-hepatitis C and anti-leukemia drugs[3].

Anti-HCV

Stanley found that nucleoside analogues of 2-C-methyl-β-D-ribofuranose as a sugar group can be used as anticancer and antiviral drugs with high biological activity[4]. As shown in the figure, 2'-C-methyluridine is an important raw material for the synthesis of 2'-C-methylcytosine nucleoside. The latter can interfere with or directly affect the metabolism of nucleic acids in the body and block the biosynthesis of nucleic acids and proteins. In terms of anti-HCV, 2'-C-methylpyrimidine nucleoside is also a key intermediate for many new anti-HCV drugs body. According to reports, in order to improve its oral bioavailability, Pierra made some structural modifications to synthesize NM283 in anti-HCV infection. Animals and clinical trials have achieved ideal results[5].

Anti-leukemia

Cytarabine (Ara-C) is a specific drug for the treatment of human acute myeloid leukemia. Studies have shown that replacing the 2′-OH of Ara-C with -CH3 can inhibit the growth of leukemia cells L120[6]. Based on this principle, Li Synthesized 2'-deoxy-2'-C-β-methylcytidine and its phosphoramidite derivatives using 2'-C-methyluridine as an intermediate in subsequent studies. Both are also highly toxic to leukemia L1210[7]. The structure of each compound is shown in the figure.

References

[1] Lam A M, Murakami E, Espiritu C, et al. PSI-7851, a pronucleotide of β-D-2′-deoxy-2′-fluoro-2′-C-methyluridine monophosphate, is a potent and pan-genotype inhibitor of hepatitis C virus replication[J]. Antimicrobial agents and chemotherapy, 2010, 54(8): 3187-3196.
[2] Murakami E, Niu C, Bao H, et al. The mechanism of action of β-d-2′-deoxy-2′-fluoro-2′-C-methylcytidine involves a second metabolic pathway leading to β-d-2′-deoxy-2′-fluoro-2′-C-methyluridine 5′-triphosphate, a potent inhibitor of the hepatitis C virus RNA-dependent RNA polymerase[J]. Antimicrobial agents and chemotherapy, 2008, 52(2): 458-464.
[3] Pontiggia R, Pontiggia O, Simian M, et al. 2-C-Methyluridine modified hammerhead ribozyme against the estrogen receptor[J]. Bioorganic & medicinal chemistry letters, 2010, 20(9): 2806-2808.
[4] Robaldo L, Montserrat J M, Iribarren A M. 10-23 DNAzyme modified with (2′ R)-and (2′ S)-2′-deoxy-2′-C-methyluridine in the catalytic core[J]. Bioorganic & medicinal chemistry letters, 2010, 20(15): 4367-4370.

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