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2'-C-Methyladenosine Sale

(Synonyms: 2'-C-甲基腺苷) 目录号 : GC41281

An adenosine analog

2'-C-Methyladenosine Chemical Structure

Cas No.:15397-12-3

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产品描述

2'-C-Methyladenosine is an inhibitor of hepatitis C virus (HCV) replication (IC50 = 0.3 µM in Huh-7 human hepatoma cells) that is not cytotoxic at concentrations up to 100 µM. It is converted intracellularly to adenosine triphosphate, which inhibits the RNA-dependent RNA polymerase nonstructural protein 5B (NS5B). It also inhibits growth of L. guyanensis in vitro (EC50 = 3 µM) and eradicates it when used at a concentration of 10 µM.

Chemical Properties

Cas No. 15397-12-3 SDF
别名 2'-C-甲基腺苷
Canonical SMILES NC1=NC=NC2=C1N=CN2[C@H]3[C@@](O)(C)[C@H](O)[C@@H](CO)O3
分子式 C11H15N5O4 分子量 281.3
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1 mM 3.5549 mL 17.7746 mL 35.5492 mL
5 mM 0.711 mL 3.5549 mL 7.1098 mL
10 mM 0.3555 mL 1.7775 mL 3.5549 mL
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Research Update

Mechanism-based inhibition of ribonucleoside diphosphate reductase from Corynebacterium nephridii by 2'-C-Methyladenosine diphosphate

Biochemistry 1996 Apr 9;35(14):4485-91.PMID:8605198DOI:10.1021/bi960138n.

The interaction of the adenosylcobalamin-dependent ribonucleoside diphosphate reductase of Corynebacterium nephridii with 2'-C-Methyladenosine diphosphate (2'-C-methylADP) has been investigated in more detail [Ong, S. P., McFarlan, S. C., & Hogenkamp, H. P. C. (1993) Biochemistry 32, 11397-11404]. This nucleotide analog partitioned between normal reduction to 2'-deoxy-2'-C-methyladenosine diphosphate and decomposition to adenine, 2-methylene-3(2H)-4-methylfuranone, and presumably pyrophosphate. Reaction of the reduced enzyme with 2'-C-methylADP caused the development of a chromophore at 318 nm that is characteristic of the modification of the enzyme by the furanone [Harris, G., Ator, M., & Stubbe, J. (1984) Biochemistry 23, 5214-5225]. Incubation of [5'-3H2]-2'-C-methylADP with reduced reductase resulted in the covalent incorporation of the radiolabel into the protein and into aquocobalamin. A similar incubation of the enzyme, the labeled nucleotide analog, and dithiothreitol resulted in the formation of three radioactive hydrophilic compounds. Mass spectroscopic analysis of one of these compounds showed the presence of 2-methylene-3(2H)-4-methylfuranone. 2'-Deoxy-2'-C-methylADP is a very effective promoter of the tritium exchange reaction between [5'-3H2]adenosylcobalamin and the solvent, confirming that the exchange reaction is an integral part of the overall reduction. All these observations are consistent with the proposal that 2'-C-methylADP serves as a substrate and a mechanism-based inhibitor of the ribonucleotide reductase of C. nephridii, indicating that the enzyme is able to catalyze the conversion of the nucleotide analog to a 2'-deoxy-2'-C-methyl-3'-ketonucleotide that can collapse to the reactive 2-methylene-3(2H)-4-methylfuranone. Surprisingly, 2'-C-methylADP did not serve as either a substrate or an inhibitor of the ribonucleoside diphosphate reductase of Escherichia coli.

Synthesis and HCV inhibitory properties of 9-deaza- and 7,9-dideaza-7-oxa-2'-C-methyladenosine

Bioorg Med Chem 2007 Aug 1;15(15):5219-29.PMID:17521911DOI:10.1016/j.bmc.2007.05.020.

As a part of an ongoing medicinal chemistry effort to identify inhibitors of the Hepatitis C Virus RNA replication, we report here the synthesis and biological evaluation of 9-deaza- and 7,9-dideaza-7-oxa-2'-C-methyladenosine. The parent 2'-C-Methyladenosine shows excellent intracellular inhibitory activity but poor pharmacokinetic profile. Replacement of the nucleoside-defining 9-N of 2'-C-Methyladenosine with a carbon atom was designed to yield metabolically more stable C-nucleosides. Modifications at position 7 were designed to exploit the importance of the hydrogen bond accepting properties of this heteroatom in modulating the adenosine deaminase (ADA) mediated 6-N deamination. 7-Oxa-7,9-dideaza-2'-C-methyladenosine was found to be a moderately active inhibitor of intracellular HCV RNA replication, whereas 9-deaza- 2'-C-Methyladenosine showed only weak activity despite excellent overlap of both of the synthesized target compounds with 2'-C-Methyladenosine's three dimensional structure. Position 7 of the nucleobase proved to be an effective handle for modulating ADA-mediated degradation, with the rate of degradation correlating with the hydrogen-bonding properties at this position.

2'-C-Methyladenosine and 2'-C-methyluridine 5'-diphosphates are mechanism-based inhibitors of ribonucleoside diphosphate reductase from Corynebacterium nephridii

Biochemistry 1993 Oct 26;32(42):11397-404.PMID:8218205DOI:10.1021/bi00093a017.

The interaction of the adenyosylcobalamin-dependent ribonucleoside diphosphate reductase of Cornyebacterium nephridii with 2'-C-Methyladenosine 5'-diphosphate (2'-MeADP) and 2'-C-methyluridine 5'-diphosphate (2'-MeUDP) has been investigated. The nucleotide analogs are converted to adenine and uracil, respectively, suggesting that they may be mechanism-based inhibitors. In addition, both analogs generate nucleotides with properties expected for the 2'-deoxy-2'-C-methylnucleotides. The nucleoside obtained after enzymatic dephosphorylation of the product formed from 2'-MeADP has been identified as 2'-deoxy-2'-C-methyladenosine by 1H NMR and mass spectroscopies. Adenine is the major product derived from 2'-MeADP, indicating that the degradation pathway predominates. During the reaction, the carbon-cobalt bond of the coenzyme is cleaved irreversibly to yield 5'-deoxyadenosine and cob(II)alamin. 2'-MeADP is a potent competitive inhibitor of the reduction of the purine nucleotides ADP and GDP, while 2'-MeUDP competitively inhibits the reduction of the pyrimidine nucleotides UDP and CDP. 2'-MeADP is a very effective promoter of the tritium exchange reaction between [5'-3H2]adenosylcobalamin and the solvent, indicating that the exchange reaction is an integral part of the overall reduction. All these observations are consistent with the reaction mechanism proposed by Stubbe and co-workers [Harris, G., Ashley, G. W., Robins, M. J., Tolman, R. L., & Stubbe, J. (1987) Biochemistry 26, 1895-1902 (1987); Stubbe, J. (1990) J. Biol. Chem. 265, 5329-5332] in which they suggest that the partitioning between reduction and inactivation occurs at the level of the 2'-deoxy-3'-ketoribonucleotide intermediate.

Concentration of 2'C-methyladenosine triphosphate by Leishmania guyanensis enables specific inhibition of Leishmania RNA virus 1 via its RNA polymerase

J Biol Chem 2018 Apr 27;293(17):6460-6469.PMID:29511088DOI:10.1074/jbc.RA117.001515.

Leishmania is a widespread trypanosomatid protozoan parasite causing significant morbidity and mortality in humans. The endobiont dsRNA virus Leishmania RNA virus 1 (LRV1) chronically infects some strains, where it increases parasite numbers and virulence in murine leishmaniasis models, and correlates with increased treatment failure in human disease. Previously, we reported that 2'-C-Methyladenosine (2CMA) potently inhibited LRV1 in Leishmania guyanensis (Lgy) and Leishmania braziliensis, leading to viral eradication at concentrations above 10 μm Here we probed the cellular mechanisms of 2CMA inhibition, involving metabolism, accumulation, and inhibition of the viral RNA-dependent RNA polymerase (RDRP). Activation to 2CMA triphosphate (2CMA-TP) was required, as 2CMA showed no inhibition of RDRP activity from virions purified on cesium chloride gradients. In contrast, 2CMA-TP showed IC50 values ranging from 150 to 910 μm, depending on the CsCl density of the virion (empty, ssRNA-, and dsRNA-containing). Lgy parasites incubated in vitro with 10 μm 2CMA accumulated 2CMA-TP to 410 μm, greater than the most sensitive RDRP IC50 measured. Quantitative modeling showed good agreement between the degree of LRV1 RDRP inhibition and LRV1 levels. These results establish that 2CMA activity is due to its conversion to 2CMA-TP, which accumulates to levels that inhibit RDRP and cause LRV1 loss. This attests to the impact of the Leishmania purine uptake and metabolism pathways, which allow even a weak RDRP inhibitor to effectively eradicate LRV1 at micromolar concentrations. Future RDRP inhibitors with increased potency may have potential therapeutic applications for ameliorating the increased Leishmania pathogenicity conferred by LRV1.

Liver-targeted prodrugs of 2'-C-Methyladenosine for therapy of hepatitis C virus infection

J Med Chem 2007 Aug 9;50(16):3891-6.PMID:17636948DOI:10.1021/jm0701021.

2'-C-Methyladenosine exhibits impressive inhibitory activity in the cell-based hepatitis C virus (HCV) subgenomic replicon assay, by virtue of intracellular conversion to the corresponding nucleoside triphosphate (NTP) and inhibition of NS5B RNA-dependent RNA polymerase (RdRp). However, rapid degradation by adenosine deaminase (ADA) limits its overall therapeutic potential. To reduce ADA-mediated deamination, we prepared cyclic 1-aryl-1,3-propanyl prodrugs of the corresponding nucleoside monophosphate (NMP), anticipating cytochrome P450 3A-mediated oxidative cleavage to the NMP in hepatocytes. Lead compounds identified in a primary rat hepatocyte screen were shown to result in liver levels of NTP predictive of efficacy after intravenous dosing to rats. The oral bioavailability of the initial lead was below 5%; therefore, additional analogues were synthesized and screened for liver NTP levels after oral administration to rats. Addition of a 2',3'-carbonate prodrug moiety proved to be a successful strategy, and the 1-(4-pyridyl)-1,3-propanyl prodrug containing a 2',3'-carbonate moiety displayed oral bioavailability of 39%.