30685-66-6Relevant academic research and scientific papers
Sulfonium-Based Homolytic Substitution Observed for the Radical SAM Enzyme HemN
Deng, Zixin,Ding, Wei,Ji, Wenjuan,Ji, Xinjian,Mandalapu, Dhanaraju,Sun, Peng,Zhang, Qi
supporting information, p. 8880 - 8884 (2020/04/01)
Sulfur-based homolytic substitution (SH reaction) plays an important role in synthetic chemistry, yet whether such a reaction could occur on the positively charged sulfonium compounds remains unknown. In the study of the anaerobic coproporphyrinogen III oxidase HemN, a radical S-adenosyl-l-methionine (SAM) enzyme involved in heme biosynthesis, we observed the production of di-(5′-deoxyadenosyl)methylsulfonium, which supports a deoxyadenosyl (dAdo) radical-mediated SH reaction on the sulfonium center of SAM. The sulfonium-based SH reactions were then investigated in detail by density functional theory calculations and model reactions, which showed that this type of reactions is thermodynamically favorable and kinetically competent. These findings represent the first report of sulfonium-based SH reactions, which could be useful in synthetic chemistry. Our study also demonstrates the remarkable catalytic promiscuity of the radical SAM superfamily enzymes.
First example of phosphoramidate approach applied to a 4′-substituted purine nucleoside (4′-Azidoadenosine): Conversion of an inactive nucleoside to a submicromolar compound versus hepatitis C virus
Perrone, Plinio,Daverio, Felice,Valente, Rocco,Rajyaguru, Sonal,Martin, Joseph A.,Lévêque, Vincent,Le Pogam, Sophie,Najera, Isabel,Klumpp, Klaus,Smith, David B.,McGuigan, Christopher
, p. 5463 - 5470 (2008/03/14)
We report on the synthesis of the anti hepatitis C virus (HCV) agent 4′-azidoadenosine (1) and the application of the phosphoramidate ProTide technology to this nucleoside. The synthesis of 1 was achieved through an epoxide intermediate followed by regio- and stereoselective ring opening by azidotrimethylsilane in the presence of a Lewis acid. Compound 1 did not inhibit HCV replication in cell culture at concentrations up to 0.1 mM. However, a submicromolar active agent could be derived from 1 by the application of the ProTide technology. All the phosphoramidates prepared were L-alanine derivatives with variations in the aryl moiety and in the ester part of the amino acid. The benzyl ester and the 1-naphthyl phosphate (18) had the best activity in replicon assay. Phosphoramidates (18-21) achieved a significant improvement in antiviral potency over the parent nucleoside (1) with no increase in cytotoxicity.
Synthetic Approaches towards Nucleocidin and Selected Analogues; anti-HIV Activity in 4'-Fluorinated Nucleoside Derivatives
Maguire, Anita R.,Meng, Wei-dong,Roberts, Stanley M.,Willetts, Andrew J.
, p. 1795 - 1808 (2007/10/02)
Nucleocidin 1 has been synthesised from the adenosine derivative 4 via the intermediacy of the dihalogeno compound 9.The latter compound showed slight but significant activity against HIV-infected cells while the isomer 10 and the monohalogeno compound 60 were inactive.Synthetic approaches towards other 4'-fluorinated nucleoside derivatives are also described.The epimeric 4'-fluorinated nucleosides 26 and 27 displayed similar activity against HIV-infected cells to that observed for the dihalogenated compound 9.
A New Synthetic Use of Nucleoside N1-Oxides
MacCoss, Malcolm,Ryu, Eung K.,White, Robert S.,Last, Robert L.
, p. 788 - 794 (2007/10/02)
The use of adenosine N1-oxide derivatives to prevent intramolecular cyclization during nucleophilic displacement reactions on the sugar moiety is described.This new synthetic use of N1-oxides is illustrated by the synthesis of 5'-O-(p-toluenesulfonyl)-2',3'-O-isopropylideneadenosine N1-oxide (6) and subsequent displacement of the 5' substituent with iodide or azide under conditions which lead exclusively to N3->5' intramolecular cyclization in the absence of the N1-oxide.Similarly, reaction of 2',3'-O-isopropylideneadenosine N1-oxide with methyltriphenoxyphosphonium iodide produces 5'-iodo-5'-deoxy-2',3'-O-isopropylideneadenosine N1-oxide (7) with no observable cyclization.In addition, 2',3'-anhydroadenosine N1-oxide (17) is shown to be stable under conditions that lead to complete N3->3' intramolecular cyclization in the unprotected 2',3'-anhydroadenosine (14).Reduction of the N1-oxide to produce the parent nucleoside is readily achieved by using hexachlorodisilane or by hydrogenating over Raney nickel.The mechanistical rationale and implications for additional nucleoside transformations are discussed.
