Structure–Activity Relationships of Neplanocin A Analogues as S-Adenosylhomocysteine Hydrolase Inhibitors and Their Antiviral and Antitumor Activities

Abstract

On the basis of the potent inhibitory activity of neplanocin A (1) against S-adenosylhomocysteine (AdoHcy) hydrolase, we analyzed the comprehensive structure-activity relationships by modifying the adenine and carbasugar moiety of 1 to find the pharmacophore in the active site of the enzyme. The introduction of 7-deazaadenine instead of adenine eliminated the inhibitory activity against the AdoHcy hydrolase, while 3-deazaadenine maintained the inhibitory activity of the enzyme, indicating that N-7 is essential for its role as a hydrogen bonding acceptor. The substitution of hydrogen at the 6'-position with fluorine increased the inhibitory activity of the enzyme. The one-carbon homologation at the 5'-position generally decreased the inhibitory activity of the enzyme, indicating that steric repulsion exists. A molecular docking study also supported these experimental data. In this study, 6'-fluoroneplanocin A (2) was the most potent inhibitor of AdoHcy hydrolase (IC50 = 0.24 μM). It showed a potent anti-VSV activity (EC50 = 0.43 μM) and potent anticancer activity in all the human tumor cell lines tested.

6′-β-Fluoro-Homoaristeromycin and 6′-Fluoro-Homoneplanocin A Are Potent Inhibitors of Chikungunya Virus Replication through Their Direct Effect on Viral Nonstructural Protein 1

“…In the present study, we identified two carbocyclic adenosine analogues, FHA and FHNA, as inhibitors of CHIKV and SFV replication. These compounds were originally designed as substrate analogue inhibitors of the host enzyme SAH hydrolase and were shown to inhibit this enzyme in vitro with 50% inhibitory concentration values of 0.37 and 0.91 M, respectively (31). In CPE reduction assays, FHA and FHNA strongly inhibited CHIKV with EC 50 values of 0.12 and 0.18 M, respectively.…”

“…Our results demonstrate that FHNA resistance was not associated with increased resistance to the inhibitory effect of SAH or due to increased activity at low SAM concentrations. We then set out to investigate whether FHNA had a direct inhibitory effect on SFV nsP1, since we have also identified an FHNA analogue with a similar inhibitory activity against the host SAH hydrolase in vitro that is completely devoid of anti-CHIKV activity in cell-based assays (31). Previously, it was shown that halo-neplanocin A analogues inhibit SAH hydrolase via a mechanism that requires the NAD ϩ and the oxidation of the compound to a 3=-keto form (32).…”

2′‐Fluoro‐6′‐methylene carbocyclic adenosine and its phosphoramidate prodrug: A novel anti‐HBV agent, active against drug‐resistant HBV mutants

“…37 FMCAP was synthesized using a known method in the literature 129,130 (Scheme 4), in which phenol was first treated with phosphorus oxychloride to generate phosphorylated phenyl dichlorophosphate 22, which was coupled with appropriate ester of L-alanine using triethyl amine in dichloromethane to give chlorophosphoramidate reagent (23,24). FMCA was then coupled with the appropriate chlorophosphoramidate reagent in tetrahydrofuran (THF) in basic condition using 1-methyl imidazole (NMI) to afford the phosphoramidate of FMCA (25,26) in good yield.…”

“…Although the majority of these molecules are synthetic in origin, several carbocyclic nucleosides have been isolated from natural sources. Out of these naturally occurring compounds, aristeromycin and neplanocin A are interesting for having demonstrated antitumor and antiviral activities.…”

Synthesis of 4a‐Carba‐d‐lyxofuranose Derivatives and Their Evaluation as Inhibitors of GH38 α‐Mannosidases

“…[5] Due to strong biological activities as well as interesting structural features, (amino)cyclopentitols attract attention of both biologists and organic chemists as potential therapeutics for the treatment of carbohydrate-metabolism-related disorders. Carbocyclic nucleosides such as neplanocin A (5), [13] aristeromycin (6) [14] and their numerous analogues [15][16][17][18][19] exhibit antiviral, antibacterial and antitumor activity. Carbocyclic nucleosides such as neplanocin A (5), [13] aristeromycin (6) [14] and their numerous analogues [15][16][17][18][19] exhibit antiviral, antibacterial and antitumor activity.…”