Enantiomeric Synthesis of d- and l-Cyclopentenyl Nucleosides and Their Antiviral Activity Against HIV and West Nile Virus

Abstract

Enantiomeric synthesis of D- and L-cyclopentenyl nucleosides and their antiviral activity against HIV and West Nile virus are described. The key intermediate (-)- and (+)-cyclopentenyl alcohols (7 and 15) were prepared from D-gamma-ribonolactone and D-ribose, respectively. Coupling of 7 with appropriately blocked purine and pyrimidine bases via the Mitsunobu reaction followed by deprotection afforded the target L-(+)-cyclopentenyl nucleosides (24-28, 31, 33, and 36). D-(-)-Cyclopentenyl nucleosides (1, 40, 43, and 52-56) were also prepared by a similar procedure for L-isomers from 15. The synthesized compounds were evaluated for their antiviral activity against two RNA viruses: HIV and West Nile virus. Among the synthesized D-(-)-nucleosides, adenine (1, neplanocin A), cytosine (55, CPE-C), and 5-fluorocytosine (56) analogues exhibited moderate to potent anti-HIV activity (EC(50) 0.1, 0.06, and 5.34 microM, respectively) with significant cytotoxicity in PBM, Vero, and CEM cells. Also, cytosine (55) and 5-fluorocytosine (56) analogues exhibited the most potent anti-West Nile virus activity (EC(50) 0.2-3.0 and 15-20 microM, respectively). Among L-(+)-nucleosides, only the cytosine (27) analogue exhibited weak anti-HIV activity (EC(50) 58.9 microM).

In-vitro Antiviral Activity of a Novel Phthalic Acid Ester Derivative Isolated from the Bangladeshi Mangrove Fern Acrostichum aureum

“…Recent studies demonstrated that palmatine acts as a protease inhibitor of flavivirus whereas, ribavirin-5′-triphosphate and paclitaxel inhibited flavivirus NS3 protein-associated NTPase [30]. Neplanocin, another naturally occurring carbocyclic nucleoside, inhibits the flaviviral NS5 protein-associated methyltransferease [31]. Most alphavirus inhibitors, which inhibit virus replication, are nucleoside analogues e.g.…”

Flaviviral Infections and Potential Targets for Antiviral Therapy

“…For example, neplanocin A (Fig. 3), a naturally occurring carbocyclic nucleoside, and related abacavir and carbovir, in which the absence of a true glycosidic bond makes the compounds chemically more stable, as they are not susceptible to enzymatic cleavage by SAH hydrolase (Song et al, 2001). A further possibility to inhibit the interactions between cap-structure and its target protein, eucaryotic initiation factor 4E (eIF4E), is the reduction of the affinity of the last to the ligand.…”

Antiviral Activity of Nucleoside Analogues against SARS-coronavirus (SARS-CoV)

“…However, ribavirin has been shown to be only weakly active in vitro against SARS-CoV, and to even enhance and prolong viral replication in mice (Barnard et al, 2006). Other agents such as isatine derivatives (Chen et al, 2005;Wu et al, 2005), small interfering RNA (Wu et al, 2005), glycyrrhizic acid derivatives (Hoever et al, 2005), peptide inhibitors (Wu et al, 2004;Zhang et al, 2006) and natural compounds like Chinese medical herb extracts (Xiao et al, 2003;Zhong et al, 2003;Li et al, 2005) The nucleoside analogues listed ( Figure 1) were synthesized as described elsewhere (Choo et al, 2006;Gadthula et al, 2005;Chen et al, 2004;Chun et al, 2000;Song et al, 2001;Chu et al, 1991;Liang et al, 1997;Sureyya et al, 2001 D-(4-8) and L-(9-13) (4) uracil (5) adenine (6) inosine (7) guanine (8) OH OH B = uracil (9) cytosine (10) adenine (11) inosine (12) guanine (13) B S B = thymine (14) cytosine (15) adenine (16) guanine ( (24) thymine (25) cytosine (26) B = 5-C1-uracil (27) thymine (28) cytosine (29) uracil (30) adenine ( The 3′-fluoro-2′,3′-dideoxy-2′,3′-didehydro-4′-ethynyl-D-and L-furanosyl nucleosides (21-26) Interestingly, …”