Chemoenzymatic approach to the synthesis of the antiviral agents penciclovir and famciclovir in isotopically chiral [13C] labelled form

Sime, John T.; Barnes, Roger D.; Elson, Stephen W.; Jarvest, Richard L.; O’Toole, Kevin

doi:10.1039/p19920001653

Cited by 17 publications

(8 citation statements)

References 7 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The [8-3Hlaci-clovir (666 GBq mmor") was obtained from Moravek Biochemicals Inc., Brea, USA (batch No.108-172-018). Isotopically chiral [4'-13Clpenciclovir was prepared within SmithKline Beecham as described previously (Sime et al, 1992), and [4'-3Hlpenci-clovlr (27.8 GBq rnmol") was prepared by the Synthetic Isotope Chemistry Unit, SmithKline Beecham Pharmaceuticals, Harlow, UK. Penciclovir-triphosphate used for DNA polymerase studies was extracted from HSV-2 infected cells (as described for HSV-1, Earnshaw et al, 1992).…”

Section: Cytotoxicity Assaymentioning

confidence: 99%

Inhibition of Varicella-Zoster Virus by Penciclovir in Cell Culture and Mechanism of Action

Bacon

Gilbart

Howard

et al. 1996

Antivir Chem Chemother

View full text Add to dashboard Cite

SummaryThe effect of penciclovir (BRL 39123) on the replication of varicella-zoster virus (VZV) in human embryonic lung fibroblasts (MRC-5 cells) was similar to aciclovir when the compounds were present continuously. However, when the compounds were withdrawn the antiviral activity of penciclovir was maintained more effectively than that of aciclovir. In the plaque reduction assay, median 50% effective concentrations (ECsos) were 3.8 I1g mr" for penciclovir and 4.2 I1g rnl" for aciclovir (n =29 clinical isolates). Similarly, penciclovir and aciclovir were equally effective in reducing the numbers of VZV-infected MRC-5 cells and in reducing VZV DNA synthesis within infected cells following continuous treatment. Within VZVinfected cells (S)-penciclovir-triphosphate was formed from penciclovir with >95% enantiomeric purity, and the concentration of penciclovir-triphosphate was 360-fold greater than aciclovir-triphosphate immediately after treatment. This phosphorylation ratio compensates for the lower affinity of VZV DNA polymerase for penciclovir-triphosphate compared with aciclovir-triphosphate (K;s =7.5 11M and 0.2 11M, respectively). When VZV-infected cultures were treated for 3 days, followed by withdrawal of the compound, inhibition of viral DNA synthesis by penciclovir was maintained for 24 h, whereas viral DNA synthesis resumed more readily after removal of aciclovir. Furthermore, following 8 h daily pulse treatment for 5 days, penciclovir was significantly more active than aciclovir in reducing VZV DNA synthesis (p =0.006, n =10 clinical isolates). The long intracellular half-life of penciclovir-triphosphate (9.1 h) compared with that of aciclovir-triphosphate (0.8 h)

show abstract

Section: Cytotoxicity Assaymentioning

confidence: 99%

Inhibition of Varicella-Zoster Virus by Penciclovir in Cell Culture and Mechanism of Action

Bacon

Gilbart

Howard

et al. 1996

Antivir Chem Chemother

View full text Add to dashboard Cite

show abstract

“…136 Although the active drugs themselves are non-chiral, enantiopure, isotopically labelled anti-herpetics famciclovir and penciclovir have been prepared enzymatically. 137 Lipase from Candida cylindracea was used to resolve racemic 13 C-labelled methyl 4-(benzyloxy)-2-(hydroxymethyl)butanoate (rac-75) on small scale (Scheme 17). The remaining (R)-75 and the formed (S)-76 could subsequently be converted to either labelled (R)-famciclovir and (R)-penciclovir, or (S)-famciclovir and (S)-penciclovir, respectively.…”

Section: Acyclic Nucleoside Analoguesmentioning

confidence: 99%

Biocatalytic routes to anti-viral agents and their synthetic intermediates

Slagman

Fessner

2021

Chem. Soc. Rev.

View full text Add to dashboard Cite

show abstract

“…Therefore, we concluded that PosG is a 1-O-β-d-glucopyranoside of 6-PosA with 2-hydroxymethyl-4-butyrolactone (α-hydroxymethyl-γ-butyrolactone). 2-Hydroxymethyl-4-butyrolactone has been reported as a synthetic chemical [17], but not as a component of a natural product.…”

Section: Identification Of Posg In Tulip Bulbsmentioning

confidence: 99%

Identification of tuliposide G, a novel glucoside ester-type tuliposide, and its distribution in tulip

Nomura

Kato

2020

Zeitschrift Für Naturforschung C

View full text Add to dashboard Cite

Tuliposides (Pos) are major defensive secondary metabolites in tulip (genus Tulipa), having 4-hydroxy-2-methylenebutanoyl and/or (3S)-3,4-dihydroxy-2-methylenebutanoyl groups at the C-1 and/or C-6 positions of d-glucose. The acyl group at the C-6 position is converted to antimicrobial lactones, tulipalins, by tuliposide-converting enzymes (TCEs). In the course of a survey of tulip tissue extracts to identify novel Pos, we found a minute high-performance liquid chromatography peak that disappeared following the action of a TCE, and whose retention time differed from those of known Pos. Spectroscopic analyses of the purified compound, as well as its enzymatic degradation products, revealed its structure as 5″-O-(6-O-(4′-hydroxy-2′-methylenebutanoyl))-β-d-glucopyranosyl-(2″R)-2″-hydroxymethyl-4″-butyrolactone, which is a novel glucoside ester-type Pos. We gave this compound the trivial name ‘tuliposide G’ (PosG). PosG accumulated in bulbs, at markedly lower levels than 6-PosA (the major Pos in bulbs), but was not found in any other tissues. Quantification of PosG in bulbs of 52 types of tulip, including 30 cultivars (Tulipa gesneriana) and 22 wild Tulipa spp., resulted in the detection of PosG in 28 cultivars, while PosG was present only in three wild species belonging to the subgenus Tulipa, the same subgenus to which tulip cultivars belong, suggesting the potential usefulness of PosG as a chemotaxonomic marker in tulip.

show abstract

Chemoenzymatic approach to the synthesis of the antiviral agents penciclovir and famciclovir in isotopically chiral [13C] labelled form

Cited by 17 publications

References 7 publications

Inhibition of Varicella-Zoster Virus by Penciclovir in Cell Culture and Mechanism of Action

Inhibition of Varicella-Zoster Virus by Penciclovir in Cell Culture and Mechanism of Action

Biocatalytic routes to anti-viral agents and their synthetic intermediates

Identification of tuliposide G, a novel glucoside ester-type tuliposide, and its distribution in tulip

Contact Info

Product

Resources

About