The multisubstrate nucleoside kinase of Drosophila melanogaster (Dm‐dNK) can be expressed in human solid tumor cells and its unique enzymatic properties makes this enzyme a suicide gene candidate. In the present study, Dm‐dNK was stably expressed in the CCRF‐CEM and H9 T‐lymphoblastoid cell lines. The expressed enzyme was localized to the cell nucleus and the enzyme retained its activity. The Dm‐dNK overexpressing cells showed ≈ 200‐fold increased sensitivity to the cytostatic activity of several nucleoside analogs, such as the pyrimidine nucleoside analogs (E)‐5‐(2‐bromovinyl)‐2′‐deoxyuridine (BVDU) and 1‐β‐d‐arabinofuranosylthymine (araT), but not to the antiherpetic purine nucleoside analogs ganciclovir, acyclovir and penciclovir, which may allow this technology to be applied in donor T cells and/or rescue graft vs. host disease to permit modulation of alloreactivity after transplantation. The most pronounced effect on the steady‐state dNTP levels was a two‐ to 10‐fold increased dTTP pool in Dm‐dNK expressing cells that were grown in the presence of 1 µm of each natural deoxyribonucleoside. Although the Dm‐dNK expressing cells demonstrated dNTP pool imbalances, no mitochondrial DNA deletions or altered mitochondrial DNA levels were detected in the H9 Dm‐dNK expressing cells.

01 Jan 2003·Synthesis

New Convergent Synthesis of Carbocyclic Nucleoside Analogues

Author: Meier, Chris ; Ludek, Olaf R.

Two convergent approaches towards the synthesis of carbocyclic nucleoside analogs will be described.Both approaches start from the stereochem. pure cyclopentenol that has been prepared enantioselectively from an alkylated cyclopentadiene.Using these approaches, carbocyclic analogs of dT, FdU and BVdU have been preparedMoreover, the conversion into the cycloSal-pronucleotide and the corresponding nucleotide will be presented for one example.

01 Nov 1995·Nucleosides and Nucleotides

A Short High Yielding Synthesis of the Potent Anti-VZV Carbocyclic Nucleoside Analogue Carba-BVDU

Author: Coomber, B. A. ; Gilbert, V. S. ; Evans, D. N. ; Paternoster, I. L. ; Anslow, A. S. ; Humber, D. C. ; Wyatt, P. G. ; Cousins, R. P. C. ; Sollis, S. L.

A short high yielding synthesis of the potent anti-varicella-zoster virus (VZV) carbocyclic nucleoside analog carba-BVDU I [R = CH:CHBr-(E), R¹ = H] starting from aminodiol II is described.Reaction of II with the acyl carbamate, EtOCH:CEtCONHCO₂Et, and subsequent ring closure under acidic conditions afforded 5-ethyl-2'-deoxy-4'a-carbauridine (I; R = Et, R¹ = H).In situ acetylation of I ( R = Et, R¹ = H) afforded 3',5'-di-O-acetyl-5-ethyl-2'-deoxy-4'a-carbauridine (I; R = Et, R¹ = Ac) in 78% overall yield from II.Radical bromination of I (R = Et, R¹ = Ac) with either bromine or NBS and subsequent treatment with triethylamine gave an efficient conversion to 3',5'-di-O-acetyl-5-(E)-(2-bromovinyl)-2'-deoxy-4'a-carbauridine [I; R = CH:CHBr-(E), R¹ = Ac].Deacetylation of I [R = CH:CHBr-(E),R¹ = Ac] afforded I [R = CH:CHBr-(E), R¹ = H] in an overall 45-33% yield from II.

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Indication	Highest Phase	Country/Location	Organization	Date
Herpes Simplex	Phase 1	United Kingdom	GSK Plc	-
Varicella Zoster Virus Infection	Phase 1	United Kingdom	GSK Plc	-
Virus Diseases	Phase 1	-	GSK Plc	-

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