Free accessResearch articleFirst published online 2006-2
The Effect of a Methyl or 2-fluoroethyl Substituent at the N-3 Position of Thymidine,3′-fluoro-3′-deoxythymi-dine and 1-β-D-arabinosylthymine on Their Antiviral and Cytostatic Activity in Cell Culture
Thymidine (Thd), 1-β-D-arabinosylthymine (ara-T) and 3′-fluoro-3′-deoxythymidine (FLT) have been substituted at N-3 by a methyl or a 2-fluoroethyl group. FLT and ara-T are markedly inhibitory against human immunodeficiency virus type 1 (HIV-1) and HIV-2, and herpes simplex virus type 1 (HSV-1) and HSV-2, respectively. Modification at N-3 of these compounds markedly decreases both the antiviral and cytostatic activity of the parent compounds FLT and ara-T except for N-3-(methyl)-Thd that proved highly cytostatic for murine leukaemia L1210 cells. The decreased biological activity of the N-3-substituted pyrimidine nucleo-side analogues coincides with a significantly lower affinity of the modified Thd analogues for the cellular and viral (activating) nucleoside kinases.
AllenLBSchroderHCLoberingHGMaidhofA & MüllerWE (1987) Cytostatic and antiherpesvirus type 1 and 2 activities of 1-β-d-arabinofuranosylthymine (araT) prodrugs. Chemotherapy33: 272–277.
2.
Al-MadhounASJohnsamuelJYanJJiWWangJZhuoJ-CLunatoAJWoollardJEHawkAECosquerGYBlueTEErikssonS & TjarksW (2002) Synthesis of a small library of 3-(carboranylalkyl)thymidines and their biological evaluation as substrates for human thymidine kinases 1 and 2. Journal of Medicinal Chemistry45: 4018–4028.
3.
Al-MadhounASJohnsamuelJBarthRFTjarksW & ErikssonS (2004) Evaluation of human thymidine kinase 1 substrates as new candidates for boron neutron capture therapy. Cancer Research64: 6280–6286.
4.
BalzariniJ & De ClercqE (1983) Role of deoxycytidine kinase in the inhibitory activity of 5-substituted 2′–deoxycytidines and cytosine arabinosides on tumor cell growth. Molecular Pharmacology23: 175–181.
5.
BalzariniJDe ClercqEAyusawaD & SenoT (1985) Murine mammary FM3A carcinoma cells transformed with the herpes simplex virus type 1 thymidine kinase gene are highly sensitive to the growth-inhibitory properties of (E)-5-(2-bromovinyl)-2′-deoxyuridine and related compounds. FEBS Letters185: 95–100.
6.
BalzariniJBabaMPauwelsRHerdewijnP & De ClercqE (1988) Anti-retrovirus activity of 3′-fluoro- and 3′-azido-substituted pyrimidine 2′,3′-dideoxynucleoside analogues. Biochemical Pharmacology37: 2847–2856.
7.
BalzariniJBohmanCWalkerRT & De ClercqE (1994) Comparative cytostatic activity of different antiherpetic drugs against herpes simplex virus thymidine kinase gene-transfected tumor cells. Molecular Pharmacology45: 1253–1258.
8.
BandyopadhyayaAKJohnsamuelJAl-MadhounASErikssonS & TjarksW (2005) Comparative molecular field analysis and comparative molecular similarity indices analysis of human thymidine kinase 1 substrates. Bioorganic and Medicinal Chemistry13: 1681–1689.
9.
CulverKWRamZWallbridgeSIshiiHOldfieldEH & BlaeseRM (1992) In vivo gene transfer with retroviral vector-producer cells for treatment of experimental tumors. Science256: 1550–1552.
10.
DahmenNKowalzickLSpadariS & KochG (1990) Arabinose furanosyl thymidine: Uptake, phosphorylation and incorporation into DNA of mammalian cells. In Vivo4: 25–32.
11.
De ClercqEHolýARosenbergISakumaTBalzariniJ & MaudgalPC (1986) A novel selective broad-spectrum anti-DNA virus agent. Nature323: 464–467.
12.
De ClercqESakumaTBabaMPauwelsRBalzariniJRosenbergI & HolýA (1987) Antiviral activity of phosphonylmethoxyalkyl derivatives of purine and pyrimidines. Antiviral Research8: 261–272.
13.
GentryGA & AswellJF (1975) Inhibition of herpes simplex virus replication by araT. Virology65: 294–296.
14.
HerdewijnPBalzariniJDe ClercqEPauwelsRBabaMBroderS & VanderhaegheH (1987) 3′-Substituted 2′,3′-dideoxynucleoside analogues as potential anti-HIV (HTLVIII/LAV) agents. Journal of Medicinal Chemistry30: 1270–1278.
15.
JohanssonM & KarlssonA (1997) Cloning of the cDNA and chromosome localization of the gene for human thymidine kinase 2. Journal of Biological Chemistry272: 8454–8458.
16.
KatlamaCGhosnJTubianaRWirdenMValantinMAHarmenbergJMardhGÖbergB & CalvezV (2004) MIV-310 reduces HIV viral load in patients failing multiple antiretroviral therapy: Results from a 4-week phase II study. AIDS18: 1299–1304.
17.
KimEYVrangLÖbergB & MeriganTC (2001) Anti-HIV type 1 activity of 3′-fluoro-3′- deoxythymidine for several different multidrug-resistant mutants. AIDS Research and Human Retroviruses17: 401–407.
18.
LunatoAJWangJWoollardJEAnisuzzamanAKMJiWRongFGIkedaSSolowayAHErikssonSIvesDHBlueTE & TjarksW (1999) Synthesis of 5-(carboranylalkylmercapto)-2′-deoxyuridines and 3-(carboranalkyl)thymidine and their evaluation as substrates for human thymidine kinases 1 and 2. Journal of Medicinal Chemistry42: 3378–3389.
19.
MillerRLIltisJP & RappF (1977) Differential effect of arabinofuranosylthymine of the replication of human herpesviruses. Journal of Virology23: 679–684.
20.
MooltenFL (1986) Tumor chemosensitivity conferred by inserted herpes thymidine kinase genes: Paradigm for a prospective cancer control strategy. Cancer Research46: 5276–5281.
21.
RubsamLZDavidsonBL & ShewachDS (1998) Superior cytotoxi-city with ganciclovir compared with acyclovir and 1-β-d-arabinofuranosylthymine in herpes simplex virusthymidine kinase-expressing cells: A novel paradigm for cell killing. Cancer Research58: 3873–3882.
22.
SaffhillR (1987) The large scale synthesis and chromatographic and spectral properties of a series of alkylated thymine and uracil-con-taining nucleosides. O2-, 3- and O4- alkylpyrimidine derivatives. Nucleosides & Nucleotides6: 679–689.
23.
ShimizuTKimuraTFunahashiTWatanebeKHoIK & YamamotoI (2005) Synthesis of N3-substituted uridine and related pyrimidine nucleosides and their antinociceptive effects in mice. Chemical & Pharmaceutical Bulletin53: 313–318.
24.
SienaertRNaesensLBrancaleADe ClercqEMcGuiganC & BalzariniJ (2002) Specific recognition of the bicyclic pyrimidine nucleoside analogs, a new class of highly potent and selective inhibitors of varicella-zoster virus (VZV), by the VZV-encoded thymidine kinase. Molecular Pharmacology61: 249–254.
