Johayem, Anass;
Raić‐Malić, Silvana;
Lazzati, Katia;
Schubiger, Pius A.;
Scapozza, Leonardo;
Ametamey, Simon M.
Synthesis and Characterization of a C(6) Nucleoside Analogue for the in vivo Imaging of the Gene Expression of Herpes Simplex Virus Type‐1 Thymidine Kinase (HSV1 TK)
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Medientyp:
E-Artikel
Titel:
Synthesis and Characterization of a C(6) Nucleoside Analogue for the in vivo Imaging of the Gene Expression of Herpes Simplex Virus Type‐1 Thymidine Kinase (HSV1 TK)
Beteiligte:
Johayem, Anass;
Raić‐Malić, Silvana;
Lazzati, Katia;
Schubiger, Pius A.;
Scapozza, Leonardo;
Ametamey, Simon M.
Beschreibung:
<jats:title>Abstract</jats:title><jats:p>The synthesis and biological evaluation of ‘6‐(1,3‐dihydroxyisobutyl)thymine’ (DHBT; <jats:bold>1</jats:bold>), which corresponds to 6‐[3‐hydroxy‐2‐(hydroxymethyl)propyl]‐5‐methylpyrimidine‐2,4(1<jats:italic>H</jats:italic>,3<jats:italic>H</jats:italic>)‐dione, is reported. DHBT (<jats:bold>1</jats:bold>) was designed as a new substrate for <jats:italic>herpes simplex</jats:italic> virus type‐1 thymidine kinase (HSV1 TK). The compound was found to be exclusively phosphorylated by HSV1 TK, and to exhibit good binding affinity (<jats:italic>K</jats:italic><jats:sub>i</jats:sub> <jats:italic>=</jats:italic> 35.3±1.3 μ<jats:sc>M</jats:sc>). Cell‐proliferation assays with HSV1‐TK‐transduced human osteosarcoma cells (143B‐TK+‐HSV1‐WT) and with both human‐thymidine‐kinase‐1‐negative (143B‐TK<jats:sup>−</jats:sup>) and non‐transduced parental (MG‐63) cells indicate that <jats:bold>1</jats:bold> is less cytotoxic than the standard drug <jats:italic>Ganciclovir.</jats:italic> Thus, DHBT (<jats:bold>1</jats:bold>) represents a promising precursor of a nontoxic reporter probe for the monitoring of HSV1 TK gene expression by means of positron‐emission tomography (PET).</jats:p>