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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)
Author(s) -
Johayem Anass,
RaićMalić Silvana,
Lazzati Katia,
Schubiger Pius A.,
Scapozza Leonardo,
Ametamey Simon M.
Publication year - 2006
Publication title -
chemistry and biodiversity
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.427
H-Index - 70
eISSN - 1612-1880
pISSN - 1612-1872
DOI - 10.1002/cbdv.200690030
Subject(s) - thymidine kinase , ganciclovir , chemistry , herpes simplex virus , thymidine , microbiology and biotechnology , nucleoside analogue , thymine , kinase , in vivo , cytotoxic t cell , nucleoside , virology , gene , in vitro , virus , biochemistry , human cytomegalovirus , biology , dna
The synthesis and biological evaluation of ‘6‐(1,3‐dihydroxyisobutyl)thymine’ (DHBT; 1 ), which corresponds to 6‐[3‐hydroxy‐2‐(hydroxymethyl)propyl]‐5‐methylpyrimidine‐2,4(1 H ,3 H )‐dione, is reported. DHBT ( 1 ) was designed as a new substrate for herpes simplex virus type‐1 thymidine kinase (HSV1 TK). The compound was found to be exclusively phosphorylated by HSV1 TK, and to exhibit good binding affinity ( K i = 35.3±1.3 μ M ). Cell‐proliferation assays with HSV1‐TK‐transduced human osteosarcoma cells (143B‐TK+‐HSV1‐WT) and with both human‐thymidine‐kinase‐1‐negative (143B‐TK − ) and non‐transduced parental (MG‐63) cells indicate that 1 is less cytotoxic than the standard drug Ganciclovir. Thus, DHBT ( 1 ) represents a promising precursor of a nontoxic reporter probe for the monitoring of HSV1 TK gene expression by means of positron‐emission tomography (PET).