Synthesis of (E)-5-(2-Radioiodovinyl)arabinosyl Uridine Analog for Probing HSV-1 Thymidine Kinase Gene

Chung-Shan Yu, Chien-Hung Wu, Li-Wu Chiang, Ren-Tsong Wang, Heng-Yen Wang, Chien-Hung Yeh, Kun-I Lin
2005 Chemistry Letters  
The genetic probe labeled with positron emitter for monitoring tumor cells transfacted by herpes simplex virus thymidine kinase gene has been intensively studied. A useful synthetic methodology was developed to synthesize (E)-5-[2-(tributylstannyl)vinyl]arabinosyl uridine (TSVAU) and to radiolabel (E)-5-{2-[ 125 I]iodovinyl}arabinosyl uridine (IVAU) substrate for herpes simplex virus type-1 thymidine kinase gene. The synthesis started from arabinosyl uridine via six steps to provide TSVAU in
more » ... yield. The subsequent radiolabeling with Na-[ 125 I]I under oxidation provided [ 125 I]IVAU in 80% radiochemical yield. Gene therapy has become one of the most promising approaches for cancer treatment. The mechanism underlying the therapy starts by delivering the suicide gene into the target cells, followed by administering the prodrugs. The presence of the suicide gene in the target cells activates the prodrugs, such as nucleoside analogs, to form toxic metabolites, which then initiate the subsequent suicidal mechanism. The most intensively studied suicide gene, HSV-1 TK (herpes simplex virus thymidine kinase), can serve bi-functionally as both therapeutic and reporter genes in this system. 2 Moreover, in vivo gene expression of HSV-1 TK can be successfully monitored by imaging its substrate analog, usually a nucleoside analog. After being phosphorylated by viral TK, the metabolite can be randomly incorporated into elongating DNA chains by cellular enzymes. 3 The localization of this event could be traced down by using a tagged nucleoside analog. Of the most excellent candidates for in vivo studies are which radiolabeled with positron emitters owing to their higher imaging quality and quantification capacity. For example, [ 124 I]FIAU (pyrimidine nucleoside) and [ 18 F]FHBG (purine nucleoside) have been coupled with PET (positron emission tomography) to provide invaluable images (Scheme 1). 4, 5 Recently, an investigation on bioactivity-guided screening of nucleosides as substrates for HSV-1 TK by Degrève et al. discovered two potential compounds: IaraU (5-iodoarabinosyl uridine) and IVAU {(E)-5-(2-iodovinyl)arabinosyl uridine} 1 (Scheme 2). 6 As part of our systematic syntheses of radiolabeled thymidine analogs, 7 we have developed a facile synthesis of the former compound [ 125 I]IaraU. 8 Though the syntheses of [ 123 I] IVAU and its precursor TSVAU {(E)-5-[2-(tributylstannyl)vinyl]arabinosyl uridine} 2 have been reported by Dougan et al., the use of acetylene during production of trans-1,2-distannyl ethene was a formidable procedure for the most medicinal chemistry laboratories. 9 Consequently, an alternative precursor bearing trimethylsilyl vinyl group was developed by Morin et al. and [ 125 I]IVAU 1 could be prepared in fair yield. 10
doi:10.1246/cl.2005.1390 fatcat:xn4x4tfpmrbefdcqv3ln5g5sbe