Synthesis and Biochemical Characterization of Tricyclothymidine Triphosphate (tc-TTP)

Hollenstein, Marcel; Leumann, Christian (2014). Synthesis and Biochemical Characterization of Tricyclothymidine Triphosphate (tc-TTP). ChemBioChem, 15(13), pp. 1901-1904. Wiley-VCH 10.1002/cbic.201402116

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Tricyclo-DNA (tc-DNA) is a conformationally restricted oligonucleotide analogue that exhibits promising properties as a robust antisense agent. Here we report on the synthesis and biochemical characterization of tc-TTP, the triphosphate of a tc-DNA nucleoside containing the base thymine. Tc-TTP turned out to be a substrate for the Vent (exo−) DNA polymerase, a polymerase that allows for multiple incorporations of tc-T nucleotides under primer extension reaction conditions. However, the substrate acceptance is rather low, as also observed for other sugar-modified analogues. Tc-TTP and tc-nucleotide-containing templates do not sustain enzymatic polymerization under physiological conditions; this indicates that tc-DNA-based antisense agents will not enter natural metabolic pathways that lead to long-term toxicity.

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