Syntheses and properties of low-polarity shape mimics of 8-oxopurines.

A number of mutations that arise in the cell come from oxidative damage to DNA bases. Oxidation of purine bases at the 8-position, yielding 8-oxoguanosine and 8-oxoadenosine, results in conformation changes that cause miscoding during DNA replication. For example, 8-oxodG in the syn conformation is complementary to adenine in the hydrogen bonding. Here, we report the synthesis, biophysical and biochemical properties of low-polarity shape mimics of 8-oxopurines. A 2-chloro-4-fluoroindole (1) nucleoside was designed as a mimic of 8-oxodG, and a 2-chloro-4-methylbenzimidazole nucleoside (2) as a mimic of 8-oxodA. Structural studies of the free nucleoside revealed that both bases are preferred syn conformation, thus mimicking the conformation of the oxopurine nucleosides. Base pairing studies showed that both compounds in the oligonucleotides pair with selectivity for purine partners. In the DNA template containing new oxopurine analogs, dATP and dGTP were incorporated opposite 1 and 2 respectively by the Klenow. Moreover, 5'-triphosphate derivatives (3 and 4) were incorporated into DNA opposite purine nucleobase. Thus the new analogs are expected to be useful as mechanistic probes cellular responses to DNA oxidative damage.