Pivaloyloxymethyl modified

Wiemer, A.J., et al. (2008). Pivaloyloxymethyl-modified isoprenoid bisphosphonates display enhanced inhibition of cellular geranylgeranylation. Bioorg Med Chem 16 3652-3660. 

Bisphosphonate inhibitors of farnesyl disphosphate synthase have been used clinically for treatment of bone diseases. Many of their effects may be mediated by depletion of geranylgeranyl diphosphate, and Wiemer and coworkers have discovered a number of novel pivaloyloxymethyl-modified isoprenoid bisphosphonates (251) that selectively inhibited geranylgeranyl diphosphate synthase. They found that addition of pivaloyloxymethyl moieties to isoprenoid bisphosphonates increased their potency towards cellular geranylgeranylation even though this modification decreased their in vitro inhibition of geranylgeranyl diphosphate synthase. Moreover, pivaloyloxymethyl modifications more effectively increased the cellular activity of the more polar isoprenoid bisphosphonates. 

A selective method which involves the selective pivaloyloxymethyl protection of the N1 of pseudouridine followed by methylation at N3 was developed to prepare the 5-benzhydryloxybis(trimethylsilyloxy)silyl, bis(2-acetoxy-ethoxy)me-thyl- protected phosphoramidite derivative (139) of the nucleoside 3-methylpseu-douridine. The methylated pseudouridine phosphoramidite was successfully used in oligonucleotide synthesis for the NMR study of helix 69 of E. coli 23S rRNA. 2-Thiouridines incorporating 2 -modified nucleoside phosphoramidites... 

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