Hydroxymethylphosphonate: Novel oligonucleotide analogue

Article abstract of DOI:10.1006/bioo.1994.1011

Thymidine(3',5')thymidine hydroxymethylphosphonate (10), the first oligonucleotide bearing hydroxymethylphosphonate function, and t-butylammonium 5'-O-monomethoxytritylthymidine 3'-O-acetoxymethylphosphonate (7), oligonucleotide monomer, were synthesized using t-butylammonium O-methylacetoxymethylphosphonate (4) as a novel phosphonylating agent. Hydroxymethylphosphonate internucleotide linkage is stable at physiological pH and resistant to 3'- and 5'-exonucleases. While retaining the neutral character of the phosphonate modification, the presence of hydroxymethyl function increases hydrophilicity of hydroxymethylphosphonateoligonucleotide and its solubility in water compared to the parent methylphosphonate analogue. Therefore, hydroxymethylphosphonate modification can be used to fine-tune the physicochemical properties of antisense oligonucleotides.