HYDROXYMETHYLPHOSPHONATE - NOVEL OLIGONUCLEOTIDE ANALOG

Thymidine(3',5')thymidine hydroxymethylphosphonate (10), the first oli gonucleotide bearing hydroxymethylphosphonate function, and t-butylamm onium 5'-O-monomethoxytritylthymidine 3'-O-acetoxymethylphosphonate (7 ), oligonucleotide monomer, were synthesized using t-butylammonium O-m ethylacetoxymethylphosphonate (4) as a novel phosphonylating agent. Hy droxymethylphosphonate internucleotide linkage is stable at physiologi cal pH and resistant to 3'- and 5'-exonucleases. While retaining the n eutral character of the phosphonate modification, the presence of hydr oxymethyl function increases hydrophilicity of hydroxymethylphosphonat e oligonucleotide and its solubility in water compared to the parent m ethylphosphonate analogue. Therefore, hydroxymethylphosphonate modific ation can be used to fine-tune the physicochemical properties of antis ense oligonucleotides. (C) 1994 Academic Press, Inc.