2ND-GENERATION ANTISENSE OLIGONUCLEOTIDES-INHIBITION OF PKC-ALPHA ANDC-RAF KINASE EXPRESSION BY CHIMERIC OLIGONUCLEOTIDES INCORPORATING 6'-SUBSTITUTED CARBOCYCLIC NUCLEOSIDES AND 2'-O-ETHYLENE GLYCOL SUBSTITUTED RIBONUCLEOSIDES

6'-substituted carbocyclic deoxyribonucleosides and 2'-O-ethylene glyc ol substituted ribonucleosides have been evaluated as building blocks for antisense oligonucleotides. Within the former class 6'-hydroxy sub stituted building blocks in combination with internucleoside phosphoro thioate linkages have the potential to enhance antisense activity. 2'- O-ethylene glycol substituted ribonucleosides generally allow for the construction of potent antisense oligonucleotides with reduced phospho rothioate content, but differences exist in their effects on biologica l activity in cell culture in spite of virtually identical effects on RNA-binding affinity. Activity enhancement was most pronounced for a 2 '-O-methoxyethyl substituent.